WO2012153162A1 - Novel method for preparation of atovaquone - Google Patents
Novel method for preparation of atovaquone Download PDFInfo
- Publication number
- WO2012153162A1 WO2012153162A1 PCT/IB2011/001507 IB2011001507W WO2012153162A1 WO 2012153162 A1 WO2012153162 A1 WO 2012153162A1 IB 2011001507 W IB2011001507 W IB 2011001507W WO 2012153162 A1 WO2012153162 A1 WO 2012153162A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- chlorophenyl
- cyclohexyl
- dihydronaphthalen
- trans
- compound
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 81
- 229960003159 atovaquone Drugs 0.000 title claims abstract description 66
- KUCQYCKVKVOKAY-CTYIDZIISA-N atovaquone Chemical compound C1([C@H]2CC[C@@H](CC2)C2=C(C(C3=CC=CC=C3C2=O)=O)O)=CC=C(Cl)C=C1 KUCQYCKVKVOKAY-CTYIDZIISA-N 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 230000008569 process Effects 0.000 claims abstract description 66
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 47
- 239000002904 solvent Substances 0.000 claims abstract description 24
- IARHYEITGOTONB-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-1-hydroxycyclohexyl]-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1CC(O)(C2C(C3=CC=CC=C3CC2)=O)CCC1C1=CC=C(Cl)C=C1 IARHYEITGOTONB-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000002841 Lewis acid Substances 0.000 claims abstract description 23
- JNBOVWFOTNYTES-UHFFFAOYSA-N 4-(4-chlorophenyl)cyclohexan-1-one Chemical compound C1=CC(Cl)=CC=C1C1CCC(=O)CC1 JNBOVWFOTNYTES-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 20
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 19
- CAUIWDWUUCGKBV-UHFFFAOYSA-N 3,4-dihydronaphthalen-1-yloxy(trimethyl)silane Chemical compound C1=CC=C2C(O[Si](C)(C)C)=CCCC2=C1 CAUIWDWUUCGKBV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000010956 selective crystallization Methods 0.000 claims abstract description 14
- 238000006317 isomerization reaction Methods 0.000 claims abstract description 9
- 238000009833 condensation Methods 0.000 claims abstract description 8
- 230000005494 condensation Effects 0.000 claims abstract description 8
- 239000007848 Bronsted acid Substances 0.000 claims abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 98
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 44
- HNGHLEVXLRASOH-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)cyclohexyl]naphthalen-1-ol Chemical compound C1=CC2=CC=CC=C2C(O)=C1C(CC1)CCC1C1=CC=C(Cl)C=C1 HNGHLEVXLRASOH-UHFFFAOYSA-N 0.000 claims description 38
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 30
- XSAGWUXGMTYHIP-UHFFFAOYSA-N 2-bromo-2-[4-(4-chlorophenyl)cyclohexyl]-3,4-dihydronaphthalen-1-one Chemical compound C1=CC(Cl)=CC=C1C1CCC(C2(Br)C(C3=CC=CC=C3CC2)=O)CC1 XSAGWUXGMTYHIP-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 18
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000001117 sulphuric acid Substances 0.000 claims description 15
- 235000011149 sulphuric acid Nutrition 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical compound [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 claims description 10
- 235000010288 sodium nitrite Nutrition 0.000 claims description 9
- 238000006297 dehydration reaction Methods 0.000 claims description 7
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- ILYPMRXBKYVKGP-UHFFFAOYSA-N 4-(4-chlorophenyl)cyclohex-3-en-1-one;ethene Chemical group C=C.C1=CC(Cl)=CC=C1C1=CCC(=O)CC1 ILYPMRXBKYVKGP-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 230000018044 dehydration Effects 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- TVVRFUOKLKGUKT-UHFFFAOYSA-N 1a,7a-dihydronaphtho[2,3-b]oxirene-2,7-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2C1O2 TVVRFUOKLKGUKT-UHFFFAOYSA-N 0.000 claims description 5
- 239000007818 Grignard reagent Substances 0.000 claims description 5
- 230000031709 bromination Effects 0.000 claims description 5
- 238000005893 bromination reaction Methods 0.000 claims description 5
- 150000004795 grignard reagents Chemical class 0.000 claims description 5
- VKRKCBWIVLSRBJ-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decan-8-one Chemical compound C1CC(=O)CCC21OCCO2 VKRKCBWIVLSRBJ-UHFFFAOYSA-N 0.000 claims description 4
- CHXRCCJFHHYDBA-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)cyclohexyl]naphthalene-1,4-dione Chemical compound C1=CC(Cl)=CC=C1C1CCC(C=2C(C3=CC=CC=C3C(=O)C=2)=O)CC1 CHXRCCJFHHYDBA-UHFFFAOYSA-N 0.000 claims description 4
- SJFRNTNMQHQMGC-UHFFFAOYSA-N 4-(4-chlorophenyl)cyclohexan-1-one;ethene Chemical group C=C.C1=CC(Cl)=CC=C1C1CCC(=O)CC1 SJFRNTNMQHQMGC-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- CDEMHJCJMMOFMB-UHFFFAOYSA-M ClC1=CC=C([Mg]Br)C=C1 Chemical compound ClC1=CC=C([Mg]Br)C=C1 CDEMHJCJMMOFMB-UHFFFAOYSA-M 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910000510 noble metal Inorganic materials 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 3
- 238000006567 deketalization reaction Methods 0.000 claims description 3
- 238000006735 epoxidation reaction Methods 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- VZHAOAUZQYXTBW-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)cyclohexen-1-yl]-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=CC(Cl)=CC=C1C1CC=C(C2C(C3=CC=CC=C3CC2)=O)CC1 VZHAOAUZQYXTBW-UHFFFAOYSA-N 0.000 claims description 2
- 229910019891 RuCl3 Inorganic materials 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims description 2
- 238000003379 elimination reaction Methods 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- WPUXXMRXJOKJRL-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)cyclohexyl]-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=CC(Cl)=CC=C1C1CCC(C2C(C3=CC=CC=C3CC2)=O)CC1 WPUXXMRXJOKJRL-UHFFFAOYSA-N 0.000 claims 3
- 239000012024 dehydrating agents Substances 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 73
- 230000015572 biosynthetic process Effects 0.000 abstract description 49
- 238000003786 synthesis reaction Methods 0.000 abstract description 47
- 229930192627 Naphthoquinone Natural products 0.000 abstract description 11
- 239000000543 intermediate Substances 0.000 abstract description 11
- 238000000926 separation method Methods 0.000 abstract description 11
- BSJMWHQBCZFXBR-UHFFFAOYSA-N 3-[4-(p-chlorophenyl)cyclohexyl]-4-hydroxy-1,2-naphthoquinone Chemical compound O=C1C(=O)C2=CC=CC=C2C(O)=C1C(CC1)CCC1C1=CC=C(Cl)C=C1 BSJMWHQBCZFXBR-UHFFFAOYSA-N 0.000 abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 30
- 239000007787 solid Substances 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 10
- -1 (4-chlorophenyl)cyclohexyl Chemical group 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 150000002791 naphthoquinones Chemical class 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000005882 aldol condensation reaction Methods 0.000 description 6
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- FRASJONUBLZVQX-UHFFFAOYSA-N 1,4-naphthoquinone Chemical compound C1=CC=C2C(=O)C=CC(=O)C2=C1 FRASJONUBLZVQX-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229910001961 silver nitrate Inorganic materials 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 150000004782 1-naphthols Chemical class 0.000 description 4
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical group C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 4
- 230000005526 G1 to G0 transition Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000011369 resultant mixture Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 229940006460 bromide ion Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- CCTJHVLTAJTPBV-UHFFFAOYSA-N 2-chloro-1,4-naphthoquinone Chemical compound C1=CC=C2C(=O)C(Cl)=CC(=O)C2=C1 CCTJHVLTAJTPBV-UHFFFAOYSA-N 0.000 description 2
- NXXDIEYTMQYWJU-UHFFFAOYSA-N 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid Chemical compound C1CC(C(=O)O)CCC1C1=CC=C(Cl)C=C1 NXXDIEYTMQYWJU-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- 239000002879 Lewis base Substances 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- HNGHLEVXLRASOH-RZDIXWSQSA-N Oc1c(ccc2ccccc12)[C@H]1CC[C@@H](CC1)c1ccc(Cl)cc1 Chemical compound Oc1c(ccc2ccccc12)[C@H]1CC[C@@H](CC1)c1ccc(Cl)cc1 HNGHLEVXLRASOH-RZDIXWSQSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- CSFWPUWCSPOLJW-UHFFFAOYSA-N hydroxynaphthoquinone Natural products C1=CC=C2C(=O)C(O)=CC(=O)C2=C1 CSFWPUWCSPOLJW-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 150000007527 lewis bases Chemical class 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000004059 quinone derivatives Chemical class 0.000 description 2
- 238000009877 rendering Methods 0.000 description 2
- 239000012056 semi-solid material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003419 tautomerization reaction Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- WOAHJDHKFWSLKE-UHFFFAOYSA-N 1,2-benzoquinone Chemical class O=C1C=CC=CC1=O WOAHJDHKFWSLKE-UHFFFAOYSA-N 0.000 description 1
- NHDODQWIKUYWMW-UHFFFAOYSA-N 1-bromo-4-chlorobenzene Chemical compound ClC1=CC=C(Br)C=C1 NHDODQWIKUYWMW-UHFFFAOYSA-N 0.000 description 1
- BFHZQEPDVMKQIZ-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)cyclohexyl]-3-pyridin-2-ylsulfanylnaphthalene-1,4-dione Chemical compound C1=CC(Cl)=CC=C1C1CCC(C=2C(C3=CC=CC=C3C(=O)C=2SC=2N=CC=CC=2)=O)CC1 BFHZQEPDVMKQIZ-UHFFFAOYSA-N 0.000 description 1
- PZQFWEVFWWOGCO-UHFFFAOYSA-N 3-(4-tert-butylcyclohexyl)-4-hydroxynaphthalene-1,2-dione Chemical compound C1CC(C(C)(C)C)CCC1C1=C(O)C2=CC=CC=C2C(=O)C1=O PZQFWEVFWWOGCO-UHFFFAOYSA-N 0.000 description 1
- 241001120493 Arene Species 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- KZNDRSRPAONOPV-UHFFFAOYSA-N O=C(C1OC11C(CC2)CCC2c(cc2)ccc2Cl)c2ccccc2C1=O Chemical compound O=C(C1OC11C(CC2)CCC2c(cc2)ccc2Cl)c2ccccc2C1=O KZNDRSRPAONOPV-UHFFFAOYSA-N 0.000 description 1
- FVAKCQBBNVFZBJ-UHFFFAOYSA-N O=C1c2ccccc2CC(C(CC2)CCC2c(cc2)ccc2Cl)=C1 Chemical compound O=C1c2ccccc2CC(C(CC2)CCC2c(cc2)ccc2Cl)=C1 FVAKCQBBNVFZBJ-UHFFFAOYSA-N 0.000 description 1
- DHSMUSOXXVRQEH-HJJRSLFLSA-N O=C1c2ccccc2CCC1C1C(C2)[C@@H]3[C@H]1[C@H]3CC2c(cc1)ccc1Cl Chemical compound O=C1c2ccccc2CCC1C1C(C2)[C@@H]3[C@H]1[C@H]3CC2c(cc1)ccc1Cl DHSMUSOXXVRQEH-HJJRSLFLSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 1
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 239000004133 Sodium thiosulphate Substances 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- 201000005485 Toxoplasmosis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- NBZANZVJRKXVBH-GYDPHNCVSA-N alpha-Cryptoxanthin Natural products O[C@H]1CC(C)(C)C(/C=C/C(=C\C=C\C(=C/C=C/C=C(\C=C\C=C(/C=C/[C@H]2C(C)=CCCC2(C)C)\C)/C)\C)/C)=C(C)C1 NBZANZVJRKXVBH-GYDPHNCVSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000010945 base-catalyzed hydrolysis reactiony Methods 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 150000003997 cyclic ketones Chemical class 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000010382 gamma-tocopherol Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 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 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000005787 mitochondrial ATP synthesis coupled electron transport Effects 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 150000002832 nitroso derivatives Chemical class 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 description 1
- 239000002478 γ-tocopherol Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/06—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation
- C07C37/07—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation with simultaneous reduction of C=O group in that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/24—Halogenated derivatives
- C07C39/42—Halogenated derivatives containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
- C07C45/513—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an etherified hydroxyl group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
- C07C45/66—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures
- C07C46/06—Preparation of quinones by oxidation giving rise to quinoid structures of at least one hydroxy group on a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
- C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
- C07C50/32—Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having two rings
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- the invention relates to a novel process for preparation of 2-[trcms-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone i.e. Atovaquone [I].
- This invention also provides a novel process for preparation of 2-[cw-4-(4'-chlorophenyl)cyclohexyl]-3- hydroxy-l ,4-naphthoquinone and process for isomerization of 2-[c/s-4-(4'- chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone to 2-[tr ns-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of a Lewis acid.
- Atovaquone 2-[ r «5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone [CAS No. 95233-18-4], which is also called Atovaquone [I], has antipneumocystic activity and is used in the treatment of Pneumocystis carinii pneumonia, as disclosed in US patent number US 4981874. Further uses of Atovaquone as a therapeutic agent for malaria, toxoplasmosis and carcinoma or fibrosarcoma are disclosed in US patent number US 5206268, US 5856362 and US 5567738, respectively.
- the mechanism of action for Atovaquone involves the inhibition of mitochondrial electron transport in cytochrome bci complex of the parasite, which is linked to pyrimidine biosynthesis (Tetrahedron Lett, 1998, 39 7629).
- WO 229/007991 A2 disclosed a method for synthesis of Atovaquone through formation of intermediates via Hunsdiecker decarboxylative condensation between 1,4- naphthoquinone and 4-(4-chlorophenyl) cyclohexane 1 -carboxylic acid in presence of silver nitrate and ammonium persulfate to obtain 2-[4-(4-chloro-phenyl)cyclohexyl]-l,4- naphthoquinone, which was further converted to 2-[4-(4-chloro-phenyl)cyclohexyl]-2,3- dichloro-2,3-dihydro-l,4-naphthoquinone by using acetic acid and chlorine followed by conversion to 2-chloro-3-[4-(4-chloro-phenyl)-cyclohexyl]-[l,4]naphthoquinone, which was further converted to Atovaquone
- WO 2010/001378 Al disclosed a method for conversion of c 5-2-(4-(4-chlorophenyl)- 3 -hydroxy- 1 ,4-naphthoquione to trara-2-(4-(4-chlorophenyl)-3 -hydroxy- 1 ,4-naphthoquione in the presence of strong acids such as sulphuric acid and methansulphonic acid.
- the present inventors have found a novel, cost effective, operation friendly, green process for preparation of the title compound.
- This invention also provides a novel process for preparation of 'c/V isomer of Atovaquone and process for converting 'c/V isomer of Atovaquone to pharmaceutically active form i.e. 'trans ' ' isomer in presence of a Lewis acid.
- an object of this invention is to provide a novel cost effective and efficient process for the synthesis of Atovaquone [I].
- Another object of the present invention is synthesis of the novel compound 2-(4-(4- chlorophenyl)-l -hydroxy cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [IV] through Mukaiyama aldol condensation of (l ,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4-chlorophenyl)cyclohexanone [III] and further conversion of the Mukaiyama adduct to Atovaquone [I].
- Yet another object of the present invention is synthesis of the novel compound 2-(4- (4-chlorophenyl)cyclohex-l -enyl)-3,4-dihydronaphthalen-l (2H)-one[V] from 2-(4-(4- chlorophenyl)- 1 -hydroxycyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one [IV] through dehydration and further conversion of it to Atovaquone [I].
- Yet another object of the present invention is synthesis of the novel compound 2-(4-
- Yet another object of the present invention is synthesis of the novel compound 2- bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l (2H)-one [VII] from 2-(4- (4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [VI] through ketone bromination and further conversion of it to Atovaquone [I].
- Yet another object of the present invention is synthesis of the novel compound 2-(4- (4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] from 2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- l(2H)-one [VII] through aromatization in presence of base and further conversion of it to Atovaquone [I].
- Yet another object of the present invention is synthesis of the novel compound 2-(4- (4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione [IX] from 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] through oxidation and further conversion of it to Atovaquone [I].
- Yet another object of the present invention is separation of 'cis ' isomer of 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol from 'trans ' isomer of 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol through an innovative crystallization process.
- Yet another object of the present invention is synthesis of cw-2-(4-(4- chlorophenyl)cyclohexyl)naphthalene-l,4-dione [XII] from cis-2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol [XI] through oxidation.
- Yet another object of the present invention is synthesis of cis isomer of Atovaquone from c/s-2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-l ,4-dione [XII].
- Yet another object of the present invention is isomerization of "cw" isomer of Atovaquone to trans isomer of Atovaquone [I] in presence of a Lewis /Bronsted acid such as titanium tetrachloride, Sulfuric acid, triflic acid, methansulphonic acid.
- a Lewis /Bronsted acid such as titanium tetrachloride, Sulfuric acid, triflic acid, methansulphonic acid.
- One aspect of the present invention is to provide 2-[trans-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone, i.e. Atovaquone [I] through a novel, cost effective, green, and eco-friendly process, without separation of any diastereomers or geometric isomers of intermediates obtained during the reactions
- a process for preparation of 2-[/r «5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4- naphthoquinone, i.e. Atovaquone [I] comprising the steps of- a) condensing (l,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4- chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent to obtain 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4-dihydronaphthalen-l(2H)- one [IV]
- step (d) in absence of step (d) optional selective crystallization of 2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [VII] to separate the 'tis ' and 'trans ' isomers of 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one [VII]
- step (f) in absence of step (f) optionally crystallizing 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] to separate the 'tis ' and 'trans' isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII]
- Another aspect of the present invention is to provide separation of 'cis ' and 'trans ' isomer of intermediates VI, VII and VIII through selective crystallization in an appropriate solvent.
- Another aspect of the present invention is to provide a method for converting 2-[cis- 4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy- 1 ,4-naphthoquinone to 2-[trans-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of Lewis/ Bronsted acid
- Another aspect of the present invention is to provide process for preparation of compound 2-(4-(4-chlorophenyl)- 1 -hydroxycyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one [IV] comprising condensation of (l,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4-chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent.
- Another aspect of the present invention is to provide, a highly efficient and atomeconomic process for synthesis of compound [III] i.e. 4-(4-chlorophenyl)cyclohexanone
- the process for making compound of formula (III), as provided comprises the steps of- a) Preparation of (4-chlorophenyl) magnesium bromide (Grignard reagent) by reacting l-bromo-4-chlorobenzene (i) with magnesium turnings in presence of catalytic amount of iodine
- Another aspect of the present invention is to provide process for synthesis of 2-[cis-4- (4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone comprising the steps of- a) converting C s-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (XI), to cis-4-(4- chlorophenyl)cyclohexyl)naphthalene-l,4-dione (XII) in presence of sulphuric acid /sodium nitrite or sodium bromate/acetic acid or acetic acid/hydrogen peroxide or ruthenium chloride/hydrogen peroxide/acetic acid
- Another aspect is to provide a process for isomerization of cis- Atovaquone i.e. 2-[cis- 4-(4'-chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone to trans- Atovaquone i.e. 2- [tra «5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of Lewis acid
- Figure I Process for synthesis of Atovaquone [I] without separation of any diastereomers or geometric isomers of intermediates obtained during the reaction.
- Figure II Process for synthesis of 'tis ' isomer of Atovaquone [XIV] from cis-2-(4- (4-chlorophenyl)cyclohexyl)naphthalen- 1 -ol [XI]
- Figure III Process for isomerization of 'tis ' isomer of Atovaquone [XIV] to Atovaquone [I] i.e. desired i trans ' isomer in presence of Lewis acid.
- Figure V The ORTEP diagram of. tra «s-2-(4-(4-chlorophenyl)-l- hydroxycyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one [IV]
- Figure VI The ORTEP diagram of cw-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one
- Figure VII The ORTEP diagram of tra «5-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen- l-ol
- the present invention relates to process for preparation of Atovaquone [I] as described in the scheme of reactions in Figure I.
- the present invention also relates to separation of 'tis ' and 'trans ' isomer of intermediates VI, VII and VIII through selective crystallization in an appropriate solvent.
- the pure 'tis ' and 'trans ' isomers of intermediates VI, VII and VIII are respectively converted into pure 'tis ' and 'trans ' isomer of intermediate [X] by means of the chemistry described in scheme A.
- Cis- Atovaquone or mixture of c/Vtra/is-Atovaquone was converted to trans- Atovaquone in presence of Lewis acid such as titanium tetrachloride, in organic solvent such as dichloromethane.
- Lewis acid such as titanium tetrachloride
- organic solvent such as dichloromethane.
- Another aspect of the present invention is to provide , a highly efficient and atom economic process for synthesis of compound [III] i.e. 4-(4-chlorophenyl)cyclohexanone which is described below (reaction Scheme of Figure IV)
- Mukaiyama aldol condensation is very well studied and widely used in organic synthesis. Mukaiyama aldol condensation is generally carried out in presence of Lewis acid or Lewis base in a polar aprotic solvent preferably halogenated solvent such as DCM at temperature range of -70 to 0 C. Lewis acids such as TiCl 4 (Mukaiyama, T. et al. Chem.
- the ORTEP diagram of compound [IV] shows that the hydroxyl group has an axial conformation, whereas other bulky groups in 1 , 4 position of the cyclohexane ring have equatorial conformation ( Figure V).
- the hydrogen atoms of the hydroxyl group form a hydrogen bond with carbonyl oxygen of the ketone functionality of the 1 - tetralone moiety.
- Mukaiyama aldol condensation product i.e. tra «5-2-(4-(4-chlorophenyl)-l- hydroxycyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [IV] was dehydrated in presence of acids such as sulfuric acid, /?-toluene sulfonic acid, methane sulfonic acid and triflic acid preferably p-toluene sulfonic acid in solvents such as dichloromethane, toluene, benzene; preferably toluene at temperature of about 25 to 1 10 °C, preferably 60 °C, which gave the diastereomeric mixture of 2-(4-(4-chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen- l(2H)-one [V].
- acids such as sulfuric acid, /?-toluene sulf
- Cis and trans isomers of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- l(2H)-one were separated through selective crystallization as it was observed that in cyclohexane, one isomer was more soluble that the other isomer and after recrystallizations in cyclohexane, one isomer was obtained in the pure form.
- the geometric isomer of compound [VII] can be separated through selective crystallization from methanol to obtain pure cis and trans isomers of compound [VII] which could be further converted into respective i.e. cis and trans isomer of Atovaquone as per the process described in Figure I.
- Cis and trans isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (VIII) were separated through selective crystallization as it was observed that in cyclohexane, one isomer was more soluble that the other isomer and after recrystallizations in cyclohexane, one isomer was obtained in the pure form.
- compound (VIII) was also converted into compound (IX) in presence of RuCl 3 / acetic acid and hydrogen peroxide (Tetrahedron Letter, 1983, 5249-5252).
- Patel et al (Tetrahedron 2007, 63, 4067) has reported conversion of ⁇ -tocopherol to corresponding ortho-quinone derivative via 5-nitroso-y-tocopherol intermediate as shown in scheme 6.
- reaction mass was allowed to stir at room temperature for 2h. TLC was checked at this point for product formation and in case the reaction was found to be incomplete, an additional 1 mol equivalent of triethylamine was added to the reaction mass. On complete consumption of reactants, the reaction mass was poured into ice water (3 L) and extracted with «-pentane (2x 1 L). After separating, the organic layer was dried over anhydrous potassium carbonate and solvent evaporated to give product as a brown oil (402.0 g, 96% yield). Generally yield of the product ranges from 90 to 97 %.
- FTIR (neat): 3022, 3060, 2958, 2935, 2888, 2832, 1638, 1600, 1485, 1359, 1337, 1251, 1 188, 1 140, 1093, 919, 860, 845, 737 cm “1 .
- reaction mass was again cooled to - 55°C and at this temperature, a solution of (l,2-dihydronaphthalen-4-yloxy)trimethylsilane (11 1.3 g, 0.515 mol) in dichloromethane (1 L) was added and allowed to stir at -55 °C for lh. After which, again reaction mixture was warmed to 0°C and then quenched with ice water (2500 mL) under vigorous stirring and diluted with dichloromethane (3000 mL). Organic layer was separated and washed with saturated sodium bicarbonate solution (500 mL) and brine.
- reaction mass was cooled to RT and solvent was evaporated under reduced pressure and 10% aqueous solution of hydrochloric acid (180 mL) was added to the residue.
- the resultant mixture was extracted with DCM (150 mL) and evaporated to give crude product (47.0 g). Generally average yield of the product ranges from 70 to 80 %.
- Example 7 Synthesis of c/s /ra/ii-4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (IX) in presence of acetic acid/ hydrogen peroxide
- Example 9 Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (IX) in presence of sodium nitrite/ 50% aqueous sulphuric acid.
- FTIR (KBr): 3370, 3078, 2944, 2928, 2900, 2859, 1695, 1594, 1490, 1451 , 1306, 1287, 1157, 1089, 944, 886, 801 , 725 cm -1 .
- Cis isomer of Atovaquone (0.5 g) was dissolved in dichloromethane (20 mL) and T1CI4 (0.5 mL)was added to it at RT. Resulting reaction mixture was heated to 40 °C and stirred for 24 h. Reaction was monitored for conversion of cis isomer of Atovaquone to trans isomer at different intervals. After 24 h, HPLC analysis showed the cis to trans ratio as 50:50.
- Example 13 Conversion of "cw” isomer of Atovaquone to "fra/is” isomer of Atovaquone in presence of Sulphuric acid.
- Cis/trans Atovaquone (0.5 g) was added in sulphuric acid (10 mL) at RT and stirred for 2 h, after which the reaction mixture was poured in ice water and product was extracted with dichloromethane, which was analyzed on HPLC as per resolution method given in US pharmacopoeia.
- Activated magnesium turnings (92.2g, 3.84 mol) were charged to a nitrogen dried reactor equipped with reflux condenser, nitrogen bubbler, thermo pocket and side arm addition funnel. Dry THF (2.0 L) and catalytic amount of iodine were added and reactor was gently heated. 1- Bromo 4-chlorobenzene (674.0 g, 3.52 mol) solution in THF (2 L) was added slowly into the above reaction mass at 50 °C to obtain corresponding Grignard reagent.
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Abstract
Provided is a process of preparation of 2-[trans,-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy- 1,4-naphthoquinone, i.e. Atovaquone [I] which is cost effective, green, and eco-friendly process, without separation of any diastereomers or geometric isomers of intermediates obtained during the reactions. Also provided is separation of 'cis' and 'trans ' isomer of intermediates VI, VII and VIII through selective crystallization in an appropriate solvent. A method for converting 2-[cis,-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone to 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of Lewis/ Bronsted acid is also provided. A process for preparation of compound 2-(4-(4- chlorophenyl)- 1 -hydroxy cyclohexyl)-3,4-dihydronaphthalen- 1 (2H)-one [IV] comprising condensation of (1,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4- chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent. The invention also encompasses a highly efficient and atomeconomic process for synthesis of compound [III] i.e. 4-(4-chlorophenyl)cyclohexanone as well as a process for synthesis of 2-[cis-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone. Further provided is a process for isomerization of cis- Atovaquone i.e. 2-[cis-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4- naphthoquinone to tnms-Atovaquone i.e. 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3- hydroxy- 1,4-naphthoquinone in presence of Lewis acid.
Description
NOVEL METHOD FOR PREPARATION OF ATOVAQUONE
Field of the Invention:
The invention relates to a novel process for preparation of 2-[trcms-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone i.e. Atovaquone [I]. This invention also provides a novel process for preparation of 2-[cw-4-(4'-chlorophenyl)cyclohexyl]-3- hydroxy-l ,4-naphthoquinone and process for isomerization of 2-[c/s-4-(4'- chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone to 2-[tr ns-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of a Lewis acid.
Background of the Invention:
2-[ r «5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone [CAS No. 95233-18-4], which is also called Atovaquone [I], has antipneumocystic activity and is used in the treatment of Pneumocystis carinii pneumonia, as disclosed in US patent number US 4981874. Further uses of Atovaquone as a therapeutic agent for malaria, toxoplasmosis and carcinoma or fibrosarcoma are disclosed in US patent number US 5206268, US 5856362 and US 5567738, respectively. The mechanism of action for Atovaquone involves the inhibition of mitochondrial electron transport in cytochrome bci complex of the parasite, which is linked to pyrimidine biosynthesis (Tetrahedron Lett, 1998, 39 7629).
There are only few reports available for the synthesis of Atovaquone employing various synthetic alternatives essentially based on Hunsdiecker decarboxylase condensation, which proceeds through a radical mechanism. However, the overall yield of
the desired product in almost all the reported processes is exceedingly poor i.e. economically far away from being attractive. Details of the reported syntheses are discussed hereinafter.
The method for synthesis of Atovaquone disclosed in US Patent No. 5,053,432 describes Hunsdiecker decarboxylative condensation between (4-(4-chlorophenyl) cyclohexane 1 -carboxylic acid and 2-chloro 1 ,4-naphthoquinone in presence of silver nitrate and ammonium persulfate to obtain 2-chloro-3-[4-(4-chloro-phenyl)-cyclohexyl]- [l,4]naphthoquinone, which was converted to (c/Vtr n5)-2-hydroxy-3-[4-(4-chloro-phenyl)- cyclohexyl]-[ 1,4] naphthoquinone and on further re-crystallization through acetonitrile, the desired product i.e. tra«s-2-hydroxy-3-[4-(4-chloro-phenyl)-cyclohexyl]- [l,4]naphthoquinone was obtained (Scheme 1). The disadvantage with this process is that overall yield is very low (4-5 %) and it requires expensive catalyst such as silver nitrate. Moreover, it also requires a number of purification steps in different solvents to obtain the g.
Scheme 1
The improved process for the Hunsdiecker decarboxylative condensation precursor i.e. oxalate mono acids in presence of ammonium persulfate, silver nitrate and phase transfer catalyst, Adogen® 464 to obtain 2-chloro-3-[4-(4-chloro-phenyl)-cyclohexyl]- [l,4]naphthoquinone has been reported by Williams and Clark [Tetrahedron Letters, 1998, 39, 7629-7632], which was subsequently converted to Atovaquone. This process reports 43% overall yield for 2-chloro-3-[4-(4-chloro-phenyl)-cyclohexyl]-[l,4]naphthoquinone. On further re-crystallization through acetonitrile, desired product i.e. tra«5-2-hydroxy-3-[4-(4- chloro-phenyl)-cyclohexyl]-[l,4]naphthoquinone was obtained (Scheme 2). Besides lower overall yield, this process also requires the expensive catalyst, silver nitrate hence rendering this process not attractive for large scale manufacturing.
Scheme 2
WO 229/007991 A2 disclosed a method for synthesis of Atovaquone through formation of intermediates via Hunsdiecker decarboxylative condensation between 1,4- naphthoquinone and 4-(4-chlorophenyl) cyclohexane 1 -carboxylic acid in presence of silver nitrate and ammonium persulfate to obtain 2-[4-(4-chloro-phenyl)cyclohexyl]-l,4- naphthoquinone, which was further converted to 2-[4-(4-chloro-phenyl)cyclohexyl]-2,3- dichloro-2,3-dihydro-l,4-naphthoquinone by using acetic acid and chlorine followed by conversion to 2-chloro-3-[4-(4-chloro-phenyl)-cyclohexyl]-[l,4]naphthoquinone, which was further converted to Atovaquone through base catalyzed hydrolysis (Scheme 3). Over all yield for the first step is very poor (20%) and moreover, chlorine gas was used in the second step. Hence, this process is not a practical process for commercial scale for obvious reasons.
Scheme 3
WO 2010/ 0001379A1 disclosed a method for synthesis of Atovaquone. In this process frcws-4-(4-chlorophenyl)cyclohexane-l-carboxylic acid was reacted with N-hydroxy pyridine-2(7H)-thione in presence of DCC to obtain tra -2-thioxopyridin-l(2H)-yl-4-(4- chlorophenyl)-cyclohexane carboxylate, which was further reacted with 1 ,4-napthoquinone under ultra violet irradiation with 400 W halogen lamp to obtain 2-[4-(4- chlorophenyl)cyclohexyl]-3-(pyridine-2-ylthio) naphthalene- 1,4 dione which was further hydrolyzed in presence of base followed by isomer separation to obtain Atovaquone (Scheme 4). However, besides higher material cost, the overall yield of the desired isomer is only 12% from the geometric isomer mixture i.e. from penultimate to ultimate.
Scheme 4
Synthesis of similar type of compound i.e. 2-(4-t-butylcyclohexyl)-3 -hydroxy- 1 ,4- naphthoquinone by employing Hunsdiecker decarboxylative condensation between 2-chloro- 1,4 naphthoquinone and 4-t-buytlcyclohexane-l-carboxylic acid was reported in EP 0077551 Bl and by Hudson et al (Eur. J. Med. Chem. 1986, 21, 271-275).
Moreover, isomerization of c/5-2-(4-t-butylcyclohexyl)-3-hydroxy-l , 4- naphthoquinone to tnms-2-(4-t-butylcyclohexyl)-3-hydroxy-l, 4-naphthoquinone in presence
of concentrated sulphuric acid was also reported (Scheme 5). This established the fact that in the presence of a strong acid such as sulphuric acid, benzylic proton a to the naphthoquinon ring gets abstracted and leads to thermodynamically more stable geometric isomer.
Scheme 5
WO 2010/001378 Al disclosed a method for conversion of c 5-2-(4-(4-chlorophenyl)- 3 -hydroxy- 1 ,4-naphthoquione to trara-2-(4-(4-chlorophenyl)-3 -hydroxy- 1 ,4-naphthoquione in the presence of strong acids such as sulphuric acid and methansulphonic acid.
Hence, it is evident from prior art that the processes reported in the literature for the industrial synthesis of Atovaquone are at present not industrially feasible processes with respect to cost and efficiencies, use of toxic chemicals and eco-hazardous operations. Hence, there is need for an eco-friendly, "green", cost effective, easy-to-operate, industrial-scale synthesis of Atovaquone.
The present inventors have found a novel, cost effective, operation friendly, green process for preparation of the title compound. This invention also provides a novel process for preparation of 'c/V isomer of Atovaquone and process for converting 'c/V isomer of Atovaquone to pharmaceutically active form i.e. 'trans'' isomer in presence of a Lewis acid. Objects of the Invention:
Thus an object of this invention is to provide a novel cost effective and efficient process for the synthesis of Atovaquone [I].
Another object of the present invention is synthesis of the novel compound 2-(4-(4- chlorophenyl)-l -hydroxy cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [IV] through Mukaiyama aldol condensation of (l ,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4-chlorophenyl)cyclohexanone [III] and further conversion of the Mukaiyama adduct to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2-(4- (4-chlorophenyl)cyclohex-l -enyl)-3,4-dihydronaphthalen-l (2H)-one[V] from 2-(4-(4- chlorophenyl)- 1 -hydroxycyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one [IV] through dehydration and further conversion of it to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2-(4-
(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [VI] from 2-(4-(4- chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one [V] through hydrogenation in presence of noble metal catalysts and further conversion of it to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2- bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l (2H)-one [VII] from 2-(4- (4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [VI] through ketone bromination and further conversion of it to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2-(4- (4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] from 2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- l(2H)-one [VII] through aromatization in presence of base and further conversion of it to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2-(4- (4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione [IX] from 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] through oxidation and further conversion of it to Atovaquone [I].
Yet another object of the present invention is separation of 'cis ' isomer of 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol from 'trans ' isomer of 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol through an innovative crystallization process.
Yet another object of the present invention is synthesis of cw-2-(4-(4- chlorophenyl)cyclohexyl)naphthalene-l,4-dione [XII] from cis-2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol [XI] through oxidation.
Yet another object of the present invention is synthesis of cis isomer of Atovaquone from c/s-2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-l ,4-dione [XII].
Yet another object of the present invention is isomerization of "cw" isomer of Atovaquone to trans isomer of Atovaquone [I] in presence of a Lewis /Bronsted acid such as titanium tetrachloride, Sulfuric acid, triflic acid, methansulphonic acid.
Summary of Invention:
One aspect of the present invention is to provide 2-[trans-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone, i.e. Atovaquone [I] through a novel, cost effective, green, and eco-friendly process, without separation of any diastereomers or geometric isomers of intermediates obtained during the reactions
A process for preparation of 2-[/r «5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4- naphthoquinone, i.e. Atovaquone [I] comprising the steps of- a) condensing (l,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4- chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent to obtain 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4-dihydronaphthalen-l(2H)- one [IV]
b) dehydration of 2-(4-(4-chlorophenyl)-l -hydroxy cyclohexyl)-3, 4-dihy dronaphthalen- l(2H)-one [IV] in organic solvent and in presence of acid such as pTSA to obtain diastereomeric mixture of 2-(4-(4-chlorophenyl)cyclohex-l-enyl)-3,4- dihydronaphthalen- 1 (2H)-one [V]
c) hydrogenation of 2-(4-(4-chlorophenyl)cyclohex-l-enyl)-3, 4-dihy dronaphthalen- l(2H)-one[V] with platinum oxide to obtain cis/trans mixture of 2-(4-(4- chlorophenyl)cyclohexyl)-3 , 4-dihy dronaphthalen- 1 (2H)-one [VI]
d) optional selective crystallization of cis/trans mixture of 2-(4-(4- chlorophenyl)cyclohexyl)-3, 4-dihy dronaphthalen- l(2H)-one [VI] to separate the 'cis '
and 'trans ' isomers of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- l(2H)-one[VI]
e) ketone bromination of cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one [VI] to obtain cis/trans mixture of 2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- 1 (2H)-one [VII]
f) in absence of step (d) optional selective crystallization of 2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [VII] to separate the 'tis ' and 'trans ' isomers of 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one [VII]
g) elimination of cis/trans mixture of 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one [VII] with a strong base to give cis/trans mixture of 2- (4-(4-chlorophenyl)cyclohexyl)naphthalen- 1 -ol [VIII]
h) in absence of step (f) optionally crystallizing 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] to separate the 'tis ' and 'trans' isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII]
i) oxidizing 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] to obtain 2-(4-(4- chlorophenyl)cyclohexyl)naphthalene- 1 ,4-dione [IX]
j) base catalyzed epoxidation of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4- dione [IX] to la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-
2,7(1 aH,7aH)-dione [X] in presence of hydrogen peroxide
k) acid catalyzed hydrolysis of la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3- b]oxirene-2,7(laH,7aH)-dione [X] to obtain 2-[tra«s-4-(4'-chlorophenyl)cyclohexyl]-
3 -hydroxy- 1 ,4-naphthoquinone [I]
Another aspect of the present invention is to provide separation of 'cis ' and 'trans ' isomer of intermediates VI, VII and VIII through selective crystallization in an appropriate solvent.
Another aspect of the present invention is to provide a method for converting 2-[cis- 4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy- 1 ,4-naphthoquinone to 2-[trans-4-(4'-
chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of Lewis/ Bronsted acid
Another aspect of the present invention is to provide process for preparation of compound 2-(4-(4-chlorophenyl)- 1 -hydroxycyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one [IV] comprising condensation of (l,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4-chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent.
Another aspect of the present invention is to provide, a highly efficient and atomeconomic process for synthesis of compound [III] i.e. 4-(4-chlorophenyl)cyclohexanone
The process for making compound of formula (III), as provided comprises the steps of- a) Preparation of (4-chlorophenyl) magnesium bromide (Grignard reagent) by reacting l-bromo-4-chlorobenzene (i) with magnesium turnings in presence of catalytic amount of iodine
b) reacting (4-chlorophenyl) magnesium bromide with 1 ,4-cyclohexanedione monoethylene ketal (ii) to obtain 8-(4-chlorophenyl)-l,4-dioxa-spiro[4.5]decan-8-ol
(iii)
c) dehydration reaction of 8-(4-chlorophenyl)-l,4-dioxa-spiro[4.5]decan-8-ol (iii) in organic solvent and in presence of p-TSA and ethylene glycol to obtain 4-(4- chlorophenyl)-cyclohex-3-enone monoethylene ketal (iv)
d) hydrogenation of 4-(4-chlorophenyl)-cyclohex-3-enone monoethylene ketal (iv) in presence of noble metal catalyst such as palladium on carbon, platinum oxide, preferentially palladium on carbon to obtain compound 4-(4-chlorophenyl)- cyclohexanone monoethylene ketal (v)
e) deketalization of 4-(4-chlorophenyl)-cyclohexanone monoethylene ketal (v) in presence of TSA in mixture of acetone: water to obtain 4-(4-chlorophenyl) cyclohexanone [III]
Another aspect of the present invention is to provide process for synthesis of 2-[cis-4- (4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone comprising the steps of-
a) converting C s-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (XI), to cis-4-(4- chlorophenyl)cyclohexyl)naphthalene-l,4-dione (XII) in presence of sulphuric acid /sodium nitrite or sodium bromate/acetic acid or acetic acid/hydrogen peroxide or ruthenium chloride/hydrogen peroxide/acetic acid
b) converting c s-4-(4-chlorophenyl)cyclohexyl)naphthalene-l ,4-dione (XII) to cis- la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (XIII) in presence of hydrogen peroxide and base.
c) converting cis- 1 a-(4-(4-chlorophenyl)cyclohexyl)naphtho [2,3 -b] oxirene- 2,7(1 aH,7aH)-dione (XIII) to give cis isomer of Atovaquone in presence of sulfuric acid.
Another aspect is to provide a process for isomerization of cis- Atovaquone i.e. 2-[cis- 4-(4'-chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone to trans- Atovaquone i.e. 2- [tra«5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of Lewis acid
Further aspects of the invention are to provide the following compounds:
a) 2-(4-(4-chlorophenyl)- 1 -hydroxycyclohexyl)-3,4-dihydronaphthalen- 1 (2H)-one [IV]
b) 2-(4-(4-chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one[V] c) 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l (2H)-one [VI] d) 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-1 (2H)-one [VII]
e) 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII]
f) 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione [IX]
g) 1 a-(4-(4-chloropheny l)cyclohexyl)naphtho [2,3 -b] oxirene-2,7( 1 aH,7aH)-dione [X] Brief description of accompanying Figures:
Figure I: Process for synthesis of Atovaquone [I] without separation of any diastereomers or geometric isomers of intermediates obtained during the reaction.
Figure II: Process for synthesis of 'tis ' isomer of Atovaquone [XIV] from cis-2-(4- (4-chlorophenyl)cyclohexyl)naphthalen- 1 -ol [XI]
Figure III: Process for isomerization of 'tis ' isomer of Atovaquone [XIV] to Atovaquone [I] i.e. desired i trans ' isomer in presence of Lewis acid.
Figure IV: High yielding process for synthesis of key intermediate i.e. 4-(4- chlorophenyl)cyclohexanone [III].
Figure V: The ORTEP diagram of. tra«s-2-(4-(4-chlorophenyl)-l- hydroxycyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one [IV]
Figure VI: The ORTEP diagram of cw-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one
Figure VII: The ORTEP diagram of tra«5-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen- l-ol
Detailed Description of the Invention
The present invention relates to process for preparation of Atovaquone [I] as described in the scheme of reactions in Figure I.
(l,2-Dihydronaphthalen-4-yloxy)trimethylsilane (II) was condensed with 4-(4- chlorophenyl)cyclohexanone (III) in presence of titanium tetrachloride in an organic solvent such as dichloromethane to give tra«5-2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3 ,4- dihydronaphthalen- l(2H)-one (IV). Compound (IV) on dehydration in presence of /?-TSA in an organic solvent such as toluene gave a mixture of diastereomers of 2-(4-(4- chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one (V), which on further hydrogenation using platinum oxide in organic solvent such as ethyl acetate, acetone preferably acetone gave c/Vtra«^-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- l(2H)-one (VI). Compound (VI) was further reacted with bromine in presence of acetic acid in an organic solvent such as diethyl ether to give cis/trans-2-bromo-2-(4-{A- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one (VII). Compound (VII) was then treated with potassium tert-butoxide in organic solvent such as dimethoxyethane to get c/Vtr «5-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (VIII), which was further converted to czVtra«5-4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (IX) in presence
of any of the following combination of reagents: sulphuric acid /sodium nitrite or sodium bromate/acetic acid or acetic acid/hydrogen peroxide or ruthenium chloride/hydrogen peroxide/acetic acid. This was subsequently converted to cis/trans-\a.-(A-(4- chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (X) in presence of hydrogen peroxide and base such as sodium carbonate. Compound (X) on hydrolysis with sulfuric acid gave Atovaquone (I).
The present invention also relates to separation of 'tis ' and 'trans ' isomer of intermediates VI, VII and VIII through selective crystallization in an appropriate solvent. The pure 'tis ' and 'trans ' isomers of intermediates VI, VII and VIII are respectively converted into pure 'tis ' and 'trans ' isomer of intermediate [X] by means of the chemistry described in scheme A. Furthermore, pure 'tis ' and 'trans ' isomer of intermediate [X] were respectively converted to 2-[cz'5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone [XIV] (Figure II) and 2-[tra«5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone [I] i.e. Atovaquone [I] through acid catalyzed hydrolysis
Cw-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (XI), was converted to cis-A-
(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (XII) in presence of any of the following combination of reagents: sulphuric acid /sodium nitrite or sodium bromate/acetic acid or acetic acid/hydrogen peroxide or ruthenium chloride/hydrogen peroxide/acetic acid, which was subsequently converted to cw-la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene- 2,7(1 aH,7aH)-dione (XIII) in presence of hydrogen peroxide and base such as sodium carbonate. Compound (X) on hydrolysis with sulfuric acid gave c/s-Atovaquone (XIV). (reaction Scheme of Figure II)
A method for converting 2-[cw-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4- naphthoquinone to 2-[tram,-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone in presence of Lewis/ Bronsted acid is also provided (reaction Scheme of Figure III)
Cis- Atovaquone or mixture of c/Vtra/is-Atovaquone was converted to trans- Atovaquone in presence of Lewis acid such as titanium tetrachloride, in organic solvent such as dichloromethane.
Another aspect of the present invention is to provide , a highly efficient and atom economic process for synthesis of compound [III] i.e. 4-(4-chlorophenyl)cyclohexanone which is described below (reaction Scheme of Figure IV)
l-Bromo-4-chlorobenzene (i) was reacted with magnesium turnings in presence of catalytic amount of iodine in organic solvent such as tetrahydrofuran to obtain corresponding Grignard reagent, which was further reacted with 1 ,4-cyclohexanedione monoethylene ketal (ii) to obtain 8-(4-chlorophenyl)-l,4-dioxa-spiro[4.5]decan-8-ol (iii) in an average 90 % isolated yield. Compound (iii) was dehydrated in presence of pTSA and ethylene glycol in organic solvent such as toluene to obtain 4-(4-chlorophenyl)-cyclohex-3-enone monoethylene ketal (iv) in 93% isolated yield, which was further hydrogenated in presence of noble metal catalyst such as palladium on carbon, platinum oxide, preferentially palladium on carbon to obtain compound 4-(4-chlorophenyl)-cyclohexanone monoethylene ketal (v). Compound (v) was deketalized in presence of ^TSA in mixture of acetone: water (50:50). After completion of deketalization, acetone was evaporated under reduced pressure to obtain aqueous slurry, which was added to dilute sodium bicarbonate solution and resulting mixture was cooled to 5 °C to obtain 4-(4-chlorophenyl) cyclohexanone [III] as light yellow solid in 88 % yield.
The addition of ethylene glycol played a crucial role in improving the yield of compound (iv). In the absence of ethylene glycol, not only the yields were found to be lower but also formation of innumerable number of impurities, rendering difficulty in crystallization of (iv).
The invention is described in further details below
A) Process for synthesis of Atovaquone [I]
Step 1 of Figure I
Mukaiyama aldol condensation is very well studied and widely used in organic synthesis. Mukaiyama aldol condensation is generally carried out in presence of Lewis acid or Lewis base in a polar aprotic solvent preferably halogenated solvent such as DCM at
temperature range of -70 to 0 C. Lewis acids such as TiCl4 (Mukaiyama, T. et al. Chem.
Lett. 1973, 101 1.; Mukaiyama, T. et al. J. Am. Chem. Soc. 1974, 96, 7503.; Mukaiyama, T. et al. Chem. Lett. 1975, 741); BF3.Et20 (Nakanura, E. et al. J. Am. Chem. Soc. 1977, 99,
961.; Sugimura, H. et al. Synlett. 1991, 153.); SnCLj (Mukaiyama, T. et al. Org. Synth. 1987, 65, 6) and Lewis bases such as CaCl2 (Denmark, S. E. et al. Acc. Chem. Res 2000, 32, 432;
Hosomi, A. et al. J. Am. Chem. Soc. 2002, 124, 536), Lithium amide (Mukaiyama, T. et al.
Chem. Lett. 2002, 182) have been reported for Mukaiyama aldol condensation.
Mukaiyama aldol condensation of (l,2-dihydronaphthalen-4-yloxy)trimethylsilane of formula [II] with 4-(4-chlorophenyl)cyclohexanone [III] was carried out in presence of Lewis acid such as titanium tetrachloride in organic solvent such as dichloromethane at temperature
-60 to -35 °C; preferably at -60 °C under inert atmosphere, (Stepl of Figure 1). After completion of reaction, titanium tetrachloride was quenched by adding chilled water at 0 °C.
Organic layer was separated and washed with 5 % aqueous solution of sodium bicarbonate and brine. Evaporation of organic solvent afforded the crude tra«s-2-(4-(4-chlorophenyl)-l- hydroxycyclohexyl)-3,4-dihydronaphthalen-l(2H)-one, which was further re-crystallized from ethyl acetate to obtain pure /ra«s-2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4- dihydronaphthalen-l(2H)-one [IV] in 85 % isolated yield.
The structure of compound [IV] has been established from single crystal X-ray diffraction studies. The crystals are monoclinic (a = 9.9256A, b=10.6118 A, c=16.91 16 A; a=90 °, β=98.4140 °, γ=90 °) having a space group of P21/c, and Z=4.
The ORTEP diagram of compound [IV] shows that the hydroxyl group has an axial conformation, whereas other bulky groups in 1 , 4 position of the cyclohexane ring have equatorial conformation (Figure V). The hydrogen atoms of the hydroxyl group form a hydrogen bond with carbonyl oxygen of the ketone functionality of the 1 - tetralone moiety.
Step 2 of Figure I
Mukaiyama aldol condensation product i.e. tra«5-2-(4-(4-chlorophenyl)-l- hydroxycyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [IV] was dehydrated in presence of acids such as sulfuric acid, /?-toluene sulfonic acid, methane sulfonic acid and triflic acid
preferably p-toluene sulfonic acid in solvents such as dichloromethane, toluene, benzene; preferably toluene at temperature of about 25 to 1 10 °C, preferably 60 °C, which gave the diastereomeric mixture of 2-(4-(4-chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen- l(2H)-one [V].
The corresponding tetra substituted α, β -unsaturated ketone, would apparently be thermodynamically most stable and expected as the desired product on dehydration, however, surprisingly compound [V] was obtained as the sole product presumably due to steric considerations. Compound [V] was characterized by NMR, IR and MS and further HPLC analysis showed that it is a mixture of two diastereomers [A] and [B].
At this stage no attempt was made to separate these stereoisomers and they were hydrogenated to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one (VI).
Step 3 of Figure I
Dehydrogenation of cyclic ketones to arenes or phenolic compounds is well known in literature. Springer et al has reported dehydrogenation of 1 -tetralone or substituted 1- tetralone derivatives to corresponding naphthalene and corresponding 1 -naphthol derivatives in presence of palladium on carbon (J.Org.Chem. 1971, 36(5) 686-689). Hence, hydrogenation of compound (V) was ruled out in presence of palladium on carbon, palladium hydroxide on carbon or Raney nickel and therefore hydrogenation was carried out in presence of 1 wt % loading of platinum oxide in mild hydrogen pressure (2-3 kg/cm2) to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l (2H)-one (VI).
2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one (VI) exists in cis and trans isomers, which was further confirmed by HPLC analysis and NMR spectroscopy.
Cis and trans isomers of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- l(2H)-one were separated through selective crystallization as it was observed that in cyclohexane, one isomer was more soluble that the other isomer and after recrystallizations in cyclohexane, one isomer was obtained in the pure form. Single crystal was obtained from the pure isomer and structure was assigned through a X-ray single crystal analysis and it was observed that obtained pure compound is c/s-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one and it shows that the crystals are monoclinic (a = 9.1928 A, b=10.9073 A, c=17.7399 A; =90 °, β=97.1320 °, γ=90 °), having a space group of P21/c, and Z=4.
The ORTEP diagram of c/.y-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- l(2H)-one, where bulky groups in 1, 4 position of the cyclohexane ring have axial -equatorial conformation is shown in figure VI.
At this stage, geometric isomers of (4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l (2H)-one were not separated for further transformations and were carried forward as such as shown in Figure I.
Step 4 of Figure I
Cw/tra«5-2-(4-(4-chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one (VI) was converted into c/,y/tra«5,-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one (VII) through ketone bromination method i.e. bromine and acetic acid.
Here also, if required, the geometric isomer of compound [VII] can be separated through selective crystallization from methanol to obtain pure cis and trans isomers of compound [VII] which could be further converted into respective i.e. cis and trans isomer of Atovaquone as per the process described in Figure I.
Step 5 of Figure I
β-bromo substituted 1-tetralone derivatives to corresponding substituted 1-naphthol derivative in presence of base such as triethylamine, piperidine, morpholine and
cyclohexylamine was reported (Tetrahedron Letter 2005, 46, 4187-92; JACS,1957, 79, 230). When c/5'/tra«5-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- 1 (2H)- one (VII) was treated with of the above reported bases, desired product was not obtained. Therefore, c5//r «5-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- l(2H)-one (VII) was treated with comparatively stronger base like alkoxides such as potassium tert-butoxide, sodium methoxide and sodium ethoxide to obtain corresponding 1 - naphthol derivative i.e. czVtram-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (VIII).
Cis and trans isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (VIII) were separated through selective crystallization as it was observed that in cyclohexane, one isomer was more soluble that the other isomer and after recrystallizations in cyclohexane, one isomer was obtained in the pure form. Single crystal was obtained from the pure isomer and structure was assigned through a X-ray single crystal analysis and it was observed that obtained pure compound is tra«5-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol and it shows that the crystals are monoclinic (a = 13.3526 A, b=7.9000 A, c=16.5550 A; a=90 °, β=96.95 °, γ=90 °), having space group of P21/c and Z value 4.
The ORTEP diagram of tra«s-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol, where bulky groups in 1, 4 position of the cyclohexane ring have equatorial conformation conformation is shown in figure VII.
DSC melting point for trans 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol is 195.14°C
Step 6 of Figure I
Arnold and Larson have reported oxidation of naphthalene derivatives in presence of acetic acid and hydrogen peroxide to afford corresponding quinone derivatives {Synthetic Communication, 1940, 250-252). However, there is no report of oxidation of 1 -naphthol derivatives to corresponding quinone derivatives under similar conditions.
When compound (VIII) was treated with hydrogen peroxide in acetic acid according to the reaction conditions reported in the abovementioned paper, it was observed that the reaction was sluggish and dark red coloured byproducts were also obtained. But, when bromide ion was added in the same reaction mixture, reaction was completed in 4 h, gave 50
% yield for compound (IX) and although the crude product was dark red coloured, number of byproducts was comparatively less. However, column flash chromatography was necessary for the separation of pure compound (IX) from crude product.
It was also observed that addition of bromide ion improves the rate of reaction presumably because of in situ oxidation of bromide ion by hydrogen peroxide to bromate and hence we thought of carrying out the reaction in presence of sodium bromate and acetic acid.
In spite of dearth of any literature procedure of such oxidation, compound (VIII) was oxidized in presence of sodium bromate/ acetic acid which yielded 66 % of compound (IX).
Alternatively, compound (VIII) was also converted into compound (IX) in presence of RuCl3/ acetic acid and hydrogen peroxide (Tetrahedron Letter, 1983, 5249-5252).
Patel et al (Tetrahedron 2007, 63, 4067) has reported conversion of γ-tocopherol to corresponding ortho-quinone derivative via 5-nitroso-y-tocopherol intermediate as shown in scheme 6.
Presumably this occurred by a concerted hydrogen transfer from phenolic hydroxyl functionality to nitroso group via a six member transition state i.e. intramolecular tautomerism
Scheme 6 The mechanistic implication of the above transformation was noted and compound
(VIII) was converted to the corresponding nitroso derivative by treating with sodium nitrite and 50 % aqueous sulphuric acid in organic solvent such as 1 ,4-dioxane at temperature 25 to 75 °C; preferably at 70 °C which, to our satisfaction yielded compound (IX) in quantitative yield (step 6 of figure I). Interestingly, in the present case the tautomerism is intermolecular not intramolecular.
There was improvement in the yield as compared to earlier methods but to obtain pure compound (IX) column chromatography could not be avoided in all processes.
Step 6 and 7 of Figure I
Compound (IX) was converted to compound (X) in presence of hydrogen peroxide and base such as sodium carbonate (J. Org Chem, 1952, 74 3910-3915), which was further hydrolyzed in presence of a Bronsted acid such as sulfuric acid to obtain compound (I) (J. Org Chem, 1952, 74 3910-3915; US 5,053,432). Crude product was further re-crystallized from acetonitrile to obtain Atovaquone [I] in 99 % purity as shown by HPLC analytical method described in US monograph for relative substance and resolution of Atovaquone, wherein no cis isomer was observed.
B) Process for synthesis of c/s-Atovaquone [XIV]
Geometric isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] i.e. cis and trans isomer were separated through selective crystallization in presence of cyclohexane, where c«-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (XI) was soluble in cyclohexane and tra«s-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen- 1 -ol precipitated out.
cz's-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (XI) was converted into 2-[cis- 4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone (XIV) i.e. cis isomer of Atovaquone, as shown in Figure II through employing chemistry as described in steps 6 and 7 and further hydrolysis of compound [XIII] in presence of sulphuric acid.
C) Process for isomerization of cis- Atovaquone to fra/ts-Atovaquone [I]
Isomerization of 'cis ' isomer of Atovaquone to 'trans ' isomer of Atovaquone was carried out in presence of a Lewis acid such as titanium tetrachloride.
Nomenclatures used for the compounds mentioned herein are as understood from the CambridgeSoft® ChemOffice software ChemDraw Ultra version 6.0.1.
Analytical Methods:
The purity was determined by HPLC using a Shimadzu LC 2010 system equipped with a column (Purosphere star RP-18e (4.6 x 150mm), 5μπι), column oven temperature 25 °C and UV visible detector (UV at 340nm). Mobile phase was buffer: acetonitrile (55:45) with flow rate 3.0 mL"1, injection volume 20 μΐ. NMR spectra were obtained at 200 and 400
MHz Bruker instruments, with CDC13 as solvent unless otherwise stated. Chemical shifts (cT) are given in ppm relative to tetramethylsilane (S = 0 ppm). IR spectra were recorded on Perkin Elmer Spectrum (Model: Spectrum 100) and absorption bands are given in cm"1. DSC was recorded on Perkin Elmer model Diamond DSC at the rate of 10 °C/min, and endothermic peak was recorded in 0 C and ΔΗ is reported in J/g. Crystal structure of the single crystal was measured on Bruker Smart Apex CCD diffractometer having software SHELXTL-PLUS at temperature 293 (2) K and wavelength 0.71073 A and Θ range for data collection is 1.56 to 28.40°.
Example 1: Synthesis of (1, 2-dihydronaphthalen-4-yloxy)trimethylsilane (II)
To a reactor equipped with reflux condenser, nitrogen bubbler, dropping funnel and thermo-pocket, were charged cc-tetralone (270.0 g, 1.85 mol) and triethylamine (514.0 g, 5.08 mol) at room temperature under nitrogen atmosphere. After stirring at room temperature for 15 min, trimethyl silyl chloride (541.0 g, 5.0 mol) was added drop wise over a period of 30- 40 min while maintaining nitrogen atmosphere and stirred for around lh at room temperature. Sodium iodide (369.0 g, 2.46 mol) was dissolved in acetonitrile (2.2 L) at RT and added to the reaction mass slowly while maintaining an internal temperature not more than 40 °C. The resultant reaction mass was allowed to stir at room temperature for 2h. TLC was checked at this point for product formation and in case the reaction was found to be incomplete, an additional 1 mol equivalent of triethylamine was added to the reaction mass. On complete consumption of reactants, the reaction mass was poured into ice water (3 L) and extracted with «-pentane (2x 1 L). After separating, the organic layer was dried over
anhydrous potassium carbonate and solvent evaporated to give product as a brown oil (402.0 g, 96% yield). Generally yield of the product ranges from 90 to 97 %.
FTIR (neat): 3022, 3060, 2958, 2935, 2888, 2832, 1638, 1600, 1485, 1359, 1337, 1251, 1 188, 1 140, 1093, 919, 860, 845, 737 cm"1.
lH NMR (CDC , 200 MHz): δ 1.85 (s, 9H), 3.89-3.94 (m, 2H), 4.34-4.38 (t, 2H), 6.79 (s, 1H), 8.69-8.81 (m, 3H), 9.0-9.02 (d, 1H).
MS (EI): Ci3H18OSi : 218.1 127; [M+H]+: 219.10
Example 2: Synthesis of 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4- dihydronaphtha!en-l(2H)-one (IV)
To a reactor equipped with, over head stirrer, reflux condenser, nitrogen bubbler, dropping funnel and thermo-pocket, was charged 4-(4-chlorophenyl)cyclohexanone ( 85.0 g, 0.41 mol) under a positive nitrogen pressure at 25 °C. Freshly dried dichloromethane (850 mL) was added to dissolve the material and the reaction mass was cooled to -35 °C. A 1 molar solution of titanium tetrachloride (85.4 g, 0.45 mol) in dry dichloromethane (550 mL) was added drop wise to the reaction mass. After compete addition of titanium tetrachloride reaction mixture was warmed to 0 °C and stirred for 1 h. Reaction mass was again cooled to - 55°C and at this temperature, a solution of (l,2-dihydronaphthalen-4-yloxy)trimethylsilane (11 1.3 g, 0.515 mol) in dichloromethane (1 L) was added and allowed to stir at -55 °C for lh. After which, again reaction mixture was warmed to 0°C and then quenched with ice water (2500 mL) under vigorous stirring and diluted with dichloromethane (3000 mL). Organic layer was separated and washed with saturated sodium bicarbonate solution (500 mL) and brine. After stripping off the DCM layer under reduced pressure, the residue was suspended
in ethyl acetate (300 mL) and resultant slurry was refluxed for lh and cooled to RT. Resultant solid were filtered off to give the product as off-white solid. (122.3 g, 84.9 % yield). Generally yield of the product ranges from 78 to 85 %.
FTIR (neat): 3441, 2945, 2927, 2858, 1654, 1598, 1397, 1230, 1046, 962, 840, 751, 610 cm"1. 1H NMR (CDCb, 400 MHz): δ 1.55(t, IH), 1.68-1.79 (m, 4H), 1.91-2.02 (m, 2H), 2.04-2.1 1 (m,2H), 2.32-2.36 (dd, IH), 2.45 (t, IH), 2.68 (dd, IH), 3.05(d, 2H), 4.98 (s, IH (OH)), 7.20- 7.37 (m, 6H), 7.52 (t,lH), 8.04 (d,lH); ,3C NMR (CDC13, 100 MHz): δ 25.5, 28.6, 28.9, 29.5, 32.0, 35.7, 43.6, 57.1, 72.8, 126.8, 127.5, 128.3, 128.4, 128.5, 131.4, 133.1, 133.9, 144.2, 145.7, 202.8; MS (EI): C22H23C102 : 354.86; [M]+: 355.85; DSC peak at 167.85 °C (10°C/min)
PXRD [20] (Cu Ka! = 1.54060 A, = 1.54443 A, Kp = 1.39225 A; 40 mA, 45 kV): 8.07, 8.81, 8.93, 9.76, 10.51, 15.60, 17.29, 17.44, 19.10, 19.32, 20.84, 22.96, 24.37, 27.96, 29.55,
Example 3: Synthesis of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen- l 2H)-one (V)
2-(4-(4-chlorophenyl)- 1 -hydroxycyclohexyl)-3,4-dihydronaphthalen- 1 (2H)-one
(122.0 g, 0.0.345mol) was charged in a reactor equipped with overhead stirrer, reflux condenser and thermo-pocket. Toluene (2 L) was added to suspended the material and p- toluene sulfonic acid (3.05 g, 2.5 mol%) was added to the reaction mass which was then heated to 60 °C and stirred for 2h. Progress of reaction was monitored on TLC. After completion of reaction, reaction mass was cooled to RT and solvent was evaporated under pressure to obtain residue. To the residue, was added ethyl acetate (1500 mL) and washed with sat. NaHC03 soln. and brine followed by evaporation of solvent to give crude product
which was further recrystallised from methanol to obtain white solid compound (V) (55.2 g, 50%). Generally yield of the product ranges from 45 to 56 %.
FTIR (neat): 3020, 3045, 2920, 2894, 2863, 2839, 1683, 1597, 1491, 1218, 1088, 818, 747 cm"
1
lH NMR (CDCb, 400 MHz): δ 1.79-1.96 (m, 2H), 2.16-2.34 (m, 6H), 2.83-2.87 (m, 1H), 3.18 (s, 2H), 3.19-3.24 (m, 1H), 5.58 (d, 1H), 7.17-7.35 (m, 6H), 7.49 (t, 1H), 8.08 (d,lH); 13C NMR (CDC13, 100 MHz): δ 27.0 (27.2), 28.3 (28.5), 28.8, 29.8 (29.9), 33.4 (33.5), 39.3(39.4), 55.7(56.0), 124.1 (124.2), 126.7, 127.4 (127.5), 128. 3 (128.31), 128.4 (128.5), 128.7, 131.5, 132.8 (132.9), 133.4, 136.0 (136.1), 144.0 (144.1), 145.4 (145.5), 198.8 (198.9); MS (EI): C22H2iC10: 336.12; [M+H]+: 337.10 DSC peak at 136.02. °C (10°C/min)
Example 4: Synthesis of c/s /r /is-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one (VI)
2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3, 4-dihydronaphthalen-l(2H)-one (51. Og, 0.151 mol) was dissolved in acetone (1.1 L) at RT and transferred to a Parr autoclave reactor. Platinum oxide (0.097 g, 3 mol %) was added to the reaction mass and flushed twice with nitrogen and once with hydrogen. Subsequently, a hydrogen pressure of 5 kg/cm was maintained for 4-5h at RT after which the platinum black was filtered off through a Celite bed. The mother liquor was evaporated under reduced pressure to give crude product which was re-crystallized from methanol to give product as white solid (43.29g, 90% yield). Generally yield of the product ranges from 85to 95 %.
Cis/tran ,s-2-(4-(4-chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one ( 10 g) was suspended in cyclohexane (100 mL) and stirred for 1 h. c .y-2-(4-(4- chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- l(2H)-one was soluble in cyclohexane and trara-2-2-(4-(4-chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one remained insoluble (4.8 g). Single crystal was generated from cyclohexane layer which contain cis-2- (4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one (Figure VI).
FTIR (neat): 2917, 2887, 2850, 1681, 1491, 1294, 1089, 1012, 749, 530 cm"1.
1H NMR (CDCI3, 400 MHz): δ 1.24-1.28 (m, 1H), 1.44-1.59 (m, 3H), 1.74-1.85 (m, 3H), 1.90- 196 (m, 3H), 2.02-2.09 (m, 2H), 2.19-2.27 (m, 1H), 2.99-3.09 (m, 2H), 7.14-7.24 (m, 2H), 7.25- 7.35 (m, 5H), 7.47-7.5 (t,lH), 8.05-8.07 (d,lH) ; MS (EI): C22H23C10 : 338.15 [M+H]+: 339.00; DSC peak at 82.95 °C (10°C/min)
Example 5: Synthesis of cis/trans-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one (VII) and method for separation of CM and trans isomers
Cw/tr «5'-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l (2H)-one (43.2 g, 0.127 mol) was charged into a reactor equipped with thermo-pocket and dropping funnel. Acetic acid (86.4 g) and diethyl ether (1.5 L) were added and the reaction mass was cooled to 0 °C. Bromine (24.5 g, 0.153 mol) was dissolved in diethyl ether (100 mL) and added drop wise to the reaction mass at 0 °C. The resultant orange solution was stirred at 0 °C for lh and gradually the temperature was allowed to increase to 15-20 °C when the reaction mass started decolourizing, after which reaction temperature was allowed to increase upto 25 °C. After
completion of reaction, dichloromethane (300 mL) was added to dissolve solid, if any, precipitated during the reaction. Organic layer was washed with water (2 x 500 mL) and then with aqueous solution of 5% sodium thiosulphate (500 mL). Solvent was removed from the reaction mass under reduced pressure to obtain product as white solid (53.1 g, 99 %). Generally yield of the product ranges from 95 to 99 %.
OV/ra«5-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)- one (39 g) was suspended in methanol (100 mL) and stirred for 1 h. cw-2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- l(2H)-one was soluble in methanol and tra«5-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one
remained insoluble. Pure trarcs-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one was obtained through filtration as white solid (19 g) and major cw-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- 1 (2H)-one was obtained after evaporation of solvent under reduced pressure as sticky semi-solid material (21 g)- 7 /i5-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one
FTIR (neat): 2929, 2850, 1687, 1599, 1490, 1454, 1292, 1234, 1090, 1013, 916, 810, 747, 631 cm"1.
1H NMR (CDCI3, 400 MHz): δ 1.29-1.33 (m, 1H), 1.44-1.48 (m, 1H), 1.58-1.65 (m, 2H), 1.83- 1.91 (m, 2H), 2.06-2.09 (d, 1H), 2.25-2.31 (m, 1H), 2.38-2.54 (m, 3H), 2.70-2.76 (t, 1H), 2.93- 2.97 (d, 1H), 3.27-3.31 (m, 1H), 7.15-7.17 (d, 2H), 7.27-7.30 (m, 3H), 7.37-7.41 (t, 1H) 7.52- 7.56 (t,lH), 8.18-8.20 (d,lH) ; 13C NMR (CDC13, 100 MHz): δ 27.0, 28.3, 29.1, 31.5, 33.9, 34.2, 43.9, 44.2, 74.7, 127.1, 128.1, 128.3, 128.4, 128.6, 128.9, 129.1, 130.3, 131.6, 133.8, 142.5, 145.2, 190.3
DSC: peak at 182.95 °C
Example 6: Synthesis of cis/trans-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (VIII) and method for separation of cis and trans isomers
VII
Potassium tert-butoxide (31.2 g, 0.278 mol) was charged into a reactor containing dimethoxyethane (500 mL) at room temperature. Temperature of the reaction mass was increased to 40 °C and to this was added a solution of cis/trans-2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one (53.0 g, 0.126 mol) in dimethoxyethane (500 mL). Temperature of the reaction mass was further increased to 80°C and was allowed to stir for 1.5 h at this temperature. Progress of reaction was monitored on TLC. After completion of reaction, reaction mass was cooled to RT and solvent was evaporated under reduced pressure and 10% aqueous solution of hydrochloric acid (180 mL) was added to the residue. The resultant mixture was extracted with DCM (150 mL) and evaporated to give crude product (47.0 g). Generally average yield of the product ranges from 70 to 80 %.
Mixture of c 5,/tra«5,-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (25 g) was suspended in cyclohexane and stirred for 1 h. cis-2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l -ol was soluble in cyclohexane and trans-2-{4-{4- chlorophenyl)cyclohexyl)naphthalen-l-ol remained insoluble. Pure trara-2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one was obtained through filtration as light orange solid (7.5 g) and major c s-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one was obtained after evaporation of solvent under reduced pressure as sticky semi-solid material (11 g). Obtained major cis-2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol was further purified by column chromatography to obtain pure c/s-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol as sticky semi-solid brown colored material (7 g).
7>a i5-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol
FTIR (neat): 3563, 3016, 2928, 2853, 2400,, 1492, 1263,1216, 1094, 807, 768,755 cm"1.
1H NMR (CDC13, 400 MHz): δ 1.63-1.85 (m, 4H), 2.06-2.09 (m, 4H), 2.68-2.70 (t, IH), 3.03- 3.08 (t, IH), 7.15-7.17(d, 2H), 7.27-7.30 (m, 3H), 7.37-7.41 (t, IH) 7.82-7.84 (d,lH), 8.12-8.14 (d,lH) ; 13C NMR (CDC13, 100 MHz): δ 33.18, 34.58, 37.01, 43.51 , 76.73, 127.1, 128.3, 129.0, 129.1 , 130.3, 131.6, 133.8, 145.71, 147.24 MS (EI): C22H2iC10: 336.12; [M-H]": 335.20
DSC: peak at 195.14°C
PXRD [20] (Cu K„i = 1.54060 A, K«2 = 1.54443 A, Kp = 1.39225 A; 40 mA, 45 kV):
10.76, 12.38, 13.00, 13.33, 13.76, 14.37, 15.51, 16.10, 17.41 , 17.73, 18.71, 19.67, 20.05, 21.36, 22.39, 23.04, 23.40, 24.02, 24.56, 26.1 1, 27.72, 28.97, 30.01, 31.78
Example 7: Synthesis of c/s /ra/ii-4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (IX) in presence of acetic acid/ hydrogen peroxide
To 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (1.2 g, 3.5 mmol) taken in a RB flask, was added acetic acid (20 mL) and stirred for 15 min at RT. Temperature of the reaction mass was increased to 80 °C and a 30% solution of H202 (5 mL) was added to it drop wise over a period of 30 min at 80 °C and stirred for another 30 min. After cooling to RT, water (50 mL) was added to the reaction mass. The resultant mixture was extracted with DCM (3x 100 mL), dried over anhydrous Na2S04 and evaporated to give crude product which was purified by column chromatography to give pure product as yellow solid. (0.4 g, 32% yield)
FTIR (neat): 3310, 2926, 2856, 1662, 1614, 1594, 1492, 1449, 1329, 1305, 1261, 1251, 1091, 1012, 937, 822, 779, cm-1.
13C NMR (CDCb, 100 MHz): δ 26.92, 27.74, 29.81, 32.16, 33.93, 34.41, 36.21 , 38.73, 43.39, 125.96, 126.00, 126.75, 126.46, 128.18, 128.46, 128.52, 128.62, 131.46, 131.68, 131.85, 131.9, 132.45, 132.53, 133.13, 133.67, 133.71, 134.1 1, 143.50, 145.28, 155.17, 155.64, 184.74, 184.90, 185.33, 185.50;
Example 8: Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (IX) in presence of acetic acid/ hydrogen peroxide/potassium bromide
To 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (1.0 g, 2.9 mmol) taken in a RB flask, were added acetic acid (20 mL) and potassium bromide (1.0 g, 8.4 mmol) and stirred for 15 min at RT. Temperature of the reaction mass was increased to 80 °C and a 30% solution of H202 (5 mL) was added to it dropwise over a period of 30 min at 80 °C and stirred for another 30 min. After cooling to RT, water (50 mL) was added to the reaction mass. The resultant mixture was extracted with DCM (3x 100 mL), dried over anhydrous Na2S04 and evaporated to give crude product which was purified by column chromatography to give pure product as yellow solid. (0.52 g, 50% yield) Example 8: Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (IX) in presence of sodium bromate/ acetic acid
2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (5.1 g, 15.1 mmol) was added to acetic acid (70 mL) and resulting reaction mass was heated to 60 °C. Sodium bromate (1.5 g, 10 mmol) was added to the above reaction mixture and stirred for 1 h at 80 °C. Water (15 mL) was added to the reaction mixture and stirred for an additional 2 h at 80 °C. The reaction mixture was cooled to RT and water (200 mL) was added to it. The resultant mixture was extracted with dichloromethane (2 x 300 mL). Combined organic layer was dried over anhydrous Na2S04 and evaporated to give crude product which was purified by column chromatography (stationary phase: Silica gel and mobile phase: 2% ethyl acetate in cyclohexane) to give pure product as yellow solid. (3.5 g, 66 % yield)
Example 9: Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (IX) in presence of sodium nitrite/ 50% aqueous sulphuric acid.
To a stirred solution of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (42.3 g, 125.9 mmol) in 1,4-dioxane (850 mL) were added 50 % aqueous sulphuric acid (170 mL) and sodium nitrite (17.4 g, 251.7mmol) at 5 °C and temperature of the resultants reaction mixture was increased to 80 °C and stirred for another 2 h. After cooling to RT, water (50 mL) was added to the reaction mass and extracted with ethyl acetate (3x 500 mL), dried over anhydrous Na2S04 and solvent was evaporated to crude product, which was further purified by column chromatography (stationary phase: Silica gel and mobile phase: 2% ethyl acetate in cyclohexane) to give pure product as yellow solid. (30.3 g, 70%)
Example 10: Synthesis of cw/i'/* «5-7a-(4-(4-chlorophenyl)cyclohexyI)naphtho[2,3- b]oxirene-2,7(laH,7aH)-dione (X)
4-(4-chlorophenyl)cyclohexyl)naphthalene-l ,4-dione (13.5 g, 38.5 mmol) was charged into a reactor along with 1,4-dioxane (135 mL) at RT. To this were added sodium carbonate (4.5 g, 42.4 mmol) and a 30% soln. of H202 (5.23 g, 154.0 mmol) and the reaction mass was refluxed for 30 min. After cooling the reaction mass to RT, water (50 mL) was added and extracted with ethyl acetate (3*300 mL). Solvent was removed under reduced pressure to give product as off-white solid (13.7 g, 96% yield).
FTIR (KBr): 3370, 3078, 2944, 2928, 2900, 2859, 1695, 1594, 1490, 1451 , 1306, 1287, 1157, 1089, 944, 886, 801 , 725 cm-1.
1H NMR (CDC13, 400 MHz): δ 1.28-1.41 (m, 2H), 1.56-1.62 (t, 2H), 1.9 (s, 4H), 3.96 (s, 1H) 7.16-7.18(d, 2H), 7.28-7.29 (d, 2H), 7.76-7.78 (t, 2H) 7.97-7.98 (d,2H), 8.03-8.05 (d,2H) ;13C NMR (CDCI3, 100 MHz): δ 26.6, 29.3, 33.3, 33.4, 34.3, 37.7, 43.3, 57.7, 58.2, 66.3, 66.9, 126.5, 126.6, 127.6, 128.4, 128.5, 131.5, 131.6, 132.8, 134.3, 134.6, 143.2, 145.2, 191.5, 192.1
Example 11: Synthesis of Atovaquone [I]
To la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (13.5g, 1.6 mmol) taken in a reactor was added cone. H2S04 (135 mL) and stirred for 5 h at RT. Water (2 L) was added to the reaction mass and extracted with DCM (3*200 mL). Solvent was evaporated under reduced pressure to give crude product which was further re- crystallized from acetonitrile to obtain pure compound as a yellow solid (10 g, 74% yield).
FTIR (KBr): 3375, 2958, 2924, 2853, 1659, 1646, 1625, 1594, 1490, 1369, 1344, 1277, 1248, 1216, 1089, 998, 822, 727, 656, 530 cm"1.
Ή NMR (CDC13, 400 MHz): δ 1.58 (q, 2H), 1.75 (d, 2H), 1.96 (d, 2H), 2.16-2.20 (m, 2H), 2.63 (t, IH), 3.16 (t, IH), 7.18 (d, 2H), 7.28 (d, 2H), 7.48 (s, IH), 7.68 (t, IH), 7.76 (t,lH), 8.07 (d, IH), 8.13 (d, IH); 13C NMR (CDCI3, 100 MHz): δ 29.18, 34.34, 34.46, 34.64, 43.22, 126, 127, 127.25, 128.43, 129.19, 129.31, 131.45, 132.86, 133.12, 135.02, 146.05, 152.98, 181.80, 184.56; MS (EI): C22Hi9C103: 366.1023; [M+Na]+: 388.95, [M-H]": 365.30; DSC peak at 220.44 °C (10°C/min)
PXRD [20] (Cu Kttl = 1.54060 A, K„2 = 1.54443 A, Kp = 1.39225 A; 40 mA, 45 kV): 7.30, 9.70, 10.79, 1 1.1 1, 1 1.83, 15.43, 16.16, 16.89, 17.39, 22.93, 24.62, 24.68, 25.35, 26.18, 26.84, 28.52, 28.70, 29.52, 30.68, 34.23, 36.84. Example 12: Conversion of "c/s" isomer of Atovaquone to "fra/is" isomer of Atovaquone in presence of Titanium tetrachloride.
Cis isomer of Atovaquone (0.5 g) was dissolved in dichloromethane (20 mL) and T1CI4 (0.5 mL)was added to it at RT. Resulting reaction mixture was heated to 40 °C and stirred for 24 h. Reaction was monitored for conversion of cis isomer of Atovaquone to trans
isomer at different intervals. After 24 h, HPLC analysis showed the cis to trans ratio as 50:50.
HPLC Retention time for cis isomer: 19.33 min
HPLC Retention time for trans isomer: 22.66 min
Example 13: Conversion of "cw" isomer of Atovaquone to "fra/is" isomer of Atovaquone in presence of Sulphuric acid.
Cis/trans Atovaquone (0.5 g) was added in sulphuric acid (10 mL) at RT and stirred for 2 h, after which the reaction mixture was poured in ice water and product was extracted with dichloromethane, which was analyzed on HPLC as per resolution method given in US pharmacopoeia.
HPLC Retention time for cis isomer: 19.33 min
HPLC Retention time for trans isomer: 22.66 min Example 14: Synthesis of c/s-4-(4-chlorophenyl)cyclohexy.)naphthalene-l,4-dione (XII) in presence of Sodium Nitrite/ sulphuric acid
1.4 mmol) in 1,4 dioxane (20 mL) were added 50 % aqueous sulphuric acid (10 mL) and sodium nitrite (0.2 g, 2.9mmol) at 5 °C and temperature of the resultant reaction mixture was increased to 80 °C and stirred for 2 h. After cooling to RT, water (50 mL) was added to the reaction mass and extracted with DCM (3x 100 mL), dried over anhydrous Na2S04 and
evaporated to give crude product which was purified by column chromatography (stationary phase: Silica gel and mobile phase: 2% ethyl acetate in cyclohexane) to give pure product as yellow solid. (0.34 g)
1H NMR (CDC13, 400 MHz): *5 1.71-1.75 (m, 2H), 1.84-1.96 (m, 4H), 2.04-2.06 (m, 2H), 6.82 (s, 1H), 7.23-7.30 (dd, 4H), 7.73-7.75 (m, 2H), 8.06-8.12 (dd, 2H) ; 13C NMR (CDC13, 100 MHz): δ 27.73, 27.84, 29.80, 34.41, 38.74, 127.1, 128.3, 129.0, 129.1 , 130.3, 131.6, 133.8, 143.49, 1555.18, 184.91,185.34.
Example 15: Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (XII) in presence of Sodium bromate/ acetic acid
To a stirred solution of c/,s-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (5.0 g, 15 mmol) in acetic acid (75 mL) was added sodium bromate (1.48 g, 9.8 mmol) at 25 °C and resulting reaction mixture was stirred for another 30 min at 80 °C after which the reaction mixture was cooled to RT. Water (50 mL) was added to the reaction mass and extracted with DCM (3x 100 mL), dried over anhydrous Na2S04 and solvent evaporated to give crude product which was purified by column chromatography (stationary phase: Silica gel and mobile phase: 2% ethyl acetate in cyclohexane) to give pure product as yellow solid. (3.0g, 58 % yield)
Example 16: Synthesis of la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene- 2,7(laH,7aH)-dione (XIII)
C/s-4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (1.85 g,) was charged into a reactor along with 1 ,4-dioxane (20 mL) at RT. Sodium carbonate (0.2 g, 2.0 mmol) was added to the above reaction mixture and a 30% soln. of H202 (1.5 ml, 20.0 mmol) was added drop wise and the reaction mass was heated to 80 °C and stirred at that temperature for 30 min. After cooling the reaction mass, water (50 mL) was added and extracted with ethyl acetate (100 mL). Solvent was removed under reduced pressure to give crude product as yellow solid (1.7 g, 90 % yield).
Example 17: Synthesis of cis-Atovaquone [XIV]
Cw-la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (1.7 g, 4.7 mmol) was taken in a reactor and to it was added dilute H2S04 (10 mL) and stirred for 20 min at RT. Water (100 mL) was added to the reaction mass and extracted with DCM (100 mL). HPLC analysis confirms ds-Atovaquone.
Retention time for c/s-Atovaquone: 19.23 min
Example 18: Synthesis of 8-(4-chlorophenyl)-l,4-dioxa-spiro[4.5]decan-8-ol (iii)
Activated magnesium turnings (92.2g, 3.84 mol) were charged to a nitrogen dried reactor equipped with reflux condenser, nitrogen bubbler, thermo pocket and side arm addition funnel. Dry THF (2.0 L) and catalytic amount of iodine were added and reactor was gently heated. 1- Bromo 4-chlorobenzene (674.0 g, 3.52 mol) solution in THF (2 L) was added slowly into the above reaction mass at 50 °C to obtain corresponding Grignard reagent. To this Grignard reagent, solution of 1,4 cyclohexanedione mono-ethylene ketal (500.0 g, 3.20 mol) in THF (2 L) was added at 40-50 °C and resulting reaction mixture was heated at 50 °C for 1 h, after which the reaction mixture was quenched with aqueous solution of ammonium chloride and solvent was evaporated to obtain crude 8-(4-chlorophenyl)-l,4-dioxa-spiro[4.5]decan-8-ol (v), which was suspended in dilute hydrochloric acid (6 L) and stirred for 30 min and after filtration, white solid was obtained as product (764.0 g, 93% yield). Generally yield of the product ranges from 88 to 95 %.
1H NMR (CDCI3, 400 MHz): δ 1.49 -1.69 (d, 2H), 1.72-1.78 (d, 2H), 2.08-2.19 (m, 4H), 3.96- 4.03 (m, 4H), 7.28-7.37 (m 2H), 7.41-7.48 (m, 2H). 13C NMR (CHC13, 100 MHz): δ 30.6, 36.5,64.2, 64.3, 72.2, 108.2, 125.9, 128.6, 132.6, 147.0.
PXRD [20] (Cu Kal = 1.54060 A, K„2 = 1.54443 A, Kp = 1.39225 A; 40 mA, 45 kV): 8.09, 8.96, 12.30, 14.84, 16.43, 17.60, 17.93, 18.88, 20.92, 22.29, 24.70, 15.59, 30.02, 30.31
xample 19: Synthesis of 4-(4-chlorophenyl)-cycIohex-3-enone monoethylene ketal
8-(4-chlorophenyl)-l ,4-dioxa-spiro[4.5]decan-8-ol (750.0 g, 2.8mol) was charged in a reactor equipped with Dean-Stark condenser and thermo-pocket. Toluene (15L) was added to suspended the material and /7-toluene sulfonic acid (15.95 g, 3mol%) and ethylene glycol (250 mL, 2.8 mol) were added to the reaction mass which was then heated to 110 °C and stirred for 6h. Reaction was monitored by TLC and after complete consumption of starting material; reaction mass was cooled to room temperature. Solvent was evaporated under reduced pressure to obtain crude product, which was suspended in 1% aqueous sodium bicarbonate solution (1.5 L) and stirred for 1 h. Resulting suspension was filtered to obtain yellow solid (669.0 g, 93 % yield). Generally yield of the product ranges from 90 to 97 %.
FTIR (neat): 2877, 1644, 1495, 1243, 1 123, 1024 cm"1.
1H NMR (CDCb, 400 MHz): δ 1.91 -1.94 (t, 2H), 2.47 (s, 2H), 2.62-2.63 (t, 2H), 4.02 (s, 4H) 5.99 (s, 1H), 7.25- 7.33 (m, 4H); I3C NMR (CHClj, 100 MHz): δ 27.8, 31.2, 36.1, 64.5, 107.5, 212.5, 122.1 , 126.4, 128.2, 132.5, 135.2, 139.8.
Example 19: Synthesis of 4-(4-chlorophenyl)-cyclohexanone [III]
4-(4-Chlorophenyl)-cyclohex-3-enone monoethylene ketal (291.0 g, 1.15 mol) was dissolved in ethyl acetate (2.3 L) at RT and transferred to a Parr autoclave reactor. Palladium on carbon (9.0 g, 3 wt %) was added to the reaction mass and flushed twice with nitrogen and
once with hydrogen. Subsequently, a hydrogen pressure of 5-7 kg/cm2 was maintained for 7h at RT. Reaction was monitored on TLC; after completion of reaction, palladium on carbon was filtered through a Celite bed. The mother liquor was evaporated under reduced pressure to give crude product as light yellow semi solid of 4-(4-Chlorophenyl)-cyclohexanone monoethylene ketal (v).
Crude 4-(4-Chlorophenyl)-cyclohexanone monoethylene ketal (v) was suspended in 50:50 acetone: water (1000 mL) at 25 °C and ^-TSA (11.5 g, 5 mol %) was added to it. The reaction mass was heated to 70 °C and stirred for 3h after which it was cooled to RT. Acetone was evaporated under reduced pressure and resultant slurry was added to sodium bicarbonate solution and stirred for 30 min at 5 °C and filtered off to afford pure product as off-white solid (198.0 g, 88 % yield). Generally yield of the product ranges from 80 to 90 %. FTIR (neat): 2939, 1712, 1490, 1 164, 1091, 1013, 833 cm-1.
1H NMR (CDC13, 200 MHz): δ 1.85 -1.93 (m, 2H), 2.18-2.22 (m, 2H), 2.49-2.59 (m, 4H) 2.98- 3.05 (m, 1H), 7.14-7.19 (m, 2H), 7.25-7.30 (m, 2H); 13C NMR (CHC13, 100 MHz): S 33.8, 41.3, 42.1, 128.0, 128.4, 132.2, 143.2, 210.7; DSC (10 °C/min): Peak at 63.39 °C
Claims
1) A process to prepare 2-[tra«s-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4- naphthoquinonnamely Atovaquone [I] comprising the steps of- i) condensing (l,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4- chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent to obtain 2-(4-(4-chlorophenyl)- 1 -hydroxy cyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)- one [IV]
ii) dehydration of 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3 ,4- dihydronaphthalen- l(2H)-one [IV] in organic solvent and in presence of acid such as pTSA to obtain diastereomeric mixture of 2-(4-(4-chlorophenyl)cyclohex-l-enyl)- 3 ,4-dihydronaphthalen- 1 (2H)-one [V]
iii) hydrogenation of 2-(4-(4-chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen- l(2H)-one[V] with Pt02 to obtain cis/trans mixture of 2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- 1 (2H)-one [VI]
iv) optional selective crystallization of cis/trans mixture of 2-(4-(4- chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- l(2H)-one [VI] to separate the 'tis ' and 'trans ' isomers of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- l(2H)-one
v) ketone bromination of cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one [VI] to obtain cis/trans mixture of 2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- 1 (2H)-one [VII]
vi) in absence of step (d) optional selective crystallization of 2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- l(2H)-one [VII] to separate the 'tis ' and 'trans ' isomers of 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one [VII]
vii) elimination of cis/trans mixture of 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)- 3,4-dihydronaphthalen-l(2H)-one [VII] with a strong base to give cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l -ol [VIII]
viii) in absence of step (f) optionally crystallizing 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] to separate the 'cis ' and 'trans' isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII]
ix) oxidizing cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] to obtain cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene- 1,4-dione [IX]
x) base catalyzed epoxidation of cis/trans mixture of 2-(4-(4- chlorophenyl)cyclohexyl)naphthalene-l,4-dione [IX] to cis/trans mixture of la-(4-(4- chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (X) in presence of hydrogen peroxide
xi) acid catalyzed hydrolysis of cis/trans mixture of la-(4-(4- chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (X) to obtain 2- [tra«5-4-(4'-chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone [I]
2) The process according to Claim 1 step i) wherein the Lewis acid used is titanium tetrachloride.
3) The process according to claim 1 step ii), wherein the dehydrating agent is selected from the group of Bronsted acids consisting of ^-toluene sulfonic acid, methane sulfonic acid and triflic acid.
4) The process according to claim 1 step ii), wherein organic solvent is selected from the group consisting of dichloromethane, toluene and benzene.
5) The process according to claim l step iv) wherein the solvent used for selective crystallization is cyclohexane.
6) The process according to claim 1 step v), wherein the bromination is carried out with bromine in acetic acid in diethyl ether.
7) The process according to claim l step vi) wherein the solvent used for selective crystallization is methanol.
8) The process according to claim 1 step vii) wherein strong base used is selected from the group consisting of potassium t-butoxide, sodium methoxide and sodium ethoxide.
9) The process according to claim 1 step viii) wherein solvent used for selective crystallization is cyclohexane.
10) The process according to claim 1 step ix) wherein oxidation reaction is carried out by acetic acid/H202 or acetic acid/NaBr03 or sulfuric acid/NaN02 or RuCl3/AcOH/H202.
1 1) The process according to claim 1 step x) wherein epoxidation reaction is carried out by sodium bicarbonate and hydrogen peroxide.
12) The process according to claim 1 step xi) wherein hydrolysis is carried out by sulfuric acid.
13) A compound 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4-dihydronaphthalen- l(2H)-one [IV].
14) Compound 2-(4-(4-chlorophenyl)- 1 -hydroxycyclohexyl)-3 ,4-dihydronaphthalen- l(2 )-one [IV] adapted for use in preparation of 2-[trans-A-(4'- chlorophenyl)cyclohexy 1] -3 -hydroxy- 1 ,4-naphthoquinone [I] .
15) A process to prepare compound 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4- dihydronaphthalen-l(2 )-one [IV] comprising condensation of (1,2- dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4- chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent.
16) The process according to claim 15, wherein Lewis acid used is titanium tetrachloride.
17) The process according to claim 15, wherein the compound 2-(4-(4-chlorophenyl)-l- hydroxycyclohexyl)-3,4-dihydronaphthalen-l(2//)-one [IV] is obtained in trans configuration.
18) The compound according to claim 17, adapted for use in preparation of 2-[trans-4- (4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone [I].
19) A compound 2-(4-(4-chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)- one[V].
20) The process according to claim 1 step ii) wherein the compound (V) is obtained in a diastereomeri mixture of [A] and [B]
21) The compound according to claim 19, adapted for use in the preparation of 2-[trans- 4-(4'-chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone [I] .
22) A compound (l,2-dihydronaphthalen-4-yloxy)trimethylsilane [II]
23) A compound 4-(4-chlorophenyl)cyclohexanone [III]
24) A compound 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [VI]
25) The compound according to claim 24, adapted for use in preparation of 2-[trans-4- (4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone [I]
26) A compound 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- l(2H)-one [VII]
27) The compound according to claim 26, adapted for use in preparation of 2-[trans-4- (4'-chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone [I]
28) A compound 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII]
29) The compound according to claim 28, adapted for use in preparation 2-[trans-4-(4'- chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone [I]
30) A compound 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione [IX]
31) The compound according to claim 30, adapted for use in preparation of 2-[trans-4- (4'-chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone [I]
32) A compound la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene- 2,7(1 aH,7aH)-dione (X)
33) The compound according to claim 32, adapted for use in preparation of 2-[trans- - (4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone [I]
34) A process for making a compound of formula (III), comprising the steps of- a) Preparation of (4-chlorophenyl)magnesium bromide (Grignard reagent) by reacting l-bromo-4-chlorobenzene with magnesium turning in presence catalytic amount of iodine
b) reacting (4-chlorophenyl)magnesium bromide with 1 ,4-cyclohexanedione monoethylene ketal to obtain 8-(4-chlorophenyl)-l,4-dioxa-spiro[4.5]decan-8-ol) c) dehydration of 8-(4-chlorophenyl)-l,4-dioxa-spiro[4.5]decan-8-ol in toluene and in presence of p-TSA and ethylene glycol to obtain 4-(4-chlorophenyl)-cyclohex-3- enone monoethylene ketal
d) hydrogenating 4-(4-chlorophenyl)-cyclohex-3-enone monoethylene ketal in presence of noble metal catalyst such as palladium on carbon, platinum oxide, to obtain compound 4-(4-chlorophenyl)-cyclohexanone monoethylene ketal
e) deketalization of 4-(4-chlorophenyl)-cyclohexanone monoethylene ketal in presence of /?TSA in mixture of acetone: water to obtain 4-(4-chlorophenyl) cyclohexanone [III]
35) A process for making a compound of formula (XIV), comprising the steps of- a) a process to convert c/ 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (XI), to m-4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (XII) in presence of sulphuric acid /sodium nitrite or sodium bromate/acetic acid or acetic acid/hydrogen peroxide or ruthenium chloride/hydrogen peroxide/acetic acid
b) a process to convert c s-4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (XII) to cis- 1 a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7( 1 aH,7aH)-dione (XIII) in presence of hydrogen peroxide and sodium bicarbonate.
c) a process of converting c«-la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3- b]oxirene-2,7(laH,7aH)-dione (XIII) to give cis isomer of Atovaquone in presence of sulfuric acid.
36) A process of isomerization of cis isomer of Atovaquone to trans- Atovaquone (2-[trans-A- (4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone) in presence of Lewis acid.
37) The process according to claim 36, wherein the Lewis acid used is titanium tetrachloride.
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CN103570520A (en) * | 2013-08-21 | 2014-02-12 | 山东鲁抗舍里乐药业有限公司 | Benzoquinones compound, preparation method and application thereof |
CN103570521A (en) * | 2013-08-21 | 2014-02-12 | 山东鲁抗舍里乐药业有限公司 | Preparation method of atovaquone |
CN106397522A (en) * | 2015-07-31 | 2017-02-15 | 中国人民解放军军事医学科学院毒物药物研究所 | 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester |
CN110724155A (en) * | 2019-11-11 | 2020-01-24 | 北京华素制药股份有限公司 | Preparation method of oxycodone aldol dimer |
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CN103570521A (en) * | 2013-08-21 | 2014-02-12 | 山东鲁抗舍里乐药业有限公司 | Preparation method of atovaquone |
CN106397522A (en) * | 2015-07-31 | 2017-02-15 | 中国人民解放军军事医学科学院毒物药物研究所 | 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester |
CN110724155A (en) * | 2019-11-11 | 2020-01-24 | 北京华素制药股份有限公司 | Preparation method of oxycodone aldol dimer |
CN111643670A (en) * | 2020-05-29 | 2020-09-11 | 新疆医科大学 | Energy dual-regulation medicine and preparation method and application thereof |
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