MXPA98008916A - Procedure for preparing oxiranometanam derivatives - Google Patents
Procedure for preparing oxiranometanam derivativesInfo
- Publication number
- MXPA98008916A MXPA98008916A MXPA/A/1998/008916A MX9808916A MXPA98008916A MX PA98008916 A MXPA98008916 A MX PA98008916A MX 9808916 A MX9808916 A MX 9808916A MX PA98008916 A MXPA98008916 A MX PA98008916A
- Authority
- MX
- Mexico
- Prior art keywords
- oxiranyl
- acid
- ester
- group
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 32
- 239000003696 aspartic proteinase inhibitor Substances 0.000 claims abstract description 6
- 229920000647 polyepoxide Polymers 0.000 claims abstract 6
- 230000003213 activating Effects 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 88
- 239000000203 mixture Substances 0.000 claims description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 57
- 150000001875 compounds Chemical class 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 50
- -1 1-oxiranyl-2-phenylethyl Chemical group 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 21
- 150000002118 epoxides Chemical class 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 17
- 238000005917 acylation reaction Methods 0.000 claims description 16
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 230000004913 activation Effects 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- 125000005842 heteroatoms Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- JOYRKODLDBILNP-UHFFFAOYSA-N ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 7
- 102000014961 Protein Precursors Human genes 0.000 claims description 6
- 108010078762 Protein Precursors Proteins 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 125000002344 aminooxy group Chemical group [H]N([H])O[*] 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- RUPAXCPQAAOIPB-UHFFFAOYSA-N Tert-Butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 claims description 4
- 235000011054 acetic acid Nutrition 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbamate Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 101710006640 DIT33 Proteins 0.000 claims description 2
- 150000001266 acyl halides Chemical group 0.000 claims description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 2
- 150000004651 carbonic acid esters Chemical class 0.000 claims description 2
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 claims 3
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 claims 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004438 haloalkoxy group Chemical group 0.000 claims 1
- LCKIEQZJEYYRIY-UHFFFAOYSA-N titanium ion Chemical group [Ti+4] LCKIEQZJEYYRIY-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- 239000000243 solution Substances 0.000 description 61
- 238000006243 chemical reaction Methods 0.000 description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 239000007787 solid Substances 0.000 description 41
- 238000007792 addition Methods 0.000 description 40
- 239000000047 product Substances 0.000 description 40
- 238000003756 stirring Methods 0.000 description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 20
- 239000000523 sample Substances 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 15
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- 229960004592 isopropanol Drugs 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 13
- 238000001816 cooling Methods 0.000 description 11
- 238000004821 distillation Methods 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000008079 hexane Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 238000010192 crystallographic characterization Methods 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 230000000269 nucleophilic Effects 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 239000004809 Teflon Substances 0.000 description 6
- JSPLKZUTYZBBKA-UHFFFAOYSA-N Trioxidane Chemical compound OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 150000001649 bromium compounds Chemical class 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000003269 fluorescent indicator Substances 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 238000005893 bromination reaction Methods 0.000 description 5
- 238000000451 chemical ionisation Methods 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 229960000583 Acetic Acid Drugs 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- VXUYXOFXAQZZMF-UHFFFAOYSA-N Titanium isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- DRXGWTUAIWQOKN-UHFFFAOYSA-L dihydroxy(dioxo)molybdenum;phosphonic acid Chemical compound OP(O)=O.O[Mo](O)(=O)=O DRXGWTUAIWQOKN-UHFFFAOYSA-L 0.000 description 4
- 150000002009 diols Chemical class 0.000 description 4
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 238000011068 load Methods 0.000 description 4
- 238000003760 magnetic stirring Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000007790 solid phase Substances 0.000 description 4
- JMSRBKPMLUGHCR-UHFFFAOYSA-N Bromohydrin Chemical compound BrC[C]1CO1 JMSRBKPMLUGHCR-UHFFFAOYSA-N 0.000 description 3
- 101700067048 CDC13 Proteins 0.000 description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
- 229940021015 I.V. solution additive Amino Acids Drugs 0.000 description 3
- 239000002033 PVDF binder Substances 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 150000001793 charged compounds Chemical class 0.000 description 3
- 230000001808 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000727 fraction Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000011141 high resolution liquid chromatography Methods 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- 125000004430 oxygen atoms Chemical group O* 0.000 description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 3
- 239000001184 potassium carbonate Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 125000006513 pyridinyl methyl group Chemical group 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004434 sulfur atoms Chemical group 0.000 description 3
- 230000001131 transforming Effects 0.000 description 3
- 239000004474 valine Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- 210000002196 Fr. B Anatomy 0.000 description 2
- 102000015787 HIV Protease Human genes 0.000 description 2
- 108010010369 HIV Protease Proteins 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N aspartic acid group Chemical group N[C@@H](CC(=O)O)C(=O)O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 125000004429 atoms Chemical group 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 230000003197 catalytic Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000009838 combustion analysis Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000004030 hiv protease inhibitor Substances 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical class CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N triclene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 2
- 150000003673 urethanes Chemical class 0.000 description 2
- MLBCURLNKYKBEQ-UHFFFAOYSA-N (2,6-DIMETHYL-PHENOXY)-ACETIC ACID Chemical compound CC1=CC=CC(C)=C1OCC(O)=O MLBCURLNKYKBEQ-UHFFFAOYSA-N 0.000 description 1
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a process for preparing oxiranemethane derivatives which are useful as intermediates for preparing aspartylprotease inhibitors, comprising the steps of activating an amino-diol, acylating the amino-diol and reacting the acylated amino-diol with a base to form an epoxy compound.
Description
PROCEDURE FOR PREPARING OXYANOMETHANAMINE DERIVATIVES
FIELD OF THE INVENTION
The present invention provides a novel process for preparing oxiranemethanamine derivatives which are useful as intermediates for preparing aspartyl protease inhibitors.
BACKGROUND OF THE INVENTION
Aspartyl proteases are enzymes that use aspartic acid residues in their active site to catalytically hydrolyze specific amide bonds in peptides. The design of molecules that effectively inhibit the function of aspartyl protease enzymes has been carried out in the recent past. These molecules have a strong affinity for the catalytic site of the enzyme but, unlike substrates of natural enzymes, they contain an appropriately located fragment, "the isostere in the transition state" (IET) that is incapable of hydrolytic cleavage. This gives these molecules the ability to inhibit the catalytic activity of enzymes.
REF .: 28562 The HIV protease is a particular aspartyl-protease enzyme that has a critical role in the maturation and replication of the Human Immunodeficiency Virus. When applied to this enzyme, the inhibitory strategy hitherto described herein results in clinically important antiviral effects. Many methods have been published to prepare protease inhibitors. One proposal is based on the preparation of a reactive precursor to the IET fragment that can be coupled to other fragments of the intended inhibitor. Examples of the preparation and use of reactive precursors of this type belonging to this invention can be found in: J. Org. Chem. 1985, 50, 4615; J. Org. Chem. 1987, 52 (8), 1487; EP 346847 (Example 19); EP 432964 (Examples 1 and 2); J. Med. Chem. 1992, 35, 1685; WO 9323388; J. Med. Chem. 1993, 36, 2300; J. Chem. Soc. Chem. Commun. 1993, 9, 737; J. Org. Chem. 1994, 59, 3656; J. Med. Chem. 1991, 34, 1222; J. Med. Chem. 1992, 35, 2103; J. Org. Chem. 1995, 60 (21), 6696. All of these prior art methods for the preparation of a precursor reactive to the IET fragment of HIV protease inhibitors suffer from one or more of the following disadvantages: the use of expensive raw materials or inaccessible, reaction conditions and commercially non-practical or hazardous reagents, laborious multiple-step reaction sequences employing unstable and / or hazardous intermediates, the production of isomeric mixtures resulting in low yields of pure substance due to processes of prolonged separation that are not practical for large-scale production.
BRIEF DESCRIPTION OF THE INVENTION
The inventor has discovered a method for producing a reactive IET precursor of formula A:
wherein X is hydrogen, an alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or aryl-heteroatom-alkyl group, wherein the heteroatom is nitrogen, oxygen or sulfur. Within the context of the substituent X and the present application, the term "alkyl" means a straight or branched chain hydrocarbon containing from 1 to 8 carbon atoms. The term "cycloalkyl" means a cyclic hydrocarbon containing from 3 to 8 carbon atoms. The term "aryl" means phenyl, naphthyl or a 5-6-membered heterocyclic ring containing one or more and, preferably, one or two heteroatoms selected from N, O and S. The aryl group may be optionally substituted with one or more alkyl groups , haloalkyl groups, halogens, amino or hydroxy groups. According to the preceding definition, group X is exemplified, but is not limited to:
CH3- (CH3) 2CH
Y and Z are both hydrogen and can independently have a stereochemical orientation that results in the (R) or (S) configuration (according to the Cahn-Ingold-Prelog nomenclature, see Angewandte Chemie Int = l Ed. Engl. , 385, (1986)) in the carbon atoms to which they are attached. R3 is a lower alkoxy group containing 1 to 8 carbon atoms which can form a straight or branched chain, part of a ring or a combination thereof; an alkenylmethoxy group; an arylalkoxy group, wherein the aryl portion is optionally substituted with halogen atoms, lower alkoxy or lower alkyl groups of one to five carbon atoms or combinations thereof; an aralkyl group, wherein the alkyl portion has from 1 to 5 carbon atoms; an aryloxyalkyl group, wherein the aryl portion is optionally substituted with halogen atoms, lower alkoxy or lower alkyl groups of one to five carbon atoms or combinations thereof. The alkyl portion contains from 1 to 5 carbon atoms; an aryl group, optionally substituted with heteroatoms or groups of heteroatoms, alkyl groups, haloalkyl groups, halogen atoms, amino or hydroxy groups; an acylated alpha-aminoalkyl group, wherein the alkyl group is defined by those found in amino acids that occur in nature and the acyl group is derived from a carboxylic acid or carbonic acid ester. According to the preceding definition of R3, the group R3C (0) is exemplified but not limited to:
In the context of R3, the term aryl is used to include such groups, substituted or unsubstituted: phenyl, naphthyl, heterocyclic rings containing one or more nitrogen, oxygen or sulfur atoms such as pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, quinolinyl, indolyl, benzothiazolyl, benzofuryl, benzoxazolyl, benzimidazolyl and the like. The term heteroatom groups is defined as a group of covalently linked atoms that contain one or more nitrogen, oxygen, sulfur or halogen atoms, commonly recognized by those skilled in the art as stable arrangements. Examples of groups of this type are ethers, sulfides, sulfones, esters, amides, nitriles and the like. The term halogen includes fluorine, chlorine and bromine. The amino acids that occur in nature include lysine, cysteine, leucine, isoleucine, tryptophan, phenylalanine, alanine, histidine, proline, glycine, methionine, serine, tyrosine, threonine, asparagine, aspartic acid, glutamic acid and valine. These examples serve to illustrate the definition but not to limit the invention in any way.
DESCRIPTION OF THE INVENTION
Accordingly, it is a principal object of the invention to provide a novel process for the production of compounds of the formula A. It is also an object of the invention to provide an improved stereospecific process for the production of compounds of the formula A. It is also an object of the invention provide an improved process for the production of compounds of the formula A, which avoids the dangerous reaction conditions and sensitive intermediates. It is also an object of this invention to provide a new process for the large-scale practical production of a compound of formula A. It is also an object of this invention to provide a process for the production of compounds of formula A by direct acylation of intermediate compounds to form an amide without the need to use protection and deprotection steps. These and other objects of the invention will be apparent from a review of the attached specification.
DESCRIPTION OF THE PREFERRED MODALITIES
The invention provides a convenient method for the production of IET fragment precursors of formula A or their functional equivalents. This method makes use of a compound of formula 1:
where X, Y and Z are as previously defined. The compound of formula 1 is obviously not convenient as an intermediate compound for the preparation of compounds of formula A or their equivalents. Ordinary experts contemplating this conversion will recognize that conventional methods require acylation of the amine, selective activation of a hydroxyl group and treatment with a base to form an epoxide. Note that the term "activation" in this context and as used hereinafter, means transforming the hydroxyl group so that a net displacement of the original oxygen atom from the rest of the molecule becomes possible. This activation is sometimes complicated by poor selectivity for distinguishing the two hydroxyl groups. When this happens, it results in lower yield and greater contamination of by-products. The above strategy is typically executed in separate stages with a treatment and isolation of intermediates using several reaction vessels. It would be advantageous to avoid this.
The above operations will apply to the preparation of amide or urethane derivatives. The acylation must precede the activation of the hydroxyl group (ie by sulfonylation) due to the increased reactivity of the amine. This is problematic if an amide derivative is used in the hydroxyl activation step due to the low yields of impure product. To avoid this, it is necessary to carry out the activation in a urethane derivative. This requires two additional steps in the total preparation of an amide derivative. This invention comprises novel means for the activation of the compound of formula 1, followed by an acylation step thereby making formula 1 an unexpectedly effective precursor for known HIV protease inhibitors. The activation strategy employed in this invention avoids the need for more conventional transformations and their associated disadvantages mentioned above. It is advantageous, because the activation step is very selective for the terminal hydroxyl group. The method allows the three stages, activation, acylation and formation of the epoxide, to be carried out, if desired, in a single reaction vessel. This can be done using a continuous sequence of operations without treatment or isolation of intermediates. In addition, upon activation of the diol prior to the acylation of the amine, the protection and deprotection steps can be eliminated when preparing amide derivatives. A preferred process by which the compound of formula 1 is converted into the compounds of formula A is based on the dehydrating bromination of the compound of formula 1 with essentially anhydrous hydrogen bromide in a solution of carboxylic acid at a temperature in the range of 5. at 60 ° C for a reaction time in the range of one hour to four days. Hydrogen bromide is present in a molar ratio to a compound of formula 1 ranging from 2 to 10. Examples of carboxylic acids useful for this purpose are formic acid, acetic acid and propionic acid. The most preferable is acetic acid. This activation step produces a product which is a mixture of the bromohydrin compound of formula 2 and the bromoester of formula 3:
wherein R 4 = H (formula 2); R4 = COH, COOH3 or C0CH2CH3 (formula 3). The product can be used directly without isolation of the hydrobromide salts. The excess acetic acid and hydrogen bromide are distilled off from the mixture of the compounds of formula 2 and formula 3 and exchanged with a suitable solvent for reaction with an acylating agent and a base. The solvents can be, but are not limited to methanol, toluene, dichloromethane, tetrahydrofuran, dimethylformamide, acetonitrile or water, depending on the acylating agent and base used. Suitable acylating agents are acyl halides, dicarbonic acid esters, activated esters and intermediates generated in situ from N-protected amino acids such as mixed anhydrides, acyl isoureas and the like. It is evident to those skilled in the art of chemical synthesis, what type of acylating agent is appropriate, based on considerations of the acyl group to be transferred, and the characteristics of the contemplated reagent such as stability and availability. In addition, the most effective combination of solvent, acylating agent, base and reaction parameters such as time and temperature, depends on the nature of the acyl group to be transferred and on the nature of the compound of formula I. These considerations will be apparent to those who are familiar with the technique. The acylation reaction mixture produced contains a mixture of acylated bromides which are collectively referred to herein as the "Activated Precursors" for formula A. This mixture, without treatment or isolation, can be contacted directly with a base for forming the epoxide of formula A. Alternatively, if desired, the acylation reaction mixture can be subjected to treatment and isolation of the acylated bromides which are contacted with a base in a separate step. In any case, the total transformation of a compound of formula 1 into a compound of formula A occurs with complete stereochemical fidelity. Examples of compounds of formula A include compounds such as [S- (R *, R *)] - (l-oxiranyl-2-phenylethyl) carbamic acid ester, 1,1-dimethylethyl ester of [S- (R *, R *)] - (1-oxiranyl-2-phenylethyl) carbamic acid ester 1, 1-dimethylethyl [R- (R *, S *)] - (1-oxiranyl-2-phenylethyl) carbamic ester [R- (R *, S *)] -l-oxiranyl-2-phenylethyl) carbamic acid phenylmethyl, N- [S- (R *, R *) - (l-oxiranyl-2-phenylethyl)] -2 - (2, 6-dimethylphenoxy) acetamide, S- (R *, R *) - (1-oxiranyl-2-phenylethyl) amide of N- (quinolin-2-yl-carbonyl-L-valine, S- (R *, R *) - N 2 - (l-oxiranyl-2-phenylethyl) amide (quinolin-2-ylcarbonyl) -L-asparagine, 1,1-dimethylethyl ester of [S- (R *, S *)] - (L-oxiranyl-2-phenylthioethyl) carbamic acid, tetrahydro-3-furanyl ester of [3S- [3R * (1R *, 2R *)]] - (l-oxy-ranyl-2-phenylethyl) carbamic acid, ester Tetrahydro- [2- [(1-methyl) -ethyl] -3-thienyl acid [2R- [2R *, 3R * (1S *, 2S *)]] - (1-oxiranyl-2-phenylethyl) carbamic acid , S, S-dioxide These compounds are represented graphically, in the same order as the previous names, as follows:
^
In any cases of ambiguity between the preceding chemical names for the representative compounds of formula A and the graphic representation, the graphic representation should have
precedence to establish the identity.
The compounds of the formula A are converted into aspartyl protease inhibitors in one or more steps depending on the inhibitor. A central step required in this method involves contacting the epoxide with a nucleophilic agent that induces ring opening and the formation of a bond with the terminal carbon of the epoxide. The atom that contributes to this new bond from the nucleophilic agent can be a carbon, nitrogen or sulfur atom. Suitable nucleophilic agents are ammonia or primary or secondary amines, mercaptide salts, carbanions generated from carbonyl compounds and the like. The primary amines can be of the formula R5NH2, wherein R5 is selected from the group consisting of alkyl, cycloalkyl and arylalkyl. The secondary amines can be of the formula RTNHR7, wherein R6 and R are independently selected from the group consisting of alkyl, cycloalkyl, arialkyl and cycloaliphatic amines that can be fused with an aromatic ring wherein the nitrogen of the cycloaliphatic amine is separated from the cycloaliphatic amine. aromatic ring for at least one carbon atom. Agents of this type are exemplified, but not limited to benzylamine, isobutylamine, cyclopentylmethylamine, piperidine, dimethylamine, 3S, 4aS, 8aS-N- (1,1-dimethylethyl) decahydro-3-isoquinolinecarboxamide, 2 (S ) -. { [(1,1-dimethylethyl) amino] -carbonyl} -4 (R) - [4- (pyridinylmethyl) oxy] piperidine, sodium diethylmalonate. Many other nucleophilic agents, suitable for this purpose, are apparent to one of ordinary skill in the art. The invention also includes the direct conversion of the mixture of acylated bromides (the activated epoxide precursors) into an aspartyl protease inhibitor or a more advanced intermediate compound leading to it. This is achieved by simultaneous or sequential contact with a base and a nucleophilic agent. The epoxide of formula A is generated in situ. The nucleophilic agents mentioned hereinabove function in the same manner. Bases suitable for the formation of the epoxide are hydroxides, carbonates, alkoxides and hydrides of alkali metals. The solvent used for this reaction may be, but is not limited to, tetrahydrofuran, methanol, ethanol or isopropanol, substantially anhydrous or mixed with water. The temperature of the reaction is in the range of minus 10 ° C to plus 90 ° C from one to 120 hours. The compound of formula A is useful as a precursor of protease inhibitors which are described in U.S. Patent 5,196,438, EP 539192-A1, EP 560268, EP 560269, WO 9410134, WO 9418192, WO 9414793, document WO 9323379, EP 434365, WO 9405639, WO 9509843, WO 9304043 and US Application Serial No. 08 / 025,703 filed March 3, 1993 as useful for the treatment of HIV infections. The compound of formula 1 can alternatively be reacted with a urethane-forming material such as an alkyl chloroformate or dialkyl dicarbonate to form a urethane which is further acylated with para-toluenesulfonyl chloride to form a primary sulfonate ester. This acylation is carried out in an organic solvent containing a base. Many choices of solvents and bases are possible and familiar to those skilled in the art. The preferred range for acylation is -25 ° C to + 25 ° C, more preferably about -5 ° C to -10 ° C. The reaction time is in the range of 1 to 48 hours, more preferably approximately 24 hours, and atmospheric pressure is preferred. The preferred stoichiometry of para-toluenesulfonyl chloride, based on the diol to be acylated, is 100 to 106 mole% and, more preferably, about 103 mole%. The sulfonate ester can be converted to the epoxy derivative by contacting it with a base in an organic solvent. Bases suitable for the formation of the epoxide are hydroxides, carbonates, alkoxides and hydrides of alkali metals. These compounds are useful for the preparation of amide containing inhibitors such as those described in U.S. Patent 5,196,438, EP 560268, EP 560269, WO 9410134, WO 9414793, WO 9323379, EP 434365, document WO 9509843, WO 9304043 and North American Application Serial No. 08 / 025,703 filed March 3, 1993, by deprotection and acylation, or inhibitors with urethane content such as those described in EP 539192-A1, WO 9418192, WO 9405639 and WO 9308184. This invention also comprises preparing an aminodiol compound of the formula
OH
or its enantiomeric form by step (a), which comprises reacting a glycidol compound of the formula:
or their enantiomeric form, respectively with an amine of the formula: R? R2NH, wherein Ri and R2 are independently selected from the group consisting of hydrogen, arylalkyl or di (aryl) alkyl, "wherein the aryl portion is attached thereto carbon carrying the amino function and optionally substituted with lower alkoxy or lower alkyl groups of 1 to 5 carbon atoms. The alkyl portion is from 1 to 5 carbon atoms, optionally substituted with hydroxy or lower alkoxy groups. The reaction is carried out in the presence of a catalyst. By specifying Ri and R2, the term aryl means a phenyl or naphthyl group. Suitable amines include benzylamine; alpha-methylbenzylamine; dibenzylamine; benzhydrylamine; 1-phenyl-2-hydroxyethylamine; and similar. The catalyst can be a transition metal catalyst, which is preferably a titanium (IV) compound such as titanium (isopropoxide) 4 at a temperature of 25 to 100 ° C. Generally, the transition metal catalyst is used at a level that is greater than one mol-equivalent with respect to the amine. The reaction is carried out in the presence of an aprotic organic solvent such as benzene, toluene or xylene. The reaction of compound 5 with the amine provides a mixture of compounds having the following structures:
In step (b), the products of step (a) are hydrogenated to replace Rx and / or R2 by hydrogen atoms. The hydrogenation of the compounds of the formulas 6 and 7 can be carried out using conventional hydrogenation conditions such as hydrogen in a pressure range of 1.05-7 kg / cm2 (15-100 psi) in the presence of a catalyst. palladium-carbon at 20 to 35 ° C for a period of 3 to 24 hours. Next, a compound of formula 4 is crystallized from the reaction mixture, essentially free of its enantiomer and of the hydrogenated derivative of the compound of formula 7. It is surprising and unexpected that the crystallization of the compound of formula 4, essentially free of Hydrogenated derivative of the isomeric compound of formula 7, occurs spontaneously and with high efficiency. No further purification is required before the use of the compound of formula 4 as an intermediate compound, and the product can also be stored in solid form, without degradation, for long periods of time. The compounds of formula A and their pharmaceutically acceptable salts can be converted by reaction with a nucleophilic agent as described herein above, into aspartyl protease inhibitors that can be used as inhibitors of HIV protease at an oral dose of 1. mg to about 5.0 g, preferably 3 mg to 3.0 g, and more preferably from about 10 mg to about 1.0 g per person per day, administered in one to three divided doses (or, for example, 300 mg per person administered once) daily or three times a day). The dose can be adjusted depending on the particular compound and the response of the individual patient. The compounds can be prepared in the form of pharmaceutical compositions according to the methods of U.S. 5,196,438, which is incorporated by reference. The following examples illustrate the invention and are not to be construed as limiting the invention.
Example 1
This example demonstrates the sequence of three continuous steps for preparing a urethane-protected a-phenylmethyloxymethronethamine.
Preparation of [S- (R *, R * >)] - (l-oxiranyl-2-phenylethyl) carbamic acid 1-dimethylethyl ester
A 1000 ml three-neck round bottom flask is equipped with a mechanical stirrer from the head area, a back-aspiration trap on both the gas inlet side and the outlet side of the reactor, a gas flushing bottle of 500 ml charged with sodium hydroxide solution for the purification and a type K thermocouple probe coated with PVDF. The reaction vessel is charged with S- (R *, R *) -3-amino-4-phenyl-1,2-butanediol, 50.02 grams (275.9 mmol), followed by glacial acetic acid, 210 ml. The mixture is stirred and the temperature rises from 22 ° C to 32 ° C. At this point, an ice / water cooling bath is placed below the container to moderate the exotherm. The temperature drops and most of the solid dissolves. The addition of hydrogen bromide gas, 100.08 grams (1236.9 mmol), through a Teflon tube of 7.6 cm outer diameter is initiated when the internal temperature is 20 ° C. The addition requires 50 minutes. During this period, the temperature is maintained between 15 ° C and 20 ° C. The gas cylinder is weighed intermittently to ensure adequate loading. The reaction vessel discharges to the scrubbing device containing 320.65 g of 6.25% (w / w) sodium hydroxide solution. When the addition of gas has been completed, a verification of the gross weight of the scrubber reveals an increase of 0.12 grams (note 1). The resulting pale yellow solution (contains a small amount of undissolved solids) is allowed to stir at room temperature. Three hours after the completion of the addition of hydrogen bromide, an aliquot of the reaction solution is removed for analysis (note 2). This reveals that aminodiol is completely consumed. Twenty-one hours after the completion of the addition of hydrogen bromide, the scrubber is exchanged for one containing 399.8 g of 15% w / w sodium hydroxide solution. The reaction mixture is sprayed with nitrogen using a Robu icrofilter cartridge (porosity of 40-100 microns) as the temperature rises from 21 ° C to 50 ° C. The total time for this operation is 2 hours, 45 minutes. During this period, the scrubber increases in weight at 19.33 g. The spraying is interrupted and the heating is interrupted. The reaction vessel is configured for distillation. During the interval of 1 hour, 25 minutes since the sweeping or spraying was interrupted, the internal temperature drops to 31 ° C. The pressure is lowered to 40 mm Hg and the vessel is heated to a maximum container temperature of 60 ° C for 1 hour, 40 minutes while the volatile components are distilled off. The collected distillate weighs 178.44 g. The pressure is increased to 80 mm Hg and toluene, 175.92 g, is charged to the reaction vessel. Distillation is resumed, maintaining a container temperature of 45-50 ° C. This process is repeated with four more charges of toluene, 180.57 g, 177.34 g, 169.35 g and 170.89 g, respectively. The total time for the distillation of toluene is 2 hours, 10 minutes. When distillation ceases, the residue, a viscous syrup (stirring is not a problem), is cooled to room temperature. Stirring is continued for 1 hour, 30 minutes while checking for acidity, the last distillate fraction of toluene (note 3). The residue in the reaction vessel is at a temperature of 19 ° C. Methanol, 200 ml, is charged, followed by di-t-butyl dicarbonate, 62.67 grams (286.8 mmol), in the form of a pure semi-solid. Next, another 380 ml charge of methanol is added. The resulting solution is cooled to 0 ° C (ice bath / methanol). When the temperature has equilibrated, triethylamine, 31.03 grams (306.6 mmol), is added dropwise over 30 minutes to maintain the reaction temperature below 1 ° C. After the addition is complete, the cooling bath is replaced by an ice / water bath. The reaction temperature is allowed to rise slowly to room temperature over 14 h (note
4) . In the space of 20 minutes of the complete addition of triethylamine, a gentle gas evolution is observed.
At the end of the 14 hour aging period, the temperature of the reaction mixture is again lowered to 0 ° C. Solid potassium carbonate, 118.63 grams (858.3 mmol), is added in portions over 20 minutes (no exotherm observed). The temperature is maintained at 0-5 ° C for 30 minutes, followed by heating to 20 ° C for 1.5 hours. The completion of the reaction is monitored by thin layer chromatography (CCD) (note 4). After 26.5 hours at 20 ° C, the conversion of the bromoacetate / bromohydrin mixture into epoxide has been completed. A 2000 ml three-neck, round-bottomed quench flask equipped with a mechanical stirrer in the head region and a PVDF coated K-type thermocouple probe is charged with 600 ml of toluene and 600 ml of water. Agitation starts. The reaction mixture is poured over 7 minutes in the quenched mixture. An ice / water bath is used to maintain the temperature between 20-25 ° C. Stirring is interrupted and phase separation occurs rapidly. The layers are separated and the aqueous layer is extracted twice with 200 ml portions of toluene. The combined toluene extract is again extracted once with 200 ml of water and then concentrated to dryness at a bath temperature of 60 ° C and at a pressure of 80 mm Hg. The residue is dissolved in toluene, 200 ml, and concentrated a second time. The white solid residue is dried at room temperature and at a pressure of about 80 mm Hg overnight, giving a final weight of 64.68 grams, m.p. 112-119 ° C (not corrected). This crude product is essentially pure by CIAR (High Resolution Liquid Chromatography) (85% based on the normalization of the peak area) (note 5). A sample of the crude or crude product weighing 1.1 g is crystallized by heating to 60 ° C in 4.5 ml of toluene. The recovery of a crop of product at room temperature gives 600 mg. The HPLC analysis establishes a purity of 98.6% (by area normalization). P.f, 123-125 ° C (not corrected); [α] D 25 = -7.30 (c = 5.0 in methanol); combustion analysis (% calculated,% found): C 68.42, 68.57 H 8.04, 7.94 N 5.32, 5.35; MS (IQ, methane) MH + expected: 264, found: 264. Proton NMR: (solution CDCI3) downfield displacement in ppm of TMS, n ° H's, multiplicity: 1.21, 9H, singlet; 2.78, 2H, mutiplete; 2.94, 3H, multiplet; 3.7, 1H, broad singlet; 4.45, ÍH, broad singlet; 7.2-7.35, 5H, multiplet.
NOTES Note 1: the weight of the cylinder load is corrected by the increase in the weight of the scrubber.
Note 2: the disappearance of aminodiol is conveniently monitored by CCD (silica gel 60 with fluorescent indicator, the mobile phase is dichloromethane: methanol: concentrated ammonium hydroxide (80: 20: 0.3 v / v; the chromatogram was developed with iodine 0 spraying with a solution at 4% w / v of phosphomolybdic acid in ethanol, followed by heating); Rf of aminodiol is 0.5). The CCD sample is prepared by adding
1 part aliquot of reaction to 3 parts of concentrated ammonium hydroxide.
Note 3: An aliquot portion of the distillate, accurately weighed, is transferred quantitatively to an Erlenmeyer flask with 30 ml of methanol and diluted with 250 ml of deionized water. Standardized 1 N sodium hydroxide solution, 25 ml, is added using a graduated pipette. Phenolphthalein indicator is added and the resulting mixture is titrated with standardized 1 N hydrochloric acid. The average > of two determinations indicates 17.2 milliequivalents of acid present in the distillate. The triethylamine loading in the next step is corrected for this amount.
Note 4: the progress in the acylation of the amine and the subsequent ring closure of the bromide mixture to give the epoxide are conveniently monitored by CCD
(silica gel 60 with fluorescent indicator, the mobile phase is 2: 1 v / v hexanes / ethyl acetate, the chromatogram was developed by spraying with a 4% w / v solution of phosphomolybdic acid in ethanol, followed by heating; the Rf values for the intermediate compound N-BOC-bromohydrin, N-BOC-epoxide and the intermediate compound N-BOC-bromoacetate are 0.42, 0.51, 0.63, respectively.
Note 5: CLAR Conditions (High Resolution Liquid Chromatography (HPLC)
column: Rainin microsorb C-18 RP 80-2225- C5 with detector guard column: UV at 210 nm sample loop: 20 microlitres mobile phase: 1: 1 acetonitrile / water flow rate: 1 ml / min sample concentration: 0.5 mg / ml in mobile phase Retention time of N-BOC-epoxide: approx. 12 min
Example 2
This example demonstrates the direct preparation of a simple amide derivative of a-phenylmethyloxy-methanamine without stages of protection and deprotection with urethane.
Preparation of [S- (R *, R *) -N- (l-oxiranyl-2-phenylethyl) -2- (2,6-dimethylphenoxy)] acetamide
Stage 1:
Aminodiol bromination
Preparation of a mixture of S- (R *, R *) - ß-amino-a-bromomethylbenzenepropanol and hydrobromide of S- (R *, R *) - β-amino-a-bromomethylbenzene propylacetate
A dry 100 ml three-neck round bottom flask containing a magnetic stir bar is charged with S- (R *, R *) -3-amino-4-phenyl-1,2-butanediol prepared in Example 1 , stage 2, 5.4385 grams (30.1 mmol), and sealed with a rubber septum before being purged with nitrogen. The flask is cooled with an ice bath for approximately 15 minutes. Next, a solution of hydrogen bromide in acetic acid (30% by weight), 34.396 grams (127.5 mmol, approximately 25 ml) is added, and stirring is started as soon as possible. The temperature rises to a maximum of 35 ° C and then drops back to 13 ° C after 5 minutes from the start of the addition. At this point, the cooling bath is removed and the internal temperature is allowed to rise to 24 ° C. Stirring is continued for four days at room temperature. The reaction vessel is equipped with a short path distillation apparatus. The heating is started and the pressure is reduced until stable distillation occurs at 45-50 ° C. When the distillation ceases at this temperature, the apparatus is discharged under a nitrogen atmosphere and 20 ml of toluene are added. Then, the distillation is resumed under the same conditions. This operation is continued until the distillate is no longer acidic (a total of five charges of toluene). The remaining residue consists of 19% by weight solids and is used directly in the acylation step that follows. A small sample of this residue is subjected to a high vacuum to remove the solvent. This sample is characterized by proton NMR and EM by chemical ionization. The results are consistent with those expected for a mixture of the aminobromohydrin and its acetate ester as the hydrobromide salts.
Stage 2:
Acylation of the crude bromination product The residue of the crude product from step 1 is diluted with dichloromethane, 26 ml, and the resulting mixture is stirred under a nitrogen atmosphere while the flask is cooled in an ice bath. 2, 6-Dimethylphenoxyacetyl Chloride is prepared in a separate vessel as follows: 2,6-dimethylphenoxyacetic acid, 5.4060 grams (29.99 mmol), is charged into a 50 ml round bottom flask equipped with a magnetic stirring rod coated with Teflon. Toluene, 15 ml, is added, stirring is initiated and thionyl chloride, 9.0 ml (123.3 mmol) is added followed by a drop of N, -dimethylformamide at room temperature. After seven hours, the reaction mixture is heated to 65 ° C for thirty minutes and allowed to cool to room temperature. The solution is concentrated at 60 ° C and at a pressure of approx. 60 mm Hg to separate all volatile components. The residue is diluted with toluene, 25 ml, and reconcentrated. This is repeated a second time to give a final residue. The internal temperature of the product solution of step 1 is 4.8 ° C when the acid chloride residue is added through a cannula transfer using a nitrogen pressure. Dichloromethane, 10 ml, is used to rinse the transfer duct and container. The internal temperature is allowed to drop to 3.5 ° C before the dropwise addition of triethylamine begins6.05 grams (59.79 mmol). This addition requires 20 minutes, and the internal temperature does not exceed 8 ° C during this time. After the addition is completed, the reaction mixture is allowed to warm to room temperature over 15 hours. Water, 20 ml, followed by additional dichloromethane, 30 ml. When filtering, the mixture is collected a solid fraction A. This is rinsed with water and dichloromethane. This is dissolved in ethyl acetate and concentrated again to dryness. The white crystalline solid weighs 1.1247 grams. This material is characterized by proton NMR, EM by chemical ionization and CCD (note 1). «The results indicate that this material is almost pure acylated aminobromohydrin. The layers of the filtrate are separated. The aqueous layer is extracted twice with dichloromethane and the extracts are combined with the organic layer from the original filtrate. The resulting solution is extracted twice with saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, and finally dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate give a fraction B of white solid, 11.56 grams. This material is characterized by proton NMR, EM by chemical ionization and CCD (note 1). The results indicate that it is a mixture of the acylated aminobromohydrin acetate ester (main component) and the acylated aminobromohydrin ester (secondary component). This mixture is used directly to prepare the epoxide in stage 3.
Stage 3:
Formation of the epoxide from crude bromides
The mixture of bromide fraction B from the previous step, 112.4 mg, is suspended in methanol, 1 ml, and the vessel containing the mixture is cooled in an ice bath. Solid potassium carbonate, 76.2 mg (0.55 mmol) is added in one portion, while stirring. After five minutes, the cooling bath is removed and the reaction mixture is allowed to warm moderately to room temperature. When 35 minutes have elapsed since the addition of the base, an aliquot of the reaction mixture is separated and examined by CCD (note 1). The results indicate a complete consumption of the bromides. One hour after the addition of the base, the reaction is treated by the addition of ether, 2 ml, followed by water, 6 ml. The two layers are separated, and the aqueous layer is extracted twice with 2 ml portions of ether. The ether extracts are combined with the original organic layer and the combined solution is dried over anhydrous sodium sulfate. Filtration of the salts and concentration of the filtrate under reduced pressure gives a colorless residue weighing 81.7 mg. This material is characterized by proton NMR and EM by chemical ionization. The results indicate that the product is pure epoxide. Characterization: EMIQ: expected molecular ion = 325; found MH + = 326 proton NMR: (solution CDC13) downfield displacement in ppm in TMS, n ° H's, multiplicity: 2.09, 6H, singlet; 2.88, 2H, doublet; 2.9-3.2, 3H, doublet of doublets, multiplet, doublet of doublets; 4.19, 2H, ab cuartete; 4.21, ÍH, multiplet; 6.88, 1H, wide doublet; 6.98, 3H, multiplet; 7.27, 5H, multiplet. Note 1: CCD conditions solid phase: silica in p / fluorescent indicator eluent: hexanes in ethyl acetate 3: 1 (v / v) development agent: iodine
bromohydrin Rf = 0.26 bromohydrin acetate Rf = 0.50 epoxide Rf = 0.28 Example 3
This example demonstrates the direct preparation of an amide derivative of a-phenylmethyloxy-arnomethanamine, derived from an N-acylated amino acid, without protection and deprotection steps with urethane.
Preparation of S- (R *, R *) - N- (quinolin-2-ylcarbonyl) -L-valine (l-oxiranyl-2-phenylethyl) amide
Stage 1:
Acylation of crude bromination products
A 100 ml three-necked round bottom flask, equipped with a Teflon-coated magnetic stirring rod, nitrogen inlet and PVDF coated K-type thermocouple probe is charged with N- (2-quinolinylcarbonyl) -L-valine, 1.00 grams (3.67 mmol), and tetrahydrofuran, 7.5 ml. The reaction vessel is purged with nitrogen, stirring is started and the flask is cooled. When the internal temperature has reached -3 ° C, N-methylmorpholine, 404 mcl (3.67 mmol) is added to the solution over a period of five minutes. This is followed by the dropwise addition of isobutyl chloroformate, 477.4 mcl (3.67 mmol), over a period of fifteen minutes. During the addition and for an additional twenty minutes, the internal temperature is maintained between -1 and -3 ° C. After this time, a solution of the aminobromohydrin acetate hydrobromide salt (purified from a crude bromination product by crystallization in isopropanol), 1348 grams (3.67 mmol), is added over two minutes. tetrahydrofuran, 5 ml, prepared in a separate container. Additional tetrahydrofuran, 2.5 ml, is used to rinse the transfer duct and the container into the reaction vessel. The temperature is still -3 ° C when another charge of N-methylmorpholine, 404 mcl (3.67 mmol) is added dropwise. This addition requires 40 minutes in order to keep the temperature below -1 ° C. When the addition is complete, the reaction mixture is maintained at that temperature for another 30 minutes. The analysis of an aliquot part of the reaction by CCD confirms the complete consumption of the amine. Ethyl acetate, 30 ml, is added and the resulting mixture is allowed to warm to room temperature. Then, it is extracted three times with 4 ml portions of water, dried over anhydrous sodium sulfate, filtered and concentrated at 60 ° C and at a pressure of 60 mm Hg. The recovered solid is dried at room temperature and at a pressure of 0.5 mm Hg. The final weight is 1.9843 grams. A sample of the crude product, 1.8843 grams, is crystallized by dissolving it in warm 50% (v / v) ethyl acetate in hexanes, 30 ml, and allowing the solution to cool to room temperature. The crystalline product is collected by filtration, rinsed with 20% ethyl acetate in hexanes (v / v), 5 ml, and dried at room temperature and at a pressure of 0.1 mm Hg overnight. The final weight is 1.1341 grams. This product is characterized by proton and carbon NMR, IR and EMIQ. The data are consistent with an essentially pure acylated bromohydrin acetate. This product is used without purification in stage 2.
Stage 2:
Epoxide ring formation
A 100 ml round bottom flask, equipped with a Teflon-coated magnetic stirring rod, is charged with the acylated bromohydrin acetate, from step 1, 1.00 grams. Methanol, 18.5 ml, is added and stirring is started. The suspension is cooled to an internal temperature of -8 ° C and maintained for twenty minutes. Over a period of five minutes, potassium carbonate, 512 mg, is added in portions at this temperature. One hour after the addition is complete, an aliquot of the reaction mixture is removed and examined by CCD. The acylated bromides are consumed completely. The reaction mixture is diluted with ethyl acetate, 40 ml, with continuous stirring at -8 ° C for an additional ten minutes. The mixture is then heated to 20 ° C and all volatile components are separated at this temperature to a minimum pressure of 60 mm Hg. The residue is resuspended and concentrated twice more from 20 ml portions of ethyl acetate. The new residue is suspended by stirring in ethyl acetate, 40 ml, for ten minutes and then filtered. The collected solid is rinsed with 10 ml of ethyl acetate, and the combined filtrate is concentrated at 20 ° C and at a minimum pressure of 60 mm Hg to remove all volatile components. Finally, the residue is concentrated twice from 10 ml portions of hexanes and dried at room temperature and at a pressure of 0.1 mm Hg for four hours. The weight of the product is 767.3 mg. This is essentially pure epoxide by CCD (note 1) and proton NMR characterization. A sample of this product, 744.8 mg, is crystallized from a hot solution in ethyl acetate, 4 ml, and hexanes, 12 ml. The purified product after drying is 550 mg.
Characterization: Proton NMR: (CDC13 solution) downfield displacement in ppm in TMS, n ° H's, multiplicity: 0.90, 3H, doublet; 0.97, 3H, doublet; 2.37, ÍH, multiplet; 2.78-3.05, 5H, overlapping multiplets; 4.08, 1H, multiplet; 4.37, 1H, doublet of doublets; 6.24, ÍH, wide doublet; 6.97, ÍH, multiplet; 7.06, 2H, overlapping doublet of doublets; 7.15, 2H, doublet; 7.66, 1H, multiplet; 7.82, 1H, multiplet; 7.92, ÍH, doublet; 8.17, ÍH, doublet; 8.26, ÍH, doublet; 8.36, ÍH, doublet; 8.56, ÍH, wide doublet.
Note 1: Solid phase CCD conditions: silica in p / fluorescent indicator eluent: methanol in 10% chloroform (v / v) development agent: phosphomolybdic acid epoxide Rf = 0.68 acylated bromohydrin acetate Rf = 0.83
Example 4
This example demonstrates the alternative sequence using three discrete steps to prepare an urethane-protected α- (phenylmethyl) oxiranomethanamine from the aminodiol compound of the formula 4.
Preparation of [S- (R *, R *)] - (l-oxiranyl-2-phenylethyl) carbamic acid 1-dimethylethyl ester
Stage 1 :
Preparation of [S- (R *, R *)] - (4-phenyl-1,2-dihydroxybutan-3-yl) -carbamic acid 1-dimethylethyl ester
A 500 ml three-neck round-bottomed flask is equipped with a mechanical stirrer on the head part and two rubber partitions, one equipped with a K-type thermocouple probe and a syringe needle discharging to a supply of nitrogen through an oil bubbler. The flask is charged with S- (R *, R *) -3-amino-4-phenyl-1,2-butanediol, 20.0 grams (110.35 mmol), and purged with nitrogen. Toluene, 100 ml, is charged, and the resulting mixture is stirred. A separate 250 ml round bottom flask is charged with di-tert-butyl dicarbonate, 25.06 grams (111.37 mmol), and toluene, 50 ml. The resulting solution is added dropwise over ten minutes to the suspension of aminodiol in toluene. This is followed by the transfer of two rinses from the addition flask and the transfer tube with toluene, 25 ml. This is achieved through a cannula using nitrogen pressure. The internal temperature of the aminodiol suspension during the addition is 21 ° C. During the next hour and twenty minutes, the temperature gradually rises to 31 ° C and the gas comes off steadily. The mixture thickens and becomes non-agitable. Additional toluene, 50 ml is added, the stirring is ended and the mixture is allowed to stand for fourteen hours under ambient conditions. The stirring is resumed and the mixture is heated to 71 ° C to produce a clear solution. This is transferred to a 1000 ml round bottom flask, and the hot solution is concentrated at 70 ° C and at a pressure of 180 mm Hg until the distillation ceases. This produces a white solid that dries in vacuum for two additional hours. The final weight is 31.37 grams (101% of theory).
Stage 2:
Preparation of [S- (R *, R *) - (4-phenyl-1- (4-methyl-benzenesulfonyloxy) -2-hydroxybutane-3-yl) -carbamic acid 1-dimethylethyl ester
A 250 ml three-neck round bottom flask is equipped with a mechanical stirrer in the head area and two rubber partitions, one equipped with a K-type thermocouple probe and a syringe needle that discharges to a supply of nitrogen through an oil bubbler. The flask is charged with the product of step 1, 19.99 grams (71.05 mmol), and purged with nitrogen. Pyridine, 40 ml, is charged to the reaction vessel, stirring is started and the vessel is placed in a thermostated cooling bath at -8.5 ° C. The resulting slurry is diluted with 5 ml of additional pyridine to facilitate stirring. A separate 50 ml round bottom flask is charged with para-toluenesulfonyl chloride, 13.96 grams (73.24 mmol), and pyridine, 15 ml. The resulting solution is added dropwise over forty-five minutes to the suspension of the diol in pyridine. This is followed by the transfer of two rinses from the addition flask and the transfer line with 5 ml of pyridine. This is achieved through a cannula using a nitrogen pressure. It prevents the internal temperature of the reaction mixture during the addition from exceeding -5 ° C. After the last transfer has been completed, the reaction is maintained between -8 and -10 ° C for twenty-four hours. The CCD analysis at this point confirms that there is no diol remaining in the reaction mixture. Water, 40 ml, is added dropwise over thirty minutes keeping the internal temperature between -5 and -10 ° C. The stirring is continued at this temperature for another fifteen minutes and then toluene, 100 ml is added. The cold mixture is poured into a 500 ml separatory funnel containing 100 ml of toluene. The reaction flask is rinsed with another 20 ml of toluene into the funnel. The layers are separated and the aqueous layer is extracted twice with 100 ml portions of toluene. The combined toluene layers are kept cool (0 ° C) and extracted twice with 400 ml portions of cold 1.0 M aqueous phosphoric acid (5 ° C), once with 200 ml of water and once with 200 ml of water. sodium chloride solution, saturated. During the extractions, a solid begins to crystallize in the solution in toluene. The mixture is diluted with additional toluene, 1000 ml, and dichloromethane, 50 ml. The resulting is dried over anhydrous sodium sulfate and filtered. The collected solid is rinsed well with dichloromethane. The combined filtrate is concentrated under reduced pressure (water bath at 50 ° C) to give a residual white solid weighing 30.08 grams (97% of theory). The product is characterized by proton NMR and CCD which indicates that it is essentially pure and consistent with a previously prepared reference sample.
Stage 3:
Formation of the epoxide ring To a 250 ml round bottom flask, equipped with a magnetic stirring rod coated with Teflon and nitrogen inlet, 10.0 grams (23 mmol) of the toluenesulfonate ester product from stage 2, carbonate, are charged. of solid potassium, 3.2 grams (23 mmol), and 100 ml methanol. The resulting mixture is stirred at room temperature. After two hours, the CCD analysis of an aliquot of the reaction reveals the absence of toluene sulfonate ester. The reaction mixture is filtered in vacuo and the collected solid is rinsed with methanol. The combined filtrates are concentrated at 40 ° C and a pressure of 100 mm Hg. The solid residue is digested with boiling ethyl acetate for ten minutes and filtered hot. The collected solid is digested as before and filtered again hot. The combined filtrates are concentrated at 40 ° C and at a pressure of 100 mm Hg and the solid residue is dried at room temperature and at a pressure of 100 mm Hg for eighteen hours. The final product is a white solid weighing 5.28 grams (87% of theory). The product is characterized by proton NMR and CCD, which indicates that it is essentially pure and consistent with a previously prepared reference sample.
Example 5
This example illustrates the utility of a compound of formula A, [S- (R *, R *)] - (l-oxiranyl-2-phenylethyl) carbamic acid, 1, 1-dimethylethyl ester, to produce a protease inhibitor. HIV
Preparation of N-. { 1- (S) - [[[3- [2 (S) -. { [(1,1-dimethylethyl) -aminol] -carbonyl} -4 (R) - [4- (pyridinylmethyl) oxy] -1-piperidini1-2 (R) -hydroxy-1 (S) - (phenylmethyl) propyl] amino] -carbonyl] -2-rnethylpropyl) -2-quinolinecarboxamide .
Stage 1 :
Epoxide coupling with an amine fragment.
A solution of water in isopropanol (10%, v / v) (1.5 1) is heated at reflux for 2.5 hours under an argon atmosphere and then cooled to room temperature. [S- (R *, R *)] - (1-oxyranyl-2-phenylethyl) carbamic acid ester 1, 1-dimethylethyl ester (271.1 g) is added and
2 (S) -. { [(1,1-dimethylethyl) amino] carbonyl} -4 (R) - [4- (pyridinylmethyl) oxy] piperidine (301 g) under the exclusion of air and the mixture is stirred for 96 hours under a positive argon pressure. The solvents are removed under reduced pressure at 32 ° C. The residue is redissolved in ethyl acetate (1.84 1) and cooled in an ice-water bath. The organic solution is extracted with KH2P041N (3 x 1012 1), followed by the addition of 2.5 N HCl (1150 ml) and 10% HCl (598 ml), keeping the internal temperature below 20 ° C. The organic phase is separated, and the aqueous phase is extracted with ethyl acetate (3 x 460 ml). Concentrated HCl (368 ml) is added, giving a final temperature of 21.1 ° C and a pH of 0. The resulting mixture is allowed to warm to room temperature and is stirred overnight under a positive nitrogen pressure. The reaction mixture is cooled in a dry ice-acetone bath and solid sodium hydroxide granules (258 g) are added, followed by 40% sodium hydroxide (570 ml), keeping the internal temperature below 21 °. C. The final pH is 11-12. The product is extracted into ethyl acetate (1 x 1 L, 1 x 1.5 L) and the combined organic solution is extracted with saturated brine (1 L). The resulting organic solution is dried over anhydrous magnesium sulfate (138.09 g) and filtered through silica gel (350 g). The filter cake is further washed with ethyl acetate (3.5 1) and concentrated to dryness under reduced pressure at 40 ° C. The solids are dried in vacuo additionally, giving 150.27 g of product. The filter cake is resuspended in ethyl acetate (3 L) and stirred for one hour. Then the mixture is filtered. The filter cake was washed with ethyl acetate (300 ml) and resuspended again in 20% methanol in ethyl acetate (3 L) with stirring. The mixture is then filtered. The filter cake is washed with ethyl acetate (300 ml). The filtrate is concentrated to dryness under reduced pressure at 40 ° C and further dried under vacuum to give an additional 78.15 g of product. The acidic ethyl acetate extracts are concentrated under reduced pressure and the residue is charged to the reaction flask. The flask is cooled in an ice-water bath. Concentrated HCl (184 ml) is charged, keeping the internal temperature below 20 ° C. The mixture is allowed to warm to room temperature and is stirred overnight under a positive nitrogen pressure. The reaction mixture is cooled in a dry-acetone ice bath and granules of sodium hydroxide (129 g) are added, followed by 40% sodium hydroxide (253 ml) until the pH reaches 12-13. During this time, the internal temperature remains below 20 ° C. The product is extracted into ethyl acetate (1 x 750 ml, 1 x 500 ml). The combined organic solution is extracted with saturated brine (500 ml) and then dried over anhydrous magnesium sulfate (70.66 g). This mixture is filtered through silica gel (177.07 g). The filter cake is washed with 20% methanol in ethyl acetate (2 L). The combined filtrates are concentrated to dryness at 40 ° C under reduced pressure, followed by an additional vacuum drying. This gives a recovered weight of 134.63 grams. The material is dissolved in a mixture of ethyl acetate and methanol 2/1 (300 ml) and filtered through a column of silica gel (500 g) eluting with 70% isopropanol in ethyl acetate. The effluent fractions are combined and concentrated under reduced pressure at 40 ° C. Additional drying under vacuum provides an additional 87.40 g of product. The total weight of the product recovered is 315.82 grams. An additional longer reaction produces another 600.27 grams of product. The two batches are combined for the next stage.
Stage 2:
Additional purification of the previous coupling product
The above pooled product, 916.09 g, is transferred to a 7-L rotary evaporation flask using THF (2548 g). The resulting suspension is concentrated by distillation using the rotary evaporator. The almost dry residue is redissolved in a mixture of deionized water (400 ml) and dichloromethane (5.6 1). This new mixture is concentrated in the same manner until all dichloromethane and THF have been distilled off. The residue, after concentration, is transferred to the reaction vessel using dichloromethane (4.4 1) and deionized water (1.5 1). Agitation starts. The temperature of the reactor content is 20 ° C. The pH of the aqueous phase is adjusted to about 12-12.5 by adding 5N sodium hydroxide solution (175 ml). This addition takes place over an hour. During this time, the content of the reactor is maintained in the temperature range of 18-21 ° C using an ice / water bath. The aqueous layer is separated and the organic layer is extracted with deionized water (2 x 1 L). The combined aqueous fractions are extracted with dichloromethane (2 x 1 L). The combined dichloromethane fractions are stirred with magnesium sulfate (501.83 g). The solid is collected by filtration and rinsed with dichloromethane (1 L). The combined filtrate (transfer rinse with dichloromethane, 600 ml) is concentrated using the rotary evaporator. The residue is dissolved in THF (2 L) and concentrated as before until about one liter of distillate has been collected. The final weight of the isolated purified product is 787.54 grams.
Stage 3:
Coupling mediated by mixed anhydrides of the amine of stage 2 and N- (2-quinolinecarbonyl) -S-valine
The reaction vessel is purged and maintained under a small positive nitrogen pressure. It is then charged with N- (2-quinolinecarbonyl) -S-valine, 211.25 g, and THF, 1.3 L. The solution resulting from the previous step is cooled by means of a dry ice / acetone bath. The charge of 4-methylmorpholine (142.76 g) begins when the internal temperature of the reactor is -4 ° C. The charge of isobutyl chloroformate (105.76 g) from a 125 ml dropping funnel begins when the reaction temperature reaches -41 ° C. The addition is completed in seven minutes. The temperature is maintained during this period. A solution is prepared by dissolving the amine from step 2 (320.15 g) in THF (650 ml). The charge of this solution to the reactor begins thirty-three minutes from the completion of the previous addition. The vessel and the transfer duct are rinsed with additional THF (50 ml). This operation is completed in thirty-five minutes. The temperature during this time is maintained between -40 ° C and -44 ° C. The stirring reaction mixture is maintained in the above temperature range for an additional thirty minutes. Next, the cooling bath is removed and the reaction temperature is allowed to rise. This has reached 21 ° C in five hours thirty minutes. The progress of the reaction is monitored by CCD analysis of reaction samples (see note 1). The reaction mixture is quenched by the addition of water (500 ml) for six hours, seven minutes from the beginning of the period of heating. The reaction mixture is concentrated by distillation under reduced pressure using the rotary evaporator (bath temperature, 40 ° C, pressure, 60 mm Hg). The removal of THF is completed in one hour. The residual reaction mass is transferred back to the reaction vessel using ethyl acetate (2 1). The solution is extracted with deionized water (2 x 1 L). The organic solution is now extracted three times with 3 N sodium hydroxide solution (2 x 650 mL, 1 x 700 mL), which is completed in fifty-five minutes, during which time an ice cooling bath is used. / water to control the internal temperature between 20 and 33 ° C. The organic solution is now extracted with deionized water (2 x 1 L.) This is completed in one hour twenty minutes The crude product is now extracted in water by slowly adding a 9.5% hydrochloric acid solution to the organic phase (1 L.) This addition is exothermic and requires cooling to maintain the temperature between 15 and 18 ° C. The aqueous extract is separated, and the organic phase is extracted again with 9.5% hydrochloric acid (400 ml). The organic phase is now separated and the hydrochloric acid extracts are combined in the reactor. This operation is completed in one hour and five minutes. The combined solution of the product in hydrochloric acid is extracted with ethyl acetate (3 x 300 ml). The aqueous solution is cooled to 2.6 ° C. Then, the pH is adjusted between 7-8 by adding 10 N sodium hydroxide (425 ml). Ethyl acetate (900 ml) is added to dissolve an oil solid that separates. The pH of the aqueous phase is further adjusted to 11 using 10 N sodium hydroxide solution (150 ml).
The organic phase is separated and the remaining aqueous phase is extracted twice with ethyl acetate (400 ml, 200 ml). All the fractions in ethyl acetate are combined and extracted three times with saturated sodium chloride solution (1 x 2 L, 2 x 600 mL). The organic phase is now stirred with approximately equal parts (w / w / w) of silica gel (49.63 g), carbon (50.28 g) and anhydrous magnesium sulfate.
(50.94 g). The suspension is filtered and the collected solid is rinsed with ethyl acetate (200 ml). The combined filtrate is concentrated by distillation using the rotary evaporator
(bath temperature, 45 ° C, pressure 60 mm Hg). The residue is dissolved in methanol (2 L) and concentrated as before. This provides 459.7 grams of raw product.
Note 1: CCD conditions to monitor the progress of the reaction are as follows. Solid phase: silica gel 60 with fluorescent indicator; mobile phase: of dichloromethane-methanol 9: 1 (v / v) containing a trace amount of ammonium hydroxide; Approximate Rf assignments: amine, 0.36; product (in the form of a dihydrochloride salt), 0.40.
Step 4 Preparation of the final product dihydrochloride salt
The reaction vessel is purged and maintained under a small positive nitrogen pressure. The crude product from step 3 (459.7 g) is transferred to the reaction vessel in the form of a methanol solution (510 ml). The weight contained on a dry basis is 436.4 g (the rest of the weight of the load is methanol). Stirring is started and 4 N HCl in dioxane solution (603 ml) is added over a period of one hour. During this time, the content of the reactor is maintained between 15 ° C and 19 ° C by means of an ice / water bath. Immediately after the addition of HCl, the reactor is charged with iso-propanol (304 ml) and additional methanol (145 ml). The mixture is heated to reflux (72 ° C) for one hour and refluxed for an additional forty-five minutes. Heating and stirring are then interrupted by allowing the solution to cool slowly. After twelve hours, the internal temperature is 21 ° 0 .. The agitation is resumed to disintegrate the solid mass and accelerate the cooling. This continues for four hours thirty, inutes. The temperature is 23 ° C.
The batch is filtered and the filter cake is rinsed with 50% (v / v) isopropanol / acetone (2 x 400 ml) and acetone (2 x 300 ml). The wet solid is transferred to a glass plate and dried at 23 ° C under a vacuum of 30 mm Hg for 23 hours. The final weight is 279.01 grams. The above process is carried out on a larger scale giving an additional 724.3 grams of the dihydrochloride salt of the crude product. The material from the two operations is pooled for final purification by recrystallization as follows: The reaction vessel is purged and maintained under a small positive nitrogen pressure. Raw dihydrochloride salt (1,003 kg) is transferred to the reaction vessel together with isopropanol / acetone 1: 2
(v / v) (6 L). The stirring is started and the mixture is heated to 60 ° C over one hour and forty minutes. This temperature is maintained during the slow addition of 50% (v / v) isopropanol / water (528 ml). The addition is completed in one hour and thirty minutes (the amount is just enough to dissolve all solids at this temperature). Fifteen minutes after completion of the addition, heating is stopped and the solution allowed to cool slowly with continuous stirring. After sixteen hours, the internal temperature is 22 ° C. An ice / water bath is used to cool the container. One hour later, the temperature is 10 ° C. The batch is filtered and the filter cake is rinsed with isopropanol / acetone 1: 2 (v / v) (2 x 1.5 L) and with acetone (2 x 1 L). The wet solid is charged to the rotary evaporator flask and suspended in isopropanol (3 1). The suspension is concentrated until near dryness and subjected to high vacuum for thirty minutes. The final weight is 973.25 grams. A dried sample of this material states that the dry weight (100% based on solids) is 853.65 grams. The reaction vessel is purged and maintained under a small positive nitrogen pressure. The recrystallized salt (973.25 g) is transferred to the reaction vessel together with isopropanol / acetone 1: 2 (v / v) (5.1 L).
The stirring is started and the mixture is heated to 60 ° C over one hour and forty minutes. This temperature is maintained during the slow addition of 50% (v / v) isopropanol / water (353 ml). The addition is completed in one hour and thirty minutes (the amount is just enough to dissolve all solids at this temperature).
Fifteen minutes after completion of the addition, heating is stopped and the solution allowed to cool slowly with continuous stirring. After sixteen hours, the internal temperature is 22 ° C. An ice / water bath is used to cool the container. One hour later, the temperature is 10 ° C. The batch is filtered and the filter cake is rinsed with isopropanol / acetone 1: 2 (v / v) (2 x 1.2 L) and with acetone (2 x 900 ml). The wet solid is transferred to a glass plate and dried at 23 ° C under a vacuum of 29-30 mm Hg for 24 hours. After weight verification, drying is resumed at a vacuum of 29.5 mm Hg for twenty-four hours at 35 ° C and an additional cooling for seventeen hours up to 23 ° C. The final weight is 807.1 grams. The purity of this product, determined by HPLC, is 99.6%. Salt becomes the free base. The base is characterized by satisfactory combustion analysis, mass spectrum (chemical ionization) and NMR (600 MHz of protons and 150 MHz of carbon). The NMR data correlate with a reference sample of confirmed structure established by X-ray crystallographic analysis of the dihydrochloride salt.
Example 6
Preparation of S- (R *, R *) -3-amino-4-phenyl-1,2-butanediol ("aminodiol")
Stage 1 :
Aminolysis of 2R-trans-3-phenylmethyl-2-oxiranomethanol ("epoxy alcohol") with aminodiphenylmethane
In a dry 5 liter three-neck round bottom flask equipped with a mechanical stirrer in the head area and a K-type thermocouple, 897 ml of dry toluene is charged. After purging with nitrogen, the solvent is heated to 50 ° C and stirring is started at 200 rpm. To the stirred toluene at 50 ° C, 525.60 grams (1849 moles) of freshly distilled titanium (IV) isopropoxide are added in one portion, followed by the addition of 272.08 grams (1485 moles) of aminodiphenylmethane over 20 minutes. The stirring solution is heated to 68 ° C and equilibrated at this temperature for 30 minutes. To the stirring solution of titanium (IV) isopropoxide / Ph2CHNH2 in toluene at 68 ° C is added, over 30 minutes, a solution of the epoxy alcohol, 230 grams (1,401 moles), in 1077 ml of dry toluene, maintaining the (internal) temperature of the reaction at 68 ° C (mild exotherm, cooling with air). Twenty-five minutes after the addition is complete, the evolution of heat is quenched and the reaction heated gently to maintain the temperature of 68 ° C for an additional 20 minutes. Samples of the reaction are taken for a CCD completion verification (note 1). When complete (no epoxy alcohol is left), the reaction mixture is cooled to 17 ° C using an ice / water bath, and 888.5 ml of 10% NaOH in saturated NaCl solution is added over 25 minutes , keeping the temperature (internal) below 24 ° C. The reaction mixture becomes viscous and is allowed to stir overnight. The reaction mixture, now mobile, is allowed to stand. The separated (upper) organic phase is separated by transfer. The aqueous phase is extracted with 1,000 ml of toluene and the extract is separated by transfer. The aqueous phase is stirred with an additional 1,000 ml of toluene and to this is added 100 grams of Celite 545. After stirring for 20 minutes, the emulsion is filtered. The clear filtrate is separated and the upper organic phase is combined with the previous extracts. The organic extracts were dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to dryness at 60 ° C, a pressure of 50 mm Hg, providing an orange oil that weighed 490.15 grams. This material is a mixture of two isomers, the desired "diphenylmethylaminodiol C-3" and "diphenylmetilaminodiol C-2". The mixture is used without further purification. The oil is tested by proton NMR using trichlorethylene as the internal standard. The yield and the ratio of isomers is determined by integration of benzhydrylmethrin resonances close to 5.0 ppm versus the resonance of trichlorethylene at 6.5 ppm. The assignment for methine resonances is based on the purification and characterization of each isomer for reference purposes. Performance of DPM-aminodiol C-3: 60.14% Performance of DPM-aminodiol C-2: 14.82% Relationship C-3 / C-2 = 4.1: 1 Characterization of the product mixture: proton NMR (solution CDC13): assignment of the chemical shift (in ppm downfield in TMS) 4.9 ppm of the C-3 isomer of methine 5.0 ppm of the C-2 isomer of methine 5.2 ppm of diphenylmethylamine-methine EMIQ (methane): expected molecular ion = 347; found MH + = 348
Stage 2:
Hydrogenolysis of the diphenylmethylamindiol mixture
A 2,000 ml stainless steel Parr reactor
(model 4522) is loaded with 95.68 grams of 10% palladium on carbon (50% moisture with water). The vessel is purged with nitrogen while 488.89 grams of the crude diphenylmethylaminodiol mixture prepared in step 1 is charged as a solution in 500 ml of methanol. An additional 200 ml of methanol is charged, and the vessel is assembled and purged again with nitrogen. After checking the pressure at 5.6 kg / cm2 (80 psi) for 1 hour, hydrogen is introduced and the content is hydrogenated at 4.2 kg / cm2 (60 psi), not allowing the internal temperature to rise above of 35 ° C. The hydrogenation conditions were maintained overnight (16 hours). A reaction sample is taken for a verification of the CCD termination (note 1). When complete (none of the diphenyl methylaminodiols is detectable), the reactor is discharged, purged with nitrogen and the contents filtered. The catalyst cake is washed with 600 ml of methanol and the combined almost colorless filtrate is concentrated at 55 ° C and a pressure of 50 m Hg. This provides a suspension of a white solid in oil weighing 456.35 grams. This suspension is concentrated twice from 500 ml of dry toluene to give 479.17 grams of white solid in oil. This mass is allowed to cool to room temperature and an additional 200 ml of toluene are added. The suspension is stirred, filtered and air dried. The white crystalline solid product is washed twice with 200 ml of toluene and dried again in air. Finally, the product is washed twice with 200 ml portions of hexanes and dried at room temperature and at a pressure of 50 mm Hg overnight. The final weight is 124.87 grams. Theoretical yield of the C3 isomer = 153.36 grams Actual dry weight of the C3 isomer = 124.87 grams Yield = 81.4% A sample of this product is converted to the t-butyl carbamate derivative for the analysis by chiral (High Resolution Liquid Chromatography) CLAR . Characterization: Proton NMR: (DMSO d6 / D20 solution) ppm of downfield displacement in TMS, n ° H's multiplicity: 2.40, ÍH, multiplet; 2.89, 2H, 3.31, ÍH, multiplet; 3.50, 2H, multiplet; 7.26, 5H, mutiplete carbon NMR: (DMSO d6) DMSO resonance a
39. 499 ppm: 39,396, 55,585, 63,921, 74,348, 125,761, 128,153, 129,393, 140,250.
EMIQ (methane): expected molecular ion = 181; found MH + = 182 IR (KBr granule) cm "1: 3344, 3305, 3283, 3086, 2918, 2712, 1608, 1492, 1376, 1097, 1079, 1058, 751, 700
Melting range: 109-111 ° C (uncorrected)
Analysis of combustion (% calculated,% found): C 66.27, 66.69 H 8.34, 8.45 N 7.73, 7.83
Specific rotation ([a] D25): -34.68 ° (c = 2.01, methanol) chiral CLAR: analysis of the t-butyl carbamate derivative column: Chiralcel OD, 25 cm x 4.6 mm mobile phase: hexane-ethanol (98: 2) flow rate: 1.0 ml / min. Temperature: 40 ° C
detector: UV at 254 nm 0.1 aufs tE k 'R T racemate 28.77 6.36 1.084 2.16 32.05 7.20 1.79 product 28.78 no peak detected at 32.05 min. tr = retention time in minutes; k '= capacity factor; R = resolution; T = tail factor.
Note 1: CCD conditions solid phase: silica for fluorescent indicator eluent: 25% (v / v) acetone in hexanes development agent: iodine or phosphomolybdic acid DPM-aminodiol C-3 Rf = 0.24 DPM-aminodiol C-2 Rf = 0.34
epoxy alcohol Rf = 0.34
aminodiphenylmethane Rf = 0.47 aminodiol (product) Rf = immobile (the two components at Rf 0.34 are distinguished by the intensity of development with iodine and phosphomolybdic acid).
Example 7
This example demonstrates the utility of benzylamine in the total conversion of the compound of formula 5 to the compound of formula 4.
Preparation of S- (R *, R *) -3-amino-4-phenyl-1,2-butanediol ("aminodiol")
In a dry 25 ml three-neck round bottom flask equipped with a Teflon-coated magnetic stirrer and a K-type thermocouple, 5 ml of dry toluene is charged. After purging with nitrogen, stirring is started and the solvent is heated to and maintained at 55 ° C using an electrical enclosure and a PID controller. To the stirred toluene at 55 ° C, 0.718 grams are added
(6.7 mmol) of benzylamine by syringe, followed by distilled titanium (IV) isopropoxide, 2.21 grams (7.78 mmol) After 15 minutes, a dry solution of the epoxy alcohol, 1,003 grams (6.11 mmol), is added in 3 ml. of toluene for 2 minutes from a separate flask through a cannula using a nitrogen pressure. The (internal) temperature of the reaction is maintained between 55-60 ° C during the addition. A total of 1 ml of dry toluene is used in two equal portions to rinse the addition flask and transfer conduit into the reaction vessel. After 8 hours at 55 ° C, the mixture is cooled for twenty minutes to 26 ° C and quenched by adding 3.8 ml of 10% sodium hydroxide solution saturated with sodium chloride. What results is stirred overnight. The separated organic phase (upper) is separated by transfer from the reaction vessel and the semi-solid residue is extracted three times with 10 ml portions of toluene. The combined extracts are shaken with one gram of Celite 545, and the suspension is filtered on a pad of additional Celite 545 (0.5 grams). The clear filtrate is concentrated under reduced pressure giving a residue weighing 1.58 grams. This product is used without further purification in the hydrogenation step. The above crude product, 1.34 grams, is transferred quantitatively to a 50 ml Hastalloy autoclave using 7 ml of methanol. The catalyst, palladium at 20% on carbon (50% moisture with water), 121.87 mg is charged to the autoclave which is then hermetically sealed. The vessel is purged first with nitrogen and then with hydrogen. The pressure is adjusted to 4.2 kg / cm2 (60 psi) and stirring is started (1474 rpm). The hydrogenation is allowed to proceed for 64 hours at room temperature. Agitation is terminated and, after an additional 5.5 hours with the container isolated from the hydrogen supply, no pressure drop is observed. The vessel is discharged, purged with nitrogen and the contents are separated and filtered on a pad of Celite 545. The filtrate is concentrated under reduced pressure, and the residue is redissolved and concentrated from toluene twice. This results in a white solid which is re-suspended in toluene, collected by filtration, rinsed with toluene and then with hexane and dried. The final solid weighs 395.6 mg which represents an overall yield of 42% from the epoxy alcohol. The melting point and the proton NMR characterization confirm that the solid is the intended product.
It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property
Claims (22)
1. A process for forming an epoxy compound of the formula: wherein X is: hydrogen, a straight or branched chain alkyl group containing from 1 to 8 carbon atoms, cycloalkyl containing from 3 to 8 carbon atoms, cycloalkylalkyl, arylalkyl, aryl, wherein aryl is phenyl, naphthyl or a 5-6 element heterocyclic ring containing one or two heteroatoms selected from N, O and S, and said aryl group is optionally substituted with one or more alkyl, halogen, amino or hydroxy groups, an aryl-heteroatom-alkyl group in which the heteroatom is nitrogen, oxygen or sulfur; Y and Z are both hydrogen and can independently have a stereochemical orientation, which results in the (R) or (S) configuration in the carbon atoms to which they are attached; and R3 is a lower alkoxy group containing 1 to 8 carbon atoms which can form a straight or branched chain, part of a ring or a combination thereof; an alkenyl ethoxy group; an arylalkoxy group, wherein the aryl portion is optionally substituted with halogen atoms, lower alkoxy or lower alkyl groups of one to five carbon atoms or combinations thereof, and the alkyl portion of the arylalkoxy group has 1 to 5 carbon atoms. carbon; an aryloxyalkyl group, wherein the aryl portion is optionally substituted with halogen atoms, lower alkoxy or lower alkyl groups of one to five carbon atoms or combinations thereof, and the alkyl portion contains 1 to 5 carbon atoms; aryl optionally substituted with heteroatoms, wherein the heteroatom is nitrogen, oxygen or sulfur, alkyl groups, haloalkyl and halogen groups, amino or hydroxy groups; acylated alpha-aminoalkyl, wherein the alkyl group is defined by those found in amino acids occurring in nature and the acyl group is derived from a carboxylic acid or a carbonic acid ester; the process is characterized in that it comprises: activating an aminodiol of the formula Formula 1 where X, Y and Z are as defined above; acylating the activated aminodiol to form the activated precursors of formula A; and reacting said activated precursors of formula A with a base to form a compound of formula A.
2. A process according to claim 1, characterized in that X is arylalkyl, wherein the aryl group is phenyl or naphthyl which may be substituted with one or more alkyl groups, halogens, haloalkyl, amino or hydroxy groups; cycloalkylalkyl groups of 3 to 8 carbon atoms and an aryl-heteroatom-alkyl group, wherein the heteroatom is one or more of N, S or 0.
3. A method according to claim 1, wherein X is CHj- (CH3) 2CH- CH3CH2CH (CH3)
4. A method according to claim 1, characterized in that R3C (0) is:
5. A process according to claim 1, characterized in that the epoxy compound is selected from the group consisting of: [1 - 1-dimethylethyl acid ester [S- (R *, R *)] - (1-oxiranyl-2-phenylethyl) ) carbamic, phenylmethyl ester of [S- (R *, R *)] - (1-oxiranyl-2-phenylethyl) carbamic acid, 1,1-dimethylethyl acid ester [R- (R *, S *)] - (1-oxiranyl-2-phenylethyl) carbamic acid, and [R- (R *, S *)] - (1-oxiranyl-2-phenylethyl) carbamic acid phenylmethyl ester.
6. A process according to claim 1, characterized in that the epoxy compound is selected from the group consisting of: [1 - 1-dimethylethyl] -s- (R *, S *)] - (1-oxiranyl-2-phenylthioethyl) ester ) carbamic, phenylmethyl ester of [S- (R *, S *)] - (1-oxiranyl-2-phenylthioethyl) carbamic acid, tetrahydro-3-furanyl ester of [3S- [3R * (IR *, 2R * )]] - (l-oxiranyl-2-phenylethyl) carbamic, and tetrahydro- [2- [(1-methyl) ethyl] -3-thienyl acid ester [2R- [2R *, 3R * (IS *, 2S *)]] - (l-oxiranyl-2-phenylethyl) -carbamic, S, S-dioxide.
7. A process according to claim 1, characterized in that the epoxy compound is selected from the group consisting of: [S- (R *, R *)] - (l-oxiranyl-2-phenylethyl) amide of N- (quinoline- 2-yl-carbonyl) -L-valine, and S- (R *, R *) - (l-oxiranyl-2-phenylethyl) amide of N2- (quinolin-2-yl-carbonyl) -L-asparagine, N - (S- (R *, S *)] - (l-oxiranyl-2-phenylthioethyl)] - 3-hydroxy-2-methylbenzamide.
8. A process according to claim 1, characterized in that the activation step comprises reacting the aminodiol with hydrobromic acid and a carboxylic acid selected from the group consisting of formic acid, acetic acid and propionic acid.
9. A process according to claim 5, characterized in that the carboxylic acid is acetic acid.
10. A process according to claim 1, characterized in that the acylation step comprises mixing the activated aminodiol with a solvent and an acylating agent.
11. A process according to claim 10, characterized in that the acylating agent is an acyl halide, an ester of dicarbonic acid or an intermediate compound generated from N-protected amino acids.
12. A process according to claim 10, characterized in that the solvent is methanol, toluene, dichloromethane, tetrahydrofuran, dimethylformamide, acetonitrile or water.
13. A process for forming an epoxide according to claim 1, characterized in that it comprises acylating the aminodiol to form a urethane before the activation step.
14. A process according to claim 13, characterized in that the activation step comprises reacting the urethane with para-toluenesulfonyl chloride to form a sulfonate ester.
15. A process according to claim 14, characterized in that the epoxy compound is selected from the group consisting of: [S- (R, R)] - (1-oxiranyl-2-f-nilethyl) 1,1-dimethylethyl ester) Carbamic acid phenylmethyl ester [S- (R *, R *)] - (1-oxiranyl-2-phenylethyl) carbamic acid ester 1, 1-dimethylethyl [R- (R *, S *)] - ( 1-oxiranyl-2-phenylethyl) carbene, phenylmethyl ester of [R- (R *, S *)] - (1-oxiranyl-2-phenylethyl) carbamic acid, 1,1-dimethylethyl ester of [S- (R *, S *)] - (1-oxiranyl-2-phenylthioethyl) carbamic, phenylmethyl ester of [S- (R *, S *)] - (1-oxiranyl-2-phenylthioethyl)] carbamic acid, ester 'tetrahydro- 3-furanyl acid [3S- [3R * (IR *, 2R *)]] - (1-oxiranyl-2-phenylethyl) carbamic acid, and tetrahydro- [2- [(1-methyl) ethyl] -3- ester acid thienyl [2R- [2R *, 3R * (ÍS *, 2S *)]] - (1-oxiranyl-2-phenylethyl) -carbamic acid, S, S-dioxide.
16. A process according to claim 1, characterized in that the epoxide is formed in situ by reacting its activated precursor with a mixture of a base and a fragment to form an aspartyl-protease inhibitor * or an advanced intermediate compound thereof.
17. A process according to claim 1, characterized in that the aminodiol is a compound of the formula OH or his enantió form was.
18. A process according to claim 16, characterized in that the aminodiol is prepared by reacting a glycidol compound of the formula: or their enantiomeric form, respectively, with an amine of the formula: R? R2NH, wherein Ri and R2 are independently selected from the group consisting of hydrogen, arylalkyl or di- (aryl) alkyl in the presence of a catalyst, to obtain a mixture of compounds of the? ü following structures: 10 wherein Ri and R2 are as defined hereinbefore; hydrogenating the mixture of formulas I and II; and crystallizing the hydrogenated mixture to obtain the aminodiol essentially free of its enantiomer and the hydrogenated derivative of the formula II.
19. A process according to claim 18, characterized in that Ri is hydrogen and R2 is diphenylmethyl.
20. A process according to claim 18, characterized in that Ri is hydrogen and R2 is benzyl.
21. A procedure in accordance with. the 25 claim 18, characterized in that the catalyst is a titanium (IV) catalyst
22. A compound of the formula: OH
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US016867 | 1996-05-07 | ||
US016857 | 1996-05-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA98008916A true MXPA98008916A (en) | 1999-04-27 |
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