CN109553518B - Preparation method of substituted phenylacetic acid derivative - Google Patents
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- CN109553518B CN109553518B CN201810969902.4A CN201810969902A CN109553518B CN 109553518 B CN109553518 B CN 109553518B CN 201810969902 A CN201810969902 A CN 201810969902A CN 109553518 B CN109553518 B CN 109553518B
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
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- C07—ORGANIC CHEMISTRY
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- 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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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
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- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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Abstract
The invention belongs to the field of drug synthesis, relates to a preparation method of substituted phenylacetic acid derivatives, and particularly relates to preparation of 2- [4- (2-oxypenthyl) phenylpropionic acid]The preparation method of (1). Comprises alkylation reaction such as nitrile alkylation reaction, ester alkylation reaction or naphthenation reaction to obtain intermediate compound of formula II-2 or formula II-2',
Description
Technical Field
The invention belongs to the field of drug synthesis, relates to a preparation method of substituted phenylacetic acid derivatives, and particularly relates to a preparation method of 2- [4- (2-oxypenthyl) phenylpropionic acid ].
Background
Substituted phenylacetic acid derivatives are disclosed in U.S. patents, such as US4161538, and have the following structural formula:
in US4161538 they have also been reported to have very good anti-inflammatory, analgesic and antipyretic activity.
When A in the general structure is oxygen, n is 1, R1A very representative substituted phenylacetic acid derivative, when methyl, is loxoprofen, having the following structural formula:
the loxoprofen is a non-steroidal anti-inflammatory propionic acid derivative drug, and the propionic acid derivative drug also comprises ibuprofen and naproxen. Loxoprofen is marketed in the form of its sodium salt by the company Sankyo in brazil, mexico and japan, respectively, loxoprofen sodium, under the trade name Loxonin in japan, Oxeno in argentina, and Loxomac in india. Suitable for oral administration in these countries, its formulation for injection is approved for sale in japan in 2006, month 1.
In the US patent 4161538, it is disclosed that loxoprofen is synthesized as shown in the scheme wherein n has the value 1 and R is1Is a methyl group, and the compound is,
the cyanoalkylation synthesis was reported as early as 1991 in journal literature, the journal of the Chinese medical industry, and was used for the synthesis of ibuprofen.
Although loxoprofen and ibuprofen belong to the same class of loxoprofen products, due to the structural difference between cyclopentanone group and isopropyl group, the specific process conditions in cyanoalkylation, such as solvent, temperature and the like, are not suitable for the synthesis of loxoprofen.
In view of the pharmaceutical use of loxoprofen, a substituted phenylacetic acid compound, in the field of medicine, there is a need to develop more processes suitable for loxoprofen synthesis, such as more preferred cyanoalkylation process or other processes.
Disclosure of Invention
The invention provides a synthesis process of substituted phenylacetic acid compounds such as loxoprofen, which comprises a cyanoalkylation process, an ester alkylation process, a naphthenic alkylation process and the like. The synthesis process of the invention can prepare the substituted phenylacetic acid compound with low cost and high yield.
First, the present invention provides a route for preparing loxoprofen intermediates by an alkylation process, which includes a cyanoalkylation process, an ester alkylation process, or a ring alkylation process, etc. The reaction formula is as follows:
wherein X is halogen, OMs, OTs, OTf; r2Represents a hydrogen atom or a low-substituted alkyl group; r1＝CN,COOH,COOR2,CH2OH,CHO。
The reaction temperature of the cyanoalkylation reaction is-10 ℃ to 150 ℃; the cyanoalkylation reaction does not require an additional solvent.
The reaction temperature of the ester alkylation reaction is-10 ℃ to 150 ℃; the ester alkylation reaction does not require an additional solvent.
The reaction temperature of the naphthenic reaction is-10 ℃ to 150 ℃; the cycloparaffination reaction does not require an additional solvent.
The prepared loxoprofen intermediate can be further used for preparing loxoprofen compounds. Such as by hydrolysis or oxidation:
wherein R is2Represents a hydrogen atom or a low-substituted alkyl group; r1＝CN,COOH,COOR2,CH2OH,CHO。
More preferably, R1Is CN or COOR2。
The hydrolysis reagent for the hydrolysis reaction may be an acid commonly used in the art such as hydrochloric acid, sulfuric acid or trifluoroacetic acid.
The cyanoalkylation process of the present invention produces a new intermediate compound of formula II-2.
Wherein R is2Represents a hydrogen atom or a low-substituted alkyl group; r1＝CN,COOR2,CH2OH,CHO。
The intermediates of the present invention are disclosed in the general formula of U.S. Pat. No. 4,4407823, however, their use is not the same. The preparation of loxoprofen compounds by further hydrolysis or oxidation is also not suggested in US 4407823. Thus, the intermediate compounds of the present invention have significant advantages.
The reaction involved in the present invention can be represented by the following reaction formula:
wherein X is halogen, OMs, OTs, OTf; r2Represents a hydrogen atom or a low-substituted alkyl group; r1＝CN,COOH,COOR2,CH2OH, CHO. Preferably, R2Is methyl, R1Is COOCH3And X is OMs.
Specifically, under the action of alkali, dimethyl adipate is subjected to cyclization reaction to prepare a compound shown in a formula A-2, the compound shown in the formula A-2 is reacted with benzyl chloride to prepare a compound shown in the formula I-1, and then ester groups are removed to prepare the compound shown in the formula I-2. The compound of formula I-2 is alkylated with a compound of formula II-1 or cyclopropane to produce a compound of formula II-2 or II-2 ". The substituted phenylacetic acid compound is prepared through further hydrolysis or oxidation.
The preferred embodiment of the invention is as follows:
2- (4- ((2-oxocyclopentyl) methyl) phenyl) propionitrile is prepared from 2-benzylcyclopentanone and o-p-toluenesulfonylceranitrile through nitrile alkylation reaction,
the prepared 2- (4- ((2-oxocyclopentyl) methyl) phenyl) propionitrile is further subjected to hydrolysis reaction to prepare loxoprofen,
the nitrile alkylation reaction is carried out without the addition of a solvent.
The preparation method provided by the invention has the following beneficial effects. First, an alternative to the preparation of substituted phenylacetic acid derivatives is provided. Second, the preparation method of the present invention is not taught by the prior art. Thirdly, dimethyl adipate is used as a starting material in the reaction process, so that the method is cheap and convenient to obtain. Fourthly, the preparation method provided by the invention is suitable for industrial scale production and has certain economic benefit.
Detailed Description
Example 1:
a500 mL single neck flask was charged with dimethyl adipate (43g, 247.2mmol), pre-dried tetrahydrofuran (250mL), and sodium hydride (14g, 350mmol) was added portionwise at room temperature. After the completion of the charge, the mixture was put in an oil bath and heated to 50 ℃ and stirred for reaction for 3.5 hours, and then TLC (phosphomolybdic acid treatment) was used to monitor the completion of the reaction. Stopping heating, moving the reaction to ice bath, cooling to 5-10 ℃, dropwise adding 3M HCl aqueous solution, adjusting the pH value of the solution to be about 4, and stirring at room temperature for 2 hours. Ethyl acetate extraction (100mL × 3), organic phases are combined, and the mixture is washed by saturated sodium bicarbonate (50mL) and saturated brine (100mL), dried by anhydrous magnesium sulfate, and the solvent is removed under reduced pressure to obtain yellow viscous liquid, and the yellow viscous liquid is purified by column chromatography, wherein the eluent ratio is (Hex: EA ═ 10:1), and components are collected and are dried by spinning to obtain pale yellow liquid A-2(36.6g, 95% yield).
Example 2:
to a dry clean 20L glass kettle was added 1.8kg benzyl chloride and 2.0kg A-2, 1.8kg sodium carbonate, 0.16kg potassium iodide, 7.5kg DMF. Stirring, heating to 90-95 ℃ with hot water, and reacting for 3-4 hours under heat preservation. And (5) after heat preservation, sampling and controlling. And after the central control is qualified, cooling to room temperature by using circulating water. 5kg of drinking water was added to wash for 10 minutes. Extracted twice more with 5kg X2 DCM. The two DCM layers were combined and washed once with 5kg of drinking water. The aqueous layers were combined and extracted once with 2kg DCM. The DCM layers were combined and the filtrate was distilled under reduced pressure at 45 ℃ until no droplets flowed out. The amount of liquid obtained, i.e., I-1, was about 3.5 kg. The above I-1 was put into a 20L clean glass kettle, and 8.9kg of 98% concentrated hydrochloric acid and 6.7kg of acetic acid were added. Stirring, heating to 90-95 ℃ with hot water, and reacting for 4-5 hours under heat preservation. And (5) after heat preservation, sampling and controlling. The end point of the reaction is detected by a dot plate. And after the central control is qualified, cooling to room temperature by using circulating water. Extracted twice with 5kg x2 DCM. The DCM layers were combined and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate. The DCM layer was separated and washed once with drinking water. The aqueous layers were combined and extracted once with 2kg DCM. The DCM layers were combined and the filtrate was distilled under reduced pressure at 45 ℃ until no droplets flowed out. The resulting liquid was I-2.
Example 3:
1910g (5eq) of AlCl was charged into a 5L reactor3And stirring and cooling to 0-10 ℃, slowly dropwise adding a mixed solution of 500g (1eq) of I-2 and 575g (1.1eq) of II-1, reacting for 4 hours at room temperature after dropwise adding, and monitoring the reaction by using a liquid phase. Pouring into ice water mixture, adding 500g concentrated hydrochloric acid and 2kg dichloromethane, stirring for 30min, and layering; the organic layer was washed with 100g of 3% hydrochloric acid, and the layers were separated, and washed with 1kg of water 1 time and separated. And (3) concentrating in a water bath at 45 ℃ to obtain 733g of crude product, wherein HPLC (high performance liquid chromatography) is 83.2%, and the purification yield is as follows: 81.7 percent.
Example 4:
4kg (5eq) of AlCl were placed in a 20L reactor3Starting stirring, slowly dripping 1742.4g (1eq) of a mixed solution of I-2 and 2252.6g (1eq) of II-1', heating to 70-75 ℃ after dripping, keeping the temperature for reaction for 4 hours, and monitoring the reaction by a liquid phase. Pouring into ice water mixture, adding 1kg concentrated hydrochloric acid and 5kg dichloromethane, stirring for 30min, layering, and extracting the water phase with 2kg dichloromethane; the combined organic layers were washed with 1kg of 3% hydrochloric acid, and then the layers were separated, and washed with 3kg of water 1 time and then the layers were separated. Concentrating in 45 deg.C water bath to obtain crude product 2371g, HPLC: 81.2%, pure yield: 84.7 percent.
Example 5:
1910g (5eq) of AlCl was charged into a 5L reactor3Stirring and cooling to 0-10 ℃, slowly dripping a mixed solution of 500g (1eq) I-2 and 500g (3eq) propylene oxide, and drippingAfter that, the mixture was placed at room temperature for 4 hours, and the reaction was monitored in a liquid phase. The reaction was monitored in the liquid phase. Pouring into ice water mixture, adding 100g concentrated hydrochloric acid and 2kg dichloromethane, stirring for 30min, and layering; the organic layer was washed with 100g of 3% hydrochloric acid, and the layers were separated, and washed with 1kg of water 1 time and separated. Concentration in 45 ℃ water bath to obtain 664g of the II-2' compound, 73.8% of HPLC, pure yield: 73.5 percent.
Example 6:
in a 3L reactor, 800g of methylene chloride were charged, 314g (232 g converted) of II-2', 20.6g of sodium bromide, 16.8g of NaHCO were added31.56g of 2,2,6, 6-tetramethylpiperidine oxide (TEMPO), cooling to 0-5 ℃, dropwise adding 1.86kg of 10% sodium hypochlorite solution, keeping the temperature for 2-3 hours after dropwise adding, controlling the sampling liquid phase, obtaining an organic phase by layering, adjusting the pH to 8 by using sodium carbonate aqueous solution, obtaining an aqueous phase by layering, adjusting the pH to 2 by using concentrated hydrochloric acid, extracting for 2 times by using 1kg of dichloromethane, combining the organic phases, concentrating at 45 ℃ in a water bath to obtain 226g of a II-3 compound, wherein the yield is 92.1%, and the purity is 98.5%.
Example 7:
730g (1eq) of the II-2 crude product is put into a 5L four-mouth bottle, 2Kg of acetic acid is added, 1Kg of concentrated hydrochloric acid is pumped in, the temperature is raised to 90-100 ℃, the temperature is kept for 2-3 hours, and the reaction is monitored by a liquid phase. The reaction solution was cooled to room temperature, extracted with 1kg of dichloromethane and layered, the pH of the organic phase sodium carbonate aqueous solution was adjusted to 8, the layers were separated to obtain an aqueous phase, the pH of concentrated hydrochloric acid was adjusted to 2, 1kg of dichloromethane was extracted 2 times, the organic phases were combined, and concentrated in a water bath at 45 ℃ to obtain 567g of the II-3 compound, with a yield of 82.1% and a purity of 98.2%.
Claims (8)
1. A compound of formula II-2, having the formula:
wherein R is2Represents a low-substituted alkyl group; r1＝CH2OH,CHO。
2. A compound of formula II-2 ", having the formula:
3. a method for preparing a compound of formula II-2, which is characterized in that the compound of formula II-1 is prepared by alkylation reaction, and the reaction formula is as follows:
wherein X is halogen, OMs, OTs, OTf; r2And R1As defined in claim 1.
4. The method according to claim 3, wherein the compound of formula II-2 is further hydrolyzed or oxidized to produce loxoprofen,
wherein R is2And R1As defined in claim 1.
5. A method for preparing a compound shown in a formula II-2' is characterized in that the compound is prepared by a naphthenation reaction of a compound shown in the formula I-2 and cyclopropane, and the reaction formula is as follows:
6. the process of claim 3 or 5, wherein the alkylation reaction is carried out in the absence of an added solvent.
7. The process according to claim 3 or 5, wherein the alkylation reaction is carried out at a reaction temperature of-10 ℃ to 150 ℃.
8. The process according to claim 5, wherein the compound of formula II-2 "is further subjected to an oxidation reaction to produce loxoprofen,
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| CN111440059B (en) * | 2020-05-14 | 2022-11-15 | 上海柏狮生物科技有限公司 | Synthetic method of loxoprofen |
| CN112079764B (en) * | 2020-10-12 | 2023-08-01 | 山东汇海医药化工有限公司 | Synthesis method of sunitinib intermediate 5-fluoroindol-2-one |
| CN113387787A (en) * | 2021-05-26 | 2021-09-14 | 杭州国瑞生物科技有限公司 | Synthesis method of 2-benzyl cyclopentanone |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09202748A (en) * | 1996-01-24 | 1997-08-05 | Permachem Asia Ltd | New propionic acid derivative and its production |
| CN102199085A (en) * | 2010-03-26 | 2011-09-28 | 上海市七宝中学 | Preparation method of 2-(4-alkylphenyl) propanoic acid |
| CN106045842A (en) * | 2016-06-16 | 2016-10-26 | 南京海融制药有限公司 | Method for preparing loxoprofen active metabolite |
| CN109467506A (en) * | 2017-09-07 | 2019-03-15 | 江苏瑞科医药科技有限公司 | A kind of preparation method of substituted phenylacetic acid derivative |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09202748A (en) * | 1996-01-24 | 1997-08-05 | Permachem Asia Ltd | New propionic acid derivative and its production |
| CN102199085A (en) * | 2010-03-26 | 2011-09-28 | 上海市七宝中学 | Preparation method of 2-(4-alkylphenyl) propanoic acid |
| CN106045842A (en) * | 2016-06-16 | 2016-10-26 | 南京海融制药有限公司 | Method for preparing loxoprofen active metabolite |
| CN109467506A (en) * | 2017-09-07 | 2019-03-15 | 江苏瑞科医药科技有限公司 | A kind of preparation method of substituted phenylacetic acid derivative |
Non-Patent Citations (4)
| Title |
|---|
| Friedel crafts Reactions of Three-Member Heterocycles I. Reaction of Propylene Oxide with Benzene;Norman Milstein;《Journal of heterocyclic chemistry》;19680630;第5卷;第337-338页 * |
| Green and Efficient: Oxidation of Aldehydes to Carboxylic Acids and Acid Anhydrides with Air;Kai-Jian Liu等;《ACS Sustainable Chem. Eng.》;20180307;第6卷;第4916-4921页 * |
| Kai-Jian Liu等.Green and Efficient: Oxidation of Aldehydes to Carboxylic Acids and Acid Anhydrides with Air.《ACS Sustainable Chem. Eng.》.2018,第6卷第4916-4921页. * |
| 布洛芬的氰烷基化合成法;陈芬儿;《中国医药工业杂志》;19911231;第203-204页 * |
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