CN-121974908-A - Preparation method of non-nereirenone intermediate

CN121974908ACN 121974908 ACN121974908 ACN 121974908ACN-121974908-A

Abstract

The invention discloses a preparation method of a non-nefarious ketone intermediate 3, which comprises the following steps of carrying out resolution reaction on the non-nefarious ketone intermediate 2 and D-diphenyl tartrate in an organic solvent to obtain resolution salt, and then carrying out acid-base reaction on the resolution salt and alkali to obtain the non-nefarious ketone intermediate 3. The preparation method has the advantages of short reaction steps, high total reaction yield, simple and safe operation, simple post-treatment steps, high purity of the prepared product, low production cost and suitability for industrial production.

Inventors

WANG XIANYANG
YE FANGGUO
WANG YANHUI
YING SHUHUAN
WANG TINGTING

Assignees

上海新礼泰药业有限公司
博志研新泰州药物技术有限公司
上海博志研新药物研究有限公司

Dates

Publication Date: 20260505
Application Date: 20230112

Claims (10)

1. A preparation method of a non-nefarious ketone intermediate 3 is characterized by comprising the steps of carrying out resolution reaction on the non-nefarious ketone intermediate 2 and D-diphenyl tartrate in an organic solvent to obtain resolution salt, and then carrying out acid-base reaction on the resolution salt and base to obtain the non-nefarious ketone intermediate 3, wherein the organic solvent is dichloromethane, and the base is one or more of sodium phosphate, sodium carbonate and sodium bicarbonate; The preparation method of the non-nefarnesone intermediate 2 comprises the following steps of carrying out a ring closure reaction on the non-nefarnesone intermediate 1 and 4-amino-5-methyl-2-hydroxypyridine in an organic solvent to obtain the non-nefarnesone intermediate 2, wherein the organic solvent is 2-butanol and/or 1-butanol; The preparation method of the non-nefardone intermediate 1 comprises the following steps of carrying out condensation reaction on 4-bromo-2-methoxybenzaldehyde and ethyl 2-cyanoacetoacetate in an organic solvent in the presence of acid and a catalyst to obtain the non-nefardone intermediate 1, wherein the organic solvent is isopropanol, the acid is acetic acid, and the catalyst is piperidine; 。
2. A process for the preparation of the non-nerenone intermediate 3 according to claim 1, wherein: In the preparation method of the non-nefarnesone intermediate 3, the volume-mass ratio of the organic solvent to the non-nefarnesone intermediate 2 is 1 mL/g-50 mL/g; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 3, the molar ratio of the D-diphenyl tartrate to the non-nereirenone intermediate 2 is 0.5-3.0; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 3, the temperature of the resolution reaction is 10-50 ℃; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 3, the resolution reaction time is 1-24 hours; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 3, the pH value of the acid-base reaction is 7-9; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 3, the temperature of the acid-base reaction is 20-80 ℃; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 3, the acid-base reaction time is 1-30 hours.
3. A process for the preparation of the non-nerenone intermediate 3 according to claim 2, wherein: in the preparation method of the non-nefarnesone intermediate 3, the volume-mass ratio of the organic solvent to the non-nefarnesone intermediate 2 is 20 mL/g-40 mL/g; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 3, the molar ratio of the D-diphenyl tartrate to the non-nereirenone intermediate 2 is 0.8-1.5; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 3, the temperature of the resolution reaction is 20-40 ℃; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 3, the resolution reaction time is 18-20 hours; And/or the number of the groups of groups, In the preparation method of the non-neridone intermediate 3, the alkali is sodium phosphate; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 3, the temperature of the acid-base reaction is 50-70 ℃; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 3, the acid-base reaction time is 5-15 hours.
4. A process for the preparation of the non-nerenone intermediate 3 according to claim 1, wherein: In the preparation method of the non-nefarious ketone intermediate 2, the volume-mass ratio of the organic solvent to the non-nefarious ketone intermediate 1 is 1 mL/g-30 mL/g; And/or the number of the groups of groups, In the preparation method of the non-nefarnesone intermediate 2, the mass ratio of the non-nefarnesone intermediate 1 to the 4-amino-5-methyl-2-hydroxypyridine is 1.0-5.0; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 2, the temperature of the cyclization reaction is 80-150 ℃; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 2, the cyclization reaction time is 1-24 hours; And/or the number of the groups of groups, The preparation method of the non-nefarious ketone intermediate 2 adopts the following post-treatment steps, and after the reaction is finished, the non-nefarious ketone intermediate 2 is obtained through cooling, crystallization and pulping.
5. The process for the preparation of non-nerenone intermediate 3 according to claim 4, wherein: in the preparation method of the non-nefarious ketone intermediate 2, the volume-mass ratio of the organic solvent to the non-nefarious ketone intermediate 1 is 1 mL/g-5 mL/g; And/or the number of the groups of groups, In the preparation method of the non-nefarnesone intermediate 2, the mass ratio of the non-nefarnesone intermediate 1 to the 4-amino-5-methyl-2-hydroxypyridine is 2.0-3.0; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 2, the temperature of the cyclization reaction is 90-140 ℃; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 2, the cyclization reaction time is 10-20 hours; And/or the number of the groups of groups, In the post-treatment step adopted in the preparation method of the non-nereirenone intermediate 2, the temperature is reduced to 40-50 ℃; And/or the number of the groups of groups, In the post-treatment step adopted in the preparation method of the non-nereirenone intermediate 2, the crystallization temperature is 0-10 ℃; And/or the number of the groups of groups, In the post-treatment step adopted in the preparation method of the non-nereirenone intermediate 2, the crystallization time is 1-10 hours; And/or the number of the groups of groups, In the post-treatment step adopted in the preparation method of the non-nelidane intermediate 2, citric acid aqueous solution is adopted for pulping.
6. A process for the preparation of the non-nerenone intermediate 3 according to claim 1, wherein: in the preparation method of the non-nefarone intermediate 1, the volume-mass ratio of the organic solvent to the 4-bromo-2-methoxybenzaldehyde is 1.0 mL/g-30.0 mL/g; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 1, the mass ratio of the 2-cyano acetoacetic acid ethyl ester to the 4-bromo-2-methoxybenzaldehyde is 1.0-5.0; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 1, the molar ratio of the acid to the 4-bromo-2-methoxybenzaldehyde is 0.01-1; And/or the number of the groups of groups, In the preparation method of the nerenone intermediate 1, the molar ratio of the catalyst to the 4-bromo-2-methoxybenzaldehyde is 0.01-1; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 1, the temperature of the condensation reaction is 10-60 ℃; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 1, the time of the condensation reaction is 1-24 hours; And/or the number of the groups of groups, The preparation method of the non-nefarious ketone intermediate 1 comprises the following post-treatment steps of crystallization, filtration and washing after the reaction is finished to obtain the non-nefarious ketone intermediate 1.
7. The process for the preparation of non-nerenone intermediate 3 according to claim 6, wherein: In the preparation method of the non-nefarone intermediate 1, the volume-mass ratio of the organic solvent to the 4-bromo-2-methoxybenzaldehyde is 2.0 mL/g-10.0 mL/g; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 1, the mass ratio of the 2-cyano acetoacetic acid ethyl ester to the 4-bromo-2-methoxybenzaldehyde is 1.0-2.0; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 1, the molar ratio of the acid to the 4-bromo-2-methoxybenzaldehyde is 0.10-0.30; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 1, the molar ratio of the catalyst to the 4-bromo-2-methoxybenzaldehyde is 0.10-0.30; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 1, the temperature of the condensation reaction is 20-50 ℃; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 1, the time of the condensation reaction is 3-4 hours; And/or the number of the groups of groups, In the post-treatment step of the preparation method of the non-nereirenone intermediate 1, the crystallization temperature is 10-20 ℃; And/or the number of the groups of groups, In the post-treatment step of the preparation method of the non-nereirenone intermediate 1, the crystallization time is 1-24 hours; And/or the number of the groups of groups, The preparation method of the non-nereirenone intermediate 1 comprises a post-treatment step, wherein an alcohol solvent is adopted for washing.
8. A preparation method of a non-nefardone intermediate 4 is characterized by comprising the steps of preparing the non-nefardone intermediate 3 according to the preparation method of the non-nefardone intermediate 3 of any one of claims 1-7, and then carrying out nucleophilic substitution reaction on the non-nefardone intermediate 3 and triethyl orthoformate in an organic solvent in the presence of acid to obtain the non-nefardone intermediate 4, wherein the organic solvent is N, N-dimethylacetamide and/or N, N-dimethylformamide; 。
9. the process for the preparation of non-nerenone intermediate 4 according to claim 8, wherein: In the preparation method of the non-nefarious ketone intermediate 4, the volume-mass ratio of the organic solvent to the non-nefarious ketone intermediate 3 is 1 mL/g-100 mL/g; And/or the number of the groups of groups, In the preparation method of the non-nefarious ketone intermediate 4, the mass ratio of the triethyl orthoformate to the non-nefarious ketone intermediate 3 is 1-5; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 4, the molar ratio of the acid to the non-nereirenone intermediate 3 is 0.10-0.50; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 4, the temperature of nucleophilic substitution reaction is 100-150 ℃; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 4, the nucleophilic substitution reaction time is 1-10 hours; And/or the number of the groups of groups, The preparation method of the non-nefarious ketone intermediate 4 comprises the following post-treatment steps of cooling, adding water and crystallizing after the reaction is finished, so as to obtain the non-nefarious ketone intermediate 4.
10. A process for the preparation of the non-nerenone intermediate 4 according to claim 9, wherein: In the preparation method of the non-nefarious ketone intermediate 4, the volume-mass ratio of the organic solvent to the non-nefarious ketone intermediate 3 is 2 mL/g-10 mL/g; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 4, the mass ratio of the triethyl orthoformate to the non-nereirenone intermediate 3 is 1.1-2.0; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 4, the molar ratio of the acid to the non-nereirenone intermediate 3 is 0.20-0.45; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 4, the temperature of the nucleophilic substitution reaction is 110-140 ℃; And/or the number of the groups of groups, In the preparation method of the non-nereirenone intermediate 4, the nucleophilic substitution reaction time is 2-3 hours; And/or the number of the groups of groups, In the post-treatment step of the preparation method of the non-nereirenone intermediate 4, the temperature is reduced to 50-60 ℃; And/or the number of the groups of groups, In the post-treatment step of the preparation method of the non-nereirenone intermediate 4, seed crystal is added for stirring crystallization; And/or the number of the groups of groups, In the post-treatment step of the preparation method of the non-nereidone intermediate 4, the crystallization temperature is 0-10 ℃; And/or the number of the groups of groups, In the post-treatment step of the preparation method of the non-nereidone intermediate 4, the crystallization time is 2-3 hours.

Description

Preparation method of non-nereirenone intermediate The application is a divisional application of an application patent application with the application date of 2023, 1 month and 12 days, the application number of 202310040625.X and the application name of 'a preparation method of a non-nefarious ketone intermediate'. Technical Field The invention relates to a preparation method of a non-neridone intermediate. Background Non-nerlidone, chemical name (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide, is useful as a non-steroidal antagonist of mineralocorticoid receptors, for the prevention and/or treatment of cardiovascular and renal diseases, such as heart failure and chronic kidney disease. CHEMMEDCHEM,2012,7,1385 report that, starting from vanillin, 10 steps of reaction produce non-nereirenone with a total yield of only 3.76%. WO2008/104306 also reports the preparation of feoneli ketone, but is not suitable for commercial production because of the low overall yield (only 5%), many intermediate colors also require spectral purification, and require a large consumption of solvents. In WO2008/104306, a specially synthesized chiral phase (internal preparation) is used for resolution, which comprises poly (N-methacryloyl-D-leucine-dicyclohexyl-methylamide) as chiral selector. Bayer reports that separation can also be performed on readily commercially available phases. It takes the form of phase CHIRALPAK AS-V,20 μm. The eluent used was a 60:40 mixture of methanol/acetonitrile. In this case, the chromatographic analysis may be carried out on a conventional chromatographic column, but preferably using techniques known to those skilled in the art, such as SMB (simulated moving bed; G. Paredes, M. Mazotti, journal of Chromatography A,1142 (2007): 56-68) or Varicol (Computers AND CHEMICALENGINEERING (2003) 1883-1901). CN112040318a reports that racemic resolution is performed using chiral substituted tartrate of general formula (IIIa) or (IIIb) as resolving agent, resulting in non-neridone with resolution yield up to 91.4%. However, the residual resolving agent is difficult to remove after resolution by the method. Therefore, there is a need to find a process for preparing non-neridone that is industrially viable, has high overall yield, low production cost and high purity of the resulting product. Disclosure of Invention The invention aims to solve the technical problems that the synthesis method of the non-nereirenone in the prior art has long reaction steps, low total yield, complex post-treatment steps, low purity of the prepared product, complex resolution steps, high production cost, inapplicability to industrial production and the like, and provides the preparation method of the non-nereirenone intermediate. The non-nereirenone intermediate is used for preparing the non-nereirenone, has the advantages of short reaction steps, high total reaction yield, simple and safe operation, simple post-treatment steps, high purity of the prepared product, low production cost and suitability for industrial production. The invention provides a preparation method of a non-nefarious ketone intermediate 3, which comprises the following steps of carrying out resolution reaction on the non-nefarious ketone intermediate 2 and D-diphenyl tartrate in an organic solvent to obtain resolution salt, and then carrying out acid-base reaction on the resolution salt and alkali to obtain the non-nefarious ketone intermediate 3; in the invention, the preparation method of the non-nerlidone intermediate 3 preferably adopts the following reaction conditions: In the preparation method of the non-nereirenone intermediate 3, the organic solvent is preferably a halogenated hydrocarbon solvent, and the halogenated hydrocarbon solvent is preferably dichloromethane. In the preparation method of the non-nefarnesone intermediate 3, the volume-mass ratio of the organic solvent to the non-nefarnesone intermediate 2 is preferably 1 g/mL-50 mL, more preferably 20 g/mL-40 mL, for example 30 mL. In the preparation method of the non-nereirenone intermediate 3, the molar ratio of the diphenyl D-tartrate to the non-nereirenone intermediate 2 is preferably 0.5-3.0, more preferably 0.8-1.5, for example 1.1. In the preparation method of the non-nelidamide intermediate 3, the temperature of the resolution reaction is preferably 10-50 ℃, more preferably 20-40 ℃, for example 30-40 ℃ or 20-25 ℃. In the preparation method of the non-nereirenone intermediate 3, the resolution reaction is preferably carried out for 1-24 hours, more preferably 18-20 hours. In the preparation method of the non-nelidamide intermediate 3, the alkali can be one or more of sodium phosphate, sodium carbonate and sodium bicarbonate. In the preparation method of the non-nelidane intermediate 3, the pH value of the acid-base reaction is preferably 7-9. In the preparation method of the non-nereirenone intermediate 3, the temperature of the aci