CN113444009B - Recovery method of candesartan cilexetil intermediate mother liquor - Google Patents
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Abstract
The invention provides a method for recovering candesartan cilexetil intermediate mother liquor, which is obtained in actual production and comprises candesartan cilexetil Sha Tanshu butyl ester, candesartan cilexetil Sha Tanshu butyl ester decomposed impurities and candesartan cilexetil diester impurities, wherein the mother liquor is not treated in the previous production procedure, and is directly treated as waste liquid, so that the waste of resources and the increase of cost are caused. The recovery method of the invention not only can avoid the interference of diester impurities when recovering and decomposing the impurities, but also can avoid the production of byproduct diester impurities as much as possible when recovering the diester impurities, and has simple operation and cheap raw materials, thereby being suitable for industrial production popularization.
Description
Technical Field
The invention relates to the field of synthesis of medicinal chemicals, in particular to a method for treating candesartan cilexetil intermediate mother liquor.
Background
Candesartan cilexetil is a prodrug of candesartan and is rapidly decomposed in vivo into the active metabolite candesartan, a selective angiotensin IIAT receptor antagonist, useful for the treatment of essential hypertension. Candesartan cilexetil has the chemical name 2-ethoxy-1- [ [2'- (1H-tetrazol-5-yl) [1,1' -biphenyl ]]-4-yl]Methyl group]-1H-benzimidazole-7-carboxylic acid-1- [ [ (cyclohexyloxy) carbonyl group]Oxy group]Ethyl ester, chemical structural formula:。
the candesartan cilexetil is an important intermediate for synthesizing the front end of candesartan cilexetil, and byproducts are generated during the synthesis of the candesartan cilexetil in the production process: diester impurities and decomposed impurities, the chemical structure of the diester impurities beingThe chemical structure of the decomposed impurities is +.>The mother liquor for preparing the candesa tert-butyl ester simultaneously contains the candesa tert-butyl ester, diester impurities and decomposed impurities, the content of the impurities is higher, the mother liquor cannot be directly recycled, the mother liquor is generally directly discharged as wastewater in the prior art, the resource waste is caused, and the cost is increased. There is no document in the prior art how to recycle the candesartan cilexetil mother liquor containing the above impurities.
Disclosure of Invention
Based on the problems, the invention discloses a recovery method of candesartan cilexetil intermediate mother liquor, which has high recovery efficiency, is simple and convenient to operate, reduces the cost of producing candesartan cilexetil, and is suitable for industrial popularization.
In order to solve the problems, the invention discloses a method for recycling candesartan cilexetil intermediate mother liquor, which comprises candesartan cilexetil Sha Tanshu butyl, candesartan cilexetil Sha Tanshu butyl decomposed impurities and candesartan cilexetil Sha Tanshu butyl diester impurities, wherein the decomposed impurities areThe diester impurity is +.>The recovery method comprises the following steps:
A. firstly, converting the decomposed impurities into candesa tert-butyl ester and recovering the candesa tert-butyl ester in the solution;
B. and converting the diester impurity into candel tert-butyl ester and recovering the candel tert-butyl ester.
Further, the method for converting the decomposed impurities into the candel tert-butyl ester and recovering the candel tert-butyl ester in the solution in the step A comprises the following steps: concentrating candesartan cilexetil intermediate mother liquor, adding a reaction solvent A, adding inorganic base A and Boc anhydride for reaction, washing with water after the reaction is finished, concentrating an organic layer, adding a recrystallization solvent A, heating to dissolve, cooling for crystallization, filtering, and recovering candesartan cilexetil to obtain a crystallization mother liquor.
Further, the inorganic base A is selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.
The reaction solvent A is a mixed solution of water and one of dichloromethane, chloroform, tetrahydrofuran and ethyl acetate, and the crystallization solvent is one of methanol and ethanol. The ratio of the mass g of the concentrated candesartan cilexetil intermediate mother solution to the volume ml of the reaction solvent A, the volume ml of the crystallization solvent A and the mass g of the Boc anhydride is 1 (1-10): 1.5-3.5: (0.1-2), preferably 1 (1-10): (1.5-3.5): (0.1 to 0.3).
Further, the method for converting the diester impurity into candel tert-butyl ester in the step B comprises the following steps: (B1) Concentrating the filtrate in the step A, adding a reaction solvent B1 and inorganic base B for reaction, and regulating the pH value to 1-2 by using acid after the reaction is finished to obtain 3-nitrophthalic acid; (B2) Reacting the obtained 3-nitrophthalic acid in ethanol solution containing sulfuric acid, concentrating the reaction solution under reduced pressure after the reaction is finished, adding a crystallization solvent B, cooling and crystallizing to obtain 3-nitrophthalic acid-1-monoethyl ester; (B3) Reacting the obtained 3-nitrophthalic acid benzene-1-monoethyl ester in ethanol solution of thionyl chloride to obtain 2-formyl chloride-3-ethyl nitrobenzoate; then, the ethyl 2-formyl chloride-3-nitrobenzoate reacts with an azide reagent in a reaction solvent B3 to obtain an isocyanate intermediate, the isocyanate intermediate reacts with tertiary butyl alcohol to be converted into candelaidic tertiary butyl ester, and the finished product is obtained by recrystallization by using a crystallization solvent B3.
Further, in the step B1, the inorganic base B is selected from one of NaOH and KOH, and the concentration is 0.1-10M, preferably 8M; the reaction solvent B1 is a mixed solution of water and one of dichloromethane, chloroform and tetrahydrofuran, and the volume ratio of the organic solvent to the water in the mixed solution is 9:1-1:1. The ratio of the volume ml of the reaction solvent B1 to the mass g of the concentrated candesartan cilexetil intermediate mother solution is 2:5-2:1, preferably 3:5. The reaction temperature in step B1 is 20-60℃and preferably 25 ℃.
Further, in the step B2, the mass ratio of the 2-carboxyl-3-nitrophthalic acid to the sulfuric acid is (1-3): 1, a step of; the crystallization solvent B2 is selected from any one of water or acetone.
Further, in the step B3, the molar ratio of the 3-nitrophthalic acid benzene-1-monoethyl ester to the thionyl chloride is 1: (1.0-3.5), the molar concentration of the dichloromethane used is 0.1-2M. In the step B3, the azide reagent is selected from one of sodium azide and trimethylsilane azide, and the molar ratio of the ethyl 2-formyl chloride-3-nitrobenzoate to the azide reagent is 1: (1-2) the reaction solvent B3 is selected from DMF, dichloromethane, tetrahydrofuran, preferably DMF. The molar ratio of isocyanate intermediate to t-butanol in step B3 was 1: (1.5-5). In the step B3, the crystallization solvent B3 is selected from one of methanol and ethanol.
The beneficial effects are that: the invention provides a method for recovering candesartan cilexetil intermediate mother liquor, which is obtained in actual production and comprises candesartan cilexetil Sha Tanshu butyl ester, candesartan cilexetil Sha Tanshu butyl ester decomposed impurities and candesartan cilexetil diester impurities, wherein the mother liquor is not treated in the previous production procedure, and is directly treated as waste liquid, so that the waste of resources and the increase of cost are caused. The recovery method of the invention not only can avoid the interference of diester impurities when recovering and decomposing the impurities, but also can avoid the production of byproduct diester impurities as much as possible when recovering the diester impurities, and has simple operation and cheap raw materials, thereby being suitable for industrial production popularization.
Detailed Description
Example 1
(1) 100 g of concentrated mother liquor of candel butyl was taken, 200ml of methylene chloride and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride were added and reacted at 25℃for 8 hours. After the reaction was completed, the layers were separated and washed. The organic layer was concentrated to give crude product. 250mL of methanol is added into the crude product, the mixture is heated to dissolve, cooled to room temperature for crystallization, 16.8g of candel tert-butyl ester is obtained by filtration, and the filtrate is used for the next reaction. Purity 99.1% and yield 82%.
(2) Concentrating the filtrate in the step (1), adding 30ml of dichloromethane, 30ml of water, adding 3g of sodium hydroxide, reacting for 12 hours at room temperature, and adjusting the pH to be=2 after the reaction is completed to obtain 30.1g of 3-nitrophthalic acid with the purity of 98.3%, wherein the yield is about 83%.
(3) And (3) dissolving the 3-nitrophthalic acid obtained in the step (2) in 100mL of ethanol solution containing 20g of sulfuric acid for reaction for 10 hours, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of pure water, cooling to 0 ℃ for crystallization, and obtaining 27.3g of 3-nitrophthalic acid-1-monoethyl ester crystals with the yield of 79% and the purity of 98.8%.
(4) And (3) reacting the 3-nitrophthalic acid-1-monoethyl ester obtained in the step (3) in 150mL of dichloromethane solution containing 16.5mL of thionyl chloride to obtain the ethyl 2-formyl chloride-3-nitrobenzoate. Subsequently ethyl 2-formyl-3-nitrobenzoate was dissolved in another 30mL of dichloromethane, 150mL of DMF was added with 8.2g of sodium azide, and the reaction was worked up to give the isocyanate intermediate. The isocyanate intermediate was then reacted with 50mL of t-butanol, and after completion of the reaction, the reaction was monitored to be evaporated to dryness and recrystallized from methanol to give 19.5g of candel t-butyl ester in 73% yield (3 steps) and 99.2% purity.
Example 2
(1) 100 g of concentrated mother liquor of candel butyl was taken, 200ml of methylene chloride and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride were added and reacted at 25℃for 8 hours. After the reaction was completed, the layers were separated and washed. The organic layer was concentrated to give crude product. 250mL of ethanol is added into the crude product, the mixture is heated to dissolve, cooled to room temperature for crystallization, 16.6g of candel tert-butyl ester is obtained by filtration, and the filtrate is used for the next reaction. Purity 99.3% and yield 81%.
(2) Concentrating the filtrate in the step (1), adding 30ml of dichloromethane, 30ml of water, adding 3g of sodium hydroxide, reacting for 12 hours, and adjusting the pH=2 after the reaction is completed to obtain 30.0g of 3-nitrophthalic acid with the purity of 98.3%, wherein the yield is about 83%.
(3) And (3) dissolving the 3-nitrophthalic acid obtained in the step (2) in 100mL of ethanol solution containing 20g of sulfuric acid for reaction for 10 hours, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of pure water, cooling to 0 ℃ for crystallization, and obtaining 27.2g of 3-nitrophthalic acid-1-monoethyl ester crystal with the yield of 79% and the purity of 98.0%.
(4) And (3) reacting the 3-nitrophthalic acid-1-monoethyl ester obtained in the step (3) in 150mL of dichloromethane solution containing 16.5mL of thionyl chloride to obtain the ethyl 2-formyl chloride-3-nitrobenzoate. Subsequently ethyl 2-formyl-3-nitrobenzoate was dissolved in another 30mL of dichloromethane, 150mL of DMF was added with 8.2g of sodium azide, and the reaction was worked up to give the isocyanate intermediate. The isocyanate intermediate was then reacted with 50mL of t-butanol, and after completion of the reaction, the reaction was monitored to be evaporated to dryness and recrystallized from methanol to give 19.9g of candel t-butyl ester in 74% yield (3 steps) with a purity of 99.6%.
Example 3
(1) 100 g of concentrated mother liquor of candel butyl was taken, 200mL of tetrahydrofuran and 50mL of water, 9g of potassium carbonate, 13g of Boc anhydride were added and reacted at 25℃for 8 hours. After the reaction was completed, the layers were separated and washed. The organic layer was concentrated to give crude product. 250mL of methanol is added into the crude product, the mixture is heated to dissolve, cooled to room temperature for crystallization and filtered. 16.1g of candesate-butyl ester was obtained and the filtrate was used in the next reaction. Purity 99.4% and yield 78%.
(2) Concentrating the filtrate in the step (1), adding 30ml of tetrahydrofuran, 30ml of water, adding 3g of sodium hydroxide, reacting for 12 hours, and adjusting the pH=2 after the reaction is completed to obtain 30.2g of 3-nitrophthalic acid with the purity of 98.9% and the yield of about 83%.
(3) And (3) dissolving the 3-nitrophthalic acid obtained in the step (2) in 100mL of ethanol solution containing 20g of sulfuric acid for reaction for 10 hours, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of pure water, cooling to 0 ℃ for crystallization, and obtaining 27.5g of 3-nitrophthalic acid-1-monoethyl ester crystals with the yield of 80% and the purity of 98.9%.
(4) And (3) reacting the 3-nitrophthalic acid-1-monoethyl ester obtained in the step (3) in 150mL of dichloromethane solution containing 16.6mL of thionyl chloride to obtain the ethyl 2-formyl chloride-3-nitrobenzoate. Subsequently ethyl 2-formyl-3-nitrobenzoate was dissolved in another 30mL of dichloromethane, 150mL of DMF was added with 8.3g of sodium azide, and the reaction was worked up to give the isocyanate intermediate. The isocyanate intermediate was then reacted with 50mL of t-butanol at room temperature, monitored for completion, evaporated to dryness and recrystallized from methanol to give 20.3g of candel t-butyl ester in 76% yield (3 steps) at 99.1% purity.
Example 4
(1) 100 g of concentrated candel butyl mother liquor was taken, 100ml of methylene chloride and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride were added and reacted at 25℃for 8 hours. After the reaction was completed, the layers were separated and washed. The organic layer was concentrated to give crude product. 250mL of methanol is added into the crude product, the mixture is heated to dissolve, cooled to room temperature for crystallization and filtered. 15.8g of candesartan cilexetil was obtained and the filtrate was used in the next reaction. Purity 99.7%, yield 77%.
(2) Concentrating the filtrate in the step (1), adding 60ml of dichloromethane and 60ml of water, adding 6g of sodium hydroxide, reacting for 12 hours at room temperature, and adjusting the pH=2 after the reaction is completed to obtain 28.8g of 3-nitrophthalic acid with the purity of 99.2% and the yield of about 79%.
(3) And (3) dissolving the 3-nitrophthalic acid obtained in the step (2) in 100mL of ethanol solution containing 20g of sulfuric acid for reaction for 10 hours, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of pure water, cooling to 0 ℃ for crystallization, and obtaining 27.0g of 3-nitrophthalic acid-1-monoethyl ester crystal with the yield of 82% and the purity of 98.6%.
(4) And (3) reacting the 3-nitrophthalic acid-1-monoethyl ester obtained in the step (3) in 150mL of dichloromethane solution containing 16.3mL of thionyl chloride to obtain the ethyl 2-formyl chloride-3-nitrobenzoate. Subsequently ethyl 2-formyl-3-nitrobenzoate was dissolved in another 30mL of dichloromethane, 150mL of DMF was added with 8.1g of sodium azide, and the reaction was worked up to give the isocyanate intermediate. The isocyanate intermediate was then reacted with 50mL of t-butanol at room temperature, monitored for completion, evaporated to dryness and recrystallized from methanol to give 19.2g of candel t-butyl ester in 72% yield (3 steps) purity 99.2%.
Example 5
(1) 100 g of concentrated candel butyl mother liquor was taken, 200ml of methylene chloride and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride were added and reacted at 25℃for 8 hours. After the reaction was completed, the layers were separated and washed. The organic layer was concentrated to give crude product. 250mL of ethanol is added into the crude product, the mixture is heated to dissolve, cooled to room temperature for crystallization and filtered. 15.5g of candesartan cilexetil was obtained and the filtrate was used in the next reaction. Purity 99.1% and yield 75%.
(2) Concentrating the filtrate in the step (1), adding 30ml of dichloromethane and 30ml of water, adding 3g of sodium hydroxide, reacting for 12 hours at room temperature, and adjusting the pH to be=2 after the reaction is completed to obtain 30.0g of 3-nitrophthalic acid with the purity of 98.8%, wherein the yield is about 83%.
(3) And (3) dissolving the 3-nitrophthalic acid obtained in the step (2) in 100mL of ethanol solution containing 20g of sulfuric acid for reaction for 10 hours, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of acetone, cooling to 0 ℃ for crystallization, and obtaining 27.4g of 3-nitrophthalic acid-1-monoethyl ester crystals with the yield of 79% and the purity of 98.5%.
(4) And (3) reacting the 3-nitrophthalic acid-1-monoethyl ester obtained in the step (3) in 150mL of dichloromethane solution containing 16.6mL of thionyl chloride to obtain the ethyl 2-formyl chloride-3-nitrobenzoate. Subsequently ethyl 2-formyl-3-nitrobenzoate was dissolved in another 30mL of dichloromethane, 150mL of DMF was added with 8.2g of sodium azide, and the reaction was worked up to give the isocyanate intermediate. The isocyanate intermediate was then reacted with 50mL of t-butanol at room temperature, monitored for completion, evaporated to dryness and recrystallized from methanol to give 19.4g of candel t-butyl ester in 73% yield (3 steps) with 99.0% purity.
Example 6
(1) 2 kg of concentrated candel butyl mother liquor was taken, 4 liters of methylene chloride and 1 liter of water, about 200g of potassium carbonate, about 300g of Boc anhydride were added and reacted at 25℃for 8 hours. After the reaction was completed, the layers were separated and washed. The organic layer was concentrated to give crude product. Adding 5L of methanol into the crude product, heating to dissolve, cooling to room temperature for crystallization, and filtering. 333.6g of Candest-butyl ester was obtained, and the filtrate was used in the next reaction. Purity 99.5%, yield 82%.
(2) Concentrating the filtrate in the step (1), adding 600ml of dichloromethane and 600ml of water, adding 60g of sodium hydroxide, reacting for 12 hours at room temperature, and adjusting pH=2 after the reaction is finished to obtain 611.2g of 3-nitrophthalic acid with the purity of 99.1% and the yield of about 85%.
(3) And (3) dissolving the 3-nitrophthalic acid obtained in the step (2) in 2L of ethanol solution containing 400g of sulfuric acid for reaction for 10 hours, evaporating the reaction solution after the reaction is finished, dissolving the residue in 3L of pure water, cooling to 0 ℃ for crystallization, and obtaining 546.2g of 3-nitrophthalic acid-1-monoethyl ester crystals with the yield of 79% and the purity of 99.8%.
(4) Reacting the 3-nitrophthalic acid-1-monoethyl ester obtained in step (3) in 3L of methylene chloride solution containing about 350mL of thionyl chloride to obtain the ethyl 2-formyl chloride-3-nitrobenzoate. Subsequently ethyl 2-formyl-3-nitrobenzoate was dissolved in another 600mL of dichloromethane, 3L of DMF and 170g of sodium azide were added, and the reaction was worked up to give the isocyanate intermediate. The isocyanate intermediate was then reacted with 1 liter of t-butanol at room temperature, monitored for completion, evaporated to dryness and recrystallized from methanol to give 399.3g of candel t-butyl ester in 75% yield (3 steps) with 99.2% purity.
Comparative example 1
(1) 100 g of concentrated candel butyl mother liquor was taken, 200ml of methylene chloride and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride were added and reacted at 80℃for 8 hours. After the reaction was completed, the layers were separated and washed. The organic layer was concentrated to give crude product. 250mL of methanol is added into the crude product, the mixture is heated to dissolve, cooled to room temperature for crystallization and filtered. 9.3g of candesate-butyl ester was obtained and the filtrate was used in the next reaction. Purity 96.2% and yield 45.1%.
The other steps were carried out under the same conditions as in example 1
Comparative example 2
(1) 100 g of concentrated candel butyl mother liquor was taken, 200ml of methylene chloride and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride were added and reacted at 25℃for 8 hours. After the reaction was completed, the layers were separated and washed. The organic layer was concentrated to give crude product. 250mL of acetone is added into the crude product, the mixture is heated to dissolve, cooled to room temperature for crystallization and filtered. 16.4g of candesate-butyl ester was obtained and the filtrate was used in the next reaction. Purity 77.7% and yield 80%.
The other steps were carried out under the same conditions as in example 1
Comparative example 3
(3) 30.1g of 3-nitrophthalic acid obtained in the step (2) is dissolved in 100mL of ethanol solution containing 5g of sulfuric acid for reaction for 10 hours, the reaction solution is evaporated to dryness after the reaction is finished, the residue is dissolved in 150mL of pure water and cooled to 0 ℃ for crystallization, 17.1g of 3-nitrophthalic acid-1-monoethyl ester crystal is obtained, the yield is 51%, and the purity is 96.6%.
The other steps were carried out under the same conditions as in example 1
Comparative example 4
(3) 30.1g of 3-nitrophthalic acid obtained in the step (2) is dissolved in 100mL of ethanol solution containing 20g of sulfuric acid for reaction for 10 hours, the reaction solution is evaporated to dryness after the reaction is finished, the residue is dissolved in 150mL of chloroform and cooled to 0 ℃ for crystallization, and 11.2g of 3-nitrophthalic acid-1-monoethyl ester crystal is obtained, the yield is 34%, and the purity is 91.3%.
The remaining procedure was as in example 1.
Claims (5)
1. A method for recovering candesartan cilexetil intermediate mother liquor is characterized in that the candesartan cilexetil intermediate mother liquor comprises candesartan Sha Tanshu butyl ester, candesartan Sha Tanshu butyl ester decomposed impurities and candesartan Sha Tanshu butyl diester impurities, and the decomposed impurities areThe diester impurity is->The candela Sha Tanshu butyl ester is +.>The recovery method comprises the following steps:
A. converting the decomposed impurities into candesa Sha Tanshu butyl ester and recovering candesa Sha Tanshu butyl ester in the solution;
B. converting the diester impurity into candesa Sha Tanshu butyl ester and then recycling;
the method for converting decomposed impurities into candesa Sha Tanshu butyl ester and recovering candesa Sha Tanshu butyl ester in the solution in the step A comprises the following steps: concentrating candesartan cilexetil intermediate mother liquor, adding a reaction solvent A, adding potassium carbonate and Boc anhydride for reaction, washing with water after the reaction is finished, concentrating an organic layer, adding a recrystallization solvent A, heating for clearing, cooling for crystallization, filtering, and recovering candesartan Sha Tanshu butyl ester to obtain a crystallization mother liquor; the recrystallization solvent A is methanol or ethanol; the reaction solvent A is a mixed solution of water and one of dichloromethane, chloroform, tetrahydrofuran and ethyl acetate;
the method for converting the diester impurity into candesa Sha Tanshu butyl ester in the step B comprises the following steps:
(B1) Concentrating the crystallization mother liquor in the step A, adding a reaction solvent B1 and inorganic base B for reaction, and regulating the pH value to 1-2 by using acid after the reaction is finished to obtain 3-nitrophthalic acid; the reaction solvent B1 is a mixed solution of water and one of dichloromethane, chloroform and tetrahydrofuran, and the volume ratio of the organic solvent to the water in the mixed solution is 9:1-1:1;
(B2) Reacting the obtained 3-nitrophthalic acid in ethanol solution containing sulfuric acid, concentrating the reaction solution under reduced pressure after the reaction is finished, adding pure water, cooling and crystallizing to obtain 3-nitrophthalic acid-1-monoethyl ester;
(B3) Reacting the obtained 3-nitrophthalic acid benzene-1-monoethyl ester in ethanol solution of thionyl chloride to obtain 2-formyl chloride-3-ethyl nitrobenzoate; then, reacting the ethyl 2-formyl chloride-3-nitrobenzoate with sodium azide in a reaction solvent B3 to obtain an isocyanate intermediate, reacting the isocyanate intermediate with tertiary butanol to convert the isocyanate intermediate into candelaidi Sha Tanshu butyl ester, and recrystallizing the butyl ester by using a recrystallization solvent B3 to obtain a refined product; the recrystallization solvent B3 is methanol or ethanol.
2. The recovery method of candesartan cilexetil intermediate mother liquor according to claim 1, wherein the ratio of the mass g of the concentrated candesartan cilexetil intermediate mother liquor to the volume ml of the reaction solvent a, the volume ml of the recrystallization solvent a, the mass g of the Boc anhydride is 1 (1-10): 1.5-3.5): (0.1-2).
3. The method for recovering candesartan cilexetil intermediate mother liquor according to claim 1 wherein the inorganic base B in step B1 is one selected from NaOH and KOH at a concentration of 0.1 to 10M; the ratio of the volume ml of the reaction solvent B1 to the mass g of the concentrated candesartan cilexetil intermediate mother solution is 2:5-2:1; the reaction temperature in step-B1 is 20-60 ℃.
4. The method for recovering candesartan cilexetil intermediate mother liquor according to claim 1, wherein the mass ratio of 3-nitrophthalic acid to sulfuric acid in step B2 is (1-3): 1.
5. the method for recovering candesartan cilexetil intermediate mother liquor according to claim 1, wherein the molar ratio of 3-nitrophthalic acid benzene-1-monoethyl ester to thionyl chloride in step B3 is 1: (1.0-3.5) using methylene dichloride with a molar concentration of 0.1-2M; the mol ratio of the ethyl 2-formyl chloride-3-nitrobenzoate to the sodium azide is 1 (1-2), and the reaction solvent B3 is selected from DMF, dichloromethane and tetrahydrofuran; the molar ratio of isocyanate intermediate to tertiary butanol in step B3 is 1 (1.5-5).
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| JP4323032B2 (en) * | 1999-11-29 | 2009-09-02 | 住友精化株式会社 | Process for producing 3-nitro-2- (Nt-butoxycarbonyl) aminobenzoates and production intermediates thereof |
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