WO2008006394A1 - Process for the preparation of optically active (4e)-5- halo-2-alkylpent-4-enoic acids and their ester derivatives - Google Patents

Process for the preparation of optically active (4e)-5- halo-2-alkylpent-4-enoic acids and their ester derivatives Download PDF

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WO2008006394A1
WO2008006394A1 PCT/EP2006/006897 EP2006006897W WO2008006394A1 WO 2008006394 A1 WO2008006394 A1 WO 2008006394A1 EP 2006006897 W EP2006006897 W EP 2006006897W WO 2008006394 A1 WO2008006394 A1 WO 2008006394A1
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WO2008006394A8 (en
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Mariano Stivanello
Cristiano Grandini
Ennio Grendele
Alessandro Falchi
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F.I.S. Fabbrica Italiana Sintetici S.P.A
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D275/00Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/06Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00Preparation of carboxylic acid esters
    • C07C67/08Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00Preparation of carboxylic acid esters
    • C07C67/14Preparation of carboxylic acid esters from carboxylic acid halides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
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    • C07B2200/07Optical isomers

Abstract

A process for the preparation of optically active (4E)-5-halo-2-alkylpent-4-enoic acids and their ester derivatives by a stereoselective synthesis which employs camphorsultam as chiral auxiliary is disclosed; in particular methyl (2S, 4E)-5-chloro-2-isopropylpent-4-enoate is prepared, which is a key intermediate in the manufacturing of the new anti-hypertension drug Aliskiren. Furthermore novel N-(5-halo-2-alkylpent-4-enoyl) camphorsultams are provided. A process for the hydrolysis of substituted N-acylcamphorsultams with strong acids is also provided.

Description

DESCRIPTION

"Process for the preparation of optically active (4E) -5- halo-2-alkylpent-4-enoic acids and their ester derivatives" Technical field of the invention

[0001] The present invention relates to a process for the preparation of optically active (4E) -5-halo-2-alkylpent- 4-enoic acids and their ester derivatives, in particular methyl (2S, 4E) -5-chloro-2-isopropylpent-4-enoate, which is a key intermediate in the manufacturing of the new anti-hypertension drug Aliskiren. Background art

[0002] Aliskiren (Rasilez) 2 is a new renin inhibitor, co- developed by the Swiss companies Novartis and Speedel, useful for the treatment of hypertension and related cardiovascular diseases.

Figure imgf000002_0001

2

[0003] This new drug, the first of a new class of peptidomimetics, offers benefits to the many patients who cannot reduce their blood pressure to target levels using current therapies. US Food and Drug Administration (FDA) has recently accepted for review Novartis' new drug application (NDA) for Rasilez .

[0004] Aliskiren can be synthesised according to the process described in EP 678503 and EP 1200384, which uses two key chiral synthons; one of them is a (2S, 4E) -5-halo- 2-isopropylpent-4-enoic acid ester derivative of formula 3,

Figure imgf000003_0001
3

[0005] wherein X is chlorine, bromine or iodine and R is an alkyl group, and specifically the compound methyl (2S,4E) -5-chloro-2-isopropylpent-4-enoate of formula 4.

Figure imgf000003_0002

4

[0006] Optically active esters of formula 3 can be obtained from the corresponding racemic acids of formula 5 through a classical chemical resolution by means of a diastereomeric salt formation with a chiral amine, followed by esterification.

Figure imgf000003_0003
5

[0007] According to EP 1200384, (4E) -5-chloro-2- isopropylpent-4-enoic acid, enriched with the (2S) enantiomer, is prepared from the corresponding racemic compound using cinchonidine in 32% yield. This approach is uneconomic not only for the high cost of cinchonidine, but also for the low overall yield and purity (the enantiomeric excess is not reported, but the wording "enriched" leads to think that a consistent amount of the undesired (2R) isomer is present) and for the need of three isolations of the diastereomeric salt . [0008] A stereoselective route to (2S, 4E) -5-halo-2- isopropylpent-4-enoic acid ester of formula 3 is described in the same document and depicted in Scheme 1. The optically active ester is prepared using the well known Evans' approach, which entails the diastereoselective base-catalysed addition of a trans- 1, 3-dihalopropene to a substituted optically active N- acyloxazolidinone, subsequent hydrolysis in alkaline medium to the acid 5, which is eventually esterified to yield the desired alkyl (2S, 4E) -5-halo-2-isopropylpent-4- enoate of formula 3. This route is hampered by the fact that the addition product is an oily substance, not prone to crystallize, that needs therefore to be purified through column chromatography or similar techniques, thus making this process unsuitable for industrial application. SCHEME 1

Figure imgf000005_0001

X1Y = Cl, Br, I

Figure imgf000005_0002

3 5

[0009] The chemical and optical purities of the final compounds are not reported in the patent , but the repetition of this process in our laboratories yielded (2S,4E) -5-chloro-2-isopropylpent-4-enoic acid of formula 6 with only moderate optical purity (95% e.e.) .

Figure imgf000005_0003

[0010] From the analysis of these known processes and their drawbacks it is clear that there is still the need of a more economical, efficient and industrially feasible process for preparing the optically active synthons of formula 3 and 5 and the specific compounds of formula 4 and 6 with better yields and purities. Brief description of the invention [0011] The present invention provides a process for preparing optically active (4E) -5-halo-2-alkylpent-4- enoic acids and their ester derivatives, in particular methyl (2S, 4E) -5-chloro-2-isopropylpent-4-enoate 4, by a stereoselective synthesis which employs camphorsultain as chiral auxiliary.

[0012] Furthermore novel N- (5-halo-2-alkylpent-4- enoyl) camphorsultarns are provided.

[0013] A simple and very efficient process for the hydrolysis of substituted N-acylcamphorsultams with a strong acid is also provided.

Detailed description of the invention

[0014] We have surprisingly found a process for the preparation of optically active 5-halo-2-alkylpent-4- enoic acids and their ester derivatives of formula 1

Figure imgf000006_0001
1 wherein R1 is C1-C6 alkyl, X is chlorine, bromine or iodine,

R2 is hydrogen, C1-C18 alkyl, optionally containing oxygen, nitrogen or halogen atoms, or any combination thereof, or aryl, optionally substituted with hydroxyl groups, C1-C4 alkoxy groups, amino groups, halogen atoms, or benzyl, optionally substituted with hydroxyl groups, C1-C4 alkoxy groups, amino groups, halogen atoms, comprising the steps of a) acylating camphorsuitam of formula 7 or its enantiomer

Figure imgf000007_0001

7 with a compound of formula 8

Rf^COZ

8 wherein Z is an activating group for the carboxylic group and R1 has the same meaning as above, b) alkylating the resulting N-acylcamphorsultam with a 1, 3-dihalopropene of formula 10

10 wherein X has the same meaning as above and Y is chlorine, bromine or iodine, either equal to or different from X, c) hydrolysing the resulting N- (5-halo-2-alkylpent-4- enoyl) camphorsultam, d) optionally esterifing the resulting 5-halo-2- alkylpent-4-enoic acid. [0015] In a second aspect of the present invention novel N- (5-halo-2-alkylpent-4-enoyl)camphorsultams of formula 11 are provided

Figure imgf000008_0001

11 wherein R1 and X have the same meaning as above and the camphorsultam ring may be either in the R or in the S configuration.

[0016] Preferred enantiomers of compounds of formula 1 are those of formula Ia, i.e., when R1 is isopropyl, with the asymmetric carbon with the S configuration.

Figure imgf000008_0002
Ia

[0017] Preferred enantiomers of compounds of formula 11 are those of formula 11a, i.e., when R1 is isopropyl, with the asymmetric carbon with the S configuration.

Figure imgf000008_0003

11a [0018] R1 is preferably C1-C4 alkyl , more preferably isopropyl . [0019] R2 is preferably hydrogen, C1-C4 alkyl , phenyl or benzyl , more preferably is methyl .

[0020] The 1, 3-dihalopropene of formula 10 is preferably a trans-1, 3-dihalopropene .

[0021] X is preferably chlorine .

[0022] Y is preferably bromine .

[0023] Z is preferably chlorine , bromine , or iodine , more preferably is chlorine .

[0024] The general process outlined above is depicted in

Scheme 2 :

SCHEME 2

Figure imgf000009_0001
Figure imgf000009_0002

10 11

Figure imgf000009_0003

11 1 (R2 = H)

Figure imgf000010_0001

1 (R2 = H) 1 (R2 ≠ H)

[0025] A preferred embodiment is a process for the preparation of methyl (2S, 4E) -5-chloro-2-isopropylpent-4- enoate 4

Figure imgf000010_0002
4 comprising the steps of e) acylating camphorsultarn with isovaleryl chloride 12, f) alkylating the resulting N-isovalerylcamphorsultam with 3-bromo-l-chloropropene 14, g) hydrolysing the resulting N- ( (2S, 4E) -5-chloro-2- isopropylpent-4-enoyl) camphorsultam 15, h) esterifing the resulting (2S,4E) -5-chloro-2- isopropylpent-4-enoic acid 6. [0026] The (R) -enantiomer of camphorsultam 7 (prepared from (R) -(-) -camphorsulfonic acid) can thus be used to synthesise the compound methyl (2S, 4E) -5-chloro-2- isopropylpent-4-enoate 4, as depicted in Scheme 3. SCHEME 3
Figure imgf000011_0001

12 13

Figure imgf000011_0002

13 14 15

Figure imgf000011_0003

15

Figure imgf000011_0004

6 4

[0027] A particularly preferred compound of formula 11 is the compound N- ( (2S,4E) -5-chloro-2-isopropylpent-4- enoyl) camphorsultam of formula 15.

Figure imgf000011_0005

15 [0028] Camphorsultam 7 (and its corresponding enantiomer) is a versatile chiral auxiliary with use in various stereoselective syntheses (for a general review see W. Oppolzer, Pure Appl. Chem. 62(7), 1241-1250, (1990)). The success of this chiral auxiliary is mainly due to its easy preparation from commercially available and relative inexpensive camphorsulfonic acid 16 and its peculiarity to form solid adducts, which can be easily isolated and purified by simple crystallization.

Figure imgf000012_0001
16

[0029] The acylation reaction of step (a) can be conveniently carried out in an organic solvent, such as toluene; a base such as pyridine may be used in stoichiometric amount or in slight excess to capture the evolution of acid; a catalytic amount of 4- dimethylaminopyridine may also be used. Preferred acylating agents of formula 8 are acyl halides, more preferred acylating agents are acyl chlorides, but also anhydrides, mixed anhydrides and even esters may be used. The acylating agent may be conveniently prepared in situ from the corresponding acid, e.g. using thionyl halide, oxalyl halide, phosphorus trihalide, phosphorus pentahalide, or phosphorus oxyhalide.

[0030] In a preferred embodiment, (R) -camphorsuitam 7 is reacted with isovaleryl chloride 12 to provide the (R) -N- isovalerylcamphorsultam 13. After quench with an acidic aqueous solution and concentration to dryness, intermediate 13 is isolated in quantitative yield and high purity (98%) .

[0031] In an alternative preferred embodiment, (R)-N- isovalerylcamphorsultam 13 can be even more conveniently prepared by heating a mixture of (R) -camphorsultam 7, isovaleric acid and thionyl chloride in toluene. After a basic work-up, intermediate 13 is isolated in quantitative yield and purity higher than 98%. In this process isovaleryl chloride 12 is produced in situ from the less expensive acid and is thermally reacted with camphorsultam without the aid of any base. [0032] The corresponding enolate of these N- acylcamphorsultams of formula 9 can add to electrophiles in step (b) with a high and predictable stereoselectivity providing the chiral intermediates of formula 11 that can be further hydrolysed in step (c) to optically active carboxylic acids.

[0033] The enolate of N-acylcamphorsultam can be prepared with a strong non-nucleophilic base; preferred bases are lithium diisopropylamide (LDA) and lithium bis- trimethylsilylamide (LiHMDS) , even more preferred is lithium bis-trimethylsilylamide. Both these preferred bases, for economical and industrial reasons, can be conveniently prepared in situ by reacting respectively diisopropylamine or hexamethyldisilazane with π-butyl or π-hexyllithium in a suitable aprotic solvent. Preferred solvents are tetrahydrofuran and mixtures of tetrahydrofuran with aromatic or aliphatic hydrocarbons. [0034] The enolate of N-acylcamphorsultams may be reacted with a 1, 3-dihalopropene of formula 10 to provide the novel compounds of formula 11. Preferred 1,3- dihalopropenes of formula 10 may be prepared by reaction of 1, 3-dichloropropene with an alkaline iodide, preferably sodium iodide, or an alkaline bromide, preferably sodium bromide. The alkylation reaction may be carried out with 1, 3-dichloropropene in the presence of a stoichiometric amount of an alkaline iodide forming in situ the more reactive trans-1-chloro-3-iodopropene. Alternatively an alkaline bromide can be used to prepare the more reactive trans-3-bromo-l-chloropropene from trans-1, 3-dichloropropene: this second solution is more convenient for economical and environmental reasons . The alkylation reaction is preferably carried out at a temperature from -20° to 200C. [0035] In a preferred embodiment, the inexpensive trans- 1, 3-dichloropropene 14 has proven to be quite unreactive with the enolate of 13 under different reaction conditions, due to the low reactivity of the allylic chloride itself or to the steric hindrance of the enolate. Thus trans-1, 3-dichloropropene is first converted into trans-3-bromo-l-chloropropene by reaction with sodium bromide in refluxing acetonitrile; the crude trans-3-bromo-l-chloropropene can be isolated after inorganic salt filtration and solvent distillation to dryness and then reacted with the enolate of the N- acylcamphorsultam 13.

[0036] In an alternative preferred embodiment, trans-1, 3- dichloropropene is reacted with 13 at low temperature in the presence of a stoichiometric amount of an alkaline iodide in a polar aprotic solvent, forming in situ trans- 1-chloro-3-iodopropene .

[0037] At the end of alkylation reaction and the consequent aqueous work-up, the key chiral intermediate 11 may be purified by crystallization from a suitable solvent, preferably from aromatic and aliphatic hydrocarbons and mixtures thereof, more preferably from mixtures of toluene and heptanes, thus enhancing its chemical and optical purity. This is a clear advantage over the prior art process that exploits Evans' chiral auxiliary. [0038] In a preferred embodiment, intermediate 15 is obtained with good overall yield from camphorsultam 7 (70%) , a good chemical purity (98%) and an excellent chiral purity (99.5%).

[0039] The hydrolysis reaction of step (c) may be carried out either in basic conditions as reported in the art for N-acylcamphorsultarns, or better in acidic conditions as outlined in the following paragraphs.

[0040] The esterification reaction of step (d) may be performed as well known in the art, e.g. with an alcohol and a strong acid in catalytic amount, or through the conversion to an acyl halide and its reaction with an alcohol .

[0041] Hydrolysis of N-acylcamphorsultams is widely documented in the literature with more than a hundred of references from 1984 until today: all these published syntheses use an aqueous alkaline hydrolysis, generally with sodium or lithium hydroxide in water, usually in the presence of hydrogen peroxide (thus actually performing a perhydrolysis reaction) . While the reported yields are good with rather simple substrates (70-90%) , they drop to 30-50% when the carbon α to the carbonyl is hindered. In these cases a recent process using tetrabutylammonium hydroxide and hydrogen peroxide (Synlett 1998, 882-884, Org. Process Res. Dev. 7(2), 168-171, 2003) was claimed to afford better yields, ranging from 60 to 70%, however still unsatisfactory and uneconomical for an industrial process. Moreover it is reported that alkaline hydrogen peroxide can react with N-acylcamphorsultams bearing double bonds (like intermediate 11) , oxidising them to epoxides and further by-products .

[0042] As a matter of fact, all our attempts to hydrolyse intermediate 15, which is particularly hindered, using the above mentioned processes, were unsuccessful and the desired (2S, 4E) -5-chloro-2-isopropylpent-4-enoic acid 6 was isolated with very unsatisfactory yields ranging from

20 to 30%. The reason for this failure is mainly due to the concurrent hydrolysis of the cyclic sulfonamido

(suitam) group, where the SO2 group lies in a part of the molecule more accessible to OH" addition than that of the amidic carbonyl . As a matter of fact the sulfonic acid 17 was always detected as the main by-product or even the major product in all our trials.

Figure imgf000017_0001

17

[0043] Furthermore we also noted in blank trials that, contrary to what stated in the literature, camphorsultam is not stable in the presence of basic hydrogen peroxide, considered essential to have reasonable yields, either under heating or even at room temperature after prolonged reaction times.

[0044] It is obvious that the efficiency and the economy of whatever stereoselective synthesis involving a chiral auxiliary is strictly related not only to the diastereoselectivity of the key step, but also to the final hydrolytic step and the possibility to recover and recycle the chiral auxiliary in a reasonable yield. The known methods of hydrolysis of hindered N- acylcamphorsultarns are instead characterised by low yields due to the concurrent hydrolysis of the cyclic sulfonamido group, the oxidation of double bonds that may be present and the limited stability in basic media of camphorsultam itself. Therefore it appears evident that there is still the need of finding a more efficient process for the hydrolysis of N-acylcamphorsultams which allows a high recovery of camphorsultam itself. [0045] We have surprisingly found a process for the preparation of optically active carboxylic acids and their ester derivatives of formula 18

R3COOR2

18 wherein R2 is hydrogen, C1-C18 alkyl, optionally containing oxygen, nitrogen or halogen atoms, or any combination thereof, or aryl, optionally substituted with hydroxyl groups, C1-C4 alkoxy groups, amino groups, halogen atoms, or benzyl, optionally substituted with hydroxyl groups, C1-C4 alkoxy groups, amino groups, halogen atoms ,

R3 is C1-C18 alkyl, C1-C18 alkenyl, C1-C18 alkynyl, C1-C18 cycloalkyl, C1-C18 cycloalkenyl, all optionally containing oxygen, nitrogen or halogen atoms, or any combination thereof, optionally substituted with aryl comprising the steps of a) hydrolysing N-acylcamphorsultam of formula 19 with a strong acid and water

Figure imgf000019_0001
19 b) optionally esterifing the resulting carboxylic acid.

[0046] R2 is preferably hydrogen, C1-C4 alkyl, phenyl or benzyl, more preferably is methyl.

[0047] R3 is preferably a C1-C18 alkyl , C1-C18 alkenyl , C1-C18 alkynyl , C1-C18 cycloalkyl , C1-C18 cycloalkenyl , all branched in the α position, optionally substituted by halogen or phenyl , more preferably is l-isopropyl-4 -halo- 3-butenyl, even more preferably is (IS, 3E) -l-isopropyl-4- chloro-3-butenyl .

[0048] For the purpose of this invention, a strong acid is an acid which has a pKa equal to or less than 1.00. The strong acid may be either organic or inorganic and is preferably chosen from the group consisting in sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, hydrobromic acid and hydriodic acid, more preferably is sulfuric acid. Preferred concentrations of the strong acid in the reaction mixture are greater than 10%, more preferred concentrations are greater than 50%.

[0049] The amount of water is very important for the success of the hydrolysis : in fact it has been observed that the reaction rate in sulfuric acid is strongly dependent and inversely proportional to the water content: on the other hand, for a complete conversion, the water content needs to be at least equimolar with the substrate. The amount of water in the reaction mixture is preferably from 1% to 30%, more preferably from 2% to 10%.

[0050] In a preferred embodiment, the hydrolysis is carried out without the addition of any other solvent, i.e. only with the strong acid and water, but it may be carried out also in the presence of organic solvents, such as alcohols or carboxylic acids.

[0051] The hydrolysis may be preferably carried out at a temperature from 0° to 600C, more preferably from 20° to 400C. [0052] The reaction may be conveniently carried out adding intermediate 19 portionwise to a solution of the strong acid and water. At the end of reaction, the mixture may be poured into water and the organic products extracted with a suitable organic solvent, preferably toluene or methylene chloride, thus obtaining, after solvent distillation, a mixture of optically active carboxylic acid 18 and camphorsultam 7.

[0053] From the above mixture, it is possible to separate camphorsultam 7 from the acid 18 by crystallization, adding an aliphatic or aromatic hydrocarbon, preferably chosen from the group consisting in pentane, hexane, heptane, cyclohexane, methyleyelohexane or mixtures thereof, more preferably a mixture of heptanes, heating the mixture up to dissolution and then cooling the solution to a suitable temperature so that camphorsultam

7 crystallises and is isolated by filtration. In this way camphorsultam 7 can be recovered in very high yields

(about 90% from 15) and high purity (about 98-99%) .

Recovered camphorsultam 7 can be successfully recycled into a subsequent batch. [0054] In a preferred embodiment, N- ( (2S,4E) -5-chloro-2- isopropylpent-4-enoyl) camphorsultam is hydrolysed with sulfuric acid to give (2S,4E) -5-chloro-2-isopropylpent-4- enoic acid 6 and camphorsultam 7; an HPLC analysis of the final reaction mixture does not reveal any trace of the unwanted hydrolysis product, namely the sulfonic acid 17 , while the other few organic impurities are below 2% each. The crude (2S,4E) -5-chloro-2-isopropylpent-4-enoic acid 6 can be isolated from mother liquors by distillation of the solvent and can be obtained in quantitative yield and a purity sufficient to be used as such in the final esterification step to obtain the chiral synthon used in Aliskiren process, namely methyl (2S, 4E) -5-chloro-2- isopropylpent-4-enoate of formula 4. Alternatively pure (2S, 4E) -5-chloro-2-isopropylpent-4-enoic acid 6 can be obtained by vacuum flash-distillation of the corresponding crude, thus isolated in very high yield (about 90%) , good chemical purity (greater than 98%) and excellent optical purity (greater than 99.5% e.e.). [0055] Finally methyl (2S,4E) -5-chloro-2-isopropylpent-4- enoate 4 can be obtained by esterification of crude

(2S,4E) -5-chloro-2-isopropylpent-4-enoic acid 6 with standard methods known to those skilled in the art, preferably refluxing the crude acid in methanol in the presence of thionyl chloride, followed by solvent distillation, an extractive work-up and a final vacuum flash-distillation. Aliskiren chiral synthon 4 and their analogues are thus obtained in excellent yield (90% overall from intermediate 15) , good chemical purity (greater than 98% (GC and HPLC) ) and excellent optical purity (greater than 99.5% e.e.).

[0056] In summary, this novel method of hydrolysis of N- acylcamphorsultarns under strong acidic conditions is particularly noteworthy and definitely superior to all processes previously described in the literature, as it shows the following advantages : a) the reaction is carried out in a very straightforward way and under standard conditions that can be easily adopted industrially; b) the conversion is quantitative and the reaction profile is very clean, with the total absence of the undesired product deriving from the hydrolysis of the cyclic sulfonamido group, namely the sulfonic acid 17; c) optical active acids and their ester derivatives 18, also when bearing a reactive double bond, are recovered with remarkably high yield, good chemical purity and outstanding optical purity, far better than those of any other method reported in the literature; d) contrary to the common knowledge, camphorsultam 7 is chemically stable enough under these highly acidic reaction conditions, and can be easily recovered with excellent yield (90%) , definitely better then all those so far reported in the literature; e) recovered camphorsultam 7 can be recycled in a following batch without any yield or purity decrease of the resulting optical active acids and ester derivatives .

[0057] The route generally used to produce camphorsultam 7 involves a 3-step process according to Scheme 4:

SCHEME 4

Figure imgf000024_0001

16 20 21 7

[0058] (R) -Camphorsulfonic acid 16 (or its enantiomer) can be converted to the corresponding sulfonyl chloride 20 through standard chemistry (e.g. with thionyl chloride), which is further reacted with ammonia, usually in situ, to generate the corresponding sulfonamide; the intramolecular reaction with the oxo group produces the camphorsulfonimine 21, usually isolated in good overall yield (above 80%) and purity through a simple crystallization. The final step involves the reduction of the imino group to obtain the wanted camphorsultam 7 : this step has been accomplished in the literature with lithium aluminium hydride (Org. Synth., 69, 154), hydrogen and Raney Nickel or sodium borohydride (EP 1182198, Synth. Coπunun. 25(21), 3323-3327 (1995)). [0059] The hydrogenation of camphorsulfonimine 21 with Raney Nickel is particularly advantageous because, contrary to what reported in the art, the catalyst may be used in moderate amount relative to camphorsulfonimine 21 (about 20%) . The hydrogenation is preferably carried out in alcoholic solvents (e.g. ethanol) and is remarkably clean and efficient. A further advantage of this process is that it may be carried out under mild reaction conditions (600C, 6 bar H2) , easily obtained in an industrial hydrogenation plant.

[0060] With the present invention we have thus provided an integrated approach to the synthesis of optically active (4E) -5-halo-2-alkylpent-4-enoic acids using Oppolzer's chiral auxiliary, ranging from the stereoselective addition of 1, 3-dihalopropene to N-acylcamphorsultams to an improved process for the hydrolysis of such addition product and to an improved process for the preparation of the chiral auxiliary itself. Such synthesis is characterized by high yields, high chemical and optical purities and straightforward industrial applicability. [0061] The following examples are set forth to aid in understanding the invention, but are not intended to limit the scope of protection. Examples

Example 1: (R) -Camphorsulfonimine 21

[0062] 1.65 kg (7.1 mol) of (R) -(-) -camphorsulfonic acid, toluene and 2 ml of dimethylformamide were heated to 700C and 0.62 L (1.01 kg, 8.5 mol) of thionyl chloride were dripped. At the end of the reaction the suspension was quenched into a mixture of toluene and 30% aqueous ammonia solution, then heated at 800C until reaction completion, cooled, filtered and washed with toluene and water, getting 1.23 kg (5.77 mol, 81% yield, 99.5% purity (GC A%) ) of camphorsulfonimine after drying. Example 2: (R) -Camphorsultarn 7

[0063] A l L steel autoclave was charged with camphorsulfonimine (88 g, 0.412 mol), 440 mL of denaturated ethanol, 176 mL of water and 17.6 g of Ni/Raney. The mixture was hydrogenated at 600C and 6 bar for 5 hours. At the end of the reaction, it was cooled, diluted with ethanol and the catalyst was filtered through dicalite. The filtrate was concentrated under vacuum, cooled to 5°C and filtered, getting 82.9 g (0.385 mol, 93%, purity 99.5% (GC A%) ) of camphorsultam after drying .

Example 3: N-isovalerylcamphorsultam 13

[0064] 1.9 kg (8.8 mol) of camphorsultam, 9.5 L of toluene, 1.6 L (1.16 kg, 11 mol) of anhydrous triethylamine and 0.11 kg (1 mol) of 4-dimethylaminopyridine were introduced into a reactor equipped with nitrogen sweep. The mixture was cooled to 00C and 1.19 L (1.17 kg, 10 mol) of isovaleryl chloride were dripped in 2 hours; the temperature was allowed to rise spontaneously to 20°/25°C at the end of the addition and the mixture stirred for 9 hours. A solution of 1.3 L of 32% hydrochloric acid in 1.9 L of purified water was added at 2O0C, the layers were separated and the aqueous layer was extracted with 2.11 L of dichloromethane . The combined organic layers were concentrated to residue under vacuum, obtaining 2.56 kg (9 mol, 97%, purity = 99% (GC A%) ) of a crystalline solid. 1H NMR (CDCl3) δ: 0.97 (m, 9H, CH3), 1.15 (s, 3H, CH3), 1.33 (m, IH), 1.42 (m, IH), 1.86-2.10 (m, 5H), 2.22 (m, IH, CH), 2.58 (2 dd, 2H), 3.46 (dd, 2H), 3.7 (t, IH), 4.15 (br s, IH, NH). MS (EI) m/z: 299 (M+), 257, 193, 151, 135, 119, 108.

Example 4: N-isovalerylcamphorsultam 13

[0065] 10 g (46.4 mmol) of camphorsultam, 40 mL of toluene, 15 mL of dimethylformamide and 7.5 g (73.4 mmol) of isovaleric acid were introduced into a round bottom flask with nitrogen sweep. 6.1 mL (10 g, 83.8 πunol) of thionyl chloride were slowly added and the solution was heated to 800C for 6 hours. At the end of the reaction the mixture was cooled to 20°/25°C and washed with 50 mL of a sodium carbonate solution; the layers were separated and the aqueous layer was extracted with 2 x 30 mL of toluene; the combined organic layers were washed with 50 mL of a sodium carbonate solution, then with 50 mL of water and concentrated to residue under vacuum, obtaining 13.8 g (46 mmol, 99%) of a brown crystalline solid with 98% purity (GC A%) .

Example 5: trans-3 -bromo-l-chloropropene 14 [0066] A reactor was charged with 1.0 kg (9.0 mol) of trans-1, 3-dicloropropene, 3 L of acetonitrile and 1.02 kg (10 mol) of sodium bromide. The suspension was heated to reflux for at least 24 hours, then cooled to 20/250C at the end of the reaction; the salts were filtered and washed with 2 x 500 mL of acetonitrile. The filtrate was distilled through a Vigreux column at atmospheric pressure and internal temperature of 80°/l00°C to remove the acetonitrile, getting 1.096 kg of a dark orange oil. Weight composition by 1H-NMR: 89% of trans-3-bromo-l- chloropropene, 8% of trans-1, 3 -dicloropropene and 3% of solvent. 1H NMR (CDC13) δ: 3.93 (m, 2H, CH2), 6.14 (m, IH, CH), 6.33 (dt, IH, CHCl). MS (EI) m/z: 156 (M+), 77. Example 6: N- ( (2S,4E) -5-chloro-2-isopropylpent-4- enoyl) camphorsultarn 15

[0067] 172.4 mL (0.48 mol) of π-butyllithium 25% in heptanes were introduced into a round bottom flask with nitrogen inlet, the solution was cooled to -5°/0°C and 99.6 mL (0.48 mol) of hexamethyldisilazane were added. At the end of the reaction the mixture was stirred for 1 hour, then cooled to -25/-200C and 110 g (0.367 mol) of N-isovalerylcamphorsultam in 330 mL of tetrahydrofuran were dripped in 1 hour. After 1 hour 133 g (0.517 mol) of traπs-3-bromo-l-chloropropene were added and the temperature was allowed to rise slowly to -5°C overnight. The reaction mixture was quenched with 10% hydrochloric acid and the organic solvents were distilled under vacuum. The residual aqueous layer was extracted with 2 x 550 mL of dichloromethane and the combined organic layers were concentrated under vacuum. The product was dissolved in warm toluene and precipitated with heptanes. The slurry was filtered at RT and washed with heptanes, obtaining 98.5 g (0.263 mol; 72%, 96% purity (GC A%) ) of crystalline solid after drying. M.p. = 194°C. 1H NMR (CDCl3) δ: 0.97 (m, 9H, CH3), 1.17 (s, 3H, CH3), 1.36 (m, IH), 1.42 (m, IH), 1.86-2.07 (m, 6H), 2.32-2.49 (m, 2H), 2.93 (m, IH), 3.48 (q, 2H), 3.9 (t, IH), 5.91 (m, IH, CH), 5.96 (d, IH, CHCl). MS (EI) m/z: 373 (M+), 338, 207, 159 , 135 .

Example 7 : N- ( (2S , 4E) -5-chloro-2 -isopropylpent-4 - enoyl) camphorsuitam 15

[0068] 736 g of lithium hexamethyldisilazide (20% in THF) were introduced into a round bottom flask with nitrogen sweep. The solution was cooled to -25/-200C and a solution of 217.3 g (0.726 mol) of N- isovalerylcamphorsultam in tetrahydrofuran was dripped in 1 hour. After 1 hour 196 g (1.2 mol) of traπs-3-bromo-l- chloropropene were added and the temperature was slowly allowed to rise to -15°C overnight. The reaction mixture was quenched with 10% hydrochloric acid and the organic solvents were distilled under vacuum. The residual aqueous layer was extracted with 2 x 400 mL of dichloromethane and the combined organic layers were concentrated to residue. The product was dissolved in warm toluene and precipitated with heptanes . The slurry was filtered at RT and washed with heptanes, obtaining 191 g (0.51 mol, 70%, 98% purity (GC A%) ) of crystalline solid after drying.

Example 8: N- ( (2S,4E) -5-chloro-2-isopropylpent-4- enoyl) camphorsultarn 15

[0069] 27.7 mL (0.0768 mol) of n-butyllithium 25% in heptanes were introduced into a round bottom flask with nitrogen sweep, cooled to -5°/0°C and 16 mL (12.4 g, 76.8 iranol) of hexamethyldisilazane were added. After 1 hour the solution was cooled to -25/-200C and a solution of 20 g (68 mmol) of N-isovalerylcamphorsultam in 60 mL of tetrahydrofuran were dripped in 1 hour. After 1 hour 11.5 g (0.104 mol) of trans-1, 3-dichloropropene and 10 g of sodium iodide were added. The mixture was stirred overnight, then 10 g (0.09 mol) of trans-1, 3- dichloropropene and 5 g of sodium iodide were added and the temperature was allowed to rise slowly to 00C. The mixture was quenched with 5% hydrochloric acid 5% and extracted with 2 x 30 mL of toluene. The organic layer was washed twice with purified water, then concentrated to residue under vacuum, obtaining 27 g of product. Example 9: methyl (2S,4E) -5-chloro-2-isopropylpent-4- enoate 4

[0070] 300 ml of sulfuric acid and 300 g (0.802 mol) of N- ( (2S,4E) -5-chloro-2-isopropylpent-4-enoyl) camphorsultam were introduced into a 1 L round bottom flask. The suspension was stirred for 3 hours at 25-300C, then quenched into 600 ml of toluene and 600 ml of water. The aqueous layer was extracted twice with 150 ml of toluene and then the combined organic layers were washed with 300 ml of water. The organic layer was treated with activated charcoal, filtered and then concentrated under vacuum. 1200 ml of heptanes were added to the residue, the mixture was heated to 450C for 30 min, then cooled to 00C and stirred for 3 hours. The suspension was filtered off and washed with heptanes, yielding 156 g (90%, purity >

99% (GC A%) ) of camphorsultarn after drying. The chiral auxiliary was reused in an analogous process. The filtrate was concentrated under vacuum to yield 156 g of

(2S,4E) -5-chloro-2-isopropylpent-4-enoic acid. 300 ml of methanol and 30 g of thionyl chloride were added, the solution was refluxed for 4 hours, then concentrated under reduced pressure. The residue was dissolved in 150 ml of heptanes and treated with a 5% solution of sodium bicarbonate. The aqueous layer was extracted with 75 ml of heptanes and then the combined organics layer were concentrated at reduced pressure . The residue was distilled at 5 mbar and T = 65 0C to give 137 g of methyl

(2S,4E) -5-chloro-2-isopropylpent-4-enoate (90% from N- acylcamphorsultam, purity > 98% (GC A%) , e.e. = 99.7%).

1H NMR (CDCl3) δ: 0.91 (dd, 6H, CH3), 1.86 (m, IH, CH),

2.23 (m, 2H, CH2), 2.31 (m, IH, CH), 3.66 (s, 3H, CH3), 5.81 (m, IH, CH), 6.00 (dt, IH, CHCl). MS (EI) m/z: 190 (M+), 155, 147, 115.

Example 10 : (2S, 4E) -5-chloro-2 -isopropylpent-4 -enoic acid 6 [0071] 150 ml of sulfuric acid and 150 g ( 0 .401 mol ) of N- acyl camphor sul tarn were introduced into a 500 ml round bottom flask. The suspension was stirred for 3 hours at

25-300C, then quenched into 300 ml of toluene and 300 ml of water. The aqueous layer was extracted twice with 75 ml of toluene and the combined organic layers washed with 150 ml of water. The organic layer was treated with activated charcoal, filtered and the filtrate concentrated under vacuum. 600 ml of heptanes were added to the residue, the mixture was heated to 450C, then cooled to 00C and stirred for 3 hours. The suspension was filtered off and washed with heptanes to yield 75 g of camphorsultam (87%) . The filtrate was concentrated under vacuum to yield 70 g of raw (2S,4E) -5-chloro-2- isopropylpent-4-enoic acid. This was distilled at 5 mbar and T = 900C to give 63 g (89%, purity > 98% (GC A%) , e.e. = 99.7%) of purified product. 1H-NMR (CDCl3) δ: 0.98

(d, 6H, CH3), 1.93 (m, IH, CH), 2.28 (m, 2H, CH2), 2.31

(m, IH, CH), 5.86 (m, IH, CH), 6.02 (dt, IH, CHCl), 11.23

(br S, IH, OH). MS (EI) m/z: 176 (M+), 141, 133, 115.

Claims

1. A process for the preparation of optically active 5- halo-2-alkylpent-4-enoic acids and their ester derivatives of formula 1
Figure imgf000034_0001
i wherein R1 is C1-C6 alkyl,
X is chlorine, bromine or iodine,
R2 is hydrogen, C1-C18 alkyl, optionally containing oxygen, nitrogen or halogen atoms, or any combination thereof, or aryl, optionally substituted with hydroxyl groups, C1-C4 alkoxy groups, amino groups, halogen atoms, or benzyl, optionally substituted with hydroxyl groups,
C1-C4 alkoxy groups, amino groups, halogen atoms, comprising the steps of a) acylating camphorsultam of formula 7 or its enantiomer
Figure imgf000034_0002
with a compound of formula 8
R1-^COZ 8 wherein Z is an activating group for the carboxylic group and R1 has the same meaning as above, b) alkylating the resulting N-acylcamphorsultam with a 1, 3-dihalopropene of formula 10
10 wherein X has the same meaning as above and Y is chlorine, bromine or iodine, either equal to or different from X, c) hydrolysing the resulting N- (5-halo-2-alkylpent-4- enoyl) camphorsuitam, d) optionally esterifing the resulting 5-halo-2- alkylpent-4-enoic acid.
2. The process according to claim 1 wherein the compound of formula 1 is a compound of formula Ia
^COOR2 Ia
3. The process according to any of the preceding claims wherein R1 is C1-C4 alkyl .
4. The process according to any of the preceding claims wherein R1 isopropyl.
5. The process according to any of the preceding claims wherein R2 is hydrogen, C1-C4 alkyl, phenyl or benzyl.
6. The process according to any of the preceding claims wherein R2 is methyl .
7. The process according to any of the preceding claims wherein the 1, 3-dihalopropene of formula 10 is preferably a trans-1, 3-dihalopropene .
8. The process according to any of the preceding claims wherein X is chlorine.
9. The process according to any of the preceding claims wherein Y is bromine.
10. The process according to any of the preceding claims wherein Z is chlorine, bromine, iodine.
11. The process according to any of the preceding claims wherein Z is chlorine .
12. The process according to any of the preceding claims wherein the compound of formula 1 is methyl (2S,4E)-5- chloro-2-isopropylpent-4-enoate .
13. The process according to any of the preceding claims wherein step (a) the compound of formula 8 is prepared in situ from the corresponding acid.
14. The process according to any of the preceding claims wherein in step (b) the N-acylcamphorsultam is reacted with a strong non-nucleophilic base to give its enolate.
15. The process according to claim 14 wherein such strong non-nucleophilic base is chosen among the group consisting in lithium diisopropylamide and lithium bis- trimethylsilylamide.
16. The process according to any of the preceding claims wherein step (b) is carried out in tetrahydrofuran or mixtures of tetrahydrofuran with aromatic or aliphatic hydrocarbons .
17. The process according to any of the preceding claims wherein in step (b) the 1, 3-dihalopropene is prepared by reaction of 1, 3-dichloropropene with an alkaline iodide or bromide .
18. The process according to claim 17 wherein the alkaline iodide is sodium iodide.
19. The process according to claim 17 wherein the alkaline bromide is sodium bromide.
20. The process according to any of the preceding claims wherein step (c) is carried out in acidic conditions.
21. The process according to any of the preceding claims wherein step (c) is carried out with a strong acid and water, such strong acid having a pKa equal to or less than 1.00.
22. The process according to claim 21 wherein in step (c) the strong acid is chosen from the group consisting in sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, hydrobromic acid and hydriodic acid.
23. The process according to claims 21-22 wherein in step (c) the strong acid is sulfuric acid.
24. The process according to claims 21-23 wherein in step (c) the concentration of the strong acid in the reaction mixture is greater than 10%.
25. The process according to claims 21-24 wherein in step (c) the concentration of the strong acid in the reaction mixture is greater than 50%.
26. The process according to claims 21-25 wherein in step (c) the amount of water in the reaction mixture is from 1% to 30%.
27. The process according to claims 21-26 wherein in step (c) the amount of water in the reaction mixture is from 2% to 10%.
28. The process according to claims 21-27 wherein in step (c) the hydrolysis is carried out without the addition of any other solvent .
29. The process according to claims 21-28 wherein in step (c) the hydrolysis is carried out at a temperature from 0° to 600C.
30. The process according to claims 21-29 wherein in step (c) the hydrolysis is carried out at a temperature from
20° to 400C.
31. The process according to claims 1-19 wherein step (c) is carried out in basic conditions.
32. The process according to any of the preceding claims wherein in step (c) camphorsultam is recovered by crystallization from an aliphatic or aromatic hydrocarbon.
33. The process according to claim 32 wherein in step (c) the aliphatic hydrocarbon is chosen from the group consisting in pentane, hexane, heptane, cyclohexane, methyleyelohexane or mixtures thereof .
34. The process according to claims 32-33 wherein in step
(c) the aliphatic hydrocarbon is a mixture of heptanes.
35. The process according to claims 32-34 wherein recovered camphorsultam is recycled in a subsequent batch.
36. The process according to any of the preceding claims wherein in step (d) the esterification is carried out with an alcohol and a strong acid in catalytic amount .
37. The process according to claims 1-35 wherein in step
(d) the esterification is carried out through the conversion to an acyl halide and its reaction with an alcohol .
38. A compound of formula 11
Figure imgf000039_0001
11 wherein R1 is C1-C6 alkyl and X is chlorine, bromine or iodine and the camphorsultam ring may be either in the R or in the S configuration.
39. The compound according to claim 38 wherein the compound of formula 11 is a compound of formula 11a
Figure imgf000040_0001
S Ha
40. The compound according to claim 38-39 wherein R1 is C1-C4 alkyl.
41. The compound according to claims 38-40 wherein R1 is isopropyl. 0
42. The compound according to claim 38-41 wherein X is chlorine .
43. The compound N- ( (2S, 4E) -5-chloro-2-isopropylpent-4- enoyl) camphorsultam.
44. A process for the preparation of methyl (2S,4E)-5-5 chloro-2-isopropylpent-4-enoate 4
Figure imgf000040_0002
4 comprising the steps of a) acylating camphorsultam with isovaleryl chloride, b) alkylating the resulting N-isovalerylcamphorsultam with 3-bromo-l-chloropropene, c) hydrolysing the resulting N- ( (2S, 4E) -5-chloro-2- isopropylpent-4-enoyl) camphorsultam, d) esterifing the resulting (2S, 4E) -5-chloro-2- isopropylpent-4-enoic acid.
45. A process for the preparation of optically active carboxylic acids and their ester derivatives of formula 18
R3COOR2 18 wherein R2 is hydrogen, C1-C18 alkyl, optionally containing oxygen, nitrogen or halogen atoms, or any combination thereof, or aryl, optionally substituted with hydroxyl groups, C1-C4 alkoxy groups, amino groups, halogen atoms, or benzyl, optionally substituted with hydroxyl groups, C1-C4 alkoxy groups, amino groups, halogen atoms,
R3 is C1-C18 alkyl, C1-C18 alkenyl, C1-C18 alkynyl, C1-C18 cycloalkyl, C1-C18 cycloalkenyl, all optionally containing oxygen, nitrogen or halogen atoms, or any combination thereof, optionally substituted with aryl Comprising the steps of a) hydrolysing N-acylcamphorsultam of formula 19 with a strong acid and water, such strong acid having a pKa equal to or less than 1.00.
Figure imgf000042_0001
19 b) optionally esterifing the resulting carboxylic acid.
46. The process according to claim 45 wherein R2 is preferably hydrogen, C1-C4 alkyl, phenyl or benzyl.
47. The process according to claims 45-46 wherein R2 is methyl .
48. The process according to claims 45-47 wherein R3 is a C1-C18 alkyl, C1-C18 alkenyl, C1-C18 alkynyl, C1-C18 cycloalkyl, C1-C18 cycloalkenyl , all branched in the α position, optionally substituted by halogen or phenyl.
49. The process according to claims 45-48 wherein R3 is l-isopropyl-4-halo-3-butenyl.
50. The process according to claims 45-49 wherein R3 is (IS, 3E) -l-isopropyl-4-chloro-3-butenyl .
51. The process according to claims 45-50 wherein in step (a) the strong acid is chosen from the group consisting in sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, hydrobromic acid and hydriodic acid.
52. The process according to claims 45-51 wherein in step (a) the strong acid is sulfuric acid.
53. The process according to claims 45-52 wherein in step (a) the concentration of the strong acid in the reaction mixture is greater than 10%.
54. The process according to claims 45-53 wherein in step (a) the concentration of the strong acid in the reaction mixture is greater than 50%.
55. The process according to claims 45-54 wherein in step (a) the amount of water in the reaction mixture is from 1% to 30%.
56. The process according to claims 45-55 wherein in step (a) the amount of water in the reaction mixture is from 2% to 10%.
57. The process according to claims 45-56 wherein in step (a) the hydrolysis is carried out without the addition of any other solvent .
58. The process according to claims 45-57 wherein in step (a) the hydrolysis is carried out at a temperature from 0° to 600C.
59. The process according to claims 45-58 wherein in step (a) the hydrolysis is carried out at a temperature from 20° to 400C.
60. The process according to claims 45-59 wherein in step (a) camphorsultam is recovered by crystallization from an aliphatic or aromatic hydrocarbon.
61. The process according to claim 60 wherein in step (a) the aliphatic hydrocarbon is chosen from the group consisting in pentane, hexane, heptane, cyclohexane, methyleyelohexane or mixtures thereof .
62. The process according to claims 60-61 wherein in step (a) the aliphatic hydrocarbon is a mixture of heptanes.
63. The process according to claims 45-62 wherein in step
(a) recovered camphorsultam is recycled into a subsequent batch.
64. The process according to claims 45-63 wherein in step
(b) the esterification is carried out with an alcohol and a strong acid in catalytic amount.
65. The process according to claims 45-63 wherein in step (b) the esterification is carried out through the conversion to an acyl halide and its reaction with an alcohol .
PCT/EP2006/006897 2006-07-14 2006-07-14 Process for the preparation of optically active (4e)-5- halo-2-alkylpent-4-enoic acids and their ester derivatives WO2008006394A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013118138A1 (en) * 2011-12-13 2013-08-15 Laboratories Ltd Mylan Novel process for the preparation of renin inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020028947A1 (en) * 1998-05-12 2002-03-07 Ono Pharmaceutical Co., Ltd. Novel intermediates and processes for the preparation of optically active octanoic acid derivatives
EP1571138A1 (en) * 2002-12-09 2005-09-07 Asahi Glass Company Ltd. Processes for producing (4e)-5-chloro-2-isopropyl-4-pentenoic ester and optically active isomer thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020028947A1 (en) * 1998-05-12 2002-03-07 Ono Pharmaceutical Co., Ltd. Novel intermediates and processes for the preparation of optically active octanoic acid derivatives
EP1571138A1 (en) * 2002-12-09 2005-09-07 Asahi Glass Company Ltd. Processes for producing (4e)-5-chloro-2-isopropyl-4-pentenoic ester and optically active isomer thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013118138A1 (en) * 2011-12-13 2013-08-15 Laboratories Ltd Mylan Novel process for the preparation of renin inhibitors

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