WO2013144979A1 - Process for the preparation of aliskiren - Google Patents

Process for the preparation of aliskiren Download PDF

Info

Publication number
WO2013144979A1
WO2013144979A1 PCT/IN2013/000201 IN2013000201W WO2013144979A1 WO 2013144979 A1 WO2013144979 A1 WO 2013144979A1 IN 2013000201 W IN2013000201 W IN 2013000201W WO 2013144979 A1 WO2013144979 A1 WO 2013144979A1
Authority
WO
WIPO (PCT)
Prior art keywords
aliskiren
ammonia
formula
compound
preparation
Prior art date
Application number
PCT/IN2013/000201
Other languages
French (fr)
Inventor
Shankar Rama
Lakshmana Rao Vadali
Nagaraju Mittapelly
Vijaya Krishna RAVI
Swamy Saidugari
Original Assignee
Maylan Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to IN1173CH2012 priority Critical
Priority to IN1173/CHE/2012 priority
Priority to IN1876CH2012 priority
Priority to IN1876/CHE/2012 priority
Application filed by Maylan Laboratories Ltd filed Critical Maylan Laboratories Ltd
Publication of WO2013144979A1 publication Critical patent/WO2013144979A1/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00Preparation of carboxylic acid amides
    • C07C231/12Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41Preparation of salts of carboxylic acids
    • C07C51/412Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13Dicarboxylic acids
    • C07C57/15Fumaric acid

Abstract

The present invention relates to an improved process for the preparation of Aliskiren and its pharmaceutically acceptable salts comprising reducing the compound of Formula-Z in presence of catalyst and ammonia. The present invention further relates to Aliskiren hemifumarate having diastereomeric impurity less than 0.2%.(F) H3C CH3 NH2 H3C 0 H3C CH3 Formula-Z

Description

PROCESS FOR THE PREPARATION OF ALISKIREN

This application claims priority to this Indian patent application numbers 1 173/CHE/2012 filed on March 28, 2012 and 1876/CHE/ 2012 filed on May 11, 2012

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of renin inhibitor Aliskiren and its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION:

Aliskiren, (2S, 4S, 5S, 7S)-N-(2-carbamoyl-2-methyIpropyl)-5-amino-4-hydroxy-2,7- diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl] octanamide having the Formula-I, a new antihypertensive has been developed which interferes with the renin- angiotensin system at the beginning of angiotensin II biosynthesis.

Figure imgf000002_0001

Formula-I

Aliskiren is marketed by Novartis as TEKTURNA® in the form of its hemifumarate salt in a once-daily formulation.

US 5,559,111 discloses Aliskiren and related compounds along with the synthesis of Aliskiren. Aliskiren hemifumarate is having 4 chiral carbon atoms; hence the synthesis for the pure Aliskiren hemifumarate substantially free of diastereomeric impurities is quite difficult and demanding. Further US 7132569, US 7009078, US 6730798 and US 6800769 claims novel intermediates used in the preparation of Aliskiren and process for the preparation of Aliskiren, which are incorporated here for reference.

In prior art US 7009078 the reduction of Azide compound (Formula-Z) is carried out in presence of ethanol amine. After completion of reaction the reaction mixture is filtered and the catalyst is washed with tert-butyl methyl ether. The filtrate is washed with sodium hydroxide and brine. To remove the ethanol amine repeated washing with water/aq. NaOH is required. The aqueous phases are extracted with tert-butyl methyl ether. The aqueous work-up decreases the yield of the final product..To overcome this problem the present inventors surprisingly found that usage of ammonia will increase the yield and purity of Aliskiren.

The present invention provides an improved process for the preparation of Aliskiren and its pharmaceutically acceptable salts thereof. Present invention further provides, Aliskiren hemifumarate having substantially free of diastereomeric impurities and process for the preparation of the same.

OBJECT AND SUMMARY OF THE INVENTION: Principle object of the present invention is to provide an improved process for the preparation of Aliskiren and its pharmaceutically acceptable salts thereof.

One aspect of the present invention provides, an improved process for the preparation of Aliskiren and its pharmaceutically acceptable salts comprising reducing the compound of Formula-Z in presence of catalyst and ammonia.

Figure imgf000003_0001

Formula-Z Another object of the present invention is to provide pure Aliskiren hemifumarate having substantially free of diastereomeric impurities.

One aspect of the present invention is to provide a process for the preparation of Aliskiren hemifumarate having substantially free of diastereomeric impurities.

Another aspect of the present invention provides Aliskiren hemifumarate of the following

Figure imgf000004_0001

having diastereomeric impurity of less than 0.2%, as measured by area percentage HPLC.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of renin inhibitors like Aliskiren and its pharmaceutically acceptable salts.

The main aspect of the present invention provides an improved process for the preparation of Aliskiren and its pharmaceutically acceptable salts comprising reducing the compound of Formula-Z in presence of catalyst and ammonia.

Figure imgf000004_0002
In prior art US 7009078 the reduction of compound of Formula-Z is carried out in presence of ethanol amine. After completion of reaction the reaction mixture is filtered and the catalyst is washed with tert-butyl methyl ether. The filtrate is washed with sodium hydroxide and brine. To remove the ethanol amine repeated washing with water/aq. NaOH is required. The aqueous phases are extracted with tert-butyl methyl ether. The aqueous work-up decreases the yield of the final product. To overcome this problem the present inventors surprisingly found that usage of ammonia will increase the yield and purity of Aliskiren. Accordingly, present invention provides an improved process for the preparation of Aliskiren and its pharmaceutically acceptable salts comprising reducing the compound of Formula-Z in presence of catalyst and ammonia in an alcoholic solvent.

In one embodiment, the catalyst used in the reduction of compound of Formula-Z is selected from Pd/C, Raney nickel or Pd(OH)2 in presence of H2 gas.

In another embodiment, the ammonia used is in the form of non-aqueous ammonia such as alcoholic ammonia. The alcoholic ammonia is selected from ethanolic ammonia and methanolic ammonia, preferably ethanolic ammonia.

In one more embodiment, the reduction is carried out in presence of alcoholic solvent like ethanol, methanol, isopropanol and n-propanol; preferably ethanol.

In one more embodiment, the compound of Formula-Z is prepared by the conventional processes disclosed in prior art for example as disclosed in US 7009078 or in our co pending patent application IN 3087/CHE/2010.

As per the present invention, the compound of Formula-Z is hydrogenated in the presence of 10% Pd/C and ethanolic ammonia solution in alcoholic solvent like ethanol. To the obtained compound, fumaric acid is added to get Aliskiren Hemifumarate. The present invention also relates to Aliskiren hemifumarate having substantially free of diastereomeric impurities. The present invention further relates to a process for the preparation of Aliskiren hemifumarate having substantially free of diastereomeric impurities.

Another aspect of the present invention is to provide Aliskiren hemifumarate of the following structure:

Figure imgf000006_0001

having diastereomeric impurity less than 0.2%, as measured by area percentage HPLC.

One embodiment of the present invention is to provide Aliskiren hemifumarate having diastereomeric impurity less than 0.18%, as measured by area percentage HPLC.

One more embodiment of the present invention is to provide Aliskiren hemifumarate having diastereomeric impurity less than 0.15%, as measured by area percentage HPLC.

One more aspect of the present invention provides, Aliskiren hemifumarate diastereomeric impurity of the following structure ALK-I.

Figure imgf000006_0002
Instrumentation:

Waters HPLC system having alliance 2695 model pump and 2487 (UV) detector with Empower chromatography software or its equivalent.

Figure imgf000007_0001

Chromatographic parameters:

Column YMC Pro CI 8, 250 x 4.6 mm, 5.0 μηι

Detector UV at 230 nm

Flow rate 1.0 mL / min.

Injection volume 10 μL

Column oven temp. 27 °C

Run time 65 minutes

Diluent Acetonitrile and water in the ratio 1 : l%v/v

Mobile Phase-A:

Weight and transfer about 1.0 g of Tetrabutyl ammonium hydrogen sulphate in 1000 mL of water and add 0.5 mL of Ortho phosphoric acid. Filter through 0.45 μιη or finer porosity membrane and degas.

Mobile Phase-B:

Prepare a degassed mixture of Acetonitrile: Methanol 55:45%v/v.

Gradient ro ram:

Figure imgf000007_0002

Standard solution

Weigh and transfer about 25.0 mg of each of standard into a 25 mL volumetric flask, dissolve in and dilute to volume with diluent. Sample solution

Weigh and transfer about 25.0 mg of each of sample into a 25 mL volumetric flask, dissolve in and dilute to volume with diluent.

Procedure:

Inject sample solution in to the chromatograph and record the chromatograms. Disregard the peaks due to blank and peak responses which are 0.05% and below apart from known impurities. Typical retention time and relative retention time are as follows (for information). It was found that Aliskiren in TKETURNA tablet (Batch No: 1205809U12TA) is having purity 99.76 at RT 19.51 and diastereomeric impurity of Formula ALK-I is 0.24% at RT 18.64.

Our co-pending Indian patent application IN 3087/CHE/2010 discloses novel process for the preparation of Aliskiren as disclosed in scheme-I.

Figure imgf000008_0001

Compound-Z

Aliskiren

SCHEME-I

The intermediate compound of Formula- Y obtained by the above process is in oil form. The intermediate compounds play a vital role in the preparation of Aliskiren and its pharmaceutically acceptable salts thereof. Considering the lengthy synthesis of Aliskiren which involves almost all the intermediates as oil, it is highly beneficial if any of the intermediate could be obtained as a crystallisable solid which can give the intermediate of good purity as well as Aliskiren of good purity. To avoid that problem and to improve the purity of Aliskiren, The present inventors tried to open the lactone compound (Formula- X) with 3-amino-2,2-dimethyl-propionitrile and not only succeeded in getting fruitful aminolysis reaction, but also isolating the corresponding amide compound of Formula-Y as pure crystalline compound of chromatographic purity greater than or equal to 99%, which is substantially free of its corresponding diastereomer. This results increase in the purity of Aliskiren.

Thus another aspect of the present invention provides process for the preparation of Aliskiren substantially free of diastereomeric impurity comprising the steps of:

a) converting the cyano group of solid compound of Formula-Y into amide group to give compound of Formula-Z;

b) reducing the azide group of compound of Formula-Z with suitable reducing agent to give Aliskiren; and

c) optionally converting Aliskiren into Aliskiren hemifumarate.

In one embodiment, the solid compound of Formula-Y is prepared by reacting compound-X with 3-Amino-2,2-dimethyl-propionitrile, characterized in that after completion of the reaction, reaction mixture containing compound of Formula-Y in water immiscible solvent selected from hydrocarbons such as toluene, xylene, pentane, hexane, preferably toluene; is washed with aqueous base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, preferably sodium bicarbonate to give solid compound of Formula-Y.

In another embodiment, cyano group of solid compound of Formula-Y is converted into compound of Formula-Z in the known manner as disclosed in co-pending Indian patent application IN 3087/CHE/2010. In one more embodiment, reduction of compound of Formula-Z is carried out in the known manner as disclosed in co-pending Indian patent application IN 3087/CHE/2010.

According to the present invention, the compound of Formula-Y is prepared by reacting compound of Formula-X with 3-amino-2,2-dimethyl-propionitrile in presence of a base like organic or inorganic base, preferably organic base such as Triethylamine, Tripropylamine, diisopropylethylamine, etc., more preferably Triethylamine and a catalyst like 2-hydroxypyridine. After completion of the reaction the reaction mass is diluted with hydrocarbon solvent such as toluene, Xylene and chlorobenzene, preferably toluene and stirred with alkali solution to remove catalyst as an alkali salt. 3-amino-2,2- dimethyl-propionitrile and Triethylamine are extracted from hydrocarbon solvent layer using an organic acid like acetic acid. The hydrocarbon solvent layer is stirred with 1- 10% aqueous base solution like sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, preferably 3-5% sodium bicarbonate solution to crystallize compound of Formula-Y. The obtained product is filtered and dried under vacuum to get the compound of Formula-Y as white solid.

All patents, patent applications, and non-patent publications cited herein by reference should be considered in their entirety. The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

Experimental procedure:

Example-l:

Figure imgf000011_0001

A mixture of compound-X (100 g), 3-Amino-2,2-dimethyl-propionitrile (74.5 g), and 2- hydroxypyridine (22.5 g) in triethylamine was stirred for about 24 hours at 60-70°C. The progress of the reaction was monitored by HPLC analysis. After completion of the reaction the reaction mass was diluted with toluene and stirred with aq NaOH solution to precipitate and remove 2-hydroxypyridine as sodium salt. The organic layer was washed with aqueous acetic acid. The organic layer was stirred with aqueous sodium bicarbonate solution to crystallize out the desired product. The product was filtered, washed with DM water followed by prechilled toluene and dried under vacuum to yield compound of Formula-Y as white solid. HPLC purity: >99%. Melting point: 62 °C.

ExampIe-2: Process for the preparation of compound-Z

Figure imgf000011_0002

Formula-Z

To a mixture of Compound-Y (13g) and ethanol (65 ml) aqueous NaOH (5g dissolved in 45 ml of DM water) and 35% Hydrogen peroxide (20 ml) was added at room temperature and stirred the at 30°- 40 °C for 2-4h. The progress of the reaction was monitored by HPLC analysis. After completion of the reaction the peroxides were quenched by stirring with sodium bisulfite solution. Thereafter product was extracted in toluene. The toluene extract was washed with ethanolamine and water. The solvent was distilled off completely under vacuum to obtain compound Z.

Example-3: Process for the preparation of Aliskiren Hemifumarate

The compound of Formula-Z (50g) was hydrogenated for 5-6 hours in the presence of 10% Pd/C (5 g) and ethanolic ammonia solution (10% w/w ammonia in ethanol ~29.4g) in ethanol (400 ml) at ambient temperature and 7 Kg/cm2 pressure. The reaction mixture was filtered and the catalyst was washed with ethanol (50 ml) and distilled to get residue. The obtained residue was co-distilled with acetonitrile (50 ml) and re-dissolved in ethanol and acetonitrile at 35-40°C. To this fumaric acid (4.5g) was added and stirred to get clear solution and filtered at 35-40°C to remove any insoluble particles. Acetonitrile (150 ml) was added to the above clear filtrate at 35-40°C and inoculated with 200mg of Aliskiren hemifumarate and agitated for 3hours to get precipitation of the product. To the above slurry acetonitrile was added and agitated for 17 hours at ambient temperature. The suspension was cooled to 0 °C and filtered off by suction after 2 hours. The product cake was washed with acetonitrile and then dried under vacuum at 35°C to yield 47g of Aliskiren hemifumarate as white crystals.

Claims

We claim:
1. A process for the preparation of Aliskiren or its pharmaceutically acceptable salts comprises reducing the compound of Formula-Z in presence of catalyst and ammonia.
Figure imgf000013_0001
Formula-Z
2. The process according to claim 1, wherein the catalyst is selected from Pd/C, Raney nickel or Pd(OH)2.
3. The process according to claim 1, wherein the ammonia is in the form of nonaqueous ammonia.
4. The process according to claim 1, wherein the ammonia is in the form of alcoholic ammonia.
5. The process according to claim 4, wherein alcoholic ammonia is selected from ethanolic ammonia and methanolic ammonia.
6. The process according to claim 1, wherein the reaction is carried out in presence of an alcoholic solvent.
7. The process according to claim 6, wherein alcoholic solvent is selected from ethanol, methanol, isopropanol and n-propanol.
8. The process according to claim 1, wherein pharmaceutically acceptable salt is Fumarate salt.
9. Aliskiren hemifumarate having diastereomeric impurity less than 0.2%.
10. Aliskiren hemifumarate according to claim 9, wherein diastereomeric impurity less than 0.15%.
PCT/IN2013/000201 2012-03-28 2013-03-27 Process for the preparation of aliskiren WO2013144979A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
IN1173CH2012 2012-03-28
IN1173/CHE/2012 2012-03-28
IN1876CH2012 2012-05-11
IN1876/CHE/2012 2012-05-11

Publications (1)

Publication Number Publication Date
WO2013144979A1 true WO2013144979A1 (en) 2013-10-03

Family

ID=48699906

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2013/000201 WO2013144979A1 (en) 2012-03-28 2013-03-27 Process for the preparation of aliskiren

Country Status (1)

Country Link
WO (1) WO2013144979A1 (en)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559111A (en) 1994-04-18 1996-09-24 Ciba-Geigy Corporation δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides
US6730798B2 (en) 2000-07-05 2004-05-04 Speedel Pharma Ag Process for the preparation of substituted octanoyl amides
US6800769B2 (en) 2000-07-25 2004-10-05 Speedel Pharma Ag Process for the preparation of substituted octanoyl amides
US7009078B1 (en) 1999-07-29 2006-03-07 Speedel Pharma Ag Production of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-arly-octanoylamides
US20060154926A1 (en) * 2002-06-11 2006-07-13 Elan Pharmaceuticals, Inc. Methods of treating alzheimer's disease using aryl alkanoic acid amides
EP2062874A1 (en) * 2007-11-20 2009-05-27 KRKA, tovarna zdravil, d.d., Novo mesto Process and intermediates for the preparation of aliskiren
US20100124550A1 (en) * 2008-11-20 2010-05-20 Auspex Pharmaceuticals, Inc. Amide inhibitors of renin
EP2189442A1 (en) * 2008-11-20 2010-05-26 Krka Tovarna Zdravil, D.D., Novo Mesto Process and intermediates for the preparation of aliskiren
WO2011148392A1 (en) * 2010-05-28 2011-12-01 Msn Laboratories Limited Process for the preparation of (2s,4s,5s,7s)-n-(2-carbamyl-2- methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3- methoxypropoxy)phenyl]-octanamide hemifumarate and its intermediates thereof

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559111A (en) 1994-04-18 1996-09-24 Ciba-Geigy Corporation δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides
US7009078B1 (en) 1999-07-29 2006-03-07 Speedel Pharma Ag Production of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-arly-octanoylamides
US7132569B2 (en) 1999-07-29 2006-11-07 Speedel Pharma Ag Preparation of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides
US6730798B2 (en) 2000-07-05 2004-05-04 Speedel Pharma Ag Process for the preparation of substituted octanoyl amides
US6800769B2 (en) 2000-07-25 2004-10-05 Speedel Pharma Ag Process for the preparation of substituted octanoyl amides
US20060154926A1 (en) * 2002-06-11 2006-07-13 Elan Pharmaceuticals, Inc. Methods of treating alzheimer's disease using aryl alkanoic acid amides
EP2062874A1 (en) * 2007-11-20 2009-05-27 KRKA, tovarna zdravil, d.d., Novo mesto Process and intermediates for the preparation of aliskiren
US20100124550A1 (en) * 2008-11-20 2010-05-20 Auspex Pharmaceuticals, Inc. Amide inhibitors of renin
EP2189442A1 (en) * 2008-11-20 2010-05-26 Krka Tovarna Zdravil, D.D., Novo Mesto Process and intermediates for the preparation of aliskiren
WO2011148392A1 (en) * 2010-05-28 2011-12-01 Msn Laboratories Limited Process for the preparation of (2s,4s,5s,7s)-n-(2-carbamyl-2- methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3- methoxypropoxy)phenyl]-octanamide hemifumarate and its intermediates thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DAMIEN BARBARAS ET AL: "Removal of Heavy Metals from Organic Reaction Mixtures: Preparation and Application of Functionalized Resins (1)", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 13, no. 6, 20 October 2009 (2009-10-20), pages 1068 - 1079, XP002712155, DOI: 10.1021/op900102a *

Similar Documents

Publication Publication Date Title
CN102633799B (en) Method for synthesizing sapropterin dihydrochloride from racemate intermediate separation route
KR101523126B1 (en) Processes and intermediates for making sweet taste enhancers
US20110054183A1 (en) Method For Manufacturing Aryl Carboxamides
CA2707334A1 (en) A process for the preparation or purification of olmesartan medoxomil
US9783506B2 (en) Process for the large scale production of 1H-[1,2,3]triazole and its intermediate 1-benzyl-1H-[1,2,3]triazole
WO2012010788A1 (en) Process for preparing aminobenzoylbenzofuran derivatives
WO2009153214A1 (en) Process for the manufacture of an intermediate in the synthesis of dabigatran
SK12992000A3 (en) Process for preparing a protected 4-aminomethyl-pyrrolidin-3-one
EP2025672B1 (en) Process for producing 1-carbamoyl-3,7-dioxo-1,4-diazepane compounds
RU2585762C2 (en) Method of producing lakosamide
EP2951158B1 (en) Process for the preparation of ivacaftor and solvates thereof
CN101591300A (en) Novel method for synthesizing lacosamide
EP1274702A1 (en) Process for the synthesis of a known tetrazol derivative
EP1926705A2 (en) Process for preparing valsartan
JP6307087B2 (en) Compounds useful for the synthesis of benzamide compounds
CZ297970B6 (en) Process for preparing (S)-3-(aminomethyl)-5-methyl-hexanoic acid (pregabalin)
WO2013079866A1 (en) Method for preparing 5-amino-benzoyl-benzofuran derivatives
CN1844110B (en) Method for synthesizing Valsartan with high optical purity
WO2003089403A1 (en) Process for preparing gabapentin
US7858812B2 (en) Process for isolation of desired isomers of nebivolol intermediates
EP2027083B1 (en) Method of preparing chiral cyclic beta-aminocarboxamides
JP4953822B2 (en) Method for producing muscarinic receptor antagonist and intermediate thereof
US8440861B2 (en) Solid forms of an N-(phenylmethyl)propanamide derivative and processes of preparation
US7592485B2 (en) Process for producing (Z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethylcyclopropane hydrochloride
CN103304511B (en) Novel synthesis method of mirabegron

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13731970

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13731970

Country of ref document: EP

Kind code of ref document: A1