WO2019098551A1 - Procédé de préparation de composé intermédiaire d'une synthèse pharmaceutique - Google Patents

Procédé de préparation de composé intermédiaire d'une synthèse pharmaceutique Download PDF

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Publication number
WO2019098551A1
WO2019098551A1 PCT/KR2018/012575 KR2018012575W WO2019098551A1 WO 2019098551 A1 WO2019098551 A1 WO 2019098551A1 KR 2018012575 W KR2018012575 W KR 2018012575W WO 2019098551 A1 WO2019098551 A1 WO 2019098551A1
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WO
WIPO (PCT)
Prior art keywords
group
reaction
formula
compound
solvent
Prior art date
Application number
PCT/KR2018/012575
Other languages
English (en)
Korean (ko)
Inventor
박종원
이석주
류인애
김봉찬
Original Assignee
주식회사 엘지화학
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 주식회사 엘지화학 filed Critical 주식회사 엘지화학
Priority to PE2020000586A priority Critical patent/PE20210839A1/es
Priority to RU2020114746A priority patent/RU2741389C1/ru
Priority to CN201880067548.4A priority patent/CN111247127B/zh
Priority to MX2020005099A priority patent/MX2020005099A/es
Priority to BR112020009568-0A priority patent/BR112020009568A2/pt
Priority claimed from KR1020180126663A external-priority patent/KR102184129B1/ko
Publication of WO2019098551A1 publication Critical patent/WO2019098551A1/fr
Priority to PH12020550635A priority patent/PH12020550635A1/en
Priority to CONC2020/0006788A priority patent/CO2020006788A2/es

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • 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 process for the preparation of the compound of formula (1), which is an essential intermediate for synthesizing dipeptidyl peptidase IV (hereinafter also referred to as "egg! 3 -”) inhibitory diabetes therapeutic agent.
  • WO-A-30106 discloses a process for preparing from the compounds of formula (I) as essential intermediates.
  • a carboxylic acid protecting group (3 ⁇ 4) of the compound of the formula (2) is obtained by deprotecting the compound of the formula (1).
  • the protecting group is butyloxycarbonyl and the leaving group is a butyl group (IV)
  • the process for preparing the compound of formula (1) has a disadvantage in that the reaction should proceed under more or less harsh conditions, a large amount of reaction solvent should be used, and an additional concentration process is required.
  • sodium hydroxide is used under basic conditions unlike the conventional method, and the yield can be remarkably improved even under mild conditions, which is economical and requires no additional concentration process, and which is economical and highly productive.
  • the present invention relates to a process for preparing a compound represented by the formula (1), wherein the carboxylic acid protecting group (3 ⁇ 4) is selectively deprotected from the two protecting groups and the protecting groups Wherein the deprotection reaction is carried out using a base in a solid form and a lower alcohol.
  • the production method according to the present invention can produce the compound of Formula 1 which is an intermediate for treating insulin-dependent diabetes mellitus in a non-insulin-dependent manner through 1) a high yield under mild conditions, 2) And 3) it is very useful because it can achieve improvement effects such as productivity increase by eliminating the concentration process.
  • reaction formula is intended to aid understanding of the present invention, and is not intended to limit the present invention in any sense.
  • 1? 2, and all three seedlings 4 are each independently hydrogen, halogen, substituted or unsubstituted 0 1- 04 alkyl.
  • ⁇ is a carbonyl group, an acyl group, a sulfonyl group, an acetyl or benzyl group, ((Butyloxycarbonyl), 0 (benzyloxycarbonyl) or 1: 3 (: (9-fluorenylmethyloxycarbonyl), and more preferably 80 (:). ?
  • the present invention is a carboxylic acid protecting group, preferably a benzyl group, a methyl group, an ethyl group, a propyl group or a butyl group, more preferably a 1: -butyl group.
  • carboxylic acid protecting group (3 ⁇ 4) of the compound of formula (2) is deprotected to obtain the compound of formula (1) by the conventional basic conditions, unlike the case of using an aqueous solution such as an aqueous solution of sodium hydroxide or a base in liquid form,
  • the present invention is characterized in that a solid-form base is used.
  • the solid form of the base used in the present invention may be sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide or combinations thereof , Preferably sodium hydroxide, is used to obtain the compound of formula (I).
  • the amount of the reaction base to be used is preferably 1 to 4 equivalents, and preferably 1 to 2 equivalents relative to the compound of formula (2).
  • a lower alcohol having 1 to 6 carbon atoms and a mixed solvent thereof are used.
  • a lower alcohol of the 1 to 6 carbon atoms may be at least one zero is selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, and a mixed solvent thereof the group consisting of (Co-solvent), preferably to use ethyl alcohol have.
  • the amount of the reaction solvent used is preferably 1 fold (mL / g) to 7 fold (mL / g), preferably 2 fold (mL / g) to 3 fold (mL / g) for the compound of Formula 2.
  • the reaction solvent of the present invention is characterized in that a small amount of reaction solvent is used, unlike the conventional production method of formula (1) according to an inexpensive condition.
  • the reaction temperature may vary depending on the reaction conditions, but in the case of the present invention, the reaction may be performed at a temperature lower than the reflux condition, for example, 30 to 80 ° C.
  • the reaction time is preferably from 1 hour to 6 hours, more preferably from 3 hours to 0 hours, but is not limited thereto.
  • the process according to the invention may further comprise the step of crystallizing the compound of formula (I) obtained as described above.
  • the solvent used for the crystallization may be one or more kinds of solvents selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol and Co-solvent thereof, but not limited thereto, Water or a mixed solvent of ethyl alcohol and water.
  • an acid can be used to adjust the pH to produce crystals, and the preferred pH is 2.5 to 3.0. 0 or less.
  • the present invention will be described in further detail with reference to the following Production Examples and Examples, but the present invention is not intended to limit the scope of the present invention in any sense. 2019/098551 1 » (: 1/10 public 018/012575

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de formule 1 qui est un intermédiaire essentiel pour synthétiser un agent thérapeutique du diabète inhibant DPP-IV par déprotection sélective d'un groupe protecteur d'acide carboxylique (p2) d'un composé de formule 2.
PCT/KR2018/012575 2017-11-16 2018-10-23 Procédé de préparation de composé intermédiaire d'une synthèse pharmaceutique WO2019098551A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
PE2020000586A PE20210839A1 (es) 2017-11-16 2018-10-23 Metodo de produccion de un compuesto intermedio para sintetizar un medicamento
RU2020114746A RU2741389C1 (ru) 2017-11-16 2018-10-23 Способ получения промежуточного соединения для синтеза лекарственного средства
CN201880067548.4A CN111247127B (zh) 2017-11-16 2018-10-23 用于合成药物的中间体化合物的生产方法
MX2020005099A MX2020005099A (es) 2017-11-16 2018-10-23 Metodo de produccion de un compuesto intermedio para sintetizar un medicamento.
BR112020009568-0A BR112020009568A2 (pt) 2017-11-16 2018-10-23 Método de produção de composto intermediário para síntese de medicamento
PH12020550635A PH12020550635A1 (en) 2017-11-16 2020-05-15 Production method of intermediate compound for synthesizing medicament
CONC2020/0006788A CO2020006788A2 (es) 2017-11-16 2020-05-29 Método de producción de un compuesto intermedio para sintetizar un medicamento

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2017-0153334 2017-11-16
KR20170153334 2017-11-16
KR10-2018-0126663 2018-10-23
KR1020180126663A KR102184129B1 (ko) 2017-11-16 2018-10-23 의약품 합성용 중간체 화합물의 제조 방법

Publications (1)

Publication Number Publication Date
WO2019098551A1 true WO2019098551A1 (fr) 2019-05-23

Family

ID=66538632

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2018/012575 WO2019098551A1 (fr) 2017-11-16 2018-10-23 Procédé de préparation de composé intermédiaire d'une synthèse pharmaceutique

Country Status (2)

Country Link
MX (1) MX2020005099A (fr)
WO (1) WO2019098551A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4256907A (en) * 1977-05-11 1981-03-17 Bayer Aktiengesellschaft Preparation of substituted vinylcyclopropane-carboxylic acid esters
JPH04316526A (ja) * 1991-04-15 1992-11-06 Asahi Chem Ind Co Ltd カルボン酸エステルのアルカリ加水分解法
KR20010079823A (ko) * 1998-09-14 2001-08-22 비날리 노엘 카르복실산의 결정화 방법
JP2008201719A (ja) * 2007-02-20 2008-09-04 Nippon Oil Corp テトラカルボン酸およびその酸二無水物の製造方法
KR101378984B1 (ko) * 2010-09-03 2014-03-27 주식회사 엘지생명과학 의약품 합성용 중간체 화합물의 제조 방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4256907A (en) * 1977-05-11 1981-03-17 Bayer Aktiengesellschaft Preparation of substituted vinylcyclopropane-carboxylic acid esters
JPH04316526A (ja) * 1991-04-15 1992-11-06 Asahi Chem Ind Co Ltd カルボン酸エステルのアルカリ加水分解法
KR20010079823A (ko) * 1998-09-14 2001-08-22 비날리 노엘 카르복실산의 결정화 방법
JP2008201719A (ja) * 2007-02-20 2008-09-04 Nippon Oil Corp テトラカルボン酸およびその酸二無水物の製造方法
KR101378984B1 (ko) * 2010-09-03 2014-03-27 주식회사 엘지생명과학 의약품 합성용 중간체 화합물의 제조 방법

Also Published As

Publication number Publication date
MX2020005099A (es) 2020-08-13

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