CN110627736B - Method for recycling 1-phenyl-5-hydroxy tetrazole - Google Patents
Method for recycling 1-phenyl-5-hydroxy tetrazole Download PDFInfo
- Publication number
- CN110627736B CN110627736B CN201910916868.9A CN201910916868A CN110627736B CN 110627736 B CN110627736 B CN 110627736B CN 201910916868 A CN201910916868 A CN 201910916868A CN 110627736 B CN110627736 B CN 110627736B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- tetrazole
- hydroxy
- compound
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses a recycling method of 1-phenyl-5-hydroxy tetrazole, belonging to the technical field of pharmaceutical chemistry. The method converts the byproduct 1-phenyl-5-hydroxy tetrazole generated in the preparation process of the rosuvastatin calcium intermediate into 1-phenyl-5-mercapto tetrazole; meanwhile, the 1-phenyl-5-mercapto tetrazole is further used for preparing rosuvastatin calcium intermediate or rosuvastatin calcium. The invention realizes the reasonable recycling of the byproduct 1-phenyl-5-hydroxy tetrazole, fully utilizes the raw materials, reduces the production cost of the rosuvastatin calcium and the intermediate thereof, and reduces the discharge of three wastes.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and relates to a method for recycling a byproduct in a preparation process of a rosuvastatin calcium intermediate, in particular to a method for recycling 1-phenyl-5-hydroxy tetrazole.
Background
Rosuvastatin calcium, chemical name: bis- [ E-7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -pyrimidin-5-yl ] (3R,5S) -3, 5-dihydroxyhept-6-enoic acid ] calcium salt (2: 1). It is a selective HMG-CoA reductase inhibitor developed and developed by Aslicon, and is marketed in several countries and regions of the United states, Japan, Europe, China, etc. The structural formula is as follows:
a compound I: [ E-7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -pyrimidin-5-yl ] (3R,5S) -3, 5-dioxo (acetonide) ylhept-6-enoic acid tert-butyl ester is an important intermediate for the preparation of rosuvastatin calcium drugs. The main synthetic route is as follows:
in the preparation of the intermediate compound I of the rosuvastatin calcium medicament, a byproduct compound II is generated: 1-phenyl-5-hydroxy tetrazole:
if the byproduct compound II is not recycled, the raw material waste is caused, the three-waste discharge is increased, and the production cost of the product is increased.
Meanwhile, the intermediate compound I of the rosuvastatin calcium medicament has high production cost and relatively high market price; if the byproduct compound II can be converted into the compound I and the final product rosuvastatin calcium, waste can be changed into valuable, and the reasonable recycling of the byproduct 1-phenyl-5-hydroxy tetrazole can be realized.
Therefore, the research on the recycling method of the byproduct 1-phenyl-5-hydroxy tetrazole has great economic and environmental protection values. However, so far, there are few reports on the recycling method of this by-product.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a method for recycling 1-phenyl-5-hydroxy tetrazole aiming at the defects of the prior art. The method realizes reasonable recycling of the byproduct 1-phenyl-5-hydroxy tetrazole, reduces production cost of rosuvastatin calcium and an intermediate thereof, and reduces discharge of three wastes.
Compound II: the 1-phenyl-5-hydroxy tetrazole mainly exists in crystallization mother liquor (including dichloromethane for leaching) after the synthesis of the compound I, and the content of a water phase is low. Before use, methanol is removed by drying under reduced pressure or the like.
The technical scheme is as follows: the purpose of the invention is realized by the following technical scheme:
the invention provides a recycling method of 1-phenyl-5-hydroxy tetrazole, which comprises the following steps:
(1) converting the compound 1-phenyl-5-hydroxy tetrazole of the formula II into a compound 1-phenyl-5-mercapto tetrazole of a formula IV;
(2) the 1-phenyl-5-mercapto tetrazole of the compound IV is further synthesized into an intermediate compound I of rosuvastatin calcium and/or rosuvastatin calcium, so that the 1-phenyl-5-hydroxy tetrazole can be recycled.
In the step (1), 1-phenyl-5-hydroxy tetrazole of a compound shown in a formula II is converted into 1-phenyl-5-chloro tetrazole or 1-phenyl-5-bromo tetrazole; then the 1-phenyl-5-chloro tetrazole or the 1-phenyl-5-bromo tetrazole is further converted into a compound 1-phenyl-5-mercapto tetrazole of a formula IV.
The method for converting the compound 1-phenyl-5-hydroxy tetrazole of the formula II into the 1-phenyl-5-chloro tetrazole comprises the following steps: the mol ratio of the 1-phenyl-5-hydroxy tetrazole to the chlorine-containing reaction reagent is 1: 0.45-3, reacting in a solvent at 20-115 ℃ for 9-12 hours; after the reaction is finished, carrying out post-treatment, concentrating the system under reduced pressure until the system is dry, and then recrystallizing with methanol or ethanol; the chlorine-containing reaction reagent is one or a mixture of more of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, triphosgene, methylene phosphorus trichloride, chlorine, cyano trichloromethane, NCS and trichloroisocyanuric acid.
The solvent is toluene, 1, 2-dichloroethane or thionyl chloride.
A preferred technical scheme of the invention is as follows: taking thionyl chloride as a solvent and a reaction reagent, adding N, N-dimethylformamide which is 1 wt% of the thionyl chloride to improve the activity of the thionyl chloride, and heating the mixture to reflux for reaction.
The method for converting the compound 1-phenyl-5-hydroxy tetrazole of the formula II into the 1-phenyl-5-bromo tetrazole comprises the following steps: the molar ratio of the 1-phenyl-5-hydroxy tetrazole to the bromine-containing reaction reagent is 1: 0.5 to 1.5, and reacting in toluene or carbon tetrachloride at the temperature of 20 to 115 ℃ for 8 to 12 hours; after the reaction is finished, carrying out post-treatment, concentrating the system under reduced pressure until the system is dry, and then recrystallizing with methanol or ethanol; the bromine-containing reaction reagent is one or a mixture of more of phosphorus tribromide, NBS, phosphorus pentabromide, phosphorus oxybromide, phosphorus oxychloride and bromine.
A preferred technical scheme of the invention is as follows: carbon tetrachloride is used as a solvent, phosphorus pentabromide is used as a reaction reagent, and the reaction is carried out under reflux.
Preferably, in the method for converting the 1-phenyl-5-hydroxy tetrazole of the compound of the formula II into the 1-phenyl-5-chloro tetrazole or the 1-phenyl-5-bromo tetrazole, the reaction temperature is 60-115 ℃.
The synthesis method of the compound 1-phenyl-5-mercapto tetrazole of the formula IV comprises the following steps: adding 1-phenyl-5-chlorine/bromine tetrazole and thiourea into an ethanol or ether solvent according to a molar ratio of 1: 1.2-2.0, heating to 50-60 ℃, and reacting for 9-12 hours; cooling to below 30 ℃, adding inorganic base, heating to 40-50 ℃, and reacting for 3-4 hours; after the reaction is finished, cooling to room temperature, adding water, concentrating to remove the solvent, extracting with ethyl acetate or dichloromethane to remove impurities, adjusting the pH value to acidity with hydrochloric acid, and precipitating a solid product.
Ethanol is preferred as a solvent in the present invention. If ethers such as isopropyl ether are used as the solvent, the conversion of the product is relatively slow.
If sodium hydrosulfide is used instead of thiourea, no target product is found in the reaction, even if the reaction temperature is increased to 80 ℃.
Preferably, the inorganic base is one or a mixture of sodium hydroxide, potassium hydroxide and cesium carbonate.
Preferably, the molar ratio of the inorganic base to the 1-phenyl-5-chloro \ bromotetrazole is 0.5-4.0: 1.
in the step (2), the method for further synthesizing the rosuvastatin calcium intermediate compound shown in the formula I by the compound shown in the formula IV 1-phenyl-5-mercapto tetrazole comprises the following steps: the compound shown in the formula IV reacts with tert-butyl (3R,5S) -6-chloro-3, 5-dioxo (acetonide) hexanoate, and then is oxidized and reacts with 2- (N-methyl-N-methylsulfonyl) amino-4- (4-fluorobenzene) group-6-isopropylpyrimidine-5-formaldehyde to obtain the compound shown in the formula I. The reaction route is as follows:
the method for recycling the 1-phenyl-5-hydroxy tetrazole is also suitable for the compound shown in the formula II-b:
the 1-phenyl-5-hydroxy tetrazole actually belongs to the same substance due to tautomerism and the two different structures.
The invention further researches a post-treatment method of the reaction:
(1) after the synthesis reaction of the 1-phenyl-5-chlorotetrazol is finished, post-treatment is carried out:
the first scheme is as follows: concentrating the system under reduced pressure to dryness, and recrystallizing with methanol or ethanol;
scheme II: concentrating the system under reduced pressure until the system is dry, adding a small amount of ethanol, reducing the pressure until the system is dry, and performing recrystallization (directly adding a solvent to the next reaction).
The experimental result shows that the reaction of the step (2) is respectively carried out by the two schemes, and the yield of the product after the post-treatment is reduced by about 10% in the first scheme under the same reaction condition, but the purity of the product is not obviously different.
(2) Post-treatment of the compound 1-phenyl-5-mercaptotetrazole synthesis reaction of formula IV:
reacting 1-phenyl-5-chlorotetrazole or 1-phenyl-5-bromotetrazole with thiourea, adding water after the reaction is finished, concentrating to remove the solvent, extracting with ethyl acetate or dichloromethane to remove a small amount of organic impurities, and adjusting the pH value to be acidic by hydrochloric acid to precipitate a solid. The pH values are adjusted to 1, 2-3 and 4-5 respectively for comparison, so that the yield of pH 2-3 is the highest.
Experiments prove that the 1-phenyl-5-mercapto tetrazole obtained by the method can be used for preparing rosuvastatin calcium intermediate and/or rosuvastatin calcium.
Has the advantages that:
according to the invention, the byproduct compound 1-phenyl-5-hydroxy tetrazole shown in formula II is converted into 1-phenyl-5-mercapto tetrazole, and then the rosuvastatin calcium and/or rosuvastatin calcium as an intermediate shown in formula I of rosuvastatin calcium are further synthesized. The method realizes reasonable recycling of the byproduct 1-phenyl-5-hydroxy tetrazole, reduces the production cost of rosuvastatin calcium and an intermediate thereof, and reduces the discharge of three wastes. Experiments prove that the recovery amount of the byproduct II is about 0.25 kg (the recovery rate reaches 90%) when 1 kg of the rosuvastatin calcium intermediate I is produced, the byproduct II is converted into the compound I according to the method, the yield of the compound I is increased within the range of 0.19-0.25 kg without calculating secondary recovery, the cost is saved by more than 10% when the same amount of the compound I is produced, and the three wastes are reduced.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of compound I synthesized by the present invention.
Detailed Description
The technical solution of the present invention is described in detail by the following specific examples, but the scope of the present invention is not limited to the examples.
Extracting 1-phenyl-5-hydroxy tetrazole from the post-synthesis treatment mother liquor of the compound of the formula I:
and combining the post-treatment crystallization mother liquor of the compound shown in the formula I, concentrating, and carrying water with toluene until the toluene is dry for later use.
Example 1
1-phenyl-5-chlorotetrazol synthesis:
20 g (0.123mol) of 1-phenyl-5-hydroxy tetrazole is placed in a reaction bottle, 100 ml of toluene is added, 11.6 g of phosphorus pentachloride (0.056mol) is added, the mixture is heated to reflux for reaction, and the reaction is finished after 10 hours. After removal of excess thionyl chloride and solvent under reduced pressure, the crude product was recrystallized once from ethanol to give 15.6 g of product with a yield of 70%.
Synthesizing 1-phenyl-5-mercapto tetrazole:
15 g (0.083mol) of 1-phenyl-5-chlorotetrazol is added, 60 ml of absolute ethyl alcohol is added, 12.2g (0.16mol) of thiourea is added, and the mixture is heated to 60 ℃ under full stirring to react for 10 hours. Cooled to 30 ℃, added with 6g of sodium hydroxide solid, slowly heated to 50 ℃ and reacted for 3 hours.
Cooling to room temperature, adding 30 ml of water into a reaction system, removing a solvent under reduced pressure, adding 50ml of dichloromethane for extraction, stirring, separating liquid, removing an organic layer, slowly adding 3mol/L hydrochloric acid into a water phase under stirring to adjust the pH value to be 2-3, separating out a solid, performing suction filtration, and performing vacuum drying to obtain 11.4 g of the solid, wherein the yield is 77%, the HPLC purity is 98.3%, and the melting point is 144-146 ℃.
If further purification is needed, the product is dissolved in alkali solution and slowly acidified to separate out solid.
Example 2
20 g (0.123mol) of 1-phenyl-5-hydroxy tetrazole is placed in a reaction bottle, 43.8 g (0.369mol) of thionyl chloride is added, 0.5 ml of DMF and 70 ml of toluene are added, heating is carried out till reflux, and the reaction is finished after 9 hours. After removal of excess thionyl chloride under reduced pressure, 22 g of crude product was obtained. 10 ml of absolute ethanol are added and the mixture is dried under reduced pressure and then is not purified.
The solid is directly added into 80 ml of absolute ethyl alcohol, 15 g (0.197mol) of thiourea is added, and the mixture is heated to 60 ℃ under full stirring and reacts for 9 h. Cooled to 25 ℃, added with 9 g of sodium hydroxide solid, slowly heated to 50 ℃ and reacted for 3 hours.
Cooling to room temperature, adding 50ml of water into the reaction system, removing the solvent under reduced pressure, adding 100 ml of dichloromethane for extraction to remove organic impurities, slowly adding 3mol/L hydrochloric acid into the water phase under stirring to adjust the pH value to be 2-3, separating out a solid, performing suction filtration, and performing vacuum drying to obtain 13.8 g of the solid, wherein the product purity is 98.0%, and the total yield in two steps is 62.8%.
Example 3
Adding 15 g (0.093mol) of 1-phenyl-5-hydroxy tetrazole, adding 100 ml of carbon tetrachloride and 21.5 g (0.05mol) of phosphorus pentabromide, heating to reflux, and reacting for 8 hours. After completion of the reaction, the reaction system was poured into 200 g of ice water. After stirring and separation, the aqueous phase was extracted twice with 100 ml of dichloromethane, the organic phases were combined, washed once with 50ml of sodium bicarbonate solution and once with 50ml of water, dried and concentrated to dryness under reduced pressure to give 16.2 g of a solid with a yield of 77.7%. The crude product is recrystallized once by ethanol for standby.
Adding 15.8 g of 1-phenyl-5-bromotetrazole (0.07mol) into 80 ml of absolute ethyl alcohol, adding 8.2 g of thiourea (0.108mol), heating to 60 ℃, reacting for 9 hours, cooling to 25 ℃, adding 5 g of sodium hydroxide solid, slowly heating to 50 ℃, and reacting for 3 hours.
Cooling to room temperature, adding 50ml of water into the reaction system, removing the solvent under reduced pressure, adding 80 ml of dichloromethane for extraction to remove organic impurities, slowly adding 3mol/L hydrochloric acid into the water phase under stirring to adjust the pH value to be 2-3, separating out a solid, performing suction filtration, and performing vacuum drying to obtain 11.2 g of the solid with the purity of 97.3% and the total yield of the two steps of 67.8%.
Example 4
The reaction operation is the same as that of the first example, but the 1-phenyl-5-chlorotetrazole is not crystallized by alcohol, and the total yield of the two steps is 59 percent.
Example 5
20 g (0.123mol) of 1-phenyl-5-hydroxy tetrazole is placed in a reaction bottle, 100 ml of toluene is added, 48.8 g of phosphorus tribromide solid (0.18mol) is added, the mixture is heated to reflux for reaction, and the reaction is finished after 9 hours. After the temperature is reduced to room temperature, the reaction mixture is carefully poured into ice water (150 g of ice and 100 g of water), 100 ml of dichloromethane is added, liquid separation is carried out (after the ice is completely melted), the water phase is extracted once with 100 ml of dichloromethane, the combined organic phase is dried by anhydrous sodium sulfate, reduced pressure distillation is carried out until no liquid flows down, ethanol is added for recrystallization once, 14.9 g of a product is obtained, and the yield is 66.9%.
14.4 g (0.08mol) of the above product was added with 60 ml of absolute ethanol, and then 7.6 g (0.1mol) of thiourea was added, and the mixture was heated to 60 ℃ with sufficient stirring to react for 10 hours. Cooled to 30 ℃, added with 13.1 g of cesium carbonate solid, slowly warmed to 50 ℃ and reacted for 3 hours.
Cooling to room temperature, adding 30 ml of water into the reaction system, removing the solvent under reduced pressure, adding 50ml of dichloromethane for extraction, stirring, separating liquid, removing an organic layer, slowly adding 3mol/L hydrochloric acid into a water phase under stirring to adjust the pH value to be 2-3, separating out a solid, performing suction filtration, and performing vacuum drying to obtain 10.7 g of the solid with the yield of 75%.
Example 6
14.6 g (0.09mol) of 1-phenyl-5-hydroxy tetrazole is added, 95 ml of carbon tetrachloride and 38.7 g (0.09mol) of phosphorus pentabromide are added, and the mixture is heated to reflux and reacted for 8 hours. After completion of the reaction, the reaction system was poured into 250 g of ice water. After stirring and separation, the aqueous phase was extracted twice with 100 ml of dichloromethane, the organic phases were combined, washed once with 50ml of sodium bicarbonate solution and once with 50ml of water, dried and concentrated to dryness under reduced pressure to give 15.1 g of a solid with a yield of 74.7%. The crude product is recrystallized once by ethanol for standby.
Adding 15 g of 1-phenyl-5-bromotetrazole (0.067mol) into 80 ml of absolute ethyl alcohol, adding 6.1 g (0.08mol) of thiourea, heating to 60 ℃, reacting for 10 hours, cooling to 25 ℃, adding 13 g of sodium hydroxide solid, slowly heating to 50 ℃, and reacting for 3 hours.
Cooling to room temperature, adding 40 ml of water into the reaction system, removing the solvent under reduced pressure, adding 75 ml of dichloromethane for extraction to remove organic impurities, slowly adding 3mol/L hydrochloric acid into the water phase under stirring to adjust the pH value to be 2-3, separating out a solid, performing suction filtration, and performing vacuum drying to obtain 10.3 g of the solid, wherein the purity is 97.6%, and the yield is 86.4%.
The melting point of the 1-phenyl-5-mercapto tetrazole obtained in the above embodiment is 143-146 ℃, which is close to the relevant literature value.
Example 7
Preparation of compound I from compound IV prepared by recovering byproduct II:
dissolving 30.6 g (0.11mol) of tert-butyl (3R,5S) -6-chloro-3, 5-dioxa (acetonide) hexanoate in 150ml of DMF, adding 17.8g of 1-phenyl-5-mercaptotetrazole (0.10mol), adding 15.2 g (0.11mol) of anhydrous potassium carbonate, heating to 90 ℃, stirring for 20h, and spotting the plate without raw materials (EA: PE is 1: 1, 1ml +1 drop of triethylamine, raw materials Rf is 0.3, and the product is at the front edge). The reaction mixture was cooled to room temperature, 600ml of isopropyl ether and 600ml of water were added, liquid separation was performed with stirring, the aqueous layer was extracted with 300ml of isopropyl ether, the organic layers were combined, washed with 600ml of water, 600ml of 10% sodium bicarbonate solution and 600ml of saturated sodium chloride, and the mixture was dried to obtain 39.4g of an oil (yield 94%).
Adding 250 ml of the oily substance and isopropyl ether into a reaction bottle, stirring at 25 ℃, adding 12.2g of ammonium heptamolybdate, and dropwise adding 30% H by mass concentration2O226.7 g (0.235mol), transAnd starting to generate the product within 3 hours, and continuing to react for 20 hours until the raw materials react completely to obtain the product with nearly single point. 300ml EA, 120ml water are added to the system, stirred well and then mixed with 300ml 10% Na2S2O3Washing the solution with 300ml of water and 300ml of saturated sodium chloride, drying and spin-drying to obtain 42.8g of oily matter, adding 3 times of isopropyl ether, heating to reflux (not completely dissolved), stirring, naturally cooling, standing in a refrigerator at the temperature of 24 ℃ below zero for 0.5h when the temperature is reduced to room temperature, carrying out suction filtration and drying to obtain 22.8g of white solid. Mother liquor spin-drying, using EA: PE ═ 1: column chromatography of 5% gave 5.6g of product, which was combined to give 28.4g of solid in 67% yield.
25.8 g (0.057mol) of the product obtained by the synthesis and 20 g (0.057mol) of 2- (N-methyl-N-methylsulfonyl) amino-4- (4-fluoro) phenyl-6-isopropylpyrimidine-5-formaldehyde are added into a reaction bottle, 400 ml of dried tetrahydrofuran is added, the temperature is reduced to below minus 70 ℃ after nitrogen replacement, and 43 ml (1.6mol/L, 0.069mol) of LiHMDS is slowly dropped. Keeping the temperature between 70 ℃ below zero and 78 ℃ below zero for reaction for about 8 hours, slowly adding ammonium chloride solid to quench the reaction. Adding a small amount of sodium chloride saturated solution, separating liquid, drying an organic phase, and concentrating under reduced pressure to dryness. Adding proper methanol to dissolve at 55 ℃, slowly cooling to 0 ℃, preserving heat and stirring for 1 hour. The mixture is filtered when the mixture is cold, and the solid is dried after being leached once by ice-cold methanol to obtain 22.4 g of a white solid product, namely the compound I with the purity of 98.6 percent and the yield of 68 percent.1H-NMR(400MHz，CDCl3)：1.20-1.22(m，6H)，1.33-1.39((m，15H)，1.41-1.50(dd，2H)，2.19-2.41(2H)，3.27-3.33(q，1H)，3.44-3.51(s+s，6H)，4.17-4.38(m，2H)，5.36-5.43(m，1H)，6.42-6.47(dd，1H)，6.98-7.04(t，2H)，7.56-7.60(m，2H)。1The H-NMR chart corresponds to the actual structure of the compound I.
As noted above, while the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limited thereto. Various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (8)
1. The method for recycling 1-phenyl-5-hydroxy tetrazole is characterized by comprising the following steps:
(1) converting the compound 1-phenyl-5-hydroxy tetrazole of the formula II into a compound 1-phenyl-5-mercapto tetrazole of a formula IV;
(2) further synthesizing rosuvastatin calcium intermediate compound I and/or rosuvastatin calcium from the compound 1-phenyl-5-mercapto tetrazole of the formula IV, and realizing recycling of the 1-phenyl-5-hydroxy tetrazole;
in the step (1), 1-phenyl-5-hydroxy tetrazole of a compound shown in a formula II is converted into 1-phenyl-5-chloro tetrazole or 1-phenyl-5-bromo tetrazole; then the 1-phenyl-5-chloro tetrazole or the 1-phenyl-5-bromo tetrazole is further converted into a compound 1-phenyl-5-mercapto tetrazole of a formula IV.
2. The method for recycling 1-phenyl-5-hydroxy tetrazole according to claim 1, wherein the method for converting 1-phenyl-5-hydroxy tetrazole which is a compound of formula II into 1-phenyl-5-chloro tetrazole comprises the following steps: the mol ratio of the 1-phenyl-5-hydroxy tetrazole to the chlorine-containing reaction reagent is 1: 0.45-3, reacting in a solvent at 20-115 ℃ for 9-12 hours; after the reaction is finished, carrying out post-treatment, concentrating the system under reduced pressure until the system is dry, and then recrystallizing with methanol or ethanol; the chlorine-containing reaction reagent is one or a mixture of more of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, triphosgene, methylene phosphorus trichloride, chlorine, cyano trichloromethane, NCS and trichloroisocyanuric acid.
3. The method for recycling 1-phenyl-5-hydroxy tetrazole according to claim 2, wherein the solvent is toluene, 1, 2-dichloroethane or thionyl chloride.
4. The method for recycling 1-phenyl-5-hydroxy tetrazole according to claim 1, wherein the method for converting 1-phenyl-5-hydroxy tetrazole which is a compound of formula II into 1-phenyl-5-bromotetrazole comprises the following steps: the molar ratio of the 1-phenyl-5-hydroxy tetrazole to the bromine-containing reaction reagent is 1: 0.5 to 1.5, and reacting in toluene or carbon tetrachloride at the temperature of 20 to 115 ℃ for 8 to 12 hours; after the reaction is finished, carrying out post-treatment, concentrating the system under reduced pressure until the system is dry, and then recrystallizing with methanol or ethanol; the bromine-containing reaction reagent is one or a mixture of more of phosphorus tribromide, NBS, phosphorus pentabromide, phosphorus oxybromide, phosphorus oxychloride and bromine.
5. The recycling method of 1-phenyl-5-hydroxy tetrazole of claim 1, wherein the synthesis method of the compound 1-phenyl-5-mercapto tetrazole of formula IV is as follows: adding 1-phenyl-5-chlorine/bromine tetrazole and thiourea into an ethanol or ether solvent according to a molar ratio of 1: 1.2-2.0, heating to 50-60 ℃, and reacting for 9-12 hours; cooling to below 30 ℃, adding inorganic base, heating to 40-50 ℃, and reacting for 3-4 hours; after the reaction is finished, cooling to room temperature, adding water, concentrating to remove the solvent, extracting with ethyl acetate or dichloromethane to remove impurities, adjusting the pH value to acidity with hydrochloric acid, and precipitating a solid product.
6. The recycling method of 1-phenyl-5-hydroxy tetrazole of claim 5, wherein the inorganic base is one or a mixture of sodium hydroxide, potassium hydroxide and cesium carbonate.
7. The recycling method of 1-phenyl-5-hydroxy tetrazole of claim 5, wherein the molar ratio of the inorganic base to the 1-phenyl-5-chloro \ bromo tetrazole is 0.5-4.0: 1.
8. the method for recycling 1-phenyl-5-hydroxy tetrazole according to claim 1, wherein in step (2), the method for further synthesizing rosuvastatin calcium intermediate compound of formula I from 1-phenyl-5-mercapto tetrazole as a compound of formula IV comprises: after the compound shown in the formula IV reacts with tert-butyl (3R,5S) -6-chloro-3, 5-dioxo (acetonide) hexanoate, the compound is oxidized and reacts with 2- (N-methyl-N-methylsulfonyl) amino-4- (4-fluorobenzene) group-6-isopropylpyrimidine-5-formaldehyde to obtain a compound shown in the formula I;
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910916868.9A CN110627736B (en) | 2019-09-26 | 2019-09-26 | Method for recycling 1-phenyl-5-hydroxy tetrazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910916868.9A CN110627736B (en) | 2019-09-26 | 2019-09-26 | Method for recycling 1-phenyl-5-hydroxy tetrazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110627736A CN110627736A (en) | 2019-12-31 |
| CN110627736B true CN110627736B (en) | 2020-11-06 |
Family
ID=68974451
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910916868.9A Active CN110627736B (en) | 2019-09-26 | 2019-09-26 | Method for recycling 1-phenyl-5-hydroxy tetrazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110627736B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112028881B (en) * | 2020-09-02 | 2023-08-15 | 能特科技有限公司 | Synthesis method of rosuvastatin calcium higher intermediate R-1 |
| CN113372286B (en) * | 2021-05-26 | 2023-01-06 | 江苏阿尔法药业股份有限公司 | Method for preparing 1-phenyl-5-mercapto tetrazole by one-step method |
| CN113372287B (en) * | 2021-07-05 | 2023-02-10 | 江苏阿尔法药业股份有限公司 | Efficient preparation method of 1-phenyl-5-mercapto tetrazole |
| CN114213350B (en) * | 2021-12-29 | 2024-03-19 | 江苏福瑞康泰药业有限公司 | Preparation method of statin drug intermediate |
| CN114487167B (en) * | 2021-12-31 | 2023-08-22 | 乳源东阳光药业有限公司 | Method for determining impurities in statin side chain |
| CN114805164A (en) * | 2022-03-30 | 2022-07-29 | 法姆瑞斯医药科技(北京)有限公司 | Recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4374994A (en) * | 1979-07-05 | 1983-02-22 | Bristol-Myers Company | Process for preparation of 5-mercaptotetrazolyl-1-acetic acid |
| WO2016125086A1 (en) * | 2015-02-03 | 2016-08-11 | Laurus Labs Private Limited | Processes for the preparation of rosuvastatin or pharmaceutically acceptable salts thereof |
-
2019
- 2019-09-26 CN CN201910916868.9A patent/CN110627736B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN110627736A (en) | 2019-12-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110627736B (en) | Method for recycling 1-phenyl-5-hydroxy tetrazole | |
| CN114805314B (en) | Synthesis method of Entecavir | |
| WO2008059551A2 (en) | Process for the preparation of imatinib and intermediates thereof | |
| CN108373468B (en) | Preparation method of N-2-pyridine-5-pyrimidine methylamine | |
| US20140187569A1 (en) | Crystalline forms of bosentan salts and processes for their preparation | |
| CN114805164A (en) | Recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole | |
| JPH06234715A (en) | Production of alanylglutamine | |
| CN104628653A (en) | Method for synthesizing key intermediate of rosuvastatin calcium | |
| HU208533B (en) | Process for selective etherification of ascorbinic acid derivatives | |
| WO2011021216A2 (en) | Improved process for the preparation of 4-(1,1-dimethylethyl)-n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide | |
| EP0236754B1 (en) | Novel process for preparing 4-acetyl isoquinolinone compounds | |
| KR20200088570A (en) | Process for Preparation of Fimasartan and Intermediate for Preparing the Same | |
| JP3989997B2 (en) | Method for producing radiosensitizer | |
| JPS6028822B2 (en) | Method for producing 4-methylimidazole-5-carboxylic acid isopropyl ester | |
| HU217445B (en) | Process for producing 2-{4-[4-(4-chloro-1-pyrazolyl)-butyl]1-piperazinyl}-pyrimidine | |
| RU2804663C2 (en) | Method of producing two 4-{[(2s)-2-{4-[5-chloro-2-(1h-1,2,3-triazol-1-yl)phenyl]-5-methoxy-2-oxopyridin-1(2h)-il} butanoyl]amino}-2-fluorobenzamide derivatives | |
| JP2009126784A (en) | Method for producing 2-iodo-3,4-dimethoxybenzonitrile | |
| WO2009017239A2 (en) | Process for producing toluidine compound | |
| KR20070110617A (en) | Improved method for preparing losartan | |
| JP3272340B2 (en) | Method for producing 1-[(cyclopent-3-en-1-yl) methyl] -5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione | |
| JPWO2010029756A1 (en) | Process for producing 5- [2- (methylthio) ethoxy] pyrimidin-2-amine | |
| JP4449211B2 (en) | 6- (1-fluoroethyl) -5-iodo-4-pyrimidone and process for producing the same | |
| JP5902671B2 (en) | Process for producing benzylpyrazole derivative and production intermediate thereof | |
| CN114560862A (en) | Synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivative thereof | |
| JP2009126785A (en) | Method for producing 2-iodo-3,4-dimethoxybenzonitrile |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 223800 No.5, Yanshan Road, Suqian eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee after: Jiangsu alpha Pharmaceutical Co.,Ltd. Address before: 223800 No.5, Yanshan Road, Suqian eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee before: ALPHA PHARMACEUTICAL Co.,Ltd. JIANGSU PROVINCE |