WO2022220608A1 - Procédé de préparation d'un intermédiaire pour la synthèse d'un agoniste du récepteur de la sphingosine-1-phosphate - Google Patents

Procédé de préparation d'un intermédiaire pour la synthèse d'un agoniste du récepteur de la sphingosine-1-phosphate Download PDF

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Publication number
WO2022220608A1
WO2022220608A1 PCT/KR2022/005396 KR2022005396W WO2022220608A1 WO 2022220608 A1 WO2022220608 A1 WO 2022220608A1 KR 2022005396 W KR2022005396 W KR 2022005396W WO 2022220608 A1 WO2022220608 A1 WO 2022220608A1
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formula
solvent
compound
chloro
reaction
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PCT/KR2022/005396
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English (en)
Korean (ko)
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김성욱
김기대
이수민
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주식회사 엘지화학
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Priority to CN202280028372.8A priority Critical patent/CN117203189A/zh
Publication of WO2022220608A1 publication Critical patent/WO2022220608A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Definitions

  • the present invention relates to a process for the preparation of key intermediates for the synthesis of sphingosine-1-phosphate receptor agonists.
  • Sphingosine-1-phosphate is produced through the intracellular ceramide pathway, and ceramide, the starting material of this synthetic pathway, has two production pathways, namely, the de novo biosynthetic pathway and It is produced in cells through the degradation of sphingomyelin, a component of the cell membrane.
  • S1P levels in each tissue are regulated by two biosynthetic sphingosine kinases (SphKs) and two biodegradable S1P phosphatases (S1P lyase and lysophospholipid phosphatases).
  • S1P lyase and lysophospholipid phosphatases The produced substance S1P mediates various cellular responses such as cell proliferation, cytoskeletal organization and migration, adhesion- and tight junction assembly, and morphogenesis. it is known They are present in plasma at high concentrations (100-1000 nM) in a form bound to albumin and other plasma proteins, while in tissues at low concentrations.
  • S1P binds to the S1P receptor, a G-protein coupled receptor, and exhibits various biological functions.
  • the sub-types of S1P receptors known to date are S1P1 to S1P5. ) receptor) 1, 5, 3, 6 and 8. These S1P receptors are responsible for leukocyte recirculation, neural cell proliferation, morphological changes, migration, endothelial function, vasoregulation and cardiovascular development ( It is known to be involved in various biological functions such as cardiovascular development.
  • S1P signaling through these receptors plays an important role in a series of responses related to multiple sclerosis, including inflammatory responses and repair processes.
  • nonselective S1P1 agonists have recently It is approved for the treatment of multiple sclerosis.
  • S1P receptors are equally widely expressed in many cells involved in the induction of multiple sclerosis.
  • S1P1 receptors play a very important role in the immune system.
  • the S1P1 receptor is mainly expressed on the surface of lymphocytes such as T cells and B cells, and reacts with S1P to participate in lymphocyte recycling.
  • the S1P concentration is higher in body fluid than in lymphoid tissue, so that lymphocytes leave the lymphoid tissue according to the difference in S1P concentration and circulate along the efferent lymph.
  • the S1P1 receptor of lymphocytes is down-regulated by the S1P1 agonist, the egress of lymphocytes from the lymphoid tissue does not occur, and eventually autoaggressive causing inflammation and tissue damage to the CNS. The infiltration of lymphocytes is reduced, and the therapeutic effect appears in multiple sclerosis.
  • fingolimod a nonselective S1P1 agonist approved as an oral multiple sclerosis treatment, when it is activated by binding to the S1P1 receptor, paradoxically, the receptor is internalized or degraded from the lymphocyte surface, resulting in functional S1P1 It acts as an antagonist.
  • Korean Patent Application Laid-Open No. 10-2014-0104376 discloses a novel compound of Formula 1 effective as an S1P receptor agonist.
  • X is C or N
  • R1 is H or optionally substituted alkyl
  • R2 is H, optionally substituted alkyl, halogen, CN, CF 3 or COCF 3 ,
  • W is C, N, C-alkoxy, C-halogen or C-CN
  • n 0, 1, 2 or 3
  • R3 to R10 are each H, alkyl, halogen, halogenoalkyl or alkoxyalkyl,
  • R11 is H
  • R12 is OH, NH 2 , or to be.
  • reaction may have the following problems in producing a clinical API.
  • the filtered solid was washed sequentially with water and MTBE, respectively, and then dried over nitrogen to 6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-2H -Naphthalen-1-one was obtained.
  • Phosphoryl chloride (POCl 3 ) was added to the reactor and the internal temperature was cooled to 0 °C. DMF was slowly added dropwise, and after stirring at an internal temperature of 50° C. for 2 hours, 6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-2H-naphthalene -1-one was added and reacted at an internal temperature of 50° C. for 3 hours. Since excessive HCl gas was generated during the reaction, a vent line was installed so that it could be neutralized by installing a NaOH trap.
  • an object of the present invention is to provide a suitable method for producing the compound of Formula 2, which is a key intermediate in a novel synthesis method of an excellent sphingosine-1-phosphate receptor agonist, in high yield.
  • R1 is hydrogen or substituted or unsubstituted alkyl
  • R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF 3 or COCF 3 ;
  • X is C or N
  • L is a leaving group
  • One aspect according to the present invention provides a method for preparing an intermediate compound of Formula 2 below, comprising substituting a leaving group for an alcohol group of the compound of Formula 3 in an ether-based single solvent.
  • R1 is hydrogen or substituted or unsubstituted alkyl
  • R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF 3 or COCF 3 ;
  • X is C or N
  • L is a leaving group
  • the 'alkyl' is a substituted alkyl
  • substituents there may be one or more substituents, and the substituents are each independently a group consisting of halogen, cyano, hydroxy, alkyloxy, oxo, unsubstituted sulfonyl and sulfonyl substituted with alkyl. It may be selected from
  • R1 of the above formula is hydrogen or C 1 -C 6 substituted or unsubstituted alkyl
  • R2 is hydrogen, C 1 -C 6 substituted or unsubstituted alkyl, halogen, CN, It may be CF 3 or COCF 3 .
  • R1 may be C 1 -C 4 substituted or unsubstituted alkyl, and R2 may be halogenyl (F, Cl, Br or I).
  • the leaving group (L) is a reactive group that provides a substitution position to the compound of Formula 2 when the compound of Formula 2 is subjected to a substitution reaction with an alcohol-based compound, but is not limited thereto, for example, chlorine (Cl), bromine (Br), iodine (I), methanesulfonate (Oms), p-toluenesulfonate (OTs) and trifluoromethanesulfonate (OTf) may be selected.
  • L may be Br.
  • the present invention provides a compound of Formula 2, which is a key intermediate in the synthesis of a sphingosine-1-phosphate receptor agonist by substituting a leaving group for the terminal alcohol group of the compound of Formula 3, specifically, the step of replacing the 'alcohol group with a leaving group' ' (hereinafter, referred to as 'leaving group substitution step') is a technical feature of remarkably lowering the production rate of the N2 isomer by performing it in an ether-based single solvent.
  • the 'single solvent' indicates that only one type of solvent is included in the reactor for the leaving group substitution reaction.
  • the inclusion of a trace amount of a heterogeneous solvent at a level that does not substantially affect the yield of the reaction product in the reactor for the leaving group substitution reaction is also not excluded from the single solvent.
  • the inclusion of a heterogeneous solvent in the content can also be viewed as the use of a single solvent.
  • the ether-based solvent is not limited thereto, but for example, dialkyl such as diethyl ether, dipropyl ether, dibutyl ether, diisoamyl ether, ethyl methyl ether, methyl propyl ether, methyl butyl ether, ethyl propyl ether, etc.
  • etheric solvents such as diphenyl ether and anisole;
  • cyclic ether solvents such as tetrahydrofuran and tetrahydropyran, etc. are mentioned.
  • the ether-based single solvent may be methyl tert-butyl ether (MTBE).
  • the compound of Formula 3 and MTBE are mixed and cooled to 0° C., and then reacted with PBr 3 to obtain a compound of Formula 2.
  • the compound of Formula 3 and MTBE are mixed, cooled to 0° C., reacted with PBr 3 , and then washed with water and filtered to obtain the compound of Formula 2 when the reaction is completed.
  • the compound of Formula 3 is prepared according to a method comprising the steps of:
  • R1, R2 and X are as defined in Formula 2 or Formula 3,
  • R3 is C 1 -C 6 substituted or unsubstituted alkyl.
  • R3 may be a C 1 -C 4 substituted or unsubstituted alkyl.
  • R3 may be a methyl group.
  • step 1) R1 and R2 substituents are introduced into the compound of Formula 4 and crystallized with a crystallization solvent including an alcohol solvent to prepare a compound of Formula 5.
  • the alcohol solvent for the crystallization is not limited thereto, but may be, for example, at least one solvent selected from methanol, ethanol, isopropyl alcohol and butanol.
  • the solvent for the crystallization may be a mixed solvent of an alcohol solvent and water.
  • a mixed solvent of an alcohol solvent and water as the crystallization solvent, there may be an effect of reducing the yield of the N2 isomer.
  • the mixed solvent for crystallization has a volume ratio of the alcohol solvent and water in terms of the yield of Chemical Formula 5: 5:1 to 1:5, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, 2:1 to 1:1, or 1.5:1 to 1:1 may be used.
  • the solvent for the crystallization may be a mixed solvent of ethanol and water.
  • the ethanol and water may be used in an EtOH:H 2 O volume ratio of 2:1 to 1:2, 2:1 to 1:1, 1.5:1 to 1:1, or 1:1.
  • the crystallization solvent is a mixed solvent of an alcohol solvent and water
  • the alcohol solvent and water may be added sequentially or simultaneously during crystallization, respectively.
  • an alcohol solvent such as EtOH
  • EtOH is added to the reaction product in which the substituent is introduced, and then cooled to 0 ° C. to 20 ° C., and then water is added to crystallize to obtain a compound of formula 5 it could be
  • it may be crystallized after purifying the reaction product in which a substituent is introduced before the crystallization.
  • the crystallization yield can be improved by removing unreacted residual compounds used in the reaction.
  • the purification may be performed using, for example, a polar solvent, and the polar solvent may be, for example, a polar organic solvent, water, or a mixed solvent thereof.
  • the polar organic solvent is not limited thereto, but may be, for example, at least one solvent selected from among ethyl acetate, hexane and dichloromethane.
  • the reaction product in which the substituent is introduced may be purified by a mixed solvent of ethyl acetate (EtOAc) and water, and then crystallized to obtain the compound of Formula 5.
  • EtOAc ethyl acetate
  • the aqueous layer is removed using ethyl acetate and water in a volume ratio of 2:1 to 1:2, It may be crystallized after removing a polar solvent other than water.
  • K 2 CO 3 used in the reaction in which the substituent is introduced is together at the time of crystallization of the reaction product It may be to prevent the precipitation or to reduce the precipitation amount to improve the purity of the crystal.
  • R1 and R2 may be those in which R1 is substituted and then R2 is substituted, R1 is substituted after R2, or R1 and R2 are simultaneously substituted.
  • R2 in the compound of Formula 4, may be substituted before R1.
  • R1 when bulky R1 is first substituted in the compound of Formula 4, for example, if bulky R1 is first substituted at the 3rd position of indazole where X is N, the production of the N2 isomer is suppressed, and the yield is improved can be
  • step 2) the compound of Formula 5 is reacted with a reducing agent to obtain a compound of Formula 3.
  • the reducing agent used in step 2) may use a conventional reducing agent capable of reducing an ester group to an alcohol, for example, sodium borohydride (NaBH 4 ), lithium borohydride (LiBH 4 ), borane (BH) 3 ) and at least one selected from diisobutylaluminum hydride (DIBAH) may be used, but is not limited thereto.
  • a conventional reducing agent capable of reducing an ester group to an alcohol for example, sodium borohydride (NaBH 4 ), lithium borohydride (LiBH 4 ), borane (BH) 3 ) and at least one selected from diisobutylaluminum hydride (DIBAH) may be used, but is not limited thereto.
  • DIBAH diisobutylaluminum hydride
  • the reducing agent may be additionally added according to the progress of the reaction.
  • the solvent that was added at the beginning of the reaction may be added together, or only the reducing agent may be added without adding a solvent.
  • the reducing agent is used to react the remaining compound of Formula 5 and methanol may have an effect of further improving the yield of the compound of Formula 3 obtained by adding methanol.
  • the reaction product may be purified to obtain the compound of Formula 3.
  • an organic solvent such as dichloromethane (DCM), isopropyl acetate and ethyl acetate, water, or a mixed solvent thereof may be used for the purification of the reaction product of the reduction reaction.
  • DCM and water are added to remove the aqueous layer, thereby further improving the yield of the compound of Formula 3 may be exhibited.
  • the compounds prepared according to the present invention can be used as key intermediates for the synthesis of sphingosine-1-phosphate receptor agonists.
  • the compound prepared according to the present invention can be used as a main intermediate in a known synthesis method of a sphingosine-1-phosphate receptor agonist, and can also be used as a main intermediate in a new synthesis method developed after the present application.
  • the use of the present invention is not limited to a particular method of synthesis of a sphingosine-1-phosphate receptor agonist.
  • the compounds prepared according to the present invention can be used for other purposes other than the synthesis of sphingosine-1-phosphate receptor agonists, and the use of the present invention is limited only to the synthesis of sphingosine-1-phosphate receptor agonists. it is not
  • the use of the preparation method of the present invention has the effect of mass-producing the compound of Formula 2 in high yield.
  • Example 1-1 Synthesis of 3-Chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester (3-Chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester)
  • Reaction ion pair chromatography was performed by HPLC, and the reaction was completed (1H-indazole-5-carboxylic acid methyl ester: N/D).
  • the external temperature was set to 0° C., and cooling was performed for 60 minutes.
  • K 2 CO 3 (10.7 kg, 77.4 mol)
  • 2-iodopropane iodopropane, 8.98 kg, 52.8 mol
  • B-complex (which is produced by NaBH 4 (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol alcohol and boron conjugated) and residual NaBH 4
  • 3N HCl 39.3 kg was slowly added for 60 minutes to maintain the pH of the reaction solution at 3.0 and distilled under reduced pressure to remove the solvent.
  • 5-bromomethyl-3-chloro- 5-bromomethyl-3-chloro- was used in the same manner as in Example 1-3, except that a DCM/MTBE 4:1 mixed solvent was used for the substitution reaction, and DCM instead of water was used for extraction of the reaction product. 1-Isopropyl-1H-indazole was obtained.
  • SG15 represents “(3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol
  • SG20 represents “ 5-bromomethyl-3-chloro- 1-isopropyl-1H-indazole”.
  • 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester was prepared in the same manner as in Example 1-1, except that water was added and crystallized without a purification step. obtained.
  • SG10 represents "3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester.
  • 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester was prepared in the same manner as in Example 1-1 except that EtOH:H 2 O was used in a volume ratio of 3:7 during crystallization. obtained.
  • 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester was prepared in the same manner as in Example 1-1 except that EtOH:H 2 O was used in a volume ratio of 1:1 during crystallization. obtained.
  • 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester was prepared in the same manner as in Example 1-1 except that EtOH:H 2 O was used in a volume ratio of 7:3 during crystallization. obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation d'un composé de formule chimique 2 défini dans la présente description, qui peut être utilisé efficacement pour la synthèse d'un agoniste du récepteur de la sphingosine-1-phosphate.
PCT/KR2022/005396 2021-04-14 2022-04-14 Procédé de préparation d'un intermédiaire pour la synthèse d'un agoniste du récepteur de la sphingosine-1-phosphate WO2022220608A1 (fr)

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CN202280028372.8A CN117203189A (zh) 2021-04-14 2022-04-14 制备用于合成鞘氨醇-1-磷酸酯受体激动剂的中间体的方法

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Citations (6)

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JP2011518154A (ja) * 2008-04-16 2011-06-23 アリーナ ファーマシューティカルズ， インコーポレイテッド （ｒ）−１−｛２−［４’−（３−メトキシプロパン−１−スルホニル）−ビフェニル−４−イル］−エチル｝−２−メチル−ピロリジンの合成に有用なプロセス
KR20140104376A (ko) * 2013-02-20 2014-08-28 주식회사 엘지생명과학 스핑고신-1-인산 수용체 효능제, 그의 제조방법 및 그를 활성성분으로서 함유하는 약제학적 조성물
KR20170034902A (ko) * 2014-07-16 2017-03-29 라이프에스씨아이 파마슈티컬스, 인크. 치료적 억제 화합물
KR20200035109A (ko) * 2017-09-07 2020-04-01 지앙수 루이케 메디컬 사이언스 앤드 테크놀로지 컴퍼니 리미티드 치환된 페닐아세트산 유도체의 제조방법
KR20200145735A (ko) * 2019-06-19 2020-12-30 주식회사 엘지화학 인돌 또는 인다졸 화합물의 제조방법
KR20220048950A (ko) * 2020-10-13 2022-04-20 주식회사 엘지화학 스핑고신-1-인산 수용체 효능제 합성을 위한 중간체의 제조 방법

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EP1984334B1 (fr) * 2006-02-15 2014-04-09 Allergan, Inc. Composes amide d'acide indole-3-carboxylique, ester, thioamide et ester de thiol porteurs de groupes aryl ou heteroaryl presentant une activite biologique antagoniste sur le recepteur sphingosine-1-phosphate (s1p)
UA107360C2 (en) * 2009-08-05 2014-12-25 Biogen Idec Inc Bicyclic aryl sphingosine 1-phosphate analogs
TW201206429A (en) * 2010-07-08 2012-02-16 Merck Serono Sa Substituted oxadiazole derivatives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011518154A (ja) * 2008-04-16 2011-06-23 アリーナ ファーマシューティカルズ， インコーポレイテッド （ｒ）−１−｛２−［４’−（３−メトキシプロパン−１−スルホニル）−ビフェニル−４−イル］−エチル｝−２−メチル−ピロリジンの合成に有用なプロセス
KR20140104376A (ko) * 2013-02-20 2014-08-28 주식회사 엘지생명과학 스핑고신-1-인산 수용체 효능제, 그의 제조방법 및 그를 활성성분으로서 함유하는 약제학적 조성물
KR20170034902A (ko) * 2014-07-16 2017-03-29 라이프에스씨아이 파마슈티컬스, 인크. 치료적 억제 화합물
KR20200035109A (ko) * 2017-09-07 2020-04-01 지앙수 루이케 메디컬 사이언스 앤드 테크놀로지 컴퍼니 리미티드 치환된 페닐아세트산 유도체의 제조방법
KR20200145735A (ko) * 2019-06-19 2020-12-30 주식회사 엘지화학 인돌 또는 인다졸 화합물의 제조방법
KR20220048950A (ko) * 2020-10-13 2022-04-20 주식회사 엘지화학 스핑고신-1-인산 수용체 효능제 합성을 위한 중간체의 제조 방법

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KR102658761B1 (ko) 2024-04-19
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