CN110938052A - Industrial preparation method of intermediate of pranlukast as anti-asthma drug - Google Patents
Industrial preparation method of intermediate of pranlukast as anti-asthma drug Download PDFInfo
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- CN110938052A CN110938052A CN201811110042.5A CN201811110042A CN110938052A CN 110938052 A CN110938052 A CN 110938052A CN 201811110042 A CN201811110042 A CN 201811110042A CN 110938052 A CN110938052 A CN 110938052A
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- butoxyphenyl
- benzamide
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- pranlukast
- phosphorus oxychloride
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract
The invention discloses a pranlukast intermediate N- (2-cyano-4-oxo-4)H‑A method for preparing chromen-8-yl) -4- (4-butoxyphenyl) benzamide (formula I for short), which specifically relates to 4-oxo-8- [4- (4-butoxyphenyl) benzamide]Preparing N- (2-cyano-4-oxo-4-formamide (formula II for short) by dehydration reaction of (E) -4H-chromene-2-formamideH‑Chromen-8-yl) -4- (4-butoxyphenyl) benzamide. The preparation method of the pranlukast intermediate compound I has the advantages of high yield, good color and high purity, and is beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of medical chemical drugs, in particular to an industrial preparation method of pranlukast intermediate.
Background
Asthma is a chronic respiratory disease, which is classified as one of four chronic diseases by the world health organization. Among the large class of asthma drugs, the leukotriene receptor antagonist class of drugs has the fastest growing market share. Pranlukast (Pranlukast) is developed by the japanese yokoku corporation, selectively inhibits leukotriene receptors, hardly affects arachidonic acid metabolic enzymes, and has no antagonistic action on acetylcholine, 5-hydroxytryptamine, and the like; has good treatment effect on special asthma and other bronchial asthma in clinical application, has huge market prospect, and is one of three large leukotriene receptor antagonists (LTRAs).
The pranlukast preparation method is more, and the most classical preparation method which is also most suitable for large-scale production is as follows: taking N- (3-acetyl-2-hydroxyphenyl) -4- (4-butoxyphenyl) benzamide as a starting material, and carrying out four-step reaction of condensation cyclization, aminolysis, dehydration and tetrazole formation to obtain the pranlukast. The preparation route is as follows:
the inventor finds in a great deal of practice that pranlukast prepared by the route has poor color, low total yield and low purity, which cannot meet the quality requirement of the preparation on the raw material medicine; moreover, since pranlukast is developed into a plain tablet form and marketed by the original research Japan country, in order to increase the compliance and safety of patients, very strict requirements are put on the color and impurities of the pranlukast raw material drug (the color is white, and the total impurities are less than 0.1%). The inventor conducts tracing research on impurities and colors, and finds that: the main reason for the low color difference and purity of pranlukast is caused by the dehydration reaction step.
In this dehydration reaction, 4-oxo-8- [4- (4-butoxyphenyl) benzamide]Preparing N- (2-cyano-4-oxo-4-formamide (formula II for short) by dehydrating (E) -4H-chromene-2-formamideH-When chromen-8-yl) -4- (4-butoxyphenyl) benzamide (formula I for short), the color of the reaction liquid becomes dark, and the obtained intermediate of formula I has low color difference and purity; the color and content of the formula-one intermediate directly affect the pranlukast color and purity.
Therefore, a new method for preparing the intermediate of the formula II is urgently needed, so that the prepared intermediate of the formula I has good color, high purity and high yield.
Disclosure of Invention
In view of the above problems, the present invention has been made to avoid the conventional preparation of pranlukast intermediate N- (2-cyano-4-oxo-4)H-Defects in the process of preparing chromen-8-yl) -4- (4-butoxyphenyl) benzamide and a novel preparation method are provided.
There are a number of reports in this dehydration step, mainly using two reagents: n, N-dimethylformamide (abbreviated as DMF) and phosphorus oxychloride (POCl)3). DMF and POCl3Vilsmeier reagent is generated, which exerts a dehydrating effect. "Xin Shuan organic synthetic chemistry" page 510 of yellow constitution main editionIt is described that: in order to accelerate the dehydration efficiency, common salt or a basic substance (such as pyridine or other tertiary amine) is often added as a dehydration aid.
In the reaction, if no dehydration assistant or salt is added as the dehydration assistant, the yield is low, the purity is low, and impurities are large, which is also reported on page 28 of Master academic paper' study on synthesis process of anti-asthma pranlukast, written by Shijust at the university of eastern science and technology, and the obtained intermediate of formula I is off-white solid, the yield is 71.2%, and the content is 87.7%; if pyridine or other tertiary amines are added as dehydration aid, although the yield and content are good, the color of the intermediate of formula I is too poor and deep red (probably due to oxidation of organic base such as pyridine or other tertiary amines), which directly affects the color of the final product pranlukast. The reaction of the step needs to ensure that the prepared intermediate of the formula I has good color, small impurities, high content and high yield, and the prior art still cannot achieve the purpose.
The inventors have surprisingly found that the yield and purity of the reaction can be greatly improved by purifying commercial technical grade phosphorus oxychloride, and that the addition of common salt or alkaline substances as a dehydration aid is not required. The color of the intermediate of formula I prepared by adopting the purified phosphorus oxychloride can meet the requirement because an alkaline substance is not required to be added as a dehydration auxiliary agent. According to the discovery, the technical scheme of the invention is as follows: and (3) under the action of DMF and the purified phosphorus oxychloride, the intermediate of the formula II is subjected to dehydration reaction to prepare the intermediate of the formula I. Wherein the temperature of the dehydration reaction is between 0 and 10 ℃, the feeding molar ratio of the di-4-oxo-8- [4- (4-butoxyphenyl) benzamide ] -4H-chromene-2-formamide and the phosphorus oxychloride is 1: 2-5.
The core technical characteristics of the invention are as follows: commercial technical grade phosphorus oxychloride is purified before use. The purification method is preferably a normal pressure distillation mode, namely that 10-20% of front fraction of commercial industrial grade phosphorus oxychloride is distilled at normal pressure and reflux temperature, and the rest 80-90% of phosphorus oxychloride is the purified commercial industrial grade phosphorus oxychloride. The distillation of the purified phosphorus oxychloride can remove some impurities or acidic substances.
The pranlukast intermediate N- (2-cyano-4-oxo-4) prepared by adopting the technical scheme provided by the inventionH-The chromen-8-yl) -4- (4-butoxyphenyl) benzamide can effectively avoid the defects of low yield, low purity, color difference and the like in the existing preparation method. The beneficial effect that this technical scheme produced has: the obtained N- (2-cyano-4-oxo-4)H-The intermediate of the chromene-8-yl) -4- (4-butoxyphenyl) benzamide has high yield, high purity or good color, and further ensures that the quality of the pranlukast bulk drug can meet the standard or customer requirements.
The invention also provides an intermediate of the formula (I), N- (2-cyano-4-oxo-4)H-Analytical method for chromen-8-yl) -4- (4-butoxyphenyl) benzamide: a chromatographic column: octadecylsilane chemically bonded silica as filler, such as Welch C18, 4.6X 250mm, 5 μm or equivalent performance column; detection wavelength: 254 nm; column temperature: 30 ℃; flow rate: 1.0 ml/min; mobile phase: methanol acetonitrile buffer = 1: 1: 1, a preparation method of a buffer solution: 6.8g of potassium dihydrogen phosphate and 1g of tetramethylammonium hydroxide were dissolved in 1000ml of water, and 5ml of triethylamine was added thereto.
The present invention will be described further with reference to examples, and various alterations and combinations made by those skilled in the art and by conventional means are intended to be included in the scope of the present invention.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
EXAMPLE 1 preparation of pranlukast intermediate N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide
Purifying phosphorus oxychloride: 100kg of commercial industrial grade phosphorus oxychloride is added into a distillation tower, 20kg of front distillate is distilled off under normal pressure, and the rest 80kg of phosphorus oxychloride is used for standby.
Adding 400kg of DMF into a dry reaction kettle, cooling to 0 ℃, dropwise adding 67kg (4 equivalents) of purified phosphorus oxychloride, controlling the temperature within 10 ℃, keeping the temperature and stirring for 30min after dropwise adding, adding 50kg of 4-oxo-8- [4- (4-butoxyphenyl) benzamide ] -4H-chromene-2-formamide, and continuing to keep the temperature and react for 4 hours. 1500kg of ice brine is added into another reaction kettle, the reaction liquid is slowly transferred into the ice brine, the temperature is not more than 10 ℃, the stirring is carried out for 30 minutes, the filter cake is pressed and washed to be neutral, and the N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide 44kg is obtained after drying, the color is similar white, the purity is 98.5 percent, and the molar yield is 92 percent.
EXAMPLE 2 preparation of pranlukast intermediate N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide
Purifying phosphorus oxychloride: 100kg of commercial industrial grade phosphorus oxychloride is added into a distillation tower, 10kg of front distillate is distilled off under normal pressure, and the rest 90kg of phosphorus oxychloride is used for standby.
Adding 400kg of DMF into a dry reaction kettle, cooling to 0 ℃, dropwise adding 84kg (5 equivalents) of purified phosphorus oxychloride, controlling the temperature within 10 ℃, keeping the temperature and stirring for 30min after dropwise adding, adding 50kg of 4-oxo-8- [4- (4-butoxyphenyl) benzamide ] -4H-chromene-2-formamide, and continuing to keep the temperature and react for 4 hours. 1500kg of ice brine is added into another reaction kettle, the reaction liquid is slowly transferred into the ice brine, the temperature is not more than 10 ℃, the stirring is carried out for 30 minutes, the filter cake is pressed and washed to be neutral, and the N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide is dried to obtain 45.2kg of white-like, the purity is 99.0 percent, and the molar yield is 94 percent.
EXAMPLE 3 preparation of pranlukast intermediate N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide
Purifying phosphorus oxychloride: 100kg of commercial industrial grade phosphorus oxychloride is added into a distillation tower, 20kg of front distillate is distilled off under normal pressure, and the rest 80kg of phosphorus oxychloride is used for standby.
Adding 400kg of DMF into a dry reaction kettle, cooling to 0 ℃, dropwise adding 33.5kg (2 equivalents) of purified phosphorus oxychloride, controlling the temperature within 10 ℃, keeping the temperature and stirring for 30min after dropwise adding, adding 50kg of 4-oxo-8- [4- (4-butoxyphenyl) benzamide ] -4H-chromene-2-formamide, and continuing to keep the temperature and react for 4 hours. 1500kg of ice brine is added into another reaction kettle, the reaction liquid is slowly transferred into the ice brine, the temperature is not more than 10 ℃, the stirring is carried out for 30 minutes, the filter cake is pressed and washed to be neutral, and 43kg of N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide is obtained after drying, the color is similar white, the purity is 98.0 percent, and the molar yield is 90 percent.
EXAMPLE 4 preparation of pranlukast
40kg of intermediate N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide and DMF200kg which are prepared by the method are added into a reaction kettle and stirred at normal temperature to be dissolved and clear. 5kg of ammonium chloride and 6.2kg of sodium azide are added, and the mixture is stirred and reacted for 2 hours at normal temperature. Adding 2kg of active carbon, performing filter pressing, transferring the filtrate to another crystallization kettle, cooling to 10 ℃, adding 200kg of methanol, adjusting the pH to 1-2 with hydrochloric acid, stirring and crystallizing for 1 hour at 10 ℃, performing filter pressing, washing a filter cake with a small amount of methanol, and drying to obtain 42.5kg of pranlukast, wherein the molar yield is 90%, the color is white, and the purity is 99.9%.
Comparative example 1
(1) Preparation of pranlukast intermediate N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide
Adding 400kg of DMF into a dry reaction kettle, cooling to 0 ℃, dropwise adding 67kg (4 equivalents) of commercial industrial grade phosphorus oxychloride, controlling the temperature within 10 ℃, keeping the temperature and stirring for 30min after dropwise adding, adding 50kg of 4-oxo-8- [4- (4-butoxyphenyl) benzamide ] -4H-chromene-2-formamide, and continuing to keep the temperature and react for 4 hours. 1500kg of ice brine is added into another reaction kettle, the reaction liquid is slowly transferred into the ice brine, the temperature is not more than 10 ℃, the stirring is carried out for 30 minutes, the filter cake is pressed and washed to be neutral, and 37kg of N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide is obtained after drying, the color is similar white, the purity is 82.5 percent, and the molar yield is 77 percent.
(2) Preparation of pranlukast
20kg of the intermediate N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide obtained in the step and DMF100kg are added into a reaction kettle and stirred at normal temperature to be dissolved and cleared. 2.5kg of ammonium chloride and 3kg of sodium azide are added, and the mixture is stirred and reacted for 2 hours at normal temperature. Adding 1kg of active carbon, performing filter pressing, transferring the filtrate to another crystallization kettle, cooling to 10 ℃, adding 100kg of methanol, adjusting the pH to 1-2 with hydrochloric acid, stirring and crystallizing for 1 hour at 10 ℃, performing filter pressing, washing a filter cake with a small amount of methanol, and drying to obtain 20.1kg of pranlukast, wherein the molar yield is 85%, the color is white, and the purity is 90.5%.
Comparative example 2
(1) Preparation of pranlukast intermediate N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide
Adding 400kg of DMF into a dry reaction kettle, cooling to 0 ℃, dropwise adding 67kg (4 equivalents) of commercial industrial grade phosphorus oxychloride, controlling the temperature within 10 ℃, preserving heat and stirring for 30min after dropwise adding. Adding 16kg of triethylamine, controlling the temperature within 10 ℃, and stirring for 15min under heat preservation after the addition. 50kg of 4-oxo-8- [4- (4-butoxyphenyl) benzamide ] -4H-chromene-2-carboxamide is added, and the reaction is continued for 3 hours with heat preservation. 1500kg of ice brine is added into another reaction kettle, the reaction liquid is slowly transferred into the ice brine, the temperature is not more than 10 ℃, the stirring is carried out for 30 minutes, the filter cake is pressed and washed to be neutral, and 39.4kg of N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide is obtained after drying, the color is dark red, the purity is 92.5 percent, and the molar yield is 82 percent.
(2) Preparation of pranlukast
20kg of intermediate N- (2-cyano-4-oxo-4H-chromen-8-yl) -4- (4-butoxyphenyl) benzamide obtained in the step and DMF90kg are added into a reaction kettle and stirred at normal temperature to be dissolved and cleared. 2.5kg of ammonium chloride and 3kg of sodium azide are added, and the mixture is stirred and reacted for 2 hours at normal temperature. Adding 1.1kg of active carbon, performing filter pressing, transferring the filtrate to another crystallization kettle, cooling to 10 ℃, adding 90kg of methanol, adjusting the pH to 1-2 with hydrochloric acid, stirring and crystallizing at 10 ℃ for 1 hour, performing filter pressing, washing a filter cake with a small amount of methanol, and drying to obtain 21.2kg of pranlukast, wherein the molar yield is 89%, the color is reddish brown, and the purity is 95.8%.
Claims (5)
1. Industrial preparation of pranlukast intermediate N- (2-cyano-4-oxo-4)H-Process for the preparation of chromen-8-yl-4- (4-butoxyphenyl) benzamide, characterized in that 4-oxo-8- [4- (4-butoxyphenyl) benzamide]The (4H) -chromene-2-formamide reacts under the combined action of DMF and distilled and purified commercial industrial grade phosphorus oxychloride to prepare pranlukast intermediate N- (2-cyano-4-oxo-4)H-Chromen-8-yl) -4- (4-butoxyphenyl) benzamide was prepared by the following route:
2. the method for preparing pranlukast intermediate according to claim 1, wherein the commercial industrial grade phosphorus oxychloride purification method is atmospheric distillation.
3. The method for preparing pranlukast intermediate according to claims 1 and 2, wherein the commercial industrial grade phosphorus oxychloride atmospheric distillation purification method specifically comprises the following steps: distilling 10-20% of front fraction of commercial industrial grade phosphorus oxychloride at normal pressure and reflux temperature, and obtaining purified commercial industrial grade phosphorus oxychloride at the rest 80-90%.
4. The method for preparing pranlukast intermediate according to claim 1, wherein the reaction temperature is 0-10 ℃.
5. The method for preparing pranlukast intermediate according to claim 1, wherein the feeding molar ratio of the reacted 4-oxo-8- [4- (4-butoxyphenyl) benzamide ] -4H-chromene-2-carboxamide to phosphorus oxychloride is 1: 2-5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101450943A (en) * | 2008-11-10 | 2009-06-10 | 河北科技大学 | Method for synthesizing drug pranlukast from tetrahydrofuran path |
| CN106588897A (en) * | 2017-02-28 | 2017-04-26 | 上海微巨实业有限公司 | New preparation method of Pranlukast |
| CN106854202A (en) * | 2016-12-05 | 2017-06-16 | 安徽峆药业股份有限公司 | A kind of new method for preparing high-purity asthma drug Pranlukast |
-
2018
- 2018-09-21 CN CN201811110042.5A patent/CN110938052A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101450943A (en) * | 2008-11-10 | 2009-06-10 | 河北科技大学 | Method for synthesizing drug pranlukast from tetrahydrofuran path |
| CN106854202A (en) * | 2016-12-05 | 2017-06-16 | 安徽峆药业股份有限公司 | A kind of new method for preparing high-purity asthma drug Pranlukast |
| CN106588897A (en) * | 2017-02-28 | 2017-04-26 | 上海微巨实业有限公司 | New preparation method of Pranlukast |
Non-Patent Citations (3)
| Title |
|---|
| 《简明化学试剂手册》编写组: "《简明化学试剂手册》", 31 December 1991 * |
| 石刚: "抗哮喘药普仑司特合成工艺的研究", 《硕士学位论文》 * |
| 陈瀛: "普仑司特的合成工艺研究", 《硕士研究生论文》 * |
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