CN111072475A - Synthesis method and application of 1-hydroxymethyl cyclopropyl acetic acid - Google Patents
Synthesis method and application of 1-hydroxymethyl cyclopropyl acetic acid Download PDFInfo
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- CN111072475A CN111072475A CN201911328194.7A CN201911328194A CN111072475A CN 111072475 A CN111072475 A CN 111072475A CN 201911328194 A CN201911328194 A CN 201911328194A CN 111072475 A CN111072475 A CN 111072475A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or 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 to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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Abstract
The invention provides a synthesis method of 1-hydroxymethyl cyclopropyl acetic acid, and the compound is an important intermediate of raw material medicine montelukast sodium and comprises the following steps: preparing a Grignard reagent by using a bromomethyl cyclopropyl acetate compound as an initial raw material and magnesium strips, magnesium chips or magnesium powder under the initiation of an initiator; in the same reaction system, nucleophilic addition is carried out on the reaction product and dried carbon dioxide to prepare a compound, namely, cyclopropyl magnesium acetate bromide; and (3) carrying out ester hydrolysis on the magnesium bromide cyclopropyl acetate under an alkaline condition to obtain the 1-hydroxymethyl cyclopropyl acetic acid. The invention effectively reduces the cost; the synthesis steps are reduced, high-risk operation in the synthesis process is eliminated, the safety risk is reduced, and the environmental pollution is reduced.
Description
Technical Field
The invention belongs to the field of organic chemistry and pharmaceutical chemistry, and particularly relates to a method for synthesizing a montelukast sodium raw material drug intermediate 1-hydroxymethyl cyclopropylacetic acid.
Background
Montelukast sodium is a drug effective in treating asthma, and pathologically, it specifically inhibits cysteinyl leukotriene (CysLT1) receptor in airway, thereby improving airway inflammation and controlling asthma symptoms. Through retrosynthetic analysis of montelukast sodium, it can be known that a key intermediate for synthesizing montelukast sodium has 1- (mercaptomethyl) cyclopropylacetic acid or a derivative thereof as a side chain moiety and 2- (2- (3(R) - (3- (2- (7-chloro-2-quinolyl) -vinyl) phenyl) -3- (hydroxy) propyl) phenyl) propanol as a main chain moiety. 1-mercaptomethylcyclopropyl acetic acid is used as a key precursor compound for forming a side chain of montelukast and is also a key intermediate for synthesizing the montelukast, but the 1-mercaptomethylcyclopropyl acetic acid is more active, and the sulfydryl is easily oxidized and is not easy to synthesize; however, an optimized synthetic route can use 1-hydroxymethylcyclopropylacetic acid as an intermediate for the synthesis of montelukast sodium instead of 1-mercaptomethylcyclopropylacetic acid. The molecular formula of 1-hydroxymethylcyclopropylacetic acid is C6H10O3, which is IUPAC named 2- [1- (hydroxymethyl) cyclopropy ] acetic acid and has the following chemical structural formula:
the existing synthetic route for preparing 1-hydroxymethyl cyclopropyl acetic acid mainly comprises the steps of firstly, carrying out ring synthesis on 1, 1-cyclopropane dimethanol, then carrying out sulfurous acid esterification on the 1, 1-cyclopropane dimethanol, then carrying out ring opening on the 1, substituting cyano groups for sulfur-containing groups in the 1-hydroxymethyl cyclopropyl dimethanol, and finally hydrolyzing the obtained 1-hydroxymethyl cyclopropyl acetonitrile under alkaline conditions to prepare the 1-hydroxymethyl cyclopropyl acetic acid. The synthetic route is as follows:
however, the synthetic technology has a long route and high cost of the adopted raw materials, on one hand, the cyanidation reaction adopts virulent sodium cyanide, so that the potential high public safety risk is realized, and the national control is very strict; on the other hand, the utilization rate of the expensive raw material 1, 1-cyclopropane dimethanol is not high, and the industrial production is seriously influenced.
In addition, the Shandong fibrate pharmaceutical company Limited (publication No. CN105541786A) takes 1, 1-cyclopropane dimethanol as a starting material, and carries out acetal exchange reaction with 2-halo-1, 1-dimethoxyethane, then the raw material is treated by organic alkali and hydrolyzed by acetic acid solution to obtain the monoacetyl protected 1-hydroxymethyl cyclopropyl methyl acetate, thereby avoiding the problems of poor diol selectivity and severe diol loss caused by mono benzoyl protection. However, the above-described method involves a plurality of complicated synthetic steps and is not an optimal choice for an industrially suitable route design.
In conclusion, the research and development of the technical personnel in the field are urgently needed to solve the problem of the synthesis method of the 1-hydroxymethyl cyclopropyl acetic acid with high yield, low cost and environmental friendliness.
Disclosure of Invention
In order to improve the efficiency of the montelukast sodium product, the preparation process is shortened, and the cost is reduced; high-risk operation in the synthesis process is removed, the safety risk is reduced, and the environmental pollution is reduced; the invention provides a synthesis method and application of 1-hydroxymethyl cyclopropyl acetic acid. The specific scheme comprises the following two steps:
A. reacting bromomethyl cyclopropyl acetate with a Grignard reagent to generate magnesium bromide cyclopropyl acetate;
B. the cyclopropyl magnesium bromide acetate is hydrolyzed to prepare the 1-hydroxymethyl cyclopropyl acetic acid.
In a preferred embodiment, step a is specifically: adding an initiator, magnesium and a solvent into the bromomethyl cyclopropyl acetate (compound I), and reacting at a certain initiation temperature; then adding carbon dioxide, and preparing the magnesium bromide cyclopropyl acetate (compound II) at a certain reaction temperature and reaction pressure.
In a preferred embodiment, the step B is specifically: and (3) carrying out ester hydrolysis on the magnesium bromide cyclopropyl acetate (compound II) under the alkaline condition to prepare the 1-hydroxymethyl cyclopropyl acetic acid (compound III).
In a preferred embodiment, the carbon dioxide is subjected to a drying treatment; the magnesium is at least one of magnesium strips, magnesium chips or magnesium powder.
In a preferred embodiment, the initiator is one of elementary iodine and red aluminum; the initiation temperature is 25-30 ℃.
In a preferred embodiment, the solvent is one of anhydrous diethyl ether, tetrahydrofuran and dichloromethane.
In a preferable embodiment, the reaction temperature is 5-10 ℃; the reaction pressure is 0.01-0.05 MPa.
In a preferred embodiment, the grignard reaction and the nucleophilic addition reaction of carbon dioxide are carried out simultaneously in the same reaction system.
In a preferred embodiment, the alkali is one of sodium hydroxide and potassium hydroxide.
The preparation method of montelukast sodium comprises the synthesis method of 1-hydroxymethyl cyclopropyl acetic acid.
The invention obtains the following beneficial effects:
the process conditions are very simple, the synthesis steps are few, the reaction yield reaches more than 90 percent, and the cost can be effectively reduced; the synthesis steps are reduced, high-risk operation in the synthesis process is eliminated, the safety risk is reduced, and the environmental pollution is reduced.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the preparation methods of the examples are illustrative only and not limiting, and that modifications to the preparation methods of the invention that are within the spirit of the invention are within the scope of the claimed invention.
Example 1
Adding 4.8g of newly planed magnesium chips, 400g of anhydrous tetrahydrofuran and 0.25g of granular iodine simple substance into a 1000ml pressure-bearing reactor, stirring and heating, controlling the temperature to be 25-30 ℃, stirring, simultaneously bubbling and introducing dried carbon dioxide into the feed liquid for 2 hours to ensure that the pressure in the reactor reaches and stabilizes at a certain pressure value in a range of 0.02-0.03 MPa, slowly and continuously adding 240g of bromomethyl cyclopropyl acetate tetrahydrofuran solution (containing 40g of bromomethyl cyclopropyl acetate), cooling the reaction feed liquid to 5-10 ℃ when the pressure value begins to decrease, maintaining the pressure in a range of 0.01-0.03 MPa in the cooling process, finishing the feeding of the bromomethyl cyclopropyl acetate tetrahydrofuran solution, continuously reacting for 0.5h at 5-10 ℃, and stopping the reaction when the pressure does not decrease.
And (3) carrying out reduced pressure distillation on the reaction liquid to recover tetrahydrofuran (which can be used indiscriminately), and concentrating until no solvent is obtained. Adding 120g of water and 8.8g of sodium hydroxide, and controlling the temperature to be 25-30 ℃ to react for 3 hours; cooling to below 15 deg.C, adding hydrochloric acid to adjust pH to 1-2, adding 50g hydrochloric acid, and controlling feed liquid temperature not to exceed 15 deg.C during the process of adding hydrochloric acid; the feed liquid is washed by 240g of ethyl acetate in portions, organic layers are combined, 2.4g of anhydrous magnesium sulfate is used for drying the organic layers, and the product 1-hydroxymethyl cyclopropyl acetic acid 22.6g with the content of 98.8 percent (HPLC) is obtained by filtering and washing, controlling the temperature to be not more than 30 ℃ and carrying out reduced pressure concentration, crystallization and filtration.
Example 2
Adding 4.8g of newly planed magnesium powder, 400g of anhydrous tetrahydrofuran and 0.25g of red aluminum into a 1000ml pressure-bearing reactor, stirring and heating, controlling the temperature to be 25-30 ℃, stirring, simultaneously bubbling and introducing dried carbon dioxide into a feed liquid for 1 hour to ensure that the pressure in the reactor reaches and stabilizes at a certain pressure value in a range of 0.02-0.03 MPa, slowly and continuously adding 240g of bromomethyl cyclopropyl acetate tetrahydrofuran solution (containing 40g of bromomethyl cyclopropyl acetate), cooling the reaction feed liquid to 5-10 ℃ when the pressure value begins to decrease, maintaining the pressure in a range of 0.01-0.03 MPa in the cooling process, finishing the continuous reaction at 5-10 ℃ when the bromomethyl cyclopropyl acetate anhydrous ether solution is fed, and stopping the reaction when the pressure is not decreased.
Distilling the above reaction liquid under reduced pressure to recover anhydrous diethyl ether (which can be used repeatedly), and concentrating until no solvent is obtained. Adding 120g of water and 8.8g of sodium hydroxide, and controlling the temperature to be 25-30 ℃ to react for 3 hours; cooling to below 15 deg.C, adding hydrochloric acid to adjust pH to 1-2, adding 50g hydrochloric acid, and controlling feed liquid temperature not to exceed 15 deg.C during the process of adding hydrochloric acid; the feed liquid is washed by 240g of ethyl acetate in portions, organic layers are combined, 2.4g of anhydrous magnesium sulfate is used for drying the organic layers, and the product 1-hydroxymethyl cyclopropyl acetic acid 22.8g with the content of 99.1 percent (HPLC) is obtained by filtering and washing, controlling the temperature to be not more than 30 ℃ and carrying out reduced pressure concentration, crystallization and filtration.
Example 3
Adding 4.8g of newly planed magnesium powder, 400g of anhydrous tetrahydrofuran and 0.25g of red aluminum into a 1000ml pressure-bearing reactor, stirring and heating, controlling the temperature to be 25-30 ℃, stirring, simultaneously bubbling and introducing dried carbon dioxide into a feed liquid for 2 hours to ensure that the pressure in the reactor reaches and stabilizes at a certain pressure value in a range of 0.02-0.03 MPa, slowly and continuously adding 240g of bromomethyl cyclopropyl acetate tetrahydrofuran solution (containing 40g of bromomethyl cyclopropyl acetate), cooling the reaction feed liquid to 5-10 ℃ when the pressure value begins to decrease, maintaining the pressure in a range of 0.01-0.03 MPa in the cooling process, continuously reacting for 0.5 hour at 5-10 ℃ after the bromomethyl cyclopropyl acetate dichloromethane solution is fed, and stopping the reaction when the pressure is not decreased.
And (3) carrying out reduced pressure distillation on the reaction liquid to recover dichloromethane (which can be used indiscriminately), and concentrating until no solvent is produced. Adding 120g of water and 8.8g of sodium hydroxide, and controlling the temperature to be 25-30 ℃ to react for 3 hours; cooling to below 15 deg.C, adding hydrochloric acid to adjust pH to 1-2, adding 50g hydrochloric acid, and controlling feed liquid temperature not to exceed 15 deg.C during the process of adding hydrochloric acid; the feed liquid is washed by 240g of ethyl acetate in portions, organic layers are combined, 2.4g of anhydrous magnesium sulfate is used for drying the organic layers, and the product 1-hydroxymethyl cyclopropyl acetic acid with the content of 22.4g and the content of 98.5 percent (HPLC) is obtained by filtering and washing, controlling the temperature not to exceed 30 ℃ and carrying out reduced pressure concentration, crystallization and filtration.
Example 4
Adding 4.8g of newly planed magnesium powder, 400g of anhydrous tetrahydrofuran and 0.25g of granular elemental iodine into a 1000ml pressure-bearing reactor, stirring and heating, controlling the temperature to be 25-30 ℃, stirring, simultaneously bubbling and introducing dried carbon dioxide into a feed liquid for 2 hours to ensure that the pressure in the reactor reaches and stabilizes at a certain pressure value in a range of 0.02-0.03 MPa, slowly and continuously adding 240g of bromomethyl cyclopropyl acetate tetrahydrofuran solution (containing 40g of bromomethyl cyclopropyl acetate), cooling the reaction feed liquid to 5-10 ℃ when the pressure value begins to decrease, maintaining the pressure in a range of 0.01-0.03 MPa in the cooling process, finishing the feeding of the bromomethyl cyclopropyl acetate tetrahydrofuran solution, continuously reacting for 0.5h at 5-10 ℃, and stopping the reaction when the pressure does not decrease.
And (3) carrying out reduced pressure distillation on the reaction liquid to recover tetrahydrofuran (which can be used indiscriminately), and concentrating until no solvent is obtained. Adding 120g of water and 8.8g of potassium hydroxide, and controlling the temperature to be 25-30 ℃ to react for 3 hours; cooling to below 15 deg.C, adding hydrochloric acid to adjust pH to 1-2, adding 50g hydrochloric acid, and controlling feed liquid temperature not to exceed 15 deg.C during the process of adding hydrochloric acid; the feed liquid is washed by 240g of ethyl acetate in portions, organic layers are combined, 2.4g of anhydrous magnesium sulfate is used for drying the organic layers, and the product 1-hydroxymethyl cyclopropyl acetic acid with the content of 22.4g and the content of 98.6 percent (HPLC) is obtained by filtering and washing, controlling the temperature to be not more than 30 ℃ and carrying out reduced pressure concentration, crystallization and filtration.
Example 5
Synthesis of montelukast sodium was prepared by reacting 1-hydroxymethylcyclopropylacetic acid prepared in any one of examples 1 to 4 with methanesulfonate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolinyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol.
Although the present invention has been described with reference to the above embodiments, the present invention is not limited to the above embodiments, which are only illustrative and not restrictive, and those skilled in the art can make various modifications without departing from the spirit and scope of the present invention as claimed in the claims.
Claims (10)
1. A synthetic method of 1-hydroxymethyl cyclopropyl acetic acid is characterized by comprising the following steps:
A. reacting bromomethyl cyclopropyl acetate with a Grignard reagent to generate magnesium bromide cyclopropyl acetate;
B. the cyclopropyl magnesium bromide acetate is hydrolyzed to prepare the 1-hydroxymethyl cyclopropyl acetic acid.
2. The method for synthesizing 1-hydroxymethylcyclopropylacetic acid according to claim 1, wherein the step a comprises the steps of: adding an initiator, magnesium and a solvent into the bromomethyl cyclopropyl acetate, and reacting at a certain initiation temperature; then adding carbon dioxide, and preparing the magnesium acetate-cyclopropyl bromide under certain reaction temperature and reaction pressure.
3. The method for synthesizing 1-hydroxymethylcyclopropylacetic acid according to claim 2, wherein the carbon dioxide is dried; the magnesium is at least one of magnesium strips, magnesium chips or magnesium powder.
4. The method for synthesizing 1-hydroxymethylcyclopropylacetic acid according to claim 1, wherein the step B comprises the steps of: and (3) carrying out ester hydrolysis on the magnesium bromide cyclopropyl acetate under an alkaline condition to prepare the 1-hydroxymethyl cyclopropyl acetic acid.
5. The method for synthesizing 1-hydroxymethyl cyclopropylacetic acid according to claim 2 or 3, wherein the initiator is one of elemental iodine and red aluminum; the initiation temperature is 25-30 ℃.
6. The method for synthesizing 1-hydroxymethylcyclopropylacetic acid according to claim 2 or 3, wherein the solvent is one of dehydrated ether, tetrahydrofuran and dichloromethane.
7. The method for synthesizing 1-hydroxymethylcyclopropylacetic acid according to claim 2 or 3, wherein the reaction temperature is 5 to 10 ℃; the reaction pressure is 0.01-0.05 MPa.
8. The method for synthesizing 1-hydroxymethylcyclopropylacetic acid according to claim 2 or 3, wherein the Grignard reaction and the nucleophilic addition reaction of carbon dioxide are carried out simultaneously in the same reaction system.
9. The method for synthesizing 1-hydroxymethylcyclopropylacetic acid according to claim 4, wherein the base is one of sodium hydroxide and potassium hydroxide.
10. A method for preparing montelukast sodium, comprising the synthesis of 1-hydroxymethylcyclopropylacetic acid according to any one of claims 1 to 9.
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| CN201911328194.7A CN111072475A (en) | 2019-12-20 | 2019-12-20 | Synthesis method and application of 1-hydroxymethyl cyclopropyl acetic acid |
| CN202011509418.7A CN112624921A (en) | 2019-12-20 | 2020-12-19 | Synthesis method and application of 1-hydroxymethyl cyclopropyl acetic acid |
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| CN112624921A (en) * | 2019-12-20 | 2021-04-09 | 牡丹江恒远药业股份有限公司 | Synthesis method and application of 1-hydroxymethyl cyclopropyl acetic acid |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050245569A1 (en) * | 2004-04-30 | 2005-11-03 | Arjanne Overeem | Process for making montelukast and intermediates therefor |
| CN101823952A (en) * | 2010-04-23 | 2010-09-08 | 大连理工大学 | Method for preparing 2,4,5-trifluorophenylacetic acid |
| CN102638981A (en) * | 2009-10-14 | 2012-08-15 | 先灵公司 | Substituted piperidines that increase p53 activity and the uses thereof |
| CN106892809A (en) * | 2015-12-20 | 2017-06-27 | 淄博诚桥医化技术有限公司 | The preparation method of the new 2 Ethylbutanoic acid of one class |
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| CN111072475A (en) * | 2019-12-20 | 2020-04-28 | 牡丹江恒远药业股份有限公司 | Synthesis method and application of 1-hydroxymethyl cyclopropyl acetic acid |
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Patent Citations (4)
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|---|---|---|---|---|
| US20050245569A1 (en) * | 2004-04-30 | 2005-11-03 | Arjanne Overeem | Process for making montelukast and intermediates therefor |
| CN102638981A (en) * | 2009-10-14 | 2012-08-15 | 先灵公司 | Substituted piperidines that increase p53 activity and the uses thereof |
| CN101823952A (en) * | 2010-04-23 | 2010-09-08 | 大连理工大学 | Method for preparing 2,4,5-trifluorophenylacetic acid |
| CN106892809A (en) * | 2015-12-20 | 2017-06-27 | 淄博诚桥医化技术有限公司 | The preparation method of the new 2 Ethylbutanoic acid of one class |
Non-Patent Citations (1)
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| 王哲清: "简述格氏反应", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112624921A (en) * | 2019-12-20 | 2021-04-09 | 牡丹江恒远药业股份有限公司 | Synthesis method and application of 1-hydroxymethyl cyclopropyl acetic acid |
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