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CN-122003420-A - Process for the preparation of (2S, 4'S, 6S) -2-methyl-6- (1-methyl-1H-1, 2, 3-triazol-4-yl) -2' - (trifluoromethyl) -4',5' -dihydrospiro [ piperidine-4, 7 '-thieno [2,3-C ] pyran ] -4' -ol

CN122003420ACN 122003420 ACN122003420 ACN 122003420ACN-122003420-A

Abstract

The present disclosure provides methods of preparing (2 s,4's,6 s) -2-methyl-6- (1-methyl-1H-1, 2, 3-triazol-4-yl) -2' - (trifluoromethyl) -4',5' -dihydrospiro [ piperidine-4, 7 '-thieno [2,3-c ] pyran ] -4' -ol (compound (I)), a stereoisomer of compound (I), a deuterated derivative of compound (I), and a deuterated derivative of a stereoisomer of compound (I).

Inventors

  • P.J. Ross

Assignees

  • 弗特克斯药品有限公司

Dates

Publication Date
20260508
Application Date
20240910
Priority Date
20230911

Claims (20)

  1. 1. A process for preparing compound I: , The method comprises the following steps: (a) Compound S4: conversion to compound S5: And (C) sum (B) Compound S5 is converted to compound I.
  2. 2. A process for preparing compound I: , The method comprises the following steps: (a) Compound S4: conversion to compound S5: ; (b) Conversion of compound S5 to compound s5·msoh: And (C) sum (C) The compound s5·msoh is converted to compound I.
  3. 3. A process for preparing compound I: , The method comprises the following steps: (a) Compound S3: conversion to compound S4: ; (b) Conversion of compound S4 to compound S5: And (C) sum (C) Compound S5 is converted to compound I.
  4. 4. A process for preparing compound I: , The method comprises the following steps: (a) Compound S3: conversion to compound S4: ; (b) Conversion of compound S4 to compound S5: ; (c) Conversion of compound S4 to compound s5·msoh: And (C) sum (D) The compound s5·msoh is converted to compound I.
  5. 5. The method of claim 3 or 4, wherein compound S3: By compound S1: Reaction with compound S2 gives: 。
  6. 6. A process as claimed in claim 1 or 3, wherein the conversion of compound S5 to compound I is carried out in the presence of at least one catalyst, a hydrogen donor agent, and optionally one or more of a base and a ligand.
  7. 7. The process of claim 2 or 4, wherein the conversion of compound s5·msoh to compound I is carried out in the presence of at least one catalyst, a hydrogen donor agent, and optionally one or more of a base and a ligand.
  8. 8. A process for preparing compound I: , The method comprises reacting compound S5: conversion to compound I, wherein the conversion of compound S5 to compound I is performed in the presence of at least one catalyst, a hydrogen donor agent, and optionally one or more of a base and a ligand.
  9. 9. A process for preparing compound I: , The method comprises the steps of combining a compound S5 MsOH: the conversion to compound I, wherein the conversion of compound s5·msoh to compound I is performed in the presence of at least one catalyst, a hydrogen donor agent, and optionally one or more of a base and a ligand.
  10. 10. The process of any one of claims 6-9, wherein the at least one catalyst is selected from the group consisting of rhodium catalysts, CRED-33, CRED-a231, and GDH-102.
  11. 11. The process of any one of claims 6-9, wherein the at least one catalyst is a rhodium catalyst.
  12. 12. The process of claim 10 or 11, wherein the rhodium catalyst is dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer.
  13. 13. The method of any one of claims 6-9, wherein the hydrogen donor agent is selected from formic acid, sodium formate, and NADP.
  14. 14. The process of any one of claims 6-9, wherein the base is triethylamine.
  15. 15. The method of any one of claims 6-9, wherein the ligand is (R, R) -N- (p-toluenesulfonyl) -1, 2-diphenylethylenediamine ((R, R) -TsDPEN).
  16. 16. The process of any one of claims 6-9, wherein the at least one catalyst is a dichloro-pentamethyl cyclopentadienyl) rhodium (III) dimer, the hydrogen donor agent is formic acid, the base is triethylamine, and the ligand is (R, R) -N- (p-toluenesulfonyl) -1, 2-diphenylethylenediamine ((R, R) -TsDPEN).
  17. 17. The process according to any one of claims 6 to 9, wherein the conversion of compound S5 to compound I is carried out at a pH value of 4 to 6.
  18. 18. The process of any one of claims 6-9, wherein the conversion of compound s5·msoh to compound I is performed at a pH value of 4-6.
  19. 19. The process of any one of claims 6-18, wherein compound I is purified by crystallization from C 1 -C 6 alkyl alcohol and water.
  20. 20. The method of claim 19, wherein the C 1 -C 6 alkyl alcohol is selected from ethanol and methanol.

Description

Process for the preparation of (2S, 4'S, 6S) -2-methyl-6- (1-methyl-1H-1, 2, 3-triazol-4-yl) -2' - (trifluoromethyl) -4',5' -dihydrospiro [ piperidine-4, 7 '-thieno [2,3-C ] pyran ] -4' -ol The present application claims the benefit of U.S. provisional application 63/537,769 filed on day 11 of 9 of 2023 and U.S. provisional application 63/539,056 filed on day 18 of 9 of 2023, both of which are incorporated herein by reference in their entireties. The present disclosure provides methods for synthesizing compounds that can inhibit apolipoprotein L1 (APOL 1). Such compounds have been shown to be useful in the treatment of APOL1 mediated diseases, such as pancreatic cancer, focal Segmental Glomerulosclerosis (FSGS), and/or non-diabetic kidney disease (NDKD). FSGS is a rare kidney disease with estimated global morbidity of 0.2 to 1.1/100,000/year. FSGS is a disease of podocytes (glomerular visceral epithelial cells) that causes progressive decline in proteinuria and kidney function. NDKD is a kidney disease that involves damage to podocytes or glomerular vascular beds that is not caused by diabetes. NDKD are diseases characterized by hypertension and progressive decline in renal function. Human genetics supports the causal role of G1 and G2 APOL1 variants in inducing kidney disease. Individuals with 2 APOL1 risk alleles have an increased risk of end-stage kidney disease (ESKD), including primary (idiopathic) FSGS, human Immunodeficiency Virus (HIV) associated FSGS, NDKD, atherosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. See, P. Dummer et al, semin Nephrol.2015, 35 (3): 222-236. FSGS and NDKD can be divided into different subgroups depending on the underlying etiology. A homogeneous subgroup of FSGS is characterized by the presence of independent common sequence variants in the apolipoprotein L1 (APOL 1) gene, termed G1 and G2, which are termed "APOL1 risk alleles". G1 encodes a pair of related non-synonymous amino acid changes (S342G and I384M), G2 encodes a 2 amino acid deletion near the C-terminus of the protein (N388 del: Y389 del), and G0 is an ancestral (low risk) allele. The unique phenotype of NDKD was also found in patients with APOL1 genetic risk variants. In APOL 1-mediated FSGS and NDKD, patients with two risk alleles present with higher levels of proteinuria and faster loss of kidney function than patients without or with only 1 APOL1 genetic risk variant. Alternatively, in AMKD, patients with one at-risk allele may also develop higher levels of proteinuria and accelerated loss of kidney function. See, G. Vajgel et al, J.Rheumatol.2019, 47 (8): 1209-1217. APOL1 is a 44 kDa protein expressed only in humans, gorillas and baboons. The APOL1 gene is expressed in a number of organs of humans, including the liver and kidneys. APOL1 is produced primarily by the liver and contains a signal peptide that allows secretion into the blood stream where it circulates in association with a subpopulation of high density lipoproteins. APOL1 is responsible for protecting against invasive parasites, the species trypanosoma brucei subspecies brucei (Trypanosoma brucei brucei/(T.b. brucei)). APOL1 is engulfed by trypanosoma brucei and transported to the lysosome where it intercalates into the lysosome membrane and forms pores that lead to parasite swelling and death. While all 3 APOL1 variants (G0, G1 and G2) possess the ability to cleave trypanosoma brucei (t.b. brucei), the APOL 1G 1 and G2 variants provide additional protection against parasite species that have evolved to inhibit the serum resistance associated protein (SRA) of APOL 1G 0, and the APOL 1G 1 and G2 variants provide additional protection against trypanosoma species that cause comatose. G1 and G2 variants circumvent inhibition of SRA, G1 provides additional protection against trypanosoma gambir (t.b. gambiense), which causes western africa sleep disorder, while G2 provides additional protection against trypanosoma rotundi (t.b. rhodesiense), which causes eastern africa sleep disorder. In the kidneys, APOL1 is expressed in podocytes, endothelial cells (including glomerular endothelial cells), and some tubular cells. Podocyte-specific expression of APOL 1G 1 or G2 (but not G0) in transgenic mice induces structural and functional changes, including proteinuria, reduced renal function, podocyte abnormalities, and glomerulosclerosis. Consistent with these data, the G1 and G2 variants of APOL1 play a role in inducing FSGS and accelerating their progression in humans. Individuals with an APOL1 risk allele (i.e., homozygous or heterozygous for an APOL 1G 1 or an APOL 1G 2 allele) are at increased risk of developing FSGS, and if they develop FSGS they will be at risk of rapidly decreasing kidney function. Thus, inhibition of APOL1 may have a positive effect on individuals carrying an APOL1 risk allele. Although the normal plasma concentration of APOL1 is relatively high and may vary by at least a factor of 20 in humans, circulating AP