CN112592336A - High-grade intermediate of rosuvastatin calcium and preparation method thereof - Google Patents
High-grade intermediate of rosuvastatin calcium and preparation method thereof Download PDFInfo
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- 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
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Abstract
The invention discloses a rosuvastatin calcium high-grade intermediate and a preparation method thereof, wherein the intermediate R1 is prepared by a Julia olefination reaction of a chiral side chain D4-2 containing a thiadiazole sulfone structure and a parent nucleus Z8.1 containing a pyrimidine formaldehyde structure. The invention discloses a novel preparation method of R1. The product of the invention has low preparation cost, high total yield and good quality, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of synthesis of medicines and medicine intermediates, in particular to a high-grade intermediate of rosuvastatin calcium and a preparation method thereof.
Background
Rosuvastatin calcium was first successfully developed by japan salt bisense corporation (US 5260440A), and later, the corporation assigned technology to Zeneca corporation of the uk (now astragazeneca) (WO 0049014a 1), and obtained US FDA approval to market in 8 months in 2003, and the drug was marketed in china in 2006 with a global sales of over $ 69 billion in 2009. Rosuvastatin calcium known as "super statin" will add a valuable new option for the treatment of dyslipidemia.
R1 (6- [ (1E) -2- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -5-pyrimidine ] ethenyl ] -2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate) is a higher intermediate for the preparation of rosuvastatin calcium.
Structural formula is
The synthesis of R1 can be divided into 3 steps: (a) synthesis of the parent nucleus (pyrimidine moiety), (b) synthesis of the side chain (chiral chain moiety), (c) combining the parent nucleus with the side chain by an olefination reaction to give R1. Among them, the olefination method mainly comprises (A) Wittig/Wittig-Horner reaction and (B) Julia reaction. According to the position of aldehyde group, further divided into:
(1) Wittig/Wittig-Horner reaction with an aldehyde group in the mother nucleus (US 5260440A, WO2004052867A1, US8049010B 2);
(2) Wittig/Wittig-Horner reaction with aldehyde group in side chain (WO 2000049014A1, WO2005054207, CN 1340052A);
(3) julia reaction, with an aldehyde group in the mother nucleus (WO 2011104725A2, WO2011121595A1, CN 107298675A);
(4) julia reaction, with the aldehyde group in the side chain (WO 2008044243A2, CN 102816152A).
As the Wittig/Wittig-Horner reaction can generate a large amount of phosphorus-containing wastewater, the Julia reaction has more advantages in industrial production; in addition, the aldehyde group molecules attached to the aromatic ring have better stability than molecules having an aliphatic aldehyde structure, and thus the Julia reaction (3) of the aldehyde group in the parent nucleus is a preferable direction of research.
As is well known, Julia olefination is the reaction of a phenyl sulfone with an aldehyde or ketone via nucleophilic addition and reductive elimination, ultimately converting to an olefin. As one of the reactants, a phenyl-sulfone is often used as Julia-Lythgoe alkylene (e.g., as
) The One-potJulia modification employs benzothiazole-sulfones (e.g., as
) While Julia-Kocienski modification employs phenyltetrazole sulfone (e.g., as in Julia-Kocienski modification
). It is therefore readily conceivable to use the above-described phenylsulfone structures in the synthesis of chiral side chains containing sulfone structures.
For example, US6875867B2 reports a chiral side chain containing a sulfone structure, as shown in structural formula I.
WO2011104725A2 refers to the above patent and proposes structure II.
ra and Rb may be the same or different and may be H, C1-C12 alkyl, C6-C12 aryl, or C7-C12 aralkyl; r is
Or
Or
Wherein R is4aIs alkyl, aryl, aralkyl or cycloalkyl, RcIs H, alkyl, aryl, alkoxy, haloalkyl, haloalkoxy, X is O, N-H, N-alkyl or S, RdIs alkyl, aryl, aralkyl, -CF3Halogen or-NO2。
WO2011121595A1 proposes a similar structural formula III.
CN107298675A proposes the following structural formula IV.
Synthesizing the chiral side chain containing the phenyl sulfone structure except 2-mercaptobenzimidazole: (
) In addition, the cost of other precursors is often quite high (e.g.
) Even requiring special customization (e.g. to be specific to the particular application
) It is difficult to give consideration to both production cost and product quality, and is not conducive to industrial application and popularization.
Disclosure of Invention
The invention aims to solve the problems and provide a high-grade intermediate R1 of rosuvastatin calcium, which has the advantages of low raw material cost, high safety factor, stable product yield and good quality.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a high-grade intermediate of rosuvastatin calcium, the structure of the intermediate R1Is of the formula
。
Another object of the present invention is to provide a method for preparing said higher intermediate of rosuvastatin calcium.
A preparation method of a high-grade intermediate of rosuvastatin calcium comprises the following steps:
s1: d4-2 and Z8.1 are taken as raw materials, initiated by a small amount of water in an organic solvent under the protection of nitrogen, and dropwise added with a mixed solution of alkali and an ether solvent to be stirred and reacted at the temperature of minus 30 to minus 80 ℃;
s2: after the reaction is finished, transferring the mixture into potassium carbonate solution for quenching, then standing and separating out an organic layer, and concentrating under reduced pressure; dissolving toluene, and washing with a sodium carbonate solution and a sodium chloride solution; then standing to separate an organic layer, and concentrating under reduced pressure to obtain a crude product R1; adding methanol into the R1 crude product for recrystallization, and drying to obtain the product; the structural formula of the chiral side chain D4-2 of the thiadiazole sulfone structure is shown as
Wherein Ra is selected from-H, alkyl, -CF3Aryl or alkaryl; i.e. the end group attached to the sulfone structure may be
、
、
、
、
、
Or
Preference is given to
. The mother nucleus Z8.1 containing the pyrimidine formaldehyde structure has a structural formula of
。
Preferably, Ra is alkyl.
Preferably, the organic solvent is selected from one or more of dichloromethane, dichloroethane, toluene, n-hexane, cyclohexane; the ether solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane and methyl tert-butyl ether.
The preparation of the chiral side chain D4-2 containing the thiadiazole sulfone structure comprises the following steps:
s1: taking (4R-CIS) -6-halomethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate (D4) and thiadiazole or derivatives thereof (D4-M) as raw materials, carrying out condensation reaction in an organic solvent under the action of alkali, carrying out reduced pressure concentration after the reaction is finished, adding dichloromethane and drinking water, stirring uniformly, standing and layering to obtain an organic layer, namely a compound D4-1 solution;
s2: taking the D4-1 solution as a raw material, taking drinking water as a solvent, dropwise adding a mixed solution of hydrogen peroxide and an oxidation catalyst into a reaction system under the action of alkali and a phase transfer catalyst, and stirring for reaction at 5-30 ℃; after the reaction is finished, standing and separating an organic layer, quenching the organic layer by using a sodium sulfite solution, and then washing the organic layer by using a sodium bicarbonate solution; standing to separate an organic layer, and concentrating under reduced pressure to obtain a D4-2 crude product; adding C1-C6 lower alcohol into the D4-2 crude product, recrystallizing, and drying to obtain a chiral side chain D4-2 containing a thiadiazole sulfone structure; reaction formula is
Structure of D4Is of the formula
X is halogen; the structural formula of D4-1 is
Ra is selected from-H, alkyl, -CF3Aryl or alkaryl.
Rais-H, alkyl, -CF3Aryl or alkylaryl, i.e. D4-M may be
、
、
、
、
、
Or
Preference is given to
。
Preferably, the base in step S1 is selected from alkali or alkaline earth metal carbonate bicarbonate, hydride, hydroxide or alkoxide; the organic solvent is selected from one or more of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), C1-C6 lower alcohol, methyl tert-butyl ether, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, cyclohexane or acetonitrile.
Preferably, the phase transfer catalyst described in step S2 is selected from quaternary ammonium salts such as benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride; the oxidation catalyst is selected from ammonium molybdate, ammonium tungstate, ammonium phosphomolybdate or ammonium phosphotungstate; the lower alcohol of C1-C6 is selected from methanol, ethanol, n-propanol, isopropanol or tert-butanol.
The invention has the following beneficial effects:
the invention discloses a novel preparation method of R1. The rosuvastatin calcium high-grade intermediate is prepared by a chiral side chain D4-2 containing a thiadiazole sulfone structure and a mother nucleus Z8.1 containing a pyrimidine formaldehyde structure through Julia olefination; the chiral side chain D4-2 containing the thiadiazole sulfone structure has a simple preparation process, the raw material D4 can be subjected to two-step reaction to obtain D4-2 with the yield of 75% (molar yield), and the high-quality key intermediate D4-2 provides guarantee for obtaining R1 with stable yield and good quality; the raw material D4-M is thiadiazole and derivatives thereof, is a common important medical intermediate, is cheap and easy to obtain, is safe and stable, and is convenient to store and transport; the method is used for the preparation reaction of R1, has the advantages of mild and easily controlled conditions, simple treatment and convenient operation, and is very suitable for industrial large-scale production.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
[ test methods ]
In the embodiment of the invention, the chiral side chain D4-2 containing a thiadiazole sulfone structure and the higher intermediate R1 of rosuvastatin calcium have the same purity and related substance test methods, and an HPLC area normalization method is adopted.
Chromatographic conditions are as follows: inertsil ODS-3V (250mm 4.6mm 5 μm);
mobile phase: a: water, B: the reaction mixture of acetonitrile and water is mixed,
gradient:
detection wavelength: 240 nm;
flow rate: 1.0 ml/min;
sample introduction amount: 20 mu L of the solution;
diluent agent: acetonitrile: water =90:10 (V/V);
sample concentration: solid: 0.2mg/mL of R1, D4-2: 0.5 mg/ml;
reaction solution: 1 drop to 5 mL.
[ Synthesis of D4-2 ]
Example 1
Feeding 120g of D4 (95-105 g after folding), 100g of sodium carbonate, 60g of 2-mercapto-5-ethyl-1, 3, 4-thiadiazole and 250g of DMAC, stirring, heating to 100-110 ℃, and then preserving heat for 8 hours. Cooling to below 100 deg.C, and concentrating under reduced pressure until no fraction is obtained. And (3) cooling, adding 550g of dichloromethane and 400g of drinking water, uniformly stirring, and standing for layering. The organic layer was a D4-1 solution.
Transferring the D4-1 solution into a reactor, feeding 150g of drinking water, 5g of sodium carbonate and 3g of tetrabutylammonium chloride, stirring and dissolving, and controlling the temperature to be 10-15 ℃. And (3) dropwise adding mixed liquid of 450g of 50% hydrogen peroxide and 6g of ammonium tungstate, and controlling the temperature to be 15-20 ℃. Stirring for 20 hours under heat preservation. After the reaction, the reaction mixture was allowed to stand for separation, and the organic layer was washed once with 300g of 5% sodium sulfite solution and once with 300g of 5% sodium bicarbonate solution. Standing to separate an organic layer, and decompressing, concentrating and drying the organic layer. Adding 500g of n-propanol, stirring, dissolving, cooling, and filtering to obtain a D4-2 wet product. Drying at 60 ℃ for 10 hours to obtain 90-100 g of D4-2 dry product, wherein the yield (molar yield) is 75.2%, the purity (HPLC) is 99.12%, and the single maximum impurity is 0.35%.
Example 2
110g of D4 (87-97 g after folding), 110g of sodium bicarbonate, 50g of 2-mercapto-5-methyl-1, 3, 4-thiadiazole and 225g of DMF are added, stirred and heated to 110-120 ℃, and then the temperature is maintained for 7 hours. Cooling to below 100 deg.C, and concentrating under reduced pressure until no fraction is obtained. And cooling, adding 500g of dichloromethane and 425g of drinking water, stirring uniformly, and standing for layering. The organic layer was a D4-1 solution.
Transferring the D4-1 solution into a reactor, feeding 130g of drinking water, 8g of sodium bicarbonate and 2.2g of tetrabutylammonium bromide, stirring and dissolving, and controlling the temperature to be 15-20 ℃. And (3) dropwise adding a mixed solution of 500g of 30% hydrogen peroxide and 5g of ammonium molybdate, and controlling the temperature to be 20-25 ℃. Stirring for 16 hours under heat preservation. After the reaction, the reaction mixture was allowed to stand for separation, and the organic layer was washed once with 225g of a 5% sodium sulfite solution and once with 225g of a 5% sodium hydrogencarbonate solution. Standing to separate an organic layer, and decompressing, concentrating and drying the organic layer. Adding 440g of isopropanol, stirring, dissolving, cooling, and filtering to obtain a D4-2 wet product. Drying at 60 ℃ for 10 hours to obtain 95-105 g D4-2 dry product with yield (molar yield) of 76.6%, purity (HPLC) of 99.56% and single maximum impurity of 0.23%.
Example 3
130g of D4 (100-110 g after folding), 90g of potassium carbonate, 70g of 2-mercapto-5-phenyl-1, 3, 4-thiadiazole and 260g of tert-butyl alcohol are added, stirred and heated to 90-100 ℃, and then the temperature is maintained for 10 hours. Cooling to below 85 deg.C, and concentrating under reduced pressure until no fraction is obtained. And cooling, adding 615g of dichloromethane and 400g of drinking water, uniformly stirring, and standing for layering. The organic layer was a D4-1 solution.
Transferring the D4-1 solution into a reactor, feeding 160g of drinking water, 6.5g of potassium bicarbonate and 4g of dodecyl trimethyl ammonium chloride, stirring and dissolving, and controlling the temperature to be 20-25 ℃. And dropwise adding a mixed solution of 835g of 30% hydrogen peroxide and 6g of ammonium phosphomolybdate, and controlling the temperature to be 25-30 ℃. Stirring for 22 hours under heat preservation. After the reaction, the reaction mixture was allowed to stand for separation, and the organic layer was washed once with 400g of a 5% sodium sulfite solution and 425g of a 5% sodium hydrogencarbonate solution, respectively. Standing to separate an organic layer, and decompressing, concentrating and drying the organic layer. 600g of tert-butyl alcohol is added, stirred, dissolved and cleared, and D4-2 wet product is obtained after cooling and suction filtration. Drying at 60 ℃ for 10 hours to obtain 87-95 g of D4-2 dry product, wherein the yield (molar yield) is 74.8%, the purity (HPLC) is 98.47%, and the single maximum impurity is 0.41%.
The invention provides an improved process which takes D4 as a raw material to obtain a key chiral side chain D4-2 with the molar yield of about 75 percent through two-step reaction, and is obviously superior to the prior art which takes Kanekaalcohol as a raw material to obtain a key side chain with the molar yield of 74 percent through three-step reaction (using additional raw materials, involving low-temperature reaction and more processing steps) (US 6875867B 2).
[ Synthesis of R1 ]
Example 4
Under the protection of nitrogen, 1500g of dichloromethane, 100g D4-2 and 80g Z8.1.1 are added, stirred, dissolved and clear, 3.25g of water is added, and the temperature is reduced to-75 ℃. A mixture of 50g of sodium tert-butoxide and 200g of tetrahydrofuran is prepared and dissolved by stirring. Dropping the mixed solution, controlling the temperature to be less than or equal to minus 70 ℃, and keeping the temperature and stirring for 2 hours. After the reaction was completed, the reaction solution was quenched into 524g of 30% potassium carbonate solution. Standing to separate an organic layer, and decompressing, concentrating and drying the organic layer. 700g of toluene are added and washed once each with 225g of 10% sodium carbonate solution and 225g of 10% sodium chloride solution. Standing to separate an organic layer, and decompressing, concentrating and drying the organic layer. Adding 1100g of methanol, stirring, dissolving, cooling, and filtering to obtain an R1 wet product. Drying for 8 hours at 60 ℃ to obtain a dry product of 108-120 g R1, wherein the purity (HPLC) is 99.46% and the single maximum impurity is 0.14%.
Example 5
Under the protection of nitrogen, 1650g of dichloroethane, 110g D4-2 and 85g Z8.1.1 are added, stirred, dissolved and cleaned, 3.55g of water is added, and the temperature is reduced to-60 ℃. A mixture of 63g of sodium isopropoxide and 237g of 2-methyltetrahydrofuran was prepared, and the mixture was stirred to dissolve. Dropping the mixed solution, controlling the temperature to be less than or equal to-56 ℃, and keeping the temperature and stirring for 1 hour. After the reaction was completed, the reaction solution was quenched by transferring to 582g of 30% potassium carbonate solution. Standing to separate an organic layer, and decompressing, concentrating and drying the organic layer. 750g of toluene are added, and the mixture is washed once with 238g of 10% sodium bicarbonate solution and once with 245g of 10% sodium chloride solution. Standing to separate an organic layer, and decompressing, concentrating and drying the organic layer. 1230g of methanol is added, stirred, dissolved and cleared, and then R1 wet product is obtained after cooling and suction filtration. Drying for 8 hours at 60 ℃ to obtain 98-106 g R1 dry product with purity (HPLC) 96.59% and single maximum impurity of 0.55%.
Example 6
1400g of n-hexane, 90g D4-2 and 75g Z8.1.1 are added under the protection of nitrogen, 3.1g of water is added after stirring and dissolving, and the temperature is reduced to-67 ℃. A mixture of 57g of sodium ethoxide and 268g of 1, 4-dioxane is prepared and stirred to be clear. Dropping the mixed solution, controlling the temperature to be less than or equal to-62 ℃, and stirring for 3 hours under the condition of heat preservation. After the reaction, the reaction solution was quenched into 566g of 30% potassium carbonate solution. Standing to separate an organic layer, and decompressing, concentrating and drying the organic layer. 680g of toluene solution were added and washed once each with 188g of 10% potassium carbonate solution and 212g of 10% sodium chloride solution. Standing to separate an organic layer, and decompressing, concentrating and drying the organic layer. 1050g of methanol is added, stirred, dissolved and cleared, and then R1 wet product is obtained after cooling and suction filtration. Drying at 60 ℃ for 8 hours to obtain a dry product of 71-86 g R1, with purity (HPLC) of 94.33% and single maximum impurity of 0.83%.
The above-described preferred embodiments of the present invention are not intended to limit the present invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the claims of the present invention.
Claims (7)
1. A high-grade intermediate of rosuvastatin calcium, which is characterized in that:
structural formula is
。
2. A preparation method of a high-grade intermediate of rosuvastatin calcium comprises the following steps:
s1: taking a chiral side chain containing a thiadiazole sulfone structure and Z8.1 as raw materials, initiating by a small amount of water in an organic solvent under the protection of nitrogen, and dropwise adding a mixed solution of alkali and an ether solvent, and stirring and reacting at-30 to-80 ℃;
s2: after the reaction is finished, transferring the mixture into potassium carbonate solution for quenching, then standing and separating out an organic layer, and concentrating under reduced pressure; dissolving toluene, and washing with a sodium carbonate solution and a sodium chloride solution; then standing to separate an organic layer, and concentrating under reduced pressure to obtain a crude product of a high-grade intermediate of rosuvastatin calcium; adding methanol into the crude rosuvastatin calcium high-grade intermediate product for recrystallization, and drying to obtain the rosuvastatin calcium high-grade intermediate product;
the chiral side chain structural formula of the thiadiazole sulfone structure is shown as
Wherein Ra is selected from-H, alkyl, -CF3, aryl, or alkaryl;
z8.1 structural formula:
。
3. the process for the preparation of higher intermediates of rosuvastatin calcium according to claim 2, wherein: ra is an alkyl group.
4. The process for the preparation of higher intermediates of rosuvastatin calcium according to claim 2, wherein: the organic solvent is selected from one or more of dichloromethane, dichloroethane, toluene, n-hexane and cyclohexane; the ether solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane and methyl tert-butyl ether.
5. The method for preparing the advanced intermediate of rosuvastatin calcium according to claim 2, wherein the chiral side chain containing thiadiazole sulfone structure is prepared, comprising the following steps:
s1: taking (4R-CIS) -6-halomethyl-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate and thiadiazole or derivatives thereof as raw materials, carrying out condensation reaction in an organic solvent under the action of alkali, concentrating under reduced pressure after the reaction is finished, adding dichloromethane and drinking water, stirring uniformly, standing for layering to obtain an organic layer, namely a compound D4-1 solution;
s2: taking the D4-1 solution as a raw material, taking drinking water as a solvent, dropwise adding a mixed solution of hydrogen peroxide and an oxidation catalyst into a reaction system under the action of alkali and a phase transfer catalyst, and stirring for reaction at 5-30 ℃; after the reaction is finished, standing and separating an organic layer, quenching the organic layer by using a sodium sulfite solution, and then washing the organic layer by using a sodium bicarbonate solution; standing to separate an organic layer, and concentrating under reduced pressure to obtain a chiral side chain crude product containing a thiadiazole sulfone structure; adding C1-C6 lower alcohol into the crude product of the chiral side chain containing the thiadiazole sulfone structure for recrystallization, and drying to obtain the chiral side chain containing the thiadiazole sulfone structure; d4 has a structural formula
X is halogen; the structural formula of D4-1 is
，Ra is selected from-H, alkyl, -CF3Aryl or alkaryl.
6. The method for preparing the chiral side chain containing the thiadiazole sulfone structure according to claim 5, wherein the chiral side chain comprises the following steps: the base in step S1 is selected from alkali metal, alkaline earth metal carbonate, bicarbonate, hydride, hydroxide or alkoxide; the organic solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide, C1-C6 lower alcohol, methyl tert-butyl ether, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, cyclohexane and acetonitrile.
7. The method for preparing the chiral side chain containing the thiadiazole sulfone structure according to claim 5, wherein the chiral side chain comprises the following steps: the phase transfer catalyst in the step S2 is selected from quaternary ammonium salts selected from benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride; the oxidation catalyst is selected from ammonium molybdate, ammonium tungstate, ammonium phosphomolybdate or ammonium phosphotungstate; the lower alcohol of C1-C6 is selected from methanol, ethanol, n-propanol, isopropanol or tert-butanol.
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| CN113754650A (en) * | 2021-08-06 | 2021-12-07 | 湖北宇阳药业有限公司 | High-selectivity synthesis method of rosuvastatin calcium intermediate |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113387944A (en) * | 2021-07-09 | 2021-09-14 | 浙江宏元药业股份有限公司 | Synthetic method of rosuvastatin calcium intermediate |
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| CN113754650A (en) * | 2021-08-06 | 2021-12-07 | 湖北宇阳药业有限公司 | High-selectivity synthesis method of rosuvastatin calcium intermediate |
| CN113754650B (en) * | 2021-08-06 | 2023-10-20 | 湖北宇阳药业有限公司 | High-selectivity synthesis method of rosuvastatin calcium intermediate |
| 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 |
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