WO2007005572A1 - Process for synthesizing a cetp inhibitor - Google Patents
Process for synthesizing a cetp inhibitor Download PDFInfo
- Publication number
- WO2007005572A1 WO2007005572A1 PCT/US2006/025511 US2006025511W WO2007005572A1 WO 2007005572 A1 WO2007005572 A1 WO 2007005572A1 US 2006025511 W US2006025511 W US 2006025511W WO 2007005572 A1 WO2007005572 A1 WO 2007005572A1
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- Prior art keywords
- compound
- formula
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- reaction
- crystalline
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000008569 process Effects 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title claims description 6
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 title description 7
- 229940125881 cholesteryl ester transfer protein inhibitor Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003112 inhibitor Substances 0.000 claims abstract description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 68
- 239000012453 solvate Substances 0.000 claims description 58
- 238000006243 chemical reaction Methods 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 36
- 239000000126 substance Substances 0.000 claims description 24
- 239000011734 sodium Substances 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 17
- 229910052708 sodium Inorganic materials 0.000 claims description 17
- 239000002585 base Substances 0.000 claims description 15
- 229910052783 alkali metal Inorganic materials 0.000 claims description 14
- 229910052700 potassium Inorganic materials 0.000 claims description 14
- -1 alkali metal cation Chemical class 0.000 claims description 13
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 238000001160 cross-polarisation magic angle spinning nuclear magnetic resonance spectrum Methods 0.000 claims description 10
- 229910052744 lithium Inorganic materials 0.000 claims description 10
- 201000001320 Atherosclerosis Diseases 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 4
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 claims description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 3
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 229910052792 caesium Inorganic materials 0.000 claims 3
- 238000006073 displacement reaction Methods 0.000 claims 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims 1
- 229940110346 PPAR gamma partial agonist Drugs 0.000 claims 1
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 229940125425 inverse agonist Drugs 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract 2
- KEWSCDNULKOKTG-UHFFFAOYSA-N 4-cyano-4-ethylsulfanylcarbothioylsulfanylpentanoic acid Chemical compound CCSC(=S)SC(C)(C#N)CCC(O)=O KEWSCDNULKOKTG-UHFFFAOYSA-N 0.000 abstract 1
- 102100037637 Cholesteryl ester transfer protein Human genes 0.000 abstract 1
- 101000880514 Homo sapiens Cholesteryl ester transfer protein Proteins 0.000 abstract 1
- 235000010290 biphenyl Nutrition 0.000 abstract 1
- 239000004305 biphenyl Substances 0.000 abstract 1
- 230000008878 coupling Effects 0.000 abstract 1
- 238000010168 coupling process Methods 0.000 abstract 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 63
- 229940125797 compound 12 Drugs 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 238000005384 cross polarization magic-angle spinning Methods 0.000 description 22
- 239000000543 intermediate Substances 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- 238000009472 formulation Methods 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- 239000000523 sample Substances 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 150000001340 alkali metals Chemical class 0.000 description 8
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 8
- 239000002002 slurry Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 208000029078 coronary artery disease Diseases 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 4
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 108010023302 HDL Cholesterol Proteins 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000001595 flow curve Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 0 *C(*C(*1)O)C1c1ccccc1 Chemical compound *C(*C(*1)O)C1c1ccccc1 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 238000005388 cross polarization Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 230000009477 glass transition Effects 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 238000008214 LDL Cholesterol Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001499 aryl bromides Chemical class 0.000 description 2
- 150000001500 aryl chlorides Chemical class 0.000 description 2
- 239000012455 biphasic mixture Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
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- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- TYRGLVWXHJRKMT-MRVPVSSYSA-N (2r)-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound OC(=O)[C@@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-MRVPVSSYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- CSVCVIHEBDJTCJ-UHFFFAOYSA-N 1-bromo-3,5-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(Br)=CC(C(F)(F)F)=C1 CSVCVIHEBDJTCJ-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- MZZLGJHLQGUVPN-HAWMADMCSA-N CC(C)c(c(F)c1)cc(-c2ccc(C(F)(F)F)cc2CN([C@@H](C)[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)O2)C2=O)c1OC Chemical compound CC(C)c(c(F)c1)cc(-c2ccc(C(F)(F)F)cc2CN([C@@H](C)[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)O2)C2=O)c1OC MZZLGJHLQGUVPN-HAWMADMCSA-N 0.000 description 1
- COJHEKPKQIRBES-UHFFFAOYSA-N CCCCCCN1C(CCC(C)=C)C1 Chemical compound CCCCCCN1C(CCC(C)=C)C1 COJHEKPKQIRBES-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000005079 FT-Raman Methods 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
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- 208000026758 coronary atherosclerosis Diseases 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- WDUDHEOUGWAKFD-UHFFFAOYSA-N ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+) Chemical compound [Fe+2].CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1 WDUDHEOUGWAKFD-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920003223 poly(pyromellitimide-1,4-diphenyl ether) Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate 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
- 239000011343 solid material Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 208000023516 stroke disease Diseases 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- CMSGWTNRGKRWGS-NQIIRXRSSA-N torcetrapib Chemical compound COC(=O)N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMSGWTNRGKRWGS-NQIIRXRSSA-N 0.000 description 1
- 229950004514 torcetrapib Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 238000001622 two pulse phase modulation pulse sequence Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- This invention relates to a process for synthesizing a chemical compound that inhibits cholesterol ester transfer protein (CETP) and to crystalline polymorphic forms of a particular compound made by this process.
- the product of the process raises HDL-cholesterol in mammals and is expected to have utility in the treatment and/or prevention of atherosclerosis and in delaying the advancement of atherosclerosis.
- CHD coronary heart disease
- stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
- CHD coronary heart disease
- stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
- CHD coronary heart disease
- stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
- CHD coronary heart disease
- stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
- CHD coronary heart disease
- CETP inhibitors raise HDL-cholesterol, and may provide a potent new tool for reducing CHD and atherosclerosis in the general population. Administration of both a CETP inhibitor and a statin may be especially valuable for treating and preventing atherosclerosis. Pharmaceuticals containing CETP inhibitors are not currently available. Pfizer's torcetrapib is a CETP inhibitor that is currently in Phase HI trials.
- the present invention provides a process for preparing compounds having formula I. These novel compounds are potent CETP inhibitors:
- the process provides a convergent synthesis of Compound I.
- the complete process comprises the synthesis of two key intermediates, II and IH.
- the key intermediates are then coupled in the last step of the process, which is shown below:
- Rl is H or Ci-4alkyl, which is optionally substituted with 1-5 F groups;
- R2, R4, and R5 are each independently selected from the group consisting of halogen,
- R3 is selected from H, halogen, Ci-4alkyl, and -OCi_4alkyl, wherein Ci_4alkyl and -OCi_4alkyl are optionally substituted with 1-5 halogens; a and b are each independently selected from integers from 1-4; c is an integer from 0-2;
- X is H or a group I metal cation (e.g. Na, K, Li, or Cs), and
- Y is a leaving group (i.e. a group that is easily displaced). Examples of leaving groups include halogen, Ci_3 alkanoate (e.g. acetate), trifluoroacetate, and triflate.
- X is H
- a base is also included in the reaction, where the base is an alkali metal salt of a strong base.
- the alkali metal may be Na, K, Li, or Cs; and in subgroups, the alkali metal may be Na or K; in other subgroups, the alkali metal may be Na; in other subgroups, the alkali metal may be K.
- alkali metal salts of strong bases include sodium amide, potassium amide, NaHMDS, KHMDS, n-butyl lithium, and t-butyl lithium.
- the use of the base yields as an intermediate compound ⁇ , with X being Na, K, Li, or Cs.
- Rl is H or C 1.3 alkyl, optionally substituted with 1-5 F.
- R* in other embodiments is Ci-2 alkyl, optionally substituted with 1-3 F.
- Rl is CH3.
- R ⁇ , R4 and R5 are each independently F, Ci .3 alkyl optionally substituted with 1-5 F, or -OCi .3 alkyl optionally substituted with 1-5 F.
- R 2 , R4 9 and R5 are each independently F, Ci_3alkyl, optionally substituted with 1-5 F, or -OCi-2alkyl, optionally substituted with 1-5F.
- R2, R4 ; and R5 are each independently selected from Ci-3alkyl, CF3, -OCH3, -OCF3, and F.
- each R2 is CH3 or CF3.
- R2 is CF3.
- R3 is Ci-3alkyl, -OCi-3alkyl , or F, wherein Ci-3alkyl and OCi-3alkyl are optionally substituted with 1-5 F.
- R3 is CH3, CF3 or F. In other embodiments, R3 is CF3.
- a is 1 or 2, and in other embodiments, a is 2. In some embodiments, b is 1-3. In other embodiments, b is 2 or 3. In other embodiments, b is 3.
- c is 0 or 1. In other embodiments, c is 0. In some embodiments, X is H, Na, or K. In other embodiments, X is Na or K.
- Y is halogen. In other embodiments Y is Cl, Br or I. In other embodiments, Y is Cl or Br. In other embodiments, Y is Cl.
- alkyl groups may be either linear or branched.
- FIG. 1 is a characteristic X-ray powder diffraction pattern of the crystalline non-solvate form of compound 12.
- FIG. 2 is a typical DSC curve of the crystalline non-solvate form of compound 12.
- FIG. 3 is a typical carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of the crystalline non-solvate form of compound 12.
- CPMAS cross-polarization magic-angle spinning
- FIG. 4 is a typical fluorine- 19 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of the crystalline non-solvate form of compound 12.
- CPMAS cross-polarization magic-angle spinning
- NMR nuclear magnetic resonance
- FIG. 5 is a characteristic X-ray powder diffraction pattern of the crystalline heptane solvate form of compound 12.
- FIG. 6 is a typical carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of the crystalline heptane solvate form of compound 12.
- CPMAS cross-polarization magic-angle spinning
- NMR nuclear magnetic resonance
- FIG. 7 is a typical fluorine-19 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of the crystalline heptane solvate form of compound 12.
- FIG. 8 is a typical carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of the amorphous form of compound 12.
- FIG. 9 is a typical fluorine- 19 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of the amorphous form of compound 12.
- FIG. 10 is a typical modulated DSC (MDSC) curve of the amorphous form of compound 12.
- X is H or a group I alkali metal (e.g. Na, K, Li, or Cs).
- the group I metal cation may be complexed with a ligand, such as TMEDA, or with an ether or polyether, such as a crown ether, that increases the reactivity of the negatively charged N of the oxazolidinone group of ⁇ .
- X may also be H.
- X is a metal cation (e.g. Na, K, Li, or Cs)
- Intermediate II can be made by the reaction of the oxazolidinone (X is H) with a metal hydride, an alkyl metal compound, or a reactive alkali metal amide.
- bases such as sodium amide, potassium amide, NaHMDS, KHMDS, n-butyl lithium, and t-butyl lithium.
- X is H
- a base is also included in the reaction, where the base is one of the bases that are used to convert the oxazolidinone to reactive compounds in which X is Na, K, Li, or Cs.
- the X groups are selected from K and Na in many embodiments.
- the group X in Example 1 is Na.
- Y is a leaving group (i.e. a group that is easily displaced).
- the leaving group is usually anionic after it has been displaced.
- the most common leaving groups are halogens, such as Cl, Br, I or F.
- the leaving may also be the deprotonated form of an organic acid, such as triflate or trifluoroacetate.
- the leaving group Y is selected from Br, Cl and I.
- the leaving group Y is selected from Br and Cl.
- the group Y is Cl for the synthesis of compound 12 in Example 1.
- the reaction is generally carried out in a polar aprotic solvent, such as HMPA, DMF, or DMAC.
- a polar aprotic solvent such as HMPA, DMF, or DMAC.
- DMF is used as the solvent.
- the reaction proceeds under mild conditions of temperature. Exemplary mild conditions are -20 0 C, -10 0 C, 0 0 C, 10 0 C, 20 0 C, 30 0 C and 40 0 C.
- the reaction, and particularly the deprotonation of the oxazolidinone with a base is often started by adding the base at reduced temperature (e.g. -20 0 C, -10 °C, or 0 0 C), and then warming the mixture to room temperature.
- compound I has the structure of formula 12:
- Example 12 The complete synthesis of 12 is shown in Example 1.
- X is Na
- X is Na
- X is Na
- X is Na
- Y is Cl.
- the example is provided to further illustrate the invention and should not be treated as limiting the invention in any way. The scope of the invention is defined by the claims.
- EDC is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
- DIPEA is diisopropylethylamine.
- DMAC is dimethylacetamide.
- DMSO is dimethylsulfoxide.
- DF is dimethylformamide.
- Halogen includes fluorine, chlorine, bromine and iodine.
- HMPA hexamethylphosphoric triamide.
- HOBT 1-Hydroxybenzotriazole.
- EP AC is isopropyl acetate.
- Me represents methyl.
- NaHMDS sodium hexamethydisilazide.
- TMEDA tetramethylethylenediamine.
- Weinreb amine is N,O-dimethylhydroxylamine.
- Intermediate 7 is made in 6 steps from readily available materials.
- the synthesis is summarized below as a 4-step synthesis of the boronic acid intermediate 5, which is isolated as a solid material.
- the boronic acid is then carried on in two more steps to the key intermediate 7, which is also isolated as a solid product.
- the boronic acid intermediate is synthesized in 4 steps as shown below, and as summarized in Scheme 2.
- THF 24 L
- CeCl 3 2.75 kg
- the resultant slurry was aged at room temperature for 1.5 hours.
- a sample was then examined under a microscope to confirm that the desired form change had occurred.
- the slurry was cooled to 9 0 C and MeMgCl was added. The rate of addition was adjusted to maintain internal temperature below 19 0 C.
- the mixture was cooled to -11 °C, and a solution of acetophenone 1 (4.0kg diluted to 1OL with THF) was added dropwise, maintaining the internal temperature below 0 0 C.
- the reaction mixture was then aged at a temperature below O 0 C for an hour.
- the reaction was quenched with 5.7L of 3N HCl in a dropwise fashion, maintaining the internal temperature below 15 0 C.
- the quenched reaction mixture was then aged at 5-10 0 C for 1.5 hours and was filtered through a plug of Solka Floe.
- Anisole 3 is diluted in acetonitrile (1.72 L, 4mL MeCN/ mMol 3). This mixture is warmed to 35 0 C, and NBS (1.1 eq, 84 g) is added in a single solid addition. The reaction is maintained at 35 0 C and is complete in 2-4 hours. The solution is concentrated to 400 mL total volume and diluted with IL of toluene. The solution is then washed with sodium thiosulfate and water to remove the succinimide byproduct. The organic layer is then concentrated and solvent switched to toluene.
- a 75 L glass reaction vessel was charged with 1.87 kg of aryl bromide 4 (7.6 MoI), which was added as 6.4 kg of a 29.1 wt% solution of 4 in toluene. This solution was diluted with 5.6 L of THF. The vessel was flushed with nitrogen, and tri-isopropylborate (1.35 eq, 2.35 L, 10.3 MoI) was added. The mixture was cooled to ⁇ -70 0 C. Then 5. 9L of 1.6 M n-BuLi in hexanes (9.5 MoI) was added slowly over 4 hours, maintaining a temperature of ⁇ -55 0 C. Thirty minutes after completion of the n-BuLi addition, the reaction was complete by LC analysis.
- the reaction was warmed to -35 0 C and quenched into 3.0 M H 2 SO 4 solution (5.6 L).
- the aqueous phase after the quench should be acidic (pH ⁇ 2).
- MTBE 7.5 L was added to the mixture to dilute the organic layer.
- the mixture was stirred (15 min) and the aqueous layer was cut away.
- the organic layer was washed with another 5.6 L of a 3.0 M H 2 SO 4 solution (15 min).
- the organic MTBE/Toluene layer was extracted twice with 1 M KOH (15.1 L first and then 7.6 L). The two KOH extractions were combined, diluted with 2- propanol (6.4 L), and cooled to 15 0 C.
- Step 1 Suzuki Coupling Reaction of Boronic Acid 5 and Aryl Chloride 13 to yield 6:
- a 3 M K 2 CO 3 solution is prepared by adding 4.71 kg of solid K 2 CO 3 to 10.3 L water. Cooling is applied to keep the solution at 20-25 0 C.
- THF (12 L), aryl chloride 13 (2.69 kg), and boronic acid 5 (2.74kg) are added to the K 2 CO 3 followed by a 1 L THF rinse.
- HPLC analysis is used to confirm the 1.00/1.00 ratio of 5/13.
- the solution is degassed by sparging with nitrogen gas for 70 min.
- the catalyst 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (42g) is added as a solid and is followed by a degassed THF rinse (1.5 L). The organic layer turns dark brown immediately. The biphasic mixture is aged at 36°-40°C with vigorous stirring. After HPLC reveals complete conversion (15-18 h), the mixture is cooled to rt and the aqueous layer is removed. To the organic layer is added heptane (25.6L) and water (25.6 L) and the layers are cut. The organic layer is washed with water (19L).
- the organic layer is treated with 680 g Darco KB-B at rt for 60 min and filtered through solka-floc with a 10%THF/Heptane rinse (-15 L).
- the solvent is switched to heptane (-35 L) at -45-50 0 C until ⁇ 0.5v% of THF is left. More heptane is added to bring the total volume to -45-50 L.
- the solution is seeded with crystals obtained from earlier runs if no seed bed forms. The slurry is slowly cooled to rt and then to -15 0 C.
- Step 2 Chlorination of 6 to 7:
- biaryl compound 6 (3.4 kg) in DMF (17L) which was maintained at 1O 0 C was added thionyl chloride (940ml), and then the mixture was warmed to room temperature. The mixture was aged until >99.8% conversion was measured by HPLC. Water (3.4 L) was then added. Seed crystals obtained from earlier batches (lwt%) were added, and the mixture was aged for 30 min more before slowly adding 5.1 L of additional water over -lhr. The solid was filtered and washed with first 20 L 1:1 DMF:water and then 3x 2OL water. The solid product 7 was dried at 20 0 C until ⁇ 0.1wt% water remained.
- the Weinreb amide 9 from the previous step (6kg, 22.5 mol) and 3,5- bis(trifluoromethyl)bromobenzene (4.85L, 28.1 mol) are dissolved in anhydrous THF (24L).
- the solution is purged with nitrogen to remove oxygen.
- the water content should be ⁇ 500ppm at this point.
- Atmospheric distillation can be carried out to azeotropically remove water if necessary.
- the solution is cooled to -1O 0 C and iso-PrMgCl in THF (56.4 mol) is slowly added (2 hours) to the reaction via addition funnel, maintaining a reaction temperature ⁇ -5°C.
- the solution is allowed to warm to 20°C and aged overnight at 20° C, until the amide is ⁇ 0.5 LCAP.
- reaction is then cooled to -10 0 C under nitrogen and is quenched slowly over 2 hours into 5N HCl (14L) that is maintained at 0-5°C.
- MTBE (12L) is added and the biphasic mixture is agitated for 5 min. After warming to 20°-25°C, it is allowed to settle for 30 min, and then the layers are separated. The organic layer is washed with water twice (12L).
- the organic layer is vacuum transferred through a 1 -micron in-line PTFE filter into a distillation flask and is then concentrated to ⁇ 12L under vacuum (internal temperature ⁇ 40°C) to a minimum agitated volume.
- the solution is then azeotropically dried with toluene and taken to a minimum agitated volume again.
- the solution containing ketone 10 is used directly in the next step.
- the ketone 10 (6 kg) is heated at 50 0 C with 0.3 eq of Al(O-i-Pr)3 (79Og) in 12L IPA and 18 L of toluene for 15.5 hours.
- the solution is cooled to ambient temperature, and solid KOH pellets (1.35 kg) are added slowly with vigorous stirring, while keeping the temperature at ⁇ 25 °C.
- 33L of IN HCl solution is added to quench the reaction, which is kept at ⁇ 25 °C. If a rag layer of solids forms, it should be filtered off.
- the rag layer is racemic oxazolidinone, and removal increases the enantiomeric excess.
- the organic layer is then washed first with 36L of 0.5N HCl, then with 6L IPA combined with 45L water, and finally with 6L IPA combined with 36L water.
- the organic layer is transferred via an inline filter.
- the solvent is switched to heptane (target volume is ⁇ 42L) at ⁇ 40 0 C until ⁇ 2 v% toluene is left. Aging at rt for 2 h gives the solid product 11.
- Oxazolidinone 11 is alkylated with 7 to yield the desired product, (45,5R)-S-[S 5 S- bis(trifluoromethyl)phenyl]-3 - ⁇ [4 ' -fluoro-5 ' -isopropyl-2 ' -methoxy-4-(trifluoromethyl)biphenyl-2- yl]methyl ⁇ -4-methyl-l,3-oxazolidin-2-one (12): DMF, NaHMDS Heptane crystallization
- the layers were cut and the organic layer was washed twice with 14L of 1:1 DMF:water followed by two 14L water washes.
- the organic layer was assayed for yield and was then filtered through 2.4 kg of silica gel to remove the excess oxazolidinone to ⁇ 0.5%.
- the silica was washed with 5% IPAC/Heptane.
- the combined organic solutions were distilled to remove IPAC to ⁇ 1%.
- the warm heptane solution was then transferred slowly into a 20 0 C heptane solution containing 10 wt% seed.
- the seed crystals were obtained initially from earlier batches of the same reaction.
- the slurry was then cooled to -20 0 C and filtered.
- the filter cake was washed with cold heptane and was then dried, yielding 4.4 kg (88%) of the desired product 12.
- the filter cake that is isolated above by filtration from heptane is initially a crystalline heptane solvate. During filtration and drying, the heptane evaporates, yielding an anhydrous non- solvated crystalline product. Heptane de-solvates at room temperature under a flow of nitrogen or air, or under vacuum. The crystalline product melts at about 69 0 C (Fig.2). The crystalline non-solvate form of compound 12 is non-hygroscopic and does not convert to a hydrate in humid or dry air.
- the crystalline non-solvate form of compound 12 does not convert to other crystalline forms on standing at room temperature, but slowly converts to the amorphous form on standing for long periods of time, and converts more rapidly to the amorphous form at elevated temperatures.
- the amorphous form of compound 12 can also be obtained from the crystalline form by milling, and from a solution in an organic solvent by spray drying or by precipitation, using water as an antisolvent.
- the crystalline product 12 obtained by the process above may be used to make pharmaceutical formulations. Because compound 12 is very poorly soluble in water, it is generally beneficial to formulate compound 12 in a form that will improve its bioavailability.
- the crystalline product 12 can be used to make pharmaceutical formulations in which the active ingredient is changed to another form, as for example a solution, as an amorphous dispersion in a polymer, or as part of a preconcentrate that yields a microemulsion after the preconcentrate is swallowed or mixed with water.
- the crystalline non-solvate form of compound 12 is a useful intermediate for making these formulations because it is readily purified and handled, is non-hygroscopic, and is stable at room temperature for moderate periods of time with respect to changing to the amorphous form.
- compositions that comprise compound 12 may comprise the crystalline non-solvate form of compound 12 in a detectable amount.
- the amount of crystalline non-solvate form of compound 12 in the solid can be quantified by the use of physical methods, such as X-ray powder diffraction (XRPD), solid-state fluorine- 19 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance spectroscopy, solid-state carbon- 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance spectroscopy, solid state Fourier-transform infrared spectroscopy, and Raman spectroscopy.
- XRPD X-ray powder diffraction
- CPMAS solid-state fluorine- 19 cross-polarization magic-angle spinning
- CPMAS solid-state carbon- 13 cross-polarization magic-angle spinning
- compositions that comprise compound 12 may comprise about 5% to about 100% by weight of the crystalline non-solvate form of compound 12 (as a % of the amount of compound 12 in the formulation).
- Pharmaceutical formulations that comprise compound 12 may comprise about 10% to about 100% by weight of the crystalline non-solvate form of compound 12.
- Pharmaceutical formulations that comprise compound 12 may comprise about 25% to about 100% by weight of the crystalline non-solvate form of compound 12.
- Pharmaceutical formulations that comprise compound 12 may comprise about 50% to about 100% by weight of the crystalline non-solvate form of compound 12.
- Pharmaceutical formulations that comprise compound 12 may comprise about 75% to about 100% by weight of the crystalline non-solvate form of compound 12.
- Pharmaceutical formulations that comprise compound 12 may comprise about 100% by weight of the crystalline non-solvate form of compound 12, so that the solid Compound 12 in the formulation is substantially phase pure crystalline non-solvate form.
- compositions that comprise Compound 12 may comprise Compound 12 in the crystalline non-solvate form in a detectable amount, even when the formulation is made to be non- crystalline, as for example a formulation of amorphous Compound 12, a formulation comprising an amorphous dispersion of Compound 12 in a water soluble polymer (e.g. polyvinylpyrrolidinone, a polyvinylpyrrolidinone copolymer, or a water soluble cellulosic polymer, such as HPMCAS), or a formulation comprising Compound 12 in solution, such as a microemulsion preconcentrate.
- a water soluble polymer e.g. polyvinylpyrrolidinone, a polyvinylpyrrolidinone copolymer, or a water soluble cellulosic polymer, such as HPMCAS
- a formulation comprising Compound 12 in solution such as a microemulsion preconcentrate.
- the crystalline Compound 12 may be present in small amounts in these formulations for many reasons, such as because the crystalline compound is not completely changed to a non-crystalline form, or is not completely dissolved, or because Compound 12 gradually converts to the crystalline non-solvate form on standing for an extended period of time.
- the pharmaceutical formulation may comprise compound 12 in the crystalline non-solvate form in a measurable amount, which may represent at least 0.1% of the total amount of Compound 12 in the formulation; or may represent at least 0.5% of the total amount of Compound 12 in the formulation; or may represent at least 1% of the total amount of Compound 12 in the formulation; or may represent at least 5% of the total amount of Compound 12 in the formulation; or may represent at least 10% of the total amount of Compound 12 in the formulation; or may represent at least 25% of the total amount of Compound 12 in the formulation; or may represent at least 50% of the total amount of Compound 12 in the formulation.
- X-ray powder diffraction studies are widely used to characterize molecular structures, crystallinity, and polymorphism.
- the X-ray powder diffraction patterns are generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with PW3040/60 console.
- a PW3373/00 ceramic Cu LEF X-ray tube K-Alpha radiation is used as the source.
- crystalline forms of compounds may further be characterized by their solid-state carbon- 13 and fluorine- 19 nuclear magnetic resonance (NMR) spectra.
- Solid-state carbon- 13 NMR spectra are obtained on a Bruker DSX 400WB NMR system using a Bruker 4 mm double resonance CPMAS probe.
- the carbon-13 NMR spectra utilize proton/carbon- 13 cross-polarization magic-angle spinning with variable-amplitude cross polarization. The samples are spun at 15.0 kHz, and a total of 1024 scans are collected with a recycle delay of 5 seconds. A line broadening of 40 Hz is applied to the spectrum before FT is performed. Chemical shifts are reported on the TMS scale using the carbonyl carbon of glycine (176.03 p.p.m.) as a secondary reference.
- the solid-state carbon-13 NMR spectra are also obtained on a Bruker DSX 500WB NMR system using a Bruker 4 mm H/X/Y CPMAS probe.
- the carbon-13 NMR spectra utilize proton/carbon- 13 cross-polarization magic-angle spinning with variable-amplitude cross polarization, total sideband suppression, and SPINAL decoupling at lOOkHz.
- the samples are spun at 10.0 kHz, and a total of 1024 scans are collected with a recycle delay of 5 seconds. A line broadening of 10 Hz is applied to the spectrum before FT is performed. Chemical shifts are reported on the TMS scale using the carbonyl carbon of glycine (176.03 p.p.m.) as a secondary reference.
- the solid-state fluorine- 19 NMR spectra are obtained on a Bruker DSX 400WB NMR system using a Bruker 4mm CRAMPS probe.
- the NMR spectra utilize a simple pulse-acquire pulse program. The samples are spun at 15.0 kHz, and a total of 128 scans are collected with a recycle delay of 5 seconds. A vespel endcap is utilized to minimize fluorine background. A line broadening of 100 Hz is applied to the spectrum before FT is performed. Chemical shifts are reported using poly(tetrafluoroethylene) (Teflon®) as an external secondary reference which is assigned a chemical shift of -122 ppm.
- Teflon® poly(tetrafluoroethylene)
- the fluorine-19 NMR spectra utilize proton/ fluorine-19 cross-polarization magic-angle spinning with variable-amplitude cross polarization, and TPPM decoupling at 62.5kHz.
- the samples are spun at 15.0 kHz, and a total of 256 scans are collected with a recycle delay of 5 seconds.
- a line broadening of 10 Hz is applied to the spectrum before FT is performed.
- Chemical shifts are reported using poly(tetrafluoroethylene) (Teflon®) as an external secondary reference, which is assigned a chemical shift of -122 ppm.
- DSC data are also acquired using TA Instruments DSC 2910 or equivalent instrumentation.
- a sample with a weight between 2 and 6 mg is weighed into an open pan. This pan is then crimped and placed in the sample position in the calorimeter cell. An empty pan is placed in the reference position. The calorimeter cell is closed and a flow of nitrogen is passed through the cell.
- the heating program is set to heat the sample at a heating rate of 10 0 C /min to a temperature of approximately 100 0 C.
- the data are analyzed using the DSC analysis program in the system software.
- the melting endotherm is integrated between baseline temperature points that are above and below the temperature range over which the endotherm is observed. The data reported are the onset temperature, peak temperature and enthalpy.
- MDSC modulated DSC
- amorphous forms of compound 12 may be present in some samples, when an additional endotherm is observed in the DSC curves that can be due to enthalpic relaxation of the amorphous phase present, modulated DSC (MDSC) is used to confirm that the extra endotherm is not due to melting of an impurity.
- MDSC uses a sinusoidal or modulated change in the heating rate instead of a single linear heating rate, as used in the traditional DSC. This allows the heat flow to be separated into reversible and nonreversible components. The glass transition of amorphous material is detected in the reversible heat flow curve as a change in the baseline, due to a change of the heat capacity of the sample.
- DSC data are acquired using a TA Instruments DSC QlOOO. Between 2 and 6 mg of sample is weighed into an open pan. This pan is then crimped and placed in the sample position in the calorimeter cell. An empty pan is placed in the reference position. The calorimeter cell is closed and a flow of nitrogen is passed through the cell. The heating program is set to heat the sample at a heating rate of 3 0 C /min with a modulation period of 60 seconds and modulation amplitude of ⁇ 1 0 C. The final temperature is chosen to be 100 0 C. When a run has been completed, the data are analyzed using the DSC analysis program in the system software.
- the melting endotherm in the total heat flow curve is integrated between baseline temperature points that are above and below the temperature range over which the endotherm is observed.
- the data reported are the onset temperature, peak temperature and enthalpy.
- the data reported are the onset temperature, midpoint temperature, endset temperature and heat capacity change.
- FIG. 1 shows a typical X-ray powder diffraction pattern of the crystalline non-solvate form.
- the crystalline non-solvate form exhibits characteristic diffraction peaks corresponding to d- spacings of 4.66, 4.59, and 4.36 angstroms.
- the crystalline non-solvate form is further characterized by the d-spacings of 11.89, 4.02, and 3.76 angstroms.
- the crystalline non-solvate form is even further characterized by the d-spacings of 12.95, 7.41, and 6.51 angstroms.
- FIG. 2 is a typical DSC curve of the crystalline non-solvate form of compound 12.
- the endotherm with an extrapolated onset temperature of 69.62 °C in FIG. 2 is due to melting (or a crystalline-amorphous phase transition).
- FIG. 3 shows a typical solid-state carbon- 13 CPMAS NMR spectrum of the crystalline non-solvate form of compound 12.
- the crystalline non-solvate form exhibits characteristic signals with chemical shift values of 123.4, 55.8, and 23.1 p.p.m. Further characteristic of the crystalline non-solvate form are the signals with chemical shift values of 124.5, 155.3, and 137.7 p.p.m. The crystalline non- solvate form is even further characterized by signals with chemical shift values of 24.8, 13.1, and 132.3 p.p.m.
- FIG. 4 shows a typical solid-state fluorine- 19 CPMAS NMR spectrum of the crystalline non-solvate form of compound 12.
- the crystalline non-solvate form exhibits characteristic signals with chemical shift values of -62.1, -63.9, and -66.0 p.p.m.
- the crystalline non-solvate form is further characterized by signals with chemical shift values of -115.2, -116.9, and -118.3 p.p.m.
- FIG. 5 shows a typical X-ray powder diffraction pattern of the crystalline heptane solvate form.
- the heptane solvate form exhibits characteristic diffraction peaks corresponding to d-spacings of 4.79, 4.62, and 4.43 angstroms.
- the crystalline heptane solvate form is further characterized by d- spacings of 4.20, 4.05 and 3.84 angstroms.
- the crystalline heptane solvate form is even further characterized by d-spacings of 13.12, 11.99, and 5.52 angstroms.
- FIG. 6 shows a typical solid-state carbon- 13 CPMAS NMR spectrum of the crystalline heptane solvate form of compound 12.
- the crystalline heptane solvate form exhibits characteristic signals with chemical shift values of 123.6, 55.9, and 77.1 p.p.m. Further characteristic of the crystalline heptane solvate form are the signals with chemical shift values of 24.6, 13.6, and 126.8 p.p.m.
- the crystalline heptane solvate form is even further characterized by signals with chemical shift values of 52.3, 130.5, and 23.2 p.p.m.
- FIG. 7 shows a typical solid-state fluorine- 19 CPMAS NMR spectrum of the crystalline heptane solvate form of compound 12.
- the crystalline heptane solvate form exhibits characteristic signals with chemical shift value of -61.8, -62.9, and -65.2 p.p.m.
- the crystalline heptane solvate form is further characterized by signals with chemical shift values of -114.8, -117.9, and -116.7 p.p.m.
- FIG. 8 shows a typical solid-state carbon- 13 CPMAS NMR spectrum of the amorphous form of compound 12.
- the amorphous form exhibits characteristic signals with chemical shift values of 54.3, 123.5, and 155.1 p.p.m. Further characteristic of the amorphous form are the signals with chemical shift values of 22.3, 76.6, and 138.1 p.p.m.
- the amorphous form is even further characterized by signals with chemical shift values of 159.8, 12.3, and 98.9 p.p.m.
- FIG. 9 shows a typical solid-state fluorine- 19 CPMAS NMR spectrum of the amorphous form of compound 12.
- the amorphous form exhibits a characteristic signal with chemical shift value of -63.3 p.p.m.
- FIG. 10 is a typical MDSC curve of the amorphous form of compound 12.
- the heat capacity change observed in the reversible heat flow curve with a midpoint temperature of 47.96 °C corresponds to the glass transition of amorphous compound 12.
- the compounds and crystalline polymorphs made by the process disclosed herein are inhibitors of CETP and have utility in increasing the amount of HDL-cholesterol and reducing the amount of LDL-cholesterol in a patient, preferably a human patient. Increases of HDL and reductions of LDL are known to a practitioner in the field of medicine to be advantageous in reducing atherosclerosis and associated diseases.
- the compounds synthesized by the process herein have very low solubility in aqueous environments, and are likely to be made into formulations that improve oral bioavailability compared with formulations that are conventionally made using solid active ingredients and excipients to make tablets.
- Crystalline products that are obtained in these preparations are readily purified, and may be formulated by dissolving them in oils and/or surfactants or dispersing them as non-crystalline dispersions in water soluble polymers, such as poly(vinylpyrrolidinone).
- An exemplary formulation of the crystalline non-solvate of Compound 12 comprises a dose of 5 mg, 10 mg, 50 mg, 100 mg, or 150 mg dissolved in sufficient oil or a mixture of an oil and a surfactant to make 565 mg of solution for use in a gelatin capsule. Such doses would be administered once or twice a day. Such formulations are well known to those of skill in the art of pharmaceutical formulations.
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06774324.5A EP1901741B1 (en) | 2005-07-01 | 2006-06-29 | Process for synthesizing a cetp inhibitor |
CA002612142A CA2612142A1 (en) | 2005-07-01 | 2006-06-29 | Process for synthesizing a cetp inhibitor |
CN200680024104XA CN101212966B (en) | 2005-07-01 | 2006-06-29 | Process for synthesizing a CETP inhibitor |
US11/922,905 US7863307B2 (en) | 2005-07-01 | 2006-06-29 | Process for synthesizing a CETP inhibitor |
EP15182403.4A EP2985022B1 (en) | 2005-07-01 | 2006-06-29 | Process for synthesizing a cetp inhibitor |
JP2008519594A JP5112307B2 (en) | 2005-07-01 | 2006-06-29 | Methods for synthesizing CETP inhibitors |
AU2006265975A AU2006265975B2 (en) | 2005-07-01 | 2006-06-29 | Process for synthesizing a CETP inhibitor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US69623305P | 2005-07-01 | 2005-07-01 | |
US60/696,233 | 2005-07-01 |
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WO2007005572A1 true WO2007005572A1 (en) | 2007-01-11 |
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PCT/US2006/025511 WO2007005572A1 (en) | 2005-07-01 | 2006-06-29 | Process for synthesizing a cetp inhibitor |
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US (1) | US7863307B2 (en) |
EP (2) | EP2985022B1 (en) |
JP (2) | JP5112307B2 (en) |
CN (2) | CN101212966B (en) |
AU (1) | AU2006265975B2 (en) |
CA (1) | CA2612142A1 (en) |
HK (1) | HK1213815A1 (en) |
WO (1) | WO2007005572A1 (en) |
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- 2006-06-29 CN CN200680024104XA patent/CN101212966B/en not_active Expired - Fee Related
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- 2006-06-29 JP JP2008519594A patent/JP5112307B2/en not_active Expired - Fee Related
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- 2006-06-29 EP EP06774324.5A patent/EP1901741B1/en not_active Not-in-force
- 2006-06-29 WO PCT/US2006/025511 patent/WO2007005572A1/en active Application Filing
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EP1901741A4 (en) | 2010-08-04 |
HK1213815A1 (en) | 2016-07-15 |
EP2985022B1 (en) | 2018-09-12 |
AU2006265975A1 (en) | 2007-01-11 |
EP1901741A1 (en) | 2008-03-26 |
CN101212966A (en) | 2008-07-02 |
US20100041724A1 (en) | 2010-02-18 |
JP2013014594A (en) | 2013-01-24 |
CN101212966B (en) | 2012-03-14 |
EP2985022A1 (en) | 2016-02-17 |
AU2006265975B2 (en) | 2011-12-15 |
US7863307B2 (en) | 2011-01-04 |
EP1901741B1 (en) | 2015-09-16 |
CA2612142A1 (en) | 2007-01-11 |
JP5112307B2 (en) | 2013-01-09 |
JP2009500341A (en) | 2009-01-08 |
CN102757397A (en) | 2012-10-31 |
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