CN108341775B - Synthetic method of rebamipide intermediate - Google Patents
Synthetic method of rebamipide intermediate Download PDFInfo
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- CN108341775B CN108341775B CN201710055712.7A CN201710055712A CN108341775B CN 108341775 B CN108341775 B CN 108341775B CN 201710055712 A CN201710055712 A CN 201710055712A CN 108341775 B CN108341775 B CN 108341775B
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- amino
- quinolone
- rebamipide
- propionic acid
- aspartic acid
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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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
Abstract
The invention discloses a key intermediate 2-amino-3- [2 (1) for synthesizing rebamipideH) -quinolone-4]A novel process for the production of propionic acid. The method comprises the step of reacting aspartic acid with 2-hydroxyquinoline to prepare the rebamipide key intermediate 2-amino-3- [2 (1)H) -quinolone-4]Propionic acid and p-chlorobenzoyl chloride are condensed to prepare rebamipide. The intermediate synthesis method has the advantages of cheap and easily-obtained raw materials, short reaction steps and good optical purity.
Description
Technical Field
The invention relates to the technical field of medical and chemical medicines, in particular to a synthetic method of a rebamipide intermediate.
Background
Rebamipide, known as 2- (4-chlorobenzoylamino) -3- (1, 2-dihydro-2-oxo-4-quinolyl) propionic acid by the Chinese cultural name, is a gastric mucosa protective agent and an anti-ulcer drug, and plays an important role in treating gastric ulcer and acute gastric mucosa injury at present. The structural formula of rebamipide is as follows:
the structure of rebamipide has a chiral center, two enantiomers exist, the activity of R-rebamipide is 1.8 times of that of S-rebamipide, and the R-rebamipide can be used as a racemate of the existing pharmaceutical composition. There are several synthetic routes for rebamipide, the most classical one reported by Uchida et al: synthesis of intermediate (R, S) -2-amino-3- [2 (1) of 4-bromomethyl quinolone and diethyl acetamidomalonateH) -quinolone-4]Propionic acid, and then the rebamipide is prepared by condensation of parachlorobenzoyl chloride; wherein, the diethyl acetamidomalonate is prepared by oximation, reduction and acetylation of diethyl malonate, and the 4-bromomethyl quinolone is prepared by condensation reaction, bromination and cyclization of aniline and acetoacetyl chloride (Uchida and other reports: the classical synthetic route of rebamipide). The method has the advantages of high yield, simple operation and easy industrialization. However, this route also has some disadvantages, such as the synthesis of the intermediate (R, S) -2-amino-3- [2 (1)H) -quinolone-4]The reaction steps of propionic acid are multiple, the production period is long, and the like. The route is as follows:
in addition, although rebamipide is used as a racemate thereof, the activity of R-rebamipide is 1.8 times that of S-rebamipide in terms of efficacy, and there is an urgent need for a better therapeutic effectA method for synthesizing rebamipide single isomer. The existing synthetic method of the rebamipide single isomer is basically in the intermediate (R, S) -2-amino-3- [2 (1)H) -quinolone-4]The single isomer is obtained by resolving propionic acid, and then the single isomer of rebamipide is correspondingly prepared by reacting the single isomer with p-chlorobenzoyl chloride. The resolution method is complicated and fussy, and needs to firstly carry out the racemate (R, S) -2-amino-3- [2 (1)H) -quinolone-4]Propionic acid esterification, resolution and hydrolysis to obtain single isomer. The preparation method of the rebamipide optical isomer is as follows:
therefore, the development of a rebamipide intermediate 2-amino-3- [2 (1) which has short synthetic steps and is easy to obtain optical isomers is urgently neededH) -quinolone-4]A propionic acid method. Specifically, the intermediate 2-amino-3- [2 (1)H) -quinolone-4]Propionic acid includes its (R) configuration, (S) configuration and racemate (R, S) configuration.
Disclosure of Invention
In view of the above problems, the present invention avoids the existing synthetic route to prepare rebamipide intermediate 2-amino-3- [2 (1)H) -quinolone-4]Defects in the propionic acid process, and provides a novel preparation method.
The technical concept of the invention is as follows: the inventor finds out through research and theoretical exploration in the literature and on the basis of a large number of experiments that the 4-position electron-deficient center of the 2-hydroxyquinoline structure is similar to the alpha-position electron-deficient center of a protonated heteroaromatic ring in Minisci reaction and can generate free radical addition reaction with a nucleophilic free radical; based on rebamipide intermediate 2-amino-3- [2 (1)H) -quinolone-4]The structural characteristics of propionic acid, the inventor finds a method for preparing the intermediate by carrying out Minisci reaction on 2-hydroxyquinoline and aspartic acid. The molecular structure of aspartic acid contains amino, which is easily oxidized by persulfate alkali metal salt, but the acidic environment of the reaction is proved to make the amino salt not easily oxidized; in addition to the two carboxyl groups in the aspartic acid structure, due to the difference in PKa, in this reactionShows a better selectivity, so that aspartic acid can react directly without additional protection.
According to the conception, the technical scheme of the invention is as follows:
adding aspartic acid, 2-hydroxyquinoline and silver nitrate into a mixed solvent of acetonitrile and water, dropwise adding alkali persulfate to react to prepare an intermediate 2-amino-3- [2 (1)H) -quinolone-4]Propionic acid.
Wherein the aspartic acid is L-aspartic acid, D-aspartic acid or racemate D, L-aspartic acid; intermediate 2-amino-3- [2 (1)H) -quinolone-4]Propionic acid is (S) -2-amino-3- [2 (1)H) -quinolone-4]Propionic acid, (R) -2-amino-3- [2 (1)H) -quinolone-4]Propionic acid or racemate (R, S) -2-amino-3- [2 (1)H) -quinolone-4]Propionic acid; the feeding molar ratio of the aspartic acid to the 2-hydroxyquinoline to the alkali metal persulfate to the silver nitrate is 1 (1-1.5): (1.5-2.5): (0.05-0.2); the reaction temperature is 50-80 ℃; the reaction time is 2-5 h; the alkali metal persulfate is sodium persulfate or potassium persulfate. The raw materials of the route, namely the aspartic acid and the 2-hydroxyquinoline, are low in price and easy to obtain, and can be purchased conveniently.
The technical scheme provided by the invention is adopted to prepare the rebamipide intermediate 2-amino-3- [2 (1)H) -quinolone-4]The propionic acid can effectively overcome the defects of multiple reaction steps, long production period, complex resolution and the like in the existing preparation method. The beneficial effect that this technical scheme produced has: the reaction steps are short, and the operation is simple and convenient; in addition, when the single optical isomer is prepared, the L-aspartic acid and the D-aspartic acid are cheap and easy to obtain, so that the complicated resolution step can be effectively avoided.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
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.
Example 1 Rebamipide intermediate 2-amino-3- [2 (1)H) -quinolone-4]Preparation of propionic acid
10g (75.1 mmol) of aspartic acid L-aspartic acid, 13.1g (90.1 mmol) of 2-hydroxyquinoline and 1.3g (7.51 mmol) of silver nitrate are added into a mixed solution of 400mL of acetonitrile and 100mL of water, the temperature is raised to 70 ℃, 300mL of 0.13g/mL potassium persulfate aqueous solution is slowly added dropwise, and after dropping, the reaction is carried out at 70 ℃ for 3 h. Cooling the reaction solution to room temperature, adding purified water 400mL, extracting with ethyl acetate 800mL 3, combining organic layers, washing with water 2000mL 3, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and crystallizing with acetone to obtain S-2-amino-3- [2 (1)H) -quinolone-4]Propionic acid 6.8g (29.3 mmol), molar yield: 39 percent. HPLC content 99.60%; m.p. 196 ℃ 198 ℃ [. alpha. ]]20=+21.5。(DMSO); 1H-NMR (600 MHz, DMSO) δ: 11.7 (bs, 1H), 8.50 (bs, 2H,), 7.74 (d, 1H), 7.41 (t, 1H), 7.27 (d, 1H), 7.11 (t, 1H), 6.40 (s, 1H), 4.00 (t, 1H), 3.30 (d, 2H) 。
EXAMPLE 2 Rebamipide intermediate 2-amino-3- [2 (1)H) -quinolone-4]Preparation of propionic acid
10g (75.1 mmol) of aspartic acid D-aspartic acid, 12.0g (82.6 mmol) of 2-hydroxyquinoline and 1.7g (9.8 mmol) of silver nitrate are added into a mixed solution of 400mL of acetonitrile and 100mL of water, the temperature is raised to 60 ℃, 300mL of 0.13g/mL potassium persulfate aqueous solution is slowly added dropwise, and after dropping, the reaction is carried out for 4h at 60 ℃. Cooling the reaction solution to room temperature, adding purified water 400mL, extracting with ethyl acetate 800mL 3, combining organic layers, washing with water 2000mL 3, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and crystallizing with acetone to obtain R-2-amino-3- [2 (1)H) -quinolone-4 ] propionic acid 6.6g (28.5 mmol), molar yield: 38 percent. [ alpha ] to]20=-20.2。(DMSO); HPLC content 99.7%.
EXAMPLE 3 Rebamipide intermediate 2-amino-3- [2 (1)H) -quinolone-4]Preparation of propionic acid
10g (75.1 mmol) of aspartic acid D, L-aspartic acid, 16.4g (112.6 mmol) of 2-hydroxyquinoline and 1.3g (7.51 mmol) of silver nitrate are added into a mixed solution of 400mL of acetonitrile and 100mL of water, the temperature is increased to 80 ℃, 300mL of 0.13g/mL potassium persulfate aqueous solution is slowly added dropwise, and after the addition is finished, the reaction is carried out at 80 ℃ for 3 h. Cooling the reaction liquidCooling to room temperature, adding purified water 400mL, extracting with ethyl acetate 800mL x 3, mixing organic layers, washing with water 2000mL x 3, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and crystallizing with acetone to obtain racemate (R, S) -2-amino-3- [2(1, S) -2-amino-3- [2H) -quinolone-4]Propionic acid 5.9g (25.5 mmol), molar yield: 34 percent. HPLC content 99.53%.
EXAMPLE 4 Rebamipide intermediate 2-amino-3- [2 (1)H) -quinolone-4]Preparation of propionic acid
10g (75.1 mmol) of aspartic acid D, L-aspartic acid, 10.9g (75.1 mmol) of 2-hydroxyquinoline and 1.9g (11.27 mmol) of silver nitrate are added into a mixed solution of 400mL of acetonitrile and 100mL of water, the temperature is increased to 80 ℃, 300mL of 0.15g/mL potassium persulfate aqueous solution is slowly added dropwise, and after the dropwise addition is finished, the reaction is carried out for 4h at 80 ℃. Cooling the reaction solution to room temperature, adding purified water 400mL, extracting with ethyl acetate 800mL 3, combining organic layers, washing with water 2000mL 3, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and crystallizing with acetone to obtain racemate (R, S) -2-amino-3- [2(1, S) -2-amino-3- [2H) -quinolone-4]Propionic acid 4.9g (21.0 mmol), molar yield: 28 percent. HPLC content 99.50%.
EXAMPLE 5 Rebamipide intermediate 2-amino-3- [2 (1)H) -quinolone-4]Preparation of propionic acid
10g (75.1 mmol) of aspartic acid D, L-aspartic acid, 16.4g (112.7 mmol) of 2-hydroxyquinoline and 1.0g (6 mmol) of silver nitrate are added into a mixed solution of 400mL of acetonitrile and 100mL of water, the temperature is raised to 60 ℃, 300mL of 0.12g/mL potassium persulfate aqueous solution is slowly added dropwise, and after dropping, the reaction is carried out at 60 ℃ for 3 h. Cooling the reaction solution to room temperature, adding purified water 400mL, extracting with ethyl acetate 800mL 3, combining organic layers, washing with water 2000mL 3, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and crystallizing with acetone to obtain racemate (R, S) -2-amino-3- [2(1, S) -2-amino-3- [2H) -quinolone-4]Propionic acid 6.1g (26.3 mmol), molar yield: 35 percent. HPLC content 99.70%.
EXAMPLE 6 Rebamipide intermediate 2-amino-3- [2 (1)H) -quinolone-4]Preparation of propionic acid
10g (75.1 mmol) of aspartic acid D, L-aspartic acid, 16.4g (112.7 mmol) of 2-hydroxyquinoline and 1.0g (6 mmol) of silver nitrate were added to 400mL of acetonitrile mixed with 100mL of waterThe solution was heated to 60 ℃ and 300mL of a 0.14g/mL aqueous solution of sodium persulfate was slowly added dropwise thereto, followed by reaction at 70 ℃ for 5 hours. Cooling the reaction solution to room temperature, adding purified water 400mL, extracting with ethyl acetate 800mL 3, combining organic layers, washing with water 2000mL 3, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and crystallizing with acetone to obtain racemate (R, S) -2-amino-3- [2(1, S) -2-amino-3- [2H) -quinolone-4]Propionic acid 5.4g (23.3 mmol), molar yield: 31 percent. HPLC content 99.53%.
Example 7-example 12
Claims (8)
1. Synthetic rebamipide intermediate 2-amino-3- [2 (1)H) -quinolone-4]The propionic acid preparation process features that aspartic acid and 2-hydroxyquinoline react under the action of alkali persulfate and silver nitrate to prepare rebamipide intermediate 2-amino-3- [2 (1)H) -quinolone-4]Propionic acid, preparation route is as follows:
2. the method of claim 1, wherein the aspartic acid is L-aspartic acid, D-aspartic acid or racemate D, the L-aspartic acid having the formula:
3. the process as claimed in claim 1, wherein the intermediate 2-amino-3- [2 (1)H) -quinolone-4]Propionic acid is (S) -2-amino-3- [2 (1)H) -quinolone-4]Propionic acid, (R) -2-amino-3- [2 (1)H) -quinolone-4]Propionic acid or racemate (R, S) -2-amino-3- [2 (1)H) -quinolone-4]Propionic acid, structural formula as follows:
4. the process as set forth in claim 1, wherein the alkali metal persulfate is sodium persulfate or potassium persulfate.
5. The method according to claim 1, wherein the solvent for the reaction is a mixed solvent of acetonitrile and water.
6. The method according to claim 1, wherein the molar ratio of aspartic acid, 2-hydroxyquinoline, alkali metal persulfate and silver nitrate is 1 (1-1.5): 1.5-2.5): 0.05-0.2.
7. The process as claimed in claim 1, wherein the reaction temperature is from 50 to 80 ℃.
8. The process as claimed in claim 1, wherein the reaction time is from 2 to 5 hours.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4578381A (en) * | 1982-07-05 | 1986-03-25 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
| WO1999009005A1 (en) * | 1997-08-15 | 1999-02-25 | The Picower Institute For Medical Research | Hiv matrix protein tyrosine position 29 pocket binders |
| CN103739499A (en) * | 2011-10-24 | 2014-04-23 | 尼科斯股份有限公司 | Quinone based nitric oxide donating compounds |
| CN104994845A (en) * | 2012-10-23 | 2015-10-21 | 尼科斯科学爱尔兰公司 | Quinone based nitric oxide donating compounds for ophthalmic use |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4578381A (en) * | 1982-07-05 | 1986-03-25 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
| WO1999009005A1 (en) * | 1997-08-15 | 1999-02-25 | The Picower Institute For Medical Research | Hiv matrix protein tyrosine position 29 pocket binders |
| CN103739499A (en) * | 2011-10-24 | 2014-04-23 | 尼科斯股份有限公司 | Quinone based nitric oxide donating compounds |
| CN104994845A (en) * | 2012-10-23 | 2015-10-21 | 尼科斯科学爱尔兰公司 | Quinone based nitric oxide donating compounds for ophthalmic use |
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