KW-4490 A PDE4 inhibitor from Kyowa Hakko Kirin

New Drug Approvals

KW 4490

cis-4-Cyano-4-(2,3-dihydro-8-methoxy-1,4-benzodioxin-5-yl)cyclohexanecarboxylic Acid 

Cyclohexanecarboxyli​c acid, 4-​cyano-​4-​(2,​3-​dihydro-​8-​methoxy-​1,​4-​benzodioxin-​5-​yl)​-​, cis–

cis-​4-​Cyano-​4-​(2,​3-​dihydro-​8-​methoxy-​1,​4-​benzodioxin-​5-​yl)​cyclohexane-​1-​carboxylic acid;

cis-​4-​Cyano-​4-​(8-​methoxy-​1,​4-​benzodioxan-​5-​yl)​cyclohexanecarboxyli​c acid

KF 66490; KW 4490;

MF C₁₇ H₁₉ N O₅

A phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action ofphosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system

PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP, thereby increasing levels of cAMP within cells.

Practical synthesis of the PDE4 inhibitor, KW-4490

ORGN 699

Arata Yanagisawa, arata.yanagisawa@kyowa.co.jp1, Koichiro Nishimura2, Tetsuya Nezu2, Kyoji…

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Flow chemistry approaches directed at improving chemical synthesis

New Drug Approvals

Flow synthesis offers many advantages when applied to the processing of difficult or dangerous chemical transformations. Furthermore, continuous production allows for rapid scale up of reactions without significant redevelopment of the routes. Importantly, it can also provide a versatile platform from which to build integrated multi-step transformations, delivering more advanced chemical architectures. The construction of multi-purpose micro and meso flow systems, that utilize in-line purification and diagnostic capabilities, creates a scenario of seamless connectivity between sequential steps of a longer chemical sequence. In this mini perspective, we will discuss our experience of target orientated multi-step synthesis as presented at the recent inaugural meeting of LEGOMEDIC at Namar University, Belgium.

The true potential of flow chemistry as an enabling technology can really only be fully appreciated when seen in the context of a target driven multi-step synthesis, aimed at the delivery of advanced chemical structures such as active pharmaceutical ingredients (APIs)…

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A REVIEW AND METHODS TO HANDLE PHOSGENE, TRIPHOSGENE SAFELY DURING DRUG SYNTHESIS

New Drug Approvals

Phosgene

Phosgene is the chemical compound with the formula COCl₂. This colorless gas gained infamy as a chemical weapon during World War I. It is also a valued industrial reagent and building block in synthesis of pharmaceuticals and other organic compounds. In low concentrations, its odor resembles freshly cut hay or grass.^[3] In addition to its industrial production, small amounts occur naturally from the breakdown and the combustion oforganochlorine compounds, such as those used in refrigeration systems.^[4] The chemical was named by combining the Greek words ‘phos’ (meaning light) and genesis (birth); it does not mean it contains any phosphorus (cf. phosphine).

TRIPHOSGENE

Triphosgene (bis(trichloromethyl) carbonate (BTC), C₃Cl₆O₃) is a chemical compound that is used as a safer substitute for phosgene, because at room temperature it is a solid crystal, as…

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CATALYTIC CARBON RADICAL AND ITS APPLICATION IN ORGANIC SYNTHESIS

Left: A manganese-oxo porphyrin system in two electron oxidation of olefins. Right: A homoscorpionate-copper family complexin atom transfer radical addition reactions.

 

 

catalytic carbon radical and its application in organic synthesis

1 Introduction

Carbon radical with high chemical reactivity, which is a typical example of the alkyl radicals. In recent years, a variety of methods to generate carbon radicals being actively studied and widely used in organic synthesis. A typical method of generating a radical by an alkyl radical initiator such as AIBN in the presence of an alkyl halide initiator and Bu 3 SnH or (Me 3 Si) 3 SiH reaction; pyrolysis Barton esters or diacyl peroxides; or a metal ion-electron oxidation reaction a) . However, these chemical reactions are measured, for small-scale laboratory use, but difficult to apply to large-scale industrial synthesis. There are some methods industrially produce alkyl radicals, for example, or a radical photo-initiator to initiate the reaction under the irradiation of alkanes, oxidation of these methods are used for self-paraffins. However, since the oxidation reaction process requires strict reaction conditions, especially at high temperatures should be completed. At such high temperatures, paraffin only homolytic CH bond occurs, and there are crack CC bond, which can be lower than the CC bond energy of CH bond. Therefore, the low selectivity of the reaction and reaction efficiency of such insufficient 2) . So far, no conventional method can be satisfactory under mild conditions, so that the CH bond paraffins are selectively cracked to produce carbon radicals. To achieve this goal, a new method to produce carbon radicals under mild conditions. The method of organic synthesis will become an indispensable tool.

Recently, we found that generated by N-hydroxy phthalimide N-phthalimide group (PINO) hydrocarbon radical can be substituted with multiple (e.g., under mild conditions: alkanes, alcohols, ethers, acetals and aldehydes) CH hydrogen atoms to form the corresponding key on the carbon free radicals which have a high selectivity and high catalytic efficiency 3) . NHPI is named “carbon radical generating catalyst” (abbreviated as CRPC). CRPC oxygenates can be synthesized using, for example, a ketone and an alkane to the corresponding carboxylic acid synthesis. CRPC also stimulated the same functional group under mild conditions to generate an addition to the alkanes with high selectivity nitroalkanes, alkyl sulfonic acids and oxidation of alkanes, wherein the reactions are difficult to achieve in the past. Also made ​​possible the synthesis of dicarboxylic acids, such as adipic acid, nitric oxide is often prepared now by-step reaction using molecular oxygen oxidation of cyclohexane can generate a high yield of adipic acid. N 2O is a compound of the greenhouse gases, it generates a greenhouse CO. 2 300-fold or even higher, and a method using nitric oxide inevitable greenhouse gas N 2 O.Manufacture of adipic acid from green to find a chemical point of view and does not produce N 2 O by-product is particularly important new synthetic methods. The reaction of alkyl radicals with CRPC catalytic alkane is an innovative approach and will have a significant impact on the chemical industry. Some reactions catalyzed by CRPC has achieved industrialization.

2 catalytic carbon radical generating new discovery methods

Grochowski and his colleagues first reported in 1977 NHPI catalytic applications, the addition to the reaction catalyzed ether diethyl azodicarboxylate (DEAD) on 4) . No detailed description of the time this reaction has not proved by the generation of PINO.However, the presence of a radical scavenger that no progress of the reaction, the reaction process as recognized ( Synthesis Scheme 1 ) below. The hydrogen atom of the hydroxyl NHPI imide groups on the turn added DEAD, thereafter the resulting product with an equilibrium N-phthalimide group, and a new radical. This step of generating the hydrogen PINO carbon atom α to the ether oxygen separation, generating new radicals A, A was added to generate a new addition of the radical B DEAD, a hydrogen atom of the ether-substituted radical B is generated on adducts C and radicals A.

Further, Masui et al reported in 1983 NHPI as one generated by electrolytic oxidation of secondary alcohols intermediate 5) . We believe PINO generated on the anode so that hydrogen atoms on the carbon α separating the alcohol, and then catalyze the oxidation products formed one ( synthesis scheme 2 ).

In the oxidation reaction of oxygen with molybdenum vanadium phosphate (NPMoV) catalyze the process of alcohol molecules can form an average composition expressed as (NH 4 ) 5 H 6 PV 8 Mo 4 O 40 , we think that alone does not lead to the use of catalysts for this reaction NPMoV But if it will enhance the binding reaction and NHPI (synthesis scheme 3 ). Found that the same reaction (path a) with the expected envisaged, but also unexpectedly found that in the presence of NHPI without NPMoV alcohol oxidation catalytic reaction (path b). The oxidation reaction is a reaction by the NHPI and molecular oxygen (a triplet radical molecules) caused and generate PINO, then replace the hydrogen atoms in the alcohol PINO generated on the corresponding ketone. In order to confirm NHPI generate PINO, in benzonitrile NHPI and oxygen molecules in the system contacts, using ESR spectrometer observed PINO generated a triplet spectrum as shown in Figure (( Figure 1 ).

CRPC has now been found PINO same function, it is possible under mild conditions to selectively replace hydrogen atoms on the CH bond of the organic matrix to generate carbon radical, itself back to NHPI. Due to the carbon radical is the active chemical substance, so the use of different types of molecules (e.g., molecular oxygen) which capture different functional groups can be introduced. The following detailed description of various catalytic reactions catalyzed NHPI, further comprising a new concept in the conventional organic synthesis and the like did not appear, therefore, NHPI will also be a major breakthrough in catalytic chemical synthesis.

3. Molecular oxygen oxidation of alkanes

Currently, the use of self-oxidation of cyclohexane to synthesize nylon-66 requires at least 2,000,000 tons of adipic acid feedstock annually. Now also widely used as a two-step reaction: the presence of a Co salt, is first converted by the air oxidation of cyclohexane to cyclohexanone / cyclohexanol (K / A oil) and then with nitric acid K / A oil synthesized adipoyl acid 6a) . The synthesis method developed in 1940 by DuPont, in principle, has been extended to still used today. The first step involves reaction of CH bond cleavage (CH bond dissociation energy: 99.5 kcal Mol -1 ), CH key must (pressure, 150 ~ 170 ℃) to break under severe reaction conditions. To avoid side reactions, cyclohexane forwarding rate must be controlled at 3% to 5%, such that the reaction efficiency is not satisfactory. The second step reaction using a large amount of nitric oxide by-product N 2 O. Because N 2 O is a matter for global warming, it is imperative that nitric oxide is not seeking a new method of adipic acid can be synthesized on the industry. Development along these lines, there have been reports on the use of hydrogen peroxide as the oxidant oxidation of cyclohexane production of adipic acid, the synthetic scheme as a green synthetic route cause of many people’s attention 6B) .

We have found using a small amount of Mn and NHPI catalyzed O 2 oxidation of cyclohexane to adipic acid ((1 atm) Eq.1 ) 7) , but it is difficult to make using only the NHPI oxidation reaction. However, after adding a small amount of Mn complexes (0.5mol%) production of adipic acid with a high selectivity, conversion rate reached about 70%. In recent years, do not use any solvents can successfully cyclohexane oxidation 8) . Since NHPI difficult to dissolve nonpolar solvent (e.g., cyclohexane), so in the absence of solvent, it is difficult to effectively catalyze the air oxidation of cyclohexane. The results showed that the preparation of a lipophilic derivative and carries the NHPI catalyst, in the absence of a solvent can efficiently catalyze the air oxidation of cyclohexane (( Figure 2 ).

Adamantane has a unique structure, and function of adamantane is an important raw material for the production of high-performance materials. Although there are many chemists experimented with molecular oxygen to oxidize adamantane, but there is no one person has access to sufficient yield and selectivity of the real purpose. In NHPI / Co catalyst system in the presence of acetic acid, molecular oxygen is generated in a yield of 85% alcohol and a small amount of adamantyl adamantanone (adamantane at 75 ℃ oxidesynthesis scheme 4 ) 9) . Allow the reaction to generate a high reaction selectivity condition mono or dihydric alcohol choice. The synthesis of this diol or triol synthetic acrylic and methacrylic resins is an important synthesis photoresist.

T-butanol used as an additive to increase the octane number of gasoline and high-purity organic solvent, the hydrated isobutylene industrially prepared tert-butanol.Isobutane oxidation to synthesize isobutanol directly is a more reasonable approach, while using the traditional auto-oxidation process is to synthesize tert-butyl hydroperoxide, the traditional synthetic methods under high pressure (10 atm), high temperature of about 200 ℃ to produce peroxide, t-butanol (yield about 75%), t-butanol (yield 21%) of 8% and the conversion rate of acetone (about 2%) 10) . In benzonitrile system generates a yield under high pressure conditions with NHPI catalyzed oxidation of isobutane 80% of tert-butyl alcohol ( Eq. 2 ) 11) .

Oxidation of alkylbenzenes 4

Molecular oxygen oxidation of benzene carboxylic acid is an important industrial organic synthesis reactions. Co catalyst 130到160 ℃ catalytic oxidation of toluene to generate the corresponding acid under high pressure, the conversion was 50% and the selectivity was about 80% benzoic acid 12) . However, the use of small amounts of NHPI and Co. (OAc) 2 as catalyst catalytic molecular oxygen oxidation of toluene can generate acid in high yield at room temperature under 1 atm (yield 81%) and traces of impure benzaldehyde ( Eq. 3 ) 13) . Under these reaction conditions, with Co (Ⅲ) Co substitution can not lead to the reaction (Ⅱ), experiments show that Co (Ⅱ) salt and oxygen reaction of Co (Ⅲ) complexes of oxygen to cause this reaction ( synthesis scheme 5 ); while using Co (Ⅲ) but not necessary to initiate the reaction to produce Co (Ⅲ) oxygen complexes, so the reaction does not occur at room temperature. When the temperature rises Co (Ⅲ) substrate is reduced to Co (Ⅱ) in turn generated Co (Ⅱ) react with oxygen molecules to form Co (Ⅲ) complexes of oxygen to initiate the reaction.Therefore, when using Co (Ⅲ) can be observed induction period. Facts have proved that the use of molecular oxygen under normal temperature and pressure catalytic oxidation of hydrocarbons such as toluene and other chemicals for oxidation is of great significance.

Terephthalate, PET resin is synthesized so that a large amount of its production, and the demand will increase in the near future. Today, with the Co / Mn / Br catalyst at high temperature by the auto-oxidation of p-xylene to terephthalic acid synthesis, the synthesis method developed by British Amoco, which is a disadvantage to discharge the gas phase system bromine, corrosion reaction device, so people eager to develop a catalyst halogen-free catalyst system.

NHPI catalyst we use a halogen-developed catalytic oxidation, the oxidation reaction with molecular oxygen to generate paraxylene terephthalic acid (Synthesis Scheme 6).Furthermore, the NHPI to generate an additional N-acetyl-acetyl phthalimide (NAPI) having high catalytic activity similar NHPI. It was found that if we use as a catalyst in a catalytic amount NAPI catalyst required to generate the same amount of terephthalic acid is a catalytic amount of NHPI half 14). In addition, we recently discovered three hydroxyimino cyanurate (THICA) having high catalytic activity. NHPI by-step catalytic oxidation of p-xylene was synthesized in a yield of 80% terephthalic acid requires NHPI catalyst 20mol%, and 3mol% THICA oxidation catalyst using the same effects can be obtained.

Oxidation of alkyl carboxylic acids synthesized heterocyclic compounds are widely used as pharmaceutical drug synthesis intermediates, such as the oxidation of nicotinic acid methyl pyridine synthesis is an important raw material synthetic vitamins.Currently, nitric oxide at high temperature and pressure 5 – ethyl-2 – methyl-pyridin-nicotinic acid, however, the key issue is also produced large amounts of nitrogen oxides. At the same time there are reports with Co / Mn / Br catalyzed oxidation of methyl pyridine synthesis from nicotinic acid, but the reaction conditions are harsh and very low selectivity 15) .

In a catalytic amount of NHPI and measurable Co. (OAc) 2 and Mn (OAc) 2 in the presence of acetic acid environment conditions, we use atmospheric oxygen were β-methyl pyridine oxidation experiments, the results obtained higher yields of niacin, And the yield can reach 77% ( Eq. 4 ) 16a) . NHPI / Co / Mn catalyst is a catalytic reaction does not produce polluting nitrogen oxides, can be very useful in the industrial synthesis. Further 3 – oxidation product methylquinoline 3 – quinolinecarboxylic acid widely found in nature, there are many reports on related pharmacological activity.However, in the past, many heavy metal salts such as KMnO 4 , CrO 3 is often used as the oxidant found to NHPI / Co / Mn catalyst system was added a small amount of NO 2oxidation of molecular oxygen issue with three – methylquinoline higher reaction yield quinoline carboxylic acid (yield 75%) ( Eq. 5 ) 16b) . Also found that even without the presence of transition metal salts can still use the NHPI / NO 2 catalyzed oxidation of quinoline molecular oxygen. Yet found using molecular oxygen oxidation of quinoline example, the reaction is so far the only successful with the oxidation reaction of molecular oxygen oxidation of quinoline.

Industrial synthesis of phenol using the two-step synthesis, the synthesis of the following steps: compressed air (5-7 atm) at 90到120 ℃ weakly alkaline systems in the cumene from the oxidation of cumene hydroperoxide (yield 20 ~ 30%), and then separating the unreacted cumene from the reaction solution was concentrated, and then treatment of the concentrated sulfuric acid to produce phenol and acetone products. While this method as early as the 1940s had established applications, but it is still the main method of industrial synthesis of phenol. However, the relatively low efficiency of the first step reaction. If the conversion of cumene to improve the yield of cumene hydrogen peroxide, the reaction will have greater usefulness. Was added to the reaction solution was found in the absence of a heavy metal salt in a small amount of acetonitrile system, indium chloride, the NHPI catalyst together with a radical initiator, AIBN can be obtained under the action of the phenol in 77% yield ( Eq. 6 ) 17) .

5. Molecular oxygen oxidation of alkenes and alkynes

Over 5.1 Synthesis of hydrogen peroxide in the olefin epoxidation

Epoxidation of olefins, especially molecular oxygen as the oxidant has a certain propylene oxide on an industrial scale. The most common method is to Halcon method (indirect oxidation method), the synthetic method has two steps: the first step is oxidized to ethylbenzene hydroperoxide from ethylbenzene, in the second stage catalytic ethylbenzene hydroperoxide as Mo completion of the epoxidation reaction oxidant epoxidation of olefins.

Previously, we found NHPI catalyst for oxidation of the secondary alcohol of molecular oxygen to form hydrogen peroxide and a ketone 19) , the reaction of hydrogen peroxide produced for the epoxidation of olefins. And a catalytic amount of hexafluoroacetone NHPI presence of 1 – phenylethanol and cis -2 – octene-oxidizing atmosphere under normal pressure, to form the corresponding hydroperoxide and then generated by the addition of hydrogen peroxide to a hexafluoroacetone mixture, and then do the real hydroperoxide oxidant reaction yield of 87% of cis – epoxide ( 7 Eq. ) 20) .Advances of the aldehyde radical intermediates generated by molecular oxygen oxidation of cis – epoxidation of the olefin to form the corresponding cis or trans – mixture of epoxide 21) . Thus, the molecular oxygen oxidation of cis – stereoselective olefin epoxidation reaction is difficult in reality.

Epoxidation process comprising two: (i) NHPI through catalytic reaction of oxygen alcohol intermediate α-hydroxy hydroperoxide ( A ) to form hydrogen peroxide, the reaction of this step is a free radical reaction; (ii) the hydrogen peroxide reaction with hexafluoroacetone in the α-hydroxy hydroperoxide ( B ) oxidizing the olefin epoxidation reaction ( Synthesis Scheme 7 ). NHPI catalyst for catalytic oxidation of secondary alcohols can also be used as an excellent synthetic method for the synthesis of hydrogen peroxide 22) .

5.2 propargyl alkyne to introduce oxygen bits

Alkyne propargyl position in CH bond dissociation energy is about 85 kcal Mol -1 , roughly equal to the allyl position olefins CH bond dissociation energy (~ 87 kcal Mol -1) 23) . Therefore, it is expected that if a catalytic NHPI O 2 oxidation to alkynes, propargyl bit can be selectively oxidized to form the corresponding α-acetylenic ketone.As we know the amount of Co, and the catalyst system comprising a complex of acetonitrile NHPI (10mol%) of 4 – octyne with O 2 molecules can be reacted at room temperature to give 4 – oct-yn-3-one, and the yield up to 75% (Eq.8) 24) . Acetylenic ketone is usually made ​​of a metal acetylide coupling reaction with an acylating agent synthesis. Propargyl oxygen into position very little literature, there is an example of SeO 2 oxidation catalyzed reaction of t-butyl peroxy alcohols 25) . The paper reported the first successful response to oxygen molecules of oxygen introduced into the reactor.

6 oxygen molecules oxidized K / A oil

K / A oil is a mixture of cyclohexanone and cyclohexanol consisting of chemical raw materials in the oil industry is an important intermediate for the production of adipic acid. Bayer – Villiger oxidation reaction can be cyclic ketones into lactones. So far, no catalysis using molecular oxygen as oxidant on Bayer – literature Villiger oxidation reaction, ε-caprolactone is cyclohexanone with peracetic acid by Bayer – Villiger Oxidation from. If the synthesis of ε-caprolactone using peracetic acid is not achieved, but the use of molecular oxygen as the oxidant K / A oil was catalytically Bayer – Villiger oxidation reaction of the synthesis, then the reaction to avoid the use of hazardous due to their peracetic acid becomes particularly important.

We NHPI has been proposed as an efficient catalyst for aerobic oxidation of secondary alcohols. NHPI oxidation of secondary alcohols to produce hydrogen peroxide, ketone and hydroxy peroxide intermediate is formed by 19) . At this point, we use exists in K / A oil oxidation of secondary alcohols of molecular oxygen to form hydrogen peroxide, which is used to generate hydrogen peroxide Bayer – oxidant Villiger reactions. The reaction of ε-caprolactone by the aerobic oxidation of the first K / A oil system cyclohexanol into hydrogen peroxide and cyclohexanone. Then the hydrogen peroxide and InCl 3 (synthesis scheme 8) 26) Villiger Oxidation – Bayer catalytically cyclohexanone. Indium trichloride is a Lewis acid which is stable in water, if the recovery reaction can also be reused.

NHPI in the presence of a catalytic amount of ethyl acetate to K / A oil first by aerobic oxidation reaction is preferably selective, then after processing for generating ammonia peroxide dicyclohexylamine (Eq. 9). Known, PDHA easily converted into a high yield of ε-caprolactam. This reaction is carried using a new synthetic method for the molecular oxygen ε-caprolactam precursors, because it does not generate a reaction byproduct ammonium sulfate is even more interesting.

7 functional groups using NHPI catalyst is added to the alkane molecules

7.1 CO is introduced into the adamantane

In CO. / O 2 using NHPI catalyst thoroughly adamantane carboxylate having a relatively high selectivity, and the environment. At 60 ℃, NHPI (10%) and CO / Air (15/1 atm) the presence of the reaction adamantyl adamantane carboxylic acid and a small amount of oxidation products having a selectivity of 56% under the conditions of (conversion rate of 75%) ( Eq. 10 ) 27) . Saturated hydrocarbons difficult CO via the hydroformylation reaction. Thus, to date, little information on the alkane radical catalyzed hydroformylation reactions reported in the literature. Can be found in some of the literature reports the use of a photoinitiator and a persulfate reaction 28) .

7.2 alkanes catalyzed nitration and sulfoxidation

Sulfoxidation nitration reaction of the aromatic compound and the reaction has been confirmed. However, there has not been a good general-purpose method for nitrification and sulfoxidation reactions. Nitration of alkanes in the industry is an important reaction, the nitric acid or NO 2 as a nitrating agent at temperatures up to 250 ~ 400 ℃ before reaction. However, under such a high temperature, CC bond cleavage is also prone, therefore, resulting in selective nitration reaction is quite poor. For example, cyclohexane, and NO at 240 ℃, 2 generates NITROCYCLOHEXANE nitration reaction, which has a yield of only 16% of 29) . NHPI and a catalytic amount of O 2 in the presence of conditions, we now cyclohexane NO 2 reactions can be found at 70 ℃ smoothly and the yield of the reaction of the nitro group can reach 70% of cyclohexane (( Scheme 9 Synthesis ). Furthermore, after the reaction by simple filtration of the catalyst may collect a certain amount of 30) . We have also achieved success with nitrate instead of NO 2 as a nitrating agent for such nitration 31) .

Only a few reports on the study of the oxidation of alkanes sulfonation. One example is the SO 2 / O 2 in the presence of an alkane by the reaction of the photoinitiator.However, the efficiency of the reaction is so low that no follow-up research reports. We found that a very small amount of adamantane with VO (acac) 2 , the SO 2 / O 2environment using the catalytic reaction of NHPI higher yield of adamantane sulfonic acid ( synthesis scheme 10 ). In addition, we also found that the reaction only by the VO (acac) 2 catalysis. Furthermore, lower alkanes such as propane can be used at room temperature, this method is effective sulfoxidation 32) .

Alkane oximation 7.3

Cyclohexanone oxime is one of the main raw material for the production of nylon-6, and its preparation method is first oxidized cyclohexane, cyclohexanone, and then reacted with hydroxylamine salt. However, because this method generates a large amount of reaction byproducts in the ammonium sulfate has many defects. We found that under argon as protective gas of cyclohexane and t-butyl nitrite and acetic acid at 80 ℃ by-step reaction of cyclohexanone oxime ( synthesis scheme 11 ). The new method has the advantage that the reaction is not oxime synthesis byproducts ammonium sulfate. In addition, one-step reaction of cyclohexanone oxime synthesis is possible, and is expected to be a breakthrough synthetic method. Furthermore since the t-butanol with NO2 is easily synthesized t-butyl nitrite, and t-butanol can be regenerated after the reaction was repeated using the reaction with high atom efficiency.

7.4 NHPI catalyst for alkane alkyl cations generated

NO is a diatomic molecule normally exists in the form of free radicals. If the removal of a hydrogen atom from NHPI generate PINO, so they can also take off the oxygen molecules, so that it can be applied as a new and NO synthesis. We try NHPI catalyst, adamantane benzonitrile reaction with NO and containing a small amount of acetic acid is obtained in a yield of 65% of N-1-adamantyl-benzamide ( synthesis scheme 12 ) 33a) .In addition, we also found that 1,3 – dihydro-isobenzofuran with acetonitrile NO reaction phthalaldehyde ( synthesis scheme 13 ) 33b) . Phthalaldehyde also be hydrolyzed by tetrabromo-o-xylene from o-xylene to get 34) . We all know that has not yet been directly from 1,3 – dihydro-isobenzofuran synthesis phthalaldehyde example. In this reaction, the resulting intermediate with a carbenium ion as the reaction of a nucleophilic reagent water hemiacetal, a hemiacetal and then the process is similar to the oxidation reaction of o-phthalaldehyde.

We found that using NHPI catalyzed with ammonium cerium nitrate (CAN) and then reaction of the alkyl radicals generated by the one-electron oxidation can generate alkyl cationic (( synthesis scheme 14 ) it is clear that this reaction process is PINO CAN NHPI and the reaction generates Under these conditions, the Ritter reaction is difficult in the past occurred in the benzyl position, now with the present synthesis method Ritter reaction becomes particularly simple 35) .

7.5 NHPI as a catalyst for reversing the polarity

Under argon atmosphere, a catalytic amount of NHPI, toluene as a solvent, BPO initiator with an aldehyde to generate a high yield of the olefin corresponding ketone.If ( Synthetic Scheme 15 ) is similar to the reaction process shows radical reactions, NHPI do polarity reversal catalyst 36) . Group by free radical addition to the addition of the olefin to generate a radical, and the addition of a nucleophilic radical having aldehyde that is easy on the H atom on the ratio of the substituent substituted NHPI, so that the chain reaction will be more stable .

8 catalyzed carbon-based radicals generated CC bond forming reactions

In organic synthesis radical coupling reaction is very useful method for forming CC bond. We have found that the possibility of using NHPI / O 2 system generates the corresponding alkanes catalyzed alkyl radicals. Therefore, we use the olefin to capture free radicals generated, we tested NHPI / O 2 catalytic alkane α, β-unsaturated ester is reacted with. In an air atmosphere, NHPI / Co. (acac) 3 as a catalyst for the reaction of methyl acrylate with adamantane. Found that the coupling product obtained in high yield with the ternary molecular oxygen, then the adamantyl radical addition to the double bond of methyl acrylate ( synthesis scheme 16 ) 37) . This reaction is considered to be the alkoxylation reaction of alkanes and a new radical coupling reaction, introduction of oxygen atoms and the CC bond formation reaction simultaneously.

NHPI / O 2 catalyzed 1,3 – dioxolane reacted with methyl acrylate, the reaction can be carried out smoothly and generate the corresponding β-hydroxy acetal (at room temperature synthesis scheme 17 ). Coupling acetal product after the acid treatment of easily converted to the corresponding ketone. This reaction is similar to the addition of the olefin group radical addition reaction, or oxidation of an olefin alkylation vital 38) .

As shown above, NHPI / O 2 can also generate α-hydroxy alcohols catalyzed carbon radicals. Thus, attempts to use α, β-unsaturated ester of α-generated capture hydroxyl radicals and the carbon found in the synthesis of α-hydroxy can-γ-lactone, α-hydroxy in the past-γ-lactone with other synthetic methods are difficult to get. Catalytic amount of Co salt and the presence of NHPI, isopropyl alcohol and methyl acrylate reaction α-hydroxy-γ, γ-dimethyl-γ-butyrolactone ( synthesis scheme 18 ). In this reaction, (i) by NHPI / Co (Ⅱ) catalysis in the presence of oxygen, the hydrogen atom on the alcohol, α-hydroxy-substituted carbon radical generator (A), (ii) A to the addition of methyl methacrylate generated on B, (iii) and then the generated oxygen atoms into the diol C, (iv) C intramolecular cyclization of the lactone.

References

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. 5 Masui, M.; Ueshima, T.;.. Ozaki, S. Chem Commun 1983, 479.

6 (a) Davis, DD Ullman’s Encyclopedia of Industrial Chemistry, 5th ed; Gerhartz, W., Ed; John Wiley and Sons:… New York, 1985; Vol A1, pp 270-272 (b) Sato,.. K.; Aoki, M.; Noyori, R. Science 1998, 281, 1646.

. 7 (a) Ishii, Y.; Iwahama, T.; Sakaguchi, S.; Nakayama, K.;… Nishiyama, YJ Org Chem 1996, 61, 4520 (b) Iwahama, T.; Shoujo, K. ; Sakaguchi, S.;.. Ishii, Y. Org Process Res Dev 1998, 2, 255..

. 8 Sawatari, N.; Yokota, T.; Sakaguchi, S.;. Ishii, YJ Org Chem 2001, 66, 7889..

. 9 Ishii, Y.; Kato, S.; Iwahama, T.;. Sakaguchi, S. Tetrahedron Lett 1996, 37, 4993.

. 10 Winlker, DE;.. Hearne, GW Ind Eng Chem 1961, 53, 655..

. 11 Sakaguchi, S.; Kato, S.; Iwahama, T.; Ishii, Y. Bull Chem Soc Jpn 1998, 71, 1237…..

. 12 Parshall, GW; Ittel, SD Homogeous Catalysis, 2nd ed; John Wiley and Sons:. New York, 1992; pp 255-261.

. 13 Yoshino, Y.; Hayashi, Y.; Iwahama, T.; Sakaguchi, S.;. Ishii, YJ Org Chem 1997, 62, 6810..

. 14 Tashiro, Y.; Iwahama, T.; Sakaguchi, S.;… Ishii, Y. Adv Synth Catal 2001, 343, 220.

15 (a) Davis, DD Ullman’s Encyclopedia of Industrial Chemistry, 5th ed; Gerhartz, W., Ed; John Wiley and Sons:… New York, 1985; Vol A27, p 587 (b) Mukhopadhyay, S… ;.. Chandalia, SB Org Process Res Dev 1999, 3, 455..

. 16 (a) Shibamoto, A.; Sakaguchi, S.; Ishii, Y. Org Process Res Dev 2000, 4, 505 (b) Sakaguchi, S.;…. Shibamoto, A.; Ishii, Y. Chem . Commun. 2002, 180.

. 17 Fukuda, O.; Sakaguchi, S.;… Ishii, Y. Adv Synth Catal 2001, 343, 809.

. 18 Kitabatake, M.; Ishioka, R. Yuki Kasankabutsu: Sono kagaku to kogyoteki riyou (Organic peroxide: chemistry and industrial application); Kagaku Kogyo Sya: Tokyo, 1972.

19 (a) Iwahama, T.;. Sakaguchi, S.; Nishiyama, Y.; Ishii, Y. Tetrahedron Lett 1995, 36, 6923 (b) Iwahama, T.;.. Yoshino, Y.; Keitoku, T. ; Sakaguchi, S.;. Ishii, YJ Org Chem 2000, 65, 6502..

. 20 Iwahama, T.; Sakaguchi, S.;. Ishii, Y. Chem Commun 1999, 727..

. 21 Mukaiyama, T.; Takai, T.; Yamada, T.;. Rhode, O. Chem Lett 1990, 1661..

. 22 Iwahama, T.; Sakaguchi, S.;… Ishii, Y. Org Process Res Dev 2000, 4, 94.

23. Golden, DM Ann. Rev. Phys. Chem. 1982, 33, 493.

. 24 Sakaguchi, S.; Takase, T.; Iwahama, T.;. Ishii, Y. Chem Commun 1998, 2037..

. 25 Chabaud, B.;. Sharpless, KBJ Org Chem 1979, 44, 4202..

. 26 Fukuda, O.; Iwahama, T.; Sakaguchi, S.;. Ishii, Y. Tetrahedron Lett 2001, 42, 3479.

. 27 Kato, S.; Iwahama, T.; Sakaguchi, S.;. Ishii, YJ Org Chem 1998, 63, 222..

28 (a) Barton, DHR;… Doller, D. Acc Chem Res 1992, 25, 504 (b) Arndtsen, BA;.. Bergman, RG; Mobley, TA;.. Peterson, TH Acc Chem Res 1995. , 28, 154.

. 29 Markofsky, SB Ullmann’s Encyclopedia Industrial Organic Chemicals; Wiley-VCH: Weinheim, 1999; Vol 6, p 3487..

. 30 Sakaguchi, S.; Nishiwaki, Y.; Kitamura, T.; Ishii, Y. Angew Chem Int Ed Engl 2001, 40, 222……

. 31 Isozaki, S.; Nishiwaki, Y.; Sakaguchi, S.;. Ishii, Y. Chem Commun 2001, 1352..

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34 Bill, JC;… Tarbell, DS Organic Syntheses, Collect Vol IV; Wiley, 1963; p 807.

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36 Tsujimoto, S.;. Iwahama, T.; Sakaguchi, S.;. Ishii, Y. Chem Commun 2001, 2352..

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How to Handle Drug Polymorphs… Case Study of Trelagliptin Succinate

New Drug Approvals

Pharmaceutical API Polymorphs… case study of Trelagliptin

SEE

PART 1………..http://drugsynthesisint.blogspot.in/p/gliptin-series.html

PART 2 ……http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

CASE STUDY WITH..Compound I having the formula

WO2008067465A1 OR US8084605  IS THE PATENT USED AND WITH FORM “A” AND AMORPHOUS FORM

Active pharmaceutical ingredients (APIs), frequently delivered to the patient in the solid-state as part of an approved dosage form, can exist in such diverse solid forms as polymorphs, pseudopolymorphs, salts, co-crystals and amorphous solids. Various solid forms often display different mechanical, thermal, physical and chemical properties that can remarkably influence the bioavailability, hygroscopicity, stability and other performance characteristics of the drug.

Hence, a thorough understanding of the relationship between the particular solid form of an active pharmaceutical ingredient (API) and its functional properties is important in selecting the most suitable form of the API for development into a drug product. In past decades, there have been significant efforts on the discovery, selection and control…

View original post 15,725 more words

The Magic of Cubane!

 

Cubane^[1]

Pentacyclo[4.2.0.0^2,5.0^3,8.0^4,7]octane

CAS 277-10-1

Cubane (C₈H₈) is a synthetic hydrocarbon molecule that consists of eight carbon atoms arranged at the corners of a cube, with one hydrogen atom attached to each carbon atom. A solid crystalline substance, cubane is one of the Platonic hydrocarbons. It was first synthesized in 1964 by Philip Eaton, a professor of chemistry at the University of Chicago.^[2] Before Eaton and Cole’s work, researchers believed that cubic carbon-based molecules could not exist, because the unusually sharp 90-degree bonding angle of the carbon atoms was expected to be too highly strained, and hence unstable. Once formed, cubane is quite kinetically stable, due to a lack of readily available decomposition paths.

The other Platonic hydrocarbons are dodecahedrane and tetrahedrane.

Cubane and its derivative compounds have many important properties. The 90-degree bonding angle of the carbon atoms in cubane means that the bonds are highly strained. Therefore, cubane compounds are highly reactive, which in principle may make them useful as high-density, high-energyfuels and explosives (for example, octanitrocubane and heptanitrocubane).

Cubane also has the highest density of any hydrocarbon, further contributing to its ability to store large amounts of energy, which would reduce the size and weight of fuel tanks in aircraft and especially rocket boosters. Researchers are looking into using cubane and similar cubic molecules inmedicine and nanotechnology.

Synthesis

The original 1964 cubane organic synthesis is a classic and starts from 2-cyclopentenone (compound 1.1 in scheme 1):^[2][3]

Reaction with N-bromosuccinimide in carbon tetrachloride places an allylic bromine atom in 1.2 and further bromination with bromine in pentane –methylene chloride gives the tribromide 1.3. Two equivalents of hydrogen bromide are eliminated from this compound with diethylamine in diethyl ether to bromocyclopentadienone 1.4

In the second part (scheme 2), the spontaneous Diels-Alder dimerization of 2.1 to 2.2 is analogous to the dimerization of cyclopentadiene to dicyclopentadiene. For the next steps to succeed, only the endo isomer should form; this happens because the bromine atoms, on their approach, take up positions as far away from each other, and from the carbonyl group, as possible. In this way the like-dipole interactions are minimized in the transition state for this reaction step. Both carbonyl groups are protected as acetals with ethylene glycol and p-toluenesulfonic acid inbenzene; one acetal is then selectively deprotected with aqueous hydrochloric acid to 2.3

In the next step, the endo isomer 2.3 (with both alkene groups in close proximity) forms the cage-like isomer 2.4 in a photochemical [2+2] cycloaddition. The bromoketone group is converted to ring-contracted carboxylic acid 2.5 in a Favorskii rearrangement with potassium hydroxide. Next, the thermal decarboxylation takes place through the acid chloride (with thionyl chloride) and thetert-butyl perester 2.6 (with t-butyl hydroperoxide and pyridine) to 2.7; afterward, the acetal is once more removed in 2.8. A second Favorskii rearrangement gives 2.9, and finally another decarboxylation gives 2.10 and 2.11.

The cube motif occurs outside of the area of organic chemistry. Prevalent non-organic cubes are the [Fe₄-S₄] clusters found pervasively iron-sulfur proteins. Such species contain sulfur and Fe at alternating corners. Alternatively such inorganic cube clusters can often be viewed as interpenetrated S₄ and Fe₄ tetrahedra. Many organometallic compounds adopt cube structures, examples being (CpFe)₄(CO)₄, (Cp*Ru)₄Cl₄, (Ph₃PAg)₄I₄, and (CH₃Li)₄.

 

It was mentioned previously that cubane was first prepared in 1964 by Dr. Philip E. Eaton. He was partnered by Thomas W. Cole and together they successfully completed the first synthesis, shown schematically below:

 

 

 

 

 

This, however, was soon simplified by N.B.Chapman who condensed the process to give cubane-1,4-dicarboxylic acid in five steps and so cubane in six:

n 1966 J C Barborak et al discovered yet another new synthesis of cubane. It was slightly unconventional in the fact that it utilised cyclobutadiene as a key substance to the process. Before this,cyclobutadiene was usually unavailable for the purposes of organic chemistry due to it’s instability. The shorter synthesis is shown below:

 

Since the synthesis of the cubane-1,4-dicarboxylic acid has become shorter and easier, a new decarboxylation method has also devised to give increased yields of the final cubane product. This has allowed the scale of production reach multikilogram batches in places (Fluorochem in California and EniChem Synthesis in Milan) eventhough cubane and its derivatives remain expensive to purchase.

Cuneane may be produced from cubane by a metal-ion-catalyzed σ-bond rearrangement.^[4][5]

Cubane is a unique molecule for its extraordinary C8 cage, very high symmetry,exceptional strain and unusual kinetic stability. The particular appeal of cubane,referred to as a landmark in the world of impossible compounds, stems from therehybridization of the carbon atoms away from the canonical sp3 configuration,that is required to bound together eight CH units in a cubic framework.There is now a revival of interest on the chemistry of cubane and its functionalized derivatives,triggered by potential applications as high-energy fuels, explosives and propellantsand intermediates in pharmaceuticalpreparations.Let us now discover the synthesis and properties of this landmark molecule of impossible chemistry

Cubanehas the highest strain energy (166kcal/mol) of any organiccompounds available in multi gram amount. It is a kineticallystable compound and only decomposite above 220 Celsius Degree.It is also one of the most dense hydrocarbons ever know.However, although many physical properties of cubane have been measured, in1980 and before, cubane was considered just a laboratory curiosity of interest only to academics.It changed, in early 1980s when Gilbert of U.S ArmyArmament and Development Command (now ARDEC) pointed out that cubane’svery high heat of formation and its exceptionally high density could make certain cubanederivatives important explosives.The effectiveness of an explosive is dependent on the energentics of the decomposition reaction,the number of moles and molecular weight of the gaseous products and also the density. The more mols of of an explosive that can be packed into the limited volume the better. . Highly nitrated cubanes can be predicted to be very dense and very powerful explosives. Octanitrocubane is calculated to be 15~30%more powerful than HMX.   Cubane, which CA index name is Pentacyclo[4.2.0.02,5.03,8.04,7]octane (7CI,8CI,9CI),has exceptional structure, strain and symmetry and it is a benchmark in organic chemistry.It has been studied extensively and much of its properties has been published.Some of the physical properties are given at right hand table.

The C-C bond length is a bit longer than obtained in the original X-ray structure determination by

Fleischer in 1964. There is not much difference between this bond length and the

C-C bond length in a simple cyclobutane.

 

SYNTHESIS

The cubane system was first synthesized over 35 years ago by Philip Eaton and Tom Cole.
It is a highly symmetric cubic cage structure having carbon atoms at the vertices of a cube.
The synthesis needs to go through brombromocyclopentadienone
dimer I and cubane-1,4,dicarboxylic acid. It is a marvel scheme of economy and simplicity.
With only minor modification, this procedure remains to this day the best available

method for large-scale synthesis of cubane-1,4,dicarboxylic acid.

 

 

 

The stereospecific in situ [4 + 2] (Diels-Alder) cyclodimerization of 4-bromocyclo-pentadienone
is the key in this kinetically controlled synthesis. However, it is still a tricky matter
and a few years later after this synthesis is published, N.B.Chapman et al in England following up
this work and improved this synthesis.

Why cubane is stable?

The reason for this, unappreciated at the time of the early predictions of instability,

 is that there are no kinetically viable paths along which cubane can rearrange thermally.

 On one hand, orbital symmetry considerations raise the energy of concerted two-bond ring

opening reactions. On the

other, there is little to be gained by breaking just one bond as there is concomitantly

only a small change in geometry, and the resulting biradical is still very strained.

Functional group transformation

Functional groups on the cubane system generally behaves very well.Functional group transformation can be applied successfully.For example, the preparation of 1,4-dinitrocubane from cubane-1,4-dicarboxylic acid.(The mechanism is provided on the right hand side.) Classical methodology is used here.

Substitution on the cubane framework is fairly easy done by the cubyl radical.
However, the problem is such that a mixture of products are obtained.
Thus, to achieve controlled substitution on the cubane framework,
we need to carefully study the chemistry of the cubane system.

 

The improvement in synthesis of

cubane-1,4-dicarboxylic acid

 

 

This is the improved synthesis by N.B Chapman et al in England.

 Basically the improvement is such that the

2-bromocyclopentadienone could be made easily and undergoes spontaneous dimerization.

The rest of the reaction is the same as the original one.

 

This synthesis now is scaled up and is conducted in small pilot plants by

Flurochem in California and EniChem Synthesis in Milan.

This method is much more superior than the old method. It is introduced by

Derek Barton et al and use the radical-induced decomposition of diester which can be

prepared easily from cubane-1,4-dicarboxylic acid.

IMPROVEMENT

This method is much more superior than the old method. It is introduced by

Derek Barton et al and use the radical-induced decomposition of diester which can be

prepared easily from cubane-1,4-dicarboxylic acid

 

IR

 

Cubane is a colorless solid. It melts at 130- 131°C, and decomposes above the melting point.

 It is soluble in CS2, CC14, CHC13, and benzene.

Spectra were obtained from 400 to 3600 cm^-l with a Beckman IR-12 spectrophotometer.

The lower limit was set by KBr cell windows. In addition a thick deposit of do was

 measured down to 200 cm^-lin a Csl cell. Since no infrared bands were found, the range

200-400 cm^-l was not examined for the other compounds.

The spectral slit widths were 1-2 cm^-l in all cases.

In the infrared spectrum, there are only noticeable absorptions in the region from

 4000 to 660 cm^-1appear at 300,1231, and 851 cm^-1.

Generally, for single-line proton magnetic resonance spectrum, the one

and only absorption appears at chemical shift=6.0ppm.

Originally there was doubt whether cubane does exist.

The geometry at each carbon atom is far from tetrahedral.

Only later, we found out that there is no kinetically viable paths exist for

the thermal rearrangement of cubane.

At same time, orbital symmetry considerations shows that

the energy of concerted two-bond ring-opening reactions is very high.

There will be very little gain in energy by breaking just one bond, as the

concomitant change in geometry is small, and the resulting biradical is still very strained

In 1964 Fleischer showed that cubane forms a stable solid at room temperature with a

crystalline structure composed of cubane molecules occupying corners of the rhombohedral

primitive unit cell (space group R3). The cubic molecular geometry gives the solid many unusual

electronic,structural, and dynamical properties compared to the other hydrocarbons.

For example, solid cubane has a relatively high melting point temperature about 405 K! and a

very high frequency for the lowest-lying intramolecular vibrational

mode (617 cm^-1). Recent work related to cubane has focused on solid cubane and cubane based

derivatives.Because of relatively weak intermolecular interaction the cohesive energy relative

to the constituent C₈H₈ is expected to be small, and most of the physical properties of

solid cubane are dominated by the properties of the C₈H₈molecule.

Pharmaceutical aspect of cubane

Because the cubane frame is rigid, substituent have precise spatial relationships to each another.

The distance across the cubane (the body diagonal) is almost the same as that between the para

positions of the benzene ring. On cubane, on can add substituents in the “benzene plane”, as

well as above and below it, so to speak. This offers fascinating position possibilities for

the synthesis of new pharmaceuticals. A number of cubane derivatives have already

been obtained which shows interesting activity in anti-AIDS and anti-tumor screens.

Although the activity or the toxicity balance of cubane is yet not know, the cubane

system is not inherently toxic. Most of cubanes are biologically innocuous.

The research of cubane pharmaceutical has just began. At least now,

cubane is a biologically stable, lipophilic platform on which the chemist

can install a wide range of substituents in a variety of well defined special relationships.

Developments in drug design programs should allow the judicious choice.

 

Dipivaloylcubane: a cubane derivatized with keto, cyano, and amide groups,

shown on the left- exhibits moderate activity against human immunodeficiency virus (HIV),

which causes AIDS, without impairing healthy cells.

Polymers of cubane:

Optically transparent cubanes and cubylcubanes have been proposed as building

blocks for rigid liquid-crystal compounds. UV active cubanes, for example cubyl ketones,

are readily transformed photochemically into coloured cyclooctatetraenes;this transformation

can be used to permanent information storage.

Another example of UV active cubane, which can be used to synthesis liquid crystals.

Polymers with cubane in the backbone or as a pendant group along a polymer chain is

focused now.

The cubane subunits in these polymers can be rearranged easily to cycloctatetraenes.

It is expected that polycyclooctatetra can be converted in to polyacetylenes by

the way of ring-opening metathesis polymerization. The polyacetylenes will have properties

which are enhanced by the chain being intrinsically part of another polymer.

These properties including stability and extrudability and etc. A example is shown below:

 

Cubane derivative could be the structural basis for a class of intrinsic small gap polymers.The small gap polymer could present intrinsic good conductivity without doping,good nonlinear optical and photoelectric properties.Investigation of oligamers with up to six units of a conjugated unsaturated cubane derivative,where all the hydrogen were removed, is carried out.The table below shows that the gap values in eV by EHT and PM3.These values suggest to us that these structures could be used to design a newclass of polymers with very small gap.

Explosive and fuels:

In the early 1980s Everett Gilbert of the U.S. Army Armament Research and Development

Command (now ARDEC) pointed out that the nitrocarbon octanitrocubane (ONC),

then unknown, has a perfect oxygen balance, and in light of the properties of the

parent hydrocarbon cubane should have a very high heat of formation per CNO₂ unit

and an exceptionally high density as well. His colleagues Jack Alster, Oscar Sandus

and Norman Slagg at ARDEC provided theoretical support for Gilbert’s

brilliant insight and estimated that ONC would have a detonation pressure

significantly greater than HMX. Later, both statistical and computational

approaches predicted a density of 2.1 ± 2.2 g /cm³ for octanitrocubane,

greater than any other C, N, O compound.

Is Cubane a really good explosives?

Quantitative evaluation of the potential of a candidate explosive before synthesis is very difficult.

Currently, estimation of energetic properties relies on the empirically derived Kamlet and Jacobs

equations:

In these equations the heat released by the decomposition, the number of moles of gas produced,

and the molecular

weight of these gases are all critical factors. Density too is crucial.

Obviously, the more molecules of a high-energy material that can be packed into the limited

volume of a shell or rocket the better. Less obvious, but more important, density affects the

detonation velocity of an explosive.

This is a specialized “linear” rate of reaction that ranges from 5 to 10 km/s in

explosives and affects the maximum detonation pressure, a direct measure of the

power of an explosive. For a given explosive, the detonation pressure is proportional

to the square of its density, so great effort is made to obtain the highest density form

of any particular explosive.

Quantitative evaluation of the potential of a candidate explosive before synthesis is very difficult.

Currently, estimation of energetic properties relies on the empirically derived Kamlet and Jacobs

equations:

In these equations the heat released by the decomposition, the number of moles of gas produced,

and the molecular

weight of these gases are all critical factors. Density too is crucial.

Obviously, the more molecules of a high-energy material that can be packed into the limited

volume of a shell or rocket the better. Less obvious, but more important, density affects the

detonation velocity of an explosive.

This is a specialized “linear” rate of reaction that ranges from 5 to 10 km/s in

explosives and affects the maximum detonation pressure, a direct measure of the

power of an explosive. For a given explosive, the detonation pressure is proportional

to the square of its density, so great effort is made to obtain the highest density form

of any particular explosive.

Numerous nitro compounds are employed commonly as military and commercial explosives.

There is a continuing search for more powerful and less shock-sensitive examples.

Such materials are also sought as potentially useful fuels and propellants.

Most interest is focused on high-density organic compounds that contain all of the

elements needed for combustion to gaseous products in the absence of air.

Nitrocubanes carrying five or more nitro groups contain enough oxygen to oxidize

all constituent carbon and hydrogen atoms to gaseous CO, CO₂, or H₂O.

Each of these, along with N₂, “explodes” from the solid to 12 gaseous molecules.

The expansion from the dense solid to a lot of gas (much expanded by the released heat)

produces the desired effect in propellants and explosives. ONC has a “perfect”

oxygen balance and would produce (were the detonation completely efficient)

eight molecules of carbon dioxide and four of dinitrogen. As ONC has no

hydrogen, no water forms when it burns; when used as propellants such zero-hydrogen

compounds leave little or no visible smoke (steam) in the plume behind the rocket;

such “low-signature” rockets are difficult to track.

On application of the Kamlet and Jacobs equations led ARDEC to predict that

octanitrocubane would be a very much better explosive (Table 1) than the classic

C-nitro compound trinitrotoluene (TNT), perhaps 15±30% better than the nitramine

HMX (the most powerful, commonly used military explosive), and at least competitive

with (and perhaps less shock-sensitive than) the newest experimental explosive CL-20

 

 

SYNTHESIS:(1)

The high strain that the cubane framework is under has already been highlighted. The researchers had to very cautiously attach a nitro group to each of the corners of the cube in order to make the desired product. The insertion of the first four nitro groups could be done by manipulating functional groups:

The key intermediate, cubane-1,3,5,7- tetracarboxylic acid (TNC), was obtained by clever application of the Brown-Kharasch photochlorocarbonylation to cubane mono-acid.

The addition of four further nitro groups proved far more difficult and new methodologies had to be developed, specifically the process of interfacial nitration. This method was used successfully to convert the sodium salt of TNC to pentanitrocubane (PNC) and then hexanitrocubane (HNC), both are stable materials.

Interfacial nitration, however, proved deficient for further nitration of HNC and again new experimental methodology had to be developed for its successful conversion to heptanitrocubane (HpNC):

Addition of excess NOCl to a solution of the lithium salt of HpNC in dichloromethane at -78°C gave the long-sought ONC:

 DIFF TYPES

For the last planned post in my Unnatural Products series, I’m going to write about Eaton’s 1981 synthesis of pentaprismane.[A] At the time, unnatural hydrocarbons were hot targets, and as the next largest prismane on the list this target was the subject of much research by groups around the world. Perhaps Eaton’s biggest rivals were the groups of Paquette and Petit, and in fact all three had, at various times, synthesised hypostrophene as an intended precursor to the target.

Unfortunately, the ‘obvious’ [2 + 2] disconnection from pentaprismane turned out to be a dead end and the photochemical ring closure was unsuccessful. The 1970s and early 1980s saw the publication of a number of other similarly creative, but sadly ill-fated, approaches based on various ring contractions, and the compound gained a well-earned reputation for extraordinary synthetic inaccessibility.

Eaton’s route began, as with the cubane and dodecahedrane syntheses previously covered in this series, with a Diels-Alder reaction. The diene used was the known tetrachlorocyclopentadienone acetal shown that upon heating neat with benzoquinone produced the endo adduct shown in excellent yield. Next, an even higher yielding photochemical [2 + 2] reaction was used to close the cage-like structure by cyclobutane formation. Treatment with lithium in liquid ammonia simultaneously reduced both ketones and removed all four chlorine atoms. The resulting diol was converted to the ditosylate, which, under carefully controlled conditions with sodium iodide in HMPA, underwent a mono-Finkelstein reaction to give the iodotosylate shown. When this was treated with t-BuLi halogen-lithium exchange, followed by an extraordinary fragmentation, gave a diene reminiscent of hypostrophene shown above. However, the extra carbon atom in the skeleton made all the difference, and unlike the parent compound, this did undergo a [2 + 2] cycloaddition when exposed to UV light. Finally, acetal hydrolysis gave homopentaprismane in 34% yield from benzoquinone, putting the group a single ring contraction from victory.[B]

With significant amounts of homopentaprismanone in hand, the group now intended to employ the transformation that had been the cornerstone of their cubane synthesis – the Favorskii rearrangement. Unfortunately, this required the introduction of a leaving group in the ketone α-position, a transformation made incredibly difficult due to the strained system and Bredt’s rule, which prevented enolisation.[C] Eventually a six-step sequence (!) to introduce a tosyloxy group was devised, beginning with a Baeyer-Villiger reaction using m-CPBA. A remarkable CH oxidation with RuO4, generated in situ, then gave the hydroxylactone. Treatment of this with diazomethane gave the corresponding δ-ketoester in almost quantitative yield. The group then reformed the starting norbornane-like bridge through use of an unusual acyloin type reaction effected by treatment with sodium in liquid ammonia. Finally, oxidation of the secondary alcohol and tosylation gave the Favorskii precursor, apparently preparable in muti-gram quantities.

Treatment with aqueous potassium hydroxide solution effected Favorskii rearrangement in excellent yield, especially considering that this was the first time the elusive pentaprimane ring system had been prepared. Finally, Eaton used the three-step decarboxylation he had developed for cubane to remove the extraneous acid and give pentaprismane in 18 steps. Awesome.[D]

References and suchlike

1. A    J. Am. Chem. Soc., 1981, 103, 2134. Much like Eaton’s seminal cubane paper, the title is a single word, ‘Pentaprismane’. I love the lack of hype.
2.  B   Although Petit had prepared this compound a full decade earlier, his approach relied on a cycloaddition of the difficult to prepare cyclobutadieneiron tricarbonyl with the acetal of tropone, and proved difficult to scale  up. In fact, in his own paper Eaton rather directly described it as ‘conceptually fascinating [but] useless synthetically’.
3. C   Eaton uses the phrase ‘invasion at the bridgehead’, which I find delightfully evocative. Makes it sound like a second world war campaign. Apparently the group initially planned, in spite of Bredt’s rule, to deprotonate the bridgehead position, relying on inductive stabilisation of the anion rather than enolate formation, but were unable to do so.
4. D  Pentaprismane is the most recent of three prismanes synthesised to date, the other two being cubane, and triprismane. Although I think triprismane looks quite silly, it was actually synthesised some 8 years previouslyby T. J. Katz in far fewer steps. Go figure.
   

 

The Amide Activating Group

 

The very first step of cubane frame substitution will be the activation of the cubane frame.

This can be done by amides. The idea is derived from the similarities between cubane and arenes.

 Both of them have C-H bonds with enhanced s character ( see structure),

 and in both the adjacent (ortho) substituents are forced to be coplanar.

A more specific example is the cubane-N,N-diisopropyl carboxamide

 reacts with excess lithium tetramethylpiperidide (LiTMP) in THF solvent.

About 3% of the deuteriation products obtained.

The diisopropyl amide activating group is used because it is inert to the amide

bases employed for ortho metalation. Although there is a problem, there is

 difficulty in hydrolyzed it the corresponding carboxylic acid.

The problem is finally solved by using borane reduction followed by the oxidation

 of the amine so produced with dimethyldioxirane or potassium permanganate (in large scale).

Transmetalation is the basis of a complete synthetic methodology for the preparation

of a great variety of the substituted cubanes.

In order to make the substitution productively, a way must be found to

make use of the small amount of anion in the equilibrium with the starting material.

Mercury salt is used here as an effective anion trap and very little starting material remain unreacted.

The mercury for lithium transmetalation resulted in nearly complete conversion of the

starting material by drawing the lithiation equilibrium to the right.

 

The amide group is important in stabilizing the intermediate lithiated cubane,

but not the mercuriated compound. Once the lithium is replaced by mercury,

 the amide group is again able to assist removal of another ortho-hydrogen atom.

In the end, the complex ortho-mercurated product mixture obtained was

 simplified by treatment with elemental iodine.

The iodine cleavage of the carbon-mercury bonds 2-iodo and 2,6-diiodo derivatives

of the starting amide in72% and 15% respectively

Cubyl Grignard Reagents

From transmetalation, a reverse transmetalation was also developed, which is basically adding Grignard reagent to the mercuriated cubane instead of the iodine. However, these processes have a great main disadvantage, the mercury is highly toxic. Thus, scale up of this method was limited.

In 1988, Bashir-Hashemi introduced transmetaltion with magnesium salts and thereby provided easy access to cubyl mono-and bis-Grignard reagents. It is a reaction of cubane diamide with an excess of LiTMP/MgBR₂ in THF and quenching with I₂ gave diiodocubane diamide of 72% yield.

The effect of the presence of electron withdrawing group     –  Cyanide

When electron withdrawing group such as cynate present, they stabilize both intermediate lithiated cubanes very well. As a result, only a small amount of LiTMP is need to achieve fairly complete deprotonation even at -78°C.

The inductive effect of the cyano group clearly enhances the reaction. However, the adding of cyano groups results in competitive lithiation and a mixture of products. However, this problem can be well trackled by adding MgBr₂.The product ratio was improved to 9:1 favoring carboxyliation ortho to the amide function.

A mixture of product formed.

Increased selectivity by adding MgBr₂

Since the reactivity of cubane metalation is enhanced greatly with presence of cyano groups, it is possible to substitute all three positions ortho to the amide in a simple reaction. For instance, 4-cyanocubanamide can be converted directly into the tri(tert-butylcarbonyl)derivative as shown below.

Through Baeyer-Villiger oxidation, ter-butyl cuybl ketones can be converted easily to the polycarboxyliated cubane.

PHENYL CUBANE

 

From the basis idea of cubyl Grignard Reagent, phenyl cubane can be synthesised. The reaction of cubane diamide with 10 equiv of LiTMP and 4.0 equivalents of MgBr2 etherate in THF at 0°C followed by the addition of 10.0 equiv of bromobenzene, gave diphenylcubane diamide in 53% yield.

The mechanism is shown below:

 

The benzyne intermediate was formed in situ from the reaction of excess of LiTMP with bromobenzene. For a similar reaction, MeMgBr is used and give 30% yield of bromo-phenylcubane diamide, the first cubane derivative containing 3 different substituents.

Now, let us look the main concern of the cubane derivatives–the nitrocubanes.

Nitrocubanes are sought to be powerful, shock-insensitive, high-density explosives. They are stable compounds with decomposition points above 200°C. Simple nitrocubane can be made from simple oxidation of amines( See Functional Group Transformation.)

If we want to add more nitro groups into the cubane nucleus, we cannot do it though transmetalation because there is unstoppable cage cleavage reactions when make adjacent nitro groups. The ab initio calculation has confirmed this destabilising effect.

We are going to discuss how to make more and more substituted nitrocubane until octanitrocubane(ONC), the ultimate power house, is synthesised.

 

1,3,5 trinitrocubane and 1,3,5,7 tetranitrocubane(TNC)

As we mention early, addition of nitro groups cannot be done through direct transmetalation. Thus, we need found some indirect route.

This is done by introducing a substituent on each of 3 ortho carbons and remove the ortho-activating group in the end.

By adding a electron-withdrawing group such as a cyano group will help the case here. This choice of original substituent is important here and when cyano group is chosen, it activates the cubane nucleus without affecting the ortho directing by the diamide (for details please refer to electron-withdrawing group-cyanite).

When the dicyano amide was treated with TMPMgBr in THF and quenched with CO₂. The ortho (to amide) carboxylic acid was the only product.

Even when the much activated tricyanoamide is treated with TMPMgBr and CO₂ ,again, the ortho position ( to amide) carboxylic acid was formed.

The removal of the carboxamido group is done through a smart yet tedious process. The cyano group is converted to acid group first. Then, it is reduced to alcohol by lithium aluminium hydride. At same time, the carboxamido is reduced to aminotetrol. The alcohols are protected as acetates and amino tetrol is converted to carboxylic acid. The carboxylic is then removed through Barton Decarboxylatio. A detail mechanism is provided below.

The cubane-1,3,5,7-teracarboxylic acid is converted to TNC on the mechanism as follow:

The whole process is very clever, but it is very long. Thus, in 1997, a improved synthesis method for TNC was proposed by making use of the photochemsitry.

Improved synthesis for TNC

In 1993, Bashir-Hashemi showed the cubane-1,3,5,7-tetracarboxylic acid chloride can be formed by applying photochemically induced chlorocarbonyl cation( the Kharasch_Brown Reaction).

For a fast reaction, a high power Hanovia of 450 watts, medium pressure Hg was used. The favoured products are cubane tetraacid chloride shown on the right hand side. The first one, cubane-1,3,5,7-tetracarboxylic acid, made up 30% overall. This reaction conveniently prepare us the important versatile intermediate .

A detail conversion process is provided below:

 

A catalyst TMSN₃ is used in converting tetraacid chloride to tetracylazide. The rest is the same as the orginal reaction.

TNC is a thermodynamic powerhouse but remarkly stable kinetically. Figure 1 shows that rapid thermal decomposition doesnot start until over 250°C.

The literature was unsupportive of this optimistic view. Poor results were also obtained initially with nitrating agent such as NO₂BF₄, acetyl nitrate, amyl nitrate etc.

Tetranitrocubylsodium can be formed directly on treatment of TNC with sodium bis(trimethylsilyl) amide in THF at -75°C. It can react with electrophiles to provide a useful and convenient way to achieve further functionalization of cubane nucleus.

More substituted nitrocubanes-

Pentanitrocubane(PNC) and Hexanitrocubane(HNC)

PNC

Base on the property of tetranitrocubylsodium, nitryl chloride(NO₂Cl) was used to further nitrate the cubane nucleus. Treatment of NO₂Cl with tetranitrocubylsodium in THF at -75°C works out 10-15% yield of pentanitrocubane(PNC). The yield increased to 30% when the solution was frozen to-180°C and allowed to warm slowly. This is called the interfacial nitration process. It is suggested that NO₂Cl oxidized tetranitrocubylsodium to a radical, which made the whole reaction worked.

Base on the property of NO₂Cl , N₂O₄ should be a better choice. The results showed that it is actually a better with 60:40 PNC to TNC ratio. The reaction is extremely clean.

PNC is colourless and highly crystalline. It is the first nitrated cubane to contain adjacent nitro groups. It behaves just TNC and other nitrocubanes, remarkly stable kinetically.

HNC

Although HNC can be prepared the same way as PNC, but the separation between PNC and HNC is extremely difficult.

However, if TIPS-substituted PNC( by N₂O₄ nitration from TIPS-sub TNC) react with potassium base (K(TMSN)₂and the nitration with N₂O₄ gave a mixture of (triisopropyl) HNC and PNC in 60:40 ratio. This step is important and crucial. The separation is now possible by column chromatography on silica gel. 30% isolated yield of PURE HNC could be obtained when further treated with SiO₂.

Synthesis for the last two nitro cubanes- heptanitrocubane and octanitrocubane

Interfacial nitration is not sufficient to further nitration for heptanitrocubane. Al though it is very good in deed, we need to find something which can successfully convert heptanitrocubane (HpNC).

HpNC

In this procedure TNC was treated with at least 4 equivalents of the base NaN(TMS)₂ (where TMS = trimethylsilyl) at ±78 C in 1:1 THF/MeTHF. After the mono sodium salt had formed, the solution was cooled to between ±125 and ±130°C giving a clear, but very viscous fluid. This was stirred vigorously as excess N₂O₄ in cold isopentane was added. After one minute, the base was quenched, and the whole mixture was added to water. This resulted reproducibly in almost complete conversion of TNC (1 g scale) to HpNC (95% by NMR), isolated crystalline in 74% yield!

ONC

However, even in the presence of excess nitrating agent (N₂O₄ or many others) no indication
of any formation of ONC was ever seen. It is suspected that anion nitration with N₂O₄ proceeds by oxidation of the carbanion to the corresponding radical.Perhaps the anion of HpNC is too stabilized for this to occur. (HpNC is significantly ionized in neutral methanol.) This concept led to the use of the more powerful oxidant nitrosyl chloride. Addition of excess NOCl to a solution of the lithium salt of HpNC in dichloromethane at 78° C followed by ozonation at 78° C gave the long-sought ONC in 45±55% isolated yield on millimole scale. The intermediate product prior to oxidation is thought to be nitrosoheptanitrocubane.

Finally, the magic molecule, the so called the impossible molecule, octanitrocubane was synthesised. But, how good are they and how useful are they? Let us discuss about it in the following section.

Properties of nitrocubane:

Neither HpNC nor ONC is detonated by hammer blows!
Both have decomposition points well above 200 C. Octanitrocubane
sublimes unchanged at atmospheric pressure at 200 C. HpNC forms beautiful, colorless, solvent-free crystals when
its solution in fuming nitric acid is diluted with sulphuric acid. Single-
crystal X-ray analysis confirmed the assigned structure and
provided an accurate density at 21 C of 2.028 g cm±3, impressively
high for a C, H, N, O compound. Although octanitrocubane
catches the imagination with its symmetry, heptanitrocubane
currently is significantly easier to make than ONC. It is
denser, and it may be a more powerful, shock-insensitive explosive
than any now in use. According to page 41 of a 2004 IUPAC guide, cubane is the “preferred IUPAC name.”

1.  ‘ ‘Cubaneand Thomas W. Cole. Philip E. Eaton and Thomas W. Cole J. Am. Chem. Soc.; 1964; 86(15) pp 3157 – 3158; doi:10.1021/ja01069a041.
2.  The Cubane System Philip E. Eaton and Thomas W. Cole J. Am. Chem. Soc.; 1964; 86(5) pp 962 – 964; doi:10.1021/ja01059a072
3.  Michael B. Smith, Jerry March, March’s Advanced Organic Chemistry, 5 th Ed., John Wiley & Sons, Inc., 2001, p. 1459. ISBN 0-471-58589-0
4.  K. Kindler, K. Lührs, Chem. Ber., vol. 99, 1966, p. 227.

• Eaton Cubane Synthesis @ SynArchive.com
• Cubane chemistry at Imperial College London

• Basketane
• Octaazacubane
• Octanitrocubane

 

 

Dimethyl cubane-1,4-dicarboxylate

dimethyl 1,4-cubanedicarboxylate;

1,4-cubanedicarboxylic acid dimethyl*ester;

methyl 4-(methoxycarbonyl)pentacyclo[4.2.0.0<2,5>.0<3,8>.0<4,7>]octanecarboxylate

Pentacyclo(4.2.0.0(2,5).0(3,8).0(4,7))octane-1,4-dicarboxylic acid dimethyl ester

CAS 29412-62-2

Molecular Weight:	220.2213
Molecular Formula:	C12H12O4
Density:	1.684g/cm3
Boiling Point(℃):	270°C at 760 mmHg
Flash Point(℃):	131.3°C
refractive_index:	1.704

An interesting   OPRD paper on the scale up of dimethyl cubane -1,4-dicarboxylate.

The work appeared in Organic Process Research and development, 2013, doi.org/10.1021/op400181g . It was carried out by an Australian group, John Tsanaktsidis, Michael Falkiner, Stuart Littler, Kenneth McRae and Paul Savage from CSIROand features a large-scale photochemical reaction which is very unusual to see in a scaled chemical process.

Extending their previous work from 1997, they scaled the following reaction.

As is the norm with such reactions the reaction requires high dilution to be successful. In this case they used a tailor made photochemical  reactor. A solution of 1 in methanol/water was pumped through the reactor at 4 L/minute and the conversion of 1 to 2 was noted as 1g/4 minutes of irradiation.

This meant a total time of 173 hours. Further processing of 2 through the double Favourskii ring contraction required significant development but eventually delivered the di-sodium salt corresponding to the di-ester of cubane.

One needs to be careful with these cubanes as they are, due to the highly strained nature of the system quite energetic materials, the do-acid and ester being more stable than the parent hydrocarbon. However the energy released upon warming above the melting point is not insignificant.

This paper represents a good demonstration of the scale-up of several very difficult chemical reactions, including excellent descriptive paragraphs of the problems and solutions. They are to be congratulated on a very nice piece of  work.

See below

A scalable process for the preparation of high purity dimethyl 1,4-cubanedicarboxylate (3) is reported.

The work described herein builds on previous synthetic work from this and other laboratories, to provide a reliable process that can be used to prepare multigram quantities of 3 in a partially telescoped, 8 step process, with minimal purification of intermediates.

Pilot-Scale Production of Dimethyl 1,4-Cubanedicarboxylate

Michael J. Falkiner , Stuart W. Littler , Kenneth J. McRae , G. Paul Savage , and John Tsanaktsidis *

CSIRO Materials Science & Engineering, Ian Wark Laboratory, Bayview Avenue, Clayton Victoria 3168,Australia

Org. Process Res. Dev., 2013, 17 (12), pp 1503–1509

DOI: 10.1021/op400181g

Publication Date (Web): November 8, 2013

http://pubs.acs.org/doi/full/10.1021/op400181g?prevSearch=cubane&searchHistoryKey=

Scheme 5. Pilot-Scale Synthesis of Dimethyl 1,4-Cubanedicarboxylate (3)

Figure 1. Cubane nucleus.

Step 5

A dry 100 L glass reactor was charged with the crude diacid 2 (1287 g), dry methanol (36 L), and Dowex ion-exchange resin 50WX8–100 (176 g) that was prewashed with 1 L of methanol. This mixture was then stirred (150 rpm), and heated under reflux for 18 h under an atmosphere of nitrogen. The mixture was then cooled to room temperature and filtered to remove the resin. The methanol solution mixture was then evaporated to dryness using a rotary evaporator (45 °C at 45 mmHg) leaving behind the crude diester 3 (863 g) as a dark brown solid. Purification by sublimation (100–120 °C/0.01 mmHg), followed by recrystallization from acetonitrile furnished the diester 3 (560 g, 30%), as a colorless solid,

mp 164.5 °C (lit. 161–162 °C).(47)

 1H NMR δ: 3.7, s, 6H 4.24, s, 6H, ring protons.

13C NMR δ: 47.03, 51.55, 55.77, 171.89.

………………………………..

http://cst-www.nrl.navy.mil/lattice/struk/c8h8.html.

http://www.ch.ic.ac.uk/local/projects/b_muir/Enter.html.

http://www.sciencedirect.com.

http://www.sciencenews.org/.

http://www.winbmdo.com/.

Bashir-Hashemi, A., New developments in cubane chemistry: phenylcubanes.

J. Am. Chem. Soc.;1988;110(21);7234-7235, 110(21), 7234-7235.

D.S.Calvao, p. m. v. b. B. A. C. J. a., Theooretical Characterization of oligocubane.

Synthetic Metals 102 (1999) 1410.

E. W. Della, E. F. M., H. K. Patney,Gerald L. Jones,; Miller, a. F. A.,

Vibrational Spectra of Cubane and Four

of Its Deuterated Derivatives.

Journal of the American Chemical Society / 101.25 / December 5, I979,7441-7457.

Galasso, V., Theoretical study of spectroscopic properties of cubane.

Chemical Physics 184 (1994) 107-114.

Kirill A. Lukin, J. L., Philip E. Eaton,*,Nobuhiro Kanomata,Juirgen Hain,Eric Punzalan,and

Richard Gilardi, Synthesis and Chemistry of 1,3,5,7-Tetranitrocubane Including

Measurement of Its Acidity, Formation of o-Nitro Anions, and

the First Preparations of Pentanitrocubane and Hexanitrocubane.

J. Am. Chem. Soc., Vol. 119, No. 41, 1997,9592-9602.

P.E.Eaton, Cubanes: starting Materials For the chemistry of 1990s and the New Century.

J. Am. Chem. Soc.;1992;31;1421-1436, 31, 1421-1436.

Philip E. Eaton, t. Y. X., t and Richard Gilardi*, Systematic Substitution on the Cubane Nucleus.

Synthesis and

Properties of 1,3,5-Trinitrocubane and 1,3,5,7-Tetranitrocubane

. J. Am. Chem. SOC.1993,115, 10195-10202.

Philip E. Eaton, R. L. G.; Zhang, a. M.-X., Polynitrocubanes: Advanced High-Density,

High-Energy Materials**. Adv. Mater. 2000, 12, No. 15, August 2.

Philip E. Eaton, Cubane: Starting Materials for the chemistry of the 1990s and the new century.

Angew.Chem.Int.Ed.Engl.1992,31,1421-1436.

Philip E. Eaton, t. Y. X., t and Richard Gilardi*, Systematic Substitution on the Cubane Nucleus.

Synthesis and

Properties of 1,3,5-Trinitrocubane and 1,3,5,7-Tetranitrocubane.

J. Am. Chem. SOC., Vol. 115, No. 22, 1993,10196-10202.

T. YILDIRIM, P. M. G., D. A. NEUMANN, P. E. EATONC and ‘T. EMRICK’, SOLID

CUBANE: A BRIEF REVIEW. Carbon Vol. 36, No. 5-6, pp. 809-815,1998.

Zhang, P. E. E. a. M.-X., Octanitrocubane: A New Nitrocarbon.

Propellants, Explosives, Pyrotechnics 27, 1 – 6 (2002).

Prozac, Fluoxetine SPECTRAL DATA

N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine

FLUOXETINE

Fluoxetine (also known by the tradenames Prozac, Sarafem, Ladose and Fontex, among others) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Fluoxetine was first documented in 1974 by scientists from Eli Lilly and Company.^[6] It was presented to the U.S. Food and Drug Administration in February 1977, with Eli Lilly receiving final approval to market the drug in December 1987. Fluoxetine went off-patent in August 2001.^[7]

Fluoxetine is approved in the US for the treatment of major depression (including pediatric depression), obsessive-compulsive disorder (in both adult and paediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder.^[8] In addition, fluoxetine is used to treat trichotillomania if cognitive behaviour therapy is unsuccessful.^[9] In combination with the atypical antipsychotic olanzapine it is known by a few brand names,^{[note 1]} including its US brand name Symbyax, which is approved for the treatment of depressive episodes as part of bipolar I disorder and in the treatment of treatment-resistant depression.

Despite the availability of newer agents, fluoxetine remains extremely popular. In 2010, over 24.4 million prescriptions for generic formulations of fluoxetine were filled in the United States alone,^[10] making it the third most prescribed antidepressant after sertraline(SSRI; became generic in 2006) and citalopram (SSRI; became generic in 2003).^[10] In 2011, 6 million prescriptions for fluoxetine were handed out in the UK.^[11]

Fluoxetine 20 mg capsules.

Uses of the pharmaceuticalProzac is an antidepressant and is used in the treatment of depression, panic attacks, and obsessive compulsive disorder. It was first released in 1988 and has been used since by upwards of 40 million people worldwide, according to a study done in 2008. A study released in the journal Public Library of Science Medicine journal in 2008 claimed that Prozac was ineffective as an antidepressant after a study done in which both patients who took the drug and patients who were given a placebo drug showed the same improvement as those who were given the real treatment.While its main usage has been to treat depression, Fluoxetine has also been used for research in the discovery the role of 5-HT in CNS physiology and pathophysiology. It has alos been used in the treatment of anorexia nervosa, bulimia nervosa, obsessive–compulsive disorder, panic disorder, premenstrual dysphoria and generalized anxiety disorder (Wong 772).
Prozac was manufactured by Eli Lilly and Company until its patent lapsed in 2001. Fluoxetine, however, is now the active ingredient in another Lilly product – Sarafem, a pill for premenstrual syndrome.

Synthesis:While several viable syntheses exist for fluoxetine, one particular synthesis is especially practical for undergraduate laboratories. While some syntheses use toxic compounds such as the reducing agent B2H6 and the chlorinating agent SOCl2 to yield fluoxetine, there is at least one synthesis that circumvents these hazardous reagents. The synthesis given by Perrine, Sabanayagam, and Reynolds instead uses the less hazardous reagents NaBH4 and KOCMe3. Furthermore, while other syntheses require use of the costly compound 4-(trifluoromethyl)phenol, the synthesis avoids this compound and instead requires the inexpensive 1-chloro-4-(trifluoromethyl)benzene. For these reasons, the synthesis given below is best suited for introductory laboratories.

The commercially available compound 3-(dimethylamino)-1-phenylpropan-1-one is reduced with sodium borohydride (NaBH4) to form 3-(dimethylamino)-1-phenylpropan-1-ol. This alcohol is deprotonated with potassium t-butoxide (KOCMe3), and the resulting alkoxide undergoes aromatic substitution onto 1-chloro-4-(trifluoromethyl)benzene. Aromatic substitution within the polar aprotic solvent DMAA yields the drug precursor “N-methyl-Prozac.” NMP is converted to Prozac (fluoxetine) via N-demethylation with cyanogen bromide (CNBr).

Patent EP0612242B1

Chemical Properties

General features

Fluoxetine hydrochloride is a white to off white crystalline solid which has a melting point of 158.4-158.9oC. It has a maximum solubility in water of 14mg/ml.

Solubility in common solvents

Freely soluble in methanol and ethanol
Soluble in acetonitrile, chloroform and acetone
Practically insoluble in toluene, cyclohexane and hexane

Optical Rotary Power-(R-Fluoxetine)	data
Type	[alpha]
Concentration	1g/100ml
Solvent	CHCl3
Optical rotary power	2 degrees
Wavelength	589nm
Temperature	22oC

MASS SPECTRUM

The high resolution NMR spectrum can be readily interpreted.

 

The main source of information that the mass spectrum provides is the molecular weight of the compound which in this case can be seen to be approximately 346u.

NMR Spectroscopy

Analysis of peaks

NMR interpretation

Chemical Shift/ppm	Assignment
7.4	A
6.9	B
5.5	C
3.0	D
2.5	E
2.0	F

The A protons are chemically equivalent due to the symmetry of the system and hence appear at the same ppm value. Each A hydrogen will couple to its neighbouring B proton and the splitting pattern will be a doublet. The electron withdrawing effect of the fluorine atoms combined with the aromatic ring current is responsible for the high chemical shift of these protons.

The B protons are again in identical chemical environments and they each couple to the neighboring A proton. A doublet is therefore observed in the spectrum.

The C is close to an electronegative oxygen atom and an aromatic ring. These withdraw electron density both inductively and mesomerically. The C sisgnal is split into a triplet by 3J coupling to the adjacent F protons.

The D proons couple to the F protons but not to the adjacent NH proton resulting in a triplet.

The E signal corresponding to the methyl group is obviously a singlet as there are no adjacent hydrogens to which the E protons can couple.The NH proton is again discounted due to its transient nature.

The F protons show a multiplet. These protons are not chemically equivalent although they have been grouped together. These hydrogens are adjacent to an asymmetric centre and are thus diastereotopic. Replacement of each hydrogen by a different group would result in opposite diastereomers. As the F protons are not equivalent they couple to each other as well as to the D and C protons which are adjacent.A compliclated multiplet therefore results.

The hydrogen shown attached to the nitrogen atom does not appear in the spectrum as such protons readily interchange in solution.

The five aromatic protons appear as amultiplet between the shifts of the A and B protons.

LINK…………http://file.selleckchem.com/downloads/nmr/S133301-Fluoxetine-hydrochloride-NMR-Selleck.pdf

X-ray Crystallography

The three dimensional structure of fluoxetine has been determined by X-ray crystallography. In the solid state the planes defined by the two aromatic rings are skewed preventing the possibility of intramolecular interactions between the rings.The methylene units of the methylpropanamine part adopt the expected conformational relationships thus minimising torsional strain.The C1-C2-C3-O4 dihedral angle is 60.6. From this it can be concluded that the propanamine side chain folds towards the phenoxy part as opposed to adopting a fully extended configuration. This folded three dimensional relationship is thought to be essential for a high affinity interaction with the serotonin uptake carrier to take place. The various substituents on the phenoxy part of fluoxetione are also very important in determining its potency and selectivity.

Although th folded propylamine part of fluoxetine plays in acrucial role in its pharmacological properties, the 3-phenyl group is also a critical aspect of its structure. It is thought that the enhancement of potency attributed to this group can be explained in terms of its interaction with a hydrophobic pocket on the serotonin uptake carrier. Evidence in support of this hypothesis is the similar potency of both enantiomers of fluoxetine. This would be expected if the afore-mentioned hydrophobic interaction is important.

Crystallographic data

formula	C17H18F3NO.HCl
formula mass	345.8
space group	Pcab
a,A	10.457 (2)
b,A	10.387 (2)
c,A	32.345 (6)
V,A	3513.1 (1.4)
Z	8
d calc g/cm3	1.307

Fluoxetine hydrochloride crystallised from water as colourless needles in the orthorhombic space group known as Pcab. Each unit cell contains eight molecules and the molecules are arranged in bilayers with the hydrophobic(trifluoromethyl) phenoxy and hydrophilic amine hydrochloride parts juxtaposed to the corresponding regions of a second fluoxetine molecule.

UV Spectroscopy

UV max/nm	E1%
227	372.0
264	29.2
268	29.3
275	21.5

Infra-red spectroscopy

• There are two or three bands between 2960 and 2850cm^-1 which correspond to C-H stretching frequencies.
• There is a sharp band due to the C-F stretching frequency between 1400-1000cm

---

Structure of the compound

N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine

---

Identification of bond types found in the molecule

	count	length (Å)	energy (KJ/mol)
C=C	6	1.4	602
C–C	10	1.4	346
C–F	3	1.4	485
C–H	17	1.1	411
C–N	2	1.4	305
C-O	2	1.4	358
H–N	1	1.0	386

---

Identification of functional groups
Phenyl group, amino group, halo group, alkoxy group

---

Identification of all chirality centers in the molecule:

---

The CAS number:
CAS Number: 54910–89-3

---

Predicted NMR spectra:

Predicted IR spectra:
Aromatic rings: 1600 and 1475
N-H bond: 3300
C-O bonds: 1300-1000
C-H bonds: broad 3000

References

1.  Altamura, AC; Moro, AR; Percudani, M (March 1994). “Clinical Pharmacokinetics of Fluoxetine” (PDF).Clinical Pharmacokinetics 26 (3): 201–214.doi:10.2165/00003088-199426030-00004.PMID 8194283.
2.  “PROZAC® Fluoxetine Hydrochloride” (PDF). TGA eBusiness Services. Eli Lilly Australia Pty. Limited. 9 October 2013. Retrieved 23 November 2013.
3.  “FLUOXETINE HYDROCHLORIDE capsule [Sandoz Inc]”. DailyMed. Sandoz Inc. January 2013. Retrieved 23 November 2013.
4.  “Fluoxetine 20 mg Capsules – Summary of Product Characteristics (SPC)”. electronic Medicines Compendium. Accord Healthcare Limited. 21 November 2012. Retrieved 23 November 2013.
5.  “Prozac, Sarafem (fluoxetine) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 23 November 2013.
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