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CN-117177964-B - Novel process for preparing sphingosine-1-phosphate receptor agonists

CN117177964BCN 117177964 BCN117177964 BCN 117177964BCN-117177964-B

Abstract

The present invention relates to a novel method for preparing a compound represented by formula 5 or a salt thereof as described herein, wherein the compound or salt can be used as a sphingosine-1-phosphate receptor agonist.

Inventors

  • JIN CHENGYU
  • JIN QIDA
  • LI XIUMIN

Assignees

  • 株式会社LG化学

Dates

Publication Date
20260508
Application Date
20220414
Priority Date
20210414

Claims (10)

  1. 1. A process for preparing the hydrochloride salt of a compound of formula 5, the process comprising the steps of: 1) A step of reacting the compound of formula 2 with the compound of formula 3 under reducing conditions to prepare a hydrochloride of the compound of formula 4, and 2) A step of converting the ester group of the hydrochloride salt of the compound of formula 4 into a carboxylic acid group to prepare the hydrochloride salt of the compound of formula 5: wherein a product obtained by crystallizing the crude product of the compound of formula 4 prepared in step 1) under hydrochloric acid conditions and at a temperature of 20 to 30 ℃ is used as a reactant in step 2) [ 2] [ 3] [ 4] [ 5] In the formulae 2 to 5, R1 is hydrogen, or substituted or unsubstituted alkyl, R2 is hydrogen, substituted or unsubstituted alkyl, halogen, CN, CF 3 or COCF 3 , R3 and R4 are each hydrogen, substituted or unsubstituted alkyl, or halogen, R5 is hydrogen, substituted or unsubstituted alkyl, or halogen, R6 is a substituted or unsubstituted alkyl group, X is C or N, and the number of the X is C or N, Y is N, O or S, and the total number of the components is two, M and n are each 0,1 or 2, and m+n >0, Wherein the substituents are independently selected from halogen, cyano, hydroxy, alkoxy, keto, unsubstituted sulfonyl, and alkyl substituted sulfonyl, Wherein step 2) is reacting the hydrochloride salt of the compound of formula 4 with water, an alcoholic solvent or a mixed solvent thereof to convert the ester group into a carboxylic acid group, and Wherein the alcoholic solvent is selected from ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol and tert-butanol.
  2. 2. The method of claim 1, wherein R1 is C 1 -C 4 substituted or unsubstituted alkyl, R2 is halogen, and the halogen is halogen, R3 and R4 are each hydrogen, or C 1 -C 4 substituted or unsubstituted alkyl, R5 is halogen, and the halogen is halogen, R6 is C 1 -C 4 substituted or unsubstituted alkyl, X is N, and the number of the X is N, Y is N, and the number of the Y is N, M >0, n >0, and m+n=3 or 4.
  3. 3. The method of claim 1, wherein The hydrochloride of the compound of formula 4 is obtained in step 1), and The hydrochloride salt of the compound of formula 5 is obtained in step 2), thereby preparing the hydrochloride salt of the compound of formula 5.
  4. 4. A process according to claim 3, wherein the reducing agent used in the reducing conditions of step 1) uses at least one or more selected from sodium triacetoxyborohydride, sodium borohydride and sodium cyanoborohydride.
  5. 5. The process according to claim 4, wherein the compound of formula 3 and the reducing agent are used in step 1) in an equivalent ratio of 1:2 to 2:1.
  6. 6. The method of claim 1, wherein step 1) is performed without the use of evaporation.
  7. 7. The process according to claim 1, wherein a product obtained by crystallizing the crude product of the compound of formula 4 prepared in step 1) with an ether-type single solvent is used as a reactant in step 2).
  8. 8. The process of claim 1, further comprising 3) a step of recrystallizing the hydrochloride salt of the compound of formula 5 one or more times.
  9. 9. The method of claim 8, wherein the recrystallizing step is performed twice using the same solvent.
  10. 10. The method of claim 1, wherein the alcoholic solvent is ethanol.

Description

Novel process for preparing sphingosine-1-phosphate receptor agonists Technical Field Cross Reference to Related Applications The present application claims priority based on korean patent application No. 10-2021-0048766 filed on 4/2021, 14, the entire contents of which are incorporated herein by reference. Technical Field The present invention relates to a novel method for synthesizing sphingosine-1-phosphate receptor agonists. Background Sphingosine-1-phosphate (S1P) is produced by the intracellular ceramide pathway, and the ceramide starting material of this synthetic pathway is produced by two production pathways, namely, the de novo biosynthesis pathway and degradation of the cell membrane component sphingomyelin in the cell. The S1P level in individual tissues is controlled by two biosynthetic sphingosine kinases (SphK) and two biodegradable S1P phosphatases (S1P lytic enzyme and lysophospholipase), and the substance S1P produced by sphingosine kinase leading to sphingosine phosphorylation is known to mediate various cellular reactions such as cell proliferation, cytoskeletal organization and migration, adhesion and tight junction assembly, and morphogenesis. S1P is present in plasma at high concentrations (100-1000 nM) in combination with other plasma proteins, including albumin, but in tissues at low concentrations. S1P binds to the G protein-coupled receptor S1P receptor and exhibits different biological functions, five S1P receptor subtypes, S1P1 to S1P5, which are named Endothelial Differentiation Gene (EDG) receptors 1,5, 3, 6 and 8, are known to date. Such S1P receptors are known to be involved in a variety of biological functions such as leukocyte recirculation, neural cell proliferation, morphological changes, migration, endothelial function, vascular regulation and cardiovascular development. In recent years, many studies have found that the S1P signaling process through these receptors plays an important role in a range of reactions associated with multiple sclerosis, including inflammatory reactions and repair processes, and indeed, non-selective S1P1 agonists have recently been approved as therapeutic agents for multiple sclerosis. S1P receptors are widely expressed in many cells associated with the induction of multiple sclerosis. In particular, the S1P1 receptor plays 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 is responsive to S1P, thereby participating in lymphocyte recycling. Under normal conditions, the concentration of S1P in body fluids is higher than in lymphoid tissue, so that the difference in S1P concentration causes lymphocytes to leave lymphoid tissue and circulate along the output lymph. However, if the S1P1 receptor in lymphocytes is down-regulated by S1P1 agonists, no outflow of lymphocytes from the lymphoid tissue occurs, thereby reducing infiltration of self-invasive lymphocytes that can cause Central Nervous System (CNS) inflammation and tissue damage. Thus, a therapeutic effect on multiple sclerosis is obtained. The non-selective S1P1 agonist fingolimod has been approved as an oral drug for the treatment of multiple sclerosis. When it binds to the S1P1 receptor and is activated, the receptor is degraded or internalized from the lymphocyte surface. Thus, paradoxically, fingolimod acts as a functional S1P1 antagonist. Regarding S1P receptor agonists, korean patent laid-open No. 10-2014-0104376 discloses a novel compound of the following formula 1 as a potent S1P receptor agonist. [ 1] In the formula (1) of the present invention, X is C or N, and the number of the X is C or N, R1 is H or a substitutable alkyl group, R2 is H, a substitutable alkyl, halogen, CN, CF 3 or COCF 3, W is C, N, C-alkoxy, C-halogen or C-CN, Q is CH 2 O or S is selected from the following residues: In the above-described structure, the first and second heat exchangers, M and n are 0, 1, 2 or 3, R3 to R10 are each H, alkyl, halogen, haloalkyl or alkoxyalkyl, R11 is H, and the R is H, R12 is OH, NH2, In one embodiment of said document, the preparation of 1- [ 1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3, 4-dihydro-naphthalen-2-ylmethyl ] -piperidine-4-carboxylic acid by the following reaction 1 is disclosed (in reaction 1, "SG35" means "1-chloro-6-hydroxy-3, 4-dihydro-naphthalene-2-carbaldehyde"). [ Reaction 1] In reaction 1, the intermediate "1- [ 1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3, 4-dihydro-naphthalen-2-ylmethyl ] -piperidine-4-carboxylic acid ethyl ester" had a viscous oil appearance during the preparation of 1- [ 1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3, 4-dihydro-naphthalen-2-ylmethyl ] piperidine-4-carboxylic acid from 1-chloro-6- (3-chloro-1H-indazol-5-ylmethoxy) -3, 4-dihydro-naphthalene-2-carbaldehyde, and after completion of the reaction, the subsequent work-up was performed as a crude material without separate purification work-