WO2015003670A1 - A new process for the preparation of elvitegravir - Google Patents
A new process for the preparation of elvitegravir Download PDFInfo
- Publication number
- WO2015003670A1 WO2015003670A1 PCT/CZ2014/000076 CZ2014000076W WO2015003670A1 WO 2015003670 A1 WO2015003670 A1 WO 2015003670A1 CZ 2014000076 W CZ2014000076 W CZ 2014000076W WO 2015003670 A1 WO2015003670 A1 WO 2015003670A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- elvitegravir
- reaction
- converted
- production
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 229960003586 elvitegravir Drugs 0.000 title claims abstract description 17
- JUZYLCPPVHEVSV-LJQANCHMSA-N elvitegravir Chemical compound COC1=CC=2N([C@H](CO)C(C)C)C=C(C(O)=O)C(=O)C=2C=C1CC1=CC=CC(Cl)=C1F JUZYLCPPVHEVSV-LJQANCHMSA-N 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- IJTJIJAEHBQGSI-UHFFFAOYSA-M [Br-].FC1=C(Cl)C=CC=C1C[Zn+] Chemical compound [Br-].FC1=C(Cl)C=CC=C1C[Zn+] IJTJIJAEHBQGSI-UHFFFAOYSA-M 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 3
- 150000001298 alcohols Chemical class 0.000 claims abstract 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract 2
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000011260 aqueous acid Substances 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 239000003223 protective agent Substances 0.000 claims 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229940126656 GS-4224 Drugs 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000002081 enamines Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NDVMCQUOSYOQMZ-UHFFFAOYSA-N 2,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)C(C(N)=O)[Si](C)(C)C NDVMCQUOSYOQMZ-UHFFFAOYSA-N 0.000 description 2
- GPVDHNVGGIAOQT-UHFFFAOYSA-N 2,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)[C@@](COC1OCCCC1)N(C=C(C(O)=O)C(C1=CC2(C)CC(C=CC)=C(*(Cl)=C)F)=O)C1=CC2F Chemical compound CC(C)[C@@](COC1OCCCC1)N(C=C(C(O)=O)C(C1=CC2(C)CC(C=CC)=C(*(Cl)=C)F)=O)C1=CC2F 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 238000006411 Negishi coupling reaction Methods 0.000 description 2
- 241000208125 Nicotiana Species 0.000 description 2
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- -1 e.g. Chemical group 0.000 description 2
- 150000001261 hydroxy acids Chemical class 0.000 description 2
- NWYYWIJOWOLJNR-RXMQYKEDSA-N l-valinol Chemical group CC(C)[C@H](N)CO NWYYWIJOWOLJNR-RXMQYKEDSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- MYNDRZPWXNINHJ-UHFFFAOYSA-N prop-2-enoyl benzoate Chemical compound C=CC(=O)OC(=O)C1=CC=CC=C1 MYNDRZPWXNINHJ-UHFFFAOYSA-N 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- DTYLXDLAOLOTKT-UHFFFAOYSA-N 1,4-dihydroquinoline-3-carboxylic acid Chemical compound C1=CC=C2CC(C(=O)O)=CNC2=C1 DTYLXDLAOLOTKT-UHFFFAOYSA-N 0.000 description 1
- HYILLTADABKYHO-UHFFFAOYSA-N 1-(bromomethyl)-3-chloro-2-fluorobenzene Chemical compound FC1=C(Cl)C=CC=C1CBr HYILLTADABKYHO-UHFFFAOYSA-N 0.000 description 1
- VQTDPCRSXHFMOL-UHFFFAOYSA-N 2,4-Dimethoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C(OC)=C1 VQTDPCRSXHFMOL-UHFFFAOYSA-N 0.000 description 1
- NJYBIFYEWYWYAN-UHFFFAOYSA-N 2,4-difluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1F NJYBIFYEWYWYAN-UHFFFAOYSA-N 0.000 description 1
- NOXAMEMDEVPGFM-UHFFFAOYSA-N 2-(5-bromo-2,4-dimethoxybenzoyl)-3-(dimethylamino)prop-2-enoic acid Chemical compound COC1=CC(OC)=C(C(=O)C(=CN(C)C)C(O)=O)C=C1Br NOXAMEMDEVPGFM-UHFFFAOYSA-N 0.000 description 1
- WITZNUZCSIOXLE-UHFFFAOYSA-N 3-benzyl-1h-quinolin-2-one Chemical class O=C1NC2=CC=CC=C2C=C1CC1=CC=CC=C1 WITZNUZCSIOXLE-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YAFWVDSOUGAFCM-YDYLCMSLSA-N CC(C)[C@@H](CO)N(C(C)(C1)C2C(C)C(Br)=C1OC)C=C(C(O)=O)C2=O Chemical compound CC(C)[C@@H](CO)N(C(C)(C1)C2C(C)C(Br)=C1OC)C=C(C(O)=O)C2=O YAFWVDSOUGAFCM-YDYLCMSLSA-N 0.000 description 1
- TXVCFUAPUFPKKR-LJQANCHMSA-N CC(C)[C@@H](CO)N(C=C1C(O)=O)c2cc(OC)c(Cc(cccc3N)c3F)cc2C1=O Chemical compound CC(C)[C@@H](CO)N(C=C1C(O)=O)c2cc(OC)c(Cc(cccc3N)c3F)cc2C1=O TXVCFUAPUFPKKR-LJQANCHMSA-N 0.000 description 1
- XWJKGGXWGHAIJZ-SCFJQAPRSA-N CC/C=C\C=C(/C)\Cl Chemical compound CC/C=C\C=C(/C)\Cl XWJKGGXWGHAIJZ-SCFJQAPRSA-N 0.000 description 1
- LAEIOAFROOJHPM-UHFFFAOYSA-N COC1=CC(OC)=C(C(=O)C(=CNC(CO)C(C)C)C(O)=O)C=C1Br Chemical compound COC1=CC(OC)=C(C(=O)C(=CNC(CO)C(C)C)C(O)=O)C=C1Br LAEIOAFROOJHPM-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- GMVIQOCPXTZUFJ-UHFFFAOYSA-L dipotassium;2-ethylpropanedioate Chemical compound [K+].[K+].CCC(C([O-])=O)C([O-])=O GMVIQOCPXTZUFJ-UHFFFAOYSA-L 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention relates to an improved process for the production of elvitegravir
- the carbonate reacts, in the presence of an organopalladium catalyst, with 3-chloro-2- fluorobenzyl zinc bromide (11) (prepared from 3-chloro-2-fluorobenzyl bromide (10) in the conditions of Negishi coupling) producing the protected benzyl quinolone derivative 12a.
- 3-chloro-2- fluorobenzyl zinc bromide (11) prepared from 3-chloro-2-fluorobenzyl bromide (10) in the conditions of Negishi coupling
- This is, in the next step, subjected to alkaline deprotection to the intermediate 13, which is, in the final step, subjected to reaction with sodium methoxide providing the end product elvitegravir (Scheme 1).
- Patent application WO 2011/004389 of Matrix Laboratories describes a synthetic procedure analogous to the method of the basic patent, using protection of the hydroxyl with the tetrahydropyranyl group (Scheme 3).
- the hydroxyl group of the enamine 22 is, in the next step, protected by a reaction with tert-butyldimethylsilyl chloride and the resulting 23 is subsequently cycled to the protected quinolone derivative 24.
- both hydrolysis of the ethyl ester and removal of the protecting TBDMS group are performed (Scheme 4).
- This invention provides an improved process for the production of elvitegravir of formula I,
- a suitable catalyst e.g. a palladium catalyst.
- the purity of the intermediate Ila according to HPLC generally exceeds 99%.
- the general protecting group PG may be, e.g., the trimethylsilyl group or other protecting groups suitable for protection of an oxygen atom, e.g., di-t-butyldimethylsilyl, benzyl, tetrahydropyranyl, tetrahydrofuranyl, others being mentioned, e.g,. in Protective Groups in Organic Synthesis, Third Edition. Theodora W. Greene, Peter G.M. Wuts, John Wiley, 1999. The compounds V and VII conveniently need not be isolated.
- elvitegravir is obtained by easy removal of the protecting groups - the protecting group on the carbonyl function is removed with water, alcohol; the protecting group on the hydroxyl is removed by reaction with a diluted aqueous acid or water at an elevated temperature. Alternatively, the deprotection can be carried out at the room temperature.
- PdCl 2 (PPh 3 ) 2 39 mg was added as a catalyst and 10 ml of a solution of 3-chloro-2- fluorobenzyl zinc bromide in tetrahydrofuran (0.5 M) was added at 60°C during 1 h; the mixture was further heated up at 60°C for 1.5 h.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201480038026.3A CN105377818B (zh) | 2013-07-11 | 2014-07-03 | 用于制备埃替拉韦的新方法 |
| HU1600128A HUP1600128A2 (en) | 2013-07-11 | 2014-07-03 | A new process for the preparation of elvitegravir |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZPV2013-544 | 2013-07-11 | ||
| CZ2013-544A CZ307255B6 (cs) | 2013-07-11 | 2013-07-11 | Nový způsob přípravy elvitegraviru |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2015003670A1 true WO2015003670A1 (en) | 2015-01-15 |
Family
ID=51229772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CZ2014/000076 WO2015003670A1 (en) | 2013-07-11 | 2014-07-03 | A new process for the preparation of elvitegravir |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN105377818B (cs) |
| CZ (1) | CZ307255B6 (cs) |
| HU (1) | HUP1600128A2 (cs) |
| WO (1) | WO2015003670A1 (cs) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315203A (zh) * | 2014-06-06 | 2016-02-10 | 上海迪赛诺化学制药有限公司 | 一种v型埃替拉韦晶体及其制备方法 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004046115A1 (ja) | 2002-11-20 | 2004-06-03 | Japan Tobacco Inc. | ４−オキソキノリン化合物及びそのｈｉｖインテグラーゼ阻害剤としての利用 |
| WO2005113509A1 (en) * | 2004-05-20 | 2005-12-01 | Japan Tobacco Inc. | Novel 4-oxoquinoline compound and use thereof as hiv integrase inhibitor |
| US20090318702A1 (en) * | 2006-03-06 | 2009-12-24 | Koji Matsuda | Process for production of 4-oxoquinoline compound |
| US7825252B2 (en) | 2006-09-12 | 2010-11-02 | Gilead Sciences, Inc. | Process and intermediates for preparing integrase inhibitors |
| WO2011004389A2 (en) | 2009-06-18 | 2011-01-13 | Matrix Laboratories Ltd | An improved process for the preparation of elvitegravir |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ304983B6 (cs) * | 2012-10-12 | 2015-03-11 | Zentiva, K.S. | Způsob výroby a nové intermediáty syntézy elvitegraviru |
| CZ304984B6 (cs) * | 2012-10-12 | 2015-03-11 | Zentiva, K.S. | Zlepšený způsob výroby a nové intermediáty syntézy elvitegraviru |
-
2013
- 2013-07-11 CZ CZ2013-544A patent/CZ307255B6/cs not_active IP Right Cessation
-
2014
- 2014-07-03 WO PCT/CZ2014/000076 patent/WO2015003670A1/en active Application Filing
- 2014-07-03 CN CN201480038026.3A patent/CN105377818B/zh not_active Expired - Fee Related
- 2014-07-03 HU HU1600128A patent/HUP1600128A2/hu unknown
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004046115A1 (ja) | 2002-11-20 | 2004-06-03 | Japan Tobacco Inc. | ４−オキソキノリン化合物及びそのｈｉｖインテグラーゼ阻害剤としての利用 |
| EP1564210A1 (en) | 2002-11-20 | 2005-08-17 | Japan Tobacco Inc. | 4-oxoquinoline compounds and utilization thereof as hiv integrase inhibitors |
| US7176220B2 (en) | 2002-11-20 | 2007-02-13 | Japan Tobacco Inc. | 4-oxoquinoline compound and use thereof as pharmaceutical agent |
| WO2005113509A1 (en) * | 2004-05-20 | 2005-12-01 | Japan Tobacco Inc. | Novel 4-oxoquinoline compound and use thereof as hiv integrase inhibitor |
| US20090318702A1 (en) * | 2006-03-06 | 2009-12-24 | Koji Matsuda | Process for production of 4-oxoquinoline compound |
| US7825252B2 (en) | 2006-09-12 | 2010-11-02 | Gilead Sciences, Inc. | Process and intermediates for preparing integrase inhibitors |
| WO2011004389A2 (en) | 2009-06-18 | 2011-01-13 | Matrix Laboratories Ltd | An improved process for the preparation of elvitegravir |
Non-Patent Citations (1)
| Title |
|---|
| THEODORA W. GREENE; PETER G.M WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY |
Also Published As
| Publication number | Publication date |
|---|---|
| CZ307255B6 (cs) | 2018-05-02 |
| CZ2013544A3 (cs) | 2015-01-21 |
| HUP1600128A2 (en) | 2016-07-28 |
| CN105377818B (zh) | 2018-03-30 |
| CN105377818A (zh) | 2016-03-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101486637B1 (ko) | 로슈바스타틴칼슘 중간생성물 및 그 제조방법 | |
| CA2878699C (en) | Process and intermediates for preparing integrase inhibitors | |
| JP2003535077A (ja) | インドール誘導体を製造する方法、および該方法の中間体 | |
| WO2012140490A2 (en) | Process for preparing quinoline derivative | |
| JP5095945B2 (ja) | ４−トリフルオロメチルニコチン酸又はその塩の製造方法 | |
| WO2015003670A1 (en) | A new process for the preparation of elvitegravir | |
| EP1251123B1 (en) | Process for preparing quinolylacrylonitrile and intermediates therefor | |
| JP2004524260A (ja) | シンバスタチンの改善された製造方法 | |
| EP2906540B1 (en) | An improved production method and new intermediates of synthesis of elvitegravir | |
| EP2906529B9 (en) | A new production method and new intermediates of synthesis of elvitegravir | |
| KR100995882B1 (ko) | 피타바스타틴 또는 그의 염의 중간체의 제조방법 | |
| KR101528359B1 (ko) | 스타틴 화합물 제조를 위한 신규한 보로네이트 에테르 화합물, 그 제조방법 및 상기 보로네이트 에테르 화합물을 이용한 스타틴 화합물 제조방법 | |
| JP3823385B2 (ja) | ２，４，５−トリフルオロ−３−ヨ−ド安息香酸およびそのエステル類の製造方法 | |
| JP5507147B2 (ja) | ピリミジニルアルコール誘導体の製造方法及びその合成中間体 | |
| JP4867071B2 (ja) | キノリン誘導体の製造方法 | |
| EP2014650A1 (en) | Process and intermediate for the production of an intermediate in the production of montelukast | |
| CA2398138C (en) | Process for the preparation of quinolylpropenal | |
| KR100843125B1 (ko) | 베타-케토에스테르 화합물의 제조방법 | |
| KR20120059148A (ko) | 피타바스타틴의 제조를 위한 키랄 중간체의 제조방법 | |
| JP4831897B2 (ja) | （２，６−ジクロロピリジン−４−イル）メタノールの製造方法 | |
| KR20110134249A (ko) | 피타바스타틴 또는 그의 염의 중간체의 제조방법 | |
| CN110105354A (zh) | 一种制备丁苯那嗪的方法 | |
| WO2007086559A1 (ja) | テトラヒドロピラン化合物の製造方法 | |
| HK1147478A (en) | Process and intermediate for the production of a tertiary alcohol as an intermediate in the synthesis of montelukast | |
| HK1209748B (en) | Process and intermediates for preparing integrase inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14744432 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 14744432 Country of ref document: EP Kind code of ref document: A1 |