CN111333496B - Preparation method of adapalene - Google Patents
Preparation method of adapalene Download PDFInfo
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- CN111333496B CN111333496B CN202010368823.5A CN202010368823A CN111333496B CN 111333496 B CN111333496 B CN 111333496B CN 202010368823 A CN202010368823 A CN 202010368823A CN 111333496 B CN111333496 B CN 111333496B
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- adapalene
- methoxyphenyl
- methyl ester
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- naphthoic acid
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- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229960002916 adapalene Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 21
- PGXNMQBGOVUZNC-UHFFFAOYSA-N methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]naphthalene-2-carboxylate Chemical compound C1C(C2)CC(C3)CC2CC13C1=CC(C2=CC3=CC=C(C=C3C=C2)C(=O)OC)=CC=C1OC PGXNMQBGOVUZNC-UHFFFAOYSA-N 0.000 claims abstract description 14
- LLKKPBJYOHZIFI-UHFFFAOYSA-N methyl 6-(4-methoxyphenyl)naphthalene-2-carboxylate Chemical compound C1=CC2=CC(C(=O)OC)=CC=C2C=C1C1=CC=C(OC)C=C1 LLKKPBJYOHZIFI-UHFFFAOYSA-N 0.000 claims abstract description 13
- VLLNJDMHDJRNFK-UHFFFAOYSA-N adamantan-1-ol Chemical compound C1C(C2)CC3CC2CC1(O)C3 VLLNJDMHDJRNFK-UHFFFAOYSA-N 0.000 claims abstract description 12
- KZLJGMNYKPEGQB-UHFFFAOYSA-N methyl 6-(4-methylphenyl)sulfonyloxynaphthalene-2-carboxylate Chemical compound C1=CC2=CC(C(=O)OC)=CC=C2C=C1OS(=O)(=O)C1=CC=C(C)C=C1 KZLJGMNYKPEGQB-UHFFFAOYSA-N 0.000 claims abstract description 9
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 0.000 claims abstract description 8
- SXLHAMYMTUEALX-UHFFFAOYSA-N (4-methoxyphenoxy)boronic acid Chemical compound COC1=CC=C(OB(O)O)C=C1 SXLHAMYMTUEALX-UHFFFAOYSA-N 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 12
- 230000001105 regulatory effect Effects 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- KPZYAGQLBFUTMA-UHFFFAOYSA-K tripotassium;phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O KPZYAGQLBFUTMA-UHFFFAOYSA-K 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- KAIPKTYOBMEXRR-UHFFFAOYSA-N 1-butyl-3-methyl-2h-imidazole Chemical class CCCCN1CN(C)C=C1 KAIPKTYOBMEXRR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 238000010992 reflux Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 19
- 238000006069 Suzuki reaction reaction Methods 0.000 abstract description 2
- 238000005804 alkylation reaction Methods 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- 238000010931 ester hydrolysis Methods 0.000 abstract description 2
- 239000002253 acid Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 4
- OIWSIWZBQPTDKI-UHFFFAOYSA-N 1-butyl-3-methyl-2h-imidazole;hydrobromide Chemical compound [Br-].CCCC[NH+]1CN(C)C=C1 OIWSIWZBQPTDKI-UHFFFAOYSA-N 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- QQAMHHZQONQBFZ-UHFFFAOYSA-N 1-(5-bromo-2-methoxyphenyl)adamantane Chemical compound COC1=CC=C(Br)C=C1C1(C2)CC(C3)CC2CC3C1 QQAMHHZQONQBFZ-UHFFFAOYSA-N 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 2
- 206010000496 acne Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- -1 1-adamantyl Chemical group 0.000 description 1
- NPMCAVBMOTZUPD-UHFFFAOYSA-N 6-bromonaphthalene-2-carboxylic acid Chemical compound C1=C(Br)C=CC2=CC(C(=O)O)=CC=C21 NPMCAVBMOTZUPD-UHFFFAOYSA-N 0.000 description 1
- 208000020154 Acnes Diseases 0.000 description 1
- 206010033733 Papule Diseases 0.000 description 1
- 206010037888 Rash pustular Diseases 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- JEUBRLPXJZOGPX-UHFFFAOYSA-N methyl 6-bromonaphthalene-2-carboxylate Chemical compound C1=C(Br)C=CC2=CC(C(=O)OC)=CC=C21 JEUBRLPXJZOGPX-UHFFFAOYSA-N 0.000 description 1
- 150000005209 naphthoic acids Chemical class 0.000 description 1
- 208000029561 pustule Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Abstract
The invention relates to a preparation method of adapalene, which comprises the steps of taking cheap and easily available 2-methoxycarbonyl-6-naphthol p-toluenesulfonate and 4-methoxyphenylboric acid as main raw materials, taking bis (triphenylphosphine) nickel chloride as a catalyst, obtaining 6- (4-methoxyphenyl) -2-naphthoic acid methyl ester through Suzuki coupling, carrying out alkylation reaction with 1-adamantanol to obtain 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoic acid methyl ester, and finally carrying out ester hydrolysis to obtain the target product adapalene. The invention has simple process, easily obtained raw materials, high yield and low cost, and the quality of the invention can reach the satisfactory level.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of a high-efficiency low-cost naphthoic acid derivative adapalene.
Background
Adapalene (Adapalene) with the chemical name 6- [3- (1-adamantyl) -4-methoxyphenyl ]]-2-naphthoic acid of the formula C 28 H 28 O 3 Molecular weight 412.5, cas:106685-40-9. The adapalene Lin Shuyu third-generation tretinoin medicine is clinically suitable for treating skin of common acne mainly represented by acnes, papules and pustules, and can also be used for treating acne on the face, chest and back.
。
The preparation methods of adapalene are relatively more so far, and mainly comprise the following methods:
method one (Bioorganic Chemistry,2011,39, 151-158):
the disadvantages of this method are: the preparation process of the raw material 6-bromo-2-naphthoic acid is complex and the market price is high.
Method two (EP 1868980B1; organic Process Research & Development 2006, 10, 285-288;Chinese Journal of Medicinal Chemistry 18,112-114):
the disadvantages of this method are: the preparation process of the raw material 6-bromo-2-naphthoic acid methyl ester is complex, and the market price is high; the raw material 4-bromo-2- (1-adamantyl) anisole has little market supply, even if the raw material can be prepared, but in the whole adapalene preparation process, the very expensive raw material 1-adamantanol is used at the beginning, so that the overall preparation cost is too high; the reaction for preparing the format reagent in the first step has strict requirements on conditions, stability and reproducibility, and has higher requirements on various equipment conditions, raw material components and the like.
Method three (CN 104003838A; the Journal of Organic Chemistry 2014, 79, 7132-7140):
the disadvantages of this method are: the raw material 4-bromo-2- (1-adamantyl) anisole has little market supply, even if the raw material can be prepared, but in the whole adapalene preparation process, the very expensive raw material 1-adamantanol is used at the beginning, so that the overall preparation cost is too high; the reaction for preparing the format reagent in the first step has strict requirements on conditions, stability and reproducibility, and has higher requirements on various equipment conditions, raw material components and the like.
For the above reasons, we explored a high-efficiency and low-cost preparation method of adapalene, and the synthetic route is as follows:
disclosure of Invention
The invention aims to solve the technical problems of providing a preparation method for efficiently producing adapalene with low cost, which has the advantages of simple process, easily available raw materials, high yield, low cost and satisfactory quality.
In order to achieve the purpose, the invention takes cheap and easily available 2-methoxycarbonyl-6-naphthol p-toluenesulfonate and 4-methoxyphenylboric acid as main raw materials, takes bis (triphenylphosphine) nickel chloride as a catalyst, obtains 6- (4-methoxyphenyl) -2-naphthoic acid methyl ester through Suzuki coupling, and then carries out alkylation reaction with 1-adamantanol to obtain 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoic acid methyl ester, and finally carries out ester hydrolysis to obtain the target product adapalene, and the specific steps are as follows:
(1) Under the nitrogen atmosphere, adding 1.0 times of 2-methoxycarbonyl-6-naphthol p-toluenesulfonate, 1.2-1.5 times of p-methoxyphenylboric acid, 2.0 times of inorganic base, 1.0-3.0% times of bis (triphenylphosphine) nickel chloride, brominated 1-butyl-3-methylimidazole and solvent into a three-port bottle, and reacting for 6-8 hours at 60-120 ℃ under stirring. Cooling the reaction liquid to 0-10 ℃, filtering, collecting a filter cake, pulping the filter cake twice with a proper amount of water, filtering, and drying to obtain a product of 6- (4-methoxyphenyl) -2-naphthoic acid methyl ester;
(2) Adding 1.0 times mole of 6- (4-methoxyphenyl) -2-naphthoic acid methyl ester and 1.2-4 times mole of 1-adamantanol into a three-mouth bottle, adding an aprotic solvent, slowly dropwise adding 2.0-3.0 times mole of concentrated sulfuric acid under stirring at room temperature for about 1-2 hours, and continuing stirring at room temperature overnight. Adding a proper amount of alkali, regulating to be weak alkaline, extracting, separating liquid, concentrating an organic phase to obtain a crude product, and recrystallizing with dichloroethane to obtain a product of 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoic acid methyl ester;
(3) 1.0 times mole of 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoic acid methyl ester and 4.0 times mole of sodium hydroxide are added into a three-port bottle, water and tetrahydrofuran are added into the bottle, and the mixture is heated and refluxed for 4 to 6 hours. Cooling the reaction solution to 0-10 ℃, regulating the pH value to be weak acid by 10% hydrochloric acid, separating out solid, filtering, collecting white solid, and recrystallizing by using a mixed solvent of tetrahydrofuran and toluene to obtain adapalene.
The synthesis process of the adapalene comprises the following formula:
。
in a preferred embodiment, in the step (1), the inorganic base is one of potassium phosphate trihydrate, potassium carbonate, and sodium carbonate.
In a preferred embodiment, in the present invention, in the step (1): the solvent is one of toluene, tetrahydrofuran and N, N-dimethylformamide.
In a preferred embodiment, in the present invention, in the step (2): the aprotic solvent is one of dichloromethane and chloroform.
The route has the advantages that:
(1) The raw material 2-methoxycarbonyl-6-naphthol p-toluenesulfonate is cheap and easy to obtain;
(2) The raw material 4-methoxy phenylboronic acid has large market quantity and sufficient supply, and is simple and easy to obtain even if prepared by the raw material;
(3) In the whole reaction process, the raw material 1-adamantanol has the highest price, and the raw material 1-adamantanol is connected at the back, so that the cost is reduced;
(4) The individual impurities in the finished product are less than 0.10 percent, and the quality meets the European pharmacopoeia requirements.
Drawings
FIG. 1 is a liquid chromatogram of adapalene as a product of the invention.
Detailed Description
The following provides representative examples of the present invention which are merely exemplary and are not intended to limit the scope of the invention described herein, which are merely illustrative of the methods of practicing the invention.
Example 1
A method for preparing adapalene, comprising the steps of:
(1) 100g (281 mmol) of 2-methoxycarbonyl-6-naphthol p-toluenesulfonate, 51.2g (337 mmol) of p-methoxyphenylboronic acid, 149.6g (562 mmol) of potassium phosphate trihydrate, 5.5g (8.4 mmol) of bis (triphenylphosphine) nickel chloride, 1.9g (8.4 mmol) of 1-butyl-3-methylimidazole bromide and 600ml of toluene were placed in a three-port flask under a nitrogen atmosphere, and reacted at 110℃for 6 hours with stirring. Cooling the reaction liquid to 0-10 ℃, filtering, collecting a filter cake, pulping the filter cake twice with a proper amount of water, filtering, and drying to obtain 66.8g of 6- (4-methoxyphenyl) -2-naphthoic acid methyl ester with the purity of 98.2% and the yield of 81.5%;
(2) 60g (205 mmol) of methyl 6- (4-methoxyphenyl) -2-naphthoate and 37.5g (246 mmol) of 1-adamantanol are added to a three-necked flask, 400ml of dichloromethane is further added, and 40.2g (410 mmol) of concentrated sulfuric acid is slowly added dropwise under stirring at room temperature, and stirring at room temperature is continued overnight after the completion of the dropwise addition for about 1 hour. Adding a proper amount of alkali, regulating to be weak alkaline, extracting, separating liquid, concentrating an organic phase to obtain a crude product, and recrystallizing with dichloroethane to obtain 71.2g of 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoic acid methyl ester with the purity of 98.5% and the yield of 81.3%;
(3) To the flask was added 70g (164 mmol) of methyl 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoate, 26.3g (656 mmol) of sodium hydroxide, 210ml of water and 210ml of tetrahydrofuran, and the mixture was refluxed for 4 hours. Cooling the reaction solution to 0-10 ℃, regulating the pH value to be weak acid by 10% hydrochloric acid, precipitating solid, filtering, collecting white solid, and recrystallizing by using a mixed solvent of tetrahydrofuran and toluene to obtain 57.2g of adapalene with the purity of 99.8% and the yield of 84.5%.
Example 2
A method for preparing adapalene, comprising the steps of:
(1) 100g (281 mmol) of 2-methoxycarbonyl-6-naphthol p-toluenesulfonate, 51.2g (337 mmol) of p-methoxyphenylboronic acid, 77.6g (562 mmol) of potassium carbonate, 5.5g (8.4 mmol) of bis (triphenylphosphine) nickel chloride, 1.9g (8.4 mmol) of 1-butyl-3-methylimidazole bromide and 500ml of tetrahydrofuran were placed in a three-necked flask under a nitrogen atmosphere, and reacted at 70℃for 8 hours with stirring. Cooling the reaction liquid to 0-10 ℃, filtering, collecting a filter cake, pulping the filter cake twice with a proper amount of water, filtering, and drying to obtain 65.2g of 6- (4-methoxyphenyl) -2-naphthoic acid methyl ester with the purity of 98.3% and the yield of 79.5%;
(2) 60g (205 mmol) of methyl 6- (4-methoxyphenyl) -2-naphthoate and 37.5g (246 mmol) of 1-adamantanol are added to a three-necked flask, 400ml of dichloromethane is further added, and 60.4g (615 mmol) of concentrated sulfuric acid is slowly added dropwise under stirring at room temperature, and stirring at room temperature is continued overnight after the completion of the dropwise addition for about 1.5 hours. Adding a proper amount of alkali, regulating to be weak alkaline, extracting, separating liquid, concentrating an organic phase to obtain a crude product, and recrystallizing with dichloroethane to obtain 72.5g of 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoic acid methyl ester with the purity of 98.2% and the yield of 82.8%;
(3) To the flask was added 70g (164 mmol) of methyl 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoate, 26.3g (656 mmol) of sodium hydroxide, 210ml of water and 210ml of tetrahydrofuran, and the mixture was refluxed at a temperature of 6 hours. Cooling the reaction solution to 0-10 ℃, regulating the PH value to be weak acid by 10% hydrochloric acid, precipitating solid, filtering, collecting white solid, and recrystallizing by using a mixed solvent of tetrahydrofuran and toluene to obtain 59.1g of adapalene with the purity of 99.9% and the yield of 87.3%.
Example 3
A method for preparing adapalene, comprising the steps of:
(1) 100g (281 mmol) of 2-methoxycarbonyl-6-naphthol p-toluenesulfonate, 51.2g (337 mmol) of p-methoxyphenylboronic acid, 59.5g (562 mmol) of sodium carbonate, 5.5g (8.4 mmol) of bis (triphenylphosphine) nickel chloride, 1.9g (8.4 mmol) of 1-butyl-3-methylimidazole bromide and 600ml of N, N-dimethylformamide were placed in a three-port flask under a nitrogen atmosphere, and reacted at 120℃for 8 hours with stirring. Cooling the reaction liquid to 0-10 ℃, filtering, collecting a filter cake, pulping the filter cake twice with a proper amount of water, filtering, and drying to obtain 64.6g of 6- (4-methoxyphenyl) -2-naphthoic acid methyl ester with the purity of 97.8% and the yield of 78.8%;
(2) 60g (205 mmol) of methyl 6- (4-methoxyphenyl) -2-naphthoate and 37.5g (246 mmol) of 1-adamantanol are added into a three-necked flask, 500ml of chloroform is added, and 60.4g (615 mmol) of concentrated sulfuric acid is slowly added dropwise under stirring at room temperature, and stirring at room temperature is continued overnight after the dropwise addition is completed for about 1.5 hours. Adding a proper amount of alkali, regulating to be weak alkaline, extracting, separating liquid, concentrating an organic phase to obtain a crude product, and recrystallizing with dichloroethane to obtain 72.7g of 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoic acid methyl ester with the purity of 98.6% and the yield of 83.0%;
(3) To the flask was added 70g (164 mmol) of methyl 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoate, 26.3g (656 mmol) of sodium hydroxide, 210ml of water and 210ml of tetrahydrofuran, and the mixture was refluxed at a temperature of 5 hours. Cooling the reaction solution to 0-10 ℃, regulating the PH value to be weak acid by 10% hydrochloric acid, precipitating solid, filtering, collecting white solid, and recrystallizing by using a mixed solvent of tetrahydrofuran and toluene to obtain 58.2g of adapalene with the purity of 99.8% and the yield of 86.0%.
Example 4
A method for preparing adapalene, comprising the steps of:
(1) 100g (281 mmol) of 2-methoxycarbonyl-6-naphthol p-toluenesulfonate, 64.1g (422 mmol) of p-methoxyphenylboric acid, 149.6g (562 mmol) of potassium phosphate trihydrate, 1.8g (2.8 mmol) of bis (triphenylphosphine) nickel chloride, 0.6g (2.8 mmol) of 1-butyl-3-methylimidazole bromide and 600ml of toluene were placed in a three-necked flask under a nitrogen atmosphere, and reacted at 110℃for 6 hours with stirring. Cooling the reaction liquid to 0-10 ℃, filtering, collecting a filter cake, pulping the filter cake twice with a proper amount of water, filtering, and drying to obtain 65.6g of the product methyl 6- (4-methoxyphenyl) -2-naphthoate, wherein the purity is 98.5%, and the yield is 80.0%;
(2) 60g (205 mmol) of methyl 6- (4-methoxyphenyl) -2-naphthoate and 62.5g (410 mmol) of 1-adamantanol are added to a three-necked flask, 400ml of dichloromethane is further added, and 40.2g (410 mmol) of concentrated sulfuric acid is slowly added dropwise under stirring at room temperature, and stirring at room temperature is continued overnight after the completion of the dropwise addition for about 1 hour. Adding a proper amount of alkali, regulating to be weak alkaline, extracting, separating liquid, concentrating an organic phase to obtain a crude product, and recrystallizing with dichloroethane to obtain 72.6g of 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoic acid methyl ester with the purity of 98.3 percent and the yield of 82.9 percent;
(3) To the flask was added 70g (164 mmol) of methyl 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoate, 26.3g (656 mmol) of sodium hydroxide, 210ml of water and 210ml of tetrahydrofuran, and the mixture was refluxed at a temperature of 6 hours. Cooling the reaction solution to 0-10 ℃, regulating the PH value to be weak acid by 10% hydrochloric acid, precipitating solid, filtering, collecting white solid, and recrystallizing by using a mixed solvent of tetrahydrofuran and toluene to obtain 58.2g of adapalene with the purity of 99.9% and the yield of 86.0%.
Claims (4)
1. A method for preparing adapalene, comprising the steps of:
(1) Adding 1.0 times of 2-methoxycarbonyl-6-naphthol p-toluenesulfonate, 1.2-1.5 times of p-methoxyphenylboric acid, 2.0 times of inorganic base, 1.0-3.0% times of bis (triphenylphosphine) nickel chloride, brominated 1-butyl-3-methylimidazole and solvent into a three-port bottle in a nitrogen atmosphere, reacting for 6-8 hours at 60-120 ℃ under stirring, cooling the reaction solution to 0-10 ℃, filtering, collecting a filter cake, pulping the filter cake twice with a proper amount of water, filtering and drying to obtain a product of 6- (4-methoxyphenyl) -2-methyl naphthoate;
(2) Adding 1.0 times mole of 6- (4-methoxyphenyl) -2-naphthoic acid methyl ester and 1.2-4 times mole of 1-adamantanol into a three-mouth bottle, adding an aprotic solvent, slowly dropwise adding 2.0-3.0 times mole of concentrated sulfuric acid under stirring at room temperature, continuously stirring at room temperature overnight after 1-2 hours are completed, adding a proper amount of alkali, regulating to be alkalescent, extracting a liquid separating, concentrating an organic phase to obtain a crude product, and recrystallizing with dichloroethane to obtain a product of 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoic acid methyl ester;
(3) Adding 1.0 times mole of 6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-naphthoic acid methyl ester and 4.0 times mole of sodium hydroxide into a three-port bottle, adding water and tetrahydrofuran, heating and refluxing for 4-6 hours, cooling the reaction liquid to 0-10 ℃, regulating the PH value to weak acidity by 10% hydrochloric acid, separating out solid, filtering, collecting white solid, and recrystallizing by using a mixed solvent of tetrahydrofuran and toluene to obtain adapalene;
the synthesis process of the adapalene comprises the following formula:
2. the method for preparing adapalene according to claim 1, wherein the inorganic base in step (1) is one of potassium phosphate trihydrate, potassium carbonate, and sodium carbonate.
3. The method for preparing adapalene according to claim 1, wherein the solvent in step (1) is one of toluene, tetrahydrofuran, and N, N-dimethylformamide.
4. The method for preparing adapalene according to claim 1, wherein the aprotic solvent in step (2) is one of dichloromethane and chloroform.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1830937A (en) * | 2006-04-18 | 2006-09-13 | 江苏中丹化工集团公司 | Method for preparing Adapalene |
| CN1872829A (en) * | 2006-04-18 | 2006-12-06 | 江苏中丹化工集团公司 | Method for preparing Adapalene |
| WO2007125542A2 (en) * | 2006-05-03 | 2007-11-08 | Usv Limited | A process for preparation of adapalene |
| CN104003838A (en) * | 2014-05-14 | 2014-08-27 | 华东理工大学 | Synthetic method of adapalene |
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| LV13736B (en) * | 2006-12-28 | 2008-09-20 | Vjaceslavs Tribulovics | Method for manufacturing 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtoic acid |
| US20100160677A1 (en) * | 2006-12-29 | 2010-06-24 | Ivars Kalvinsh | Process for preparation of 6-[3-(1-admantyl)-4-methoxyphenyl]-2-naphtoic acid. |
| SG11201506609VA (en) * | 2013-03-15 | 2015-09-29 | Probiodrug Ag | Novel inhibitors |
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| CN1830937A (en) * | 2006-04-18 | 2006-09-13 | 江苏中丹化工集团公司 | Method for preparing Adapalene |
| CN1872829A (en) * | 2006-04-18 | 2006-12-06 | 江苏中丹化工集团公司 | Method for preparing Adapalene |
| WO2007125542A2 (en) * | 2006-05-03 | 2007-11-08 | Usv Limited | A process for preparation of adapalene |
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Denomination of invention: A preparation method of Adaparin Effective date of registration: 20231225 Granted publication date: 20231013 Pledgee: China Merchants Bank Limited by Share Ltd. Wuhan branch Pledgor: WUHAN NUOAN PHARMACY Co.,Ltd. Registration number: Y2023980074081 |