WO2022220608A1 - Method for preparing intermediate for synthesis of sphingosine-1-phosphate receptor agonist - Google Patents

Method for preparing intermediate for synthesis of sphingosine-1-phosphate receptor agonist Download PDF

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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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PCT/KR2022/005396
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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/en
Publication of WO2022220608A1 publication Critical patent/WO2022220608A1/en

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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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Abstract

The present invention relates to a novel method for preparing a compound of chemical formula 2 set forth in the present specification, which can be effectively used for the synthesis of a sphingosine-1-phosphate receptor agonist.

Description

스핑고신-1-인산 수용체 효능제 합성을 위한 중간체의 제조방법Preparation of intermediates for the synthesis of sphingosine-1-phosphate receptor agonists
관련 출원과의 상호 인용Cross-Citation with Related Applications
본 출원은 2021년 04월 14일자 한국특허출원 제10-2021-0048764호에 기초한 우선권의 이익을 주장하며, 해당 한국특허출원이 문헌에 개시된 모든 내용은 본 명세서의 일부로서 포함된다.This application claims the benefit of priority based on Korean Patent Application No. 10-2021-0048764 dated April 14, 2021, and all contents disclosed in the Korean patent application are incorporated as a part of this specification.
기술분야technical field
본 발명은 스핑고신-1-인산 수용체 효능제의 합성을 위한 주요 중간체의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of key intermediates for the synthesis of sphingosine-1-phosphate receptor agonists.
스핑고신-1-인산(sphingosine-1-phosphate, S1P)는 세포 내 세라미드 경로(intracellular ceramide pathway)를 통해서 생성되며, 이러한 합성 경로의 출발물질인 세라미드는 두 가지 생성 경로, 즉 de novo 생합성 경로와 세포막 구성물질인 스핑고미엘린(sphingomyelin)의 분해(degradation)을 통해서 세포 내에 생성된다. 각 조직에서의 S1P level은 두 개의 생합성 스핑고신 키나제(sphingosine kinases; SphKs)와 두 개의 생분해 S1P 포스파타제(S1P lyase 및 lysophospholipid phosphatases)에 의해 조절되는데, 스핑고신이 스핑고신 키나제에 의해 인산화(phosphorylation)되면서 생성되는 물질인 S1P는 세포의 증식(proliferation), 세포골격 조직 및 이동(cytoskeletal organization and migration), 부착-(adherence-) 및 tight junction assembly, 그리고 형태발생 (morphogenesis)과 같은 다양한 세포반응을 매개하는 것으로 알려져 있다. 이들은 혈장에서 알부민을 비롯한다른 혈장 단백질에 결합된 형태로 높은 농도(100~1000 nM)로 존재하는 반면 조직에서는 낮은 농도로 존재하고 있다.Sphingosine-1-phosphate (S1P) 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). 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.
S1P는 G-단백질 커플링된 수용체인 S1P 수용체에 결합하여 다양한 생물학적 기능을 나타내는데, 현재까지 알려진 S1P 수용체의 서브-타입은 S1P1~S1P5의 5 가지로 이들은 각각 내피 분화 유전자 수용체(endothelial differentiation gene (EDG) receptor) 1, 5, 3, 6 및 8로 명명된다. 이러한 S1P 수용체들은 백혈구 재순환(leukocyte recirculation), 신경 세포 증식(neural cell proliferation), 형태 변형(morphological changes), 이동(migration), 내피 기능(endothelial function), 맥관긴장조절(vasoregulation) 및 심장혈관계 발생(cardiovascular development)과 같은 다양한 생물학적 기능에 관여하는 것으로 알려져 있다.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.
최근의 많은 연구에서는, 이들 수용체를 통한 S1P 신호전달과정이 염증반응과 수복(repair) 과정을 포함한 다발성 경화증과 관계된 일련의 반응에 있어 중요한 역할을 하는 것으로 밝히고 있으며, 실제로 비선택적인 S1P1 효능제가 최근 다발성 경화증 치료제로 승인 받았다. S1P 수용체들은 다발성 경화증 유발과 관계된 많은 세포에서 동일하게 널리 발현되는데, 특히 S1P1 수용체는 면역체계에 있어 매우 중요한 역할을 하고 있다. S1P1 수용체는 T세포 및 B세포와 같은 림프구(lymphocyte) 표면에서 주로 발현되며, S1P와 반응하여 림프구의 재순환에 관여하게 된다. 정상 상태에서 S1P 농도는 림프양 조직(lymphoid tissue) 보다 체액에서 더 높기 때문에 림프구는 S1P 농도차에 따라 림프양 조직으로부터 떠나 원심성 림프(efferent lymph)를 따라 순환하게 된다. 그러나, S1P1 효능제에 의해서 림프구의 S1P1 수용체가 하향-조절(down-regulation)되면 림프양 조직으로부터 림프구의 이탈(egress)이 일어나지 않게 되고, 결국 CNS로 염증과 조직 손상을 일으키는 자가공격성(autoaggressive) 림프구의 침윤이 감소하게 되어 다발성 경화증에 치료 효과가 나타나게 된다. 경구용 다발성 경화증 치료제로 허가 받은 비선택적인 S1P1 효능제인 핀골리모드(fingolimod)의 경우, S1P1 수용체에 결합하여 활성화되면 역설적으로 수용체가 림프구 표면으로부터 내재화(internalization) 또는 분해(degradation)되어 기능적인 S1P1 길항(antagonism)으로 작용하게 된다.A number of recent studies have revealed that S1P signaling through these receptors plays an important role in a series of responses related to multiple sclerosis, including inflammatory responses and repair processes. In fact, 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. In particular, 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. In a normal state, 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. However, when 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. In the case of 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.
이러한 S1P 수용체 효능제와 관련하여, 대한민국 공개특허공보 제10-2014-0104376호에서는 S1P 수용체 효능제로서 효과적인 하기 화학식 1의 신규 화합물을 개시하고 있다.In relation to these S1P receptor agonists, Korean Patent Application Laid-Open No. 10-2014-0104376 discloses a novel compound of Formula 1 effective as an S1P receptor agonist.
[화학식 1][Formula 1]
Figure PCTKR2022005396-appb-I000001
Figure PCTKR2022005396-appb-I000001
상기 화학식 1에서,In Formula 1,
X는 C 또는 N 이고,X is C or N;
R1은 H 또는 치환될 수 있는 알킬이고,R1 is H or optionally substituted alkyl,
R2는 H, 치환될 수 있는 알킬, 할로겐, CN, CF3 또는 COCF3이고, R2 is H, optionally substituted alkyl, halogen, CN, CF 3 or COCF 3 ,
W는 C, N, C-알콕시, C-할로겐 또는 C-CN 이고,W is C, N, C-alkoxy, C-halogen or C-CN,
Q는 CH2O 또는
Figure PCTKR2022005396-appb-I000002
이고,Q is CH 2 O or
Figure PCTKR2022005396-appb-I000002
ego,
S는 하기의 잔기로부터 선택된다:S is selected from the following residues:
Figure PCTKR2022005396-appb-I000003
Figure PCTKR2022005396-appb-I000003
Figure PCTKR2022005396-appb-I000004
Figure PCTKR2022005396-appb-I000004
Figure PCTKR2022005396-appb-I000005
Figure PCTKR2022005396-appb-I000005
Figure PCTKR2022005396-appb-I000006
Figure PCTKR2022005396-appb-I000006
Figure PCTKR2022005396-appb-I000007
Figure PCTKR2022005396-appb-I000007
Figure PCTKR2022005396-appb-I000008
Figure PCTKR2022005396-appb-I000008
Figure PCTKR2022005396-appb-I000009
Figure PCTKR2022005396-appb-I000009
Figure PCTKR2022005396-appb-I000010
Figure PCTKR2022005396-appb-I000010
상기 구조식에서in the above structure
m, n은 0, 1, 2 또는 3이고,m, n are 0, 1, 2 or 3,
R3 내지 R10은 각각 H, 알킬, 할로겐, 할로게노 알킬 또는 알콕시 알킬이고,R3 to R10 are each H, alkyl, halogen, halogenoalkyl or alkoxyalkyl,
R11은 H,
Figure PCTKR2022005396-appb-I000011
이고,R11 is H;
Figure PCTKR2022005396-appb-I000011
ego,
R12는 OH, NH2,
Figure PCTKR2022005396-appb-I000012
Figure PCTKR2022005396-appb-I000013
또는
Figure PCTKR2022005396-appb-I000014
이다.R12 is OH, NH 2 ,
Figure PCTKR2022005396-appb-I000012
Figure PCTKR2022005396-appb-I000013
or
Figure PCTKR2022005396-appb-I000014
to be.
상기 문헌의 구체적인 예시에 있어서, 다음의 반응식 1로 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]피페리딘-4-카르복실산을 제조하는 것을 개시하고 있다(반응식 1에서 "SG35"는 "1-클로로-6-하이드록시-3,4-디하이드로-나프탈렌-2-카르발데히드"를 일컫는다).In a specific example of the above document, 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro- Disclosed is the preparation of naphthalen-2-ylmethyl]piperidine-4-carboxylic acid ("SG35" in Scheme 1 is "1-chloro-6-hydroxy-3,4-dihydro-naphthalene- 2-carbaldehyde").
[반응식 1][Scheme 1]
Figure PCTKR2022005396-appb-I000015
Figure PCTKR2022005396-appb-I000015
상기 반응식 1에서 1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-카르발데히드를 제조하는 단계를 상세하게 살펴보자면 다음과 같다.preparing 1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carbaldehyde in Scheme 1 Let's take a look in detail:
(1-1) (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올의 합성(1-1) Synthesis of (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol
1H-인다졸-5-카르복실산 메틸에스터를 디메틸포름아미드에 녹이고, 0℃에서 아이소프로필아이오다이드와 소듐 하이드라이드를 천천히 적가한 후에 50℃에서 8시간 동안 교반하였다. 1N 염산용액을 넣고 에틸아세테이트로 추출하였다. 브라인(brine)으로 세척하고 무수 마그네슘 설페이트로 건조한 다음 여과한 여액을 감압 증류하였다. 칼럼 크로마토그래피로 분리하여 1-아이소프로필-1H-인다졸-5-카르복실산 메틸에스터를 얻었다.1H-Indazole-5-carboxylic acid methyl ester was dissolved in dimethylformamide, and isopropyl iodide and sodium hydride were slowly added dropwise at 0°C, followed by stirring at 50°C for 8 hours. A 1N hydrochloric acid solution was added, followed by extraction with ethyl acetate. After washing with brine and drying over anhydrous magnesium sulfate, the filtered filtrate was distilled under reduced pressure. Separation by column chromatography gave 1-isopropyl-1H-indazole-5-carboxylic acid methyl ester.
상기에서 얻어진 1-아이소프로필-1H-인다졸-5-카르복실산 메틸에스터를 디메틸폴름아미드에 녹이고, N-클로로숙신이미드(NCS)를 적가한 후, 실온에서 18시간 동안 교반하였다. 물을 넣고 에틸아세테이트로 추출하였다. 브라인으로 세척하고 무수 마그네슘설페이트로 건조한 다음 여과한 여액을 감압 증류하였다. 잔류물을 칼럼 크로마토그래피로 분리하여 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스터를 얻었다.The 1-isopropyl-1H-indazole-5-carboxylic acid methyl ester obtained above was dissolved in dimethylformamide, and N-chlorosuccinimide (NCS) was added dropwise, followed by stirring at room temperature for 18 hours. Water was added and extraction was performed with ethyl acetate. After washing with brine, drying over anhydrous magnesium sulfate, the filtered filtrate was distilled under reduced pressure. The residue was separated by column chromatography to give 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester.
상기에서 얻어진 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스터를 테트라하이드로퓨란에 녹인 후, 리튬알루미늄보로하이드라이드를 적가하였다. 실온에서 1시간 동안 교반한 후 물과 6N 수산화나트륨 수용액과 물을 차례로 넣었다. 셀라이트를 적가하고 여과한 여액을 감압 증류하였다. 잔류물을 칼럼크로마토그래피로 분리하여 (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올을 얻었다.After the above-obtained 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester was dissolved in tetrahydrofuran, lithium aluminum borohydride was added dropwise. After stirring at room temperature for 1 hour, water, 6N aqueous sodium hydroxide solution and water were sequentially added. Celite was added dropwise, and the filtered filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol.
(1-2) 1-클로로-6-하이드록시-3,4-디하이드로-나프탈렌-2-카르발데히드의 합성(1-2) Synthesis of 1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carbaldehyde
먼저, 6-메톡시-3,4-디하이드로나프탈렌-1(2H)-온을 톨루엔에 용해한 용액에 N,N-디메틸포름아미드(DMF) 및 염화포스포릴(phosphorous oxychloride, POCl3)를 0℃에서 적가한 다음 70℃에서 6시간 동안 교반하였다. 이 반응 혼합물을 얼음에 부은 다음 에틸 아세테이트로 추출하였다. 유기층을 브라인으로 세척한 후 건조 및 농축하고 나서, 얻어진 잔기를 실리카겔 칼럼 크로마토그래피(헥산:에틸 아세테이트=20:1 내지 10:1)로 정제하여 1-클로로-6-메톡시-3,4-디하이드로-2-나프탈렌카르발데히드를 얻었다.First, in a solution of 6-methoxy-3,4-dihydronaphthalen-1(2H)-one in toluene, N,N-dimethylformamide (DMF) and phosphoryl chloride (phosphorous oxychloride, POCl 3 ) were added to 0 It was added dropwise at ℃ and stirred at 70 ℃ for 6 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 to 10:1) to 1-chloro-6-methoxy-3,4- Dihydro-2-naphthalenecarbaldehyde was obtained.
다음으로 1-클로로-6-메톡시-3,4-디하이드로-2-나프탈렌카르발데히드를 디클로로메탄에 용해한 용액에 알루미늄 클로라이드(AlCl3)를 0℃에서 첨가한 다음 50℃에서 6시간 동안 교반하였다. 이 반응 혼합물을 얼음에 부은 다음 에틸 아세테이트로 추출하였다. 유기층을 건조 및 농축하고 나서, 얻어진 잔기를 실리카겔 칼럼 크로마토그래피(헥산:테트라하이드로퓨란=5:1 내지 3:1)로 정제하여 1-클로로-6-하이드록시-3,4-디하이드로-2-나프탈렌카르발데히드를 얻었다.Next, aluminum chloride (AlCl 3 ) was added to a solution of 1-chloro-6-methoxy-3,4-dihydro-2-naphthalenecarbaldehyde in dichloromethane at 0° C. and then at 50° C. for 6 hours. stirred. The reaction mixture was poured into ice and extracted with ethyl acetate. After drying and concentration of the organic layer, the obtained residue was purified by silica gel column chromatography (hexane:tetrahydrofuran=5:1 to 3:1) to 1-chloro-6-hydroxy-3,4-dihydro-2 -Naphthalenecarbaldehyde was obtained.
(1-3) 1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-카르발데히드의 합성(1-3) Synthesis of 1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carbaldehyde
상기에서 얻은 (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올과 1-클로로-6-하이드록시-3,4-디하이드로-2-나프탈렌카르발데히드를 톨루엔에 녹인 후, 트라이부틸포스핀(PBu3)과 1,1'-(아조디카르보닐)디피페리딘(ADD)를 적가하였다. 실온에서 18시간 동안 교반한 후 과량의 헥산을 넣어주었다. 여과 후 감압 증류하고 잔류물을 칼럼 크로마토그래피로 정제하여 1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-카르발데히드를 얻었다.(3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol obtained above and 1-chloro-6-hydroxy-3,4-dihydro-2-naphthalenecarbaldehyde were dissolved in toluene. After dissolving, tributylphosphine (PBu 3 ) and 1,1'-(azodicarbonyl)dipiperidine (ADD) were added dropwise. After stirring at room temperature for 18 hours, an excess of hexane was added. After filtration, distillation was performed under reduced pressure, and the residue was purified by column chromatography to obtain 1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene- 2-carbaldehyde was obtained.
그러나 상기 반응은 임상 API를 생산하는데 있어서 다음과 같은 문제가 있을 수 있다.However, the reaction may have the following problems in producing a clinical API.
먼저, 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스터를 합성하는 과정에서는 N2 이성질체의 생성 비율에 따른 문제가 있을 수 있고, (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올의 합성에 사용되는 LAH(Lithium aluminium hydride)는 대규모 합성(large scale synthesis)에 사용하기에는 안정성 측면에서 매우 제한적이며, 수분에 쉽게 분해되는 단점을 가지고 있다.First, in the process of synthesizing 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester, there may be a problem depending on the production rate of the N2 isomer, (3-chloro-1-isopropyl Lithium aluminum hydride (LAH) used for the synthesis of -1H-indazol-5-yl)-methanol has very limited stability in terms of stability and is easily decomposed in water. .
또한, 1-클로로-6-메톡시-3,4-디하이드로-2-나프탈렌카르발데히드를 얻기 위한 빌스마이어-핵 반응(Vilsmeier-Haack reaction) 시 70℃의 고온에서 반응함에 따라 발열 문제가 발생할 수 있다. 그리고, 1-클로로-6-하이드록시-3,4-디하이드로-2-나프탈렌카르발데히드를 얻기 위한 반응에 있어서, AlCl3 사용에 따른 반응기 오염이나 위험 시약의 사용에 따른 안정성 문제가 있을 수 있으며, AlCl3 사용 시 반응 멈춤 또는 부반응 진행으로 batch fail의 발생에 따른 안정성 문제가 있을 뿐 아니라 총 수율도 70%로 수율 개선의 필요성이 있다.In addition, during the Vilsmeier-Haack reaction to obtain 1-chloro-6-methoxy-3,4-dihydro-2-naphthalenecarbaldehyde, the exothermic problem arises as it reacts at a high temperature of 70 ° C. can occur And, in the reaction to obtain 1-chloro-6-hydroxy-3,4-dihydro-2-naphthalenecarbaldehyde, there may be stability problems due to reactor contamination due to the use of AlCl 3 or the use of hazardous reagents. In addition, there is a stability problem due to the occurrence of batch fail due to reaction stop or side reaction progress when AlCl 3 is used, and the total yield is 70%, so there is a need to improve the yield.
또한, (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올과 1-클로로-6-하이드록시-3,4-디하이드로-나프탈렌-2-카르발데히드의 커플링 반응에 이용되는 1,1'-(아조디카르보닐)디피페리딘(ADD)의 경우 낮은 수율 문제와 비용 측면에서 바람직하지 않다.In addition, coupling of (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol with 1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carbaldehyde In the case of 1,1'-(azodicarbonyl)dipiperidine (ADD) used in the reaction, it is not preferable in terms of low yield and cost.
이에 따라 본 발명의 발명자들은 상기 1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-카르발데히드와 같은 중간체 화합물을 보다 단순한 공정을 통해 높은 수율로 대량 생산하기 위해 하기 반응식 2과 같은 새로운 합성법을 고안한 바 있다.Accordingly, the inventors of the present invention prepared 1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carbaldehyde and In order to mass-produce the same intermediate compound in high yield through a simpler process, a new synthesis method as shown in Scheme 2 below has been devised.
[반응식 2][Scheme 2]
Figure PCTKR2022005396-appb-I000016
Figure PCTKR2022005396-appb-I000016
상기 반응식 2에서 1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-6-일메톡시)-3,4-디하이드로-나프탈렌-2-카르발데히드를 제조하는 단계를 상세하게 살펴보자면 다음과 같다(반응식 2에서 "SG26"은 "6-하이드록시-3,4-디하이드로-2H-나프탈렌-1-온"을 일컫는다).preparing 1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-6-ylmethoxy)-3,4-dihydro-naphthalene-2-carbaldehyde in Scheme 2 In detail, it is as follows (in Scheme 2, "SG26" refers to "6-hydroxy-3,4-dihydro-2H-naphthalen-1-one").
(2-1) 5-브로모메틸-3-클로로-1-아이소프로필-1H-인다졸의 합성(2-1) Synthesis of 5-bromomethyl-3-chloro-1-isopropyl-1H-indazole
반응기에 디클로로메탄(DCM) 및 메틸 tert-부틸 에테르(MTBE) 및 (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올을 투입하고 내부 온도를 0℃까지 냉각시켰다. 반응물에 PBr3를 70분 동안 천천히 적가한 후에 80분 동안 반응을 진행시켰다. HPLC를 이용하여 이온쌍 크로마토그래피(ion-pair chromatography, IPC)를 진행하고 반응이 완결되어(3% > (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올), 수산화나트륨을 120분 동안 천천히 투입하여 반응을 종결시켰다. 반응 혼합물에 DCM을 투입하고 30분 동안 교반한 후, 층분리하여 수층을 제거하고 유기층을 물로 세척 후 유기층을 감압증류하여 5-브로모메틸-3-클로로-1-아이소프로필-1H-인다졸을 얻었다.Dichloromethane (DCM), methyl tert-butyl ether (MTBE) and (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol were added to the reactor, and the internal temperature was cooled to 0°C. After slowly adding PBr 3 dropwise to the reaction material for 70 minutes, the reaction was allowed to proceed for 80 minutes. Ion-pair chromatography (IPC) was performed using HPLC and the reaction was completed (3% > (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol), The reaction was terminated by slowly adding sodium hydroxide for 120 minutes. After DCM was added to the reaction mixture and stirred for 30 minutes, the layers were separated to remove the aqueous layer, the organic layer was washed with water, and the organic layer was distilled under reduced pressure to 5-bromomethyl-3-chloro-1-isopropyl-1H-indazole. got
(2-2) 6-하이드록시-3,4-디하이드로-2H-나프탈렌-1-온의 합성(2-2) Synthesis of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one
반응기에 물에 녹인 HBr 및 6-메톡시-3,4-디하이드로-2H-나프탈렌-1-온을 투입하고 외부온도 120℃에서 52시간 환류반응시켰다. HPLC를 이용하여 IPC를 진행하고 반응이 완결되어(3% > 6-메톡시-3,4-디하이드로-2H-나프탈렌-1-온), 내부온도를 10℃까지 냉각시킨 후 생성된 고체를 여과하였다. 물로 세척 후 질소로 건조하여 6-하이드록시-3,4-디하이드로-2H-나프탈렌-1-온(SG26)을 얻었다.HBr and 6-methoxy-3,4-dihydro-2H-naphthalen-1-one dissolved in water were added to the reactor and refluxed at an external temperature of 120° C. for 52 hours. After IPC was carried out using HPLC and the reaction was completed (3% > 6-methoxy-3,4-dihydro-2H-naphthalen-1-one), the resulting solid was cooled to 10° C. filtered. After washing with water and drying with nitrogen, 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (SG26) was obtained.
(2-3) 6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-2H-나프탈렌-1-온의 합성(2-3) Synthesis of 6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-2H-naphthalen-1-one
반응기에 5-브로모메틸-3-클로로-1-아이소프로필-1H-인다졸, 6-하이드록시-3,4-디하이드로-2H-나프탈렌-1-온, K2CO3 및 DMF를 투입하고 내부온도 25℃에서 3시간 반응시켰다. HPLC를 이용하여 IPC를 진행하고, 6-하이드록시-3,4-디하이드로-2H-나프탈렌-1-온이 5% 잔류하여 5-브로모메틸-3-클로로-1-아이소프로필-1H-인다졸을 추가로 투입하여 반응을 완결(1% > 6-하이드록시-3,4-디하이드로-2H-나프탈렌-1-온)시켰다. 반응기에 물을 투입하고 내부온도를 0℃로 냉각시킨 뒤 생성된 고체를 여과하였다. 여과된 고체를 물과 MTBE 각각에 의해 순차적으로 세척한 후 질소로 건조하여 6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-2H-나프탈렌-1-온을 얻었다.5-Bromomethyl-3-chloro-1-isopropyl-1H-indazole, 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one, K 2 CO 3 and DMF were added to the reactor and reacted for 3 hours at an internal temperature of 25°C. IPC was performed using HPLC, and 5% of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one remained, so 5-bromomethyl-3-chloro-1-isopropyl-1H- Additional indazole was added to complete the reaction (1% > 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one). After adding water to the reactor and cooling the internal temperature to 0°C, the resulting solid was filtered. 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.
(2-4) 1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-6-일메톡시)-3,4-디하이드로-나프탈렌-2-카르발데히드의 합성(2-4) Synthesis of 1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-6-ylmethoxy)-3,4-dihydro-naphthalene-2-carbaldehyde
반응기에 염화포스포릴(POCl3)를 투입하고 내부온도를 0℃로 냉각시켰다. DMF을 천천히 적가하고, 내부온도 50℃에서 2시간 동안 교반한 후 6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-2H-나프탈렌-1-온을 투입하고 내부온도 50℃에서 3시간 동안 반응시켰다. 반응 중 과량의 HCl 가스가 발생하므로 NaOH 트랩(trap)을 설치하여 중화될 수 있도록 통풍관(vent line)을 설치하였다. HPLC를 이용하여 IPC를 진행하고 반응이 완결되어 내부온도를 0℃로 냉각한 뒤 다른 반응기에 차가운 물, 헥산(Hex) 및 MTBE를 투입하고 위 반응 혼합물을 90분 동안 천천히 적가하여 결정을 생성시켰다. 생성된 고체를 여과하고, 물과 MTBE/HEX 혼합용매 각각에 의해 순차적으로 세척한 후 건조하여 1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-6-일메톡시)-3,4-디하이드로-나프탈렌-2-카르발데히드를 얻었다.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. After IPC was carried out using HPLC and the reaction was completed, the internal temperature was cooled to 0 °C, cold water, hexane (Hex) and MTBE were added to another reactor, and the reaction mixture was slowly added dropwise for 90 minutes to form crystals. . The resulting solid was filtered, washed sequentially with water and a mixed solvent of MTBE/HEX, respectively, and dried to 1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-6-ylmethoxy) -3,4-dihydro-naphthalene-2-carbaldehyde was obtained.
위와 같은 반응에 의한다면 N2 이성질체의 생성 비율을 개선하면서, 빌스마이어-핵 반응에 따른 발열 문제를 해소할 수 있을 뿐만 아니라, ADD를 사용하지 않고서도 커플링 반응을 수행할 수 있는 바, 스핑고신-1-인산 수용체 효능제 합성의 핵심 중간체를 화합물의 안정성 및 제조 조건의 안정성을 확보한 상태에서 보다 단순한 공정을 통해 대량 생산할 수 있을 것으로 기대되고 있다.According to the above reaction, it is possible to not only solve the exothermic problem caused by the Vilsmeier-nuclear reaction while improving the production rate of the N2 isomer, but also perform the coupling reaction without using ADD, sphingosine. It is expected that the key intermediate for synthesizing the -1-phosphate receptor agonist can be mass-produced through a simpler process while ensuring the stability of the compound and the stability of the manufacturing conditions.
이에 본 발명의 목적은 우수한 스핑고신-1-인산 수용체 효능제의 새로운 합성법에 있어서 핵심 중간체인 화학식 2의 화합물을 높은 수율로 생산하기 위한 적합한 방법을 제공하는 것에 있다. Accordingly, 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.
[화학식 2][Formula 2]
Figure PCTKR2022005396-appb-I000017
Figure PCTKR2022005396-appb-I000017
상기 화학식 2에 있어서,In Formula 2,
R1은 수소, 또는 치환 또는 비치환 알킬이고,R1 is hydrogen or substituted or unsubstituted alkyl;
R2는 수소, 치환 또는 비치환 알킬, 할로겐, CN, CF3 또는 COCF3이고,R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF 3 or COCF 3 ;
X는 C 또는 N이고,X is C or N;
L은 이탈기(leaving group)이다.L is a leaving group.
위와 같은 목적을 달성하기 위하여, In order to achieve the above purpose,
본 발명에 따른 일 측면은 에테르계 단일 용매 하에서 화학식 3의 화합물의 알코올기를 이탈기로 치환하는 단계를 포함하는 하기 화학식 2의 중간체 화합물의 제조방법을 제공한다. 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.
[화학식 2][Formula 2]
Figure PCTKR2022005396-appb-I000018
Figure PCTKR2022005396-appb-I000018
[화학식 3][Formula 3]
Figure PCTKR2022005396-appb-I000019
Figure PCTKR2022005396-appb-I000019
상기 화학식 2 및 화학식 3에 있어서,In Formula 2 and Formula 3,
R1은 수소, 또는 치환 또는 비치환 알킬이고,R1 is hydrogen or substituted or unsubstituted alkyl;
R2는 수소, 치환 또는 비치환 알킬, 할로겐, CN, CF3 또는 COCF3이고,R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF 3 or COCF 3 ;
X는 C 또는 N이고,X is C or N;
L은 이탈기(leaving group)이다.L is a leaving group.
상기 '알킬'이 치환된 알킬인 경우 치환기는 하나 이상일 수 있으며, 상기 치환기는 각각 독립적으로 할로겐, 시아노, 하이드록시, 알킬옥시, 옥소, 비치환 설포닐 및 알킬로 치환된 설포닐로 이루어진 군으로부터 선택되는 것일 수 있다.When the 'alkyl' is a substituted alkyl, 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
본 발명의 일 구체예에 따르면, 상기 화학식의 R1은 수소, 또는 C1-C6의 치환 또는 비치환 알킬이고, R2는 수소, C1-C6의 치환 또는 비치환 알킬, 할로겐, CN, CF3 또는 COCF3일 수 있다.According to one embodiment of the present invention, 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 .
본 발명의 다른 구체예에 따르면, 상기 R1은 C1-C4의 치환 또는 비치환 알킬이고, R2는 할로겐일(F, Cl, Br 또는 I)일 수 있다. According to another embodiment of the present invention, R1 may be C 1 -C 4 substituted or unsubstituted alkyl, and R2 may be halogenyl (F, Cl, Br or I).
본 발명의 일 구체예에 따르면, 상기 이탈기(L)는 화학식 2의 화합물이 알코올계 화합물과 치환 반응 시 화학식 2의 화합물에 치환 위치를 제공하는 반응기로서, 이에 제한되는 것은 아니나 예를 들어 염소(Cl), 브로민(Br), 아이오딘(I), 메탄설포네이트(Oms), p-톨루엔설포네이트(OTs) 및 트리플루오로메탄설포네이트(OTf)로부터 선택되는 것일 수 있다.According to one embodiment of the present invention, 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.
본 발명의 다른 구체예에 따르면, 상기 L은 Br일 수 있다.According to another embodiment of the present invention, L may be Br.
본 발명은 화학식 3의 화합물의 말단 알코올기를 이탈기로 치환함으로써 스핑고신-1-인산 수용체 효능제의 합성에 있어서 핵심 중간체인 화학식 2의 화합물을 제공하는데, 구체적으로 상기 '알코올기를 이탈기로 치환하는 단계'(이하, '이탈기 치환 단계'라 함)는 에테르계 단일 용매 하에서 수행함으로써 N2 이성질체의 생성 비율을 현저히 낮추는 것을 하나의 기술적 특징으로 한다.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.
본 발명에 있어서, 상기 '단일 용매'는 이탈기 치환 반응을 위한 반응기에 하나의 종류의 용매만이 포함되는 것을 나타낸다. 이때 이탈기 치환 반응을 위한 반응기에 반응 생성물의 수율에 실질적으로 영향을 미치지 않는 수준의 미량의 이종의 용매가 포함되는 것 또한 단일 용매로부터 배제되는 것은 아니다. 예컨대, 이탈기 치환 반응을 위한 총 용매의 부피를 기준으로 5 부피% 이하, 4 부피% 이하, 3 부피% 이하, 2 부피 % 이하, 1 부피 % 이하, 0.5 부피% 이하, 또는 0 부피%(즉, 전혀 포함되지 않음)의 함량으로 이종의 용매가 포함되는 것도 단일 용매의 사용으로 볼 수 있다.In the present invention, the 'single solvent' indicates that only one type of solvent is included in the reactor for the leaving group substitution reaction. In this case, 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. For example, 5% by volume or less, 4% by volume or less, 3% by volume or less, 2% by volume or less, 1% by volume or less, 0.5% by volume or less, or 0% by volume based on the volume of the total solvent for the leaving group substitution reaction ( That is, it is not included at all), and the inclusion of a heterogeneous solvent in the content can also be viewed as the use of a single solvent.
상기 에테르계 용매는 이에 제한되는 것은 아니나, 예를 들어 디에틸에테르, 디프로필에테르, 디부틸에테르, 디이소아밀에테르, 에틸메틸에테르, 메틸프로필에테르, 메틸부틸에테르, 에틸프로필에테르 등의 디알킬에테르계 용매; 디페닐에테르, 아니솔 등의 아릴알릴에테르계 용매; 또는 테트라히드로푸란, 테트라히드로피란 등의 환형 에테르계 용매 등을 들 수 있다.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; arylallyl ether solvents such as diphenyl ether and anisole; Or cyclic ether solvents, such as tetrahydrofuran and tetrahydropyran, etc. are mentioned.
본 발명에 따른 일 구체예에서, 상기 에테르계 단일 용매는 메틸 터셔리부틸 에테르(methyl tert-butyl ether, MTBE)일 수 있다.In one embodiment according to the present invention, the ether-based single solvent may be methyl tert-butyl ether (MTBE).
본 발명에 따른 다른 구체예에 있어서, 상기 화학식 3의 화합물과 MTBE를 혼합하고 0℃로 냉각한 후, PBr3와 반응시켜 화학식 2의 화합물을 수득하는 것일 수 있다.In another embodiment according to the present invention, 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.
본 발명에 따른 또 다른 구체예에 있어서, 상기 화학식 3의 화합물과 MTBE를 혼합하고 0℃로 냉각한 후 PBr3와 반응시킨 후 반응이 종결되면 물로 세척 및 여과하여 화학식 2의 화합물을 수득하는 것일 수 있다.In another embodiment according to the present invention, 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. can
본 발명에 따른 다른 측면에서, 상기 화학식 3의 화합물은 다음의 단계를 포함하는 방법에 따라 제조된다:In another aspect according to the present invention, the compound of Formula 3 is prepared according to a method comprising the steps of:
1) 하기 화학식 4의 화합물에 R1 및 R2 치환기를 도입하고 알코올 용매를 포함하는 결정화 용매에 의해 결정화하여 화학식 5의 화합물을 수득하는 단계, 및1) introducing R1 and R2 substituents to the compound of Formula 4 below and crystallizing with a crystallization solvent including an alcohol solvent to obtain a compound of Formula 5, and
2) 상기 화학식 5의 화합물을 환원제와 반응시켜 화학식 3의 화합물을 수득하는 단계:2) reacting the compound of Formula 5 with a reducing agent to obtain a compound of Formula 3:
[화학식 4][Formula 4]
Figure PCTKR2022005396-appb-I000020
Figure PCTKR2022005396-appb-I000020
[화학식 5][Formula 5]
Figure PCTKR2022005396-appb-I000021
Figure PCTKR2022005396-appb-I000021
상기 화학식 4 및 화학식 5에 있어서,In Formulas 4 and 5,
상기 R1, R2 및 X는 상기 화학식 2 또는 화학식 3에서 정의되어 있는 바와 같으며, Wherein R1, R2 and X are as defined in Formula 2 or Formula 3,
상기 R3는 C1-C6의 치환 또는 비치환된 알킬이다.R3 is C 1 -C 6 substituted or unsubstituted alkyl.
본 발명의 일 구체예에 따르면, 상기 R3는 C1-C4의 치환 또는 비치환 알킬일 수 있다. According to one embodiment of the present invention, R3 may be a C 1 -C 4 substituted or unsubstituted alkyl.
본 발명의 다른 구체예에 따르면, 상기 R3는 메틸기일 수 있다.According to another embodiment of the present invention, R3 may be a methyl group.
상기 1) 단계에서는 화학식 4의 화합물에 R1 및 R2 치환기를 도입하고 알코올 용매를 포함하는 결정화 용매에 의해 결정화하여 화학식 5의 화합물을 제조한다. In 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.
상기 결정화를 위한 알코올 용매는 이에 제한되는 것은 아니나, 예를 들어 메탄올, 에탄올, 이소프로필알코올 및 부탄올 중에서 선택되는 1종 이상의 용매일 수 있다.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.
본 발명에 따른 일 구체예에 있어서, 상기 결정화를 위한 용매는 알코올 용매 및 물의 혼합 용매일 수 있다. 상기 결정화 용매로서 알코올 용매와 물의 혼합 용매를 이용함으로써 N2 이성질체 수율을 저감하는 효과가 있을 수 있다.In one embodiment according to the present invention, the solvent for the crystallization may be a mixed solvent of an alcohol solvent and water. By using 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.
본 발명에 따른 다른 구체예에 있어서, 상기 결정화를 위한 혼합 용매는 화학식 5의 수율의 측면에서 알코올 용매 및 물의 부피비가 5:1 내지 1:5, 4:1 내지 1:4, 3:1 내지 1:3, 2:1 내지 1:2, 2:1 내지 1:1 또는 1.5:1 내지 1:1로 사용되는 것일 수 있다.In another embodiment according to the present invention, 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.
본 발명에 따른 일 구체예에 있어서, 상기 결정화를 위한 용매는 에탄올 및 물의 혼합 용매일 수 있다. 구체적으로, 상기 에탄올과 물이 EtOH:H2O의 부피비 2:1 내지 1:2, 2:1 내지 1:1, 1.5:1 내지 1:1, 또는 1:1로 사용되는 것일 수 있다.In one embodiment according to the present invention, the solvent for the crystallization may be a mixed solvent of ethanol and water. Specifically, 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.
본 발명에 따른 다른 구체예에 있어서, 상기 결정화 용매가 알코올 용매와 물의 혼합 용매일 때 결정화 시 알코올 용매 및 물은 각각 순차적으로, 또는 동시에 투입되는 것일 수 있다.In another embodiment according to the present invention, when 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.
본 발명에 따른 또 다른 구체예에 있어서, 상기 치환기가 도입된 반응 생성물에 알코올 용매, 예컨대 EtOH를 투입한 후 0℃ 내지 20℃로 냉각한 후 물을 투입하여 결정화함으로써 화학식 5의 화합물을 수득하는 것일 수 있다.In another embodiment according to the present invention, an alcohol solvent, such as 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
본 발명에 따른 일 구체예에 있어서, 상기 결정화 전에 치환기가 도입된 반응 생성물을 정제한 후 결정화하는 것일 수 있다. 반응 생성물을 정제함으로써 반응에 이용된 미반응 잔류 화합물을 제거함으로써 결정화 수율을 향상시키는 효과를 나타낼 수 있다.In one embodiment according to the present invention, it may be crystallized after purifying the reaction product in which a substituent is introduced before the crystallization. By purifying the reaction product, the crystallization yield can be improved by removing unreacted residual compounds used in the reaction.
상기 정제는 예를 들어 극성 용매를 사용하여 수행할 수 있으며, 상기 극성 용매는 예를 들어 극성 유기 용매, 물, 또는 이들의 혼합 용매가 사용될 수 있다.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.
상기 극성 유기 용매는 이에 제한되는 것은 아니나, 예를 들어 에틸아세테이트, 헥산 및 다이클로로메탄 중에서 선택되는 1종 이상의 용매일 수 있다.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.
본 발명에 따른 다른 구체예에 있어서, 상기 치환기가 도입된 반응 생성물을 에틸아세테이트(EtOAc) 및 물의 혼합 용매에 의해 정제한 후 결정화하여 화학식 5의 화합물을 수득하는 것일 수 있다.In another embodiment according to the present invention, 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.
본 발명에 따른 또 다른 구체예에 있어서, 상기 치환기가 도입된 반응 생성물을 25℃ 내지 35℃로 냉각한 후 2:1 내지 1:2의 부피비의 에틸아세테이트 및 물을 이용하여 수층을 제거하고, 물 이외의 극성 용매를 제거한 후에 결정화하는 것일 수 있다.In another embodiment according to the present invention, after cooling the reaction product in which the substituent is introduced to 25 ° C to 35 ° C, 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.
본 발명에 따른 일 구체예에 있어서, 상기 치환기가 도입된 반응 생성물을 극성 유기 용매와 물의 혼합 용매에 의해 정제한 후 결정화함으로써 치환기가 도입 반응 시 이용된 K2CO3가 반응 생성물의 결정화 시 함께 석출되는 것을 예방 또는 석출량을 감소시켜 결정의 순도를 향상시키는 것일 수 있다.In one embodiment according to the present invention, by crystallizing the reaction product in which the substituent is introduced is purified by a mixed solvent of a polar organic solvent and 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.
본 발명에 있어서, 상기 R1 및 R2의 치환기는 R1 치환 후 R2 치환, R2 치환 후 R1 치환 또는 R1 및 R2가 동시에 치환되는 것일 수 있다. In the present invention, the substituents of 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.
본 발명에 따른 일 구체예에 있어서, 상기 화학식 4의 화합물에 R2가 R1보다 먼저 치환되는 것일 수 있다. 화학식 4의 화합물에 부피가 큰(bulky) R1이 먼저 치환되는 경우 예를 들면 X가 N 인 인다졸의 3번 위치에 부피가 큰 R1이 먼저 치환되면 N2 이성질체의 생성이 억제되고, 수율이 개선될 수 있다.In one embodiment according to the present invention, in the compound of Formula 4, R2 may be substituted before 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
상기 2) 단계에서는 화학식 5의 화합물을 환원제와 반응시켜 화학식 3의 화합물을 수득한다.In step 2), the compound of Formula 5 is reacted with a reducing agent to obtain a compound of Formula 3.
상기 2) 단계에서 사용되는 환원제는 에스테르기를 알코올로 환원할 수 있는 통상의 환원제를 사용할 수 있으며, 예를 들어 소듐 보로하이드라이드(NaBH4), 리튬 보로하이드라이드(LiBH4), 보레인(BH3) 및 디이소뷰틸알루미늄 하이드라이드(DIBAH)로부터 선택되는 하나 이상을 사용할 수 있으나, 이에 제한되는 것은 아니다.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.
본 발명에 따른 일 구체예에 있어서, 상기 화학식 5의 화합물의 환원 반응 시 반응 초기에 환원제와 용매를 함께 투입한 후에, 반응의 진행에 따라 추가적으로 환원제를 더 투입하는 것일 수 있다. 추가적으로 환원제를 더 투입할 때 반응 초기에 함께 투입하였던 용매를 함께 추가하거나, 또는 용매를 추가하지 않고 환원제만을 추가할 수도 있다 In one embodiment according to the present invention, after the reducing agent and the solvent are added together at the beginning of the reaction during the reduction reaction of the compound of Formula 5, the reducing agent may be additionally added according to the progress of the reaction. When additionally adding a reducing agent, 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.
본 발명에 따른 다른 구체예에 있어서, 상기 화학식 5의 화합물의 환원 반응 시 반응 초기에 환원제와 MeOH와 같은 용매를 함께 투입한 후에, 반응이 진행됨에 따라 잔류의 화학식 5의 화합물을 반응시키기 위해 환원제와 메탄올을 추가 투입함으로써 수득되는 화학식 3의 화합물의 수율을 더욱 개선하는 효과를 나타낼 수 있다.In another embodiment according to the present invention, after adding a reducing agent and a solvent such as MeOH together at the beginning of the reaction during the reduction reaction of the compound of Formula 5, as the reaction proceeds, 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.
본 발명에 따른 일 구체예에 있어서, 상기 화학식 5의 화합물의 환원 반응이 종결된 후 반응 생성물을 정제하여 화학식 3의 화합물을 수득하는 것일 수 있다. 이때, 상기 환원 반응의 반응 생성물의 정제에는 디클로로메탄(DCM), 아이소프로필아세테이트 및 에틸아세테이트와 같은 유기 용매, 물, 또는 이들의 혼합 용매가 사용될 수 있다.In one embodiment according to the present invention, after the reduction reaction of the compound of Formula 5 is terminated, the reaction product may be purified to obtain the compound of Formula 3. In this case, 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.
본 발명에 따른 다른 구체예에 있어서, 상기 화학식 5의 화합물의 환원 반응이 종결된 후 DCM 및 물을 투입하여 수층을 제거함으로써 화학식 3의 화합물의 수율을 더욱 개선하는 효과를 나타낼 수 있다.In another embodiment according to the present invention, after the reduction reaction of the compound of Formula 5 is terminated, DCM and water are added to remove the aqueous layer, thereby further improving the yield of the compound of Formula 3 may be exhibited.
본 발명에 따라 제조되는 화합물은 스핑고신-1-인산 수용체 효능제의 합성을 위한 주요 중간체로 이용될 수 있다. 본 발명에 따라 제조되는 화합물은 스핑고신-1-인산 수용체 효능제의 공지된 합성 방법의 주요 중간체로 이용될 수 있으며, 본 출원 이후에 개발되는 새로운 합성 방법의 주요 중간체로도 이용될 수 있는 것이지, 본 발명의 용도가 스핑고신-1-인산 수용체 효능제의 특정한 합성 방법에 한정되는 것은 아니다.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. However, the use of the present invention is not limited to a particular method of synthesis of a sphingosine-1-phosphate receptor agonist.
또한, 본 발명에 따라 제조되는 화합물은 스핑고신-1-인산 수용체 효능제의 합성 이외에 다른 용도로도 사용될 수 있는 것이며, 본 발명의 용도가 스핑고신-1-인산 수용체 효능제의 합성에만 제한되는 것은 아니다.In addition, 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
본 발명의 제조방법을 이용하면 화학식 2의 화합물을 높은 수율로 대량 생산할 수 있는 효과가 있다.The use of the preparation method of the present invention has the effect of mass-producing the compound of Formula 2 in high yield.
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 본 발명이 속한 분야에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples and the like will be described in detail to help the understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art to which the present invention pertains.
실시예 1-1. 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르(3-Chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester)의 합성Example 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)
Figure PCTKR2022005396-appb-I000022
Figure PCTKR2022005396-appb-I000022
1H-인다졸-5-카르복실산 메틸 에스테르(1H-Indazole-5-carboxylic acid methyl ester) (6.2 kg, 35.19 mol), N-클로로숙신이미드(NCS, 5.64 kg, 42.2 mol), 디메틸포름아마이드(DMF, 31.0 ml, 5 fold)를 반응기에 투입 후, 반응 혼합물의 내부 온도를 75℃로 승온하여 1.5 시간 반응하였다. 1H-Indazole-5-carboxylic acid methyl ester (6.2 kg, 35.19 mol), N-chlorosuccinimide (NCS, 5.64 kg, 42.2 mol), dimethylform After the amide (DMF, 31.0 ml, 5 fold) was added to the reactor, the internal temperature of the reaction mixture was raised to 75° C. and reacted for 1.5 hours.
HPLC로 반응 이온쌍 크로마토그래피(IPC)를 진행하고 반응이 완료되어 (1H-인다졸-5-카르복실산 메틸 에스테르:N/D) 외부 온도를 0℃로 설정하여 60분간 냉각을 진행하였다. 반응기 내부온도를 50℃로 유지하면서 K2CO3(10.7 kg, 77.4 mol)와 2-아이오도프로판(iodopropane, 8.98 kg, 52.8 mol)을 첨가하여 60℃에서 120 분간 알킬화(alkylation) 반응을 진행하였다.Reaction ion pair chromatography (IPC) 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. While maintaining the reactor internal temperature at 50 ℃, K 2 CO 3 (10.7 kg, 77.4 mol) and 2-iodopropane (iodopropane, 8.98 kg, 52.8 mol) were added to carry out an alkylation reaction at 60 ℃ for 120 minutes did.
HPLC로 반응 IPC를 진행한 결과 메틸 3-클로로-1H-인다졸-5-카르복실레이트가 19.3%잔류하여 K2CO3 (2.14 kg, 15.5 mol)과 2-iodopropane (1.80 kg, 10.6 mol)를 2회 추가 투입하였다. 메틸 3-클로로-1H-인다졸-5-카르복실레이트가 2.4% 잔류하여 K2CO3 (1.08 kg, 7.75 mol)과 2-iodopropane (0.9 kg, 5.3 mol)을 추가투입한 후 반응을 종결시켰다. (1% > 메틸 3-클로로-1H-인다졸-5-카르복실레이트). As a result of the reaction IPC by HPLC, 19.3% of methyl 3-chloro-1H-indazole-5-carboxylate remained, K 2 CO 3 (2.14 kg, 15.5 mol) and 2-iodopropane (1.80 kg, 10.6 mol) was added twice. After 2.4% of methyl 3-chloro-1H-indazole-5-carboxylate remained, K 2 CO 3 (1.08 kg, 7.75 mol) and 2-iodopropane (0.9 kg, 5.3 mol) were added to terminate the reaction. did it (1%>methyl 3-chloro-1H-indazole-5-carboxylate).
반응 혼합물을 30℃로 냉각시키고 물(43.4 L)과 EtOAc(43.4 L)를 투입한 뒤 30분간 교반 후 층분리하여 수층을 제거한 뒤 물(31.0 L)을 투입하여 유기층을 추가 세척하였다. 감압증류로 EtOAc를 제거한 후 EtOH(24.8 L)를 투입하고 40℃로 승온하여 맑은 용액(clear solution)이 되도록 가열하였다. 반응기를 냉각하여 내부 온도가 20℃가 되도록 유지한 후 물(24.8 L)을 천천히 적가하여 결정이 생성되도록 하였다. 생성된 고체를 30분간 숙성 후 결정을 여과하고 물(31.0 L)로 2회 세척 후 질소 건조하여 표제 화합물(6.56 kg, Net yield 64.9%)을 수득하였다.The reaction mixture was cooled to 30 °C, water (43.4 L) and EtOAc (43.4 L) were added, stirred for 30 minutes, the layers were separated to remove the aqueous layer, and then water (31.0 L) was added to further wash the organic layer. After removing EtOAc by distillation under reduced pressure, EtOH (24.8 L) was added, and the temperature was raised to 40° C. and heated to become a clear solution. After cooling the reactor to maintain the internal temperature at 20° C., water (24.8 L) was slowly added dropwise to form crystals. After aging the resulting solid for 30 minutes, the crystals were filtered, washed twice with water (31.0 L), and dried with nitrogen to obtain the title compound (6.56 kg, Net yield 64.9%).
1H NMR (400MHz, CDCl3): 1.58 (d, 6H), 3.96 (s, 3H), 4.81 (m, 1H), 7.42 (d, 1H), 8.06 (dd, 1H), 8.44 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ): 1.58 (d, 6H), 3.96 (s, 3H), 4.81 (m, 1H), 7.42 (d, 1H), 8.06 (dd, 1H), 8.44 (s, 1H) ).
실시예 1-2. (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올Example 1-2. (3-Chloro-1-isopropyl-1H-indazol-5-yl)-methanol ((3-Chloro-1-isopropyl-1H-indazol-5-yl)-methanol)의 합성Synthesis of ((3-Chloro-1-isopropyl-1H-indazol-5-yl)-methanol)
Figure PCTKR2022005396-appb-I000023
Figure PCTKR2022005396-appb-I000023
반응기에 THF (34.2 L, 6 fold)와 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르(실시예 1-1, 5.7 kg, 22.6 mol)을 투입하고 내부 온도를 60℃까지 승온시켰다. 반응물에 NaBH4(1.68 kg, 44.4 mol)와 MeOH(5.7 L, 1 fold)를 80분간 천천히 적가한 뒤 30분간 반응을 진행시켰다. 90분 간격으로 NaBH4(0.44 kg, 11.6 mol)를 넣고 MeOH(1.69 L, 0.3 fold)를 2회 투입하고 30분간 반응한 뒤 HPLC를 이용하여 IPC를 진행하였다. THF (34.2 L, 6 fold) and 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester (Example 1-1, 5.7 kg, 22.6 mol) were added to the reactor, and the internal temperature was heated to 60 °C. NaBH 4 (1.68 kg, 44.4 mol) and MeOH (5.7 L, 1 fold) were slowly added dropwise to the reactant for 80 minutes, and then the reaction was allowed to proceed for 30 minutes. NaBH 4 (0.44 kg, 11.6 mol) was added at intervals of 90 minutes, MeOH (1.69 L, 0.3 fold) was added twice, reacted for 30 minutes, and then IPC was performed using HPLC.
3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르가 14.3% 잔류하여 NaBH4 (0.22 kg, 5.8 mol)만 추가투입하고 120분 반응하였다. 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르가 2.5%로 잔류하여 반응을 종결시키고 내부 온도가 10 ℃ 가 되도록 냉각을 진행하였다.14.3% of 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester remained, so only NaBH 4 (0.22 kg, 5.8 mol) was additionally added, followed by reaction for 120 minutes. 3-Chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester remained at 2.5% to terminate the reaction, and cooling was performed so that the internal temperature was 10°C.
B-complex(NaBH4에 의해서 생성되는 것으로 (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올의 알코올에 보론(boron)이 컨쥬게이트되어 있는 복합체) 및 잔류 NaBH4를 제거하기 위하여 3N HCl (39.3 kg)을 60분간 천천히 투입하여 반응액의 pH를 3.0으로 유지하고 감압증류하여 용매를 제거하였다. 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 To remove , 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.
잔류물에 DCM (28.5 L)과 물 (57.0 L)를 투입한 뒤 층분리하여 수층을 제거하고 물(42.8 L)로 추가 세척한 뒤 감압증류하여 표제 화합물(4.32 kg, Net yield 85%)을 수득하였다.After adding DCM (28.5 L) and water (57.0 L) to the residue, the layer was separated to remove the aqueous layer, washed with water (42.8 L), and distilled under reduced pressure to obtain the title compound (4.32 kg, Net yield 85%). obtained.
1H NMR (400MHz, CDCl3): 1.5~1.7 (m, 6H), 1.82 (m, 1H), 3.72 (m, 1H), 4.70~5.10 (m, 2H), 7.30~7.50 (m, 2H), 7.62 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ): 1.5-1.7 (m, 6H), 1.82 (m, 1H), 3.72 (m, 1H), 4.70-5.10 (m, 2H), 7.30-7.50 (m, 2H) , 7.62 (s, 1H).
실시예 1-3: 5-브로모메틸-3-클로로-1-아이소프로필-1H-인다졸 (5-Bromomethyl-3-chloro-1-isopropyl-1H-indazole)의 합성Example 1-3: Synthesis of 5-Bromomethyl-3-chloro-1-isopropyl-1H-indazole (5-Bromomethyl-3-chloro-1-isopropyl-1H-indazole)
Figure PCTKR2022005396-appb-I000024
Figure PCTKR2022005396-appb-I000024
반응기에 MTBE(43.3 L, 8 fold), (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올(실시예 1-2, 4.32 kg, 19.3 mol)를 투입하고 내부 온도를 0℃까지 냉각시켰다. 반응물에 PBr3(3.64 kg, 13.5 mol)를 90분간 천천히 투입하고 180분간 반응을 진행시켰다. MTBE (43.3 L, 8 fold), (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol (Example 1-2, 4.32 kg, 19.3 mol) was added to the reactor and the internal temperature was cooled to 0 °C. PBr 3 (3.64 kg, 13.5 mol) was slowly added to the reaction product for 90 minutes, and the reaction was allowed to proceed for 180 minutes.
HPLC를 이용하여 IPC를 진행하고 반응이 완결되어 (실시예 1-2: N/D) 1.5N NaOH(34.7 L)를 60분간 천천히 투입하고 30분간 교반하여 반응을 종결시켰다. 반응 혼합물에 물(21.7 L)을 투입하여 10분간 교반 및 층분리하여 수층을 제거하고 물 (17.3 L)로 추가 세척한 뒤 유기층을 감압증류하여 표제 화합물(4.97 g, Net yield 90.0%)을 합성하였다.IPC was performed using HPLC, and when the reaction was completed (Example 1-2: N/D), 1.5N NaOH (34.7 L) was slowly added for 60 minutes and stirred for 30 minutes to terminate the reaction. Water (21.7 L) was added to the reaction mixture, stirred for 10 minutes, and the layers were separated to remove the aqueous layer, further washed with water (17.3 L), and the organic layer was distilled under reduced pressure to synthesize the title compound (4.97 g, Net yield 90.0%). did.
1H NMR (400MHz, CDCl3): 1.53 (d, 6H), 4.7 (s, 2H), 4.88 (m, 1H), 7.51-7.6 (m, 2H), 7.68 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ): 1.53 (d, 6H), 4.7 (s, 2H), 4.88 (m, 1H), 7.51-7.6 (m, 2H), 7.68 (s, 1H).
실험예 1.Experimental Example 1. (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올의 알코올을 이탈기로 치환하는 반응 시 반응 용매의 평가(3-Chloro-1-isopropyl-1H-indazol-5-yl)-Evaluation of the reaction solvent in the reaction of replacing the alcohol of methanol with a leaving group
참고 합성예 1Reference Synthesis Example 1
치환 반응 시 DCM/MTBE 4:1의 혼합 용매를 사용하고, 반응 생성물의 추출 시 물이 아닌 DCM를 이용한 것 외에 상기 실시예 1-3과 동일한 방법에 따라 5-브로모메틸-3-클로로-1-아이소프로필-1H-인다졸을 수득하였다.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.
상기 참고 합성예 1의 제조 시 DCM과 MTBE 하에서 이탈기 치환 반응을 수행하면 반응기 기벽에 점성있는 오일(sticky oil)이 코팅되는 현상이 지속적으로 관찰되었으며, 이는 NaOH로 반응 종결 시 용해되어 사라지는 것을 확인할 수 있었다.When the leaving group substitution reaction was performed under DCM and MTBE during the preparation of Reference Synthesis Example 1, a phenomenon in which a viscous oil was coated on the reactor wall was continuously observed, and it was confirmed that it was dissolved and disappeared when the reaction was terminated with NaOH. could
반응 중 생성되는 점성있는 오일의 성분을 확인하기 위하여 HPLC로 분석한 결과 N2:N1 이성질체가 1.5:1의 비율로 N2 이성질체의 비율이 매우 높은 것으로 확인되었다. 또한, 이탈기로 치환되지 않고 (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올의 형태로 잔류하는 것으로 확인되었다.As a result of HPLC analysis to check the components of the viscous oil produced during the reaction, it was confirmed that the ratio of the N2 isomer to the N2:N1 isomer was 1.5:1, and the ratio of the N2 isomer was very high. In addition, it was confirmed that it was not substituted with a leaving group and remained in the form of (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol.
이러한 결과에 따라 (3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올의 알코올기를 이탈기로 치환하는 반응 시 MTBE 단일 용매를 사용하는 것이 N2 이성질체 제거 및 수율 개선에 효과적일 수 있음을 확인하였다.According to these results, the use of a single solvent of MTBE in the reaction of replacing the alcohol group of (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol with a leaving group may be effective in removing the N2 isomer and improving the yield. It was confirmed that it is possible.
(3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올의 알코올기를 이탈기로 치환하는 반응 시 반응 용매 및 추출 조건에 따른 N2 이성질체 및 표제 화합물((3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올)의 수율을 측정한 결과를 하기 표 1에 나타내었다.(3-Chloro-1-isopropyl-1H-indazol-5-yl)-N2 isomer and the title compound according to the reaction solvent and extraction conditions in the reaction of replacing the alcohol group of methanol with a leaving group ((3-chloro-1- The results of measuring the yield of isopropyl-1H-indazol-5-yl)-methanol) are shown in Table 1 below.
하기 표 1에서, "SG15"는 "(3-클로로-1-아이소프로필-1H-인다졸-5-일)-메탄올"를 나타내며, "SG20"은 "5-브로모메틸-3-클로로-1-아이소프로필-1H-인다졸"을 나타낸다. In Table 1 below, “SG15” represents “(3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol”, and “SG20” represents “ 5-bromomethyl-3-chloro- 1-isopropyl-1H-indazole".
EntryEntry 반응 및 추출 condition Reaction and extraction conditions N2 isomerN2 isomer
HPLC HPLC
(% PAR)(% PAR) 		SG20SG20
HPLC HPLC
(% PAR)(% PAR)
1One SG15 (for entry 2,3,4)SG15 (for entry 2,3,4) 15.615.6 84.484.4
22 DCM/MTBE =4: 1 반응 진행,DCM 2 fold 투입하여Stick oil 용해, DCM 추출DCM/MTBE = 4: 1 reaction proceeds, DCM 2 folds is added to dissolve Stick oil, DCM extraction 14.014.0 86.086.0
33 DCM/MTBE =4: 1 반응 진행MTBE 3 fold 투입하여 추출DCM/MTBE =4: 1 reaction proceeds Extraction by adding 3 folds of MTBE 2.42.4 97.697.6
44 MTBE 8 fold 반응 진행, MTBE 추출MTBE 8 fold reaction progress, MTBE extraction 1.31.3 98.798.7
55 SG15 (for entry 6,7)SG15 (for entry 6,7) 20.620.6 79.479.4
66 DCM/MTBE =4: 1 반응 진행MTBE 3 fold 투입하여 추출DCM/MTBE =4: 1 reaction proceeds Extraction by adding 3 folds of MTBE 3.83.8 96.296.2
77 MTBE 8 fold 반응 진행, MTBE 추출MTBE 8 fold reaction progress, MTBE extraction 1.71.7 98.398.3
상기 표 1에서도 확인할 수 있는 바와 같이, MTBE 단일 용매 하에서 알코올의 이탈기로의 치환 반응을 수행하고, MTBE를 이용하여 추출할 때 N2 이성질체를 2% 미만으로 저감할 수 있음을 확인하였다. As can be seen in Table 1 above, it was confirmed that the substitution reaction of the alcohol with the leaving group was performed under a single solvent of MTBE, and the N2 isomer could be reduced to less than 2% when extracted using MTBE.
실험예 2.Experimental Example 2. 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르의 합성 시 결정화 용매의 평가 1Evaluation of the crystallization solvent in the synthesis of 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester 1
참고 합성예 2Reference Synthesis Example 2
알킬화 반응을 종결한 후 정제 단계 없이 물을 투입하여 결정화한 것을 제외하고 상기 실시예 1-1과 동일한 방법으로 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르를 수득하였다.After completion of the alkylation reaction, 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.
참고 합성예 3Reference Synthesis Example 3
반응 혼합물을 정제하고 EtOAc를 제거한 후 EtOH 대신 동량의 n-헥산을 투입하여 결정화하는 것을 제외하고 상기 실시예 1-1과 동일한 방법으로 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르를 수득하였다.3-Chloro-1-isopropyl-1H-indazole-5- in the same manner as in Example 1-1, except that the reaction mixture was purified and EtOAc was removed, and the same amount of n-hexane was added instead of EtOH for crystallization. The carboxylic acid methyl ester was obtained.
참고 합성예 4Reference Synthesis Example 4
반응 혼합물을 정제하고 EtOAc를 제거한 후 EtOH 대신 동량의 이소프로필알코올(IPA)을 투입하여 결정화하는 것을 제외하고 상기 실시예 1-1과 동일한 방법으로 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르를 수득하였다.3-chloro-1-isopropyl-1H-indazole in the same manner as in Example 1-1, except that the reaction mixture was purified and EtOAc was removed, and the same amount of isopropyl alcohol (IPA) was added instead of EtOH for crystallization. A-5-carboxylic acid methyl ester was obtained.
실시예 1-1과 참고 합성예 2 내지 4에 따라 수득되는 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르의 함량과 N2 이성질체의 함량을 비교 평가한 결과, 유기 용매를 사용하지 않은 참고 합성예 2 이외에 실시예 1-2, 참고 합성예 3 및 4는 N2 이성질체 제거율의 측면에서 모두 우수한 것을 확인하였다.As a result of comparative evaluation of the content of 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester obtained according to Example 1-1 and Reference Synthesis Examples 2 to 4 and the content of the N2 isomer, It was confirmed that Examples 1-2, Reference Synthesis Examples 3 and 4 other than Reference Synthesis Example 2 that did not use an organic solvent were all excellent in terms of N2 isomer removal rate.
특히, EtOH와 물의 혼합 용매를 이용한 실시예 1-2의 경우 N2 이성질체의 제거율과 표제 화합물의 회수율의 측면에서 모두 우수한 효과를 나타내는 것을 확인하였다. In particular, in the case of Example 1-2 using a mixed solvent of EtOH and water, it was confirmed that both the removal rate of the N2 isomer and the recovery rate of the title compound showed excellent effects.
알킬화 반응 및 정제 후 결정화 용매에 따른 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르의 수율을 측정한 결과를 하기 표 2 및 표 3에 나타내었다.The results of measuring the yield of 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester according to the crystallization solvent after the alkylation reaction and purification are shown in Tables 2 and 3 below.
하기 표 2 및 표 2에서, "SG10"는 "3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르"를 나타낸다.In Tables 2 and 2 below, "SG10" represents "3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester".
EntryEntry 결정화 방법 (fold)Crystallization method (fold) HPLC ratio HPLC ratio
N1(%)N1 (%) N2(%)N2 (%)
-- SG10 정제 후 사용
(정제 조건: H2O (10) / EA(10) 2회 →H2O (3) 수세 후 증류)Use after SG10 purification
(Purification conditions: H 2 O (10) / EA (10) twice → H 2 O (3) After washing with water) 		77.677.6 22.422.4
1One EtOH (5) →H2O (10) slow addition for 1h →aging for 1h → filterEtOH (5) →H 2 O (10) slow addition for 1h →aging for 1h → filter 87.487.4 12.612.6
22 IPA (5) →H2O (10) slow addition for 1h →aging for 1h → filterIPA (5) →H 2 O (10) slow addition for 1h →aging for 1h → filter 90.690.6 9.49.4
33 t-BuOH (5) →H2O (10) slow addition for 1h →aging for 1h → filtert-BuOH (5) →H 2 O (10) slow addition for 1h →aging for 1h → filter 90.490.4 9.69.6
44 EA (1) →H2O (10) slow addition for 1h→5 ℃→aging for 1h → filterEA (1) →H 2 O (10) slow addition for 1h→5 ℃→aging for 1h → filter 84.484.4 15.615.6
55 t-BuOH (1.5) →H2O (4.5) slow addition for 1h →aging for 1h → filtert-BuOH (1.5) →H 2 O (4.5) slow addition for 1h →aging for 1h → filter 83.983.9 16.116.1
66 DCM (0.1) →H2O (10) slow addition for 1h →aging for 1h → filterDCM (0.1) →H 2 O (10) slow addition for 1h →aging for 1h → filter 87.187.1 12.912.9
77 EtOH (1.5), DCM (0.1) →H2O (4.5) slow addition for 1h →aging for 1h → filterEtOH (1.5), DCM (0.1) →H 2 O (4.5) slow addition for 1h →aging for 1h → filter 87.587.5 12.512.5
EntryEntry Scale
(g)Scale
(g) 		결정화 조건
(Fold)Crystallization conditions
(Fold) 		Purity (HPLC % PAR) -288 nmPurity (HPLC % PAR) -288 nm N.Y
(%)NY
(%)
F/CF/C 모액mother liquor
N2
IsomerN2
Isomer 		SG10SG10 N2 IsomerN2 Isomer SG10SG10
00 -- SG10SG10 17.617.6 82.482.4 -- -- --
1One 22 EtOH (3) →heating 50 ℃ →H2O (5) dropwise, stirring 1 hr, filterEtOH (3) →heating 50 ℃ →H 2 O (5) dropwise, stirring 1 hr, filter 10.310.3 89.789.7 59.659.6 40.440.4 --
22 22 HEX (3) heating 50 ℃ →H2O (3) dropwise, stirring 1 hr, filterHEX (3) heating 50 ℃ →H 2 O (3) dropwise, stirring 1 hr, filter 7.67.6 92.492.4 40.340.3 59.759.7 --
33 22 IPA (3) heating 50 ℃ →H2O (5) dropwise, stirring 1 hr, filterIPA (3) heating 50 ℃ →H 2 O (5) dropwise, stirring 1 hr, filter 9.49.4 90.690.6 52.252.2 47.847.8 --
44 3030 EtOH (3) heating 50 ℃ →H2O (3) dropwise, stirring 1 hr, filterEtOH (3) heating 50 ℃ →H 2 O (3) dropwise, stirring 1 hr, filter 5.6NMR (4.8)5.6 NMR (4.8) 94.494.4 53.253.2 46.846.8 84.284.2
55 3030 EtOH (3) heating 50 ℃ →H2O (4) dropwise, stirring 1 hr, filterEtOH (3) heating 50 ℃ →H 2 O (4) dropwise, stirring 1 hr, filter 9.3 NMR (8.0)9.3 NMR (8.0) 90.790.7 59.859.8 40.240.2 86.086.0
66 3030 EtOH (3) heating 50 ℃ →H2O (3) dropwise, 0 ℃, stirring 1 hr, filterEtOH (3) heating 50 ℃ →H 2 O (3) dropwise, 0 ℃, stirring 1 hr, filter 9.3
NMR (9.6)9.3
NMR (9.6) 		90.790.7 -- -- 88.688.6
77 3030 EtOH (3) heating 50 ℃ →H2O (4) dropwise, 0 ℃, stirring 1 hr, filterEtOH (3) heating 50 ℃ →H 2 O (4) dropwise, 0 ℃, stirring 1 hr, filter 11.3
NMR (11.0)11.3
NMR (11.0) 		88.788.7 69.569.5 30.530.5 92.392.3
상기 표 2의 실험 시 결정화 용매로서 t-BuOH 또는 DCM을 이용할 경우 결정화 도중 응집 현상(aggregation)이 관찰되었으며, IPA를 사용할 경우 총 수율(net yield)의 측면에서 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르의 손실이 증가하는 현상이 관찰되었다.또한, 상기 표 3에서 확인할 수 있는 바와 같이, N2 isomer를 약 17% 함유한 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르를 이용하여 결정화 용매로서 EtOH, IPA 및 n-hexane 각각을 이용하여 결정화를 진행한 결과 약 10% 의 N2 isomer가 제거되는 것을 확인할 수 있었다. When using t-BuOH or DCM as the crystallization solvent in the experiment of Table 2, aggregation was observed during crystallization, and when using IPA, 3-chloro-1-isopropyl- An increase in the loss of 1H-indazole-5-carboxylic acid methyl ester was observed. In addition, as can be seen in Table 3 above, 3-chloro-1-isopropyl containing about 17% N2 isomer As a result of crystallization using -1H-indazole-5-carboxylic acid methyl ester using EtOH, IPA, and n-hexane as a crystallization solvent, it was confirmed that about 10% of the N2 isomer was removed.
상기 표 2 및 표 3을 통해 결정화 용매로서 EtOH을 사용하였을 경우 N2 isomer 제거와 회수율 모두 우수한 것을 확인할 수 있었다. 또한 anti-solvent로 사용하는 H2O의 사용량이 많을수록, 숙성 온도가 낮은 수록 N2 isomer의 제거 효과는 떨어지는 것을 확인할 수 있었다.Through Table 2 and Table 3, when EtOH was used as the crystallization solvent, it was confirmed that both the N2 isomer removal and the recovery rate were excellent. In addition, it was confirmed that the higher the amount of H 2 O used as an anti-solvent, the lower the aging temperature, the lower the N2 isomer removal effect.
실험예 3.Experimental Example 3. 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르의 합성 시 결정화 용매의 평가 2Evaluation of the crystallization solvent in the synthesis of 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester 2
참고 합성예 5Reference Synthesis Example 5
결정화 시 EtOH:H2O를 3:7의 부피비로 사용한 것을 제외하고 상기 실시예 1-1과 동일한 방법으로 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르를 수득하였다.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.
참고 합성예 6Reference Synthesis Example 6
결정화 시 EtOH:H2O를 1:1의 부피비로 사용한 것을 제외하고 상기 실시예 1-1과 동일한 방법으로 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르를 수득하였다.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.
참고 합성예 7Reference Synthesis Example 7
결정화 시 EtOH:H2O를 7:3의 부피비로 사용한 것을 제외하고 상기 실시예 1-1과 동일한 방법으로 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르를 수득하였다.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.
참고 합성예 5 내지 7에 따라 수득되는 3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르의 함량과 N2 이성질체의 함량을 비교 평가한 결과, EtOH의 사용량이 증가할수록, H2O의 사용량이 감소할수록 잔류 N2 이성질체의 함량이 감소하는 것을 확인하였다. As a result of comparative evaluation of the content of 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester obtained according to Reference Synthesis Examples 5 to 7 and the content of the N2 isomer, as the amount of EtOH increased, , it was confirmed that as the amount of H 2 O decreased, the content of the residual N2 isomer decreased.
특히, EtOH 사용량이 증가할 경우 많은 수율 손실 현상이 관찰되었으며, N2 성질체의 저감, 표제 화합물의 회수율의 측면에서 EtOH 및 H2O는 각각 반응 생성물의 4 fold의 양으로 1:1의 비율로 사용하는 것이 효과적임을 확인하였다.In particular, a lot of yield loss was observed when the amount of EtOH used was increased, and in terms of reduction of the N2 isomer and the recovery rate of the title compound, EtOH and H 2 O were each 4 fold of the reaction product in a ratio of 1:1. It was found to be effective to use.
3-클로로-1-아이소프로필-1H-인다졸-5-카르복실산 메틸 에스테르의 결정화 시 사용한 EtOH 및 H2O의 부피비에 따른 수율을 측정한 결과를 하기 표 4에 나타내었다.The results of measuring the yield according to the volume ratio of EtOH and H 2 O used in the crystallization of 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester are shown in Table 4 below.
EntryEntry EtOH (fold)EtOH (fold) H2O (fold)H 2 O (fold) N2 isomer
(% PAR）N2 isomer
(% PAR) 		NMR assay
（％）NMR assay
(%) 		N.Y
（％）NY
(%)
1One 33 77 14.714.7 82.482.4 62.8+α62.8+α
22 77 77 2.002.00 96.896.8 77.777.7
33 55 55 4.504.50 90.690.6 80.080.0
44 55 55 5.105.10 92.992.9 81.281.2
55 55 55 4.744.74 89.389.3 80.480.4
66 77 33 1.801.80 99.899.8 52.952.9
77 33 33 5.605.60 89.689.6 84.084.0

Claims (8)

  1. 에테르계 단일 용매 하에서 하기 화학식 3의 화합물의 알코올기를 이탈기로 치환하는 단계를 포함하는 하기 화학식 2의 중간체 화합물의 제조방법:A method for preparing an intermediate compound of Formula 2, comprising substituting a leaving group for an alcohol group of a compound of Formula 3 in the presence of a single etheric solvent:
    [화학식 2][Formula 2]
    Figure PCTKR2022005396-appb-I000025
    Figure PCTKR2022005396-appb-I000025
    [화학식 3][Formula 3]
    Figure PCTKR2022005396-appb-I000026
    Figure PCTKR2022005396-appb-I000026
    상기 화학식 2 및 화학식 3에 있어서,In Formula 2 and Formula 3,
    R1은 수소, 또는 치환 또는 비치환 알킬이고,R1 is hydrogen or substituted or unsubstituted alkyl,
    R2는 수소, 치환 또는 비치환 알킬, 할로겐, CN, CF3 또는 COCF3이고,R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF 3 or COCF 3 ;
    X는 C 또는 N이고,X is C or N;
    L은 이탈기(leaving group)이다.L is a leaving group.
  2. 청구항 1에 있어서,The method according to claim 1,
    상기 에테르계 단일 용매는 디알킬에테르계 용매, 아릴알킬에테르계 용매 또는 환형 에테르계 용매인 것인 제조방법.The ether-based single solvent is a dialkyl ether-based solvent, an arylalkyl ether-based solvent or a cyclic ether-based solvent.
  3. 청구항 1에 있어서,The method according to claim 1,
    상기 에테르계 단일 용매는 메틸 터셔리부틸 에테르(Methyl Tertiary Butyl Ether, MTBE)인 것인 제조방법.The method for producing the ether-based single solvent is methyl tertiary butyl ether (Methyl Tertiary Butyl Ether, MTBE).
  4. 청구항 1에 있어서,The method according to claim 1,
    상기 화학식 3의 화합물은 다음의 단계를 포함하는 방법에 따라 제조되는 것인 제조방법:The compound of Formula 3 is prepared according to a method comprising the following steps:
    1) 하기 화학식 4의 화합물에 R1 및 R2 치환기를 도입하고 알코올 용매를 포함하는 결정화 용매에 의해 결정화하여 화학식 5의 화합물을 수득하는 단계, 및1) introducing R1 and R2 substituents to the compound of Formula 4 below and crystallizing with a crystallization solvent including an alcohol solvent to obtain a compound of Formula 5, and
    2) 상기 화학식 5의 화합물을 환원제와 반응시켜 화학식 3의 화합물을 수득하는 단계:2) reacting the compound of formula (5) with a reducing agent to obtain a compound of formula (3):
    [화학식 4][Formula 4]
    Figure PCTKR2022005396-appb-I000027
    Figure PCTKR2022005396-appb-I000027
    [화학식 5][Formula 5]
    Figure PCTKR2022005396-appb-I000028
    Figure PCTKR2022005396-appb-I000028
    상기 화학식 4 및 화학식 5에 있어서,In Formulas 4 and 5,
    상기 R1, R2 및 X는 상기한 바와 같고,Wherein R1, R2 and X are as described above,
    상기 R3는 C1-C6의 치환 또는 비치환된 알킬이다.R3 is C 1 -C 6 substituted or unsubstituted alkyl.
  5. 청구항 4에 있어서,5. The method according to claim 4,
    단계 1)에서 상기 결정화 용매는 알코올 용매 및 물의 혼합 용매인 것인 제조방법.In step 1), the crystallization solvent is a mixed solvent of an alcohol solvent and water.
  6. 청구항 5에 있어서,6. The method of claim 5,
    상기 결정화 용매는 EtOH:H2O의 부피비 2:1 내지 1:1의 혼합 용매인 것인 제조방법.The crystallization solvent is EtOH:H 2 O in a volume ratio of 2:1 to 1:1 of a mixed solvent of a manufacturing method.
  7. 청구항 4에 있어서,5. The method according to claim 4,
    단계 2)에서 화학식 5의 화합물의 환원 반응 후 극성 유기 용매 및 물의 혼합 용매에 의해 정제하여 화학식 3의 화합물을 수득하는 것인 제조방법.After the reduction reaction of the compound of formula (5) in step 2), purification with a mixed solvent of a polar organic solvent and water is used to obtain the compound of formula (3).
  8. 청구항 1에 있어서,The method according to claim 1,
    R1은 C1-C4의 치환 또는 비치환된 알킬이고,R1 is C 1 -C 4 substituted or unsubstituted alkyl,
    R2는 할로겐이며,R2 is halogen,
    L은 염소(Cl), 브로민(Br), 아이오딘(I), 메탄설포네이트(Oms), p-톨루엔설포네이트(OTs) 및 트리플루오로메탄설포네이트(OTf)로부터 선택되는 이탈기인 것인 제조방법.L is a leaving group selected from chlorine (Cl), bromine (Br), iodine (I), methanesulfonate (Oms), p-toluenesulfonate (OTs) and trifluoromethanesulfonate (OTf) A method for manufacturing phosphorus.
PCT/KR2022/005396 2021-04-14 2022-04-14 Method for preparing intermediate for synthesis of sphingosine-1-phosphate receptor agonist WO2022220608A1 (en)

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