WO2012055350A1 - 一种福沙那韦衍生物的制备方法及相关中间体 - Google Patents
一种福沙那韦衍生物的制备方法及相关中间体 Download PDFInfo
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- WO2012055350A1 WO2012055350A1 PCT/CN2011/081322 CN2011081322W WO2012055350A1 WO 2012055350 A1 WO2012055350 A1 WO 2012055350A1 CN 2011081322 W CN2011081322 W CN 2011081322W WO 2012055350 A1 WO2012055350 A1 WO 2012055350A1
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- salt
- ion source
- formula
- sodium
- potassium
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- 238000002360 preparation method Methods 0.000 title abstract description 16
- MLBVMOWEQCZNCC-OEMFJLHTSA-N fosamprenavir Chemical class C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 MLBVMOWEQCZNCC-OEMFJLHTSA-N 0.000 title abstract 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 229910001414 potassium ion Inorganic materials 0.000 claims abstract description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910001415 sodium ion Inorganic materials 0.000 claims abstract description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 7
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 6
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims abstract description 6
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims abstract description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910001424 calcium ion Inorganic materials 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 238000010531 catalytic reduction reaction Methods 0.000 claims abstract description 5
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 4
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical class CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002147 dimethylamino group Chemical class [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims abstract description 4
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical class CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims abstract description 4
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims abstract description 4
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims abstract description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 150000002500 ions Chemical class 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 125000001664 diethylamino group Chemical class [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical class CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical group NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 3
- 239000001639 calcium acetate Substances 0.000 claims description 3
- 229960005147 calcium acetate Drugs 0.000 claims description 3
- 235000011092 calcium acetate Nutrition 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical group [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical class CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical class CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 150000005332 diethylamines Chemical class 0.000 abstract 1
- 150000003947 ethylamines Chemical class 0.000 abstract 1
- 229960004592 isopropanol Drugs 0.000 abstract 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 abstract 1
- -1 tetrahydro-3-furanyl Chemical group 0.000 description 17
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 15
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 14
- 239000000203 mixture Substances 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000011575 calcium Substances 0.000 description 9
- 229910052791 calcium Inorganic materials 0.000 description 9
- YNTOKMNHRPSGFU-UHFFFAOYSA-N n-Propyl carbamate Chemical compound CCCOC(N)=O YNTOKMNHRPSGFU-UHFFFAOYSA-N 0.000 description 9
- 125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 description 9
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- XQKKWWCELHKGKB-UHFFFAOYSA-L calcium acetate monohydrate Chemical compound O.[Ca+2].CC([O-])=O.CC([O-])=O XQKKWWCELHKGKB-UHFFFAOYSA-L 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- QAGXLSHSYNBWNS-UHFFFAOYSA-N (2-methylpropylamino)-(1-phenyl-3-phosphonooxybutan-2-yl)carbamic acid Chemical compound CC(C)CNN(C(CC1=CC=CC=C1)C(C)OP(=O)(O)O)C(=O)O QAGXLSHSYNBWNS-UHFFFAOYSA-N 0.000 description 2
- 229910001413 alkali metal ion Inorganic materials 0.000 description 2
- 229960001830 amprenavir Drugs 0.000 description 2
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 229940122440 HIV protease inhibitor Drugs 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940067460 calcium acetate monohydrate Drugs 0.000 description 1
- PMDQGYMGQKTCSX-HQROKSDRSA-L calcium;[(2r,3s)-1-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-[[(3s)-oxolan-3-yl]oxycarbonylamino]-4-phenylbutan-2-yl] phosphate Chemical compound [Ca+2].C([C@@H]([C@H](OP([O-])([O-])=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 PMDQGYMGQKTCSX-HQROKSDRSA-L 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000004030 hiv protease inhibitor Substances 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229940113354 lexiva Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000013022 venting Methods 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
Definitions
- the invention relates to the technical field of flavanavir derivatives, in particular to the technical field of preparation of flavanavir derivatives, in particular to a preparation method of a fosanavir derivative and related intermediates. Background technique
- Fasanavir calcium trade name: LEXIVA, chemical name: [(3S)-oxe-3-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl- a calcium salt of (2-methylpropyl)amino]p-phenyl-3-phosphoryloxy-butan-2-yl]carbamate having the formula: wherein X is a calcium ion:
- Fosanavir calcium is a prodrug of the HIV protease inhibitor Amprenavir (APV, Agenerase), developed by GlaxoSmithKline (GSK) and Vertex Pharmaceuticals to phosphorylate APV into calcium.
- AAV HIV protease inhibitor
- GSK GlaxoSmithKline
- Vertex Pharmaceuticals to phosphorylate APV into calcium.
- the salt its solubility in water at 25 ° C is increased from 0.04 mg / ml to 100 mg / ml, which is convenient for absorption in the gastrointestinal tract and rapidly converted into ATV.
- the US FDA approved the release of 700mg tablets (excluding calcium salts).
- 50mg/ml of oral suspension was approved (excluding calcium salt).
- WO2000004033 Method for the preparation of fosavana calcium: treatment of (3S) tetrahydro-3-furanyl (lS, 2R)-3-[[(4-nitrophenyl)-sulfonyl) with a palladium on carbon catalyst ] (isobutyl)amino-1-benzyl-2-(phosphonooxy)propyl-carbamate, reacted with hydrogen at room temperature, washed with filtration, added with acetic acid 4 Torr, cooled and crystallized, filtered Wash and vacuum dry.
- WO2000004033 also reports the preparation of fosannavir sodium: (3S) tetrahydro-3-furanyl (lS, 2R)-3-[[(4-nitrophenyl)-sulfonyl] (isobutyl) Amino-1-benzyl-2-(phosphonooxy)propyl-carbamate, reacted with sodium hydroxide, reacted with hydrogen at room temperature, filtered and washed, then added with calcium acetate, cooled and crystallized, filtered Wash and vacuum dry.
- the object of the present invention is to overcome the above disadvantages of the prior art, to provide a preparation method of a fosanavir derivative and related intermediates, and the preparation method of the fosanavir derivative saves cost and improves productivity , suitable for large-scale promotion and application.
- a derivative of fosannavir is provided a preparation method, which comprises reacting a compound of the formula II or an ammonium salt thereof with a metal ion source in a solvent to obtain a compound of the formula III, and then catalytically reducing the compound of the formula III to the formula I Compound,
- X is a metal ion
- m represents a valence of the metal ion
- m*n 2.
- the metal ion source is a 4 ⁇ ion source, a sodium ion source or a potassium ion source
- the X is 4 ⁇ ions, sodium ions or potassium ions
- the solvent is methanol, ethanol, n-propanol, and different Propanol, n-butanol or sec-butanol.
- the source of calcium ions is tetrahydroacetic acid
- the source of sodium ions is sodium hydrogencarbonate, sodium carbonate, sodium acetate or sodium hydroxide
- the source of potassium ions is potassium hydrogencarbonate, potassium carbonate or potassium hydroxide.
- the catalytic reduction is carried out using hydrogen as a reducing agent under a palladium carbon catalyst.
- the ammonium salt thereof is monomethylamine salt, dimethylamine salt, monoethylamine salt, diethylamine salt, isopropylamine salt, di-n-butylamine salt, dipropylamine salt, tert-butylamine salt or dicyclohexyl group. Amine salt.
- the compound of formula I is 4-bend (3S)tetrahydro-3-furanyl (lS,2R)-3-[[(4-aminophenyl)-sulfonyl] (isobutyl) Amino-1-benzyl-2-(phosphonooxy)propyl-carbamate, sodium (3S) tetrahydro-3-furanyl (lS,2R)-3-[[(4-amino) Phenyl)-sulfonyl](isobutyl)aminobenzylidene-2-(phosphonooxy)propyl-carbamate or potassium(3S)tetrahydro-3-furanyl (lS,2R) -3-[[(4-Aminophenyl)-sulfonyl](isobutyl)amino-1-benzyl-2-(phosphonooxy)propyl-carbamate.
- an intermediate for the preparation of a fosnavir derivative characterized in that the intermediate has the structural formula shown by the following formula III:
- the present invention reacts a compound represented by the formula or its ammonium salt with a metal ion source in a solvent to obtain a compound of the formula III, and catalytically reduces the compound of the formula III after separation or purification.
- a compound of the formula I the cost is saved, the yield is improved, and it is suitable for large-scale application.
- the dry product is dissolved in 120 ml of propanol and 0.2 g of O% Pd/C.
- the autoclave is closed, firstly replaced with nitrogen three times, then replaced with hydrogen three times, the hydrogen pressure is raised to l.OMpa, hydrogen is passed at room temperature for 24 hours, until the reaction is complete, venting
- the material was taken out, filtered, and the filtrate was concentrated under reduced pressure for 60 ml. Then, the mixture was poured into 100 ml of water at room temperature and crystallized.
- the present invention gives a compound of the formula II or an amine salt thereof such as monomethylamine salt, dimethylamine salt, monoethylamine salt, diethylamine salt, isopropylamine salt, di-n-butylamine salt, dipropylamine salt, tert-butylamine salt or Dicyclohexylamine salt, dissolved in a suitable solvent such as methanol, ethanol, propanol, isopropanol or industrial methylated alcohol, and added to an aqueous solution and an alkali metal ion source such as calcium acetate, sodium hydroxide, potassium hydroxide,
- X is an alkali metal ion such as calcium ion, sodium ion, potassium ion, catalytic reduction in the presence of a suitable reducing agent such as hydrogen and a palladium on carbon catalyst.
- the preparation method of the fosanavir derivative of the invention saves the cost, improves the yield, and is suitable for large-scale popularization and application.
- the invention has been described with reference to specific embodiments thereof. However, it is apparent that various modifications and changes can be made without departing from the spirit and scope of the invention. Accordingly, the specification and drawings are to be regarded as
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- 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种福沙那韦衍生物的制备方法,将式II所示的化合物或其铵盐在溶剂中与金属离子源反应得到式III所示的化合物,分离或提纯后,将式III所示的化合物催化还原为式I所示的化合物,其中,X是金属离子,较佳地,金属离子源是钙离子源、钠离子源或钾离子源,X是钙离子、钠离子或钾离子,溶剂是甲醇、乙醇、正丙醇、异丙醇、正丁醇或仲丁醇,催化还原是在钯碳催化剂下以氢作为还原剂进行的,其铵盐是一甲胺盐、二甲胺盐、一乙胺盐、二乙胺盐、异丙胺盐、二正丁胺盐、二丙胺盐、叔丁胺盐或二环己基胺盐,还提供了福沙那韦衍生物的制备方法相关的中间体,本发明的福沙那韦衍生物的制备方法节约了成本,提高了产率,适于大规模推广应用。
Description
一种福沙那韦衍生物的制备方法及相关中间体 本申请要求于 2010 年 10 月 29 日提交中国专利局、 申请号为 201010525670.7、 发明名称为"一种福沙那韦衍生物的制备方法及相关中间体" 的中国专利申请的优先权, 其全部内容通过引用结合在本申请中。 技术领域
本发明涉及福沙那韦衍生物技术领域,特别涉及福沙那韦衍生物的制备技 术领域, 具体是指一种福沙那韦衍生物的制备方法及相关中间体。 背景技术
福沙那韦钙, 商品名: LEXIVA , 化学名: [(3S)-氧杂环戊 -3-基] N-[(2S,3R)-4-[(4-氨基苯基)磺酰 -(2-甲基丙基)氨基]小苯基 -3-磷酰氧基 -丁烷 -2- 基]氨基甲酸酯钙盐, 其结构式如下式 I所示, 其中 X为钙离子:
福沙那韦钙是 HIV蛋白酶抑制剂安普那韦 ( Amprenavir, APV, Agenerase ) 的前体药, 由葛兰素史克(GSK )公司与 Vertex制药公司合作开发, 将 APV 磷酸化再制成钙盐, 其在 25°C水中溶解度由 0.04mg/ml提高至 100mg/ml, 便 于胃肠道吸收,迅速转化为 ATV。 2003年 10月 20日美国 FDA批准片剂 700mg (不计钙盐)上市, 2007年 6月 14日批准混悬口服液 50mg/ml (不计钙盐)。 未经治疗的成人患者, 口服 FPV1400mg, bid或 FPV1400mg加服 RTV200mg, qd: 有治疗史的患者, FPV1400mg加 RTV200mg, bid。 FPV至今在欧盟、 南
美和非洲 30多个国家批准上市, 临床用于 HIV感染和 AIDS的治疗。 品种专 利 ZL99810838.3于 2019年 7月 15日期满。 PCT专利 WO2000004033对福沙 那韦钙的晶形以及制备过程作了报道。
WO2000004033 所报道的福沙那韦钙的制备方法: 用碳载钯催化剂处理 (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-硝基苯基) -磺酰基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙基-氨基甲酸酯, 在室温下与氢气反应, 过滤洗涤后, 加入乙 酸 4丐, 冷却结晶, 过滤洗涤, 真空干燥。 申请人根据其提供的方法制备, 产率 在 78-79%, 成本高, 产率低。
WO2000004033 还报道了福沙那韦钠的制备方法: (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-硝基苯基) -磺酰基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙基-氨 基甲酸酯, 与氢氧化钠反应后, 在室温下与氢气反应, 过滤洗涤后, 加入乙酸 钙, 冷却结晶, 过滤洗涤, 真空干燥。 申请人根据其提供的方法制备, 产率在 77-79%, 成本高, 产率低。
而且钠 (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-硝基苯基) -磺酰基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙基-氨基甲酸酯溶于水和乙醇, 钙 (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-硝基苯基) -磺酰基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙基-氨 基甲酸酯在水或乙醇中的溶解度极小。 因此, 需要提供一种新的福沙那韦衍生物的制备方法, 其可以节约成本, 提高产率。 发明内容
本发明的目的是克服了上述现有技术中的缺点,提供一种福沙那韦衍生物 的制备方法及相关中间体, 该福沙那韦衍生物的制备方法节约了成本,提高了 产率, 适于大规模推广应用。
为了实现上述目的,在本发明的第一方面,提供了一种福沙那韦衍生物的
制备方法, 其特点是, 将式 II所示的化合物或其铵盐在溶剂中与金属离子源 反应得到式 III所示的化合物, 然后将式 III所示的化合物催化还原为式 I所示 的化合物,
其中, 所述 X是金属离子, m表示金属离子的价数, m*n=2。
较佳地, 所述金属离子源是 4丐离子源、 钠离子源或钾离子源, 所述 X是 4丐 离子、 钠离子或钾离子, 所述溶剂是甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇或 仲丁醇。
更佳地, 所述钙离子源是乙酸 4丐, 所述钠离子源是碳酸氢钠、 碳酸钠、 醋 酸钠或氢氧化钠, 所述钾离子源是碳酸氢钾、 碳酸钾或氢氧化钾。
较佳地, 所述催化还原是在钯碳催化剂下以氢作为还原剂进行的。
较佳地, 所述其铵盐是一甲胺盐、 二甲胺盐、 一乙胺盐、 二乙胺盐、 异丙 胺盐、 二正丁胺盐、 二丙胺盐、 叔丁胺盐或二环己基胺盐。
更佳地, 所述式 I所示的化合物是 4弓 (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-氨基 苯基) -磺酰基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙基-氨基甲酸酯、 钠 (3S) 四氢 -3-呋喃基 (lS,2R)-3-[[(4-氨基苯基) -磺酰基] (异丁基)氨基小苯甲基 -2- (膦 酰氧基)丙基-氨基甲酸酯或钾 (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-氨基苯基) -磺酰 基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙基-氨基甲酸酯。
在本发明的第二方面,提供了一种制备福沙那韦衍生物的中间体, 其特点 是, 所述中间体具有如下式 III所示的结构式:
III,
其中, 所述 X是 4丐离子, m为 2, n为 1。
本发明的有益效果具体在于:本发明将式 Π所示的化合物或其铵盐在溶剂 中与金属离子源反应得到式 III所示的化合物,分离或提纯后将式 III所示的化 合物催化还原为式 I所示的化合物, 节约了成本, 提高了产率, 适于大规模推 广应用。 具体实施方式
为了能够更清楚地理解本发明的技术内容,特举以下实施例详细说明。但 是应当理解, 这些描述只是进一步说明本发明的特征和优点, 而不是对本发明 权利要求的限制。 实施例 1
15g (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-氨基苯基) -磺酰基] (异丁基)氨基小 苯甲基 -2- (膦酰氧基)丙基-氨基甲酸酯溶于 45ml甲醇, 并加热至 55°C , 滴加入 4.2g乙酸 4弓一水化合物和 150ml水组成的混合液, 滴加结束后, 在 55°C保温 半小时, 冷却至 20°C , 过滤烘干。
干品溶于 200ml甲醇, 加入 0.3gl0%Pd/C, 将此混合物在氢气中搅拌 20 小时。 将催化剂滤出。
滤液减压浓缩剩余 100ml后, 室温下滴入 150ml水中析晶, 滴毕, 室温搅 拌半小时后过滤,真空干燥得 13.2g钙 (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-氨基苯 基) -磺酰基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙基-氨基甲酸酯。 收率: 89.34% 实施例
在洁净干燥的 250ml 四口烧瓶中, 投入 10g(3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-氨基苯基) -磺酰基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙基-氨 基甲酸酯, 加入 30ml无水乙醇溶解, 并加热至 50°C , 滴加入 2.8g 乙酸钠和 100ml水组成的混合液, 滴加结束后, 在 50°C保温半小时,保温毕, 水浴 60°C 减压蒸去溶剂至干, 加入 100ml甲基叔丁基醚打浆析晶, 过滤烘干。
在洁净干燥的高压釜中, 投入烘干物质、 120ml甲醇和 0.2glO%Pd/C, 关 闭高压釜, 先氮气置换三次, 再用氢气置换三次, 升高氢气压力至 l.OMpa, 室温下通氢 24小时, 直至化合物 2反应完全, 放空, 取出物料, 过滤, 滤液 减压浓缩至干, 加入异丙醇 60ml加热至回流溶解 10分钟后, 冷却至室温, 再 冷却至 0 ~ 5°C保温 1 小时, 过滤, 真空干燥得 7.30g 钠 (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-氨基苯基) -磺酰基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙基-氨 基甲酸酯, 收率: 88.35 %。 实施例 3
10.5g (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-硝基苯基) -磺酰基] (异丁基)氨基小 苯甲基 -2- (膦酰氧基)丙基-氨基甲酸酯的二乙胺盐(Π ), 溶于 30ml无水乙醇, 并加热至 50°C , 滴加入 2.8g乙酸钙一水化合物和 100ml水组成的混合液, 滴
加结束后, 在 50°C保温半小时, 再冷却至室温, 过滤烘干。
干品溶于 120ml丙醇和 0.2glO%Pd/C, 关闭高压釜, 先氮气置换三次, 再 用氢气置换三次, 升高氢气压力至 l.OMpa, 室温下通氢 24小时, 直至反应完 全, 放空, 取出物料, 过滤, 滤液减压浓缩剩余 60ml后, 室温下滴入 100ml 水中析晶, 滴毕, 室温搅拌半小时后过滤, 真空干燥得 8.9g钙 (3S)四氢 -3-呋 喃基 (lS,2R)-3-[[(4-氨基苯基) -磺酰基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙 基-氨基甲酸酯, 收率: 90.23%。 实施例 4
在洁净干燥的 250ml 四口烧瓶中, 投入 10g (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-硝基苯基) -磺酰基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙基-氨 基甲酸酯(Π ), 加入 30ml甲醇溶解, 并加热至 50°C , 滴加入 2.8g乙酸 4丐一水 化合物和 100ml水组成的混合液, 滴加结束后, 在 50保温半小时, 再冷却至 20 °C , 过滤。
烘干得 8.3g钙 (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-硝基苯基) -磺酰基] (异丁基) 氨基 -1-苯甲基 -2- (膦酰氧基)丙基 -氨基甲酸酯 (III), 收率: 96.74%。 实施例 5
在洁净干燥的 250ml 四口烧瓶中, 投入 10g(3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-硝基苯基) -磺酰基] (异丁基)氨基 -1-苯甲基 -2- (膦酰氧基)丙基-氨 基甲酸酯( II ) , 加入 30ml无水乙醇溶解, 并加热至 55 °C , 滴加入 2.0g乙酸钠 和 100ml水组成的混合液, 滴加结束后, 在 55°C保温半小时, 保温毕, 水浴 60°C减压蒸去溶剂至干, 加入 100ml甲基叔丁基醚打浆析晶, 过滤。
烘干得 8g钠 (3S)四氢 -3-呋喃基 (lS,2R)-3-[[(4-硝基苯基) -磺酰基] (异丁基) 氨基 -1-苯甲基 -2- (膦酰氧基)丙基 -氨基甲酸酯 (III), 收率: 92.41%。
本发明将式 II所示的化合物或其胺盐如一甲胺盐、 二甲胺盐、 一乙胺盐、 二乙胺盐、 异丙胺盐、 二正丁胺盐、 二丙胺盐、 叔丁胺盐或二环己基胺盐, 溶 解在合适的溶剂中如甲醇、 乙醇、 丙醇、 异丙醇或工业甲基化酒精, 并加入水 溶液和碱金属离子源如乙酸钙、 氢氧化钠、 氢氧化钾, 反应得到式 III所示的化 合物, 其中 X为碱金属离子如钙离子、 钠离子、 钾离子, 在合适的还原剂(如 氢)和碳载钯催化剂的存在下, 催化还原。
综上, 本发明的福沙那韦衍生物的制备方法节约了成本, 提高了产率, 适 于大规模推广应用。 在此说明书中, 本发明已参照其特定的实施例作了描述。 但是, 艮显然仍 可以作出各种修改和变换而不背离本发明的精神和范围。 因此,说明书和附图 应被认为是说明性的而非限制性的。
Claims
1、 一种福沙那韦衍生物的制备方法, 其特征在于, 将式 II所示的化合物 或其铵盐在溶剂中与金属离子源反应得到式 m所示的化合物, 分离或提纯后, 将式 m所示的化合物催化还原为式 I所示的化合物,
III,
I,
其中, 所述 X是金属离子, m表示金属离子的价数, m*n=2。
2、根据权利要求 1所述的福沙那韦衍生物的制备方法, 其特征在于, 所述 金属离子源是 4丐离子源、 钠离子源或钾离子源, 所述 X是 4丐离子、 钠离子或钾 离子, 所述溶剂是甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇或仲丁醇。
3、 根据权利要求 2所述的福沙那韦衍生物的制备方法, 其特征在于, 所述 钙离子源是乙酸钙, 所述钠离子源是碳酸氢钠、 碳酸钠、 醋酸钠或氢氧化钠, 所述钾离子源是碳酸氢钾、 碳酸钾或氢氧化钾。
4、 根据权利要求 1所述的福沙那韦衍生物的制备方法, 其特征在于, 所述 催化还原是在钯碳催化剂下以氢作为还原剂进行的。
5、根据权利要求 1所述的福沙那韦衍生物的制备方法, 其特征在于, 所述 其铵盐是一甲胺盐、二甲胺盐、 一乙胺盐、二乙胺盐、异丙胺盐、二正丁胺盐、 二丙胺盐、 叔丁胺盐或二环己基胺盐。
6、 一种制备福沙那韦衍生物的中间体, 其特征在于, 所述中间体具有如 下式 III所示的结构式:
III,
其中, 所述 X是 4丐离子, m为 2, n为 1。
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WO2000004033A1 (en) | 1998-07-18 | 2000-01-27 | Glaxo Group Limited | Calcium (3s) tetrahydro-3-furanyl(1s,2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -1-benzyl-2- (phosphonooxy) propylcarbamate |
WO2011033469A1 (en) * | 2009-09-16 | 2011-03-24 | Ranbaxy Laboratories Limited | Process for the preparation of fosamprenavir calcium |
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WO2000004033A1 (en) | 1998-07-18 | 2000-01-27 | Glaxo Group Limited | Calcium (3s) tetrahydro-3-furanyl(1s,2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -1-benzyl-2- (phosphonooxy) propylcarbamate |
CN1324363A (zh) * | 1998-07-18 | 2001-11-28 | 葛兰素集团有限公司 | 钙(3s)四氢-3-呋喃基(1s,2r)-3-[[(4-氨基苯基)磺酰基](异丁基)氨基]-1-苯甲基-2-(膦酰氧基)丙基氨基甲酸酯 |
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ANONYMOUSLY: "Crystalline form of diethylamine salt and calcium salt of (S)-tetrahydrofuran-3-yl (2S,3R)-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenyl-3-(phosphonooxy)butan-2-ylcarbamate (IPCOM000202279D)", IP.COM, 13 December 2010 (2010-12-13), XP013142973 * |
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