CN111116693B - Method for preparing sofosbuvir by combining 3, 3-diaryl acrolein and Grignard reagent - Google Patents
Method for preparing sofosbuvir by combining 3, 3-diaryl acrolein and Grignard reagent Download PDFInfo
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- CN111116693B CN111116693B CN201911377924.2A CN201911377924A CN111116693B CN 111116693 B CN111116693 B CN 111116693B CN 201911377924 A CN201911377924 A CN 201911377924A CN 111116693 B CN111116693 B CN 111116693B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/12—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides
- B01J31/128—Mixtures of organometallic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/49—Esterification or transesterification
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0201—Oxygen-containing compounds
- B01J31/0205—Oxygen-containing compounds comprising carbonyl groups or oxygen-containing derivatives, e.g. acetals, ketals, cyclic peroxides
- B01J31/0207—Aldehydes or acetals
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/12—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides
- B01J31/122—Metal aryl or alkyl compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a method for preparing sofosbuvir by catalyzing 3, 3-diaryl acrolein with a combined Grignard reagent, which comprises the following steps: after the compound 2 is catalyzed and activated, the compound is condensed with a compound 3 to obtain sofosbuvir shown in a formula 1; the catalytic activation adopts the following mode: compound 2 is catalytically activated with 3, 3-diarylacrolein in combination with a Grignard reagent. The invention can reduce the generation of disubstituted by-products and provide the yield and purity of the product.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of sofosbuvir.
Background
Sofosbuvir, also known as: sofosbuvir, english name: sofosbuvir, chemical name: (S) -isopropyl 2- (((S) - ((((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate, CAS number: 1190307-88-0, the structural formula is as follows (Compound 1):
sofosbuvir is a hepatitis C virus treatment drug developed by the American Gilidde pharmaceutical Co., Ltd, is marketed in the United states and European Union at the earliest in 2013 and 2014 respectively, and is called as a liver disease resistant drug 'Ji first generation', 'Ji second generation' and 'Ji third generation' respectively by a Sofosbuvir single preparation, a Sofosbuvir + Ledipasvir compound preparation and a Sofosbuvir + Vipatasvir compound preparation, and is a hepatitis C treatment drug with a very good effect on the market in recent years, and can cure most hepatitis C diseases.
The preparation of sofosbuvir bulk drug is currently generally obtained by carrying out catalytic activation on a compound 2 and then condensing the compound with a compound 3 in the industry:
the activated catalyst used is reported to be magnesium chloride [ reference 1: WO2018015821], aluminium reagents [ reference 2: organic letters,19(9), 2218-2221; 2017; WO2016160646], grignard reagents such as the commonly used tert-butyl magnesium chloride [ reference 3: US 20110251152; CN 107253971; WO 2015158317; WO2018015821 ]. The currently commercially used activating catalyst is tert-butyl magnesium chloride, which is obtained by selective removal of hydrogen from the hydroxyl group at position 5 on the sugar ring, and condensation with compound 3.
However, when the compound 2 is subjected to catalytic dehydrogenation by using a grignard reagent, hydrogen at the 3-position hydroxyl group is easily removed to generate an intermediate compound 5, and the intermediate compound reacts with the compound 3 to generate a disubstituted byproduct compound 6 (the process is as follows), so that the yield of the product and the purity of the product are affected.
Disclosure of Invention
The invention aims to provide a method for preparing sofosbuvir by catalyzing 3, 3-diaryl acrolein and combining a Grignard reagent, so that the generation of disubstituted by-products is reduced, and the product yield and purity are improved.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for preparing sofosbuvir by combining 3, 3-diaryl acrolein with Grignard reagent catalysis, which comprises the following steps: after the compound 2 is catalyzed and activated, the compound is condensed with a compound 3 to obtain sofosbuvir shown in a formula 1; the catalytic activation adopts the following mode: catalytically activating compound 2 with 3, 3-diarylacrolein together with a grignard reagent;
preferably, the 3, 3-diarylacrolein is at least one of 3, 3-diphenylacrolein, 3-bis (4-methylphenyl) acrolein, 3-bis (4-methoxyphenyl) acrolein, and 3, 3-bis (4-ethylphenyl) acrolein.
Preferably, the feeding molar ratio of the 3, 3-diaryl acrolein to the compound 2 is 0.05-0.2: 1.
in the present invention, the selection of the Grignard reagent, the conditions for catalytic activation, and the conditions for condensation reaction can be referred to the prior art.
Preferably, the format reagent is t-BuMgCl.
Preferably, the molar ratio of the compound 2 to the format reagent to the compound 3 is 1: 1-2: 1.1-1.5.
Preferably, the preparation is carried out in THF.
The invention particularly recommends that the method for preparing sofosbuvir by combining 3, 3-diaryl acrolein with Grignard reagent catalysis is carried out according to the following steps: adding a compound 2, THF and 3, 3-diarylacrolein into a reaction vessel, stirring, cooling to-10-0 ℃ (preferably-5 ℃), dropwise adding t-BuMgCl THF solution under the protection of nitrogen, after dropwise adding is completed within 0.5-2 hours (preferably 1 hour), naturally increasing the temperature to 0-10 ℃ (preferably 5 ℃), and stirring for 15-20 hours (preferably 18 hours); and then, adding a THF solution of the compound 3 dropwise, keeping the temperature until the HPLC detection content of the compound 2 is less than 1% after the addition is completed for 3-5 hours, and separating and purifying after the reaction is completed to obtain the sofosbuvir.
Preferably, the separation and purification are carried out according to the following steps: after the reaction is finished, adjusting the pH value to 6-7 by using 5-10% (5%) dilute hydrochloric acid, decompressing and distilling THF, adding ethyl acetate, fully stirring, separating an organic layer at 20-25 ℃, washing the organic layer at 20-25 ℃ by using a sodium carbonate solution, combining water layers, adding ethyl acetate for back extraction, combining the organic layers, washing by using clear water, separating the organic layer, evaporating the organic solvent to dryness, adding dichloromethane into residual liquid, heating and refluxing for 2-3 hours, cooling to 5-15 ℃, preserving heat for 15-18 hours, filtering, and leaching filtrate by using a small amount of dichloromethane to obtain a white product, namely sofosbuvir.
The invention has the beneficial effects that: according to the invention, the 3, 3-diaryl acrolein is combined with the Grignard reagent to catalyze and activate the compound 2, so that the generation of disubstituted by-products is reduced, and the yield and purity of the product are improved.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples, but the scope of the present invention is not limited thereto:
example 1
In a 1000mL four-necked flask, compound 2(20 g, 77mmol), THF (250 g) and 3, 3-diphenylacrolein (0.8 g, 3.8mmol) were added, stirred, and cooled to-5 ℃. Under nitrogen protection, 1.7M t-BuMgCl solution in THF (85.6 g, 128mmol) was added dropwise over 1 hour, the temperature was naturally raised to 5 ℃ and stirred for 18 hours. A solution of compound 3(44 g, 97mmol) in THF (220 g of THF) is then added dropwise over 3-5 h. Then the incubation was continued until less than 1% of compound 2 (HPLC trace, found to be 0.8% disubstituted by-product) was obtained for about 20 hours. After the reaction, the pH was adjusted to 6-7 with 5% dilute hydrochloric acid, THF was distilled off in about 300 g under reduced pressure, ethyl acetate (200 g) was added, stirring was carried out for half an hour, the organic layer was separated at 20-25 ℃, the organic layer was washed with 5% sodium carbonate (2 × 100 g) at 20-25 ℃, the aqueous layer was combined, ethyl acetate (100 g) was added for back extraction, the organic layer was combined, washed with clear water (100 g), the organic layer was separated, and the organic solvent was evaporated to dryness (normal pressure in the early stage and reduced pressure in the late stage). Adding 210 g of dichloromethane into residual liquid, heating and refluxing for 2-3 hours, cooling to 10 ℃, preserving heat for 18 hours, filtering, leaching filtrate by using a small amount of dichloromethane, and obtaining a white product: 35.1 g, yield: 86.2 percent. HPLC purity: 99.8 percent. Melting point: and the temperature is 95.8-98.6 ℃, and the crystal form 1 product is obtained.
The structure validation data is as follows:
mass spectrum (ESI-MS): [ M + H ]]+530 (M529); nuclear magnetic hydrogen spectrum (1H-NMR)(CDCl3,600MHz)： 1.23-1.41(m，12H),3.70(brs，1H)，4.11-4.56(m，6H),454(q, 1H),5.00(t, 1H),6.18(d, 1H), 7.18-7.36(m, 5H),7.47(d, 1H),9.55(brs, 1H); infrared Spectrum (IR, KBr) (cm)-1): 3350, 3250, 2984, 2909, 1732, 1717, 1676, 1495, 1456, 1281, 1265, 1092, 1082941, 822, 797, 768; elemental analysis (C)22H29FN3O9P,%) (measured/calculated): c49.86/49.91, H5.59/5.52, N7.91/7.94.
Example 2
In a 1000mL four-necked flask, compound 2(20 g, 77mmol), THF (250 g) and 3, 3-bis (4-methylphenyl) acrolein (0.9 g, 3.8mmol) were charged, stirred, and cooled to-5 ℃. Under nitrogen protection, 1.7M t-BuMgCl solution in THF (85.6 g, 128mmol) was added dropwise over 1 hour, the temperature was naturally raised to 5 ℃ and stirred for 18 hours. A solution of compound 3(44 g, 97mmol) in THF (220 g of THF) is then added dropwise over 3-5 h. Then the incubation was continued until less than 1% of compound 2 (HPLC trace, measured as disubstituted by-product 1.1%) for about 20 hours. After the reaction, the pH was adjusted to 6-7 with 5% dilute hydrochloric acid, THF was distilled off in about 300 g under reduced pressure, ethyl acetate (200 g) was added, stirring was carried out for half an hour, the organic layer was separated at 20-25 ℃, the organic layer was washed with 5% sodium carbonate (2 × 100 g) at 20-25 ℃, the aqueous layer was combined, ethyl acetate (100 g) was added for back extraction, the organic layer was combined, washed with clear water (100 g), the organic layer was separated, and the organic solvent was evaporated to dryness (normal pressure in the early stage and reduced pressure in the late stage). Adding 210 g of dichloromethane into residual liquid, heating and refluxing for 2-3 hours, cooling to 10 ℃, preserving heat for 18 hours, filtering, leaching filtrate by using a small amount of dichloromethane, and obtaining a white product: 34.2 g, yield: 84.0 percent. HPLC purity: 99.7 percent.
Comparative example 1
In a 1000mL four-necked flask, Compound 2(20 g, 77mmol), THF (250 g) was added, stirred, and cooled to-5 ℃. Under the protection of nitrogen, 1.7M t-BuMgCl solution in THF (85.6 g, 128mmol) was added dropwise over 1h, the temperature was naturally raised to 5 ℃ and stirred for 18 h. A solution of compound 3(44 g, 97mmol) in THF (220 g of THF) is then added dropwise over 3-5 h. Then the incubation was continued until less than 1% of compound 2 (HPLC trace, measured as disubstituted by-product 4.5%) for about 20 hours. After the reaction, the pH was adjusted to 6-7 with 5% dilute hydrochloric acid, THF was distilled off in about 300 g under reduced pressure, ethyl acetate (200 g) was added, stirring was carried out for half an hour, the organic layer was separated at 20-25 ℃, the organic layer was washed with 5% sodium carbonate (2 × 100 g) at 20-25 ℃, the aqueous layer was combined, ethyl acetate (100 g) was added for back extraction, the organic layer was combined, washed with clear water (100 g), the organic layer was separated, and the organic solvent was evaporated to dryness (normal pressure in the early stage and reduced pressure in the late stage).
Adding 210 g of dichloromethane into residual liquid, heating and refluxing for 2-3 hours, cooling to 10 ℃, preserving heat for 18 hours, filtering, leaching filtrate by using a small amount of dichloromethane, and obtaining a white product: 30.2 g, yield: 74.2 percent. HPLC purity: 99.3 percent.
Claims (10)
1. A method for preparing sofosbuvir by combining 3, 3-diaryl acrolein with Grignard reagent catalysis, which comprises the following steps: after the compound 2 is catalyzed and activated, the compound is condensed with a compound 3 to obtain sofosbuvir shown in a formula 1; the method is characterized in that: the catalytic activation adopts the following mode: catalytically activating compound 2 with 3, 3-diarylacrolein together with a grignard reagent;
2. the method of claim 1, wherein: the 3, 3-diaryl acrolein is at least one of 3, 3-diphenyl acrolein, 3-di (4-methylphenyl) acrolein, 3-di (4-methoxyphenyl) acrolein and 3, 3-di (4-ethylphenyl) acrolein.
3. The method of claim 1, wherein: the feeding molar ratio of the 3, 3-diaryl acrolein to the compound 2 is 0.05-0.2: 1.
4. the method of claim 2, wherein: the feeding molar ratio of the 3, 3-diaryl acrolein to the compound 2 is 0.05-0.2: 1.
5. the method of any of claims 1-4, wherein: the Grignard reagent is t-BuMgCl.
6. The method of any of claims 1-4, wherein: the molar ratio of the compound 2 to the Grignard reagent to the compound 3 is 1: 1-2: 1.1-1.5.
7. The method of any of claims 1-4, wherein: the preparation is carried out in THF.
8. The method of any of claims 1-4, wherein: the method for preparing the sofosbuvir by combining the 3, 3-diaryl acrolein with the Grignard reagent in a catalytic manner is carried out according to the following steps: adding a compound 2, THF and 3, 3-diarylacrolein into a reaction vessel, stirring, cooling to-10-0 ℃, dropwise adding t-BuMgCl THF solution under the protection of nitrogen, after dropwise adding for 0.5-2 hours, naturally raising the temperature to 0-10 ℃, and stirring for 15-20 hours; and then, adding a THF solution of the compound 3 dropwise, keeping the temperature until the HPLC detection content of the compound 2 is less than 1% after the addition is completed for 3-5 hours, and separating and purifying after the reaction is completed to obtain the sofosbuvir.
9. The method of any of claims 1-4, wherein: the method for preparing the sofosbuvir by combining the 3, 3-diaryl acrolein with the Grignard reagent in a catalytic manner is carried out according to the following steps: adding a compound 2, THF and 3, 3-diarylacrolein into a reaction vessel, stirring, cooling to-5 ℃, dropwise adding a t-BuMgCl THF solution under the protection of nitrogen, naturally raising the temperature to 5 ℃ after dropwise adding for 1 hour, and stirring for 18 hours; and then, adding a THF solution of the compound 3 dropwise, keeping the temperature until the HPLC detection content of the compound 2 is less than 1% after the addition is completed for 3-5 hours, and separating and purifying after the reaction is completed to obtain the sofosbuvir.
10. The method of claim 8, wherein: the separation and purification are carried out according to the following steps: after the reaction is finished, adjusting the pH value to be 6-7 by using 5-10% dilute hydrochloric acid, decompressing and distilling THF, adding ethyl acetate, fully stirring, separating an organic layer at 20-25 ℃, washing the organic layer at 20-25 ℃ by using a sodium carbonate solution, combining water layers, adding ethyl acetate for back extraction, combining the organic layers, washing by using clear water, separating the organic layer, evaporating the organic solvent to dryness, adding dichloromethane into residual liquid, heating and refluxing for 2-3 hours, cooling to 5-15 ℃, preserving heat for 15-18 hours, filtering, and leaching filtrate by using a small amount of dichloromethane to obtain a white product, namely sofosbuvir.
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