WO2006043595A1 - Procédé de synthèse d'un dérivé de 2-cyano-4-fluoropyrrolidine - Google Patents

Procédé de synthèse d'un dérivé de 2-cyano-4-fluoropyrrolidine Download PDF

Info

Publication number
WO2006043595A1
WO2006043595A1 PCT/JP2005/019209 JP2005019209W WO2006043595A1 WO 2006043595 A1 WO2006043595 A1 WO 2006043595A1 JP 2005019209 W JP2005019209 W JP 2005019209W WO 2006043595 A1 WO2006043595 A1 WO 2006043595A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
acid
methyl
amino
Prior art date
Application number
PCT/JP2005/019209
Other languages
English (en)
Japanese (ja)
Inventor
Yohei Yamashita
Masahiko Hayakawa
Takahiro Nigawara
Original Assignee
Astellas Pharma Inc.
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
Application filed by Astellas Pharma Inc. filed Critical Astellas Pharma Inc.
Publication of WO2006043595A1 publication Critical patent/WO2006043595A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a pharmaceutical, particularly an inhibitor of dipeptidyl peptidase IV (hereinafter referred to as DPP-IV), more specifically, for example, type 1 diabetes, type 2 diabetes, insulin resistance disease, and 4-Fluoro-1-( ⁇ [4-methyl-1- (methanesulfol) piperidin-4-yl] amino ⁇ acetyl) pyrrolidine-2 useful as a therapeutic and Z or preventive for obesity
  • DPP-IV dipeptidyl peptidase IV
  • the present invention relates to a novel process for producing carbo-tolyl (hereinafter referred to as compound A) or a salt thereof, and a novel 2-aminocarbo-4-fluoropyrrolidine derivative useful as an intermediate in the process.
  • Compound A or a salt thereof has DPP-IV inhibitory action, such as insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes), insulin resistance disease, obesity, etc. It is known to be useful for the treatment and prevention of Z or prevention (Patent Document 1).
  • Patent Document 1 describes that Compound A was produced according to the following production method (hereinafter referred to as Production Method X)! RU
  • Patent Document 2 As a method for producing another 2-cyan-4-fluoropyrrolidine derivative, the following production method (hereinafter referred to as production method Y) is known (Patent Document 2).
  • iPr isopropyl and NEt (iPr) represents N-ethyldiisopropylamine.
  • Patent Document 1 International Publication No. WO 2004/009544 Pamphlet
  • Patent Document 2 International Publication No. WO 03/002553 Pamphlet
  • Production Method 2 shown below is an excellent production method for Compound A or a salt thereof, and According to the production method, the novel 2-aminocarbonyl-4-fluoropyrrolidine derivative represented by the following formula (I) used as a raw material is an excellent intermediate for efficiently producing Compound A.
  • the headline and the present invention were completed.
  • R 1 represents H or a protecting group for an amino group. The same applies below. ]
  • R 1 a protecting group for an amino group is preferred.
  • a protecting group for this amino group a lower alkyl carboxy carb or a lower alkyl carbo yl is preferred.
  • Tert- Butoxycarbol, acetyl, bivaloyl or methoxycarbole are particularly preferred. Of these, tert-butoxycarbol is the most preferred!
  • the intermediate including the final target compound can be purified by crystallization.
  • the higher the purity of the raw material compound the more the side reactions in that step can be suppressed and the generation of impurities can be reduced. Therefore, in industrial production, it is particularly required that the purity of the compound that is the precursor of the final target compound is high.
  • halogen solvents such as dichloroethane, trichloroethane, chloroform, and dichloromethane should be avoided as much as possible.
  • the fat solubility of compounds should be increased. Is important.
  • the compound (I) when the compound (I) is present as a precursor of the compound represented by the formula ( ⁇ ), which is the final product, and particularly R 1 is a protecting group for an amino group.
  • R 1 is a protecting group for an amino group.
  • the presence of the protecting group can be expected to cause crystallization of the precursor. Expected to lead to avoidance.
  • the solubility in solvents other than the base and logogen solvents it is expected that the solubility in solvents other than the base and logogen solvents will be improved, and the use of these halogen solvents can be avoided.
  • lower alkyl refers to a straight or branched alkyl of C.
  • methyl, ethynole, propyl, butynole, pentyl or hexyl or structural isomers such as isopropyl, preferably methyl, ethyl, isopropyl
  • tert-butyl particularly preferably methyl or tert-butyl.
  • the "protecting group for an amino group” refers to a compound in which a carbonylamino group is not eliminated depending on the reaction conditions in the step of converting a carbonylamino group into a cyano group and the protecting group is removed.
  • a protecting group that can be removed under reaction conditions that do not affect the functional groups of the group, particularly the cyano group and the methanesulfo-lumino group for example, Greene and Utz ( Wuts), “Protective Groups in Organic Synthesis (Third Edition)” can be referred to.
  • the functional group in the compound of the present invention is not removed depending on the basic conditions in the step of converting a force sulfonylamino group into a cyano group, and in the step of removing the protecting group. It is desirable that the protecting group be removable under acidic conditions that do not affect the methanesulfonylamino group.
  • the protecting group be removable under acidic conditions that do not affect the methanesulfonylamino group.
  • preferred are lower alkyloxycarbols and lower alkylcarbo- yls, and more preferred are tert-butoxycarbole, acetyl, bivaloyl, and methoxycarbole. Of these, tert-butoxycarbonyl is particularly preferred.
  • the compounds represented by the formulas (I) and (i) have an asymmetric carbon, and therefore have optical isomers.
  • the present invention includes a mixture or an isolated product of these optical isomers, and a production method using them.
  • optical isomers (2S, 4S), that is, a compound represented by the following formula is preferred.
  • the present invention also includes a compound in which a part of the compound of the present invention is labeled with a radioisotope, and a compound in which a part of the compound is labeled with a radioisotope. Production methods using products are also included.
  • the present invention includes salts, hydrates and solvates of the compounds of the present invention, and production methods using salts formed, hydrated or solvated compounds.
  • Specific examples of such salts include salts with organic salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid.
  • Salts with organic acids such as succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid
  • Salts with inorganic bases containing metals such as sodium, potassium, calcium and magnesium
  • salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ortho, quaternary ammonium salts, etc.
  • the functional group can be easily transferred to the appropriate protective group at the raw material or intermediate stage, that is, the functional group. It may be effective in terms of manufacturing technology to replace the base. Thereafter, if necessary, the protecting group can be removed to obtain the desired compound.
  • a functional group include a carboxyl group and an amino group, and the protecting groups thereof are listed in the “Protective Groups in Organic Synthesis (Third Edition)” of [List above; i L]. These may be used as appropriate according to the reaction conditions.
  • R 1 has the above-mentioned meaning, X represents a leaving group, and R represents lower alkyl.
  • R 1 in each compound may be the same or different.
  • the leaving group represented by X may be any group that becomes a leaving group in the N-alkylation reaction.
  • halogen such as black mouth, bromo, iodine, etc .
  • methanesulfo- Examples include sulfo groups such as Nole, trifnoleolomethaneshonhoninole, ethanesunorehoninole, benzeneshonhononole, p-tonolene sulfone.
  • This production method is a method for producing a compound represented by formula (B), which is a raw material for producing a compound represented by formula (I) in the following production method 1. It can be produced by converting an ester group into a carboxyl group.
  • a typical example is a hydrolysis reaction of a lower alkyl ester, and the reaction includes aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as jetyl ether, tetrahydrofuran (THF) and dioxane.
  • Halogenated hydrocarbons such as dichloromethane, dichloroethane, black mouth form, etc.
  • Alcohols such as methanol (MeOH), ethanol (EtOH), 2-propanol (iPrOH); dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (
  • DMSO methyl methacrylate
  • aprotic polar solvents such as sulfuric acid, hydrochloric acid and hydrobromic acid, and organic such as formic acid and acetic acid Acid
  • mineral acids such as sulfuric acid, hydrochloric acid and hydrobromic acid, and organic such as formic acid and acetic acid Acid
  • a base such as sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate or ammonia, and cooled or heated to reflux, and the reaction temperature is appropriately selected according to the reaction conditions can do.
  • a base such as sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate or ammonia
  • the reaction temperature is appropriately selected according to the reaction conditions can do.
  • the method described in the above-mentioned “Protective Groups in Organic Synthesis (Third Edition)” or a method similar thereto may be applied.
  • one method involves subjecting an optionally protected amine represented by (To 1) and an acetyl pyrrolidine derivative having a leaving group represented by (To 2) to N-alkyly reaction, which is necessary.
  • the secondary amine of the alkyl adduct is protected or deprotected
  • another method is an acetic acid derivative having an optionally protected amine represented by (i-3) and
  • the pyrrolidine derivative represented by i-4) is subjected to a condensation reaction, and the secondary amine of the condensate is protected or deprotected as necessary.
  • Any reaction is a method obvious to those skilled in the art, a method equivalent thereto, or a modified method thereof, a method described in Reference Examples, a method described in Examples, a method analogous thereto, or a modified method thereof. It can be easily manufactured using the method.
  • Compound (i-1), which is the starting compound of this production method, is obtained by the method of Reference Example 2 or Reference Example 7 below or a method analogous thereto, and Compound (i-2) is Reference Example 4 or Reference Reference below.
  • compound (i-3) can be obtained from the following Reference Example 1 to the method of Reference Example 3 below or the method analogous thereto, or the following Reference Example 1, Reference Example 2, below.
  • the compound (i-4) is converted into the Journal of Organic Chemistry, by a method combining any of the following Reference Example 3, Reference Example 6 and Reference Example 7 below, or a method based on a combination thereof. It can be produced by the method described on page 41, page 1653 (1976) or a method analogous thereto.
  • This production method is a method for producing a compound represented by the formula (I), which is a compound of the present invention, from the above-mentioned compound (B) as a raw material.
  • a reactive derivative of compound (B) can also be used.
  • the reactive derivative include acid halides such as acid chloride and acid bromide; acid azide; N-hydroxybenzotriazole (HOBt), Active esters with ⁇ -nitrophenol, N-hydroxysuccinimide, etc .; Symmetric acid anhydrides; Mixed acid anhydrides with bivaloyl halide, P-toluenesulfonate, etc .; Mixed acid anhydrides of carbonic acid esters obtained by reacting with alkyl esters of halocarbonic acids such as phosphoric acid mixed acid anhydrides obtained by reacting with diphenylphosphorylyldiphenylphosphoryl azide, etc.
  • a method in which ammonia is allowed to act on a mixed acid anhydride of a carbonate obtained by reacting compound) with a halocarbonic acid alkyl ester is preferable because it can be easily and easily applied.
  • dicyclohexylcarbodiimide, 1,1, -carbolbis-1H-imidazole, jetylphosphoryl is preferable because it can be easily and easily applied.
  • a condensing agent such as cyanide, 1-ethyl-3- (3-dimethylaminopropyl) carpositimide hydrochloride (EDCI).
  • the reaction varies depending on the reactive derivative and condensing agent used, but water; halogenated hydrocarbons; aromatic hydrocarbons; ethers; ethyl acetate (EtOAc), isopropyl acetate (i PrOAc), methyl propionate, Esters such as ethyl propionate and isopropyl propionate; acetonitrile; aprotic polar solvent; or a mixed solvent thereof, etc., in a solvent inert to the reaction, cooled, cooled to room temperature, or room temperature to heated.
  • EtOAc ethyl acetate
  • i PrOAc isopropyl acetate
  • Esters such as ethyl propionate and isopropyl propionate
  • acetonitrile such as ethyl propionate and isopropyl propionate
  • acetonitrile such as ethyl propionate and isopropyl propionate
  • This production method is a method for producing a compound A represented by the formula (IV) from a compound represented by the formula (I) as a raw material.
  • reaction varies depending on the reaction reagent used, the reaction is cooled in a solvent inert to the reaction, such as aromatic hydrocarbons; ethers; rosin, logogen hydrocarbons; pyridine;
  • a solvent inert such as aromatic hydrocarbons; ethers; rosin, logogen hydrocarbons; pyridine;
  • the reaction can be carried out under cooling, at room temperature or at room temperature to overheating, and the reaction temperature can be appropriately selected according to the reaction conditions.
  • R 1 is a protecting group for an amino group
  • the compound A represented by the formula ( ⁇ ) is obtained by subjecting it to a step of removing R 1 after the step of converting the above aminocarbonyl group to a cyano group.
  • a reaction for removing R 1 which is a protecting group of an amino group a method described in ci described in “Protective Groups in Organic synthesis (Third Edition)” or a method equivalent thereto can be applied.
  • a protecting group for an amino group that can be removed using reaction conditions that do not affect the cyano group and methanesulfol group present in the compound subjected to this step, such as acidic conditions, should be adopted as R 1. Is preferred.
  • Reference Example 3 To 5.6 g of the compound of Reference Example 2, 28 mL of MeOH and 12 mL of a 10% (w / v) aqueous sodium hydroxide solution were added, and the mixture was stirred with heating at 45 ° C. for 90 minutes. The solvent was distilled off under reduced pressure, and 30 mL of tap water and 30 mL of toluene were added to the residue and separated. The aqueous layer was stirred with ice-cooling and 30 mL of 1 M hydrochloric acid was added to acidify the pH. . 100 mL of black mouth form was added and dissolved by heating, followed by separation.
  • the aqueous layer was extracted twice with 100 mL of black mouth form, and the organic layer was evaporated under reduced pressure.
  • (2S, 4S) -4-Fluoropyrrolidine-2-carboxylic acid methyl ester monohydrochloride (5.0 g) was added with acetonitrile (25 mL) and N-ethyldiisopropylamine (10 mL), and the salt was stirred with ice cooling.
  • Chloroacetyl chloride (2.4 mL) was added at 18 ° C. or lower, and washed with acetonitrile (5 mL). The reaction solution was stirred at 7 ° C or lower for 3 hours, and the solvent was distilled off under reduced pressure.
  • the solution was washed with 5.0 mL and stirred at 5 ° C or lower for 2 hours.
  • the reaction solution was separated, the aqueous layer was extracted once with 10 mL of iPrOAc, the organic layer was dried over magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure.
  • Example 2 The compound of Example 2 (2.0 g) was added with 20 mL of dichloromethane, and 1.27 g of P-toluenesulfonic acid monohydrate was added with heating and stirring at around 40 ° C. The reaction solution was heated and stirred at around 40 ° C for 2 hours, and then the precipitated crystals were filtered to obtain (2S, 4S) -4-fluorine-1-( ⁇ [4-methyl-1- (methanesulfurol ) Piperidine-4-yl] amino ⁇ acetyl) pyrrolidine-2-carbo-tolulu P-toluenesulfonate monohydrate (2.21 g) was obtained as white crystals.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a pour objet un nouveau procédé de synthèse du 4-fluoro-1-({[4-méthyl-1-(méthanesulfonyl)pipéridin-4-yl]amino}acétyl)pyrrolidine-2-carbonitrile ou d’un sel de ce composé. Ledit composé ou son sel peuvent être employés en tant que médicaments, plus spécifiquement en tant qu’inhibiteurs de la dipeptidylpeptidase IV. La présente invention a également pour objet un nouveau dérivé de 2-aminocarbonyl-4-fluoropyrrolidine employé comme intermédiaire dudit procédé de synthèse. Selon ledit procédé, le précurseur doit cristalliser dans le milieu réactionnel, ceci permettant d'améliorer le rendement et d'éviter une purification sur colonne. Le précurseur présente une oléosolubilité améliorée, ce qui induit une meilleure solubilité dans les solvants autres que les solvants halogénés. L’utilisation de solvants halogénés doit pouvoir être évitée.
PCT/JP2005/019209 2004-10-22 2005-10-19 Procédé de synthèse d'un dérivé de 2-cyano-4-fluoropyrrolidine WO2006043595A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004-307520 2004-10-22
JP2004307520A JP2008019168A (ja) 2004-10-22 2004-10-22 ２−シアノ−４−フルオロピロリジン誘導体の製造法

Publications (1)

Publication Number Publication Date
WO2006043595A1 true WO2006043595A1 (fr) 2006-04-27

Family

ID=36203010

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2005/019209 WO2006043595A1 (fr) 2004-10-22 2005-10-19 Procédé de synthèse d'un dérivé de 2-cyano-4-fluoropyrrolidine

Country Status (2)

Country Link
JP (1) JP2008019168A (fr)
WO (1) WO2006043595A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008114857A1 (fr) 2007-03-22 2008-09-25 Kyorin Pharmaceutical Co., Ltd. Procédé de préparation d'un dérivé d'aminoacétylpyrrolidinecarbonitrile
US7754757B2 (en) 2004-02-05 2010-07-13 Kyorin Pharmaceutical Co., Ltd. Bicycloester derivative
US7915427B2 (en) 2006-03-08 2011-03-29 Kyorin Pharmaceuticals Co., Ltd. Process for producing aminoacetyl pyrrolidine carbonitrile derivative and intermediate for production thereof
US8476470B2 (en) 2008-08-07 2013-07-02 Kyorin Pharmaceutical Co., Ltd. Process for production of bicyclo[2.2.2]octylamine derivative

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002038541A1 (fr) * 2000-11-10 2002-05-16 Taisho Pharmaceutical Co., Ltd. Derives de cyanopyrrolidine
WO2003057666A2 (fr) * 2001-12-26 2003-07-17 Guilford Pharmaceuticals Inhibiteurs de la dipeptidyl peptidase iv
JP2004026820A (ja) * 2002-05-09 2004-01-29 Taisho Pharmaceut Co Ltd ジペプチジルペプチダーゼｉｖ阻害剤
WO2004009544A1 (fr) * 2002-07-23 2004-01-29 Yamanouchi Pharmaceutical Co., Ltd. Derive de 2-cyano-4-fluoropyrrolidine ou de son sel
WO2004026822A2 (fr) * 2002-09-19 2004-04-01 Abbott Laboratories Compositions pharmaceutiques utiles comme inhibiteurs de la peptidase-iv dipeptidyl (dpp-iv)

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002038541A1 (fr) * 2000-11-10 2002-05-16 Taisho Pharmaceutical Co., Ltd. Derives de cyanopyrrolidine
WO2003057666A2 (fr) * 2001-12-26 2003-07-17 Guilford Pharmaceuticals Inhibiteurs de la dipeptidyl peptidase iv
JP2004026820A (ja) * 2002-05-09 2004-01-29 Taisho Pharmaceut Co Ltd ジペプチジルペプチダーゼｉｖ阻害剤
WO2004009544A1 (fr) * 2002-07-23 2004-01-29 Yamanouchi Pharmaceutical Co., Ltd. Derive de 2-cyano-4-fluoropyrrolidine ou de son sel
WO2004026822A2 (fr) * 2002-09-19 2004-04-01 Abbott Laboratories Compositions pharmaceutiques utiles comme inhibiteurs de la peptidase-iv dipeptidyl (dpp-iv)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7754757B2 (en) 2004-02-05 2010-07-13 Kyorin Pharmaceutical Co., Ltd. Bicycloester derivative
US8053465B2 (en) 2004-02-05 2011-11-08 Kyorin Pharmaceutical Co., Ltd. Bicycloester derivative
US7915427B2 (en) 2006-03-08 2011-03-29 Kyorin Pharmaceuticals Co., Ltd. Process for producing aminoacetyl pyrrolidine carbonitrile derivative and intermediate for production thereof
WO2008114857A1 (fr) 2007-03-22 2008-09-25 Kyorin Pharmaceutical Co., Ltd. Procédé de préparation d'un dérivé d'aminoacétylpyrrolidinecarbonitrile
JPWO2008114857A1 (ja) * 2007-03-22 2010-07-08 杏林製薬株式会社 アミノアセチルピロリジンカルボニトリル誘導体の製造方法
US8143427B2 (en) 2007-03-22 2012-03-27 Kyorin Pharmaceutical Co., Ltd. Method for producing aminoacetylpyrrolidinecarbonitrile derivative
US8476470B2 (en) 2008-08-07 2013-07-02 Kyorin Pharmaceutical Co., Ltd. Process for production of bicyclo[2.2.2]octylamine derivative

Also Published As

Publication number Publication date
JP2008019168A (ja) 2008-01-31

Similar Documents

Publication Publication Date Title
AU2015414743B2 (en) Process for the preparation of kinase inhibitors and intermediates thereof
US20050182262A1 (en) Preparation of amino acid amides
JP2008533141A (ja) オピオイド調節物質の製造方法
US20170204065A1 (en) Process for the preparation of kinase inhibitors and intermediates thereof
WO2020096042A1 (fr) Procédé de fabrication de composé diméthoxybenzène
WO2006043595A1 (fr) Procédé de synthèse d'un dérivé de 2-cyano-4-fluoropyrrolidine
WO2020095452A1 (fr) Procédé de fabrication de composé diméthoxybenzène
JP5017101B2 (ja) 不斉四置換炭素原子含有化合物の製法
KR101783679B1 (ko) ２－（사이클로헥실메틸）－ｎ－｛２－［（２ｓ）－1－메틸피롤리딘－２－일］에틸｝－１，２，３，４－테트라하이드로이소퀴놀린－７－설폰아마이드의 제조 방법
JP5663559B2 (ja) ３−｛［（２ｒ）−１−メチルピロリジン−２−イル］メチル｝−５−［２−（フェニルスルホニル）エチル］１ｈ−インドールの合成
WO2008029924A1 (fr) Dérivé d'aminoalkylcarboxamide cyclique
JP4688292B2 (ja) 純粋な鏡像体であるｎ−メチル−ｎ−［（１ｓ）−１−フェニル−２−（（３ｓ）−３−ヒドロキシピロリジン−１−イル）エチル］−２，２−ジフェニルアセトアミドの製造方法
JP5977289B2 (ja) イソキノリン誘導体又はその塩の新規製造方法
JP5073497B2 (ja) テトラ置換−５−アザスピロ［２．４］へプタン誘導体の製法およびその光学活性中間体
CA3214107A1 (fr) Nouveau procede de synthese de derives de 5-{5-chloro-2-[(3s)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoleine-2(1h)-carbonyl]phenyl}-1,2-dimethyl-1h-pyrrole-3-acide carboxylique et son application pour la production de composes pharmaceutiques
WO2005000810A1 (fr) Procede de production d'un compose heterocyclique azote
JP2005220079A (ja) ピロリジン化合物の合成とその結晶
JP2009508961A (ja) アミノ酸誘導体の製法
JP3266603B2 (ja) ３−（７−アミジノ−２−ナフチル）−２−フェニルプロピオン酸誘導体の製造方法
JP2000026408A (ja) 対掌体的に純粋なピロリジン誘導体、その塩、それらの製造方法
JP3266603B6 (ja) ３−（７−アミジノ−２−ナフチル）−２−フェニルプロピオン酸誘導体の製造方法
Burdzhiev et al. Synthesis of piperidinones incorporating an amino acid moiety as potential SP antagonists
WO2019098551A1 (fr) Procédé de préparation de composé intermédiaire d'une synthèse pharmaceutique
KR100483317B1 (ko) α-페닐-α-프로폭시벤젠아세트산 1-메틸-4-피페리디닐에스테르 염산염의 제조방법
JPWO2004058710A1 (ja) 新規ベンズアミド誘導体及びその製造法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05805148

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP