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CN-122010930-A - Method for preparing refined crystals of non-nefardone and intermediate by using non-nefardone racemate

CN122010930ACN 122010930 ACN122010930 ACN 122010930ACN-122010930-A

Abstract

The invention discloses a method for preparing refined crystals of non-nefarnesone and intermediates from a non-nefarnesone racemate. The intermediate non-nefarone diastereomer salt (III) is prepared by chiral substituted tartrate, and then the non-nefarone diastereomer salt (III) is subjected to alkaline hydrolysis to prepare the non-nefarone (IIa). According to the invention, by adding the refining crystallization method of the intermediate non-nefarnesoid diastereomer salt (III), the ee value obtained by the intermediate non-nefarnesoid diastereomer salt (III) prepared by the method is higher than 99.5%, the e.e value in the non-nefarnesoid bulk drug is basically presented as 100% on the basis, and the resolving agent tartaric acid ester in the free non-nefarnesoid enantiomer is not detected, so that the product loss and the three wastes are avoided from being generated due to multiple dissociation, the production and manufacturing cost is greatly reduced, the product yield prepared by the method is high, the three wastes are polluted with low cost, the preparation process is simple to operate, the reaction condition is mild, the production cost is saved, and the method is suitable for industrial production.

Inventors

  • LI DONGDONG
  • HOU YONG
  • SHEN WENGUANG
  • WANG CHUNCHAO
  • SUN YUNBEI
  • SONG LIANGWEI
  • ZHOU HUANRAN
  • ZHAO ZHENNAN
  • LI JUNGUANG

Assignees

  • 罗欣药业(上海)有限公司
  • 山东罗欣药业集团恒欣药业有限公司
  • 山东罗欣药业集团股份有限公司
  • 山东裕欣药业有限公司

Dates

Publication Date
20260512
Application Date
20251208

Claims (10)

  1. 1. A process for the preparation of non-nefardone in racemic form, said process comprising the steps of: (1) The non-nefardone racemate (II) reacts with D- (+) -dibenzoyl tartaric acid (IV) in a solvent to prepare an intermediate non-nefardone diastereomer salt (III) wet product, and the fine product of the non-nefardone diastereomer salt (III) is obtained by a refining crystallization method; (2) Preparing a refined product of the intermediate non-netilone diastereomer salt (III) by alkali dissociation, pH adjustment and post treatment in a solvent; the synthetic route is as follows:
  2. 2. The process for preparing non-nefardone according to claim 1, wherein the molar ratio of compound II to compound IV in step (1) is 1:0.5-1, preferably 1:0.5-0.65, and the solvent for the reaction of compound II with compound IV is an ethanol and water mixture.
  3. 3. The method for preparing the non-nefardone by the non-nefardone racemization according to claim 1, wherein in the step (1), the refined crystallization method of the intermediate non-nefardone diastereomer salt (III) essence comprises the following steps of dissolving a wet non-nefardone diastereomer salt (III) in a solvent, adding water for crystallization, and carrying out post-treatment to obtain the non-nefardone diastereomer salt (III) essence.
  4. 4. A process for the preparation of a non-nefarious ketone as claimed in claim 3 wherein the non-nefarious ketone diastereomeric salt (III) wet dissolution solvent is one or both of DMF, DMA, NMP, preferably DMF.
  5. 5. A process for the preparation of a non-nefarious ketone as claimed in claim 3, wherein the mass to volume ratio of the non-nefarious ketone racemate (II) to the non-nefarious ketone diastereomeric salt (III) wet product is 1:2 to 8g/ml, such as 1:3.75g/ml, 1:7.31g/ml, 1:4g/ml.
  6. 6. A process for the preparation of a non-nefarious ketone as claimed in claim 3 wherein the wet dissolution temperature of the non-nefarious ketone diastereomeric salt (III) is 40 to 80 ℃, preferably 60 to 80 ℃.
  7. 7. The method for preparing non-nefardone according to claim 3, wherein the volume ratio of crystallization water to dissolution solvent added in the method for refining and crystallizing the wet product of non-nefardone diastereomer salt (III) is 1-8:1, and more preferably the volume ratio of crystallization water to dissolution solvent added is 2-6:1, and the post-treatment is cooling, filtering, washing and drying.
  8. 8. The process for preparing non-nefardone according to claim 1, wherein the solvent in step (2) is N, N-dimethylformamide, N-dimethylacetamide, methanol and water, ethanol and water or acetonitrile and water, further preferably ethanol and water in a volume ratio of 2 to 3:1, the base is an inorganic base selected from ammonia, sodium hydroxide, sodium carbonate, potassium bicarbonate, sodium phosphate or potassium phosphate, preferably sodium phosphate, or an organic base selected from triethylamine, N-diisopropylethylamine, pyridine, sodium t-butoxide, sodium ethoxide or sodium methoxide, preferably triethylamine or sodium ethoxide.
  9. 9. The method for preparing the non-nefardone according to claim 1, wherein the step (2) is characterized in that the pH temperature is adjusted to 20-80 ℃, preferably 25-60 ℃ by using alkali, the pH value adjusted by the alkali is=7.0-9.0, preferably the pH value is=7.5-8.0, the post-treatment comprises the steps of concentrating, adding water for crystallization, cooling, filtering, washing with water, drying to obtain a non-nefardone (IIa) crude product, and further refining to obtain a non-nefardone (IIa) fine product.
  10. 10. The method for preparing the non-nefarious ketone according to claim 9, wherein the mass-volume ratio of the refined non-nefarious ketone diastereomer salt (III) to the added crystallization water is 1:10-20 g/ml.

Description

Method for preparing refined crystals of non-nefardone and intermediate by using non-nefardone racemate Technical Field The invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing refined crystals of non-nefardone and intermediates from a non-nefardone racemate. Background Non-nelidane (Finerenone), chemical name (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide, structural formula: The compound of formula (II) is a racemate of non-nelidane: The expression "enantiomers of non-nefarious ketone" relates to compounds of formulae IIa and IIb, non-nefarious ketone being a non-steroidal antagonist of the mineralocorticoid receptor and being useful as a medicament for the prophylaxis and/or treatment of cardiovascular and renal diseases such as heart failure and diabetic nephropathy, wherein only the enantiomer of formula IIa is active. In the disclosed research-grade synthesis (WO 2008/104306 A1), a specially synthesized chiral phase (internal preparation) is used, which comprises N- (dicyclohexylmethyl) -N2-methacryloyl-D-leunamide as chiral selector. It has now been found that it is also possible to carry out the separation on readily commercially available phases. It was CHIRALPAK AS-V phase, 20 μm, and the eluent used was a 60:40 mixture of methanol/acetonitrile. In this case, chromatography may be carried out on a conventional chromatographic column, but preferably using techniques known to those skilled in the art, such as SMB. While SMB separation can provide relatively good yields and optical purity, the cost of purchase and the challenges of operation of such equipment under GMP conditions are enormous, with the attendant high costs. The chiral phases used are also very expensive and have only a limited lifetime and must be replaced frequently in continuous production runs. This is not optimal for production process considerations unless a second device is present to ensure continuous operation, which can bring additional costs. Furthermore, solvent recovery is a time-limiting step, particularly in the case of products prepared on the ton scale, requiring the purchase of large falling film evaporators and consuming a large amount of energy. Patent CN112041318a mentions that the compound of formula (II) is resolved by D- (+) -dibenzoyltartaric acid to obtain the non-nefarone enantiomer, in which D- (+) -dibenzoyltartaric acid first reacts with the racemate of formula (II) to form the diastereomeric salt of non-nefarone, and then further the solution of ethanol/water and sodium phosphate is used to adjust the pH and stirring for 18 hours, and the crude product of non-nefarone (IIa) is obtained after the treatment, but the patent also mentions that the removal difficulty of D- (+) -dibenzoyltartaric acid in non-nefarone (IIa) is greater in the process of scale up, and the reprocessing is required until <0.1%. Patent CN117986250a mentions that the resolution of the compound of formula (II) with D- (+) -di-o-methylbenzoyl tartaric acid gives the diastereomeric salt of non-nelidane, and further gives the crude product of non-nelidane (IIa), the preparation process is similar to patent CN112041318 a. In the preparation method of the non-nefarnesone (IIa), the preparation method of the WO2008/104306A1 is limited to a test research stage, and is difficult to realize industrialization, currently, the main current preparation of the non-nefarnesone (IIa) is basically obtained by resolving a non-nefarnesone racemate by using chiral substituted diastereoisomeric tartrate in the reports of a patent CN112041318A and a patent CN117986250A, and further obtaining the non-nefarnesone (IIa) through base ionization. However, the existing resolution technique has the problems that (1) the purity of the obtained non-netilone diastereomer salt e.e is not high, and (2) the residual fluctuation of the resolving agent substituted tartrate impurity in the non-netione (IIa) prepared in multiple batches is large, and part of the residual content is high and needs to be treated again. As a comparative experiment described in patent CN117986250A, the resolution of the non-nefarnesone racemate was carried out using D- (+) -dibenzoyltartaric acid, the ee value of the obtained non-nefarnesone diastereomer salt was 96.7%, the further prepared non-nefarnesone (IIa) ee value was 96.7%, the impurity residue of the resolving agent D- (+) -dibenzoyltartaric acid was 0.50%, while the resolution of the non-nefarnesone racemate was carried out using D- (+) -diphthalic acid, the ee value of the obtained non-nefarnesone diastereomer salt was 97.2%, the further prepared non-nefarnesone (IIa) ee value was 97.0%, and the impurity residue of the resolving agent D- (+) -diphthalic acid was 0.04%. Although patent CN117986250a further improves the ee purity of the diastereomeric salt of the non-nelidane, greatly reduces the residue of the resolvin