CN104610200A - Preparation method of NS5B (nonstructural protein 5B) polymerase inhibitor intermediates - Google Patents
Preparation method of NS5B (nonstructural protein 5B) polymerase inhibitor intermediates Download PDFInfo
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- CN104610200A CN104610200A CN201510022319.9A CN201510022319A CN104610200A CN 104610200 A CN104610200 A CN 104610200A CN 201510022319 A CN201510022319 A CN 201510022319A CN 104610200 A CN104610200 A CN 104610200A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
Abstract
The invention discloses a preparation method of NS5B (nonstructural protein 5B) polymerase inhibitor intermediates. The preparation method comprises the following steps: D-glyceraldehyde acetonide and 2-(triphenyl-phosphanylidene)-propionate are taken as starting materials and have a docking reaction under heating; an intermediate shown in the formula 1 reacts with strong oxidizer under an alkaline condition to oxidize an ethylenic linkage into geminal diol; an intermediate shown in the formula 2 reacts with an acylation reagent and an oxidation reagent to prepare a sulfate intermediate; an intermediate shown in the formula 3 reacts with a fluorinating reagent under alkaline action and has cyclization reaction with strong acid to prepare an intermediate shown in the formula 4; the intermediate shown in the formula 4 reacts with a hydroxyl protective agent under the catalysis of organic base so as to protect an alcoholic hydroxyl group. The starting materials are sold in quantity in the market, the preparation method is suitable for industrial production; part of the intermediates can be subjected to next synthesis directly without refining treatment, the technological operation is simple and convenient, a target product has high yield, and high adaptability to industrial production is realized.
Description
Technical field
The present invention relates to a kind of preparation method of NS5B AG14361 (Suo Feibuwei) intermediate, belong to pharmaceutical chemistry synthesis field.
Background technology
Hepatitis C (being called for short hepatitis C, the third liver) is that one infects by hepatitis C virus (HCV) viral hepatitis caused.According to World Health Organization's statistics, the infection rate of global third liver is about 3%, about 1.8 hundred million people's HCV infection, annual new hepatitis C case about 3.5 ten thousand example.Hepatitis C is global prevalence, can cause the downright bad and fibrosis of liver chronic inflammatory diseases, has 1% ~ 5% can develop into liver cirrhosis even hepatocellular carcinoma (HCC) and dead in 100 patients.
Suo Feibuwei is the most effective medicine for the treatment of HCV virus, and this medicine can be rated as the medicine of pound of attaching most importance to most in 2013 of FDA approval.And the fluoro-2-methyl D of important intermediate (2R)-2-deoxidation-2--erythro form pentonic acid gamma-lactone 3, the 5-dibenzoate synthesizing this medicine is also more and more subject to the attention in market.At present, all there is many defects in the synthesis technique of (2R)-2-deoxidation-2-fluoro-2-methyl D-erythro form pentonic acid gamma-lactone 3,5-dibenzoate mostly, as: synthetic route length, complex operation, be not easy to carry out large-scale industrial production; Starting raw material market is rare, expensive, be difficult on a large scale; Fluoro-reaction yield is low, Isomers content is higher, need repeatedly process, loss of material is serious, yield is low; (2R)-2-deoxidation-2-fluoro-2-methyl D-erythro form pentonic acid gamma-lactone 3,5-dibenzoate foreign matter content that polystep reaction prepares is higher, and purity is lower.
For this reason, be badly in need of a kind of new technical scheme and solve above-mentioned technical problem.
Summary of the invention
The object of this invention is to provide a kind of preparation method of NS5B AG14361 (Suo Feibuwei) intermediate, i.e. the fluoro-2-methyl D of (2R)-2-deoxidation-2--erythro form pentonic acid gamma-lactone 3,5-dibenzoate preparation method.
The technical solution used in the present invention is:
A preparation method for NS5B AG14361 intermediate, its preparation process comprises:
The preparation of a, intermediate formula 1:
With D-Glycerose third ketal and 2-triphenylphosphine vinylpropionate for starting raw material, under heating, carry out docking reaction;
The preparation of b, intermediate formula 2:
Ethylene linkage in the basic conditions, is oxidized to together with glycol through strong oxidizer reaction by intermediate formula 1;
The preparation of c, intermediate formula 3:
Intermediate formula 2 is reacted with acylating reagent and oxidising agent and is prepared sulfuric ester intermediate;
The preparation of d, intermediate formula 4:
Intermediate formula 3, under alkali effect, through fluorination reagent reaction, then obtains intermediate formula 4 through strong acid ring-closure reaction;
The preparation of e, Suo Feibuwei intermediate:
Intermediate formula 4, under organic base catalytic, is protected alcoholic extract hydroxyl group through hydroxy-protecting agent reaction.
Further, in a step, temperature of reaction is 0 ~ 80 DEG C, reaction solvent is isopropyl ether, tetrahydrofuran (THF), toluene, normal hexane or methyl tertiary butyl ether.
Further, in described b step, strong oxidizer is potassium permanganate or sodium permanganate, alkali used is salt of wormwood, sodium carbonate or sodium bicarbonate, temperature of reaction is-30 ~ 30 DEG C, reaction solvent is one or more mixtures in acetone, tetrahydrofuran (THF), ethylene glycol.
Further, in described step c, described acylating reagent is sulfur oxychloride, described oxygenant is clorox or hydrogen peroxide, and temperature of reaction is-10 ~ 30 DEG C, reaction solvent is one or more mixtures in tetrahydrofuran (THF), acetonitrile, toluene, pyridine.
Further, in described Step d, described fluorination reagent is hydrofluoric acid triethylamine salt, hydrofluoric acid pyridinium salt or diethylin sulfur trifluoride, described strong acid are hydrochloric acid or sulfuric acid, temperature of reaction are 5 ~ 50 DEG C, reaction solvent is tetrahydrofuran (THF) or acetonitrile.
Further, in described step e, described hydroxy-protecting agent is Benzoyl chloride or benzoyl oxide, described organic bases is DMAP, piperidines or pyridine, temperature of reaction is 5 ~ 50 DEG C.
Advantage of the present invention is: starting raw material D-Glycerose third ketal and 2-triphenylphosphine vinylpropionate market on sale in a large number, be suitable for large-scale industrial production; Moiety intermediate can directly carry out next step synthesis without refinement treatment, and technological operation is easy, and route yield is high; Fluoro-reaction yield is high, and isomer is easy to control; Each step reaction solvent is all recyclable to be applied mechanically, and pollute little, target product purity is high, is very suitable for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is process route chart of the present invention.
Embodiment
Embodiment 1
Prepared by intermediate formula 1:
In reaction flask, add 80mL isopropyl ether, 26.9g D-Glycerose third ketal, stirring and dissolving, drip isopropyl ether (50g/150mL) solution of 2-triphenylphosphine vinylpropionic acid ethyl ester; Drip and finish, be warming up to 50 DEG C of reactions, GC monitors reaction; Raw material reaction is complete, removes isopropyl ether under reduced pressure, then with the making beating of 300mL ether, filters, and filter cake with the making beating of 300mL ether, merges organic phase again, is evaporated to dry 27.5g yellow oil.GC purity 94.8%.Yield: 93%.
Prepared by intermediate formula 2:
In reaction flask, add 150mL acetone respectively, 30mL ethylene glycol, 20g intermediate formula 1, adds 25g sodium bicarbonate, stirring and dissolving, is cooled to-5 ~-10 DEG C, drips 84g 40% sodium permanganate solution, and drip and finish ,-5 ~-10 DEG C of reactions, TLC monitors reaction; React complete, add 50mL aqueous solution of sodium bisulfite and carry out cancellation, then remove acetone under reduced pressure, add 150mL ethyl acetate, stir, leave standstill separatory, aqueous layer with ethyl acetate (100mL × 2) extracts, merge organic phase, respectively with water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, suction filtration, be evaporated to dry, obtain 22.3g oily matter.This oily matter toluene and sherwood oil are refined, and dry, obtain 15.2g white solid product.Yield 65%, purity 99.3%.
Prepared by intermediate formula 3:
In reaction flask, add 15g intermediate formula 2,80mL acetonitrile, 16.2g triethylamine, stirring and dissolving, is cooled to 0 ~ 5 DEG C, drips 8.4g sulfur oxychloride; Drip and finish, react at 0 ~ 5 DEG C, TLC monitors reaction; Intermediate 2 acidylate is complete, starts to drip 120g chlorine bleach liquor; Drip and finish, react at 0 ~ 5 DEG C, TLC monitors reaction; React complete, drip sodium sulfite solution and carry out cancellation, starch potassium iodide paper nondiscoloration; Stir 30min, concentrating under reduced pressure steams except acetonitrile, add 150mL ethyl acetate, leave standstill separatory, aqueous layer with ethyl acetate (100mL × 2) extracts, merge organic phase, with sodium hydrogen carbonate solution, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, is evaporated to dry, obtain 21.4g oily product, directly carry out next step reaction.
Prepared by intermediate formula 4:
In reaction flask, add 20g intermediate formula 3,8.3g triethylamine, 16.5g hydrofluoric acid triethylamine salt respectively, 100mL tetrahydrofuran (THF), stirring, be warming up to 65 DEG C of reactions, TLC monitors reaction; Raw material reaction is complete, is down to room temperature, suction 30mL concentrated hydrochloric acid, be warming up to 65 DEG C of back flow reaction again, react 2 hours, add 45g bariumchloride/aqueous solution, stirring reaction 2 hours, adds 300mL toluene and carries out reflux water-dividing, after 3 hours, be down to room temperature, leave standstill, separate toluene, add 80mL acetonitrile, obtain intermediate 4 acetonitrile solution, directly carry out next step reaction.
The preparation of Suo Feibuwei intermediate:
Under anhydrous and oxygen-free condition, add intermediate formula 3 acetonitrile solution in reaction flask, 2g DMAP and 24.8g Benzoyl chloride, stir, be cooled to 15 ~ 20 DEG C of reactions, TLC monitors reaction; React complete, remove acetonitrile under reduced pressure, add 100mL ethyl acetate and 100mL saturated sodium bicarbonate solution, stir, leave standstill separatory, aqueous layer with ethyl acetate (100mL × 2) extracts, and merges organic phase, washs with sodium chloride solution, anhydrous sodium sulfate drying, suction filtration, is evaporated to dry, obtains yellow-brown solid crude product.This crude product 6 times amount Virahols are refined, and obtain 19.3g faint yellow solid product.Yield: 83%, purity: 98.5%.
Embodiment 2:
Prepared by intermediate formula 1:
In reaction flask, add 80mL toluene, 26.9g D-Glycerose third ketal, stirring and dissolving, drip toluene (50g/150mL) solution of 50g 2-triphenylphosphine vinylpropionic acid ethyl ester; Drip and finish, be warming up to 60 DEG C of reactions, GC monitors reaction; Raw material reaction is complete, removes toluene under reduced pressure, then with the making beating of 300mL normal hexane, filters, and filter cake with the making beating of 300mL normal hexane, merges organic phase again, is evaporated to dry 28.1g yellow oil.GC purity 95.6%.Yield: 95%.
Prepared by intermediate formula 2:
In reaction flask, add 150mL acetone respectively, 30mL ethylene glycol, 20g intermediate formula 1, adds 20g sodium carbonate, stirring and dissolving, is cooled to-5 ~-10 DEG C, adds 22g potassium permanganate in batches; Finish ,-5 ~-10 DEG C of reactions, TLC monitors reaction; React complete, add 50mL aqueous solution of sodium bisulfite and carry out cancellation, then remove acetone under reduced pressure, add 150mL ethyl acetate, stir, leave standstill separatory, aqueous layer with ethyl acetate (100mL × 2) extracts, merge organic phase, respectively with water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, suction filtration, be evaporated to dry, obtain 24.5g oily matter.This oily matter toluene and sherwood oil are refined, and dry, obtain 16.1g white solid product.Yield 69%, purity 99.5%.
Prepared by intermediate formula 3:
In reaction flask, add 15g intermediate formula 2,80mL tetrahydrofuran (THF), 17.3gDIPEA, stirring and dissolving, is cooled to 0 ~ 5 DEG C, drips 8.5g sulfur oxychloride; Drip and finish, react at 0 ~ 5 DEG C, TLC monitors reaction; Intermediate formula 2 acidylate is complete, starts to drip 120g chlorine bleach liquor; Drip and finish, react at 0 ~ 5 DEG C, TLC monitors reaction; React complete, drip sodium sulfite solution and carry out cancellation, starch potassium iodide paper nondiscoloration; Stir 30min, concentrating under reduced pressure steams except tetrahydrofuran (THF), add 150mL ethyl acetate, leave standstill separatory, aqueous layer with ethyl acetate (100mL × 2) extracts, merge organic phase, with sodium hydrogen carbonate solution, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, is evaporated to dry, obtain 20.8g oily product, directly carry out next step reaction.
Prepared by intermediate formula 4:
In reaction flask, add 20g intermediate formula 3,7.3g pyridine, 14.8g hydrofluoric acid pyridinium salt respectively, 100mL tetrahydrofuran (THF), stir, be warming up to back flow reaction, TLC monitors reaction; Raw material reaction is complete, is down to room temperature, suction 30mL concentrated hydrochloric acid, be warming up to back flow reaction again, react 2 hours, add 45g bariumchloride/aqueous solution, stirring reaction 2 hours, adds 300mL toluene and carries out reflux water-dividing, after 3 hours, be down to room temperature, leave standstill, separate toluene, add 80mL acetonitrile, obtain intermediate formula 4 acetonitrile solution, directly carry out next step reaction.
The preparation of Suo Feibuwei intermediate:
Under anhydrous and oxygen-free condition, add intermediate formula 3 acetonitrile solution, 3g piperidines and phenylformic acid in reaction flask, stir, be cooled to 15 ~ 20 DEG C of reactions, TLC monitors reaction; React complete, remove acetonitrile under reduced pressure, add 100mL ethyl acetate and 100mL saturated sodium bicarbonate solution, stir, leave standstill separatory, aqueous layer with ethyl acetate (100mL × 2) extracts, and merges organic phase, washs with sodium chloride solution, anhydrous sodium sulfate drying, suction filtration, is evaporated to dry, obtains yellow-brown solid crude product.This crude product 6 times amount Virahols are refined, and obtain 19.8g faint yellow solid product.Yield: 85%, purity: 98.1%
Embodiment 3:
Prepared by intermediate formula 1:
In reaction flask, add 80mL tetrahydrofuran (THF), 26.9g D-Glycerose third ketal, stirring and dissolving, drip tetrahydrofuran (THF) (50g/150mL) solution of 50g 2-triphenylphosphine vinylpropionic acid ethyl ester; Drip and finish, be warming up to 45 DEG C of reactions, GC monitors reaction; Raw material reaction is complete, removes tetrahydrofuran (THF) under reduced pressure, then with the making beating of 300mL ether, filters, and filter cake with the making beating of 300mL ether, merges organic phase again, is evaporated to dry 27.8g yellow oil.GC purity 94.2%.Yield: 94%.
Prepared by intermediate formula 2:
In reaction flask, add 150mL tetrahydrofuran (THF) respectively, 30mL ethylene glycol, 20g intermediate formula 1,20g adds salt of wormwood, stirring and dissolving, is cooled to-5 ~-10 DEG C, adds 24.3g potassium permanganate in batches; Finish ,-5 ~-10 DEG C of reactions, TLC monitors reaction; React complete, add 50mL aqueous solution of sodium bisulfite and carry out cancellation, then remove acetone under reduced pressure, add 150mL ethyl acetate, stir, leave standstill separatory, aqueous layer with ethyl acetate (100mL × 2) extracts, merge organic phase, respectively with water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, suction filtration, be evaporated to dry, obtain 26.3g oily matter.This oily matter toluene and sherwood oil are refined, and dry, obtain 16.6g white solid product.Yield 71%, purity 99.2%.
Prepared by intermediate formula 3:
In reaction flask, add 15g intermediate formula 2,80mL toluene, 12.5g pyridine, stirring and dissolving, is cooled to 0 ~ 5 DEG C, drips sulfur oxychloride; Drip and finish, react at 0 ~ 5 DEG C, TLC monitors reaction; Intermediate formula 2 acidylate is complete, starts to drip 120g chlorine bleach liquor; Drip and finish, react at 0 ~ 5 DEG C, TLC monitors reaction; React complete, drip sodium sulfite solution and carry out cancellation, starch potassium iodide paper nondiscoloration; Stir 30min, concentrating under reduced pressure steams except toluene, add 150mL ethyl acetate, leave standstill separatory, aqueous layer with ethyl acetate (100mL × 2) extracts, merge organic phase, with sodium hydrogen carbonate solution, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, is evaporated to dry, obtain 22.6g oily product, directly carry out next step reaction.
Prepared by intermediate formula 4:
In reaction flask, add 20g intermediate formula 3,7.6g piperidines, 13.6g diethylin sulfur trifluoride respectively, 100mL acetonitrile, stir, be warming up to back flow reaction, TLC monitors reaction; Raw material reaction is complete, is down to room temperature, suction 30mL concentrated hydrochloric acid, be warming up to back flow reaction again, react 2 hours, add 45g bariumchloride/aqueous solution, stirring reaction 2 hours, adds 300mL toluene and carries out reflux water-dividing, after 3 hours, be down to room temperature, leave standstill, separate toluene, add 80mL acetonitrile, obtain intermediate formula 4 acetonitrile solution, directly carry out next step reaction.
The preparation of Suo Feibuwei intermediate:
Under anhydrous and oxygen-free condition, add intermediate formula 3 acetonitrile solution, 2g pyridine and benzoyl oxide in reaction flask, stir, be cooled to 15 ~ 20 DEG C of reactions, TLC monitors reaction; React complete, remove acetonitrile under reduced pressure, add 100mL ethyl acetate and 100mL saturated sodium bicarbonate solution, stir, leave standstill separatory, aqueous layer with ethyl acetate (100mL × 2) extracts, and merges organic phase, washs with sodium chloride solution, anhydrous sodium sulfate drying, suction filtration, is evaporated to dry, obtains yellow-brown solid crude product.This crude product 6 times amount Virahols are refined, and obtain 18.8g faint yellow solid product.Yield: 81%, purity: 98.6%.
Claims (6)
1. a preparation method for NS5B AG14361 intermediate, is characterized in that: preparation process comprises:
The preparation of a, intermediate formula 1:
With D-Glycerose third ketal and 2-triphenylphosphine vinylpropionate for starting raw material, under heating, carry out docking reaction;
The preparation of b, intermediate formula 2:
Ethylene linkage in the basic conditions, is oxidized to together with glycol through strong oxidizer reaction by intermediate formula 1;
The preparation of c, intermediate formula 3:
Intermediate formula 2 is reacted with acylating reagent and oxidising agent and is prepared sulfuric ester intermediate;
The preparation of d, intermediate formula 4:
Intermediate formula 3, under alkali effect, through fluorination reagent reaction, then obtains intermediate formula 4 through strong acid ring-closure reaction;
The preparation of e, Suo Feibuwei intermediate:
Intermediate formula 4, under organic base catalytic, is protected alcoholic extract hydroxyl group through hydroxy-protecting agent reaction.
2. the preparation method of a kind of NS5B AG14361 intermediate according to claim 1, it is characterized in that: in described a step, temperature of reaction is 0-80 DEG C, reaction solvent is isopropyl ether, tetrahydrofuran (THF), toluene, normal hexane or methyl tertiary butyl ether.
3. the preparation method of a kind of NS5B AG14361 intermediate according to claim 1, it is characterized in that: in described b step, strong oxidizer is potassium permanganate or sodium permanganate, alkali used is salt of wormwood, sodium carbonate or sodium bicarbonate, temperature of reaction is-30 ~ 30 DEG C, reaction solvent is one or more mixtures in acetone, tetrahydrofuran (THF), ethylene glycol, ethylene glycol.
4. the preparation method of a kind of NS5B AG14361 intermediate according to claim 1; it is characterized in that: in described step c; described acylating reagent is sulfur oxychloride, described oxygenant is clorox or hydrogen peroxide, and temperature of reaction is-10 ~ 30 DEG C, reaction solvent is one or more mixtures in tetrahydrofuran (THF), acetonitrile, toluene, pyridine.
5. the preparation method of a kind of NS5B AG14361 intermediate according to claim 1, it is characterized in that: in described Step d, described fluorination reagent is hydrofluoric acid triethylamine salt, hydrofluoric acid pyridinium salt or diethylin sulfur trifluoride, described strong acid are hydrochloric acid or sulfuric acid, temperature of reaction are 5 ~ 50 DEG C, reaction solvent is tetrahydrofuran (THF) or acetonitrile.
6. the preparation method of a kind of NS5B AG14361 intermediate according to claim 1; it is characterized in that: in described step e, described hydroxy-protecting agent is Benzoyl chloride or benzoyl oxide, described organic bases is DMAP, piperidines or pyridine, temperature of reaction is 5 ~ 50 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418547A (en) * | 2015-11-17 | 2016-03-23 | 海门慧聚药业有限公司 | Preparation for sofosbuvir key intermediate |
| WO2017077552A1 (en) * | 2015-11-03 | 2017-05-11 | Mylan Laboratories Limited | Process for the preparation of sofosbuvir |
| CN110256422A (en) * | 2019-07-02 | 2019-09-20 | 天津国际生物医药联合研究院 | A kind of synthetic method of mannosidase inhibitor Kifunensine |
-
2015
- 2015-01-16 CN CN201510022319.9A patent/CN104610200A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| PEIYUAN WANG 等: "An Efficient and Diastereoselective Synthesis of PSI-6130: A Clinically Efficacious Inhibitor of HCV NS5B Polymerase", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017077552A1 (en) * | 2015-11-03 | 2017-05-11 | Mylan Laboratories Limited | Process for the preparation of sofosbuvir |
| US10344009B2 (en) | 2015-11-03 | 2019-07-09 | Mylan Laboratories Limited | Process for the preparation of sofosbuvir |
| CN105418547A (en) * | 2015-11-17 | 2016-03-23 | 海门慧聚药业有限公司 | Preparation for sofosbuvir key intermediate |
| CN110256422A (en) * | 2019-07-02 | 2019-09-20 | 天津国际生物医药联合研究院 | A kind of synthetic method of mannosidase inhibitor Kifunensine |
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