WO2013120464A1 - Procédé de préparation de rivaroxaban fondé sur l'économie de 1,1'-carbonyldiimidazole - Google Patents

Procédé de préparation de rivaroxaban fondé sur l'économie de 1,1'-carbonyldiimidazole Download PDF

Info

Publication number
WO2013120464A1
WO2013120464A1 PCT/CZ2013/000014 CZ2013000014W WO2013120464A1 WO 2013120464 A1 WO2013120464 A1 WO 2013120464A1 CZ 2013000014 W CZ2013000014 W CZ 2013000014W WO 2013120464 A1 WO2013120464 A1 WO 2013120464A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
preparation
formula
solvent
cyclization
Prior art date
Application number
PCT/CZ2013/000014
Other languages
English (en)
Inventor
Ales Halama
Radim Krulis
Jiri BRICHAC
Original Assignee
Zentiva, K.S.
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 Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2013120464A1 publication Critical patent/WO2013120464A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention relates a new method of performing of the cyclization reaction providing the 2- oxo- 1 , 3 -oxazoli dine heterocycle during the chemical synthesis of rivaroxaban, which is an active pharmaceutical substance used for preparation of a drug from the therapeutic group of anticoagulants.
  • Rivaroxaban chemically ( l S)-5-chloro-N-( ⁇ 2-oxo-3-[4-(3-oxomo holin-4-yl)phenyl]-l ,3- oxazolidin-5-yl ⁇ methyl)thiophene-2-carboxamide, described by formula (1), was developed by the company Bayer Healthcare (WOO 1/47919, 2001). Rivaroxaban is applied in the clinical practice as the active ingredient of an orally available anticoagulant that is commercially marketed as Xarelto and is used in the prevention and treatment of arterial or venous thromboembolic disorders. In its effect, rivaroxaban is characterized by direct selective inhibition of the FXa coagulation enzyme ⁇ Drugs of the Future 2006, 31(6): 484-493).
  • chiral building blocks e.g. (iS)-glycidyl phtalimide (4), (Sy3-aminopropane-l ,2-diol (5), (i?)-epichlorohydrin (6) and (i?)-glycidyl butyrate (7), as well as carbonylation agents, e.g. ⁇ , ⁇ -carbonyldiimidazole (8, abbreviated CDI), alkyl chloroformates 9) and phosgene (10).
  • chiral building blocks e.g. (iS)-glycidyl phtalimide (4), (Sy3-aminopropane-l ,2-diol (5), (i?)-epichlorohydrin (6) and (i?)-glycidyl butyrate (7), as well as carbonylation agents, e.g. ⁇ , ⁇ -carbonyldiimidazole (8, abbrevi
  • a substantial structural feature of rivaroxaban (1) is represented by the 3, 5 -substituted 2-oxo- 1 ,3-oxazolidine heterocycle described by the general chemical formula (11), wherein Ri means a substituted aryl and R 2 means a substituted alkyl.
  • Ri means a substituted aryl
  • R 2 means a substituted alkyl.
  • carbonylation agents of general formula (12) are used, wherein both X and Y mean a suitable leaving group, e.g. a halogen, alcoxy group or 1H- imidazol- l -yl.
  • the carboxylation agents which may be e.g.
  • CDI (8), alkyl chloroformates (9) or phosgene (10), are the source of the carbonyl group in the target heterocycle.
  • the starting compounds for the preparation of 3, 5 -substituted 2-oxo- l ,3-oxazolidines include variously substituted l -alkyl-2-(arylamino)ethanols of formula (13), wherein R ⁇ means a substituted aryl and R 2 means a substituted alkyl; see Scheme 1.
  • the present invention relates to a new and industrially applicable method of carrying out the carbonylation reaction in the preparation of intermediates of rivaroxaban, which is characterized by saving of the expensive carboxylation agent (CDI), which makes it possible to reduce costs of commercial production of rivaroxaban.
  • CDI carboxylation agent
  • the invention provides a convenient method of performing the cyclization reaction in the preparation of rivaroxaban intermediates that is characterized by a reduced consumption of the expensive carboxylation agent CDI.
  • the invention consists in a method of cyclizing 2-((2i?)-2-hydroxy-3- ⁇ [4-(3-oxomorpholin-4- yl)phenyl]amino ⁇ propyl)-l H-isoindol-l,3(2H)-dione of formula (14) to 2-( ⁇ (55)-2-oxo-3-[4- (3-oxomorpholin-4-yl)phenyl]- l ,3-oxazolidin-5-yl ⁇ methyl)- l H-isoindol- l ,3(2H)-dione of formula (15), characterized by a process consisting of the following steps:
  • step (b) cyclization of the mixture of the compounds obtained in step (a) in a solvent or a mixture of solvents suitable for cyclization in the presence of a suitable base as the catalyst;
  • a C 4 to C ⁇ ether, polyethylene glycol, a Ci to C6 chlorinated solvent or their mixtures in any proportions can be used as a suitable solvent for the preparation of the compound (15) in step (a), preferably a solvent selected from the group of tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, ierf-butylmethylether, diie i-butylether, polyethylene glycol PEG-200 to PEG- 800, dichloromethane, chloroform, 1 ,1 ,2-trichloroethylene, chlorobenzene or their mixtures in any proportions.
  • a metal alkoxide of formula (17), wherein R means a linear or branched C i to Cs alkyl and M means an alkali metal, can be used as a suitable base for preparation of the compound (15) in step (b).
  • An alkoxide selected from the group of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert- butoxide, lithium ferf-butoxide can be used as a suitable metal alkoxide in step (b).
  • a suitable base can also be used in step (b), selected from the group of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, methyllithium, n-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazide.
  • Potassium tert- butoxide or its solution in an organic solvent is preferably used as the base in step (b).
  • a solvent selected from the group of a C4 to C8 ether, polyethylene glycol, a C I to C6 chlorinated solvent or their mixtures in any proportions can be used as suitable solvents for the preparation of the compound (15) in step (b).
  • the preparation of the compound (15) is also characterized in that the cyclization in step (b) is carried out at a temperature in the range of from 40°C to the boiling point of the solvent.
  • the process of preparation of the compound (15) is finalized by its isolation from the reaction mixture, which is characterized in that the isolation in step (c) is carried out in such a way that the separated product is filtered off from the reaction mixture, washed with a C ⁇ to C5 alcohol and/or water and the isolated product is dried.
  • the present invention relates to a method of carrying out the cyclization of 2-((2 ?)-2-hydroxy- 3 - ⁇ [4-(3 -oxomorpholin-4-yl)phenyl]amino ⁇ propyl)- 1 H-isoindol- 1 ,3(2H)-dione of formula (14) to 2-( ⁇ (55)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]- l ,3-oxazolidin-5-yl ⁇ methyl)-lH- isoindol- l ,3(2H)-dione of formula (15), see Scheme 3.
  • the method according to the invention is characterized by making use of the possibility of cyclization of the reaction intermediate, 2- ((2 ⁇ )-2-hydroxy-3-(N-(4-(3-oxomorpholin-4-yl)phenyl)- lH-imidazol-yl- l - carboxamido)propyl)- l H-isoindol- l ,3(2H)-dione of formula (16), by treatment with bases or with heat during its melting, see path (b) in Scheme 4. Compared to the prior process, see path (a) in Scheme 3, the consumption of the expensive carbonylation agent is saved.
  • the cyclization method according to the invention is used, only 1 to 1.5 equivalents of CDI per 1 equivalent of the starting compound (14) are consumed, while 4 CDI equivalents were consumed in the original method.
  • the invention is based on the surprising finding that in the reaction of the compound (14) with CDI, the reaction intermediate (16) is formed very quickly, which is unexpectedly stable and can even be isolated from the reaction mixture in the solid state. Due to relatively high stability of the reaction intermediate (16) the conversion of the compound (14) to the target cyclic product (15) only proceeds very slowly and under treatment with an unusually big excess of the carbonylation agent (CDI). The observed phenomenon is surprising as very similar reactions of related compounds run easily and with the use of just one CDI equivalent per one equivalent of the compound cyclized (US2007032472). A high consumption of CDI (ca. 4 equivalents) during cyclization of the compound (14) to the cyclic product (15) was also confirmed by a comparative experiment, see Example 1.
  • a suitable base that can, moreover, be used in significantly lower amounts than the equivalent of the cyclized compound (e.g. 0.2 eq. according to Example 8) has turned out to be more convenient for cyclization of the compound (16).
  • the target product (15) was obtained from the isolated compound (16) by the action of a suitable base with the yield of 78% (calculated on the starting compound (14)), see Example 7.
  • the method wherein first a mixture of the compounds (16) and (15) is prepared from the compound (14) by treatment with 1 to 1.5 equivalents of CDI and subsequently a suitable base is added to the mixture to finalize the cyclization of the compound (16) to the cyclic product (15), has proved to be still more convenient.
  • the process of cyclization of the compound (14) makes it possible to reproducibly obtain the cyclic product (15), characterized by the chemical purity of 99.8% and higher.
  • the compound (15) prepared by the method of the invention can be further used for synthesis of rivaroxaban (1), which is the active substance in an anticoagulant drug.
  • a convenient and distinguishing feature from the former method of cyclization of the compound (14) to the compound (15) consists in the use of a lower amount of the expensive carbonylation agent. The reduced amount of the carbonylation agent used is compensated by use of a cheap base.
  • Fig. 1 presents the record of an LC MS analysis of the product (mixture of (15) and (16)) in accordance with Example 2.
  • Fig. 2 presents the record of an LC MS analysis of the product (mixture of (15) and (16)) in accordance with Example 6.
  • Fig. 3 presents the record of an LC MS analysis of the product (16) in accordance with Example 4.
  • Fig. 4 presents the record of an LC MS analysis of the product (15) in accordance with Example 7.
  • Fig. 5 presents the MS spectrum of the compound (16) prepared by the process in accordance with Example 4.
  • the mixture of the compounds (15) and (16), prepared by the process of Example 2 was heated in a sand bath.
  • the solid substance started to melt when the bath temperature exceeded 150°C; the temperature was gradually increased to 180°C and the mixture was heated at this temperature for 30 minutes.
  • After cooling the re-melted material was suspended in 75 ml of ethanol and the suspension was thoroughly stirred up. This was followed by filtration, washing of the cake with 25 ml of ethanol and vacuum drying at 120°C. 25.6 g of a white powder with the melt, point of 216 to 218°C was obtained; HPLC 99.8%; the yield, calculated on to starting material (14) from Example 2 was 77%.
  • the mixture was boiled for another 15 minutes and after that cooled to ca. 40°C, which was followed by filtration, washing of the cake with THF (25 ml) and drying. 17.8 of an off-white powder that first melts at 165-175°C, then re-crystallizes and melts again at 215 to 217°C was obtained.
  • the isolated product was a mixture of 39.6% of the compound (15) and 60.4% of the compound (16), see Fig. 2.
  • the mass spectra were obtained with the use of an API 3000 mass spectrometer based on triple quadrupole (AB Sciex, USA), which was connected to an HPLC 200 series liquid chromatograph (Perkin-Elmer, USA). 10 ⁇ , of the sample was sprayed onto a inetex column, 150 x 4.6 mm; 2.6 ⁇ (Phenomenex, USA).
  • the mobile phase consisted of a mixture of ACN - 10 mM ammonium formate, pH 6.3.
  • the gradient program was as follows: isocratically 30% ACN up to 4 min, then gradient to 100% ACN up to 18 min.
  • the flow rate of the mobile phase was 600 ⁇ /min.
  • An APCI ion source in the positive full scan mode was used for detection in the mass spectrometer.
  • the temperature of the ion source was 300°C, the scanning range was from m/z 50 to m/z 1000 and nitrogen with the flow of 12 arbitrary units was used as the nebulization gas.
  • the wavelength of 230 nm was used for detection in the PDA detector.
  • the Analyst 1.4.1. software (AB Sciex, USA) was used for data acquisition.
  • Melting points of the prepared substances were measured on a Kofler block with the sample heating rate of 10°C/min (up to 120°C) and 4°C/min (over 120°C).
  • the measured values of melting points or melting intervals, respectively, are given in the respective Examples.
  • the wavelength used for the detection was 260 nm

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de réalisation de la cyclisation du composé de formule (14) en composé (15), un intermédiaire non cyclique (16) étant tout d'abord préparé par le traitement avec 1 à 1,5 équivalent de 1,1'-carbonyldiimidazole de formule (8), qui est ensuite transformé en le produit cyclique (15) par traitement avec de la chaleur ou une base. Le présent procédé de cyclisation du composé (14) en composé (15) est préféré et se distingue des procédés antérieurs par l'utilisation d'une quantité réduite de l'agent de carbonylation coûteux, qui est composé par l'utilisation d'une base (17) peu coûteuse, R signifiant un alkyle et M signifiant un métal alcalin.
PCT/CZ2013/000014 2012-02-17 2013-02-12 Procédé de préparation de rivaroxaban fondé sur l'économie de 1,1'-carbonyldiimidazole WO2013120464A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ20120114A CZ2012114A3 (cs) 2012-02-17 2012-02-17 Zpusob prípravy rivaroxabanu zalozený na úspore 1,1´ -karbonyldiimidazolu
CZPV2012-114 2012-02-17

Publications (1)

Publication Number Publication Date
WO2013120464A1 true WO2013120464A1 (fr) 2013-08-22

Family

ID=47713715

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2013/000014 WO2013120464A1 (fr) 2012-02-17 2013-02-12 Procédé de préparation de rivaroxaban fondé sur l'économie de 1,1'-carbonyldiimidazole

Country Status (2)

Country Link
CZ (1) CZ2012114A3 (fr)
WO (1) WO2013120464A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104730165A (zh) * 2015-03-23 2015-06-24 成都百裕科技制药有限公司 一种利伐沙班的高效液相色谱检测方法
WO2015104605A1 (fr) 2014-01-08 2015-07-16 Wockhardt Limited Procédé de préparation de rivaroxaban ou d'un sel pharmaceutiquement acceptable de ce dernier
CN108546265A (zh) * 2018-06-22 2018-09-18 苏州中联化学制药有限公司 一种利伐沙班中间体的合成方法
CN111039937A (zh) * 2019-12-16 2020-04-21 浙江海翔药业股份有限公司 一种利伐沙班中间体的制备方法
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047919A1 (fr) 1999-12-24 2001-07-05 Bayer Aktiengesellschaft Oxazolidinones substituees et leur utilisation dans le domaine de la coagulation sanguine
WO2004060887A1 (fr) 2003-01-07 2004-07-22 Bayer Healthcare Ag Procede de production de 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyle)-phenyle]-1,3-oxazolidine-5-yle}-methyle)-2-thiophene-carboxamide
DE102004002044A1 (de) * 2004-01-15 2005-08-04 Bayer Healthcare Ag Herstellverfahren
US20070032472A1 (en) 2004-04-19 2007-02-08 Symed Labs Limited Novel process for the preparation of linezolid and related compounds
WO2008155034A1 (fr) * 2007-06-20 2008-12-24 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones substitués et leur utilisation
WO2009023233A1 (fr) 2007-08-14 2009-02-19 Concert Pharmaceuticals, Inc. Dérivés d'oxazolidinones substituées

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047919A1 (fr) 1999-12-24 2001-07-05 Bayer Aktiengesellschaft Oxazolidinones substituees et leur utilisation dans le domaine de la coagulation sanguine
US7157456B2 (en) 1999-12-24 2007-01-02 Bayer Healthcare Ag Substituted oxazolidinones and their use in the field of blood coagulation
WO2004060887A1 (fr) 2003-01-07 2004-07-22 Bayer Healthcare Ag Procede de production de 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyle)-phenyle]-1,3-oxazolidine-5-yle}-methyle)-2-thiophene-carboxamide
DE102004002044A1 (de) * 2004-01-15 2005-08-04 Bayer Healthcare Ag Herstellverfahren
US20070032472A1 (en) 2004-04-19 2007-02-08 Symed Labs Limited Novel process for the preparation of linezolid and related compounds
WO2008155034A1 (fr) * 2007-06-20 2008-12-24 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones substitués et leur utilisation
WO2009023233A1 (fr) 2007-08-14 2009-02-19 Concert Pharmaceuticals, Inc. Dérivés d'oxazolidinones substituées

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DRUGS OF THE FUTURE, vol. 31, no. 6, 2006, pages 484 - 493
J.MED.CHEM., vol. 48, no. 19, 2005, pages 5900 - 5908
SUSANNE ROEHRIG ET AL: "Discovery of the Novel Antithrombotic Agent 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene2-carboxamide (BAY-59-7939): An Oral, Direct Factor Xa Inhibitor", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 48, no. 19, 22 September 2005 (2005-09-22), pages 5900 - 5908, XP002680548, ISSN: 0022-2623, [retrieved on 20050818], DOI: 10.1021/JM050101D *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015104605A1 (fr) 2014-01-08 2015-07-16 Wockhardt Limited Procédé de préparation de rivaroxaban ou d'un sel pharmaceutiquement acceptable de ce dernier
CN104730165A (zh) * 2015-03-23 2015-06-24 成都百裕科技制药有限公司 一种利伐沙班的高效液相色谱检测方法
CN104730165B (zh) * 2015-03-23 2016-05-25 成都百裕科技制药有限公司 一种利伐沙班的高效液相色谱检测方法
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
CN108546265A (zh) * 2018-06-22 2018-09-18 苏州中联化学制药有限公司 一种利伐沙班中间体的合成方法
CN111039937A (zh) * 2019-12-16 2020-04-21 浙江海翔药业股份有限公司 一种利伐沙班中间体的制备方法

Also Published As

Publication number Publication date
CZ2012114A3 (cs) 2013-02-20

Similar Documents

Publication Publication Date Title
WO2013120464A1 (fr) Procédé de préparation de rivaroxaban fondé sur l'économie de 1,1'-carbonyldiimidazole
JP6820836B2 (ja) 変異イソクエン酸デヒドロゲナーゼ阻害剤としてのフェニルキノリノン誘導体
JP6466171B2 (ja) 新規アミン誘導体またはその塩
EP2722330B1 (fr) Nouveau procédé pour la synthèse d'un intermédiaire du rivaroxaban, la 4-{4-[(5s)-5-(aminométhyl)-2-oxo-1,3-oxazolidin-3-yl]phényl}morpholin-3-one
CA2810478A1 (fr) Procedes de preparation de 4-{4-[5(s)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one
JP7450024B2 (ja) ＦＸＩａ阻害剤及びその調製方法と医薬用途
JP2017509609A (ja) 新規フェニルアゼチジンカルボキシレート又はカルボキサミド化合物
JP2023501799A (ja) Ｒｏｃｋ阻害剤及びその製造方法と用途
KR20030051747A (ko) 벤족사지논 유도체, 그의 제조 및 용도
SK136199A3 (en) Asymmetric synthesis of benzoxazinones via new intermediates
CN111039937B (zh) 一种利伐沙班中间体的制备方法
EP3309158B1 (fr) Forme cristalline k du rivaroxaban et procédé de préparation
KR20120101551A (ko) Ｍｇｌｕｒ５ 수용체의 알로스테릭 조절자로서 바이사이클릭 티아졸
JP7205529B2 (ja) オキサゾリジノン化合物の製造方法
KR20010076389A (ko) 벤젠술폰아미드 화합물, 이의 제조 방법 및 이를 함유하는약제 조성물
WO2012041263A2 (fr) Procédé de fabrication d'une 2-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]- l,3-oxazolidin-5-yl}méthyl)-lh-isoindol-l,3(2h)-dione à la pureté optique élevée
KR20170023158A (ko) 2-아미노 치환 벤즈알데히드 화합물을 제조하는 방법
CN104628730B (zh) 一类光学纯手性环状n,n‑缩醛的合成方法
CN108610306B (zh) 一种2h-1,4-噻嗪-3(4h)-酮衍生物的合成方法
CN111471041B (zh) 一种噁唑烷酮类抗菌药物中间体的合成方法
KR20220018486A (ko) 4-페닐-5-알콕시카르보닐-2-티아졸-2-일-1,4-디히드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라히드로-1H-이미다조[1,5-a]피라진-2-일]-카르복실산을 제조하는 대체 방법
Bredikhina et al. From racemic epichlorohydrin to a single enantiomer of the drug timolol maleate
Nag et al. Application of primary allylamine derivatives of Baylis-Hillman adducts to heterocyclic synthesis: Generation of 5-benzyl-4 (3H)-pyrimidinones and 2-benzylidene-2, 3-dihydropyrrolizin-1-ones
JP2018535240A (ja) ベンゾピラン誘導体の精製方法、ベンゾピラン誘導体の結晶形およびベンゾピラン誘導体の結晶形の製造方法
CN109438513B (zh) 含有取代膦酰胺酯的ido1抑制剂、其制备方法及应用

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: 13708649

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13708649

Country of ref document: EP

Kind code of ref document: A1