CN113444009A - Recovery method of candesartan cilexetil intermediate mother liquor - Google Patents
Recovery method of candesartan cilexetil intermediate mother liquor Download PDFInfo
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C07—ORGANIC CHEMISTRY
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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
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- C07C263/00—Preparation of derivatives of isocyanic acid
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Abstract
The invention provides a recovery method of a candesartan cilexetil intermediate mother liquor, which is characterized in that the candesartan cilexetil intermediate mother liquor obtained in actual production comprises candesartan tert-butyl ester, candesartan tert-butyl ester decomposition impurities and candesartan tert-butyl ester diester impurities, the mother liquor is not treated in the previous production procedure and is directly treated as waste liquor, so that the waste of resources and the cost are increased. The recovery method of the invention can avoid the interference of diester impurities when recovering decomposition impurities and the generation of byproduct diester impurities when recovering the diester impurities, has simple and convenient operation and low cost of raw materials, and is suitable for industrial production and popularization.
Description
Technical Field
The invention relates to the field of synthesis of medical chemicals, in particular to a method for treating candesartan cilexetil intermediate mother liquor.
Background
Candesartan cilexetil is a precursor drug of candesartan, is rapidly decomposed in vivo into the active metabolite candesartan, is a selective angiotensin IIAT receptor antagonist, and is suitable for treating essential hypertension. The chemical name of candesartan cilexetil is 2-ethoxy-1- [ [2'- (1H-tetrazole-5-yl) [1,1' -biphenyl ] group]-4-yl]Methyl radical]-1H-benzimidazole-7-carboxylic acid-1- [ [ (cyclohexyloxy) carbonyl]Oxy radical]Ethyl ester, chemical structural formula:
。
the candesartan cilexetil is an important intermediate for synthesizing the front end of candesartan cilexetil, and a byproduct is generated during the synthesis of the candesartan cilexetil in the production process: diester impurities and decomposition impurities, the chemical structure of the diester impurities is
The chemical structure of the decomposed impurities is
The method has the advantages that the impurities of the tert-butyl ester, diester and decomposition impurities exist in the mother liquor for preparing the tert-butyl ester, the content of the impurities is high, the mother liquor cannot be directly recycled, the mother liquor is generally directly discharged as wastewater in the prior art, the waste of resources is caused, and the cost is increased. There is no document in the prior art that discloses how to recycle a mother liquor of tert-butyl kainate 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 the advantages of high recovery efficiency, simple and convenient operation, reduction of the production cost of candesartan cilexetil and suitability for industrial popularization.
In order to solve the problems, the invention discloses a recovery method of a candesartan cilexetil intermediate mother liquor, wherein the candesartan cilexetil intermediate mother liquor comprises candesartan tert-butyl ester, candesartan tert-butyl ester decomposition impurities and candesartanThe di-tert-butyl desartan has the impurity of di-tert-butyl ester, and the decomposed impurity is
The diester impurity is
The recovery method comprises the following steps:
A. firstly, converting the decomposed impurities into tert-butyl kainate and recovering the tert-butyl kainate in the solution;
B. and converting the diester impurities into tert-butyl kainate and then recovering.
Further, the method for decomposing impurities and converting the impurities into the tert-butyl kainate and recycling the tert-butyl kainate in the solution in the step A comprises the following steps: concentrating the candesartan cilexetil intermediate mother liquor, adding a reaction solvent A, adding an 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 for clearing, cooling for crystallization, filtering, and recovering the tert-butyl ester of candesartan to obtain a crystallized 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 one of dichloromethane, trichloromethane, tetrahydrofuran and ethyl acetate and water, and the crystallization solvent is one of methanol and ethanol. 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 crystallization solvent A and the mass g of the Boc anhydride is 1 (1-10) to (1.5-3.5): (0.1-2), preferably 1 (1-10) and (1.5-3.5): (0.1-0.3).
Further, the method for converting the diester impurities into tert-butyl kainate in the step B comprises the following steps: (B1) concentrating the filtrate obtained in the step A, adding a reaction solvent B1 and an inorganic base B for reaction, and adjusting the pH to 1-2 with acid after the reaction is finished to obtain 3-nitrophthalic acid; (B2) reacting the obtained 3-nitrophthalic acid in an ethanol solution containing sulfuric acid, concentrating the reaction solution under reduced pressure after the reaction is finished, adding a crystallization solvent B, and cooling and crystallizing to obtain 3-nitrophthalic acid-1-monoethyl ester; (B3) reacting the obtained 3-nitrophthalic acid benzene-1-monoethyl ester in an ethanol solution of thionyl chloride to obtain 2-formyl chloride-3-ethyl nitrobenzoate; and then reacting the 2-formyl chloride-3-ethyl nitrobenzoate with an azide reagent in a reaction solvent B3 to obtain an isocyanate intermediate, reacting the isocyanate intermediate with tert-butyl alcohol to convert the isocyanate intermediate into tert-butyl Kammadi, and recrystallizing by using a crystallization solvent B3 to obtain a refined product.
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, trichloromethane 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 liquor is 2:5-2:1, preferably 3: 5. The reaction temperature in step B1 is 20-60 deg.C, preferably 25 deg.C.
Furthermore, in the step B2, the mass ratio of the 2-carboxyl-3-nitrophthalic acid to the sulfuric acid is (1-3): 1; the crystallization solvent B2 is selected from water or acetone.
Further, in step B3, the molar ratio of benzene-1-monoethyl 3-nitrophthalate to thionyl chloride is 1: (1.0-3.5) and the molar concentration of the dichloromethane used is 0.1-2M. In the step B3, the azide reagent is selected from sodium azide and one of trimethylsilyl 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 and tetrahydrofuran, preferably DMF. The molar ratio of isocyanate intermediate to tertiary butanol in step B3 was 1: (1.5-5). The crystallization solvent B3 in the step B3 is selected from one of methanol and ethanol.
Has the advantages that: the invention provides a recovery method of a candesartan cilexetil intermediate mother liquor, which is characterized in that the candesartan cilexetil intermediate mother liquor obtained in actual production comprises candesartan tert-butyl ester, candesartan tert-butyl ester decomposition impurities and candesartan tert-butyl ester diester impurities, the mother liquor is not treated in the previous production procedure and is directly treated as waste liquor, so that the waste of resources and the cost are increased. The recovery method of the invention can avoid the interference of diester impurities when recovering decomposition impurities and the generation of byproduct diester impurities when recovering the diester impurities, has simple and convenient operation and low cost of raw materials, and is suitable for industrial production and popularization.
Detailed Description
Example 1
(1) 100 g of concentrated mother liquor of Kandel tert-butyl ester was added with 200ml of dichloromethane and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride, and reacted at 25 ℃ for 8 hours. After the reaction is finished, the layers are separated and washed. The organic layer was concentrated to give the crude product. Adding 250mL of methanol into the crude product, heating to dissolve the mixture, cooling to room temperature for crystallization, filtering to obtain 16.8g of tert-butyl kainate, and using the filtrate for the next reaction. Purity 99.1%, yield 82%.
(2) Concentrating the filtrate obtained in the step (1), adding 30ml of dichloromethane and 30ml of water, adding 3g of sodium hydroxide, reacting at room temperature for 12 hours, and adjusting the pH =2 after the reaction is completed to obtain 30.1g of 3-nitrophthalic acid, wherein the purity is 98.3% and 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 to react for 10h, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of pure water, cooling to 0 ℃ and crystallizing to obtain 27.3g of 3-nitrophthalic acid-1-monoethyl ester crystals, wherein the yield is 79%, and the purity is 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 2-formyl chloride-3-ethyl nitrobenzoate. Then, ethyl 2-formylchloro-3-nitrobenzoate was dissolved in another 30mL of dichloromethane, and 150mL of DMF and 8.2g of sodium azide were added to react and obtain an isocyanate intermediate through post-treatment. The isocyanate intermediate was then reacted with 50mL of t-butanol, after monitoring the completion of the reaction, evaporated to dryness and recrystallized from methanol to yield Kandedi-t-butyl ester 19.5g, 73% yield (3 steps) and 99.2% purity.
Example 2
(1) 100 g of concentrated mother liquor of Kandel tert-butyl ester was added with 200ml of dichloromethane and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride, and reacted at 25 ℃ for 8 hours. After the reaction is finished, the layers are separated and washed. The organic layer was concentrated to give the crude product. Adding 250mL of ethanol into the crude product, heating to dissolve the mixture, cooling to room temperature for crystallization, filtering to obtain 16.6g of tert-butyl kainate, and using the filtrate for the next reaction. Purity 99.3%, yield 81%.
(2) Concentrating the filtrate obtained in the step (1), adding 30ml of dichloromethane and 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, wherein the purity is 98.3% and 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 to react for 10h, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of pure water, cooling to 0 ℃ and crystallizing to obtain 27.2g of 3-nitrophthalic acid-1-monoethyl ester crystals, wherein the yield is 79%, and the purity is 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 2-formyl chloride-3-ethyl nitrobenzoate. Then, ethyl 2-formylchloro-3-nitrobenzoate was dissolved in another 30mL of dichloromethane, and 150mL of DMF and 8.2g of sodium azide were added to react and obtain an isocyanate intermediate through post-treatment. The isocyanate intermediate was then reacted with 50mL of t-butanol, after monitoring the completion of the reaction, evaporated to dryness and recrystallized from methanol to yield 19.9g of tert-butyl kainate, 74% yield (3 steps) and 99.6% purity.
Example 3
(1) 100 g of the concentrated mother liquor of Kandel tert-butyl ester was added with 200mL of tetrahydrofuran and 50mL of water, 9g of potassium carbonate, 13g of Boc anhydride, and reacted at 25 ℃ for 8 hours. After the reaction is finished, the layers are separated and washed. The organic layer was concentrated to give the crude product. Adding 250mL of methanol into the crude product, heating to dissolve the mixture, cooling to room temperature for crystallization, and filtering. 16.1g of Kandedi tert-butyl ester was obtained, and the filtrate was used in the next reaction. Purity 99.4%, yield 78%.
(2) Concentrating the filtrate obtained in the step (1), adding 30ml of tetrahydrofuran and 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, wherein the purity is 98.9% and 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 to react for 10h, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of pure water, cooling to 0 ℃ and crystallizing to obtain 27.5g of 3-nitrophthalic acid-1-monoethyl ester crystals, wherein the yield is 80%, and the purity is 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 2-formyl chloride-3-ethyl nitrobenzoate. Then, ethyl 2-formylchloro-3-nitrobenzoate was dissolved in another 30mL of dichloromethane, and 150mL of DMF and 8.3g of sodium azide were added to react and obtain an isocyanate intermediate through post-treatment. The isocyanate intermediate was then reacted with 50mL of t-butanol at room temperature, after monitoring the completion of the reaction, evaporated to dryness and recrystallized using methanol to give 20.3g of tert-butyl kainate, with a yield of 76% (3 steps) and a purity of 99.1%.
Example 4
(1) 100 g of concentrated mother liquor of tert-butyl kainate is added with 100ml of dichloromethane and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride and reacted for 8 hours at 25 ℃. After the reaction is finished, the layers are separated and washed. The organic layer was concentrated to give the crude product. Adding 250mL of methanol into the crude product, heating to dissolve the mixture, cooling to room temperature for crystallization, and filtering. 15.8g of tert-butyl kainate is obtained, and the filtrate is used for the next reaction. The purity was 99.7% and the yield was 77%.
(2) Concentrating the filtrate obtained in the step (1), adding 60ml of dichloromethane and 60ml of water, adding 6g of sodium hydroxide, reacting at room temperature for 12 hours, 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 to react for 10h, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of pure water, cooling to 0 ℃ and crystallizing to obtain 27.0g of 3-nitrophthalic acid-1-monoethyl ester crystal, wherein the yield is 82%, and the purity is 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 2-formyl chloride-3-ethyl nitrobenzoate. Then, ethyl 2-formylchloro-3-nitrobenzoate was dissolved in another 30mL of dichloromethane, and 150mL of DMF and 8.1g of sodium azide were added to react and obtain an isocyanate intermediate through post-treatment. The isocyanate intermediate was then reacted with 50mL of t-butanol at room temperature, after monitoring the completion of the reaction, evaporated to dryness and recrystallized with methanol to give 19.2g of tert-butyl kainate in 72% yield (3 steps) and 99.2% purity.
Example 5
(1) 100 g of concentrated mother liquor of tert-butyl kainate is added with 200ml of dichloromethane and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride and reacted for 8 hours at 25 ℃. After the reaction is finished, the layers are separated and washed. The organic layer was concentrated to give the crude product. Adding 250mL of ethanol into the crude product, heating to dissolve the mixture, cooling to room temperature for crystallization, and filtering. 15.5g of tert-butyl kainate is obtained, and the filtrate is used for the next reaction. Purity 99.1%, yield 75%.
(2) Concentrating the filtrate obtained in the step (1), adding 30ml of dichloromethane and 30ml of water, adding 3g of sodium hydroxide, reacting at room temperature for 12 hours, and adjusting the pH =2 after the reaction is completed to obtain 30.0g of 3-nitrophthalic acid, wherein the purity is 98.8% and 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 to react for 10h, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of acetone, cooling to 0 ℃ and crystallizing to obtain 27.4g of 3-nitrophthalic acid-1-monoethyl ester crystals, wherein the yield is 79%, and the purity is 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 2-formyl chloride-3-ethyl nitrobenzoate. Then, ethyl 2-formylchloro-3-nitrobenzoate was dissolved in another 30mL of dichloromethane, and 150mL of DMF and 8.2g of sodium azide were added to react and obtain an isocyanate intermediate through post-treatment. The isocyanate intermediate was then reacted with 50mL of t-butanol at room temperature, after monitoring the completion of the reaction, evaporated to dryness and recrystallized from methanol to yield 23.4 g of tert-butyl kainate, 73% yield (3 steps) and 99.0% purity.
Example 6
(1) 2 kg of concentrated mother liquor of Kandel tert-butyl ester was added with 4 l of dichloromethane and 1 l of water, about 200g of potassium carbonate, about 300g of Boc anhydride, and reacted at 25 ℃ for 8 hours. After the reaction is finished, the layers are separated and washed. The organic layer was concentrated to give the crude product. Adding 5L of methanol into the crude product, heating to dissolve, cooling to room temperature for crystallization, and filtering. 333.6g of Kandedi tert-butyl ester is obtained, and the filtrate is used for the next reaction. Purity 99.5%, yield 82%.
(2) The filtrate obtained in step (1) was concentrated, 600ml of methylene chloride and 600ml of water were added, 60g of sodium hydroxide was added, and the reaction was carried out at room temperature for 12 hours, and after completion of the reaction, pH =2 was adjusted to obtain 611.2g of 3-nitrophthalic acid with a purity of 99.1% and a yield of about 85%.
(3) And (3) dissolving the 3-nitrophthalic acid obtained in the step (2) in 2 liters of ethanol solution containing 400g of sulfuric acid to react for 10 hours, evaporating the reaction solution after the reaction is finished, dissolving the residue in 3 liters of pure water, cooling to 0 ℃ and crystallizing to obtain 546.2g of 3-nitrophthalic acid-1-monoethyl ester crystals, wherein the yield is 79 percent, and the purity is 99.8 percent.
(4) Reacting the 1-monoethyl 3-nitrophthalate obtained in step (3) in 3L/mL of dichloromethane solution containing about 350mL of thionyl chloride to obtain ethyl 2-formylchloro-3-nitrobenzoate. Then, ethyl 2-formylchloro-3-nitrobenzoate was dissolved in another 600mL of dichloromethane, 3L of DMF and 170g of sodium azide were added, and the reaction was post-treated to obtain an isocyanate intermediate. The isocyanate intermediate was then reacted with 1 liter of tert-butanol at room temperature, after monitoring the completion of the reaction, evaporated to dryness and recrystallized from methanol to yield 399.3g of tert-butyl kainate, 75% yield (3 steps) with a purity of 99.2%.
Comparative example 1
(1) 100 g of concentrated mother liquor of tert-butyl kainate is added with 200ml of dichloromethane and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride and reacted for 8 hours at 80 ℃. After the reaction is finished, the layers are separated and washed. The organic layer was concentrated to give the crude product. Adding 250mL of methanol into the crude product, heating to dissolve the mixture, cooling to room temperature for crystallization, and filtering. 9.3g of tert-butyl kainate was obtained, and the filtrate was used in the next reaction. The purity was 96.2% and the yield was 45.1%.
The rest of the procedure conditions were the same as in example 1
Comparative example 2
(1) 100 g of concentrated mother liquor of tert-butyl kainate is added with 200ml of dichloromethane and 50ml of water, 9g of potassium carbonate, 13g of Boc anhydride and reacted for 8 hours at 25 ℃. After the reaction is finished, the layers are separated and washed. The organic layer was concentrated to give the crude product. Adding 250mL of acetone into the crude product, heating to dissolve the mixture, cooling to room temperature for crystallization, and filtering. 16.4g of tert-butyl kainate was obtained, and the filtrate was used in the next reaction. Purity 77.7% and yield 80%.
The rest of the procedure conditions were the same as in example 1
Comparative example 3
(3) And (3) dissolving 30.1g of 3-nitrophthalic acid obtained in the step (2) in 100mL of ethanol solution containing 5g of sulfuric acid to react for 10h, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of pure water, cooling to 0 ℃ and crystallizing to obtain 17.1g of 3-nitrophthalic acid-1-monoethyl ester crystals, wherein the yield is 51%, and the purity is 96.6%.
The rest of the procedure conditions were the same as in example 1
Comparative example 4
(3) And (3) dissolving 30.1g of 3-nitrophthalic acid obtained in the step (2) in 100mL of ethanol solution containing 20g of sulfuric acid to react for 10h, evaporating the reaction solution after the reaction is finished, dissolving the residue in 150mL of trichloromethane, cooling to 0 ℃ and crystallizing to obtain 11.2g of 3-nitrophthalic acid-1-monoethyl ester crystal, wherein the yield is 34% and the purity is 91.3%.
The remaining process conditions were the same as in example 1.
Claims (7)
1. The recovery method of the candesartan cilexetil intermediate mother liquor is characterized in that the candesartan cilexetil intermediate mother liquor comprises candesartan tert-butyl ester, candesartan tert-butyl ester decomposition impurities and candesartan tert-butyl ester diester impurities, and the decomposition impurities are candesartan tert-butyl ester decomposition impurities
The diester impurity is
The recovery method comprises the following steps:
A. firstly, converting the decomposed impurities into tert-butyl kainate and recovering the tert-butyl kainate in the solution;
B. and converting the diester impurities into tert-butyl kainate and then recovering.
2. The recovery method of candesartan cilexetil intermediate mother liquor according to claim 1, wherein the method for converting the decomposed impurities into the tert-butyl ester and recovering the tert-butyl ester in the solution in the step A comprises the following steps: concentrating the candesartan cilexetil intermediate mother liquor, adding a reaction solvent A, adding an 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 for clearing, cooling for crystallization, filtering, and recovering the tert-butyl ester of candesartan to obtain a crystallized mother liquor.
3. The recovery method of candesartan cilexetil intermediate mother liquor according to claim 2, wherein 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 selected from a mixed solution of one of dichloromethane, chloroform, tetrahydrofuran and ethyl acetate and water, the crystallization solvent is selected from one of methanol and ethanol, and 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 crystallization solvent A and the mass g of Boc anhydride is 1 (1-10): 1.5-3.5): (0.1-2), preferably 1 (1-10) and (1.5-3.5): (0.1-0.3).
4. The recovery method of candesartan cilexetil intermediate mother liquor according to claim 1, wherein the method for converting the diester impurity into tert-butyl candesartan in step B comprises: (B1) concentrating the filtrate obtained in the step A, adding a reaction solvent B1 and an inorganic base B for reaction, and adjusting the pH to 1-2 with acid after the reaction is finished to obtain 3-nitrophthalic acid; (B2) reacting the obtained 3-nitrophthalic acid in an ethanol solution containing sulfuric acid, concentrating the reaction solution under reduced pressure after the reaction is finished, adding a crystallization solvent B, and cooling and crystallizing to obtain 3-nitrophthalic acid-1-monoethyl ester; (B3) reacting the obtained 3-nitrophthalic acid benzene-1-monoethyl ester in an ethanol solution of thionyl chloride to obtain 2-formyl chloride-3-ethyl nitrobenzoate; and then reacting the 2-formyl chloride-3-ethyl nitrobenzoate with an azide reagent in a reaction solvent B3 to obtain an isocyanate intermediate, reacting the isocyanate intermediate with tert-butyl alcohol to convert the isocyanate intermediate into tert-butyl Kammadi, and recrystallizing by using a crystallization solvent B3 to obtain a refined product.
5. The recovery method of candesartan cilexetil intermediate mother liquor according to claim 4, wherein the inorganic base B in step B1 is selected from one of NaOH and KOH, and has a concentration of 0.1-10M, preferably 8M; the reaction solvent B1 is a mixed solution of water and one of dichloromethane, trichloromethane and tetrahydrofuran, the volume ratio of an organic solvent to water in the mixed solution is 9:1-1:1, and the mass g ratio of ml of the reaction solvent B1 to the concentrated candesartan cilexetil intermediate mother liquor is 2:5-2:1, preferably 3: 5; the reaction temperature in step B1 is 20-60 deg.C, preferably 25 deg.C.
6. The recovery method of candesartan cilexetil intermediate mother liquor according to claim 4, wherein the mass ratio of the 2-carboxy-3-nitrophthalic acid to the sulfuric acid in the step B2 is (1-3): 1; the crystallization solvent B2 is selected from water or acetone.
7. The recovery method of candesartan cilexetil intermediate mother liquor according to claim 4, wherein the molar ratio of 3-nitrophthalic acid benzene-1-monoethyl ester to thionyl chloride in step B3 is 1: (1.0-3.5), wherein the molar concentration of the used dichloromethane is 0.1-2M; in the step B3, the azide reagent is selected from sodium azide and one of trimethylsilyl 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 tertiary butanol in step B3 was 1: (1.5-5); the crystallization solvent B3 in the step B3 is selected from one of methanol and ethanol.
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Citations (2)
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| US5693636A (en) * | 1991-06-28 | 1997-12-02 | Smithkline Beecham Corporation | Bicyclic fibrinogen antagonists |
| JP2001151745A (en) * | 1999-11-29 | 2001-06-05 | Sumitomo Seika Chem Co Ltd | METHOD FOR PRODUCING 3-NITRO-2-(N-t-BUTOXYCARBONYL)- AMINOBENZOATES AND INTERMEDIATE FOR PRODUCING THE SAME ESTERS |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5693636A (en) * | 1991-06-28 | 1997-12-02 | Smithkline Beecham Corporation | Bicyclic fibrinogen antagonists |
| JP2001151745A (en) * | 1999-11-29 | 2001-06-05 | Sumitomo Seika Chem Co Ltd | METHOD FOR PRODUCING 3-NITRO-2-(N-t-BUTOXYCARBONYL)- AMINOBENZOATES AND INTERMEDIATE FOR PRODUCING THE SAME ESTERS |
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| FUNK, PETR等: "Preparation of 2-phenyl-3-hydroxyquinoline-4(1H)-one-5-carboxamides as potential anticancer and fluorescence agents", 《RSC ADVANCES》 * |
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