NZ623851B2 - Process for the preparation of 1-acyl-4-phenylsulfonylprolinamide derivatives and new intermediates - Google Patents
Process for the preparation of 1-acyl-4-phenylsulfonylprolinamide derivatives and new intermediates Download PDFInfo
- Publication number
- NZ623851B2 NZ623851B2 NZ623851A NZ62385112A NZ623851B2 NZ 623851 B2 NZ623851 B2 NZ 623851B2 NZ 623851 A NZ623851 A NZ 623851A NZ 62385112 A NZ62385112 A NZ 62385112A NZ 623851 B2 NZ623851 B2 NZ 623851B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- halogen
- alkyl
- mmol
- added
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000000543 intermediate Substances 0.000 title abstract description 4
- 150000003147 proline derivatives Chemical class 0.000 claims abstract description 11
- -1 thio compound Chemical class 0.000 claims description 118
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 105
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 56
- 150000001875 compounds Chemical class 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 239000002253 acid Substances 0.000 claims description 41
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 150000002367 halogens Chemical group 0.000 claims description 37
- 239000000460 chlorine Substances 0.000 claims description 32
- 239000011780 sodium chloride Substances 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- 150000003568 thioethers Chemical class 0.000 claims description 15
- UIVATUPCWVUVIM-UHFFFAOYSA-N 1-aminocyclopropane-1-carbonitrile Chemical compound N#CC1(N)CC1 UIVATUPCWVUVIM-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 239000011593 sulfur Substances 0.000 claims description 13
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 12
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 12
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 9
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims description 8
- 230000002829 reduced Effects 0.000 claims description 8
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
- FODOUIXGKGNSMR-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate;hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O FODOUIXGKGNSMR-UHFFFAOYSA-L 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 230000001131 transforming Effects 0.000 claims description 6
- 239000007818 Grignard reagent Substances 0.000 claims description 5
- 229960002591 Hydroxyproline Drugs 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 150000004795 grignard reagents Chemical class 0.000 claims description 5
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 230000001590 oxidative Effects 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012425 OXONE® Substances 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- HVAHYVDBVDILBL-UHFFFAOYSA-M potassium;oxidooxy hydrogen sulfate Chemical group [K+].OS(=O)(=O)OO[O-] HVAHYVDBVDILBL-UHFFFAOYSA-M 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- IIVWHGMLFGNMOW-UHFFFAOYSA-N 2-methylpropane Chemical group C[C](C)C IIVWHGMLFGNMOW-UHFFFAOYSA-N 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- IGDCULTXZZBKHT-UHFFFAOYSA-M sodium;2-ethylhex-2-enoate Chemical compound [Na+].CCCC=C(CC)C([O-])=O IGDCULTXZZBKHT-UHFFFAOYSA-M 0.000 claims 1
- 208000002223 Abdominal Aortic Aneurysm Diseases 0.000 abstract description 3
- 208000007474 Aortic Aneurysm Diseases 0.000 abstract description 3
- 208000007342 Diabetic Nephropathy Diseases 0.000 abstract description 3
- 206010061835 Diabetic nephropathy Diseases 0.000 abstract description 3
- 208000005764 Peripheral Arterial Disease Diseases 0.000 abstract description 3
- 206010062585 Peripheral arterial occlusive disease Diseases 0.000 abstract description 3
- 206010003210 Arteriosclerosis Diseases 0.000 abstract description 2
- 108090000613 Cathepsin S Proteins 0.000 abstract description 2
- 206010012601 Diabetes mellitus Diseases 0.000 abstract description 2
- 208000008466 Metabolic Disease Diseases 0.000 abstract description 2
- 201000001320 atherosclerosis Diseases 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 113
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 106
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 98
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 82
- 239000000243 solution Substances 0.000 description 78
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- 239000000203 mixture Substances 0.000 description 63
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 58
- 239000000725 suspension Substances 0.000 description 58
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
- 238000007792 addition Methods 0.000 description 43
- 238000003756 stirring Methods 0.000 description 42
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- 229940093499 ethyl acetate Drugs 0.000 description 37
- NWVZBYSIQYNHDL-UHFFFAOYSA-N C(#N)C1(CC1)[NH-] Chemical compound C(#N)C1(CC1)[NH-] NWVZBYSIQYNHDL-UHFFFAOYSA-N 0.000 description 32
- 239000012267 brine Substances 0.000 description 29
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 27
- MFRIHAYPQRLWNB-UHFFFAOYSA-N Sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 27
- 238000001816 cooling Methods 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 26
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 25
- 239000000284 extract Substances 0.000 description 25
- 239000010410 layer Substances 0.000 description 23
- 239000002244 precipitate Substances 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 21
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- 239000012043 crude product Substances 0.000 description 19
- 238000002425 crystallisation Methods 0.000 description 17
- 230000005712 crystallization Effects 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 15
- 229940113088 dimethylacetamide Drugs 0.000 description 15
- 238000000132 electrospray ionisation Methods 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000005755 formation reaction Methods 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
- RMVRSNDYEFQCLF-UHFFFAOYSA-N Thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 239000006260 foam Substances 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 8
- 150000003840 hydrochlorides Chemical class 0.000 description 8
- IKEZYFNZQYNPNX-UHFFFAOYSA-N 4-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)benzenethiol Chemical compound FC(F)(F)COC1=CC=C(S)C(C(F)(F)F)=C1 IKEZYFNZQYNPNX-UHFFFAOYSA-N 0.000 description 7
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 229940092714 benzenesulfonic acid Drugs 0.000 description 7
- 125000004432 carbon atoms Chemical group C* 0.000 description 7
- 150000002596 lactones Chemical class 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 238000007098 aminolysis reaction Methods 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000001184 potassium carbonate Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- HRZFUMHJMZEROT-UHFFFAOYSA-L 7681-57-4 Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 5
- 241000282326 Felis catus Species 0.000 description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M Potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229940001584 sodium metabisulfite Drugs 0.000 description 5
- 235000010262 sodium metabisulphite Nutrition 0.000 description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 5
- PCEIEQLJYDMRFZ-UHFFFAOYSA-N (1-cyanocyclopropyl)azanium;chloride Chemical compound Cl.N#CC1(N)CC1 PCEIEQLJYDMRFZ-UHFFFAOYSA-N 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-Bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- SLYFSUMTQPAMMM-UHFFFAOYSA-N 3-[4-bromo-2-(trifluoromethyl)phenyl]sulfanylpropanamide Chemical compound NC(=O)CCSC1=CC=C(Br)C=C1C(F)(F)F SLYFSUMTQPAMMM-UHFFFAOYSA-N 0.000 description 4
- CSKNSYBAZOQPLR-UHFFFAOYSA-N Benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 150000008054 sulfonate salts Chemical class 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 229940117913 Acrylamide Drugs 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LZTRCELOJRDYMQ-UHFFFAOYSA-N Triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 description 3
- HRPVXLWXLXDGHG-UHFFFAOYSA-N acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 3
- 239000012455 biphasic mixture Substances 0.000 description 3
- 230000003197 catalytic Effects 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- KLGSHNXEUZOKHH-JBUOLDKXSA-N hydron;methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate;chloride Chemical compound Cl.COC(=O)[C@@H]1C[C@@H](O)CN1 KLGSHNXEUZOKHH-JBUOLDKXSA-N 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 238000005191 phase separation Methods 0.000 description 3
- 239000001187 sodium carbonate Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- SKCBKBCACWDALV-UHFFFAOYSA-N 1-(trifluoromethyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(C(F)(F)F)CC1 SKCBKBCACWDALV-UHFFFAOYSA-N 0.000 description 2
- GTDXPJJHRWOFDI-UHFFFAOYSA-N 1-methylcyclopropane-1-carbonyl chloride Chemical compound ClC(=O)C1(C)CC1 GTDXPJJHRWOFDI-UHFFFAOYSA-N 0.000 description 2
- DIZKLZKLNKQFGB-UHFFFAOYSA-N 1-methylcyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(C)CC1 DIZKLZKLNKQFGB-UHFFFAOYSA-N 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N 2,2,2-trifluoroethyl alcohol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- ZWRMSOMIVOVMQX-UHFFFAOYSA-M 2-(2-aminoethyldisulfanyl)ethanamine;palladium(2+);chloride Chemical compound [Cl-].[Pd+2].NCCSSCCN ZWRMSOMIVOVMQX-UHFFFAOYSA-M 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-Methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-M 2-ethylhexanoate Chemical compound CCCCC(CC)C([O-])=O OBETXYAYXDNJHR-UHFFFAOYSA-M 0.000 description 2
- BDFAOUQQXJIZDG-UHFFFAOYSA-N 2-methylpropane-1-thiol Chemical compound CC(C)CS BDFAOUQQXJIZDG-UHFFFAOYSA-N 0.000 description 2
- YKSLWUIOZVWLGX-UHFFFAOYSA-N 4-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)-1-tritylsulfanylbenzene Chemical compound FC(F)(F)C1=CC(OCC(F)(F)F)=CC=C1SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 YKSLWUIOZVWLGX-UHFFFAOYSA-N 0.000 description 2
- KRLKXOLFFQWKPZ-UHFFFAOYSA-N 4-(bromomethyl)pyridine Chemical compound BrCC1=CC=NC=C1 KRLKXOLFFQWKPZ-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- XBPGBNVNPXUGPS-UHFFFAOYSA-N 4-bromo-2-(trifluoromethyl)benzenethiol Chemical compound FC(F)(F)C1=CC(Br)=CC=C1S XBPGBNVNPXUGPS-UHFFFAOYSA-N 0.000 description 2
- IIEZBYBGNUWCEP-UHFFFAOYSA-N 4-fluoro-2-(trifluoromethyl)-1-tritylsulfanylbenzene Chemical compound FC(F)(F)C1=CC(F)=CC=C1SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 IIEZBYBGNUWCEP-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N Bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
- 238000006418 Brown reaction Methods 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 241000400611 Eucalyptus deanei Species 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000002051 biphasic Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052792 caesium Inorganic materials 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 238000001944 continuous distillation Methods 0.000 description 2
- 230000001808 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000002178 crystalline material Substances 0.000 description 2
- 238000010192 crystallographic characterization Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- LVSJLTMNAQBTPE-UHFFFAOYSA-N disodium tetraborate Chemical compound [Na+].[Na+].O1B(O)O[B-]2(O)OB(O)O[B-]1(O)O2 LVSJLTMNAQBTPE-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000006138 lithiation reaction Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 2
- PIOZZBNFRIZETM-UHFFFAOYSA-L magnesium;2-carbonoperoxoylbenzoic acid;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].OOC(=O)C1=CC=CC=C1C([O-])=O.OOC(=O)C1=CC=CC=C1C([O-])=O PIOZZBNFRIZETM-UHFFFAOYSA-L 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- SVIHRJIEKRFYDN-UHFFFAOYSA-N propanamide Chemical group [CH2]CC(N)=O SVIHRJIEKRFYDN-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 239000004328 sodium tetraborate Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- BHOKTYCNSCTRTD-JTQLQIEISA-N (2S)-1-(benzenesulfonyl)pyrrolidine-2-carboxamide Chemical class NC(=O)[C@@H]1CCCN1S(=O)(=O)C1=CC=CC=C1 BHOKTYCNSCTRTD-JTQLQIEISA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DRNWNTAANHEQMK-UHFFFAOYSA-N 1-bromo-3-chloro-2-fluorobenzene Chemical compound FC1=C(Cl)C=CC=C1Br DRNWNTAANHEQMK-UHFFFAOYSA-N 0.000 description 1
- BJMSXWLXFYZHIU-UHFFFAOYSA-N 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound CN1C=CC(B2OC(C)(C)C(C)(C)O2)=N1 BJMSXWLXFYZHIU-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- UERAGXKMOXUWPC-UHFFFAOYSA-N 2-bromo-1-fluoro-3-(trifluoromethyl)benzene Chemical compound FC1=CC=CC(C(F)(F)F)=C1Br UERAGXKMOXUWPC-UHFFFAOYSA-N 0.000 description 1
- VQPGLDBLAJVZOE-UHFFFAOYSA-N 2-chloro-3-fluorobenzenethiol Chemical compound FC1=CC=CC(S)=C1Cl VQPGLDBLAJVZOE-UHFFFAOYSA-N 0.000 description 1
- AIPWPTPHMIYYOX-UHFFFAOYSA-N 3-bromo-2-methylpyridine Chemical compound CC1=NC=CC=C1Br AIPWPTPHMIYYOX-UHFFFAOYSA-N 0.000 description 1
- YFXYEMZYOMNQLD-UHFFFAOYSA-N 4-bromo-2-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC(Br)=CC=C1S(Cl)(=O)=O YFXYEMZYOMNQLD-UHFFFAOYSA-N 0.000 description 1
- IGMYEVQPXWKFQF-UHFFFAOYSA-N 4-fluoro-2-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C(C(F)(F)F)=C1 IGMYEVQPXWKFQF-UHFFFAOYSA-N 0.000 description 1
- LOPJANCIZXDRRR-UHFFFAOYSA-N 4-fluoro-2-(trifluoromethyl)benzenethiol Chemical compound FC1=CC=C(S)C(C(F)(F)F)=C1 LOPJANCIZXDRRR-UHFFFAOYSA-N 0.000 description 1
- ISRRJSGFXLQXDK-UHFFFAOYSA-N C(#N)C1(CC1)NC(=O)N1C(CCC1)C(=O)C1(CC1)C(F)(F)F Chemical compound C(#N)C1(CC1)NC(=O)N1C(CCC1)C(=O)C1(CC1)C(F)(F)F ISRRJSGFXLQXDK-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 230000037261 ClH Effects 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N Dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 238000000023 Kugelrohr distillation Methods 0.000 description 1
- 101710009221 LD Proteins 0.000 description 1
- 239000002879 Lewis base Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N N,N-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N Propanamide Chemical class CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- WMXCDAVJEZZYLT-UHFFFAOYSA-N Tert-Butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N Tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N Triphenylphosphine oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- SWUPLEAGZOKLNX-UHFFFAOYSA-N [4-fluoro-2-(trifluoromethyl)phenyl]boronic acid Chemical compound OB(O)C1=CC=C(F)C=C1C(F)(F)F SWUPLEAGZOKLNX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- MVFGXYPEQHIKIX-UHFFFAOYSA-N acetic acid;heptane Chemical compound CC(O)=O.CCCCCCC MVFGXYPEQHIKIX-UHFFFAOYSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000005591 charge neutralization Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000002140 halogenating Effects 0.000 description 1
- KWHDXJHBFYQOTK-UHFFFAOYSA-N heptane;toluene Chemical compound CCCCCCC.CC1=CC=CC=C1 KWHDXJHBFYQOTK-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N iodine atom Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- 230000004301 light adaptation Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- USSBDBZGEDUBHE-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O USSBDBZGEDUBHE-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000004430 oxygen atoms Chemical group O* 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- JIWDQJYCCQFDAF-UHFFFAOYSA-N potassium;2-methylpropan-2-olate;oxolane Chemical compound [K+].CC(C)(C)[O-].C1CCOC1 JIWDQJYCCQFDAF-UHFFFAOYSA-N 0.000 description 1
- VLYFRFHWUBBLRR-UHFFFAOYSA-L potassium;sodium;carbonate Chemical compound [Na+].[K+].[O-]C([O-])=O VLYFRFHWUBBLRR-UHFFFAOYSA-L 0.000 description 1
- PSBAZVJEUNOIDU-UHFFFAOYSA-L potassium;sodium;diacetate Chemical compound [Na+].[K+].CC([O-])=O.CC([O-])=O PSBAZVJEUNOIDU-UHFFFAOYSA-L 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000010963 scalable process Methods 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical class CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The disclosure relates to the preparation of 1-acyl-4-phenylsulfonylprolinamide derivatives of formula I. The proline derivatives of the formula I are preferential inhibitors of the cysteine protease Cathepsin S and may have usein the treatment of metabolic diseases like diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease and diabetic nephropathy. The disclosure also relates to intermediates of this process. abdominal aortic aneurysm, peripheral arterial disease and diabetic nephropathy. The disclosure also relates to intermediates of this process.
Description
Case 30706
PROCESS FOR THE PREPARATION OF 1-ACYL
PHENYLSULFONYLPROLINAMIDE DERIVATIVES AND NEW INTERMEDIATES
The invention relates to a process for the preparation of proline derivatives of the formula
wherein,
R is selected from C -alkyl or from
wherein R is selected from C -alkyl, halogen-C -alkyl or from phenyl
1-7 1-7
which is optionally substituted by halogen;
R is selected from halogen or halogen-C -alkyl; and
R is selected from hydrogen, halogen, halogen-C -alkyl, C -alkoxy, halogen-C -
1-7 1-7 1-7
alkoxy or from a 5- or 6-membered heterocyclic ring containing one or two nitrogen atoms, the
ring which is optionally substituted by C -alkyl or halogen.
The proline derivatives of the formula I are preferential inhibitors of the cysteine protease
Cathepsin S and are therefore useful to treat metabolic diseases like diabetes, atherosclerosis,
abdominal aortic aneurysm, peripheral arterial disease and diabetic nephropathy (PCT Publ. WO
2010/121918).
Object of the present invention is to provide a scalable process for the manufacture of the
compounds of formula I, or at least to provide the public with a useful choice.
In one aspect, the present invention provides a process which comprises the steps:
a) transforming an alcohol of formula II
RAU / 17.10.2012
wherein R has the meaning as above into the sulfonate of the formula III
wherein R has the meaning as above and R is C -alkyl, halogen-C -alkyl or phenyl
1-7 1-7
which is optionally substituted by C -alkyl, nitro or bromo;
b) reacting the sulfonate of formula III with a thio compound of formula IV
2 3 6
wherein R and R are as outlined above and R is hydrogen or a protecting group to form
the thioether of the formula V
1 2 3
wherein R , R and R are as outlined above and
c) oxidizing the thioether of formula V to form the proline derivative of formula I, wherein
1 2 3
R , R and R are as outlined above, and wherein the process is further characterized in that the
alcohol of formula II
is prepared by
a1) reacting a hydroxy proline ester of formula VI
R VI
wherein R is C -alkyl
with a carbonyl compound of formula VII
R CO Y VII
wherein R is as above and Y is halogen or OH to form a carbonyl proline ester of formula
R IX
wherein R and R are as above;
b1) subsequent forming of a sulfonate of formula X
1 7 8
wherein R and R are as above and R is C -alkyl optionally substituted by halogen or
phenyl which is optionally substituted by C -alkyl, nitro or bromo and
c1) converting the sulfonate of formula X in the presence of an amino cyclopropane
carbonitrile of the formula XI
NC NH
into the alcohol of formula II.
The following definitions are set forth to illustrate and define the meaning and scope of the
various terms used to describe the invention herein.
The term “C -alkyl”, alone or in combination with other groups, refers to a branched or
straight-chain monovalent saturated aliphatic hydrocarbon radical of one to seven carbon atoms,
particularly one to four carbon atoms. This term is further exemplified by radicals such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl or heptyl and its
isomers.
The term “C -alkyl”, alone or in combination with other groups, refers to a branched or
straight-chain monovalent saturated aliphatic hydrocarbon radical of one to nine carbon atoms,
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, pentyl, cyclopentyl, hexyl,
cyclohexyl, heptyl, octyl, nonyl and its isomers.
The term “halogen-C -alkyl” refers to a halogen substituted C -alkyl radical wherein
1-7 1-7
halogen has the meaning as outlined below. Particular “halogen-C -alkyl” radicals are the
fluorinated C -alkyl radicals such as CF , CH CF , CH (CF ) , CH (CH ) (CF ), C F , but more
1-7 3 2 3 3 2 3 3 4 9
particular CF .
The term “C -alkoxy” refers to a branched or straight-chain monovalent saturated
aliphatic hydrocarbon radical of one to seven carbon atoms, preferably 1 to 4 carbon atoms
attached to an oxygen atom. Examples of “alkoxy” are methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, pentoxy, hexyloxy or heptoxy. Particularly used are the alkoxy groups
specifically exemplified herein.
The term “mono- or di- (C -alkyl)-amino”, alone or in combination with other groups,
refers to one or two branched or straight-chain monovalent saturated aliphatic hydrocarbon
radicals of one to seven carbon atoms, preferably 1 to 4 carbon atoms, attached to a nitrogen
atom. Optionally, in case of “di-(C -alkyl)-amino”, the two C -alkyl radicals can be connected
1-7 1-7
to form a saturated heterocycle containing a nitrogen atom. Examples of “mono- or di- (C -
alkyl)-amino” are methylamino, dimethylamino, ethylamino, diethylamino, pyrrolidinyl,
ethylmethylamino, ethylpropylamino or piperidinyl.
The term “halogen-C -alkoxy” refers to a halogen substituted C -alkoxy radical wherein
1-7 1-7
halogen has the meaning as outlined below. Particular “halogen-C -alkoxy” radicals are the
fluorinated C -alkoxy radicals such as OCF , OCH CF , OCH (CF ) , OCH(CH )(CF ), OC F ,
1-7 3 2 3 3 2 3 3 4 9
but more particular OCH CF or OCH(CH )(CF ).
2 3 3 3
The term “5- or 6-membered heterocyclic ring containing one or two nitrogen atoms”
relates to an optionally substituted 5- or 6-membered heteroaryl radical containing one or two
nitrogen atoms selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl or
imidazolyl, more particularly to pyridinyl or pyrazolyl. A suitable substituent is the C -alkyl
group, whereby the methyl group is particularly used or is a halogen atom, whereby chlorine is
particularly used.
The term “aryl” refers to a phenyl radical that is optionally attached to one to three
substituents selected from C -alkyl, C -alkoxy and mono- or di- (C -alkyl)-amino.
1-7 1-7 1-7
The term “halogen” refers to a fluorine, chlorine, bromine or iodine atom.
Formation of the alcohol of formula II:
In the process of the present invention, the alcohol of the formula II
wherein R has the meaning as above is accessible either by
a1) reacting a hydroxy proline ester of formula VI
R VI
wherein R is C -alkyl
with a carbonyl compound of formula VII
R CO Y
wherein R is as above and Y means halogen or OH to form a carbonyl proline ester of
formula IX
R IX
wherein R and R are as above;
b1) subsequent forming of a sulfonate of formula X
1 7 8
wherein R and R are as above and R is C -alkyl optionally substituted by halogen or
phenyl which is optionally substituted by C -alkyl, nitro or bromo and
c1) converting the sulfonate of formula X in the presence of amino cyclopropane
carbonitrile of the formula XI
NC NH
into the alcohol of formula II.
Also described herein is a process where the alcohol of formula II is obtained by:
a2) transforming the sulfonate salt of the formula XII
R OH
wherein R is C -alkyl or phenyl which is optionally substituted by C -alkyl into the
1-7 1-7
amide of formula XIII
O XIII
wherein R is as above, and subsequently
b2) converting the amide of formula XIII in the presence of an aminocyclopropane
carbonitrile of the formula XI
NC NH
into the alcohol of formula II.
In a particular embodiment the alcohol of formula II obtained by the process steps a1) to c1)
or a2) to b2) as described above is a chiral isomer of the formula
wherein R has the meaning as above.
Step a1):
Step a1) requires the reaction of the hydroxy proline ester of formula VI with a carbonyl
compound of formula VII to form a carbonyl proline ester of formula IX.
This reaction can follow principles known to the skilled in the art for the formation of
amides.
The carbonyl compound of formula VII can be a carbonyl chloride or a carboxylic acid.
The coupling with carboxylic acids as a rule makes use of the common coupling agents for
amide bond formation, e.g. summarized in Chemical Reviews, volume 111 (2011), pages 6557
to 6602, such as DCC or DIC.
In a particular embodiment carbonyl chlorides are used which as a rule are prepared in situ
by converting the respective carboxylic acid with a common halogenating agent like e.g.
oxalylchloride or thionylchloride.
In a particular embodiment of the present invention the hydroxyproline ester of formula VI
is the commercially available hydroxyproline methylester hydrochloride.
The reaction as a rule is performed in an inert organic solvent such as dichloromethane,
tetrahydrofurane or toluene at temperatures of –10°C to 25 °C.
Suitably a tertiary amine like triethylamine or diisopropylethylamine is present.
The carbonyl proline ester of formula IX can either be isolated using methods known to the
skilled in the art or advantageously kept in solution and transferred to the following reaction step
b1).
Step b1):
Step b1) requires the formation of the sulfonate of formula X.
A common sulfonating agent like methanesulfonyl chloride, benzene sulfonyl chloride or
p-toluene sulfonyl chloride can as a rule be used.
Accordingly R particularly has the meaning of methyl, phenyl or p-tolyl, more
particularly of methyl.
The reaction advantageously takes place in the reaction environment of the former step
applying reaction temperatures of –10°C to 40°C.
The sulfonate of formula X can be isolated using methods known to the skilled in the art such as
by extraction from the reaction mixture using a suitable solvent like dichloromethane and by a
subsequent crystallization for instance in isobutyl acetate.
Step c1):
Step c1) requires the conversion of the sulfonate of formula X in the presence of
aminocyclopropane carbonitrile of the formula XI and the formation of the alcohol of formula II.
The reaction encompasses an initial hydrolysis of the ester function suitably with an
inorganic aqueous base such as with an aqueous alkali hydroxide like sodium hydroxide,
potassium hydroxide or lithium hydroxide at temperatures of 0°C to 30°C, followed by
intermediary formation of a lactone.
The aminocyclopropane carbonitrile of formula XI can be reacted as free base or as a
suitable salt, particularly the hydrochloride salt. The most suitable form is the hydrochloride salt.
The lactone aminolysis using an aminocyclopropane carbonitrile salt, such as the
hydrochloride salt, is accelerated by addition of at least stoichiometric amounts of an alkali
10
alkyl- or arylcarboxylate salt MR COO, wherein M = Li, Na, K or Cs, particularly Na, and R
= C -alkyl or aryl. In particular, sodium 2-ethylhexanoate can be used to promote the reaction.
Alternatively, the lactone aminolysis using an aminocyclopropane carbonitrile salt, such as
the hydrochloride salt, is accelerated by addition of substoichiometric amounts of an alkali alkyl-
10
or arylcarboxylate salt MR COO, wherein M and R are as defined above, particularly sodium
2-ethylhexanoate, in combination with the addition of stoichiometric amounts of a suitable base,
such as triethylamine.
In case of using an aminocyclopropane carbonitrile as free base, the lactone aminolysis is
accelerated by addition of stoichiometric or substoichiometric amounts of an alkali alkyl- or
10
arylcarboxylate salt MR COO, wherein M and R are as defined above, particularly sodium 2-
ethylhexanoate, or by addition of stoichiometric or substoichiometric amounts of an alkyl- or
10
arylcarboxylic acid R COOH, wherein R is as defined above, particularly 2-ethylhexanoic
acid.
An organic solvent such as tetrahydrofuran can be added, the reaction is performed at
temperatures of 40°C to 130°C, particularly 50°C to 70°C.
Product separation from the reaction mixture can follow procedures known to the skilled in
the art such as by extraction with a suitable solvent like ethyl acetate and a subsequent
crystallization of the resulting product also with a suitable organic solvent or mixtures thereof
like ethylacetate / heptane.
Alternatively the alcohol of formula II can be synthesized as follows:
Step a2)
Step a2) requires the transformation of a sulfonate salt of the formula XII into the amide of
formula XIII.
Suitable sulfonate salts of formula XII is either the methane sulfonate salt (R = methyl) or
the p-toluene sulfonate salt (R = p-tolyl).
These sulfonate salts can be synthesized by methods known in the literature, e.g. reported
in Journal of Organic Chemistry, volume 71, pages 7133 to 7145.
The formation of the amide can follow principles known to the skilled in the art and as
described above in step a1).
Product separation from the reaction mixture can follow procedures known to the skilled in
the art such as by extraction with a suitable solvent like dichloromethane and a subsequent
crystallization of the resulting product also with a suitable organic solvent or mixtures thereof
like ethylacetate / heptane.
Step b2)
Step b2) requires the conversion of the amide of formula XIII in the presence of
aminocyclopropane carbonitrile of the formula XI into the alcohol of formula II.
The aminocyclopropane carbonitrile of formula XI can be reacted as free base or as a
suitable salt, particularly the hydrochloride salt. The most suitable form is the hydrochloride salt.
The lactone aminolysis using an aminocyclopropane carbonitrile salt, such as the
hydrochloride salt, is accelerated by addition of at least stoichiometric amounts of an alkali
10
alkyl- or arylcarboxylate salt MR COO, wherein M = Li, Na, K or Cs, particularly Na, and R
= C -alkyl or aryl. In particular, sodium 2-ethylhexanoate can be used to promote the reaction.
Alternatively, the lactone aminolysis using an aminocyclopropane carbonitrile salt, such as
the hydrochloride salt, is accelerated by addition of substoichiometric amounts of an alkali alkyl-
10
or arylcarboxylate salt MR COO, wherein M and R are as defined above, particularly sodium
2-ethylhexanoate, in combination with the addition of stoichiometric amounts of a suitable base,
such as triethylamine.
In case of using an aminocyclopropane carbonitrile as free base, the lactone aminolysis is
accelerated by addition of stoichiometric or substoichiometric amounts of an alkali alkyl- or
10
arylcarboxylate salt MR COO, wherein M and R are as defined above, particularly sodium 2-
ethylhexanoate, or by addition of stoichiometric or substoichiometric amounts of an alkyl- or
10
arylcarboxylic acid R COOH, wherein R is as defined above, particularly 2-ethylhexanoic
acid.
The reaction usually is performed in polar solvents such as tetrahydrofuran,
dichloromethane, water, or mixtures thereof, or under neat conditions, at temperatures of 40°C to
130°C, particularly 50°C to 70°C.
Product separation from the reaction mixture can follow procedures known to the skilled in
the art such as by extraction with a suitable solvent like ethyl acetate and a subsequent
crystallization of the resulting product also with a suitable organic solvent or mixtures thereof
like ethylacetate / heptane.
The alcohol of the formula II
1 R 4
wherein R is selected from C alkyl or from , wherein R is selected from
methyl or trifluoromethyl is not known in the art and thus is a particular embodiment of the
present invention.
In a further particular embodiment of the process of the invention R has the meaning of
wherein R is selected from C -alkyl, halogen-C -alkyl or from phenyl which is
1-7 1-7
optionally substituted by halogen.
More particularly R has the meaning of methyl or of trifluoromethyl.
In a further particular embodiment the alcohol of formula II is a chiral isomer of the
formula
wherein R has the meaning as above.
Formation of the thio compound of formula IV:
Thio compound of formula IV with R = H
The thio compound of formula IV
2 3 6
wherein R and R are as above and R is hydrogen can be prepared by
a3) deprotecting a compound of formula XX
R XX
2 3 9
wherein R and R are as above and R stands for a tertiary alkyl group of the formula
11 12 13
wherein R , R and R independently of each other stand for C -alkyl
with an acid;
or by
b3) deprotecting a compound of formula XX
2 3 9
wherein R and R are as above and R stands for trityl with an acid in the presence of a
reductive agent;
c3) lithiating a halogenated compound of formula XXI
R XXI
wherein R and R are as above and X stands for a halogen atom and a subsequent
treatment with sulfur;
or by
d3) reacting a halogenated compound of formula XXI
R XXI
wherein R and R are as above and X stands for a halogen atom with a Grignard reagent
and by a subsequent treatment with sulfur.
Step a3)
Process variant a3) requires deprotecting a compound of formula XX wherein R stands for
a tertiary alkyl group with an acid.
R particularly has the formula
11 12
wherein R , R and R independently of each other stand for C -alkyl and more
particularly for C -alkyl. Even more particularly R stands for tert-butyl.
Compounds of formula XX are either commercially available or accessible by methods
readily available to the skilled in the art.
Compounds of formula XX with R = tert-butyl can be prepared by converting the
respective fluoro precursor compound with 2-methylpropane thiol in the presence of an alkali
alkoxide.
Suitable acids can be selected from aqueous mineral acids like aqueous hydrochloric acid
or aqueous sulfuric acid or by organic acids like trifluoro acetic acid.
An organic solvent like dichloromethane may be present when an organic acid is used.
The reaction conditions and the isolation of the thio compound of the formula IV depend
on the acid used but its adaptation can follow methods known to the skilled in the art..
Step b3)
stands
Process variant b3) requires deprotecting a compound of formula XX wherein R
for trityl with trifluoro acetic acid in the presence of a reductive agent.
A suitable reductive agent is triethylsilane.
An organic solvent like dichloromethane may be present.
The reaction conditions and the isolation of the thio compound of the formula IV can
follow methods known to the skilled in the art.
Step c3)
Process variant c3) involves lithiating a halogenated compound of formula XXI and a
subsequent treatment with sulfur.
X particularly stands for bromo.
Suitable lithiating agents can be selected from commercially available lithiating agents like
butyl lithium.
The lithiation as a rule takes place in the presence of an organic solvent such as in toluene
at temperatures between –80°C and –20°C.
A chelating agent, such as diethyl ether or di-n- propyl ether is suitably present as well.
Subsequent sulfur treatment can happen at temperatures between –80°C and –40°C usually
in the same reaction environment as for the lithiation.
The isolation of the thio compound of the formula IV can follow methods known to the
skilled in the art.
Step d3)
Process variant d3) involves reacting a halogenated compound of formula XXI with a
Grignard reagent and a subsequent treatment with sulfur.
X particularly stands for bromo.
Suitable Grignard agents can be selected from commercially available Grignard agents like
isopropyl magnesium chloride or isopropyl magnesium chloride/lithium chloride in
tetrahdydrofuran.
The Grignard reaction as a rule takes place in the presence of the organic solvent the
Grignard reagent is commercially available such as in tetrahydrofurane.
The reaction temperature is suitably held between 0°C and 40°C, particularly at about
room temperature.
Subsequent sulfur treatment can happen at temperatures between -20°C and 20°C usually
in the same reaction environment as for the Grignard reaction.
The isolation of the thio compound of the formula IV can follow methods known to the
skilled in the art.
Thio compound of formula IV with R = protecting group
Suitable protecting groups can be selected from 2-carbamoyl-ethyl, C -alkoxycarbonyl-
ethyl-, or mono or di- C -alkyl aminocarbonyl-ethyl.
R = 2-carbamoyl-ethyl was found to be particularly suitable.
These compounds can be prepared following the scheme below. X has the meaning of a
halogen atom, particularly bromine, R and R are as above.
Scheme 1:
O NH
O NH
SH 3
O R -Z
IV, R = CH CH C(O)NH
2 2 2
The 2-carbamoyl-ethyl protecting group can be installed by reacting the corresponding
thiophenol with acrylamide in the presence of a catalytic (or stoichiometric) amount of a suitable
base, e.g. sodium tetraborate, in a suitable polar solvent, such as methanol or water or mixtures
thereof. For other, substituted propionamide or –ester protecting groups the reacting acryl amide
is replaced accordingly. The resulting protected thiophenol can then be manipulated using
methods known to the person skilled in the art. As example, a bromine atom can be replaced by a
- or 6-membered heterocyclic ring R as defined above by reacting it with a suitable reactant
R -Z, wherein Z = B(OH) , B(OMe) , B(OEt) , B(OiPr) , 4,4,5,5-tetramethyl-[1,3,2]-dioxa-
2 2 2 2
boryl)-, Sn(n-Bu) , MgX, ZnX or Si(OEt) , particularly B(OH) or 4,4,5,5-tetramethyl-[1,3,2]-
3 3 2
dioxaboryl)-. In the particular cases, the reaction is performed in the presence of a catalytic
amount of a suitable transition metal complex, e.g. [1,1’-bis(diphenylphosphino)ferrocene]di-
chloropalladium(II) or tetrakis(triphenylphoshin)palladium(0), stoichiometric amounts of a
suitable base, e.g. potassium carbonate, sodium carbonate or potassium phosphate, in a suitable
solvent, such as for example dimethylformamide, dimethylacetamide, toluene, tetrahydrofuran,
tert-butanol, N-methylpyrrolidone or dioxane, optionally and preferably as mixtures thereof with
water, at elevated temperatures from 40°C to 140°C, particularly from 50°C to 70°C.
Optionally, the reactants R -Z as described above, particularly Z = 4,4,5,5-tetramethyl-
[1,3,2]-dioxaboryl)-, can be formed in situ starting from the appropriate R -X, wherein X has the
meaning of a halogen atom, particularly bromine or iodine, and reacting it with
4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) in the presence of an appropriate base,
e.g. potassium acetate or sodium acetate, and a catalytic amount of a suitable palladium complex,
such as [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in a suitable solvent e.g.
dimethylformamide, at temperatures of 60°C to 120°C, particularly 70°C to 90°C, and reacted
further in one pot with the protected halothiophenol, particulary using similar, more particularly
the same solvent and palladium complex.
Step a)
Step a) requires the transformation of an alcohol of the formula II into the sulfonate of the
formula III.
In a particular embodiment a chiral isomer of the alcohol of the formula II having the
formula
wherein R has the meaning as above is used.
The sulfonation follows methods known to the skilled in the art applying common
commercially available sulfonating agents. Particular sulfonating agent is benzenesulfonyl
chloride or methanesulfonyl chloride.
As a rule a tertiary amine such as triethylamine is present. The reaction may be accelerated
by addition of a suitable Lewis base, e.g.4-(dimethylamino) pyridine.
The reaction as a rule takes place in an organic solvent such as in tertrahydrofuran at
temperatures of -10°C to 40°C.
The isolation of the sulfonate of formula III can follow methods known to the skilled in the
art.
The sulfonate of formula III
wherein R has the meaning as above and R is C -alkyl, halogen-C -alkyl or phenyl
1-7 1-7
which is optionally substituted by C -alkyl, nitro or bromo is also described herein.
In a further particular embodiment R has the meaning of
wherein R is selected from C -alkyl, halogen-C -alkyl or from phenyl which is
1-7 1-7
optionally substituted by halogen and R has the meaning of C -alkyl or phenyl which is
optionally substituted by C -alkyl.
More particularly R has the meaning of methyl or of trifluoromethyl and R the meaning
of methyl or phenyl.
In a further particular embodiment the sulfonate of formula III is a chiral isomer of the
formula
IIIa
wherein R and R are as above.
Step b)
Step b) requires reacting the sulfonate of formula III with a thio compound of formula IV
to form the thioether of the formula V.
The reaction is suitably performed in the presence of a base, such as an alkali alcoholate or
an alkali carbonate.
More particularly a lithium-, sodium- or potassium tert-butylate is used.
An inert organic solvent like tetrahydrofuran or dimethyl acetamide, or mixtures thereof, is
suitably present.
The reaction temperature can be selected between 10°C and 90°C.
The thioether of formula V can be separated from the reaction mixture following
procedures known to the skilled in the art such as by extraction with a suitable solvent like ethyl
acetate or tert-butyl methyl ether. Further purification may be achieved by crystallization in a
suitable solvent like toluene, n-heptane, 2-butanol or mixtures thereof.
The thioether of the formula V
1 2 3
wherein R , R and R are as outlined above is not known in the art and thus is a particular
embodiment of the present invention.
In a further particular embodiment
R has the meaning of
wherein R is selected from C -alkyl, halogen-C -alkyl or from phenyl which is
1-7 1-7
optionally substituted by halogen,
R has the meaning of halogen or halogen-C -alkyl and
R has the meaning of halogen-C -alkoxy or of a 5- or 6-membered heterocyclic ring
containing one or two nitrogen atoms, the ring which is optionally substituted by C -alkyl or
halogen.
More particularly
R has the meaning of methyl or trifluoromethyl,
R has the meaning of trifluoromethyl or chlorine and
R has the meaning of 2,2,2-trifluoroethoxy, 2-methylpyridyl, 1-methyl-1H-pyrazol
yl or 2,2,2-trifluoromethylethoxy.
In a further particular embodiment the thioether of the formula V is a chiral isomer of the
formula
N Va
even more particular
1 2 3
wherein R , R and R have the meaning as above.
Step c)
Step c) requires oxidizing the thioether of formula V to form the proline derivative of
formula I.
The oxidation reaction can be performed with a commercially available oxidating agent
such as with potassium peroxymonosulfate, that is, as example, available as a triple salt in
Oxone®, or magnesium monoperoxyphthalate hexahydrate.
A polar organic solvent like methanol or acetonitrile is suitably used. Optionally water or
aqueous inorganic acids like sulfuric acid or phosphoric acid may further be added.
The reaction temperature can be selected between 0°C and 60°C.
The proline derivative of formula I can be separated from the reaction mixture following
procedures known to the skilled in the art such as by extraction with a suitable solvent like ethyl
acetate. Further purification may be achieved by crystallization in a suitable solvent like acetone,
isopropanol, water or mixtures thereof.
In a particular embodiment of the present invention the proline derivatives of the formula I
are chiral isomers of the formula
even more particular of formula
1 2 3
wherein R , R and R are as outlined below.
In a further particular embodiment
R has the meaning of
wherein R is selected from C -alkyl, halogen-C -alkyl or from phenyl which is
1-7 1-7
optionally substituted by halogen,
R has the meaning of halogen or halogen-C -alkyl and
R has the meaning of halogen-C -alkoxy or of a 5- or 6-membered heterocyclic ring
containing one or two nitrogen atoms, the ring which is optionally substituted by C -alkyl or
halogen.
More particularly
R has the meaning of methyl or of trifluoromethyl,
R has the meaning of trifluoromethyl or chlorine and
R has the meaning of 2,2,2-trifluoroethoxy, 2-methylpyridyl, 1-methyl-1H-pyrazolyl
or 2,2,2-trifluoromethylethoxy.
Examples:
General part:
All solvents and reagents were obtained from commercial sources and were used as
received. The reactions were as a rule followed by TLC (TLC plates F254, Merck) or LC (liquid
chromatography) or GC (gas chromatography) analysis. Proton NMR spectra were obtained on
Bruker 300, 400 or 600 MHz instruments with chemical shifts (δ in ppm) reported relative to
tetramethylsilane as internal standard in the following format: chemical shift in ppm (peak form,
coupling constant if applicable, integral). NMR abbreviations are as follows: s, singlet; d,
doublet; t, triplet; q, quadruplet; quint, quintuplet; sext, sextuplet; hept, heptuplet; m, multiplet;
br, broadened. Purity was analyzed by reverse phase HPLC. HPLC was performed on Agilent
1100 & 1200 equipment. Elemental analyses were performed by Solvias AG (Mattenstrasse,
Postfach, CH-4002 Basel, Switzerland). Column chromatography was carried out on silica gel 60
(32-60 mesh, 60 Å) or on prepacked columns (Isolute Flash Si). Mass spectra were recorded on
an Agilent 6520 QTOF spectrometer for ESI (electrospray ionization) & APCI (atmospheric
pressure chemical ionization), that is achieved simultaneously (multimode), and on an Agilent
5975 instrument for EI (electron ionization) mode, with either positive (pos.) or negative (neg.)
charged ion detection. If not otherwise stated, positive charged ions are detected.
Alcohol formation:
A1. Preparation of (2S,4S)hydroxy(1-trifluoromethyl-cyclopropanecarbonyl)-
pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
a.) (1S,4S)Oxooxaazonia-bicyclo[2.2.1]heptane methanesulfonate
MsOH
EtOAc, 45°C
(1S,4S)Oxooxaaza-bicyclo[2.2.1]heptanecarboxylic acid tert-butyl ester
(100.0 g, 469 mmol) was dissolved in ethyl acetate (970 mL) and methanesulfonic acid
(43.5 mL, 659 mmol) was added at 45°C. The mixture was stirred for 16 h at 45°C. The
suspension was cooled to room temperature, filtered, and the precipitate was washed with ethyl
acetate (240 mL) and dried in vacuo to yield the title compound as a white crystalline solid
(94.2 g, 96%). MS (EI, neg): m/z = 113 [cation – H] , 69 [cation – H – CO ] , 68 [cation – H –
HCO ] . H NMR (DMSO-d6, 600 MHz): δ 2.12 (dd, J = 1.2 Hz, 12.0 Hz, 1H), 2.33 (s, 3H),
2.59 (d, J = 12.0 Hz, 1H), 3.33 and 3.50 (ABX, J = 12.0 Hz, J = 1.9 Hz, J = 0 Hz, each
AB AX BX
1H), 4.58 (s, 1H), 5.41 (s, 1H), 9.74 (br s, 2H).
b) (1S,4S)(1-Trifluoromethyl-cyclopropanecarbonyl)oxaaza-bicyclo[2.2.1]heptan-
3-one
(COCl)
toluene / DMF, rt
N 2. NEt H
toluene, rt
O CF
1-Trifluoromethyl-cyclopropanecarboxylic acid (167.0 g, 1084 mmol) was suspended in
toluene (500 mL) and then dimethylformamide (3.6 mL, 47 mmol) was added. The mixture was
cooled to 2°C (ice bath) and a solution of oxalyl chloride (90 mL, 1037 mmol) in toluene
(167 mL) was added dropwise (within 25 min). The mixture was then stirred for additional
min, followed by 4 h at room temperature. Subsequently, it was cooled to 0°C again (dry ice /
methanol bath) and (1S,4S)oxooxaazonia-bicyclo[2.2.1]heptane methanesulfonate
(200 g, 956 mmol), tetrahydrofuran (330 mL) and triethylamine (500 mL, 3.59 mol) were slowly
added, keeping the reaction temperature below 5°C. Especially after addition of 50% of
triethylamine, the reaction becomes strongly exothermic and efficient cooling is essential. The
mixture was stirred for 20 h at room temperature, before it was poured onto an aqueous citric
acid solution (10 % in water, 1.6 L) and the phases were separated. The aqueous phase was
extracted with ethyl acetate (3 x 500 mL). The combined organic extracts were washed with
brine (500 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product (245 g,
brown oil) was dissolved in dichloromethane (330 mL) before ethyl acetate (130 mL) and
heptane (660 mL) were added and dichloromethane was carefully distilled off in vacuo. The
product started to crystallize. The suspension was cooled to 2°C (ice bath) and stirred for 1 h,
before it was filtered. The precipitate was washed with ethyl acetate / heptane 1:9 (v/v, 300 mL)
and dried in vacuo to afford the title compound as a light brown powder (219 g, 92%). H NMR
(CDCl , 400 MHz): δ 1.17-1.25 (m, 1H), 1.30 (dd, J = 5.3 Hz, 8.3 Hz, 1H), 1.37-1.46 (m, 2H),
2.13 and 2.37 (AB, J = 10.7 Hz, each 1H), 3.63 and 3.73 (AB, J = 12.1 Hz, each 1H), 4.99
AB AB
(s, 1H), 5.21 (s, 1H).
c) (1S,4S)(1-Methyl-cyclopropanecarbonyl)oxaaza-bicyclo[2.2.1]heptanone
(COCl)
CH Cl /DMF, rt
O 2 2
2. NEt
CH Cl , rt
1-Methyl-cyclopropanecarboxylic acid (56.4 g, 552 mmol) was dissolved in
dichloromethane (365 mL) and dimethylformamide (405 μl, 5.2 mmol) was added. The mixture
was cooled to 2°C and oxalyl chloride (70.8 g, 547 mmol) was added dropwise. It was allowed
to warm and stirred for 90 min at room temperature. After that, it was added to a suspension of
(1S,4S)oxooxaazonia-bicyclo[2.2.1]heptane methanesulfonate (110 g, 526 mmol) in
dichloromethane (400 mL). The resulting suspension was cooled to 2°C and triethylamine
(256 mL, 1.84 mol) was added slowly (exothermic). After stirring for 70 min at room
temperature, a solution of citric acid (81.0 g, 421 mmol) in water (550 mL) was added at 2°C.
After separation of the phases, the aqueous phase was extracted with dichloromethane (300 mL).
The combined organic extracts were washed with water (400 mL) and concentrated in vacuo to a
volume of ca. 500 mL. Ethyl acetate (330 mL) was added and the residual dichloromethane was
distilled off in vacuo (internal temperature 40°C). Further ethyl acetate (50 mL) was added,
internal temperature was increased to 50°C and heptane (800 mL) was added slowly.
Crystallization started after addition of ca. 300 mL heptane. The suspension was stirred for 12 h
at room temperature and filtered.The crystals were washed with cold heptane (400 mL) and dried
in vacuo at 40°C to afford the title compound as colorless crystals (88.45 g, 86%). mp. 101-
102°C. MS (ESI & APCI): m/z = 196.1 [M + H] . H NMR (CDCl , 600 MHz); δ 0.60-0.67 (m,
2H), 0.87-0.91 (m, 1H), 1.13-1.17 (m, 1H), 1.39 (s, 3H), 2.04 (dd, J = 1.2 Hz, 10.9 Hz, 1H), 2.32
(d, J = 10.8 Hz, 1H), 3.59 and 3.69 (AB, J = 11.5 Hz, each 1H), 4.97 (s, 1H), 5.18 (s, 1H).
d) (2S,4S)Hydroxy(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine
carboxylic acid (1-cyano-cyclopropyl)-amide
ClH O
Na-ethylhexanoate
water, 53°C N
O HO
(1S,4S)(1-Trifluoromethyl-cyclopropanecarbonyl)oxaaza-bicyclo[2.2.1]heptan
one (220 g, 883 mmol), 1-amino-cyclopropanecarbonitrile hydrochloride (140 g, 1.18 mol) and
sodium 2-ethylhexanoate (97%, 230 g, 1.34 mol) were dissolved in water (1.32 L). The mixture
was stirred for 20 h at 53°C. After cooling to room temperature, tetrahydrofuran (880 mL) was
added and the mixture was acidified by addition of concentrated hydrochloric acid (37% m/m,
47 mL), followed by the addition of sodium chloride (440 g). After extraction with ethyl acetate
(1 x 1.4 L, 3 x 550 mL), the combined organic extracts were dried over sodium sulfate and
concentrated in vacuo. At a volume of ca. 1.5 L, the product started to crystallize upon addition
of seed crystals. The volume of the suspension was further reduced to ca. 500 mL and cooled to
2°C (ice bath). After stirring for 60 min, the crystals were filtered off, washed with ethyl acetate
/ heptane 1:1 (v/v, 600 mL) and heptane (300 mL), and dried in vacuo to provide the title
compound as off-white crystals (255.0 g, 87%). H NMR (CDCl , 400 MHz): δ 1.18-1.29 (m,
4H), 1.30-1.42 (m, 2H), 1.50-1.59 (m, 2H), 2.17-2.26 (m, 1H), 2.29 (d, J = 14.5 Hz, 1H), 3.73
and 3.96 (ABX, J = 11.8 Hz, J = 4.3 Hz, J = 0 Hz, each 1H), 4.43-4.53 (m, 2H), 4.81 (br
AB AX BX
d, J = 8.3 Hz, 1H), 7.73 (s, 1H).
A2. Preparation of (2S,4S)hydroxy(1-trifluoromethyl-cyclopropanecarbonyl)-
pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
a) (2S,4R)Methanesulfonyloxy(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-
2-carboxylic acid methyl ester
F C COCl
Cl 1)
2) MeSO Cl
Et N, CH Cl , 0°C
3 2 2
To a stirred suspension of 1-trifluoromethylcyclopropanecarboxylic acid (40.4 g, 263
mmol) and DMF (0.4 mL, 5.25 mmol) in dichloromethane (50 mL) was added oxalyl chloride
(36.7 g, 289 mmol) under stirring at room temperature over 2 h (vigorous gas evolution!). After
additional stirring for 0.5 h (the gas evolution has stopped), the clear acid chloride solution was
transferred into an 100 mL addition funnel and added under vigorous stirring at 0°C over 0.5 h to
a suspension of hydroxyproline methyl ester hydrochloride (45.4 g, 250 mmol) and triethylamine
(101 g, 1000 mmol) in dichloromethane (950 mL). After additional stirring at 0°C for 1 h,
methanesulfonyl chloride (31.5 g, 275 mmol) was added over 0.5 h, stirring at 0°C was
continued for 0.5 h and the cold suspension was hydrolyzed with 1 M HCl (500 mL, pH = 1).
After warming to room temperature the organic layer was washed with 5% brine (500 mL) and
the two aqueous layers were extracted with dichloromethane (250 mL). The combined organic
layers were dried (Na SO ) and evaporated (35-45°C/≥10 mbar) affording beige, crystalline
crude product (91.4 g) which was dissolved in isoproppyl acetate (360 mL) at ~70°C.
Crystallization, which started upon cooling and seeding, was completed by stirring at room
temperature, followed by drop wise addition of heptane (540 mL) and stirring at -20°C for 4 h.
Filtration and washing with cold isoproppyl acetate-heptane 2 : 3 gave after drying (10
mbar/55°C/4 h) the product (83.2 g, 92.6%) as an off-white, crystalline powder, mp. 123-124°C.
1
[α] = -26.6 (c 1.0; CHCl ). H NMR (CDCl , 400 MHz) δ 1.10-1.42 (m, 4H), 2.18-2.30 (m,
D 3 3
1H), 2.58-2.70 (m, 1H), 3.06 & 3.76 (s, each 3H), 3.90 (dd, J = 12.8 Hz, J = 3.2 Hz, 1H), 4.32
(d, J = 12.8 Hz, 1H), 4.68 (t, J = 8.3 Hz, 1H), 5.33 (s, 1H). ESI-MS (m/z) [M+H] 360 (100).
b) (2S,4S)Hydroxy(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine
carboxylic acid (1-cyano-cyclopropyl)-amide
1) 2 M NaOH, rt
N NC NH .HCl
Na 2-ethylhexanoate, 70°C H
To the (2S,4R)methanesulfonyloxy(1-trifluoromethyl-cyclopropanecarbonyl)-
pyrrolidinecarboxylic acid methyl ester (71.9 g, 200 mmol) were added under stirring and ice-
cooling 2.0 M NaOH (120.0 mL, 240.0 mmol) all at once. The ice bath was removed and the
white suspension was stirred at room temperature for 1 h. After neutralization by the addition of
2.0 M HCl (20.0 mL, 40.0 mmol; pH ~7), 1-aminocyclopropanecarbonitrile hydrochloride (23.7
g 200 mmol) and sodium 2-ethylhexanoate (37.7 g, 220 mmol) were added all at once and the
biphasic reaction mixture was stirred at 70°C for 22 h and then cooled to ~35°C.
Dichloromethane (100 mL) and NaCl (16 g) were added and stirring was continued until the
NaCl was dissolved (~15 min). After acidification with 25% HCl (~12 mL, pH ~1), the reaction
mixture was extracted with dichloromethane (3 x 200 mL) and all three organic layers were
washed separately with 5% NaHCO (40 mL pH ~8). The combined organic layers were dried
(Na SO ), filtered, and evaporated (35-50°C/≥5 mbar), affording beige, crystalline residue (88.5
g) which was dissolved in isobutyl acetate (500 mL) at ~110°C. Crystallization, which started
after seeding and cooling, was completed by stirring at room temperature for 1 h and at -20°C for
4 h. Filtration and washing with cold isobutyl acetate gave after drying (10 mbar/55°C/4 h) the
title product (47.7 g, 72.0%) as an off white, crystalline powder, mp. 156-157°C. [α] = -68.9
(c 1.0; CHCl ). H NMR (CDCl , 400 MHz) δ 1.15-1.45 (m, 6H), 1.50-1.60 (m, 2H), 2.17-2.29
(m, 2H), 3.72 (dd, J = 11.8 Hz, J = 4.0 Hz, 1H), 3.98 (d, J = 11.8 Hz, 1H), 4.40-4.52 (m, 2H),
4.95 (d, J = 9.7 Hz, 1H), 7.93 (s, 1H). ESI-MS (m/z) [M+H] 332 (56).
A3. Preparation of (2S,4S)hydroxy(1-methyl-cyclopropanecarbonyl)-pyrrolidine
carboxylic acid (1-cyano-cyclopropyl)-amide
Naethylhexanoate N
water, 50°C
O HO
(1S,4S)(1-Methyl-cyclopropanecarbonyl)oxaaza-bicyclo[2.2.1]heptanone
(100 g, 512 mmol), 1-amino-cyclopropanecarbonitrile hydrochloride (62.0 g, 523 mmol), and
sodium 2-ethylhexanoate (97%, 96.5 g, 563 mmol) were dissolved in water (500 mL). The
mixture was stirred for 16 h at 50°C. After cooling to room temperature, dichloromethane
(500 mL) was added, the mixture was acidified by addition of hydrochloric acid (25% m/m,
13.8 mL, 106 mmol), and sodium chloride (120 g) was added. The mixture was stirred for 1 h,
phases were separated, the aqueous layer was extracted with dichloromethane (3 x 330 mL) and
the combined organic extracts were concentrated in vacuo to a volume of ca. 1.1 L. Ethyl acetate
(1.1 L) was added, the mixture was concentrated in vacuo to a volume of ca. 1 L and heptane
(1 L) was added within 30 min. The resulting suspension was stirred for 2 h at 2°C, filtered, the
precipitate was washed with cold ethyl acetate / heptane 1:1 (v/v, 340 mL) and heptane (340 mL)
and dried in vacuo to afford the title compound as light yellow crystals (129.4 g, 90%). MS (ESI
& APCI): m/z = 278.1 [M + H] . H NMR (CDCl , 600 MHz): δ 0.60-0.65 (m, 2H), 0.89-0.92
(m, 1H), 0.95-0.98 (m, 1H), 1.20-1.26 (m, 2H), 1.33 (s, 3H), 1.50-1.57 (m, 2H), 2.13 (ddd, J =
.0 Hz, 9.0 Hz, 14.1 Hz, 1H), 2.39 (br d, J = 14.3 Hz, 1H), 3.76 (dd, J = 4.3 Hz, 11.6 Hz, 1H),
3.85 (d, J = 11.6 Hz, 1H), 4.48- 4.53 (m, 1H), 4.57 (d, J = 9.0 Hz, 1H), 4.70 (br s, 1H), 7.92 (br
s, 1H).
A4. Preparation of (2S,4S)hydroxy(1-methyl-cyclopropanecarbonyl)-pyrrolidine
carboxylic acid (1-cyano-cyclopropyl)-amide
a) 1-Methyl-cyclopropanecarbonyl chloride
SOCl
CO H
2 COCl
cat. DMF, 40°C
To 1-methyl-cyclopropanecarboxylic acid (100.1 g, 1000 mmol) and DMF (0.37 g, 5.0
mmol) was carefully added under stirring at ~40°C thionylchloride (125.0 g, 1050 mmol) over 1
h. After additional stirring at 40°C for 1h, the crude product (122.3 g) was distilled through a
Vigreux column affording the title product (114.8 g, 96.8%) as a bright yellow liquid, bp. 129-
130°C/~1000 mbar. H NMR (CDCl , 400 MHz) δ 0.98 (m, 2H), 1.40 (s, 3H), 1.59 (m, 2H).
b) (2S,4R)Methanesulfonyloxy(1-methyl-cyclopropanecarbonyl)-pyrrolidine
carboxylic acid methyl ester
H COCl
+ 1)
2) MeSO Cl
Cl N
Et N, cat. DMAP, CH Cl , 0°C
3 2 2 O
To a suspension of hydroxyproline methyl ester hydrochloride (36.3 g, 200 mol),
triethylamine (65.8 g, 650 mmol) and dimethylaminopyridine (1.25 g, 10 mmol) in
dichloromethane (800 mL) was added at 0°C the 1-methyl-cyclopropanecarbonyl chloride (24.9
g, 210 mmol) over 0.5 h. After additional stirring for 2 h, methanesulfonyl chloride (28.64 g, 250
mmol; note 7) was added over 0.5 h and stirring at 0°C was continued for 1 h. The cold reaction
mixture was transferred into a separatory funnel and washed with 1 M HCl (400 mL) and 10%
brine (400 mL). The aqueous layers were extracted with dichloromethane (400 mL) and the
combined organic layers were dried over Na SO . Filtration and evaporation of the solvent (35-
45°C/≥10 mbar) afforded crude, crystalline product (63.8 g) which was dissolved in isobutyl
acetate (250 mL) at ~70°C. After seeding at ~50°C, crystallization was completed by cooling to
room temperature and stirring at -20°C overnight. Filtration and washing with cold isobutyl
acetate gave after drying (50°C/10 mbar/3 h) the title product (57.5 g, 94.2%) as a white,
1
crystalline powder, mp. 102-103°C. [α] = -10.3 (c 1.0; CHCl ). H NMR (CDCl , 400 MHz) δ
D 3 3
0.50-0.70 (m, 2H), 0.90 (m, 1H), 1.10 (m, 1H), 1.34 (s, 3H), 2.23 (m, 1H), 2.59 (m, 1H), 3.06 (s,
3H), 3.74 (s, 3H), 3.95 (d, 1H), 4.25 (d, 1H), 4.63 (br t, 1H), 5.35 (s, 1H).
c) (2S,4S)Hydroxy(1-methyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-
cyano-cyclopropyl)-amide
1) 2 M NaOH, rt
NC NH .HCl
N 2 O
O Na 2-ethylhexanoate, 70°C
To 2 M NaOH (60.0 mL, 120 mmol) was added at 0°C the (2S,4R)methanesulfonyloxy-
1-(1-methyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid methyl ester (30.54 g, 100
mmol) all at once. The ice bath was removed and the white suspension was warmed to room
temperature over 1 h. After the addition of 2 M HCl (10.0 mL, 20 mmol) 1-
aminocyclopropanecarbonitrile hydrochloride (11.86 g, 100 mmol) and sodium 2-ethylhexanoate
(18.28 g,110 mmol) were added all at once and the biphasic reaction mixture was stirred at 70°C
for 21 h . After cooling to ~35°C, dichloromethane (50 mL) and NaCl (8.0 g) were added and
stirring was continued until the NaCl was dissolved. The reaction mixture was acidified with
% HCl (8 mL), transferred into a separatory funnel, and extracted with dichloromethane (4 x
150 mL). All four organic layers were washed sequentially with 5% NaHCO (20 mL). The
combined organic layers were dried (Na SO ), filtered, and evaporated to dryness (40°C/≥5
mbar) affording a beige, crystalline residue (38.5 g) which was redissolved in dichloromethane
(200 mL). Solvent exchange with ethyl acetate was accomplished at the rotary evaporator by
portion-wise addition of ethyl acetate (350 mL) at 60–80°C/950 mbar and at the same time
distilling off dichloromethane. The crystal suspension was cooled to room temperature and
stirred at -20°C over night. Filtration and washing with cold ethyl acetate afforded after drying
(50°C/10 mbar/4 h) the title product (20.8 g, 75.0%) as an off white, crystalline powder, mp.
1
159.5-160.5°C. [α] = -111.0 (c 1.0; CHCl ). H NMR (CDCl , 400 MHz) δ 0.58-0.67 (m, 2H),
D 3 3
0.86-1.02 (m, 2H), 1.18-1.28 (m, 2H), 1.33 (s, 3H), 1.48-1.59 (m, 2H), 2.09-2.18 (m, 1H), 2.36
(d, J = 14 Hz, 1H), 3.76 and 3.86 (AB, J = 11.7 Hz, J = 4.3 Hz, J = 0 Hz, each 1H), 4.50
AB AX BX
(quint, J = 4.6 Hz, 1H), 4.55 (d, J = 8.9 Hz, 1H), 4.75 (d, J = 9.1 Hz, 1H), 7.98 (s, 1H).
B. Thio compound formation:
B1. Preparation of 2-chloro((S)-2,2,2-trifluoromethyl-ethoxy)-benzenethiol
a) 2-Chlorofluorotritylsulfanyl-benzene
F CCOOH
SCPh
Ph COH
F Cl
CH Cl , rt
F Cl
2-Chlorofluoro-benzenethiol (250 g, 1.54 mol) was dissolved in dichloromethane
(1.25 L) and trifluoroacetic acid (120 mL, 1.57 mol) followed by triphenylmethanol (400 g,
1.54 mol) were added at room temperature (ice bath cooling necessary during addition of
triphenylmethanol). The mixture was stirred for 1.5 h at room temperature, concentrated and
dried in vacuo to yield the title compound as a yellow solid (622 g, 99% purity by HPLC, 99%),
that was used without further purification in the next step. H NMR (CDCl , 400 MHz): δ 6.55
(ddd, J = 2.9 Hz, 8.0 Hz, 8.9 Hz, 1H), 6.91 (dd, J = 6.2 Hz, 8.9 Hz, 1H), 6.97 (dd, J = 2.9 Hz,
8.6 Hz, 1H), 7.20-7.27 (m, 9H), 7.34-7.39 (m, 6H).
b) 2-Chloro((S)-2,2,2-trifluoromethyl-ethoxy)tritylsulfanyl-benzene
F C OH
SCPh
SCPh
NaOtBu
F C O Cl
DMA, 50°C 3
F Cl
(S)-1,1,1-Trifluoro-propanol (100 g, 877 mmol) was dissolved in dimethylacetamide
(600 mL) and the solution was cooled to 2°C (ice bath). A solution of sodium tert-butoxide
(77.5 g, 790 mmol) in dimethylacetamide (100 mL) was added at 2°C and the mixture was
stirred for 15 min. This solution was treated with a solution of 2-chlorofluorotritylsulfanyl-
benzene (200 g, 494 mmol) in dimethylacetamide (100 mL) at room temperature and
subsequently stirred for 3 h at 50°C. It was then poured into a mixture of brine (200 mL), ice
(1.2 kg) and water (2.0 L), and extracted with tert-butyl-methylether (2 x 1000 mL). The
combined organic extracts were washed with brine / water 1:1 (v/v, 300 mL) and concentrated in
vacuo to give the crude product as a yellow viscous oil. The oil was dissolved in ethanol (1.6 L),
before water (240 mL) was slowly added at room temperature. The resulting suspension was
stirred for 14 h, cooled to 2°C (ice bath) and stirred for another 2 h, before it was filtered. The
solid was washed with ethanol / water 4:1 (v/v, 500 mL) and dried in vacuo to afford the title
compound as a white crystalline solid (238 g, 97%). H NMR (CDCl , 400 MHz): δ 1.43 (d, J =
6.5 Hz, 3H), 4.50 (qq, J = 6.2 Hz, 6.2 Hz, 1H), 6.44 (dd, J = 2.8 Hz, 8.7 Hz, 1H), 6.84 (d, J =
2.7 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 7.18-7.27 (m, 9H), 7.33-7.39 (m, 6H).
c) 2-Chloro((S)-2,2,2-trifluoromethyl-ethoxy)-benzenethiol
Et SiH
SCPh
F CCOOH
CH Cl , rt F C O Cl
F C O Cl 2 2 3
2-Chloro((S)-2,2,2-trifluoromethyl-ethoxy)tritylsulfanyl-benzene (220 g,
441 mmol) was dissolved in dichloromethane (800 mL) and trifluoroacetic acid (165 mL,
2.15 mol) was added at room temperature, followed by triethylsilane (110 mL, 674 mmol, ice
bath cooling necessary). After stirring for 30 min at room temperature, the mixture was
concentrated in vacuo. A potassium hydroxide solution (2M in water, 1.1 L) was added to the
residue, and the suspension was stirred for 15 min. After filtration, the remaining solid was
washed with water. The combined filtrate was acidified to pH < 2 by addition of hydrochloric
acid (25% in water, 330 mL) and extracted with tert-butyl-methylether (3 x 500 mL). The
combined organic extracts were washed with an aqueous potassium hydrogencarbonate solution
(1M, 330 mL), dried over sodium sulfate, and concentrated in vacuo. The turbid oil was treated
with heptane (80 mL) and filtered. The remaining solid was further washed with heptane
(20 mL). The combined filtrate was concentrated and dried in vacuo to yield the title compound
as a colorless liquid (105 g, 93%). H NMR (CDCl , 400 MHz): δ 1.49 (dd, J = 6.5 Hz, 0.5 Hz,
3H), 3.75 (s, 1H), 4.55 (qq, J = 6.2 Hz, 6.2 Hz, 1H), 6.79 (dd, J = 3.0 Hz, 8.9 Hz, 1H), 7.03 (d,
J = 2.7 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H).
B2. Preparation of 4-(2,2,2-trifluoro-ethoxy)trifluoromethyl-benzenethiol
a) 4-Fluorotrifluoromethyltritylsulfanyl-benzene
1. PPh
THF/H O, rt
S 2 SCPh
2. Ph COH
CF CF
3 CF COOH 3
CH Cl , rt
Triphenylphosphine (126.2 g, 481 mmol) was dissolved in tetrahydrofuran (155 mL) and a
solution of 4-fluorotrifluoromethyl-benzenesulfonyl chloride (40.0 g, 152 mmol) in
tetrahydrofuran (80 mL) was added within 30 min at 22°C internal temperature. The yellow
suspension was stirred for 15 min at room temperature, then water (48 mL) was added and the
resulting clear solution stirred for 20 min. Concentrated sodium hydroxide solution (32% m/m in
water, 34 mL, 367 mmol) and water (260 mL) were added, the tetrahydrofuran was distilled off
completely in vacuo and the resulting aqueous suspension was filtered. The filtered solids
(triphenylphosphine and triphenylphosphine oxide) were washed thoroughly with water
(360 mL), the combined filtrates were acidified by addition of aqueous hydrochloric acid (25%
m/m in water, 40.0 mL, 307 mmol), extracted with dichloromethane (1 x 200 mL, 1 x 60 mL)
and the combined organic extracts (ca. 260 mL) were used in the following step without further
treatment.
Triphenylmethanol (39.7 g, 149.4 mmol) was dissolved in the solution of crude 4-fluoro
trifluoromethyl-benzenethiol in dichloromethane (ca. 260 mL) of the preceding step and a
solution of trifluoroacetic acid (21.2 g, 186 mmol) in dichloromethane (20 mL) was added at
room temperature. After stirring for 15 h, the mixture was basified by subsequent addition of
water (20 mL), concentrated aqueous sodium hydroxide solution (32% m/m, 26.9 g, 215 mmol)
and water again (240 mL). Phases were separated, the aqueous layer was extracted with
dichloromethane (100 mL) and the combined organic extracts concentrated in vacuo at 50°C to
a volume of ca. 330 mL. Ethanol (400 mL) was continuously added to the distillation, while the
overall volume was kept constant (solvent exchange). The solution (ca. 300 mL) was allowed to
cool to room temperature, crystallization started at 42°C. The suspension was stirred for 18 h at
room temperature and for 1 h at 0°C. After filtration, the precipitate was washed with cold
ethanol (100 mL) and dried in vacuo at 40°C to give rise to the title compound as a white
crystalline solid (52.5 g, 79%). MS (EI): m/z = 243 [CPh ] . H NMR (CDCl , 600 MHz): δ 6.73
(ddd, J = 2.8 Hz, 8.3 Hz, 8.3 Hz, 1H), 7.04 (dd, J = 5.4 Hz, 8.8 Hz, 1H), 7.18-7.25 (m, 10H),
7.35-7.37 (m, 6H). Anal. Calcd for C26H18F4S: C, 71.22; H, 4.14; S, 7.31; F, 17.33. Found: C,
71.16; H, 4.26; S, 7.15; F, 17.09.
b) 4-(2,2,2-Trifluoro-ethoxy)trifluoromethyltritylsulfanyl-benzene
F C OH
SCPh
SCPh KOtBu
THF/NMP, 45°C
F C O CF
F CF
Potassium tert-butoxide (98% m/m, 39.17 g, 342.1 mmol) was suspended in
tetrahydrofuran (190 mL) and a solution of trifluoroethanol (35.65 g, 356.4 mmol) in
tetrahydrofuran (28 mL) was added at room temperature (exothermic). The mixture was stirred
for 15 min, and a solution of 4-fluorotrifluoromethyltritylsulfanyl-benzene (125 g,
285 mmol) in 1-methylpyrrolidon (240 mL) and tetrahydrofuran (290 mL) was added. The
resulting brown solution was stirred for 30 min at room temperature, followed by 2 h at 45°C
internal temperature. After that, water (720 mL), brine (125 mL), and tert-butyl-methylether
(720 mL) were added and phases were separated. The organic layer was washed with a solution
of sodium chloride (59.3 g, 1015 mmol) in water (380 mL) and concentrated in vacuo at 40°C to
a volume of ca. 400 mL. The solution was diluted with ethanol (300 mL), and additional ethanol
(480 mL) was continuously added to the distillation, while the overall volume was kept constant
at ca. 700 mL (solvent exchange). The resulting suspension was stirred for 14 h at room
temperature and 1 h at 0°C before water (140 mL) was added and the suspension was stirred for
further 1.5 h at 0°C. After filtration, the precipitate was washed with cold ethanol / water 5:1
(v/v, 288 mL) and dried in vacuo to yield the title compound as fine yellow crystals (140.9 g,
95%). MS (EI): m/z = 243 [CPh ] . H NMR (CDCl , 600 MHz): δ 4.26 (q, J = 8.0 Hz, 2H), 6.61
(dd, J = 2.9 Hz, 8.8 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 2.9 Hz, 1H), 7.18-7.25 (m,
9H), 7.33-7.37 (m, 6H).
c) 4-(2,2,2-Trifluoro-ethoxy)trifluoromethyl-benzenethiol
Et SiH
SCPh
F CCOOH
F C O CF
F C O CF
CH Cl , rt
4-(2,2,2-Trifluoro-ethoxy)trifluoromethyltritylsulfanyl-benzene (100 g, 193 mmol)
was dissolved in dichloromethane (600 mL) and trifluoroacetic acid (44.9 g, 386 mmol) was
added at room temperature, followed by a solution of triethylsilane (24.9 g, 214 mmol) in
dichloromethane (75 mL) at 18°C (ice bath cooling). The yellow mixture was stirred for 3 h at
room temperature. Water (600 mL) was then added and dichloromethane was distilled off in
vacuo under vigorous stirring. Tert-butyl-methylether (600 mL) was added and the resulting
biphasic mixture was basified by addition of a concentrated aqueous sodium hydroxide solution
(32% m/m, 54 mL, 583 mmol) to pH 12. Phases were separated, the aqueous layer was extracted
with tert-butyl-methylether (400 mL), acidified by addition of hydrochloric acid (25% m/m in
water, 35 mL, 268 mmol) to pH 3, and extracted with tert-butyl-methylether (600 mL). The
organic extract was washed with a solution of sodium hydrogencarbonate (16.1 g, 193 mmol) in
water (500 mL), and water (500 mL) and concentrated in vacuo to afford the title compound as a
light yellow liquid (49.7 g, 90%). MS (ESI & APCI, neg): m/z = 275.0 [M – H] . H NMR
(CDCl , 600 MHz): δ 3.66 (q, J = 2.5 Hz, 1H), 4.36 (q, J = 8.0 Hz, 2H), 6.99 (dd, J = 2.9 Hz,
8.6 Hz, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H).
B3. Preparation of 4-(2,2,2-trifluoro-ethoxy)trifluoromethyl-benzenethiol
a1) 1-Bromo(2,2,2-trifluoro-ethoxy)trifluoromethyl-benzene
F C OH
NaOtBu, DMF,
F C O CF
F CF
THF, 80°C
To a 2.4 M solution of sodium-tert-butoxide in THF (156.3 mL, 375 mmol, Chemetall)
was added DMF (38.5 mL, 500 mmol) and then 2,2,2-trifluoroethanol (41.27 g, 413 mmol).
After the addition of 2-bromofluorobenzotrifluoride (60.8 g, 250 mmol) the reaction mixture
was heated to reflux and stirred at ~80°C for 7 h. After cooling to 25°C, TBME (800 mL) was
added and the reaction mixture was washed with 1M HCl (400 mL), 5% NaHCO (400 mL) and
% brine (400 mL). The organic layer was dried (Na SO ), filtered and evaporated to dryness
(60°C/≥5 mbar), affording the crude title product (80.0 g, 99.1%) as a yellow oil which was
used without purification in the next step H NMR (CDCl , 400 MHz) δ 4.38 (q, J = 7.9 Hz, 2H),
6.98 (dd, J = 8.6 Hz, J = 2.7 Hz, 1H), 7.28 (d, J = 2.7 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H).
b1) 4-(2,2,2-Trifluoro-ethoxy)trifluoromethyl-benzenethiol
1) BuLi 2) S
toluene, -75°C
F C O CF
F C O CF
To a solution of 1-bromo(2,2,2-trifluoro-ethoxy)trifluoromethyl-benzene (80.8 g 250
mmol) in toluene (1000 mL) was added diethyl ether (52 mL, 500 mmol). After cooling to -
75°C, 2.5 M butyllithium in toluene (105 mL, 263 mmol) was added at -75°C over 30 min and
stirring at -75°C was continued for 30 min. Sulfur powder (8.8 g, 275 mmol) was then added at -
75°C all at once and stirring was continued for 7h. The cold yellow suspension was poured to a
stirred mixture of toluene (1000 mL) and 0.5M NaOH (1000 mL). After vigorous stirring for 5
min the two layers were separated and the aqueous layer was extracted with toluene (500 mL).
The aqueous layer was cooled to ~10°C, acidified with 6M HCl (~150 mL) and extracted with
dichloromethane (1000 mL). The dichloromethane layer was washed with 10% brine (1000 mL),
dried with Na SO , filtered and evaporated to dryness (60°C/≥5 mbar) affording crude yellow
oily product (58.2 g). Purification by distillation gave the title product (55.1 g, 79.8%) as bright
yellow oil, bp. 84-86°C/2.3 mbar. H NMR (CDCl , 400 MHz) δ 3.66 (q, J = 2.4 Hz, 1H), 4.36
(q, J = 8.1 Hz, 2H), 6.98 (dd, J = 8.6 Hz, J = 2.7 Hz, 1H), 7.23 (d, J = 2.7 Hz, 1H), 7.39 (d, J =
8.6 Hz, 1H).
b2) 4-(2,2,2-Trifluoro-ethoxy)trifluoromethyl-benzenethiol
1) i-PrMgCl LiCl, THF, 20°C
2) S , 0°C
F C O CF
F C O CF
To a solution of 1-bromo(2,2,2-trifluoro-ethoxy)trifluoromethyl-benzene (16.2 g, 50
mmol) in THF (200 mL) was added at 20°C under stirring 1.3 M isopropylmagnesium
chloride/lithium chloride (1 : 1) in THF (46.2 mL ≅ 45.2 g, 60 mmol Turbo-Grignard,
Chemetall) over 30 min. After stirring at 20°C for 2 h the clear, yellow solution was cooled to
0°C and sulfur powder (1.84 g, 57.5 mmol) was added all at once. Stirring at 0°C was continued
for 2 h and the reaction mixture was hydrolyzed under vigorous stirring with 0.5 M HCl (200
mL) and extracted twice with TBME (200 mL & 100 mL). The two organic layers were washed
with 0.5 M NaOH (200 mL), the NaOH layer was acidified under ice cooling with 6 M HCl (20
mL) and extracted with TBME (200 mL). The TBME layer was washed with 10% brine (100
mL), dried (Na2SO4), filtered and evaporated (≤60°C/≥5 mbar) affording the crude title product
(11.4 g) as a yellow oil which was purified by Kugelrohr distillation (11.1 g, 80.4%), bp. ≈
90°C/2 mbar. H NMR (CDCl , 400 MHz) δ 3.66 (q, J = 2.4 Hz, 1H), 4.36 (q, J = 8.1 Hz, 2H),
6.98 (dd, J = 8.6 Hz, J = 2.7 Hz, 1H), 7.23 (d, J = 2.7 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H).
B4. Preparation of 2-chloro((S)-2,2,2-trifluoromethyl-ethoxy)-benzenethiol
a) 1-bromochloro((S)-2,2,2-trifluoromethyl-ethoxy)-benzene
Br F C OH Br
NaOtBu, DMF,
F Cl F C O Cl
THF, 80°C
To 2.4 M sodium-tert-butoxide in THF (156.3 mL, 375 mmol) was added under stirring
(S)-1,1,1-trifluoro-propanol (47.1 g, 413 mmol), DMF (77.0 mL, 1000 mmol) and 1-bromo
chlorofluoro-benzene (52.4 g, 250 mmol). The reaction mixture was heated to reflux and
stirred at ~80° for 19 h. After cooling to room temperature TBME (1000 mL) was added and the
reaction mixture was washed with 1M HCl (500 mL), 5% NaHCO3 (500 mL) and 10% brine
(400 mL). The aqueous layers were extracted with TBME (400 mL) and the organic layers was
dried (Na SO ), filtered and evaporated to dryness (≤60°C/≥5 mbar) affording 75.8 g crude title
product. Distillation through a Vigreux columnwas gave as colorless oil (71.5 g, 94.2%), bp.
~70°C/0.1 mbar. H NMR (CDCl , 400 MHz) δ 1.50 (dd, J = 6.4 Hz, J = 0.5 Hz, 3H), 4.59
3 1 2
(hept, J = 6.2 Hz, 1H), 6.76 (dd, J = 8.9 Hz, J = 3.0 Hz, 1H), 7.09 (d, J = 2.7 Hz, 1H), 7.52 (d,
J = 8.9 Hz, 1H).
b) 2-Chloro((S)-2,2,2-trifluoromethyl-ethoxy)-benzenethiol
Br SH
1) i-PrMgCl LiCl, THF, 20°C
2) S , 0°C
F C O Cl 8 F C O Cl
To a solution of 1-bromochloro((S)-2,2,2-trifluoromethyl-ethoxy)-benzene (15.2
g, 50 mmol) in THF (200 mL) was added under stirring at 20°C 1.3 M isopropylmagnesium
chloride/lithium chloride (1:1) in THF (50.0 mL ≅ 49.0 g, 65 mmol Turbo-Grignard, Chemetall)
over 30 min. After additional stirring at 20°C for 2 h the yellow solution was cooled to -5°C and
Sulfur (1.92 g, 60 mmol) was added all at once. After stirring at 0°C for 2 h the ice bath was
removed and the reaction mixture was hydrolyzed with 1 M HCl (125 mL). The reaction mixture
was extracted twice with TBME (200 mL & 100 mL) and the organic layers were washed with 1
M NaOH (125 mL). The NaOH layer was separated, cooled to ~10°C and acidified with 6 M
HCl (25 mL). After extraction with TBME (200 mL) and washing with 10% brine (100 mL) the
organic layer was dried (Na SO ), filtered and evaporated (≤50°C/≥5 mbar) affording (10.1 g,
78.7%) crude title product as a yellow oil. H NMR (CDCl , 400 MHz) δ 1.49 (dd, J = 6.5 Hz,
J = 0.5 Hz, 3H), 3.75 (s, 1H), 4.55 (hept, J = 6.2 Hz, 1H), 6.79 (dxd, J = 8.9 Hz, J = 3.0 Hz,
2 1 2
1H), 7.03 (d, J = 2.7 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H).
B5. Preparation of 3-[4-(2-methyl-pyridinyl)trifluoromethyl-phenylsulfanyl]-
propionamide
a) 4-Bromotrifluoromethyl-benzenethiol
SO Cl
Br CF
Br CF toluene/H O, 0°C
4-Bromotrifluoromethyl-benzenesulfonyl chloride (375 g, 1.16 mol) was dissolved in
toluene (1.5 L) and a solution of triphenylphosphine (994 g, 3.79 mol) in toluene (1.5 L) was
added at 5 – 10°C within 45 min. The yellow suspension was stirred at 0 – 5°C for 30 min, then
water (360 mL) was added at 5 – 12°C (strongly exothermic) and the resulting colorless
suspension was stirred for 20 min at room temperature. After filtration, the precipitate was
washed with toluene (1 L). The combined organics were extracted with a potassium hydroxide
solution (1M in water, 2.8 L). During extraction, 3 layers were formed. The upper layer was
discarded, the other two were washed with toluene (1 L). The aqueous phase was acidified to pH
3-4 by addition of citric acid (280 g, 1.46 mol). After addition of n-heptane (1 L), the precipitate
was filtered off and washed with n-heptane (500 mL). The layers of the combined filtrate were
separated and the aqueous phase was extracted with n-heptane (1.5 L). The combined organic
extracts were dried over sodium sulfate. Silica gel (250 g) was then added, the slurry was stirred
for 10 min at room temperature, filtered and the filtered silica gel washed with n-heptane (1 L).
The combined filtrate was concentrated and dried in vacuo at 45°C to afford 291.2 g (98%) of
the title compound as a colorless liquid, that was used without further purification in the next
step. MS (EI): m/z = 256.9, 254.9 [M + H]+. 1H NMR (CDCl , 400 MHz): δ 3.76 (q, J = 2.8 Hz,
1H), 7.26 (d, J = 8.3 Hz, 1H), 7.48 (dd, J = 2.0 Hz, 8.5 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H).
b) 3-(4-Bromotrifluoromethyl-phenylsulfanyl)-propionamide
SH S NH
cat. Na B O 2
2 4 7
MeOH/H O, rt
Br CF Br CF
4-Bromotrifluoromethyl-benzenethiol (259.2 g, 1.01 mol) was dissolved in methanol
(1.3 L) and water (2.6 L), then acrylamide (130 g, 1.82 mol), followed by sodium tetraborate
(25.9 g, 129 mmol) were added at room temperature. The suspension was stirred for 40 h. After
filtration, the solid was washed with water (2.6 L) and n-heptane (2.6 L) and dried in vacuo to
yield the title compound as a white powder (325.6 g, 98%). MS (EI): m/z = 330.0, 328.0 [M +
H] . H NMR (d6-DMSO, 400 MHz): δ 2.40 (t, J = 7.2 Hz, 2H), 3.24 (t, J = 7.2 Hz, 2H), 6.92
(bs, 1H), 7.37 (bs, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.82-7.88 (m, 2H).
c1) 3-[4-(2-Methyl-pyridinyl)trifluoromethyl-phenylsulfanyl]-propionamide
K CO S
2 3 2
S NH
cat. Pd(dppf) Cl
Br CF
DMF/H O, 50°C
3-(4-Bromotrifluoromethyl-phenylsulfanyl)-propionamide (300 g, 914 mmol) was
dissolved in N,N-dimethylformamide (3.0 L) and potassium carbonate (300 g, 2.17 mol). Then,
2-methylpyridineboronic acid pinacol ester (285 g, 1.3 mol) and water (240 mL) were added.
The solution was degassed and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(30 g, 41 mmol) was added. The mixture was stirred for 20 h at 50°C. After cooling to room
temperature, it was poured onto ice cold water (5°C, 5 L) and extracted with ethyl acetate (1 x
3.5 L, 2 x 1.5 L). The combined organic extracts were washed with brine / water (1:1 v/v,
750 mL) and brine (750 mL), before methanol (600 mL) was added and the mixture was dried
over sodium sulfate. Silica gel (400 g) was added, the slurry was filtered and washed with ethyl
acetate / methanol (9:1 v/v, 1.5 L). The combined filtrates were concentrated in vacuo. The
residue was suspended in toluene (600 mL) and n-heptane (300 mL) and stirred for 5 min at
60°C and for 1 h at room temperature. The precipitate was filtered off, washed with toluene / n-
heptane (4:1 v/v, 300 mL) and n-heptane (300 mL), and dried in vacuo to afford 230.3 g of
brown crystalline material. The crystals were further purified by trituration in isopropanol /
heptane (1:1 v/v, 600 mL) for 30 min at room temperature and 30 min at 0 – 4°C (ice bath). The
precipitate was filtered off, washed with n-heptane / isopropanol (4:1 v/v, 300 mL), and dried in
vacuo at 65°C to yield the title compound as a light brown crystalline solid (215.7 g, 69%). MS
(EI): m/z = 341.1 [M + H] . H NMR (d6-DMSO, 400 MHz): δ 2.48 (t, J = 7.2 Hz, 2H), 2.54 (s,
3H), 3.32 (t, J = 7.2 Hz, 2H), 6.95 (bs, 1H), 7.41 (bs, 1H), 7.58 (dd, J = 1.6 Hz, 5.4 Hz, 1H),
7.68 (s, 1H), 7.77 (d, J = 9.1 Hz, 1H), 8.02-8.08 (m, 2H), 8.52 (d, J = 5.1 Hz, 1H).
c2) 3-[4-(2-Methyl-pyridinyl)trifluoromethyl-phenylsulfanyl]-propionamide (one pot
from bromopicoline)
KOAc
Pd(dppf)Cl
DMF, 80°C
2. Pd(dppf)Cl
F C Br 2 3
K CO
DMF/H O, 60°C
4-Bromomethylpyridine (6.0 g, 34.9 mmol) was dissolved in dimethylformamide
(60 mL) before potassium acetate (10.0 g, 102 mmol) and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-
bi(1,3,2-dioxaborolane) (10 g, 39.4 mmol) were added at room temperature. The solution was
degassed and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (400 mg, 547 mol)
was added. The brown reaction mixture was stirred for 22 h at 80°C. After cooling to room
temperature, 3-(4-bromotrifluoromethyl-phenylsulfanyl)-propionamide (8.0 g, 24.4 mmol),
potassium carbonate (8.0 g, 57.9 mmol), dimethylformamide (20 mL), and water (16 mL) were
added. The mixture was degassed, stirred for 30 min at room temperature and further [1,1’-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) (400 mg, 547 mol) was added. The
resulting brown reaction mixture was stirred for 20 h at 60°C. After cooling to room temperature,
it was poured onto water (150 mL) and extracted with ethyl acetate (1 x 80 mL, 2 x 40 mL). The
combined organic extracts were washed with brine / water (1:1 v/v, 20 mL) and brine (20 mL),
methanol (16 mL) was added and the mixture was dried over sodium sulfate. Silica gel (16 g)
was added, the slurry was filtered and washed with ethyl acetate / methanol (9:1 v/v, 40 mL).
The combined filtrates were concentrated in vacuo. The residue was treated with toluene / n-
heptane (1:1 v/v, 24 mL) and the resulting suspension was stirred for 30 min at room temperature.
After filtration, the precipitate was washed with toluene / n-heptane (4:1 v/v, 10 mL) and n-
heptane (10 mL) and dried in vacuo to afford the title compound as brown crystals (5.7 g, 71%).
MS (EI): m/z = 341.1 [M + H] . H NMR (d6-DMSO, 400 MHz): δ 2.48 (t, J = 7.2 Hz, 2H),
2.54 (s, 3H), 3.32 (t, J = 7.2 Hz, 2H), 6.95 (bs, 1H), 7.41 (bs, 1H), 7.58 (dd, J = 1.6 Hz, 5.4 Hz,
1H), 7.68 (s, 1H), 7.77 (d, J = 9.1 Hz, 1H), 8.02-8.08 (m, 2H), 8.52 (d, J = 5.1 Hz, 1H).
B6. Preparation of 3-[4-(1-methyl-1H-pyrazolyl)trifluoromethyl-phenylsulfanyl]-
propionamide
S NH
S NH
cat. Pd(PPh ) O
Br CF K CO
DMF/H O, 50°C
3-(4-Bromotrifluoromethyl-phenylsulfanyl)-propionamide (160 g, 488 mmol) was
dissolved under Ar in N,N-dimethylformamide (1.5 L) before 1-methyl(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolanyl)-1H-pyrazole (143 g, 687 mmol), potassium carbonate (160 g,
1.16 mol), and water (130 mL) were added. The solution was degassed and tetrakis(triphenyl-
phosphine)palladium(0) (24.0 g, 20.8 mmol) was added. The mixture was stirred for 16 h at
50°C. After cooling to room temperature, the mixture was poured onto water (5 L) and extracted
with ethyl acetate (1 x 3 L, 2 x 1 L). The combined organic extracts were washed with brine
(1 L), the volume was reduced in vacuo to ca. 2 L and dried over sodium sulfate. The resulting
filtrate was further reduced in vacuo until precipitation occurred and a homogeneous slurry was
formed. Tert-butyl methyl ether (1 L) was then added in portions to the distillation, keeping the
overall volume constant (solvent exchange). The suspension was cooled to 5°C (ice bath) and
filtered. The precipitate was washed with tert-butyl methyl ether (500 mL) and dried in vacuo to
provide 141 g of the title compound as brown crystalline solid (88%). MS (ESI & APCI): m/z =
330.1 [M + H] . H NMR (CDCl , 600 MHz): δ 2.54 (t, J = 7.4 Hz, 2H), 3.27 (t, J = 7.4 Hz, 2H),
.39 (bs, 1H), 5.52 (bs, 1H), 7.56 (s, 1H), 7.57 (s, 1H), 7.66 (s, 1H), 7.73 (bs, 1H), 7.77 (d, J =
0.7 Hz, 1H).
B7. Preparation of 4-(2-methyl-pyridinyl)trifluoromethyl-benzenethiol hydrochloride
a) 4-(4-Fluorotrifluoromethyl-phenyl)methyl-pyridine
Fe Pd
Br Ph
toluene, 2 M K CO , 90°C
2 3 F
To a stirred suspension of 4-fluoro(trifluoromethyl)phenylboronic acid (42.6 g, 205
mmol) in toluene (200 mL) were added 4-bromomethylpyridine (34.4 g, 200 mmol) and 2 M
aqueous potassium carbonate (200 mL). After the addition of 1,1'-bis(diphenylphosphino)-
ferrocene-palladium(II)dichloride dichloromethane complex (81.7 mg, 0.1 mmol), the two-phase,
yellowish reaction mixture was stirred under reflux at 88°C for 23 h. The resultant brownish
reaction mixture was cooled to room temperature and extracted with toluene (200 mL). After
washing with 10% brine (200 mL), the toluene layer was dried with Na SO (50 g) and then
treated under stirring with charcoal (2 g) for 30 min. Filtration and evaporation (50°C/≥10 mbar)
afforded the crude title product (50.7 g, 99.4%) as an off-white, crystalline residue which was
used without purification in the next step. H NMR (CDCl , 400 MHz) δ 2.64 (s, 3H), 7.25-7.36
(m, 3H), 7.76-7.82 (m, 1H), 7.84 (dd, J = 6.7 Hz, J = 2.4 Hz, 1H), 8.58 (d, J = 5.0 Hz, 1H).
ESI-MS (m/z) [M+H] 256.3 (100).
b) 4-(4-tert-Butylsulfanyltrifluoromethyl-phenyl)methyl-pyridine
t-BuSH, NaOtBu
DMF, THF, 50°C
To a solution of 4-(4-Fluorotrifluoromethyl-phenyl)methyl-pyridine (51.0 g, ~200
mmol) in THF (100 mL) were carefully added at room temperature 2-methylpropanethiol
(23.5 g, 260 mmol) and DMF (29.2 g, 400 mmol). Sodium-tert-butoxide solution 25% in THF
(96.1 g = 106 mL, 250 mmol, Chemetall) was added over 50 min and the beige suspension was
stirred at 50°C for 17 h. The brownish suspension was transferred into a separatory funnel, filled
with TBME (500 mL), and washed with water (500 mL) and with 10% brine (500 mL). The two
aqueous layers were extracted with TBME (300 mL) and the combined organic layers were dried
(Na SO ). Filtration and evaporation (45°C/≥10 mbar) afforded crude title product (65.5 g,
100.6%) as a brown oil which was used without purification in the next step. H NMR (CDCl ,
400 MHz) δ 1.39 (s, 9H), 2.65 (s, 3H), 7.33 (d, J = 5.1 Hz, 1H), 7.39 (s, 1H), 7.73 (dd, J = 8.1
Hz, J = 1.9 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 1.9, 1H), 8.60 (d, J = 5.4, 1H). ESI-
MS (m/z) [M+H] 326 (100).
c) 4-(2-Methyl-pyridinyl)trifluoromethyl-benzenethiol hydrochloride
M HCl
100°C
N HCl
4-(4-tert-Butylsulfanyltrifluoromethyl-phenyl)methyl-pyridine (65.1 g, ~200 mmol)
was dissolved in 5 M HCl (800 mL) and the yellowish solution was warmed up and stirred at
100°C under reflux for 22 h. After cooling (~1 h) and stirring at room temperature for 0.5 h, the
beige suspension was filtered and the filter cake was washed with deionized water (400 mL) and
acetone (200 mL) and then dried (50°C/≥10 mbar/24 h) to give 57.4 g (93.9%) of the title
compound as an off-white, crystalline powder, mp. >270°C (dec.). H NMR (CDCl + 2 drops
TFA, 400 MHz) δ 2.96 (s, 3H), 4.06 (q, J = 3.3 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.74 (dd, J =
8.3 Hz, J = 2.1 Hz, 1H), 7.84 (d, J = 1.9 Hz, 1H), 7.93 (dd, J = 6.3 Hz, J = 1.9 Hz, 1H), 7.97
2 1 2
(d, J = 1.9, 1H), 8.79 (d, J = 6.2 Hz, 1H), 9.96 (s, 14H, TFA), 15.18 (br s, 1H). ESI-MS (m/z)
[M-HCl] 270 (100).
B8. Preparation of 4-(1-methyl-1H-pyrazolyl)trifluoromethyl-benzenethiol
S SH
HCl (25%)
100°C
4-(4-tert-Butylsulfanyltrifluoromethyl-phenyl)methyl-1H-pyrazole (40.0 g,
127 mmol) was suspended in hydrochloric acid (25% w/w, 780 mL) and stirred at 100°C under
reflux. Part of the hydrochloric acid was distilled off (ca. 80 mL). After the reaction was
complete as shown by HPLC, it was cooled to 85°C, water (240 mL) was added, and the mixture
was cooled further to 20°C. The pH was adjusted to 4.0 by addition of a solution of sodium
hydroxide (32% w/w, ca. 480 mL) in water (960 mL). The aqueous phase was extracted with 2-
methyltetrahydrofuran (2 x 320 mL), the combined organic extracts were washed with a solution
of sodium chloride (40.0 g) in water (400 mL) and concentrated in vacuo. The residue was
redissolved in tetrahydrofuran (260 mL), concentrated in vacuo, dissolved again in
tetrahydrofuran (110 mL) and filtered in order to remove inorganic salts. The precipitate was
washed with tetrahydrofuran (30 mL) and the combined filtrate was concentrated in vacuo to
obtain the title compound as light brown solid (32.4 g, 98.6%), that was used without further
purification in the next step.
C. Product formation
C1. Preparation of (2S,4R)[2-chloro((S)-2,2,2-trifluoromethyl-ethoxy)-
benzenesulfonyl](1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic
acid (1-cyano-cyclopropyl)-amide
a) Benzenesulfonic acid (3S,5S)(1-cyano-cyclopropylcarbamoyl)(1-trifluoromethyl-
cyclopropanecarbonyl)-pyrrolidinyl ester
PhSO Cl
NEt O
DMAP
THF, rt
(2S,4S)Hydroxy(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic
acid (1-cyano-cyclopropyl)-amide (100.0 g, 301.8 mmol) was dissolved in tetrahydrofuran
(500 mL). The mixture was cooled to 2°C (ice bath), benzenesulfonyl chloride (99%, 48 mL,
370.5 mmol), 4-(dimethylamino)pyridine (98%, 2.0 g, 16.0 mmol), and triethylamine (75.0 mL,
539 mmol) were added subsequently and the mixture was stirred for 15 min. The reaction was
allowed to warm to room temperature and stirred for 20 h. After cooling to 2°C (ice bath), water
(150 mL) and methanol (350 mL) were added. Tetrahydrofuran was distilled off carefully in
vacuo (ca. 500 mL) and water (500 mL) was added slowly. After addition of 300 mL water,
crystallization was induced by addition of seed crystals. The resulting suspension was stirred for
min at 2°C (ice bath) and filtered. The solid was washed with methanol / water 1:2 (v/v,
300 mL) and heptane (300 mL) and dried in vacuo to afford the title compound as off-white
crystals (140.8 g, 99%). H NMR (CDCl , 400 MHz): δ 1.06-1.27 (m, 4H), 1.28-1.41 (m, 2H),
1.44-1.54 (m, 2H), 2.26 (ddd, J = 5.9 Hz, 9.4 Hz, 14.2 Hz, 1H), 2.59 (ddd, J = 3.8 Hz, 3.8 Hz,
14.2 Hz, 1H), 3.90 and 4.03 (ABX, J = 12.5 Hz, J = 4.0 Hz, J = 5.2 Hz, each 1H), 4.57
AB AX BX
(br d, J = 5.1 Hz, 1H), 5.02-5.09 (m, 1H), 7.08 (br s, 1H), 7.61 (t, J = 7.8 Hz, 2H), 7.71 (t, J =
7.5 Hz, 1H), 7.95 (d, J = 7.2 Hz, 2H).
b) (2S,4R)[2-Chloro((S)-2,2,2-trifluoromethyl-ethoxy)-benzenesulfonyl](1-tri-
fluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-
amide
Step 1: (2S,4R)[2-Chloro((S)-2,2,2-trifluoromethyl-ethoxy)-phenylsulfanyl](1-
trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-
amide
CF 3
F C O Cl
K CO
O DMA/THF, rt
Benzenesulfonic acid (3S,5S)(1-cyano-cyclopropylcarbamoyl)(1-trifluoromethyl-
cyclopropanecarbonyl)-pyrrolidinyl ester (225 g, 477 mmol) was dissolved in
dimethylacetamide (1.125 L) and potassium carbonate (166.5 g, 1.193 mol) was added. At room
temperature, a solution of 2-chloro((S)-2,2,2-trifluoromethyl-ethoxy)-benzenethiol (142 g,
553.2 mmol) in tetrahydrofuran (135 mL) was added slowly, keeping the internal temperature
below 29°C (ice bath cooling necessary). The mixture was stirred for 5.5 h at room temperature.
After addition of ice (700 g) and water (2 L), the mixture was extracted with tert-butyl-
methylether (1 x 1.5 L, 3 x 750 mL). The combined organic extracts were washed with brine
(450 mL) and concentrated in vacuo to yield the title compound as a brown viscous oil (300.4 g).
The crude product (containing dimethylacetamide) was used in the next step without further
purification.
Step 2: (2S,4R)[2-Chloro((S)-2,2,2-trifluoromethyl-ethoxy)-benzenesulfonyl]
(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-
amide
CF CF
Oxone®
MeOH/H O, rt
Cl Cl
CF CF
Oxone® (1.5 kg, 2.44 mol) was suspended in methanol (1.225 L) and water (385 mL) and
a solution of (2S,4R)[2-chloro((S)-2,2,2-trifluoromethyl-ethoxy)-phenylsulfanyl](1-
trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-
amide (crude product, containing dimethylacetamide, 90.5% purity m/m, 300.4 g, 477.2 mmol)
in methanol (800 mL) was added at a reaction temperature of 10 – 18°C (ice bath cooling
necessary). The mixture was stirred for 20 h at room temperature. The suspension was filtered
and the remaining solid was washed with methanol (900 mL). Water (900 mL) was added to the
filtrate and methanol was distilled off in vacuo. The resulting solution was extracted with tert-
butyl-methylether (2 x 900 mL). The combined organic extracts were washed with a solution of
sodium metabisulfite (40.0 g, 206 mmol) in water (450 mL), a potassium hydrogencarbonate
solution (1M in water, 450 mL), and brine (450 mL). After drying over sodium sulfate, silica gel
(300 g) was added. The resulting suspension was filtered and the remaining silica gel was
washed with tert-butyl-methylether (900 mL). The combined filtrates were concentrated in
vacuo and azeotroped with methanol (2 x 500 mL). The crude product (white foam, 270 g) was
dissolved in methanol (450 mL) and added to water (4 L) with vigorous stirring. The suspension
was stirred for 18 h at room temperature, filtered and the solid was washed with water (900 mL)
and heptane (900 mL). After drying in vacuo, the title compound was obtained as an amorphous
white solid (259 g, 97.6% purity by HPLC, 88% over 2 steps). MS (ESI & APCI): m/z = 602.1
+ + 1
[M + H] , 619.1 [M + NH ] . H NMR (CDCl , 400 MHz): δ 1.11-1.21 (m, 2H), 1.30-1.43 (m,
1H), 1.35-1.40 (m, 1H), 1.42-1.47 (m, 1H), 1.49-1.56 (m, 3H), 1.57 (d, J = 7.1 Hz, 3H), 2.16-
2.23 (m, 1H), 2.86 (ddd, J = 5.6 Hz, 8.3 Hz, 14.2 Hz, 1H), 3.85 (dd, J = 7.5 Hz, 13.6 Hz, 1H),
4.34-4.39 (m, 1H), 4.72 (br d, J = 13.3 Hz, 1H), 4.76-4.84 (m, 2H), 7.02 (dd, J = 2.5 Hz, 9.0 Hz,
1H), 7.18 (d, J = 2.5 Hz, 1H), 7.60 (s, 1H), 8.00 (d, J = 8.9 Hz, 1H).
C2. Preparation of (2S,4R)(1-methyl-cyclopropanecarbonyl)[4-(2,2,2-trifluoro-
ethoxy)trifluoromethyl-benzenesulfonyl]-pyrrolidinecarboxylic acid (1-cyano-
cyclopropyl)-amide
a1) Benzenesulfonic acid (3S,5S)(1-cyano-cyclopropylcarbamoyl)(1-methyl-cyclo-
propanecarbonyl)-pyrrolidinyl ester
PhSO Cl
DMAP
H CH Cl , rt
(2S,4S)Hydroxy(1-methyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-
cyano-cyclopropyl)-amide (62.0 g, 224 mmol) and 4-(dimethylamino)pyridine (98%, 1.5 g,
12.0 mmol) were dissolved in dichloromethane (370 mL), benzenesulfonyl chloride (31.1 mL,
242 mmol), followed by triethylamine (49.8 mL, 358 mmol) were added at room temperature
and the mixture was stirred for 16 h. After that, it was diluted with water (140 mL) and acidified
by addition of hydrochloric acid (25% m/m, 21.4 mL). The phases were separated and the
organic layer was washed with water (160 mL). The combined aqueous phases were extracted
with dichloromethane (160 mL), the combined organic extracts were concentrated in vacuo to a
volume of 430 mL. The solvent was exchanged via continuous distillation in vacuo (internal
temperature 40°C, 670 – 170 mbar) to ethanol (670 mL added), the overall volume was kept
constant (430 mL). The resulting solution was allowed to cool to room temperature and seed
crystals (ca. 10 mg) were added to initiate crystallization. After crystallization had started, the
suspension was stirred for 30 min at room temperature, heptane (430 mL) was added within
50 min and it was stirred for 12 h. The suspension was then filtered, the precipitate was washed
with heptane / ethanol 2:1 (v/v, 321 mL) and heptane (107 mL) and dried in vacuo at 40°C to
yield the title compound as a white crystalline solid (80.0 g, 85%). MS (ESI & APCI): m/z =
418.1 [M + H] . H NMR (CDCl , 600 MHz): δ 0.59-0.64 (m, 1H), 0.65-0.69 (m, 1H), 0.80-0.90
(m, 1H), 0.99-1.05 (m, 1H), 1.12-1.21 (m, 2H), 1.30 (s, 3H), 1.47-1.53 (m, 2H), 2.15 (ddd, J =
.8 Hz, 9.2 Hz, 14.6 Hz, 1H), 2.70 (br d, J = 14.0 Hz, 1H), 3.83 (dd, J = 3.8 Hz, 12.3 Hz, 1H),
4.08 (dd, J = 5.3 Hz, 12.4 Hz, 1H), 4.55 (br s, 1H), 5.04-5.08 (m, 1H), 7.49 (br s, 1H), 7.61 (t,
J = 7.8 Hz, 2H), 7.70 (t, J = 7.5 Hz, 1H), 7.96 (d, J = 7.6 Hz, 2H).
b1) (2S,4R)(1-Methyl-cyclopropanecarbonyl)[4-(2,2,2-trifluoro-ethoxy)
trifluoromethyl-phenylsulfanyl]-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
F C O CF
N 3 3
KOtBu
DMA/THF, rt
A solution of 4-(2,2,2-trifluoro-ethoxy)trifluoromethyl-benzenethiol (56.1 g, 196 mmol)
in tetrahydrofuran (93 mL) was added at room temperature to a suspension of potassium tert-
butoxide (22.8 g, 203 mmol) in tetrahydrofuran (370 mL). The orange-brown clear solution was
stirred for 20 min and a solution of benzenesulfonic acid (3S,5S)(1-cyano-
cyclopropylcarbamoyl)(1-methyl-cyclopropanecarbonyl)-pyrrolidinyl ester (74.4 g,
178 mmol) in dimethylacetamide (240 mL) was added. The mixture was stirred for 15 h at room
temperature. Water (550 mL) and ethyl acetate (500 mL) were added and phases were separated.
The aqueous layer was extracted with ethyl acetate (500 mL), the combined organic extracts
were washed with a solution of sodium chloride (124 g) in water (1.1 L) (2 x 600 mL) and
concentrated in vacuo to a volume of ca. 260 mL. Toluene (600 mL) was added, the mixture
again concentrated in vacuo to a volume of ca. 260 mL and further toluene (240 mL) was added.
The warm mixture (internal temperature 45°C) was filtered, the precipitate was washed with
toluene (120 mL) and the combined filtrate was allowed to slowly cool to room temperature
(within 60 min). Crystallization started at 26°C internal temperature. The suspension was stirred
for 1 h at 22°C, heptane (620 mL) was added within 45 min and the suspension was stirred for
17 h at room temperature before it was filtered. The precipitate was washed with toluene /
heptane 1:1 (v/v, 240 mL) and heptane (120 mL) and dried in vacuo at 40°C to provide the title
compound as off-white crystals (87.7 g, 96.1% purity, 88%). MS (ESI & APCI): m/z = 536.1 [M
+ H] . H NMR (CDCl , 600 MHz): δ 0.58-0.62 (m, 1H), 0.64-0.68 (m, 1H), 0.89-0.93 (m, 1H),
1.04-1.09 (m, 1H), 1.16-1.22 (m, 2H), 1.31 (s, 3H), 1.45-1.55 (m, 2H), 1.88-1.94 (m, 1H), 2.79-
2.85 (m, 1H), 3.83-3.88 (m, 1H), 3.91-3.98 (m, 2H), 4.41 (q, J = 7.9 Hz, 2H), 4.61 (dd, J =
4.7 Hz, 8.0 Hz, 1H), 7.12 (dd, J = 2.9 Hz, 8.6 Hz, 1H), 7.31 (d, J = 2.8 Hz, 1H), 7.61 (d, J =
8.6 Hz, 1H), 8.04 (br s, 1H).
b2) (2S,4R)(1-Methyl-cyclopropanecarbonyl)[4-(2,2,2-trifluoro-ethoxy)
trifluoromethyl-phenylsulfanyl]-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
F C O CF N
N 3 3
LiOtBu, THF, rt
To a stirred suspension of 4-(2,2,2-trifluoro-ethoxy)trifluoromethyl-benzenethiol (30.4
g, 110 mmol) and benzenesulfonate (3S,5S)(1-cyano-cyclopropylcarbamoyl)(1-methyl-
cyclopropanecarbonyl)-pyrrolidinyl ester (41.7 g, 100 mmol) in THF (50 mL) was added at
room temperature 20% lithium tert-butoxide in THF (44.0 g ≅ 49.5 mL, 110 mmol) over 40 min.
After stirring at room temperature for 18 h, the reaction mixture was hydrolyzed with deionized
water (400 mL) and extracted twice with ethyl acetate (400 mL & 200 mL). Both organic layers
were washed with 10% brine (200 mL), combined, dried over Na SO , and filtered. Evaporation
of the solvent and careful drying (45°C/≥10 mbar) gave 56.3 g crude product as voluminous, off-
white foam, which was dissolved in 250 mL toluene at 50°C. The crystallization, which started
during cooling, was completed after stirring at room temperature for 1 h by the dropwise
addition of 200 mL heptane (note 11), followed by stirring at room temperature for 20 h.
Filtration and drying (50°C/10 mbar/3 days for removal of toluene to ~1%) yielded 51.2 g
(95.7%) title product as an off-white crystalline powder, mp. 66-76°C. [α] = -67.5 (c 1.0;
CHCl ). H NMR (CDCl , 400 MHz) δ 0.55-0.70 (m, 2H), 0.87-0.95 (m, 1H), 1.02-1.10 (m, 1H),
1.13-1.23 (m, 2H), 1.31 (s, 3H), 1.42-1.55 (m, 2H), 1.85-1.97 (m, 1H), 2.74-2.85 (m, 1H), 3.80-
4.00 (m, 3H), 4.40 (q, J = 7.8 Hz, 2H), 4.60 (dd, J = 8.1 Hz, J = 4.6 Hz, 1H), 7.11 (dd, J = 8.6
1 2 1
Hz, J = 2.7 Hz, 1H), 7.30 (d, J = 3.0 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 8.05 (s, 1H).
c1) (2S,4R)(1-Methyl-cyclopropanecarbonyl)[4-(2,2,2-trifluoro-ethoxy)
trifluoromethyl-benzenesulfonyl]-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-
amide
MMPP
MeOH, 50°C
To a solution of magnesium monoperoxyphthalate hexahydrate (11.8 g, 20 mmol, assay
84%) in methanol (100 mL) was added under stirring a solution of (2S,4R)[2-chloro(2,2,2-
trifluoro-ethoxy)-phenylsulfanyl](1-methyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic
acid (1-cyano-cyclopropyl)-amide (10.7 g, 20 mmol) in methanol (30 mL) over 15 min. After
stirring at 50°C for 8 h, additional magnesium monoperoxyphthalate hexahydrate (13.0 g, 22
mmol) was added all at once and the white suspension was stirred for further 16 h. The reaction
mixture was cooled to room temperature and the excess magnesium monoperoxyphthalate was
destroyed by dropwise addition of 39% aqueous sodium bisulfite (~9 mL). After removal of the
main part of the methanol by rotary evaporation (45°C / ≥80 mbar), dichloromethane (100 mL)
was added to the white slurry and the mixture was carefully neutralized under stirring to pH 7 by
the addition of 1 M NaOH (~95 mL). The organic layer was washed with 5% NaHCO (50 mL)
and both aqueous layers were extracted with dichloromethane (50 mL). The combined organic
layers were dried (Na SO ), filtered, and evaporated (40°C/≥10 mbar), affording a white
voluminous foam (11.51 g) which was dissolved in isopropanol (50 mL) at ~60°C. Deionized
water (100 mL) was added under stirring over 30 min and the resulting white suspension was
stirred at room temperature for 3 h and filtered to yield after washing with isopropanol-water 1 :
2 (~20 mL) and drying (50°C / 10 mbar / 4h) the title product (10.6 g, 93.3%) as a white
1
crystalline powder, mp. 125.5-129.5°C. [α] = -75.1 (c 1.0; CHCl ). H NMR (CDCl , 400
D 3 3
MHz) δ 0.59-0.80 (m, 2H), 1.04-1.24 (m, 4H), 1.36 (s, 3H), 1.44-1.56 (m, 2H), 2.21 (m, 1H),
2.73 (m, 1H), 3.88 (dd, J = 12.5 Hz, J = 7.5 Hz, 1H), 4.16 (m, 1H), 4.51 (q, J = 7.8 Hz, 2H),
4.69 (dd, J = 12.5 Hz, J = 4.0 Hz, 1H), 4.75 (dd, J = 8.3 Hz, J = 5.1 Hz, 1H), 7.25 (dd, J =
1 2 1 2 1
9.0 Hz, J = 2.7 Hz, 1H), 7.53 (d, J = 2.7 Hz, 1H), 7.97 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H). ESI-MS
(m/z) [M+H] (100).
c2) (2S,4R)(1-Methyl-cyclopropanecarbonyl)[4-(2,2,2-trifluoro-ethoxy)
trifluoromethyl-benzenesulfonyl]-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-
amide
Oxone®
Na HPO
MeOH/H O, rt O
F C F C
CF CF
Oxone® (264.6 g, 430 mmol) and disodium hydrogenphosphate (457.2 g, 2.72 mol) were
suspended in methanol (570 mL) and water (810 mL) and a solution of (2S,4R)(1-methyl-
cyclopropanecarbonyl)[4-(2,2,2-trifluoro-ethoxy)trifluoromethyl-phenylsulfanyl]-
pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide (90.0 g, 168 mmol) in methanol
(600 mL) was added at room temperature within 30 min. The mixture was stirred for 90 h at
room temperature. The suspension was warmed to 40°C, filtered and the filtered solid was
washed with methanol (1000 mL). The combined filtrate was concentrated in vacuo to a volume
of 1.1 L and dichloromethane (900 mL) was added. After phase separation, the aqueous layer
was extracted with dichloromethane (450 mL), the combined organic extracts were washed with
a solution of sodium thiosulfate (26.6 g, 168 mmol) in water (900 mL) and water (900 mL),
filtered, and concentrated in vacuo to a volume of ca. 220 mL. Isopropanol (900 mL) was then
added and the solution was concentrated in vacuo to a volume of ca. 500 mL. Water (500 mL)
was added at 50°C and the solution was allowed to cool to room temperature (crystallization
started). Additional water (500 mL) was added slowly and the crystal suspension was stirred for
h at room temperature. The suspension was filtered, the precipitate was washed with water /
isopropanol 2:1 (v/v, 270 mL) and water (270 mL) and dried in vacuo at 50°C to yield the title
compound as colorless crystals (87.0 g, 91%). mp. 126.0-127.0°C. MS (ESI & APCI): m/z =
568.1 [M + H] . H NMR (CDCl , 600 MHz): δ 0.62-0.66 (m, 1H), 0.73-0.78 (m, 1H), 1.07-1.14
(m, 2H), 1.15-1.21 (m, 2H), 1.36 (s, 3H), 1.46-1.54 (m, 2H), 2.21 (ddd, J = 5.4 Hz, 8.4 Hz,
13.8 Hz, 1H), 2.71-2.77 (m, 1H), 3.89 (dd, J = 7.5 Hz, 12.4 Hz, 1H), 4.13-4.19 (m, 1H), 4.51 (q,
J = 7.7 Hz, 2H), 4.69 (dd, J = 3.8 Hz, 12.4 Hz, 1H), 4.75 (dd, J = 5.1 Hz, 8.3 Hz, 1H), 7.25 (dd,
J = 2.7 Hz, 8.9 Hz, 1H), 7.53 (d, J = 2.6 Hz, 1H), 7.97 (br s, 1H), 8.19 (d, J = 8.8 Hz, 1H). Anal.
Calcd for C23H23F6N3O5S: C, 48.68; H, 4.08; N, 7.40; S, 5.65; F, 20.09. Found: C, 48.59; H,
4.05; N, 7.53; S, 5.76; F, 20.08.
C3. Preparation of (2S,4R)[4-(2-methyl-pyridinyl)trifluoromethyl-
benzenesulfonyl](1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic
acid (1-cyano-cyclopropyl)-amide
Step 1: (2S,4R)[4-(2-Methyl-pyridinyl)trifluoromethyl-phenylsulfanyl](1-trifluoro-
methyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
S NH
NaOtBu
DMA/THF, rt
3-[4-(2-Methyl-pyridinyl)trifluoromethyl-phenylsulfanyl]-propionamide (200 g,
588 mmol) was dissolved in tetrahydrofuran (1.0 L) before sodium tert-butoxide (55.5 g,
578 mmol) was added and the fine suspension was stirred for 2 h at room temperature. N,N-
dimethylacetamide (500 mL) was added and the solution was stirred for further 1.5 h. A solution
of benzenesulfonic acid (3S,5S)(1-cyano-cyclopropylcarbamoyl)(1-trifluoromethyl-cyclo-
propanecarbonyl)-pyrrolidinyl ester (237.5 g, 504 mmol) in N,N-dimethylacetamide (500 mL)
was added and the brown, clear solution was stirred for 40 h. The mixture was diluted with water
(3 L) and extracted with tert-butyl methyl ether (1 x 2 L, 3 x 1 L). The combined organic extracts
were washed with an aqueous sodium carbonate solution (1 M, 1.0 L) and brine (1.0 L), dried
over sodium sulfate, and concentrated in vacuo to yield the title compound as a brown gum
(327.8 g). The crude product (containing dimethylacetamide) was used in the next step without
further purification. For characterization purposes, a 4 g sample of crude material was purified
by filtration over silica gel (20 g, eluent: ethyl acetate (200 mL)). 3.3 g of purified material were
obtained as an off-white solid. MS (EI): m/z = 583.1 [M + H] . H NMR (CDCl , 300 MHz): δ
1.10-1.36 (m, 6H), 1.49-1.58 (m, 2H), 1.99-2.12 (m, 1H), 2.65 (s, 3H), 2.90-3.02 (m, 1H), 3.92
& 4.02 (ABX, J = 11.9 Hz, J = 4.8 Hz, J = 5.8 Hz, each 1H), 4.12-4.22 (m, 1H), 4.71 (dd,
AB AX BX
J = 4.7 Hz, 7.8 Hz, 1H), 7.31 (d, J = 5.3 Hz, 1H), 7.37 (br s, 1H), 7.60-7.69 (m, 2H), 7.80 (d, J =
8.3 Hz, 1H), 7.93 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H).
Step 2: (2S,4R)[4-(2-Methyl-pyridinyl)trifluoromethyl-benzenesulfonyl](1-trifluoro-
methyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
CF CF
Oxone®
2 M H SO
MeOH/H O, rt
F C F C
(2S,4R)[4-(2-Methyl-pyridinyl)trifluoromethyl-phenylsulfanyl](1-trifluoro-
methyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
(crude product, containing dimethylacetamide, 89.4% purity m/m, 327.8 g, 503 mmol) was
dissolved in methanol (930 mL) and sulfuric acid (1 M in water, 3.7 L) at 0 – 5°C (ice bath).
Oxone® (980 g, 1590 mmol) was added in one portion (slightly exotherm) and the mixture was
stirred for 20 h at room temperature. Celite (100 g) was then added, the mixture was filtered and
the precipitate was washed with water / methanol (4:1 v/v, 500 mL). Sodium metabisulfite
(183 g, 965 mmol) was added in small portions to the combined filtrate (exotherm). Ethyl acetate
(1.5 L) was added and the biphasic mixture was basified to pH > 8 by addition of an aqueous
ammonia solution (25% m/m, 1.2 L). After phase separation, the aqueous layer was extracted
with ethyl acetate (2 x 1.2 L), the combined organic extracts were washed with water / brine (1:1
v/v, 750 mL) and brine (750 mL), dried over sodium sulfate, and concentrated in vacuo at 55°C.
The crude product was dissolved in dichloromethane / methanol (100:3 v/v, 1.45 L) and silica
gel (500 g) was added. The slurry was filtered and washed with dichloromethane / methanol
(100:3 v/v, 2.9 L). The combined filtrates were concentrated in vacuo at 55°C. The residue, a
white foam (279.2 g), was dissolved in ethanol (1600 mL) at 70°C before pre-warmed water
(60 – 65°C, 800 mL) was added quickly and the resulting mixture was slowly cooled. The
suspension was stirred for 20 h at room temperature, before it was filtered. The precipitate was
washed with ethanol / water (1:1 v/v, 800 mL) and n-heptane (800 mL), and dried in vacuo at
55°C to afford the title compound as colorless crystals (228.1 g, 74% over 2 steps). MS (ESI &
APCI): m/z = 615.1 [M + H] . H NMR (CDCl , 600 MHz): δ 1.11-1.22 (m, 2H), 1.32-1.42 (m,
2H), 1.46-1.57 (m, 4H), 2.24-2.30 (m, 1H), 2.69 (s, 3H), 2.86 (ddd, J = 5.7 Hz, 8.0 Hz, 14.1 Hz,
1H), 3.88 (dd, J = 7.1 Hz, 13.3 Hz, 1H), 4.14-4.19 (m, 1H), 4.83 (dd, J = 1.7 Hz, 13.3 Hz, 1H),
4.88 (dd, J = 5.6 Hz, 8.6 Hz, 1H), 7.35 (dd, J = 1.4 Hz, 5.2 Hz, 1H), 7.40 (bs, 1H), 7.63 (bs, 1H),
8.01 (dd, J = 1.8 Hz, 8.2 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.68 (d, J =
5.2 Hz, 1H).
C4. Preparation of (2S,4R)[4-(1-methyl-1H-pyrazolyl)trifluoromethyl-
benzenesulfonyl](1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic
acid (1-cyano-cyclopropyl)-amide
Process variant 1:
Step 1: (2S,4R)[4-(1-Methyl-1H-pyrazolyl)trifluoromethyl-phenylsulfanyl](1-tri-
fluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
S NH
CF 3
NaOtBu
DMA/THF, rt
3-[4-(1-Methyl-1H-pyrazolyl)trifluoromethyl-phenylsulfanyl]-propionamide (16.3 g,
49.6 mmol) was dissolved in tetrahydrofuran (80 mL) before sodium tert-butoxide (4.7 g,
48.9 mmol) was added and the fine suspension was stirred for 2 h at room temperature. N,N-
dimethylacetamide (40 mL) was added and the mixture was stirred for further 2.5 h at room
temperature. A solution of benzenesulfonic acid (3S,5S)(1-cyano-cyclopropylcarbamoyl)
(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinyl ester (20 g, 42.4 mmol) in N,N-di-
methylacetamide (40 mL) was added and the yellow, fine suspension was stirred for 42 h at
room temperature. The mixture was diluted with water (240 mL) and extracted with tert-butyl
methyl ether (1 x 160 mL, 3 x 80 mL). The combined organic extracts were washed with an
aqueous sodium carbonate solution (1 M, 80 mL) and brine (80 mL), dried over sodium sulfate
and concentrated in vacuo to yield the title compound as a light brown foam (27.1 g). The crude
product (containing dimethylacetamide) was used in the next step without further purification.
For characterization purposes, a 2 g sample of crude material was purified by column
chromagraphy on silica gel (eluent: gradient ethyl acetate / heptane 4:1 (v/v) to ethyl acetate).
Likewise, 1.7 g of purified material were obtained. MS (ESI & APCI): m/z = 572.1 [M + H] ,
589.2 [M + NH ] . H NMR (CDCl , 600 MHz): δ 1.12-1.22 (m, 3H), 1.28-1.34 (m, 3H), 1.49-
1.54 (m, 2H), 2.02 (ddd, J = 5.6 Hz, 8.2 Hz, 13.6 Hz, 1H), 2.88 (ddd, J = 5.7 Hz, 5.7 Hz, 13.7 Hz,
1H), 3.89-3.99 (m, 2H), 3.97 (s, 3H), 4.04-4.09 (m, 1H), 4.69 (dd, J = 5.2 Hz, 8.2 Hz, 1H), 7.55
(d, J = 8.2 Hz, 1H), 7.60 (bs, 1H), 7.62 (dd, J = 1.8 Hz, 8.2 Hz, 1H), 7.69 (s, 1H), 7.77 (d, J =
1.8 Hz, 1H), 7.79 (s, 1H).
Step 2: (2S,4R)[4-(1-Methyl-1H-pyrazolyl)trifluoromethyl-benzenesulfonyl](1-
trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-
amide
Oxone® N
Na HPO
MeOH/H O, rt
Oxone® (53.0 g, 86.2 mmol) and disodium hydrogenphosphate (13.0 g, 91.4 mmol) were
suspended in methanol (45 mL) and water (16 mL) and a solution of (2S,4R)[4-(1-methyl-1H-
pyrazolyl)trifluoromethyl-phenylsulfanyl](1-trifluoromethyl-cyclopropanecarbonyl)-
pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide (crude product, containing dimethyl-
acetamide, 89.3% purity m/m, 11.2 g, 17.5 mmol) in methanol (30 mL) was added at 5 – 15 °C
internal temperature within 15 min. The bright yellow suspension was stirred for 20 h at room
temperature. After filtration, the remaining solid was washed with methanol (50 mL). Water
(30 mL) was added to the combined filtrate before methanol was distilled off in vacuo. The
aqueous residue was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts
were washed subsequently with a solution of sodium metabisulfite (1.9 g, 10.0 mmol) in water
(30 mL), a saturated aqueous sodium hydrogencarbonate solution (30 mL), and brine (30 mL),
dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in
dichloromethane / methanol (100:3 (vol/vol), 50 mL) and filtered over a plug of silica gel (20 g).
The plug was washed with dichloromethane / methanol (100:3 vol/vol, 100 mL) and the
combined filtrate was concentrated in vacuo. The crude product, a yellow foam (9.4 g), was
dissolved in ethyl acetate (25 mL) and toluene (94 mL), concentrated in vacuo to a volume of ca.
80 mL, and stirred for 1.5 h at room temperature. The suspension was filtered and the remaining
solid was washed with toluene (20 mL) and n-heptane (20 mL) and dried in vacuo. The resulting
white crystalline material (7.15 g) was again dissolved in acetone (35 mL) and water (70 mL).
The resulting emulsion was seeded and the suspension was stirred vigorously for 20 h at room
temperature. After filtration, the precipitate was washed with acetone / water (1:4 (v/v), 20 mL)
and n-heptane (20 mL) and dried in vacuo to give the title compound as colorless crystals (6.03 g,
+ + 1
57% over 2 steps). MS (ESI & APCI): m/z = 604.1 [M + H] , 621.1 [M + NH ] . H NMR
(CDCl , 600 MHz): δ 1.10-1.22 (m, 2H), 1.30-1.35 (m, 1H), 1.35-1.41 (m, 1H), 1.45-1.59 (m,
4H), 2.22-2.28 (m, 1H), 2.84 (ddd, J = 5.9 Hz, 8.0 Hz, 14.3 Hz, 1H), 3.84 (dd, J = 7.1 Hz,
13.2 Hz, 1H), 4.00 (s, 3H), 4.08-4.14 (m, 1H), 4.81 (d, J = 13.3 Hz, 1H), 4.86 (dd, J = 5.8 Hz,
8.6 Hz, 1H), 7.65 (bs, 1H), 7.80-7.83 (m, 2H), 7.89 (s, 1H), 7.99 (d, J = 1.6 Hz, 1H), 8.12 (d, J =
8.4 Hz, 1H).
Process variant 2:
Step 1: (2S,4R)[4-(1-Methyl-1H-pyrazolyl)trifluoromethyl-phenylsulfanyl](1-tri-
fluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
CF 3
NaOtBu
O THF, rt
(3S,5S)(1-Cyano-cyclopropylcarbamoyl)(1-trifluoromethyl-cyclopropanecarbonyl)-
pyrrolidinyl ester (52.4 g, 111 mmol) and 4-(1-methyl-1H-pyrazolyl)trifluoromethyl-
benzenethiol (32.4 g, 122 mmol) were dissolved in tetrahydrofuran (250 mL). A solution of
sodium tert-butoxide in tetrahydrofuran (25% w/w, 44.8 g, 49.2 mL, 116 mmol) was added at
internal temperature of 20°C – 28°C within 20 min. The mixture was stirred for 18 h at room
temperature. After that, a solution of sodium chloride in water (10% w/w, 250 mL) and 2-
methyltetrahydrofuran (250 mL) were added. The phases were separated, the organic layer was
washed with a solution of sodium chloride in water (10% w/w, 250 mL) and concentrated in
vacuo. The crude product was dissolved in acetonitrile (250 mL), concentrated in vacuo,
redissolved again in acetonitrile (250 mL) and filtered over charcoal to remove inorganic salts.
The filtered material was washed with acetonitrile (100 ml) and the combined filtrates were
concentrated in vacuo to yield crude title compound as a foam that was used in the next step
without further purification (64.0 g, 97.6% purity by HPLC, 98.3%).
Step 2: (2S,4R)[4-(1-Methyl-1H-pyrazolyl)trifluoromethyl-benzenesulfonyl](1-
trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-
amide
MMPP
MeCN, 50°C
(2S,4R)[4-(1-Methyl-1H-pyrazolyl)trifluoromethyl-phenylsulfanyl](1-trifluoro-
methyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
(crude product, 97.6% purity, 64.0 g, 109 mmol) was dissolved in acetonitrile (480 mL) and
magnesium monoperoxyphthalate hexahydrate (76.0 g, 154 mmol) was added. The resulting
white suspension was stirred for 5 h at 50°C. After that, a suspension of magnesium
monoperoxyphthalate hexahydrate (76.0 g, 154 mmol) in acetonitrile (150 mL) was added and
the mixture was stirred for further 16 h at 50°C. After cooling to 20°C, water (480 mL) and a
solution of sodium metabisulfite in water (40% w/w, 56.8 mL, 109 mmol) were added. The
mixture was basified to pH 8 by addition of an aqueous sodium hydroxide solution (3 M, ca.
290 mL), extracted with dichloromethane (1 L), the organic phase was washed with saturated
aqueous sodium hydrogencarbonate solution (1 L) and concentrated in vacuo. The residue was
dissolved in dichloromethane (300 mL) and filtered to remove solid impurities. The solvent of
the filtrate was exchanged to ethanol by continuous distillation while keeping the volume
constant (ca. 750 mL ethanol used). The desired product started to crystallize. The resulting
suspension was stirred for 12 h at 0°C, filtered, the precipitate was washed with cold ethanol
(50 mL) and dried in vacuo at 45°C to obtain the title compound as white crystals (50.0 g,
+ + 1
74.9%). MS (ESI & APCI): m/z = 604.1 [M + H] , 621.1 [M + NH ] . H NMR (CDCl ,
600 MHz): δ 1.10-1.22 (m, 2H), 1.30-1.35 (m, 1H), 1.35-1.41 (m, 1H), 1.45-1.59 (m, 4H), 2.22-
2.28 (m, 1H), 2.84 (ddd, J = 5.9 Hz, 8.0 Hz, 14.3 Hz, 1H), 3.84 (dd, J = 7.1 Hz, 13.2 Hz, 1H),
4.00 (s, 3H), 4.08-4.14 (m, 1H), 4.81 (d, J = 13.3 Hz, 1H), 4.86 (dd, J = 5.8 Hz, 8.6 Hz, 1H),
7.65 (bs, 1H), 7.80-7.83 (m, 2H), 7.89 (s, 1H), 7.99 (d, J = 1.6 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H).
C5. Preparation of (2S,4R)(1-methyl-cyclopropanecarbonyl)[4-(2-methyl-pyridin
yl)trifluoromethyl-benzenesulfonyl]-pyrrolidinecarboxylic acid (1-cyano-cyclo-
propyl)-amide
Step 1: (2S,4R)(1-Methyl-cyclopropanecarbonyl)[4-(2-methyl-pyridinyl)
trifluoromethyl-phenylsulfanyl]-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
S NH
NaOtBu
DMA/THF, rt
3-[4-(2-Methyl-pyridinyl)trifluoromethyl-phenylsulfanyl]-propionamide (15.0 g,
44.1 mmol) was dissolved in tetrahydrofuran (75 mL), before sodium tert-butoxide (4.15 g,
43.2 mmol) was added and the fine suspension was stirred for 2 h at room temperature. N,N-
dimethylacetamide (37 mL) was added and the solution was stirred for further 2 h. A solution of
benzenesulfonic acid (3S,5S)(1-cyano-cyclopropylcarbamoyl)(1-methyl-cyclopropanecar-
bonyl)-pyrrolidinyl ester (15.7 g, 37.7 mmol) in N,N-dimethylacetamide (37 mL) was added
and the brown, clear solution was stirred for 65 h at room temperature. After that, the mixture
was diluted with cold water (240 mL) and extracted with tert-butyl methyl ether (1 x 180 mL,
x 90 mL). The combined organic extracts were washed with aqueous sodium carbonate
solution (1 M, 90 mL) and brine (90 mL), dried over sodium sulfate and concentrated in vacuo to
yield the title compound as a brown gum (22.05 g). The crude product (containing
dimethylacetamide) was used in the next step without further purification. MS (EI): m/z = 529.1
[M + H] . H NMR (CDCl , 400 MHz): δ 0.56-0.66 (m, 2H), 0.87-0.93 (m, 1H), 1.04-1.09 (m,
1H), 1.18-1.22 (m, 2H), 1.31 (s, 3H), 1.45-1.57 (m, 2H), 1.95-2.04 (m, 1H), 2.65 (s, 3H), 2.95-
3.01 (m, 1H), 3.91 & 4.02 (ABX, J = 11.3 Hz, J = 5.6 Hz, J = 6.5 Hz, each 1H), 4.14-4.22
AB AX BX
(m, 1H), 4.66 (dd, J = 4.3 Hz, 8.1 Hz, 1H), 7.31 (dd, J = 1.5 Hz, 5.3 Hz, 1H), 7.37 (bs, 1H), 7.69
& 7.80 (ABX, J = 8.2 Hz, J = 0 Hz, J = 2.0 Hz, each 1H), 7.93 (d, J = 1.9 Hz, 1H), 8.06
AB AX BX
(bs, 1H), 8.60 (d, J = 5.1 Hz, 1H).
Step 2: (2S,4R)(1-Methyl-cyclopropanecarbonyl)[4-(2-methyl-pyridinyl)
trifluoromethyl-benzenesulfonyl]-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
Oxone®
H 1 M H SO H
MeOH/H O, rt
F C F C
(2S,4R)(1-Methyl-cyclopropanecarbonyl)[4-(2-methyl-pyridinyl)
trifluoromethyl-phenylsulfanyl]-pyrrolidinecarboxylic acid (1-cyano-cyclopropyl)-amide
(crude product, containing dimethylacetamide, 90.2% purity m/m, 22.1 g, 37.7 mmol) was
dissolved in methanol (70 mL) and sulfuric acid (1 M in water, 280 mL) at 0 – 5°C (ice bath).
Oxone® (73.5 g, 120 mmol) was added in one portion (slightly exotherm) and the mixture was
stirred for 20 h at room temperature. Celite (7.5 g) was then added and the mixture was filtered.
The precipitate was washed with water / methanol (4:1 v/v, 40 mL). Sodium metabisulfite
(14.0 g, 73.6 mmol) was added in small portions to the combined filtrate (exotherm). Ethyl
acetate (120 mL) was added and the pH of the biphasic mixture was adjusted to pH > 8 by
addition of an aqueous ammonia solution (25% m/m, 90 mL). After phase separation, the
aqueous layer was extracted with ethyl acetate (2 x 120 mL). The combined organic extracts
were washed with water / brine (1:1 v/v, 60 mL) and brine (60 mL), dried over sodium sulfate,
and concentrated in vacuo at 55°C. The crude product (21.7 g) was dissolved in dichloromethane
/ methanol (100:3 v/v, 120 mL). Silica gel (40 g) was added and the slurry was filtered and
washed with dichloromethane / methanol (100:3 v/v, 240 mL). The combined filtrates were
concentrated in vacuo at 55°C. The residue, a white foam (18.1 g), was dissolved in ethanol
(95 mL) at 70°C and pre-warmed water (60 – 65°C, 135 mL) was added quickly. The clear
solution was seeded and the resulting mixture was slowly cooled. The suspension was stirred for
h at room temperature and filtered. The precipitate was washed with ethanol / water (1:2 v/v,
50 mL) and n-heptane (50 mL) and dried in vacuo at 55°C to yield the title compound as fine
white powder (14.1 g, 71% over 2 steps). MS (ESI & APCI): m/z = 561.2 [M + H] . H NMR
(CDCl , 600 MHz): δ 0.62-0.67 (m, 1H), 0.74-0.80 (m, 1H), 1.08-1.15 (m, 2H), 1.15-1.21 (m,
2H), 1.38 (s, 3H), 1.46-1.54 (m, 2H), 2.27 (ddd, J = 5.6 Hz, 8.4 Hz, 13.9 Hz, 1H), 2.69 (s, 3H),
2.77 (ddd, J = 5.7 Hz, 8.4 Hz, 13.4 Hz, 1H), 3.93 (dd, J = 7.6 Hz, 12.4 Hz, 1H), 4.21-4.27 (m,
1H), 4.73 (dd, J = 3.9 Hz, 12.4 Hz, 1H), 4.78 (dd, J = 5.0 Hz, 8.4 Hz, 1H), 7.36 (dd, J = 1.4 Hz,
.2 Hz, 1H), 7.41 (s, 1H), 7.89 (bs, 1H), 8.01 (dd, J = 1.8 Hz, 8.2 Hz, 1H), 8.17 (d, J = 1.5 Hz,
1H), 8.32 (d, J = 8.3 Hz, 1H), 8.68 (d, J = 5.2 Hz, 1H).
C6. Preparation of (2S,4R)[4-(2-methyl-pyridinyl)trifluoromethyl-phenylsulfanyl]-
1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinecarboxylic acid (1-cyano-
cyclopropyl)-amide
SH O
NaOtBu, THF, 50°C
To a stirred suspension of methanesulfonic acid (3S,5S)(1-cyano-
cyclopropylcarbamoyl)(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidinyl ester (20.5 g,
50 mmol) and 4-(2-methyl-pyridinyl)trifluoromethyl-benzenethiol hydrochloride (17.6 g,
57.5 mmol) in THF (75 mL) was added at 0°C 25% sodium tert-butoxide in THF (43.2 g, 112.5
mmol) over 30 min and the reaction mixture was stirred at 50°C for 4.5 h. After cooling to 10°C,
the reaction mixture was added to dichloromethane (250 mL) and washed twice with deionized
water (2 x 250 mL). The organic layer was dried (Na SO ), filtered, and evaporated by rotary
evaporation (45°C/≥10 mbar), affording the crude title product (30.9 g, 106%) as a beige,
amorphous foam which was used without further purification in the next step. H NMR (CDCl ,
400 MHz) δ 1.10-1.35 (m, 6H), 1.47-1.58 (m, 2H), 2.00-2.11 (m, 1H), 2.65 (s, 3H), 2.92-3.01 (m,
1H), 3.92 & 4.02 (ABC, J = 11.8 Hz, J = 5.0 Hz, J = 6.2 Hz, each 1H), 4.17 (quint, J ≈
AB AC BC
.5 Hz, 1H), 4.72 (dd, J = 8.1 Hz, J = 4.8 Hz, 1H), 7.31 (dd, J = 5.1 Hz, J = 1.5 Hz, 1H), 7.37
1 2 1 2
(s, 1H), 7.62 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.80 (dd, J = 8.1 Hz, J = 1.9 Hz, 1H), 7.93 (d, J
= 2.1 Hz, 1H), 8.60 (d, J = 5.1 Hz, 1H). ESI-MS (m/z) [M+H] 583 (40).
Claims (32)
1. Process for the preparation of proline derivatives of formula I wherein, 5 R is selected from C -alkyl or from wherein R is selected from C -alkyl, halogen-C -alkyl or from phenyl 1-7 1-7 which is optionally substituted by halogen; R is selected from halogen or halogen-C -alkyl; and 10 R is selected from hydrogen, halogen, halogen-C -alkyl, C -alkoxy, halogen-C - 1-7 1-7 1-7 alkoxy or from a 5- or 6-membered heterocyclic ring containing one or two nitrogen atoms, the ring which is optionally substituted by C -alkyl or halogen; comprising the steps a) transforming an alcohol of formula II wherein R has the meaning as above into the sulfonate of the formula III wherein R has the meaning as above and R is C -alkyl, halogen-C -alkyl or phenyl 1-7 1-7 which is optionally substituted by C -alkyl, nitro or bromo b) reacting the sulfonate of formula III with a thio compound of formula IV 2 3 6 wherein R and R are as outlined above and R is hydrogen or a protecting group to form the thioether of the formula V 1 2 3 wherein R , R and R are as outlined above and 10 c) oxidizing the thioether of formula V to form the proline derivative of formula I wherein 1 2 3 R , R and R are as outlined above and wherein the process is further characterized in that the alcohol of formula II is prepared by a1) reacting a hydroxy proline ester of formula VI R VI wherein R is C -alkyl with a carbonyl compound of formula VII R CO Y VII 5 wherein R is as above and Y is halogen or OH to form a carbonyl proline ester of formula R IX wherein R and R are as above; b1) subsequent forming of a sulfonate of formula X 1 7 8 wherein R and R are as above and R is C -alkyl optionally substituted by halogen or phenyl which is optionally substituted by C -alkyl, nitro or bromo and c1) converting the sulfonate of formula X in the presence of an amino cyclopropane carbonitrile of the formula XI NC NH into the alcohol of formula II.
2. Process of claim 1, wherein R is a residue of the formula wherein R is selected from C -alkyl, halogen-C -alkyl or from phenyl which is 1-7 1-7 5 optionally substituted by halogen.
3. Process of claim 1, wherein R is selected from halogen or halogen-C -alkyl; and R is selected from halogen-C -alkoxy or from a 5- or 6-membered heterocyclic ring containing one or two nitrogen atoms, the ring which is optionally substituted by C -alkyl 10 or halogen.
4. Process of claim 1, wherein the residue of the formula stands for 15 wherein R and R are as above.
5. Process of claim 1, wherein the proline derivatives of the formula I are chiral isomers of the formula
6. Process of any one of claims 1 to 5, wherein the transformation in step a) is performed with a sulfonating agent in the presence of an organic solvent at temperature of -10°C to 40°C.
7. Process of any one of claims 1 to 5, wherein the reaction in step b) is performed in the presence of a base in an organic solvent at temperature between 10°C and 90°C. 5
8. Process of any one of claims 1 to 5, wherein the oxidation in step c) is performed with an oxidating agent in the presence of an organic solvent at temperature between 0°C and 60°C.
9. Process of claim 8, wherein the oxidating agent is potassium peroxymonosulfate or magnesium monoperoxyphthalate hexahydrate.
10. Process of claim 1, wherein the alcohol of formula II is a chiral isomer of the formula wherein R has the meaning as above.
11. Process of claim 1, wherein the reaction in step a1) is performed in an organic solvent at temperatures between -10°C and 25°C.
12. Process of claim 1, wherein the reaction in step b1) is performed with a sulfonating 15 agent, in an organic solvent at temperatures between -10°C and 40°C.
13. Process of claim 1, wherein the reaction in step c1) is performed in the presence of a 10 10 carboxylate salt NaR COO, wherein R = C -alkyl or aryl in a solvent at temperatures between 40°C and 130°C.
14. Process of claim 13, wherein sodium 2-ethylhexenoate is used. 20 15. Process of claim 1, wherein the thio compound of formula IV R IV 2 3 6 wherein R and R are as above and R is hydrogen is prepared by a3) deprotecting a compound of formula XX R XX 2 3 9 wherein R and R are as above and R stands for a tertiary alkyl group of the formula 11 12 13 wherein R , R and R independently of each other stand for C -alkyl with an acid; 5 or by b3) deprotecting a compound of formula XX 2 3 9 wherein R and R are as above and R stands for trityl with trifluoro acetic acid in the presence of a reductive agent; 10 c3) lithiating a halogenated compound of formula XXI R XXI wherein R and R are as above and X stands for a halogen atom and a subsequent treatment with sulfur; or by
15 d3) reacting a halogenated compound of formula XXI R XXI and R are as above and X stands for a halogen atom with a Grignard reagent wherein R and by a subsequent treatment with sulfur.
16. Process of claim 15 wherein R in the compound of formula XX used for the reaction in step a3) is tert.butyl.
17. Process of claim 15 wherein the acid used in the reaction step a3) is selected from an aqueous mineral acid or an organic acid. 5
18. Process of claim 15, wherein the reductive agent used in the reaction step b3) is triethyl silane.
19. Process of claim 15, wherein the reaction in step c3) is performed with butyl lithium as lithiating agent in an organic solvent at temperatures between -80°C to -20°C.
20. Process of claim 15, wherein the reaction with sulfur in step c3) is performed in an 10 organic solvent at temperatures between -80°C to -40°C.
21. Process of claim 15, wherein the reaction in step d3) is performed with a Grignard reagent selected from isopropyl magnesium chloride or from isopropyl magnesium chloride / lithium chloride in an organic solvent at temperature between 0°C to 40°C.
22. Process of claim 15, wherein the reaction with sulfur in step d3) is performed in an 15 organic solvent at temperatures between -20°C to 20°C.
23. Alcohol of formula II wherein R is selected from C -alkyl or from 20 wherein R is selected from methyl or trifluoromethyl.
24. Alcohol of claim 23, having the structure wherein R has the meaning as above .
25. Thioether of formula V wherein R is selected from C -alkyl or from wherein R is selected from C -alkyl, halogen-C -alkyl or from phenyl 1-7 1-7 10 which is optionally substituted by halogen; R is selected from halogen or halogen-C -alkyl; and R is selected from hydrogen, halogen, halogen-C -alkyl, C -alkoxy, halogen-C - 1-7 1-7 1-7 alkoxy or from a 5- or 6-membered heterocyclic ring containing one or two nitrogen atoms, the ring which is optionally substituted by C -alkyl or halogen. 15
26. Thioether of claim 25 wherein, R has the meaning of wherein R is selected from C -alkyl, halogen-C -alkyl or from phenyl which is 1-7 1-7 optionally substituted by halogen; R has the meaning of halogen or halogen-C -alkyl; and R has the meaning of halogen-C -alkoxy or of a 5- or 6-membered heterocyclic ring 5 containing one or two nitrogen atoms, the ring which is optionally substituted by C -alkyl or halogen.
27. Thioether of claim 25 or 26, wherein, R has the meaning of methyl or of trifluoromethyl; R has the meaning of trifluoromethyl or chlorine; and 10 R has the meaning of 2,2,2-trifluoroethoxy, 2-methylpyridyl, 1-methyl-1H-pyrazol yl or 2,2,2-trifluoromethylethoxy.
28. Thioether of any one of claims 25 to 27, having the structure N Va 1 2 3 wherein R , R and R are as above. 15
29. Thioether of any one of claims 25 to 28, having the structure 1 2 3 , R and R are as above. wherein R
30. A process according to any one of claims 1 to 22, for the preparation of proline derivatives of formula I, substantially as herein described with reference to any example thereof.
31. Alcohol of formula II according to claim 23 substantially as herein described with reference to any example thereof. 5
32. Thioether of formula V according to claim 25 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11188728 | 2011-11-11 | ||
EP11188728.7 | 2011-11-11 | ||
PCT/EP2012/072078 WO2013068434A1 (en) | 2011-11-11 | 2012-11-08 | Process for the preparation of 1-acyl-4-phenylsulfonylprolinamide derivatives and new intermediates |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ623851A NZ623851A (en) | 2015-06-26 |
NZ623851B2 true NZ623851B2 (en) | 2015-09-29 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2776392B1 (en) | Process for the preparation of 1-acyl-4-phenylsulfonylprolinamide derivatives and new intermediates | |
AU2009260044B2 (en) | A process for the preparation of the apoptosis promoter ABT-263 | |
KR101467477B1 (en) | Novel antiviral pyrrolopyridine derivatives and a preparation method thereof | |
JP6832946B2 (en) | How to prepare kinase inhibitors and their intermediates | |
JP2023116769A (en) | Method for producing edoxaban | |
CA2549598A1 (en) | N-substituted-n-sulfonylaminocyclopropane compounds and pharmaceutical use thereof | |
BG63536B1 (en) | Biphenylamidine derivatives | |
JP4274739B2 (en) | Method for producing acetylthiopyrrolidine derivatives | |
NZ623851B2 (en) | Process for the preparation of 1-acyl-4-phenylsulfonylprolinamide derivatives and new intermediates | |
TW202039467A (en) | Process for preparing sulfonamide compounds | |
MX2010013403A (en) | 1-(2-ethyl-butyl) -cyclohexanecarboxylic acid ester as an intermediate in the preparation of pharmaceutically active amides. | |
WO2008119772A1 (en) | Amide derivatives as inhibitors of aspartyl proteases | |
KR960002727B1 (en) | Azulene derivatives, thromboxane a2 and prostaglandin endoperoxide receptor antagonist, and the method of manufacturing the same | |
DE602005002738T2 (en) | SYNTHESIS PROCEDURE AND BENZOXATHYLINDICLE PRODUCTS | |
JP2023548914A (en) | Pyrrolinone compounds and their synthesis method | |
CN112930338A (en) | Process for the preparation of amino acid derivatives | |
JP2019014716A (en) | Method for producing 4,4,7-trifluoro-1,2,3,4-tetrahydro-5h-1-benzazepine compound and intermediate for synthesis thereof | |
US5187311A (en) | Methylthiophenol derivatives and p-methylthiophenyl chloroformates and processes for producing these derivatives | |
JP4513517B2 (en) | 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid ester and process for producing the same | |
AU781355B2 (en) | Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists | |
JP4556057B2 (en) | Novel biphenyloxyacetic acid derivatives and methods for producing and using the same | |
TW201605826A (en) | Method for producing 2-pyridone compound | |
JPH07291965A (en) | Novel pyrrolidine derivative | |
JP2004131418A (en) | METHOD FOR PRODUCING 2-(N-omega-HYDROXYALKYL)AMINOMETHYL-1-SUBSTITUTED PYRROLIDINE | |
NZ514170A (en) | Benzo-1, 3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists |