CN110092727B - Synthetic method of laquinimod intermediate 2-amino-6-chlorobenzoic acid - Google Patents

Synthetic method of laquinimod intermediate 2-amino-6-chlorobenzoic acid Download PDF

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CN110092727B
CN110092727B CN201910331199.9A CN201910331199A CN110092727B CN 110092727 B CN110092727 B CN 110092727B CN 201910331199 A CN201910331199 A CN 201910331199A CN 110092727 B CN110092727 B CN 110092727B
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methylaniline
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谭回
李维平
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Shenzhen Second Peoples Hospital
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a synthetic method of laquinimod intermediate 2-amino-6-chlorobenzoic acid, which is characterized in that 3-chloro-2-methylaniline reacts under the action of a protective agent and an oxidant to obtain 2-amino-6-chlorobenzoic acid, and the reaction process comprises the following steps: 1) uniformly mixing 3-chloro-2-methylaniline, a protective agent and a solvent S1, and stirring and reacting at 40-50 ℃ for 1-2 h to obtain a mixture I; 2) uniformly mixing an oxidant, water and a solvent S2, introducing protective gas, controlling the reaction temperature to be 145-155 ℃ and the reaction pressure to be 5-7 atmospheres to obtain a mixture II, dropwise adding the mixture I into the mixture II, controlling the dropwise adding time to be 50-70 min, then controlling the temperature to be 160-175 ℃ and the reaction pressure to be 8-10 atmospheres, and continuously reacting for 6-8 h and cooling to obtain a mixture III; 3) adding hydrochloric acid and a solvent S3 into the mixture III, controlling the reaction temperature to be 75-90 ℃, controlling the reaction pressure to be normal pressure, reacting for 0.5-1 h, and cooling to obtain a mixture IV; 4) adding a solvent S4 into the mixture IV, standing for layering, washing an organic phase with water, drying a drying agent, and concentrating and evaporating to remove the solvent to obtain a product. The method has low cost of raw materials and high yield.

Description

Synthetic method of laquinimod intermediate 2-amino-6-chlorobenzoic acid
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a synthetic method of a laquinimod intermediate 2-amino-6-chlorobenzoic acid.
Background
Laquinimod (Laquinimod) chemically known as 5-chloro-1, 2-dihydro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinolinecarboxamide is a structural analogue of roquinacre (linoamine). Laquinimod is an immunoregulatory drug developed by Teva pharmaceutical company and Active biotechnology, is mainly used for treating multiple sclerosis, and is convenient to use and weak in adverse reaction compared with other drugs for treating multiple sclerosis such as interferon and mitoxantrone. Laquinimod can completely inhibit murine chronic experimental autoimmune encephalomyelitis (chaae) by eliminating leukocyte infiltration of the central nervous system, reduce inflammation, demyelination and axonal injury in an EAE (experimental autoimmune encephalomyelitis) animal model, can be anti-inflammatory and can protect nerves, has stronger inhibition effect than that of the laquinimod, and has 20 times of the immunosuppression effect of the laquinimod compared with the exposed dosage directly.
In the prior art, laquinimod (compound 5) is often synthesized using the following route.
Figure BDA0002037732410000011
2-amino-6-chlorobenzoic acid is a raw material and an intermediate for synthesizing laquinimod. Invention patent
CN201610292940 provides a method for synthesizing 2-amino-6-chlorobenzoic acid, which comprises the steps of taking 2-chloro-6-nitrobenzoic acid as a raw material, reducing nitro to obtain 2-amino-6-chlorobenzoic acid:
Figure BDA0002037732410000021
the method has high cost of raw materials, and substances with strong irritation, such as cerium chloride, are used in the process, so that the method is not beneficial to safe operation.
Disclosure of Invention
The invention aims to provide a synthetic method of a laquinimod intermediate 2-amino-6-chlorobenzoic acid, which has the advantages of low cost of raw materials, high yield and avoidance of use of irritant substances.
In order to achieve the purpose, the invention adopts the following technical scheme:
Figure BDA0002037732410000022
the synthetic method of the laquinimod intermediate 2-amino-6-chlorobenzoic acid is characterized in that 3-chloro-2-methylaniline reacts under the action of a protective agent and an oxidant to obtain the 2-amino-6-chlorobenzoic acid, and the reaction process comprises the following steps:
1) uniformly mixing 3-chloro-2-methylaniline, a protective agent and a solvent S1, and stirring and reacting at 40-50 ℃ for 1-2 h to obtain a mixture I;
2) uniformly mixing an oxidant, water and a solvent S2, introducing protective gas, controlling the reaction temperature to be 145-155 ℃ and the reaction pressure to be 5-7 atmospheres to obtain a mixture II, dropwise adding the mixture I into the mixture II, controlling the dropwise adding time to be 50-70 min, then controlling the temperature to be 160-175 ℃ and the reaction pressure to be 8-10 atmospheres, and continuously reacting for 6-8 h and cooling to obtain a mixture III;
3) adding hydrochloric acid and a solvent S3 into the mixture III, controlling the reaction temperature to be 75-90 ℃, controlling the reaction pressure to be normal pressure, reacting for 0.5-1 h, and cooling to obtain a mixture IV;
4) adding a solvent S4 into the mixture IV, standing for layering, washing an organic phase with water, drying a drying agent, and concentrating and evaporating to remove the solvent to obtain a product.
The preparation method of the oxidant comprises the following steps: uniformly mixing ferric trichloride, manganese dioxide and potassium dichromate, and activating at 150-180 ℃ for 30-60 min under the condition of isolating oxygen to obtain the product; the molar ratio of the ferric trichloride to the manganese dioxide to the potassium dichromate is 1 (8-10) to 16-18; the manganese dioxide is freshly prepared.
The protective agent is di-tert-butyl dicarbonate, the solvent S1 is benzene, chlorobenzene or fluorobenzene, the solvent S2 is tetrahydrofuran, the solvent S3 is dioxane, the solvent S4 is toluene or chloroform, the protective gas is nitrogen or argon, and the drying agent is anhydrous sodium sulfate or anhydrous magnesium sulfate.
The molar ratio of the 3-chloro-2-methylaniline to the protective agent is 1 (1.2-1.4), the molar ratio of the 3-chloro-2-methylaniline to the manganese dioxide in the oxidant is 1 (2.1-3.2), and the dosage ratio of the 3-chloro-2-methylaniline to the solvent S1, the solvent S2 and the water is 1g, (3-5) mL, (4-6) mL, (0.5-1.2) g.
The concentration of the hydrochloric acid is 20% by mass; the molar ratio of the 3-chloro-2-methylaniline to the hydrogen chloride in the hydrochloric acid is 1 (1.6-2.2); the volume ratio of the hydrochloric acid to the solvent S3 is 1 (1.5-3); the volume ratio of the solvent S4 to the solvent S3 is 1 (2-4).
The reaction principle of the invention is shown as the following formula:
Figure BDA0002037732410000031
in the prior literature, the method for methyl oxidation of aromatic ring into carboxyl is mostly obtained by direct oxidation with strong oxidant. The reaction process of the invention is a process for oxidizing methyl on a benzene ring of 3-chloro-2-methylaniline into carboxyl. Since amino groups which are easily oxidized exist in the structure of the raw material 3-chloro-2-methylaniline, it is necessary to pre-protect the amino groups and to adjust the oxidizing property of the oxidizing agent. The invention adopts ferric trichloride, newly-prepared manganese dioxide and potassium dichromate which are mixed according to a proportion as an oxidant, and the oxidant has moderate oxidizability under the proportion: the reaction condition of independent potassium dichromate plus acidity is adopted, so that the oxidizing property is strong, and even protected amino groups can be oxidized; the reaction condition of newly prepared manganese dioxide + acidity is adopted, the oxidability is weak, and incomplete oxidation products such as aldehyde groups and the like can be generated from methyl. Meanwhile, the oxidizability of the metal oxidizer is often weak in alkalinity and strong in acidity, and is enhanced with the enhancement of the acidity. Therefore, proper acidity is also important for the regulation of oxidation. Ferric trichloride is added into the system, and under the condition of the existence of a proper amount of water, the system can show proper weak acidity, the oxidation can be regulated, and the generation of peroxidation and incomplete oxidation products can be reduced or avoided. The method adopts a mode of dropwise adding the reactant solution into the oxidant solution, can quickly finish the oxidation reaction as much as possible, and avoids incomplete oxidation caused by overlarge concentration of the reactant and relatively small concentration of the oxidant. And after the oxidation reaction is finished, carrying out deprotection on amino by adopting an acid system to finally obtain the 2-amino-6-chlorobenzoic acid.
Compared with the prior art, the invention has the advantages that:
1. 3-chloro-2-methylaniline is used as a raw material, so that the cost is low;
2. the reaction yield is high;
3. less by-products.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
The synthesis method of 2-amino-6-chlorobenzoic acid comprises the following steps:
1) uniformly mixing 3-chloro-2-methylaniline, di-tert-butyl dicarbonate and benzene, and stirring at 46 ℃ to react for 1.5h to obtain a mixture I;
2) uniformly mixing an oxidant, water and tetrahydrofuran, introducing argon, controlling the reaction temperature to be 150 ℃ and the reaction pressure to be 6 atmospheres to obtain a mixture II, dropwise adding the mixture I into the mixture II, controlling the dropwise adding time to be 65min, then controlling the temperature to be 171 ℃ and the reaction pressure to be 9 atmospheres, continuously reacting for 7.5 hours, and cooling to obtain a mixture III;
3) adding hydrochloric acid and dioxane with the mass fraction of 20% into the mixture III, controlling the reaction temperature to be 85 ℃, the reaction pressure to be normal pressure, reacting for 45min, and cooling to obtain a mixture IV;
4) and adding chloroform into the mixture IV, standing for layering, washing an organic phase with water, drying with anhydrous sodium sulfate, and concentrating and evaporating to remove the solvent by using a rotary evaporator to obtain a product. The molar yield was 99.1% and the GC purity 98.5%.
In the above step, the method for preparing the oxidizing agent: uniformly mixing ferric trichloride, newly-prepared manganese dioxide and potassium dichromate, and activating for 50min at 170 ℃ by using a vacuum drying oven under the protection of argon gas to obtain the product; the molar ratio of ferric trichloride, manganese dioxide and potassium dichromate is 1:9: 17.
The molar ratio of 3-chloro-2-methylaniline to di-tert-butyl dicarbonate is 1:1.3, the molar ratio of 3-chloro-2-methylaniline to manganese dioxide in the oxidant is 1:2.8, and the dosage ratio of 3-chloro-2-methylaniline to benzene, tetrahydrofuran and water is 1g:4mL:5mL:0.8 g.
The molar ratio of the 3-chloro-2-methylaniline to the hydrogen chloride in the hydrochloric acid is 1: 2; the volume ratio of the hydrochloric acid to the dioxane is 1: 2.5; the volume ratio of chloroform to dioxane is 1:3.
Example 2
The synthesis method of the 2-amino-6-chlorobenzoic acid comprises the following steps:
1) uniformly mixing 3-chloro-2-methylaniline, di-tert-butyl dicarbonate and chlorobenzene, and stirring and reacting at 40 ℃ for 1h to obtain a mixture I;
2) uniformly mixing an oxidant, water and tetrahydrofuran, introducing nitrogen, controlling the reaction temperature to be 145 ℃ and the reaction pressure to be 5 atmospheres to obtain a mixture II, dropwise adding the mixture I into the mixture II, controlling the dropwise adding time to be 50min, then controlling the temperature to be 160 ℃ and the reaction pressure to be 8 atmospheres, continuously reacting for 6h, and cooling to obtain a mixture III;
3) adding hydrochloric acid and dioxane with the mass fraction of 20% into the mixture III, controlling the reaction temperature to be 75 ℃, the reaction pressure to be normal pressure, reacting for 0.5h, and cooling to obtain a mixture IV;
4) and adding toluene into the mixture IV, standing for layering, washing an organic phase with water, drying with anhydrous magnesium sulfate, and concentrating and evaporating to remove the solvent by using a rotary evaporator to obtain a product. The molar yield was 97.8% and the GC purity 98.1%.
In the above step, the method for preparing the oxidizing agent: uniformly mixing ferric trichloride, newly prepared manganese dioxide and potassium dichromate, and activating for 30min at 150 ℃ by using a vacuum drying oven under the protection of argon gas to obtain the manganese dioxide-potassium dichromate; the molar ratio of ferric trichloride, manganese dioxide and potassium dichromate is 1:8: 16.
The molar ratio of 3-chloro-2-methylaniline to di-tert-butyl dicarbonate is 1:1.2, the molar ratio of 3-chloro-2-methylaniline to manganese dioxide in the oxidant is 1:2.1, and the dosage ratio of 3-chloro-2-methylaniline to chlorobenzene, tetrahydrofuran and water is 1g:3mL:4mL:0.5 g.
The molar ratio of the 3-chloro-2-methylaniline to the hydrogen chloride in the hydrochloric acid is 1: 1.6; the volume ratio of the hydrochloric acid to the dioxane is 1: 1.5; the volume ratio of toluene to dioxane was 1:2.
Example 3
The synthesis method of 2-amino-6-chlorobenzoic acid comprises the following steps:
1) uniformly mixing 3-chloro-2-methylaniline, di-tert-butyl dicarbonate and fluorobenzene, and stirring at 50 ℃ to react for 2h to obtain a mixture I;
2) uniformly mixing an oxidant, water and tetrahydrofuran, introducing argon, controlling the reaction temperature to be 155 ℃ and the reaction pressure to be 7 atmospheres to obtain a mixture II, dropwise adding the mixture I into the mixture II, controlling the dropwise adding time to be 70min, then controlling the temperature to be 175 ℃ and the reaction pressure to be 10 atmospheres, continuously reacting for 8 hours and cooling to obtain a mixture III;
3) adding hydrochloric acid and dioxane with the mass fraction of 20% into the mixture III, controlling the reaction temperature to be 90 ℃, the reaction pressure to be normal pressure, reacting for 1h, and cooling to obtain a mixture IV;
4) and adding chloroform into the mixture IV, standing for layering, washing an organic phase, drying by using a drying agent, and concentrating and evaporating by using a rotary evaporator to remove the solvent to obtain a product. The molar yield was 99.5% and the GC purity was 99.2%.
In the above steps, the method for preparing the oxidizing agent: uniformly mixing ferric trichloride, newly-prepared manganese dioxide and potassium dichromate, and activating for 60min at 180 ℃ by using a vacuum drying oven under the protection of argon gas to obtain the product; the molar ratio of ferric trichloride, manganese dioxide and potassium dichromate is 1:10: 18.
The molar ratio of 3-chloro-2-methylaniline to di-tert-butyl dicarbonate is 1:1.4, the molar ratio of 3-chloro-2-methylaniline to manganese dioxide in the oxidant is 1:3.2, and the dosage ratio of 3-chloro-2-methylaniline to fluorobenzene, tetrahydrofuran and water is 1g:5mL:6mL:1.2 g.
The molar ratio of the 3-chloro-2-methylaniline to the hydrogen chloride in the hydrochloric acid is 1: 2.2; the volume ratio of the hydrochloric acid to the dioxane is 1: 3; the volume ratio of chloroform to dioxane is 1: 4.
Example 4
The reaction pressure before the mixture I was added dropwise to the mixture II was set to 2 atmospheres, the reaction temperature was set to 100 ℃, and other reaction conditions and material use ratios were the same as in example 1, with a molar yield of 45.3% and a GC purity of 65.2%.
Example 5
The reaction pressure before the mixture I was added dropwise to the mixture II was set to 10 atmospheres, the reaction temperature was set to 170 ℃, and other reaction conditions and material use ratios were the same as in example 1, with a molar yield of 80.5% and a GC purity of 76.3%.
Example 6
The reaction pressure after the dropwise addition of the mixture I to the mixture II was set to 5 atm, the reaction temperature was set to 140 ℃ and the other reaction conditions and the material ratio were the same as in example 1, the molar yield was 68.6% and the GC purity was 71.5%.
Example 7
After the mixture I was added dropwise to the mixture II, the reaction pressure was set to 14 atmospheres, the reaction temperature was set to 200 ℃, the other reaction conditions and the material ratio were the same as in example 1, the molar yield was 83.2%, and the GC purity was 87.2%.
Example 8
Ferric trioxide in the oxidant was removed and only fresh manganese dioxide and potassium dichromate remained, and the other reaction conditions and material use ratios were the same as in example 1, with a molar yield of 42.3% and a GC purity of 55.2%.
Example 9
Fresh manganese dioxide in the oxidant was removed and only ferric trichloride and potassium dichromate remained, and other reaction conditions and material use ratios were the same as in example 1, with a molar yield of 72.3% and a GC purity of 67.1%.
Example 10
The potassium dichromate in the oxidant was removed and only ferric trichloride and fresh manganese dioxide were retained, and the other reaction conditions and material use ratios were the same as in example 1, and no target product was detected.
Example 11 product Structure analysis
Taking the product of example 1 as an example, the structural analysis data are as follows.
1) Melting point
169-161 ℃ and the reported value is 158-160 ℃.
2) Nuclear magnetic analysis
Hydrogen spectrum:1H-NMR (DMSO): δ 11.1(1H), δ 7.12(1H), δ 7.06(1H), δ 6.73(1H), δ 6.28 (2H). The various hydrogens are assigned to the product structure as follows:
Figure BDA0002037732410000071
and (4) performing nuclear magnetic analysis, wherein the structure of the product accords with that of a target substance, namely 2-amino-6-chlorobenzoic acid.

Claims (3)

1. The synthetic method of the laquinimod intermediate 2-amino-6-chlorobenzoic acid is characterized in that 3-chloro-2-methylaniline reacts under the action of a protective agent and an oxidant to obtain the 2-amino-6-chlorobenzoic acid, and the reaction process comprises the following steps:
1) uniformly mixing 3-chloro-2-methylaniline, a protective agent and a solvent S1, and stirring and reacting at 40-50 ℃ for 1-2 h to obtain a mixture I;
2) uniformly mixing an oxidant, water and a solvent S2, introducing protective gas, controlling the reaction temperature to 145-155 ℃ and the reaction pressure to 5-7 atmospheres to obtain a mixture II, dropwise adding the mixture I into the mixture II, controlling the dropwise adding time to be 50-70 min, then controlling the temperature to 160-175 ℃ and the reaction pressure to be 8-10 atmospheres, continuously reacting for 6-8 h, and cooling to obtain a mixture III;
3) adding hydrochloric acid and a solvent S3 into the mixture III, controlling the reaction temperature to be 75-90 ℃, controlling the reaction pressure to be normal pressure, reacting for 0.5-1 h, and cooling to obtain a mixture IV;
4) adding a solvent S4 into the mixture IV, standing for layering, washing an organic phase with water, drying a drying agent, and concentrating and evaporating to remove the solvent to obtain a product;
the preparation method of the oxidant comprises the following steps: uniformly mixing ferric trichloride, manganese dioxide and potassium dichromate, and activating at 150-180 ℃ for 30-60 min under the condition of isolating oxygen to obtain the product; the molar ratio of the ferric trichloride to the manganese dioxide to the potassium dichromate is 1 (8-10) to 16-18; the manganese dioxide is prepared newly;
the protective agent is di-tert-butyl dicarbonate, the solvent S1 is benzene, chlorobenzene or fluorobenzene, the solvent S2 is tetrahydrofuran, the solvent S3 is dioxane, the solvent S4 is toluene or chloroform, the protective gas is nitrogen or argon, and the drying agent is anhydrous sodium sulfate or anhydrous magnesium sulfate.
2. The method for synthesizing laquinimod intermediate 2-amino-6-chlorobenzoic acid according to claim 1, wherein the molar ratio of 3-chloro-2-methylaniline to di-tert-butyl dicarbonate is 1 (1.2-1.4), the molar ratio of 3-chloro-2-methylaniline to manganese dioxide in the oxidant is 1 (2.1-3.2), and the dosage ratio of 3-chloro-2-methylaniline to solvent S1, solvent S2 and water is 1g (3-5) mL (4-6) mL (0.5-1.2) g.
3. The method for synthesizing laquinimod intermediate 2-amino-6-chlorobenzoic acid according to claim 1, wherein the hydrochloric acid concentration is 20% by mass; the molar ratio of the 3-chloro-2-methylaniline to the hydrogen chloride in the hydrochloric acid is 1 (1.6-2.2); the volume ratio of the hydrochloric acid to the solvent S3 is 1 (1.5-3); the volume ratio of the solvent S4 to the solvent S3 is 1 (2-4).
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