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EP-4739650-A1 - NEW PROCESS FOR THE PREPARATION OF SPECIALIZED PRO-RESOLVING MEDIATORS (SPMS)

EP4739650A1EP 4739650 A1EP4739650 A1EP 4739650A1EP-4739650-A1

Abstract

The subject of invention is new process for the preparation of esters, carboxylic acids and their pharmaceutically acceptable salts of formula (I): (I) via a compound of formula (IV): (IV) and the preparation of new intermediates applied in the new synthetic route.

Inventors

  • MOLNÁR, József
  • BAJUSZ, Szabolcs
  • SZÁNTAI, Zsófia
  • NIERNER, Csilla Ilona
  • VAJDA, ERVIN

Assignees

  • Vinresol KFT.

Dates

Publication Date
20260513
Application Date
20240627

Claims (13)

  1. 1. A process for the preparation of a compound of formula (I): wherein, R represents H atom or Ci-4 alkyl; and n equals 1 and z equals 2, or n equals 2 and z equals 1; or a pharmaceutically accepted salt thereof, wherein the process comprises: Step 1) Sonogashira coupling of a compound comprising a terminal acetylene group and a protected hydroxyl group with a corresponding compound comprising a vinyl iodide structure and an unprotected hydroxyl group; followed by Step 2) selective reduction of the triple bond formed in Step 1) to a double bond with Z stereochemistry; followed by Step 3) hydroxyl deprotection; and if desired followed by Step 4) ester hydrolysis to carboxylic acid, and if desired salt formation.
  2. 2. A process according to claim 1, wherein in Step 1) the compound comprising a terminal acetylene group and a protected hydroxyl group is a compound of formula (II): wherein R" represents a silyl protecting group, and n is as defined above; and the compound comprising a vinyl iodide structure and an unprotected hydroxyl group of Step 1) is a compound of formula (III): wherein R’ represents Ci-4 alkyl, and z is as defined above.
  3. 3. A process according to claim 1 or 2, wherein in Step 1) is obtained a compound of formula (IV): wherein R’, R”, n and z are as defined above.
  4. 4. A process according to any of claims 1 to 3, wherein in Step 2) is obtained a compound of formula (V): wherein R’, R’, n and z are as defined above.
  5. 5. A process according to any one of claims 1 to 4, wherein in Step 3) is obtained a compound of formula (lb): wherein R’, n and z are as defined above.
  6. 6. A process according to any of claims 2 to 5, wherein R” is selected from dimethylisopropyl silyl (DMIPS), diethyl-isopropyl silyl (DEIPS), 2-norbornyl-dimethyl silyl (NDMS), di-terc-butyl-isobutyl silyl (BIBS), terc-butyl -di phenyl silyl (TBDPS), terc-butyl-dimethyl- silyl (TBDMS), tribenzyl silyl, triphenyl silyl, diphenyl-methyl silyl (DPMS), di-t-butyl-methyl silyl (DTBMS), terc-butyl-methoxyphenyl silyl (TBMPS), terc-butoxy-diphenyl silyl (DPTBOS), and dimethyl-thexyl silyl (DMTS).
  7. 7. A process according to claim 6, wherein R” is terc-butyl-dimethyl-silyl (TBDMS).
  8. 8. A process according to any of claims 1 to 7, wherein in Step 4) is obtained a compound of formula (la): wherein n and z are as defined above; or a pharmaceutically acceptable salt thereof.
  9. 9. A process according to any of claims 1 to 8, for the preparation of a compound of formula (I’) wherein R n and z are as defined above, wherein the process comprises in Step 1) a compound comprising a terminal acetylene group and a protected hydroxyl group, of formula (Ila) wherein TBDMS represents tert-buthyl-dimethyl-silyl; and n is as defined above; is reacted with the corresponding compound comprising a vinyl iodide structure and an unprotected hydroxyl group, of formula (III’) wherein R’ represents Ci-4 alkyl, preferably methyl and ethyl; and z is as defined above; and in Step 2) the triple bond of the compound of formula (IVa’) thus obtained wherein TBDMS, R’, an and z are as defined above, is reduced by selective reduction to a double bond with Z stereochemistry; and in Step 3) the tert-buthyl-dimethyl-silyl protecting group of the compound of formula (Va’) thus obtained wherein TBDMS, R’, n and z are as defined above; is removed to obtain a compound of formula (lb’) wherein R’, n and z are as defined above; and if desired in Step 4) the ester group of compound of formula (lb’) is hydrolysed, to obtain a compound of formula (la’) wherein n and z are as defined above; and if desired the carboxylic acid of formula (la’) is transforemed into its salt, preferably into its alkly metal salt, more preferably into its sodium or its potassium salt.
  10. 10. A compound of formula (IV): wherein, R’ represents Ci-4 alkyl; R” represents a silyl protecting group; and n equals 1 and z equals 2, or n equals 2 and z equals 1.
  11. 11. A compound of formula (Va):
  12. 12. A compound of formula (Illa): wherein R’ means Ci-4 alkyl.
  13. 13. A compound of formula (Illb):

Description

New Process for the Preparation of Specialized Pro-resolving Mediators (SPMs) The subject of the invention The subject of the invention is a new process for the preparation of esters, carboxylic acids and their salts of formula (I) and the new intermediates applied in the synthetic route of the present invention as well as their preparation. Background of the invention Numerous potential medical treatments have been identified for the molecules that can economically be produced with our invention, especially Maresinl (Marl) and Protectin DI (PD1): Such treatments include vulvar pain (US2020121617A 1 Treatment of Vulvar Pain), vitiligo (WO2022193029 Specialized pro-resolving mediators as melanocyte growth promoter and pro-survival factors and uses thereof), vascular injury (US2020113861A1 Compounds and Methods for Modulating Vascular Injury), ischemic stroke (WO2013044176A2 Methods and Compositions for the Treatment of Ischemic Stroke), skin inflammation and oxidative stress caused by UVB (Cezar, T. L. C, Martinez, R. M., Rocha, C. da, Melo, C. P. B., Vale, D. L., Borghi, S. M., Casagrande, R. (2019). Treatment with maresin 1, a docosahexaenoic acid- derived pro-resolution lipid, protects skin from inflammation and oxidative stress caused by UVB irradiation. Scientific Reports). Clinical trials are run for various indications, such as macula degradation and newborns retina injuries. Due to high biological activities of these SPMs, developments of new high efficacy drug products with extremely low daily doses are expected in the near future. Process for the preparation of a compounds according to formula (I) has been described in several articles. Spur et. al. (Tetrahedron Letters 53 (2012) 4169-4172) synthetize the molecule by Sonogashira coupling. One of the coupling agents (2) is prepared according to Scheme 1 in the cited article as follows: A new approach was applied for achieving the required stereochemistry of the hydroxyl group. The main disadvantage of the process of viny-iodide (2) is the use of special reagents (e.g. m-chloro-peroxy-benzoic acid), catalysts (e.g. (S,S)-(salen)Co(III)(OAc), Lindlar catalyst) and solvents (e.g. benzene) that makes industrial scale-up impossible. Takai olefin synthesis, used for synthesis of vinyl iodide group, is also difficult to apply in industrial environment. According to the article hydroxyl group of vinyl-iodide (2) is protected by triethyl-silyl protecting group. The coupling agent (3) is prepared according to a well-known reaction scheme below: However, according to our experiments, the process of terminal acetylene formation by LDA is not economical at scale-up, as the yield is decreasing significantly. Spur et. al. perform the Sonogashira coupling and final steps of the synthesis as shown below: The synthesis is widely used in the literature and the hydroxyl group of acetylene derivatives (3) is unprotected in the process. Due to the unprotected hydroxyl group, the yield of selective reduction of triple bond by Zn(Cu/Ag) catalyst is low. Not only low yield but significant increase of decomposition products is also expected. It is also worth to mention the limitation of using the special catalyst Zn(Cu/Ag) for industrial scale. Petasis et. al. (Tetrahedron Letters, 53(14), 1695-1698) perform Sonogashira coupling by vinyl-iodide (5) and acetylene structure (22). Following steps of synthesis contain well-known reactions and reagents: Main advantages of the process are the use of well-known robust reactions and the use of non-special reagents. Hydroxyl groups of both coupling agents are protected and this provides good yield and proper impurity profile of the product of Sonogashira coupling. The process cannot be applied for industrial scale due to the requirement of using special reagents (e.g. CBr4, Lindlar catalyst for the preparation of (22)) and special reactions (e.g. Takai olefin synthesis, Lindlar reduction for (5)). Having Sonogashira coupling completed, both hydroxyl groups undergo deprotection, and a robust and scalable reduction is performed by Zn powder. However, a significant decrease of yield is expected in reduction with Zn powder with unprotected hydroxyl groups. The protection strategy of Petasis et. al. results in yield of merely 36%. Aursnes et al. (Org. Biomol. Chem., 12(3), 432-437) perform Sonogashira coupling by using vinyl-bromide (21) and acetylene derivative (5). Further steps of the synthesis are well- known from literature: Protectin D1 The process has significant advantages due to the application of robust reactions with non-special reagents. The protection of hydroxyl groups of both coupling agents (21, 5) provides good yields and proper impurity profile of product of Sonogashira coupling (22). Disadvantages of the process include the bromination step for preparation of vinyl-iodide (21) which is difficult to scale-up and involves the use of dangerous bromine. Further disadvantage is the use of sensitive Lindlar cat