WO2021253376A1 - Preparation method for phosphamide compound used for synthesizing chiral drug - Google Patents
Preparation method for phosphamide compound used for synthesizing chiral drug Download PDFInfo
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- WO2021253376A1 WO2021253376A1 PCT/CN2020/097026 CN2020097026W WO2021253376A1 WO 2021253376 A1 WO2021253376 A1 WO 2021253376A1 CN 2020097026 W CN2020097026 W CN 2020097026W WO 2021253376 A1 WO2021253376 A1 WO 2021253376A1
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title abstract description 4
- 229940079593 drug Drugs 0.000 title abstract description 4
- -1 phosphamide compound Chemical class 0.000 title abstract description 3
- 230000002194 synthesizing effect Effects 0.000 title abstract description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 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 10
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 10
- 239000003513 alkali Substances 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
- 239000003960 organic solvent Substances 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 239000007788 liquid Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 2
- 238000004537 pulping Methods 0.000 abstract 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 21
- 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 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 208000005176 Hepatitis C Diseases 0.000 description 4
- 238000010009 beating Methods 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
- 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
- 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
- 208000015181 infectious disease Diseases 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
- 239000000203 mixture Substances 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 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
- 206010003445 Ascites Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000019707 Cryoglobulinemic vasculitis Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229940126656 GS-4224 Drugs 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
- 238000005481 NMR spectroscopy Methods 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
- 210000000683 abdominal cavity Anatomy 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 201000003278 cryoglobulinemia Diseases 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
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 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
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group 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
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction 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 System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
Definitions
- the invention relates to the field of medicinal chemistry, in particular to a preparation method of a phosphoramide compound.
- Hepatitis C virus (HCV) infection is a worldwide epidemic. There are more than 200 million chronically infected people worldwide. The chronic infection rate in Egypt is 15%, Pakistan is 4.8%, and China is 3.2%, ranking among the top three in the world.
- the clinical manifestations of hepatitis C virus infection are diverse, ranging from inflammation to severe cirrhosis and liver cancer.
- Chronic hepatitis C can also be complicated by certain extrahepatic manifestations, including rheumatoid arthritis, conjunctival keratitis sicca, lichen planus, glomerulonephritis, mixed cryoglobulinemia, B-cell lymphoma, and late onset Skin porphyria, etc., may be caused by the body's abnormal immune response.
- liver cirrhosis when hepatitis C liver cirrhosis is decompensated, various complications can occur, such as ascites and abdominal cavity infection, upper gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, liver failure and other manifestations.
- Sofosbuvir English name Sofosbuvir, is a breakthrough drug developed by Gilead Sciences for the treatment of chronic hepatitis C. It was approved by the U.S. Food and Drug Administration in December 2013 and listed in the United States in January 2014. It was approved by the European Drug Administration in January 2014. The Bureau approved the listing in the European Union. Sofosbuvir alone or in combination (in combination with Ledipasvir or Velpatasvir) can treat all-genotype hepatitis C, with a cure rate of more than 95%.
- Patent application CN109689065A discloses a method for obtaining compound II by grinding intermediate compound I in a mixed solution of ethyl acetate/hexane containing pentafluorophenol, triethylamine and dimethylaminopyridine in the presence of pentafluorophenol, triethylamine and dimethylaminopyridine. The yield About 46.7%.
- Patent application CN109689672A discloses a method for preparing compound I to obtain compound II by using heptane/EtOAc as the beating solvent, and the one-step yield is only 3.57%.
- the prior art usually uses mixed organic solvents as the beating solvent to prepare compound II, but this type of method has low yield and high cost, which is not conducive to industrial production. Therefore, it is urgent to find a method that can prepare compound II with high purity and high yield. Methods.
- the present invention aims to provide an improved method for synthesizing isopropyl ((S)-(perfluorophenoxy (phenoxy) phosphoryl)-L-alanine).
- the present invention provides a method for preparing isopropyl((S)-(perfluorophenoxy(phenoxy)phosphoryl)-L-alanine), the route is as follows:
- the compound I is added to the aqueous alkali solution, stirred, and filtered to obtain the compound II, wherein the alkali is sodium bicarbonate.
- the stirring is performed at a low temperature, and the temperature is controlled at 1-10°C; preferably 2-4°C.
- the rotation speed of the stirring is 200-300 revolutions per minute; preferably 250-300 revolutions per minute.
- the pH value of the aqueous alkali solution is 8-10; preferably, the pH value is 8-9.
- the volume-to-mass ratio of the aqueous sodium bicarbonate solution to compound I is 3-5:1; preferably 4:1.
- the preparation route of Compound I is as follows:
- the preparation method of the compound I is: mixing L-alanine isopropyl hydrochloride and dichloromethane, adding phenyl dichlorophosphate, and adding triethylamine dropwise. After stirring for 3 hours, the dichloromethane solution of pentafluorophenol and triethylamine was added dropwise. After the reaction was completed, dichloromethane and water were added, stirred and separated, collected the organic phase, and concentrated under reduced pressure to obtain a solid.
- volume-mass ratio refers to the ratio of the volume of the solution in milliliters to the mass of solids in grams. For example, if the volume of a saturated sodium bicarbonate aqueous solution is 30 ml, and the mass of compound I is 10 g, it is saturated The volume-to-mass ratio of sodium bicarbonate aqueous solution and compound I is 3:1.
- the raw materials and reagents used in this example are all analytically pure, and each product has been analyzed and confirmed by hydrogen NMR spectroscopy.
- HPLC detection conditions are as follows:
- Chromatographic column octadecyl silane bonded silica gel as filler.
- Mobile phase A potassium dihydrogen phosphate solution (adjust the pH to 3.0 with phosphoric acid)-acetonitrile (90:10).
- Injection volume 20 ⁇ L.
- the inventor unexpectedly discovered that selecting a specific pH value and a specific volume-to-mass ratio NaHCO 3 aqueous solution as the solvent for beating, and controlling the temperature and stirring speed during beating can produce compounds with high yield and high purity. II.
- the reaction system does not require organic solvents, reducing the discharge of a large amount of organic solvent waste liquid, and the process is environmentally friendly, green and pollution-free.
Abstract
Description
Claims (10)
- 一种异丙基((S)-(全氟苯氧基(苯氧基)磷酰基)-L-丙氨酸的制备方法,其特征在于,路线如下:A method for preparing isopropyl ((S)-(perfluorophenoxy (phenoxy) phosphoryl)-L-alanine), which is characterized in that the route is as follows:将化合物I加入至碱水溶液中搅拌,过滤得到化合物II,其中所述碱为碳酸氢钠。Compound I is added to the aqueous alkali solution, stirred, and filtered to obtain compound II, wherein the alkali is sodium bicarbonate.
- 如权利要求1所述的制备方法,其特征在于,搅拌在低温下进行,温度控制在1-10℃。The preparation method according to claim 1, wherein the stirring is carried out at a low temperature, and the temperature is controlled at 1-10°C.
- 如权利要求2所述的制备方法,其特征在于,搅拌在低温下进行,温度控制在2-4℃。The preparation method according to claim 2, wherein the stirring is carried out at a low temperature, and the temperature is controlled at 2-4°C.
- 如权利要求1所述的制备方法,其特征在于,搅拌的转速为:每分钟200-300转。The preparation method according to claim 1, wherein the rotation speed of the stirring is 200-300 revolutions per minute.
- 如权利要求4所述的制备方法,其特征在于,搅拌的转速为每分钟250转。The preparation method according to claim 4, wherein the rotation speed of the stirring is 250 revolutions per minute.
- 如权利要求1所述的制备方法,其特征在于,碱水溶液的pH值为8-10。The preparation method according to claim 1, wherein the pH of the aqueous alkali solution is 8-10.
- 如权利要求6所述的制备方法,其特征在于,碱水溶液的pH值为8-9。8. The preparation method according to claim 6, wherein the pH of the aqueous alkali solution is 8-9.
- 如权利要求1-7任一项所述的制备方法,其特征在于,碳酸氢钠水溶液与化合物I的体积质量比为3-5:1。7. The preparation method according to any one of claims 1-7, wherein the volume-to-mass ratio of the sodium bicarbonate aqueous solution to the compound I is 3-5:1.
- 如权利要求8所述的制备方法,其特征在于,碳酸氢钠水溶液与化合物I的体积质量比为4:1。8. The preparation method of claim 8, wherein the volume-to-mass ratio of the sodium bicarbonate aqueous solution to the compound I is 4:1.
Priority Applications (1)
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PCT/CN2020/097026 WO2021253376A1 (en) | 2020-06-19 | 2020-06-19 | Preparation method for phosphamide compound used for synthesizing chiral drug |
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PCT/CN2020/097026 WO2021253376A1 (en) | 2020-06-19 | 2020-06-19 | Preparation method for phosphamide compound used for synthesizing chiral drug |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018033139A1 (en) * | 2016-08-19 | 2018-02-22 | 正大天晴药业集团股份有限公司 | Preparation method for chiral phosphate ester |
CN109689065A (en) * | 2016-06-24 | 2019-04-26 | 埃默里大学 | For treating the phosphinylidyne aminate of hepatitis type B virus |
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 |
CN111087421A (en) * | 2019-12-24 | 2020-05-01 | 南京正大天晴制药有限公司 | Preparation method of phosphamide compound for chiral drug synthesis |
-
2020
- 2020-06-19 WO PCT/CN2020/097026 patent/WO2021253376A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109689065A (en) * | 2016-06-24 | 2019-04-26 | 埃默里大学 | For treating the phosphinylidyne aminate of hepatitis type B virus |
WO2018033139A1 (en) * | 2016-08-19 | 2018-02-22 | 正大天晴药业集团股份有限公司 | Preparation method for chiral phosphate ester |
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 |
CN111087421A (en) * | 2019-12-24 | 2020-05-01 | 南京正大天晴制药有限公司 | Preparation method of phosphamide compound for chiral drug synthesis |
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