CN111087421A - Preparation method of phosphamide compound for chiral drug synthesis - Google Patents
Preparation method of phosphamide compound for chiral drug synthesis Download PDFInfo
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- CN111087421A CN111087421A CN201911341578.2A CN201911341578A CN111087421A CN 111087421 A CN111087421 A CN 111087421A CN 201911341578 A CN201911341578 A CN 201911341578A CN 111087421 A CN111087421 A CN 111087421A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- -1 phosphamide compound Chemical class 0.000 title claims abstract description 7
- 229940079593 drug Drugs 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 title abstract description 5
- 230000015572 biosynthetic process Effects 0.000 title abstract description 4
- 238000003786 synthesis reaction Methods 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 21
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims abstract description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 229960003767 alanine Drugs 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 238000013019 agitation Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- 239000003960 organic solvent Substances 0.000 abstract description 5
- 238000004537 pulping Methods 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 4
- 239000007864 aqueous solution Substances 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 4
- 208000005176 Hepatitis C Diseases 0.000 description 4
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 4
- 229960002063 sofosbuvir Drugs 0.000 description 4
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 4
- 208000010710 hepatitis C virus infection Diseases 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- VTSRCHXIIMBAKT-WNQIDUERSA-N (2s)-2-aminopropanoic acid;2-chloropropane Chemical compound CC(C)Cl.C[C@H](N)C(O)=O VTSRCHXIIMBAKT-WNQIDUERSA-N 0.000 description 2
- 208000006154 Chronic hepatitis C Diseases 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 1
- 206010056519 Abdominal infection Diseases 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000019707 Cryoglobulinemic vasculitis Diseases 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 241000097929 Porphyria Species 0.000 description 1
- 208000010642 Porphyrias Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 201000003278 cryoglobulinemia Diseases 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 201000011200 hepatorenal syndrome Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- VRTWBAAJJOHBQU-KMWAZVGDSA-N ledipasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N([C@@H](C1)C=2NC(=CN=2)C=2C=C3C(F)(F)C4=CC(=CC=C4C3=CC=2)C=2C=C3NC(=NC3=CC=2)[C@H]2N([C@@H]3CC[C@H]2C3)C(=O)[C@@H](NC(=O)OC)C(C)C)CC21CC2 VRTWBAAJJOHBQU-KMWAZVGDSA-N 0.000 description 1
- 229960002461 ledipasvir Drugs 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- FHCUMDQMBHQXKK-CDIODLITSA-N velpatasvir Chemical compound C1([C@@H](NC(=O)OC)C(=O)N2[C@@H](C[C@@H](C2)COC)C=2NC(=CN=2)C=2C=C3C(C4=CC5=CC=C6NC(=NC6=C5C=C4OC3)[C@H]3N([C@@H](C)CC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)=CC=CC=C1 FHCUMDQMBHQXKK-CDIODLITSA-N 0.000 description 1
- 229960000863 velpatasvir Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/242—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of hydroxyaryl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of a phosphamide compound for chiral drug synthesis, which adopts NaHCO with specific pH value and specific volume-mass ratio3The aqueous solution is used as a solvent for pulping, and the temperature and the stirring speed during pulping are controlled, so that the compound II can be prepared with high yield and high purity. The reaction system does not need organic solvent, reduces the discharge of a large amount of organic solvent waste liquid, and has the advantages of environment-friendly process, greenness and no pollution.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a phosphamide compound.
Background
Hepatitis C Virus (HCV) infection is a worldwide epidemic with more than 2 billion of chronically infected people worldwide, with a chronic infection rate of 15% in egypt, 4.8% in pakistan, 3.2% in china, and the top three in the world. The clinical manifestations of hepatitis c virus infection are diverse, mild to inflammation and severe to cirrhosis and liver cancer. Chronic hepatitis c may also be complicated by certain extrahepatic manifestations, including rheumatoid arthritis, keratoconjunctivitis sicca, lichen planus, glomerulonephritis, mixed cryoglobulinemia, B-cell lymphoma, and delayed porphyria cutanea dermalis, which may be the result of an abnormal immune response in the body. And various complications can occur when the hepatitis C cirrhosis is in the decompensation stage, such as ascites abdominal infection, upper gastrointestinal hemorrhage, hepatic encephalopathy, hepatorenal syndrome, liver failure and the like.
Sofosbuvir, known as Sofosbuvir in English, is a breakthrough drug developed by Gilidd science Inc. for treating chronic hepatitis C, is approved to be marketed in the United states by the U.S. food and drug administration in 12 months in 2013, and is approved to be marketed in the European Union by the European drug administration in 1 month in 2014. Sofosbuvir can be used alone or in a compound way (combined with Ledipasvir or Velpatasvir) to treat the whole-gene type hepatitis C, and the cure rate is over 95 percent.
In the synthesis process of the sofosbuvir, an industrially common preparation method relates to a step of converting an intermediate I (SR-P) into an intermediate II (S-P), and the specific reaction is as follows:
patent application CN109689065A discloses a process for obtaining compound II with a yield of about 46.7% by grinding intermediate compound I in a mixed solution of ethyl acetate/hexane containing pentafluorophenol, triethylamine and dimethylaminopyridine. Patent application CN109689672A discloses a process for the preparation of compound I to compound II with a one step yield of only 3.57% using heptane/EtOAc as slurrying solvent.
In the prior art, a mixed organic solvent is usually used as a pulping solvent to prepare the compound II, but the method has low yield and high cost and is not beneficial to industrial production, so that a method for preparing the compound II with high purity and high yield is urgently needed to be found.
Disclosure of Invention
The invention aims to provide an improved synthesis method of isopropyl ((S) - (perfluorophenoxy (phenoxy) phosphoryl) -L-alanine.
In one aspect, the invention provides a method for preparing isopropyl ((S) - (perfluorophenoxy (phenoxy) phosphoryl) -L-alanine, the route is as follows:
the method is characterized in that a compound I is added into an aqueous alkali solution, stirred and filtered to obtain a compound II, wherein the alkali is sodium bicarbonate.
In some embodiments, the volume to mass ratio of the aqueous sodium bicarbonate solution to compound I is 3-5: 1; preferably 4: 1.
In some embodiments, the stirring is performed at a low temperature, the temperature being controlled at 1-10 ℃; preferably 2-4 deg.c.
In some embodiments, the rotational speed of the agitation is 200-.
In some embodiments, the pH of the aqueous base is from 8 to 10; preferably, the pH is 8 to 9.
In some embodiments, the route of preparation of compound I is as follows:
in some embodiments, the compound I is prepared by a process comprising: mixing L-alanine isopropyl hydrochloride and dichloromethane, adding phenyl dichlorophosphate, and dropwise adding triethylamine. And (3) dropwise adding dichloromethane solution of pentafluorophenol and triethylamine, after the reaction is finished, adding dichloromethane and water, stirring and separating, collecting an organic phase, and concentrating under reduced pressure to obtain a solid.
The term "volumetric to mass ratio" in the present invention is the ratio of the volume of the solution in milliliters to the mass of the solid in grams, for example, if the volume of the saturated aqueous sodium bicarbonate solution is 30ml and the mass of compound I is 10g, the volumetric to mass ratio of the saturated aqueous sodium bicarbonate solution to compound I is 3: 1.
Detailed Description
To facilitate the understanding of the present invention by those skilled in the art, the following specific description will be given by way of specific examples:
all the raw material reagents used in the example are analytically pure, and all the products are confirmed by nuclear magnetic hydrogen spectrum analysis.
The HPLC detection conditions were as follows:
a chromatographic column: octadecylsilane chemically bonded silica gel as filler
Mobile phase A: potassium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid) -acetonitrile (90:10)
Mobile phase B: methanol-acetonitrile (60:40)
Linear gradient elution, elution procedure is as follows:
flow rate: 1.0ml/min
Column temperature: 40 deg.C
Wavelength: 210nm
Sample introduction amount: 20 μ l
Preparation example 1 preparation of compound I:
20g of L-alanine isopropyl hydrochloride and 100ml of dichloromethane are mixed, the temperature is controlled to be less than-50 ℃, and 25g of phenyl dichlorophosphate is added. Controlling the temperature between-60 ℃ and-50 ℃, and dropwise adding 24g of triethylamine. Stirring for 3h while keeping the temperature at minus 60 ℃ to minus 50 ℃, and dropwise adding a dichloromethane solution of pentafluorophenol and triethylamine (22 g of pentafluorophenol is dissolved in 20ml of dichloromethane at 0 ℃ to 10 ℃, 12g of triethylamine is dropwise added, and stirring for 30min while keeping the temperature at the end of dripping). After dropping, the reaction is carried out for 2 h. 100ml of methylene chloride and 200ml of water were added to the solution, and the mixture was stirred and separated. Collecting the organic phase, decompressing and concentrating at 35-40 ℃ and concentrating to obtain solid.
Preparation of example compound II:
80g of the solid prepared in preparation example 1 is weighed each time, added into an aqueous alkali solution, stirred for 1 hour under the controlled temperature and rotation speed, centrifuged, filtered and dried to obtain a white solid, namely the compound II.
The specific conditions and operations are shown in the following table, and the purity and yield of compound II are calculated.
Through the series of examples, the inventor unexpectedly finds that only NaHCO with specific pH value and specific volume-to-mass ratio is selected3The aqueous solution is used as a pulping solvent, the compound II can be prepared with high yield and high purity by controlling the temperature and the stirring speed during pulping, and meanwhile, the reaction system does not need an organic solvent, so that the discharge of a large amount of organic solvent waste liquid is reduced, and the process is environment-friendly, green and pollution-free.
Claims (10)
1. A preparation method of isopropyl ((S) - (perfluorophenoxy (phenoxy) phosphoryl) -L-alanine comprises the following steps:
the method is characterized in that a compound I is added into an aqueous alkali solution, stirred and filtered to obtain a compound II, wherein the alkali is sodium bicarbonate.
2. The process according to claim 1, wherein the volume-to-mass ratio of the aqueous sodium bicarbonate solution to the compound I is 3-5: 1.
3. The process according to claim 2, wherein the volume to mass ratio of the aqueous sodium bicarbonate solution to the compound I is 4: 1.
4. The method according to claim 1, wherein the stirring is carried out at a low temperature, and the temperature is controlled to be 1 to 10 ℃.
5. The method according to claim 4, wherein the stirring is carried out at a low temperature and the temperature is controlled to be 2 to 4 ℃.
6. The method of claim 1, wherein the stirring speed is 200-300 rpm.
7. The method of claim 6, wherein the agitation is performed at a speed of 250 revolutions per minute.
8. The process according to claim 1, wherein the aqueous alkali solution has a pH of from 8 to 10.
9. The process according to claim 8, wherein the aqueous alkali solution has a pH of from 8 to 9.
10. The process according to claim 1, wherein compound I is prepared by the following route:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911341578.2A CN111087421B (en) | 2019-12-24 | 2019-12-24 | Preparation method of phosphamide compound for chiral drug synthesis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911341578.2A CN111087421B (en) | 2019-12-24 | 2019-12-24 | Preparation method of phosphamide compound for chiral drug synthesis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111087421A true CN111087421A (en) | 2020-05-01 |
| CN111087421B CN111087421B (en) | 2022-10-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911341578.2A Active CN111087421B (en) | 2019-12-24 | 2019-12-24 | Preparation method of phosphamide compound for chiral drug synthesis |
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| Country | Link |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021253376A1 (en) * | 2020-06-19 | 2021-12-23 | 南京正大天晴制药有限公司 | Preparation method for phosphamide compound used for synthesizing chiral drug |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016181313A1 (en) * | 2015-05-11 | 2016-11-17 | Lupin Limited | A process for the preparation of sofosbuvir intermediates & its polymorph |
| CN107759632A (en) * | 2016-08-19 | 2018-03-06 | 正大天晴药业集团股份有限公司 | A kind of preparation method of chiral phosphorus acid esters |
| CN109689672A (en) * | 2016-09-07 | 2019-04-26 | 阿堤亚制药公司 | 2 '-- N replaced for RNA virus treatment6The purine nucleotides replaced |
| CN109689065A (en) * | 2016-06-24 | 2019-04-26 | 埃默里大学 | For treating the phosphinylidyne aminate of hepatitis type B virus |
-
2019
- 2019-12-24 CN CN201911341578.2A patent/CN111087421B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016181313A1 (en) * | 2015-05-11 | 2016-11-17 | Lupin Limited | A process for the preparation of sofosbuvir intermediates & its polymorph |
| CN109689065A (en) * | 2016-06-24 | 2019-04-26 | 埃默里大学 | For treating the phosphinylidyne aminate of hepatitis type B virus |
| CN107759632A (en) * | 2016-08-19 | 2018-03-06 | 正大天晴药业集团股份有限公司 | A kind of preparation method of chiral phosphorus acid esters |
| CN109689672A (en) * | 2016-09-07 | 2019-04-26 | 阿堤亚制药公司 | 2 '-- N replaced for RNA virus treatment6The purine nucleotides replaced |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021253376A1 (en) * | 2020-06-19 | 2021-12-23 | 南京正大天晴制药有限公司 | Preparation method for phosphamide compound used for synthesizing chiral drug |
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| Publication number | Publication date |
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| CN111087421B (en) | 2022-10-18 |
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