ITMI20071722A1 - PROCEDURE FOR THE PREPARATION OF ACID (S) (+) - 3- (AMINOMETHYL) -5-METHYLESANOIC - Google Patents
PROCEDURE FOR THE PREPARATION OF ACID (S) (+) - 3- (AMINOMETHYL) -5-METHYLESANOIC Download PDFInfo
- Publication number
- ITMI20071722A1 ITMI20071722A1 ITMI20071722A ITMI20071722A1 IT MI20071722 A1 ITMI20071722 A1 IT MI20071722A1 IT MI20071722 A ITMI20071722 A IT MI20071722A IT MI20071722 A1 ITMI20071722 A1 IT MI20071722A1
- Authority
- IT
- Italy
- Prior art keywords
- methyl
- formula
- carbamate
- salt
- compound
- Prior art date
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- -1 AMINOMETHYL Chemical class 0.000 title claims description 48
- 238000000034 method Methods 0.000 title claims description 33
- 239000002253 acid Substances 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title claims description 9
- 150000003839 salts Chemical class 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 47
- 239000002904 solvent Substances 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 239000012948 isocyanate Substances 0.000 claims description 7
- 150000002513 isocyanates Chemical class 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 230000008707 rearrangement Effects 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- UATSLDZQNXAKMA-UHFFFAOYSA-N 3-(2-methylpropyl)pentanedioic acid Chemical compound CC(C)CC(CC(O)=O)CC(O)=O UATSLDZQNXAKMA-UHFFFAOYSA-N 0.000 claims description 3
- UUWMCUBVFZVIHO-UHFFFAOYSA-N 3-[(methoxycarbonylamino)methyl]-5-methylhexanoic acid Chemical compound COC(=O)NCC(CC(C)C)CC(O)=O UUWMCUBVFZVIHO-UHFFFAOYSA-N 0.000 claims description 3
- ALSNTDXXJVBREI-UHFFFAOYSA-N 5-methyl-3-(2-oxo-2-propoxyethyl)hexanoic acid Chemical compound CCCOC(=O)CC(CC(C)C)CC(O)=O ALSNTDXXJVBREI-UHFFFAOYSA-N 0.000 claims description 3
- BCHVTAOVSUTNTH-UHFFFAOYSA-N 5-methyl-3-[2-(2-methylpropoxy)-2-oxoethyl]hexanoic acid Chemical compound CC(C)COC(=O)CC(CC(C)C)CC(O)=O BCHVTAOVSUTNTH-UHFFFAOYSA-N 0.000 claims description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 238000001640 fractional crystallisation Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- CIPKRPBULZORRK-UHFFFAOYSA-N 3-[(ethoxycarbonylamino)methyl]-5-methylhexanoic acid Chemical compound CCOC(=O)NCC(CC(C)C)CC(O)=O CIPKRPBULZORRK-UHFFFAOYSA-N 0.000 claims description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 2
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 claims description 2
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229960000948 quinine Drugs 0.000 claims description 2
- 150000003509 tertiary alcohols Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 101150041968 CDC13 gene Proteins 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229960004592 isopropanol Drugs 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- NRXIYKWMCOQUTK-UHFFFAOYSA-N 3-(2-methoxy-2-oxoethyl)-5-methylhexanoic acid Chemical compound COC(=O)CC(CC(C)C)CC(O)=O NRXIYKWMCOQUTK-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000006085 Schmidt reaction Methods 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229950011008 tetrachloroethylene Drugs 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- AYXYPKUFHZROOJ-UHFFFAOYSA-N 3-(azaniumylmethyl)-5-methylhexanoate Chemical compound CC(C)CC(CN)CC(O)=O AYXYPKUFHZROOJ-UHFFFAOYSA-N 0.000 description 1
- XLSGYCWYKZCYCK-UHFFFAOYSA-N 4-(2-methylpropyl)oxane-2,6-dione Chemical compound CC(C)CC1CC(=O)OC(=O)C1 XLSGYCWYKZCYCK-UHFFFAOYSA-N 0.000 description 1
- PHIRKRGTQXYWOT-UHFFFAOYSA-N 5-methyl-3-(2-octoxy-2-oxoethyl)hexanoic acid Chemical compound CCCCCCCCOC(=O)CC(CC(C)C)CC(O)=O PHIRKRGTQXYWOT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- KAPVFJRZKDNPRE-PRCZDLBKSA-N C[C@H]1NC(O[C@H]1C1=CC=CC=C1)=O.O1[C-]=NC(C1)=O Chemical compound C[C@H]1NC(O[C@H]1C1=CC=CC=C1)=O.O1[C-]=NC(C1)=O KAPVFJRZKDNPRE-PRCZDLBKSA-N 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 238000006105 Hofmann reaction Methods 0.000 description 1
- 238000007167 Hofmann rearrangement reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000006644 Lossen rearrangement reaction Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- RRUDCFGSUDOHDG-UHFFFAOYSA-N acetohydroxamic acid Chemical compound CC(O)=NO RRUDCFGSUDOHDG-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- XMEORSGHQPZTCP-UHFFFAOYSA-N dichloromethane;1,1,1-trichloroethane Chemical compound ClCCl.CC(Cl)(Cl)Cl XMEORSGHQPZTCP-UHFFFAOYSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical class [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
“PROCEDIMENTO PER LA PREPARAZIONE DI ACIDO (S)(+)-3-(AMMINOMETIL)-5-METILESANOICO” "PROCEDURE FOR THE PREPARATION OF (S) (+) - 3- (AMMINOMETHYL) -5-METHYLESANOIC ACID"
CAMPO DELL’INVENZIONE FIELD OF THE INVENTION
La presente invenzione riguarda un nuovo procedimento per la preparazione di pregabalina, o acido (S)(+)-3-(amminometil)-5-metilesanoico, di formula (I) The present invention relates to a new process for the preparation of pregabaline, or (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid, of formula (I)
STATO DELLA TECNICA STATE OF THE TECHNIQUE
La pregabalina è nota da US 6,197,819 ed è impiegata nel trattamento del dolore neuropatico periferico, dell’epilessia e dei disturbi d’ansia generalizzata. US 5,637,767 ne descrive la preparazione per risoluzione del racemo dell’acido 3-amminometil-5-metilesanoico per formazione di sali diastereomerici con acidi o basi omochirali, separazione della coppia di diastereoisomeri per cristallizzazione frazionata o per cromatografia, seguita da idrolisi del sale. US 6,359,169 ne descrive la preparazione attraverso una reazione enantioselettiva, utilizzando un ausiliario chirale, ad esempio l’ossazolidone di Evans (4R,5S )-4-metil-5-fenil-2-ossazolidinone, che premette di effettuare una alchilazione asimmetrica per introdurre lo stereocentro desiderato. Dopo l' alchilazione asimmetrica, normalmente condotta a temperature criogeniche, è necessaria la rimozione dell’ ausiliario chirale, relativamente costoso, con un conseguente ulteriore aggravio dei costi e dei tempi di produzione. US 2005/0283023 riporta la preparazione di pregabalina mediante una risoluzione cinetica enzimatica di un ciano-diestere secondo il seguente schema Pregabaline is known from US 6,197,819 and is used in the treatment of peripheral neuropathic pain, epilepsy and generalized anxiety disorders. US 5,637,767 describes its preparation by resolution of the 3-aminomethyl-5-methylhexanoic acid raceme for the formation of diastereomeric salts with homochiral acids or bases, separation of the pair of diastereoisomers by fractional crystallization or by chromatography, followed by hydrolysis of the salt. US 6,359,169 describes its preparation through an enantioselective reaction, using a chiral auxiliary, for example the Evans oxazolidone (4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone, which allows to carry out an asymmetric alkylation to introduce the desired stereocenter. After the asymmetric alkylation, normally carried out at cryogenic temperatures, it is necessary to remove the relatively expensive chiral auxiliary, with a consequent further increase in costs and production times. US 2005/0283023 reports the preparation of pregabaline by means of an enzymatic kinetic resolution of a cyano-diester according to the following scheme
Il processo sopra riportato è commercialmente praticabile, ma presenta evidenti svantaggi. In particolare, l’enantiomero non idrolizzato deve essere riciclato in un passaggio chimico di racemizzazione, inoltre è richiesto l’impiego di idrogeno sotto pressione per la riduzione del nitrile e l’uso di Nichel Raney, che è tossico e di difficoltoso utilizzo. The above process is commercially viable, but has obvious disadvantages. In particular, the non-hydrolyzed enantiomer must be recycled in a chemical racemization step, in addition, the use of hydrogen under pressure is required for the reduction of nitrile and the use of Nickel Raney, which is toxic and difficult to use.
Organic Process Research & Development 1997; 1: 26-38, riporta la sintesi di pregabalina, secondo lo schema sotto riportato, a partire da un diestere non chirale per idrolisi enzimatica con PLE (Porcine Liver Esterase) in acqua e DMSO a pH=8, ottenendo il monoestere chirale con una resa del 98% ed una purezza enantiomerica dell’ 85% (l’enantiomero prevalente è quello S ). Il monoestere è quindi convertito in presenza di litio metossido e formammide nella corrispettiva monoammide da cui, per riarrangiamento di Hofmann, si ottiene pregabalina Organic Process Research & Development 1997; 1: 26-38, reports the synthesis of pregabaline, according to the scheme below, starting from a non-chiral diester by enzymatic hydrolysis with PLE (Porcine Liver Esterase) in water and DMSO at pH = 8, obtaining the chiral monoester with a yield of 98% and an enantiomeric purity of 85% (the prevailing enantiomer is that S). The monoester is then converted in the presence of lithium methoxide and formamide into the corresponding monoamide from which, by Hofmann rearrangement, pregabaline is obtained
La risoluzione enzimatica risulta essere condizionata drasticamente dalla concentrazione dei reagenti, in quanto è selettiva unicamente a basse concentrazioni; questo fatto ne limita notevolmente l' applicazione su larga scala. The enzymatic resolution appears to be drastically conditioned by the concentration of the reagents, as it is selective only at low concentrations; this fact considerably limits its application on a large scale.
È stato qui trovato un procedimento alternativo per la preparazione di pregabalina che supera gli svantaggi dei precedenti metodi. Il nuovo procedimento fa uso di una procedura di arricchimento enantiomerico che permette di ottenere un prodotto di elevata purezza enantiomerica mediante precipitazione e cristallizzazione di sali diastereoisomeri. Il nuovo procedimento impiega inoltre reagenti poco costosi e non richiede apparecchiature speciali come reattori criogenici o idrogenatori ad alta pressione. An alternative process for the preparation of pregabaline has been found here which overcomes the disadvantages of the previous methods. The new process makes use of an enantiomeric enrichment procedure which allows to obtain a product of high enantiomeric purity by precipitation and crystallization of diastereomeric salts. The new process also uses inexpensive reagents and does not require special equipment such as cryogenic reactors or high pressure hydrogenators.
DESCRIZIONE DETTAGLIATA DELL'INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Oggetto dell’ invenzione è un procedimento per la preparazione dell’ acido (S)(+)-3-(amminometil)-5-metilesanoico di formula (I), od un suo sale, The subject of the invention is a process for the preparation of (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid of formula (I), or a salt thereof,
comprendente: comprising:
a) la reazione di un composto di formula (II) a) the reaction of a compound of formula (II)
con un alcol di formula ROH, dove R è C1-C10alchile oppure arile-C1-C6alchile; opzionalmente in presenza di una base organica, e, se desiderato, in presenza di un solvente, ad ottenere un estere dell’acido 3-isobutil glutarico di formula (III), od un suo sale, with an alcohol of formula ROH, where R is C1-C10alkyl or aryl-C1-C6alkyl; optionally in the presence of an organic base, and, if desired, in the presence of a solvent, to obtain an ester of 3-isobutyl glutaric acid of formula (III), or a salt thereof,
dove R è come prima definito; where R is as defined above;
b) la conversione di un composto di formula (III), o un suo sale, per riarrangiamento via formazione di nitrene/isocianato, in un solvente di formula RrOH, dove R1è C1- C6alchile, arile oppure arile-C1- C6alchile, ad ottenere un composto di formula (IV), od un suo sale, b) the conversion of a compound of formula (III), or a salt thereof, by rearrangement via formation of nitrene / isocyanate, into a solvent of formula RrOH, where R1 is C1-C6alkyl, aryl or aryl-C1-C6alkyl, to obtain a compound of formula (IV), or a salt thereof,
dove R e Ri sono come sopra definiti; where R and Ri are as defined above;
c) l’idrolisi di un composto di formula (IV), od un suo sale, ad ottenere un acido di formula (V), o un suo sale, c) the hydrolysis of a compound of formula (IV), or a salt thereof, to obtain an acid of formula (V), or a salt thereof,
OH OH
HN N r OR, HN N r OR,
o (V) o (V)
dove Ri è come prima definito; where Ri is defined as above;
d) l' arricchimento enantiomerico di un composto di formula (V) nel suo enantiomero (S); d) the enantiomeric enrichment of a compound of formula (V) in its enantiomer (S);
e) l’idrolisi acida dell’ enatiomero (S) di un composto di formula (V) a formare l’acido ( S)(+)-3-(amminometil)-5-metilesanoico; e, se desiderato, la sua conversione in un suo sale. e) the acid hydrolysis of the enatiomer (S) of a compound of formula (V) to form the acid (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid; and, if desired, its conversion into one of its salt.
Un sale di un composto di formula (I), (III), (IV) o (V) è ad esempio un sale farmaceuticamente accettabile, preferibilmente un sale di addizione con un acido, ad esempio cloridrato, solfato, acetato, alchilsolfonato; oppure un sale con sale una base, ad esempio un sale di litio, sodio, potassio, magnesio o alluminio. A salt of a compound of formula (I), (III), (IV) or (V) is for example a pharmaceutically acceptable salt, preferably an addition salt with an acid, for example hydrochloride, sulfate, acetate, alkylsulfonate; or a salt with a base salt, for example a salt of lithium, sodium, potassium, magnesium or aluminum.
Un gruppo C1-C10alchile, che può essere lineare o ramificato, è ad esempio un gruppo C1- C8alchile, preferibilmente un gruppo A C1-C10alkyl group, which can be linear or branched, is for example a C1-C8alkyl group, preferably a
le gruppo C1- C6alchile o un residuo C1- C6alchile, che può essere lineare o ramificato, è preferibilmente un gruppo o un residuo C1-C4alchile, più preferibilmente metile, etile, propile, butile o isobutile, in particolare metile o etile. the C1-C6alkyl group or a C1-C6alkyl residue, which can be linear or branched, is preferably a C1-C4alkyl group or residue, more preferably methyl, ethyl, propyl, butyl or isobutyl, in particular methyl or ethyl.
Un gruppo arile-C1C6alchile è ad esempio fenile-C1C6alchile o naftile-C1-C6alchile; in particolare fenile-C1-C4alchile. Detto gruppo può essere sostituito da 1 a 5 sostituenti indipendentemente scelti tra alogeno, nitro, ciano e C1-C6dialchil-amino, ad esempio dimetil-, dietil-, o diisopropilammino. An aryl-C1C6alkyl group is for example phenyl-C1C6alkyl or naphthyl-C1-C6alkyl; in particular phenyl-C1-C4alkyl. Said group can be substituted by 1 to 5 substituents independently selected from halogen, nitro, cyano and C1-C6dyalkyl-amino, for example dimethyl-, diethyl-, or diisopropylamino.
Un gruppo arile è ad esempio fenile o naftile, in particolare fenile. Detto gruppo può essere sostituito sostituito da 1 a 5 sostituenti indipendentemente scelti tra C1- C6dialchil-amino, nitro, ciano e alogeno. An aryl group is for example phenyl or naphthyl, in particular phenyl. Said group can be substituted substituted by 1 to 5 substituents independently selected from C1-C6dyalkyl-amino, nitro, cyano and halogen.
Un alogeno è ad esempio cloro, fluoro, bromo o iodio; in particolare cloro o bromo. A halogen is for example chlorine, fluorine, bromine or iodine; in particular chlorine or bromine.
Un alcol di formula ROH è ad esempio un alcol primario, dove R è preferibilmente C1-C8alchile o fenile C1- C4alchile, in particolare metanolo, etanolo, propanolo, isopropanolo, isobutanolo, ottanolo, alcol benzilico; più preferibilmente metanolo. An alcohol of formula ROH is for example a primary alcohol, where R is preferably C1-C8alkyl or phenyl C1-C4alkyl, in particular methanol, ethanol, propanol, isopropanol, isobutanol, octanol, benzyl alcohol; more preferably methanol.
La reazione tra un composto di formula (II) ed un alcol di formula ROH può essere condotta ad una temperatura compresa tra approssimativamente 15°C e la temperatura di riflusso della miscela di reazione, preferibilmente tra circa 20 e circa 50°C. I tempi di reazione possono variare da circa 1 a 24 h. The reaction between a compound of formula (II) and an alcohol of formula ROH can be carried out at a temperature comprised between approximately 15 ° C and the reflux temperature of the reaction mixture, preferably between about 20 and about 50 ° C. Reaction times can vary from about 1 to 24 hours.
La reazione può essere opzionalmente condotta in presenza di una base organica, ad esempio una C1- C4trialchilammina, tipicamente metil-dietilammina, trietilammina, tributilammina oppure etil-diisopropilammina, in particolare trietilammina. The reaction can optionally be carried out in the presence of an organic base, for example a C1-C4tryalkylamine, typically methyl-diethylamine, triethylamine, tributylamine or ethyl-diisopropylamine, in particular triethylamine.
La reazione può essere opzionalmente condotta in un solvente, scelto ad esempio tra un solvente dipolare aprotico, tipicamente dimetilformammide, dimetilacetammide, acetonitrile, dimetilsolfossido; un chetone, tipicamente acetone o metilisobutilchetone; un etere, tipicamente tetraidro furano, metil-terz-butiletere o diossano; un solvente clorurato, tipicamente diclorometano tricloroetano e tetracloroetilene o cloroformio; un alcol terziario quale, ad esempio alcol terbutilico, alcol teramilico; o un solvente apolare, tipicamente toluene o esano; o una miscela da due a quattro, preferibilmente di due o tre, di detti solventi tra loro. The reaction can optionally be carried out in a solvent, selected for example from an aprotic dipolar solvent, typically dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide; a ketone, typically acetone or methyl isobutyl ketone; an ether, typically tetrahydro furan, methyl-tert-butylether or dioxane; a chlorinated solvent, typically dichloromethane trichloroethane and tetrachlorethylene or chloroform; a tertiary alcohol such as, for example, terbutyl alcohol, teramyl alcohol; or a non-polar solvent, typically toluene or hexane; or a mixture of two to four, preferably two or three, of said solvents with each other.
Quando la reazione è condotta in presenza di un solvente la quantità di alcol di formula ROH impiegata può essere circa uguale o superiore a 1 mole per mole di substrato di formula (II); preferibilmente è compresa tra circa 1,1 e 2,1. When the reaction is carried out in the presence of a solvent, the quantity of alcohol of formula ROH used can be approximately equal to or greater than 1 mole per mole of substrate of formula (II); preferably it is comprised between about 1.1 and 2.1.
Preferibilmente la reazione è condotta impiegando solamente lo stesso alcol di formula ROH come solvente. Preferably the reaction is carried out using only the same alcohol of formula ROH as solvent.
I seguenti composti di formula (III): The following compounds of formula (III):
3-isobutil-glutarato di propile, Propyl 3-isobutyl-glutarate,
3-isobutil-glutarato di isobutile, Isobutyl 3-isobutyl-glutarate,
3-isobutil-glutarato di ottile; Octyl 3-isobutyl glutarate;
ed i loro sali sono nuovi e sono un oggetto dell’invenzione. and their salts are new and are an object of the invention.
II riarrangiamento di un composto di formula (III), o un suo sale, ad ottenere rispettivamente un composto di formula (IV) o un suo sale, via formazione di nitrene/isocianato, può essere condotto ad esempio in accordo alle reazioni di Schmidt, Lossen, Hofmann oppure Curtius. The rearrangement of a compound of formula (III), or a salt thereof, to obtain respectively a compound of formula (IV) or a salt thereof, via the formation of nitrene / isocyanate, can be carried out for example according to the Schmidt reactions, Lossen, Hofmann or Curtius.
Un solvente di formula R1- OH è preferibilmente un C1-C4alcanolo, ad esempio metanolo, etanolo o i-propanolo; più preferibilmente metanolo o i-propanolo. A solvent of formula R1-OH is preferably a C1-C4alkanol, for example methanol, ethanol or i-propanol; more preferably methanol or i-propanol.
I composti di formula (IV) e i loro sali sono nuovi e sono un oggetto dell’ invenzione. The compounds of formula (IV) and their salts are new and are an object of the invention.
Esempi specifici di composti di formula (IV) sono: Specific examples of compounds of formula (IV) are:
{ 4-metil-2- [( 1 -metossicarbonil)-metil-] -pentii } -carbammato di metile, { 4-metil-2- [( 1 -etossicarbonil)-metil-] -pentii } -carbammato di metile, {4-metil-2-[(l-propossicarbonil)-metil-]-pentil} -carbammato di metile, {4-metil-2-[(l-butossicarbonil)-metil-] -pentii }-carbammato di metile, { 4-metil-2- [( 1 -isobutilossicarbonil)-metil-] -pentii } -carbammato di metile, { 4-metil-2- [( 1 -ottilossicarbonil)-metil] -pentii } -carbammato di metile, { 4-metil-2- [( 1 -metossicarbonil)-metil-]-pentil } -carbammato di etile, { 4-metil-2- [( 1 -etossicarbonil)-metil] -pentii } -carbammato di etile, { 4-metil-2- [(1 -propossicarbonil)-metil] -pentii } -carbammato di etile, {4-metil-2-[(l-butossicarbonil)-metil] -pentii} -carbammato di etile, { 4-metil-2- [(1 -isobutilossicarbonil)-metil] -pentii } -carbammato di etile, { 4-metil-2- [( 1 -ottilossicarbonil)-metil] -pentii } -carbammato di etile, { 4-metil-2- [( 1 -metossicarbonil)-metil]-pentil } -carbammato di isopropile, { 4-metil-2- [( 1 -etossicarbonil)-metil] -pentii } -carbammato di isopropile, {4-metil-2-[(1-propossicarbonil)-metil]-pentil}-carbammato di isopropile, {4-metil-2-[(1-butossicarbonil)-metil]-pentil}-carbammato di isopropile, { 4-metil-2- [(1 -isobutilossicarbonil)-metil]-pentil }-carbammato di isopropile, e {4-methyl-2- [(1 -methoxycarbonyl) -methyl-] -pentii} -methyl carbamate, {4-methyl-2- [(1-ethoxycarbonyl) -methyl-] -pentii} -methyl carbamate, {4-methyl-2 - [(1-propoxycarbonyl) -methyl -] - pentyl} -methyl carbamate, {4-methyl-2 - [(1-butoxycarbonyl) -methyl-] -pentii} -methyl carbamate, {4-methyl-2- [(1-isobutyloxycarbonyl) -methyl-] -pentii} -methyl carbamate, {4-methyl-2- [(1-octyloxycarbonyl) -methyl] -pentii} -methyl carbamate, { 4-methyl-2- [(1-methoxycarbonyl) -methyl -] - pentyl} -ethylcarbamate, {4-methyl-2- [(1 -ethoxycarbonyl) -methyl] -pentii} -ethylcarbamate, {4 -methyl-2- [(1-propoxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2 - [(1-butoxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl -2- [(1-isobutyloxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1-octyloxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2 - [(1-methoxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2- [ (1-ethoxycarbonyl) -methyl] -pentii} -isopropyl carbamate, {4-methyl-2 - [(1-propoxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2 - [(1 -butoxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2- [(1-isobutyloxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, and
{ 4-metil-2- [( 1 -ottilossicarbonil)-metil] -pentii } -carbammato di isopropile. La reazione di Schmidt può essere condotta in accordo a metodi noti, ad esempio per trattamento di un composto di formula (III) con acido idrazoico in presenza di acido solforico. Alternativamente il riarrangiamento può avvenire secondo la reazione di Lossen, facendo reagire un composto di formula (III) con un agente alogenante, preferibilmente cloruro di tionile oppure cloruro di ossalile. Successivamente, per reazione con una acil-idrossilammina, preferibilmente acetil-idrossilammina, si ottiene il corrispettivo acido idrossamico acilato. Il trattamento di quest’ultimo con un idrossido alcalino porta alla formazione dell’ isocianato, che converte spontaneamente in un composto di formula (IV). {4-methyl-2- [(1-octyloxycarbonyl) -methyl] -pentii} -carbamate of isopropyl. The Schmidt reaction can be carried out according to known methods, for example by treating a compound of formula (III) with hydrazoic acid in the presence of sulfuric acid. Alternatively, the rearrangement can take place according to the Lossen reaction, by reacting a compound of formula (III) with a halogenating agent, preferably thionyl chloride or oxalyl chloride. Subsequently, by reaction with an acyl-hydroxylamine, preferably acetyl-hydroxylamine, the corresponding acylated hydroxamic acid is obtained. The treatment of the latter with an alkaline hydroxide leads to the formation of isocyanate, which spontaneously converts into a compound of formula (IV).
In accordo con la reazione di Hofmann, si trasforma l’acido carbossilico di formula (III) nella corrispettiva ammide secondo metodi noti, e trattando poi quest’ ultima con un ipoalogenito alcalino, preferibilmente ipoclorito di sodio si ottiene l isocianato, che converte spontaneamente in un composto di formula (IV). In accordance with the Hofmann reaction, the carboxylic acid of formula (III) is transformed into the corresponding amide according to known methods, and then treating the latter with an alkaline hypohalite, preferably sodium hypochlorite, isocyanate is obtained, which spontaneously converts into a compound of formula (IV).
Infine, secondo la reazione di Curtius, si può far reagire un composto di formula (III) con un agente alogenante, preferibilmente cloruro di tionile oppure cloruro di ossalile, e successivamente per trattamento con sodio azide oppure direttamente con difenilfosforilazide, in presenza di una base organica, in particolare trietilammina, diisopropiletilammina oppure piridina, a formare la corrispettiva acil-azide. La acil-azide per riscaldamento viene convertita nel corrispondente isocianato, che converte spontaneamente in un composto di formula (IV). Finally, according to the Curtius reaction, a compound of formula (III) can be reacted with a halogenating agent, preferably thionyl chloride or oxalyl chloride, and subsequently by treatment with sodium azide or directly with diphenylphosphorylazide, in the presence of a base organic, in particular triethylamine, diisopropylethylamine or pyridine, to form the corresponding acyl-azide. The acyl-azide by heating is converted into the corresponding isocyanate, which spontaneously converts into a compound of formula (IV).
Le reazioni di riarrangiamento sopra riportate possono essere condotte in accordo a metodi noti, ad esempio ad una temperatura compresa tra circa 10 e 100°C, preferibilmente tra 50 e 90°C, per un tempo compreso tra 2 e 15 h, preferibilmente tra 5 e 10 h. The rearrangement reactions reported above can be carried out according to known methods, for example at a temperature between about 10 and 100 ° C, preferably between 50 and 90 ° C, for a time between 2 and 15 h, preferably between 5 and 10 h.
L’idrolisi di un composto di formula (IV), od un suo sale, è preferibilmente una idrolisi basica e può essere condotta secondo metodi noti, ad esempio mediante reazione in acqua in presenza di una base alcalina o alcalino-terrosa, tipicamente sodio o potassio idrossido. The hydrolysis of a compound of formula (IV), or a salt thereof, is preferably a basic hydrolysis and can be carried out according to known methods, for example by reaction in water in the presence of an alkaline or alkaline-earth base, typically sodium or potassium hydroxide.
L’arricchimento enantiomerico di un composto di formula (V), od un suo sale, nel suo enantiomero (S) può essere ottenuto attraverso la formazione di un suo sale diastereomerico con una base chirale, seguita dalla separazione della coppia di diastereoisomeri, e successiva idrolisi del sale diastereomerico deH’enantiomero (S) del composto di formula (V). The enantiomeric enrichment of a compound of formula (V), or a salt thereof, in its enantiomer (S) can be obtained through the formation of its diastereomeric salt with a chiral base, followed by the separation of the pair of diastereomers, and subsequent hydrolysis of the diastereomeric salt of the (S) enantiomer of the compound of formula (V).
Una base chirale può essere un ammina chirale, ad esempio scelta tra quelle riportate in “ S.H . Wilen - Tables of Resolving Agents and Optical Resolutions Un. of Notre Dame Press”, ad esempio S-(-)-feniletilammina, S-(-)-naftiletilammina, brucina e chinina, preferibilmente S-(-)-feniletilammina. A chiral base can be a chiral amine, for example chosen from those reported in “S.H. Wilen - Tables of Resolving Agents and Optical Resolutions Un. of Notre Dame Press ”, for example S - (-) - phenylethylamine, S - (-) - naphthylethylamine, brucine and quinine, preferably S - (-) - phenylethylamine.
La reazione di un composto di formula (V) con una base chirale ad ottenere un suo sale diastereomerico può essere condotta in un solvente, ad esempio in acqua; in un solvente clorurato come cloroformio, dicloroetano, tricloroetano e tetracloroetilene; in un solvente apolare come benzene, clorobenzene, toluene e cicloesano; in un estere, come ad esempio acetato di etile o acetato di metile; in un solvente dipolare aprotico, ad esempio acetonitrile, dimetilacetammide, dimetilsolfossido, dimetil formammide e N-metilpirrolidone; un chetone, ad esempio acetone, etilchetone e metilisobutilchetone; un etere ad esempio diossano, tetraidrofurano, metil-terz-butiletere; in un alcol ad esempio metanolo, etanolo o i-propanolo; oppure in una miscela da due a quattro, preferibilmente due o tre, di detti solventi; in particolare miscele acqua e alcol oppure acqua e acetone; preferibilmente in acqua o miscele acqua e alcol. The reaction of a compound of formula (V) with a chiral base to obtain a diastereomeric salt thereof can be carried out in a solvent, for example in water; in a chlorinated solvent such as chloroform, dichloroethane, trichloroethane and tetrachlorethylene; in a non-polar solvent such as benzene, chlorobenzene, toluene and cyclohexane; in an ester, such as ethyl acetate or methyl acetate; in an aprotic dipolar solvent, for example acetonitrile, dimethylacetamide, dimethyl sulfoxide, dimethyl formamide and N-methylpyrrolidone; a ketone, for example acetone, ethyl ketone and methyl isobutyl ketone; an ether, for example dioxane, tetrahydrofuran, methyl-tert-butylether; in an alcohol such as methanol, ethanol or i-propanol; or in a mixture of two to four, preferably two or three, of said solvents; in particular mixtures of water and alcohol or water and acetone; preferably in water or water and alcohol mixtures.
La separazione della coppia di diastereoisomeri può essere ottenuta ad esempio per cristallizzazione frazionata dallo stesso solvente di reazione o per cromatografia. The separation of the pair of diastereomers can be obtained, for example, by fractional crystallization from the reaction solvent itself or by chromatography.
La purezza ottica della miscela di sali diastereoisomeri, così ottenuta, è tipicamente intorno al 98%; preferibilmente intorno al 99%. Tale purezza può essere opzionalmente aumentata fino a circa il 99,5% o più, mediante tecniche note. Ad esempio, il sale diastereoisomerico può essere di nuovo sciolto nello stesso precedente solvente, e quindi ricristallizzato, ottenendo così un suo ulteriore arricchimento enantiomerico. The optical purity of the mixture of diastereomeric salts thus obtained is typically around 98%; preferably around 99%. This purity can optionally be increased up to about 99.5% or more, by known techniques. For example, the diastereoisomeric salt can be dissolved again in the same previous solvent, and then recrystallized, thus obtaining a further enantiomeric enrichment thereof.
I composti di formula (V), in particolare come enantiomero (S), ed i loro sali, in particolare con una base chirale, preferibilmente con S-(-)-feniletilammina, sono nuovi e sono un ulteriore oggetto dell’ invenzione. The compounds of formula (V), in particular as enantiomer (S), and their salts, in particular with a chiral base, preferably with S - (-) - phenylethylamine, are new and are a further object of the invention.
Esempi specifici di composti di formula (V) in particolare come enantiomero (S), ed i loro sali, in particolare con una base chirale, preferibilmente con S-(-)-feniletilammina, sono: Specific examples of compounds of formula (V) in particular as enantiomer (S), and their salts, in particular with a chiral base, preferably with S - (-) - phenylethylamine, are:
{4-metil-2-[(1-carbossi)-metil]-pentil}-carbammato di metile, Methyl {4-methyl-2 - [(1-carboxy) -methyl] -pentyl} -carbamate,
{4-metil-2-[(1-carbossi)-metil]-pentil}-carbammato di etile, e Ethyl {4-methyl-2 - [(1-carboxy) -methyl] -pentyl} -carbamate, and
{ 4-metil-2- [( 1 -carbossi)-metil] -pentii } -carbammato di isopropile. {4-methyl-2- [(1 -carboxy) -methyl] -pentii} -carbamate of isopropyl.
L’idrolisi del sale diastereomerico dell’ enantiomero (S) di un composto di formula (V) ad ottenere l enantiomero (S) del composto di formula (V), può essere effettuata per trattamento con una quantità circa uguale o superiore a 1 mole per mole di substrato, preferibilmente compresa tra circa 1,1 e 2,1, di un acido minerale, ad esempio acido cloridrico o solforico, come noto. The hydrolysis of the diastereomeric salt of the enantiomer (S) of a compound of formula (V) to obtain the enantiomer (S) of the compound of formula (V), can be carried out by treatment with an amount approximately equal to or greater than 1 mole per mole of substrate, preferably comprised between about 1.1 and 2.1, of a mineral acid, for example hydrochloric or sulfuric acid, as known.
L’idrolisi dell’ enantiomero (S) di un composto di formula (V) ad ottenere un composto di formula (I), cioè l’acido (S)(+)-3-(amminometil)-5-metilesanoico è tipicamente un’idrolisi acida, e può essere condotta ad esempio per trattamento con un acido minerale, tipicamente con acido cloridrico come noto. The hydrolysis of the enantiomer (S) of a compound of formula (V) to obtain a compound of formula (I), i.e. the (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid is typically a acid hydrolysis, and can be carried out for example by treatment with a mineral acid, typically with hydrochloric acid as known.
Se desiderato l’acido (S)(+)-3-(amminometil)-5-metilesanoico può essere convertito in un suo sale, ad esempio un sale farmaceuticamente accettabile, in accordo a metodi noti. Analogamente, un composto di formula (III), (IV) o (V) può essere convertito in un suo sale, o viceversa, in accordo a metodi noti. If desired, the (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid can be converted into one of its salt, for example a pharmaceutically acceptable salt, according to known methods. Similarly, a compound of formula (III), (IV) or (V) can be converted into a salt thereof, or vice versa, according to known methods.
L’acido (5X+)-3-(amminometil)-5-metilesanoico, od un suo sale, così ottenuto, ha una purezza enantiomerica intorno al 98%; preferibilmente intorno al 99%, più preferibilmente intorno al 99,8% o più, che ben soddisfa i requisiti regolatori per i farmaci. The (5X +) - 3- (aminomethyl) -5-methylhexanoic acid, or one of its salt, thus obtained, has an enantiomeric purity of around 98%; preferably around 99%, more preferably around 99.8% or more, which satisfies the regulatory requirements for drugs well.
La purezza enantiomerica è definita come S/(S+R)xlOO, dove S ed R sono rispettivamente le quantità degli enantiomeri ( S ) ed ( R ). In accordo all’invenzione il termine singolo enantiomero ( S ) o ( R ) significa che la purezza enantiomerica è almeno pari a circa 96% o maggiore, preferibilmente almeno pari a circa 99%. The enantiomeric purity is defined as S / (S + R) x100, where S and R are the quantities of the enantiomers (S) and (R) respectively. According to the invention, the term single enantiomer (S) or (R) means that the enantiomeric purity is at least equal to about 96% or greater, preferably at least equal to about 99%.
Il composto di formula (II) è noto e può essere preparato ad esempio come descritto in WO 96/38405. The compound of formula (II) is known and can be prepared for example as described in WO 96/38405.
I seguenti esempi illustrano l’invenzione. The following examples illustrate the invention.
Esempio 1 - SINTESI DEL 3-ISOBUTIL-GLUTARATO DI METILE (III) Example 1 - SYNTHESIS OF METHYL (III) 3-ISOBUTYL-GLUTARATE
In un pallone a tre colli da 1 1, sotto atmosfera di azoto, sono aggiunti anidride 3-isobutilglutarica (50,0 g; 0,290 mol), metanolo (500 mi) e trietilammina (29,3 g; 0,290 mol); la soluzione così ottenuta è mantenuta sotto agitazione a temperatura ambiente per circa 16-18 h. Al termine della reazione il solvente viene evaporato, la miscela viene ripresa con acqua (200 mi), acidificata a pH 3-4 con acido cloridrico 37% ed estratta con toluene (3 x 150 mi). Le fasi organiche riunite vengono evaporate a pressione ridotta, si ottiene un olio di colore giallo chiaro (58,6 g; resa: 95%). 3-isobutylglutaric anhydride (50.0 g; 0.290 mol), methanol (500 ml) and triethylamine (29.3 g; 0.290 mol) are added to a 1 1 three-necked flask under a nitrogen atmosphere; the solution thus obtained is kept under stirring at room temperature for about 16-18 h. At the end of the reaction the solvent is evaporated, the mixture is taken up with water (200 ml), acidified to pH 3-4 with hydrochloric acid 37% and extracted with toluene (3 x 150 ml). The combined organic phases are evaporated under reduced pressure, a light yellow oil is obtained (58.6 g; yield: 95%).
1H-NMR (300 MHz, CDC13, 28°C): δ 3,65 (s,3H); 2,40 (m, 5H); 1,60 (m, 1H); 1,20 (m, 2H); 0,90 (d, 6H). 1H-NMR (300 MHz, CDC13, 28 ° C): δ 3.65 (s, 3H); 2.40 (m, 5H); 1.60 (m, 1H); 1.20 (m, 2H); 0.90 (d, 6H).
Procedendo in modo analogo si ottengono: Proceeding in the same way we obtain:
3-isobutil-glutarato di propile, Propyl 3-isobutyl-glutarate,
3-isobutil-glutarato di isobutile, e Isobutyl 3-isobutyl-glutarate, e
3-isobutil-glutarato di ottile. Octyl 3-isobutyl-glutarate.
Esempio 2 - SINTESI DI {4-METIL-2-[(1-METOSSICARBONIL)-METIL-]-PENTIL-}-CARBAMMATO DI ISOPROPILE (IV) Example 2 - SYNTHESIS OF {4-METHYL-2 - [(1-METHOXYCARBONIL) -METHYL -] - PENTYL -} - ISOPROPYL (IV) CARBAMATE
In un pallone a tre colli da 50 mi sotto atmosfera di azoto sono aggiunti 3-isobutilglutarato di metile (60,0 g; 0,297 mol) ed una soluzione di trietilammina (33,0 g; 0,327 mol) in iso-propanolo (500 mi). Si scalda la soluzione alla temperatura di riflusso e si aggiunge difenilfosforilazide (85,9 g; 0,312 mol) in circa 2 h; a termine dell’aggiunta si lascia all’ ebollizione per circa 1 h. Si raffredda a temperatura ambiente e si versa la miscela di reazione in una soluzione di idrossido di sodio al 5% p/p (500 mi), si estrae con toluene (3 x 500 mi), e le fasi organiche riunite vengono lavate con acqua (250 mi). Si concentra a pressione ridotta la fase organica ottenendo 62,0 g di un olio di colore giallo chiaro; resa 80%. Methyl 3-isobutylglutarate (60.0 g; 0.297 mol) and a solution of triethylamine (33.0 g; 0.327 mol) in iso-propanol (500 ml) are added to a 50 ml three-necked flask under nitrogen atmosphere. ). The solution is heated to reflux temperature and diphenylphosphorylazide (85.9 g; 0.312 mol) is added in about 2 h; at the end of the addition it is left to boil for about 1 h. It is cooled to room temperature and the reaction mixture is poured into a 5% w / w sodium hydroxide solution (500 ml), extracted with toluene (3 x 500 ml), and the combined organic phases are washed with water (250 ml). The organic phase is concentrated under reduced pressure to obtain 62.0 g of a light yellow oil; yield 80%.
1H-NMR (300 MHz, CDC13, 28°C): δ 5,00-4, 75 (m, 2H di cui uno scambiabile con D2O); 3,60 (s, 3H); 3,20 (m, 1H); 3,00 (m, 1H); 2,20 (d,2H); 2,05 (m, 1H); 1,60 (m, 1H); 1,20-1,00 (m, 8H); 0,80 (dd, 6H). 1H-NMR (300 MHz, CDC13, 28 ° C): δ 5.00-4.75 (m, 2H of which one exchangeable with D2O); 3.60 (s, 3H); 3.20 (m, 1H); 3.00 (m, 1H); 2.20 (d, 2H); 2.05 (m, 1H); 1.60 (m, 1H); 1.20-1.00 (m, 8H); 0.80 (dd, 6H).
Esempio 3 - SINTESI DI {4-METIL-2-[(1-METOSSICARBONIL)-METIL-]-PENTIL-}-CARBAMMATO DI METILE (IV) Example 3 - SYNTHESIS OF {4-METHYL-2 - [(1-METHOXYCARBONIL) -METHYL -] - PENTYL -} - METHYL (IV) CARBAMATE
In un pallone a tre colli da 50 mi sotto atmosfera di azoto sono aggiunti 3-isobutilglutarato di metile (3,4 g; 17 mmol) ed una soluzione di trietilammina (1,9 g; 19 mmol) in metanolo (25 mi). Si scalda la soluzione alla temperatura di riflusso e si aggiunge difenilfosforilazide (2,2 g; 18 mmol) in circa 2-3 h; a termine dell’aggiunta si lascia all’ ebollizione per circa 1 h. Si raffredda a temperatura ambiente e si versa la miscela di reazione in una soluzione di idrossido di sodio al 10% p/p (30 mi), si estrae con toluene (3 x 25 mi) e le fasi organiche riunite vengono lavate con acqua (2 x 25 mi). Si concentra a pressione ridotta la fase organica lavata, ottenendo 3,5 g di un olio di colore giallo chiaro; resa 80%. Methyl 3-isobutylglutarate (3.4 g; 17 mmol) and a solution of triethylamine (1.9 g; 19 mmol) in methanol (25 ml) are added to a 50 ml three-necked flask under nitrogen atmosphere. The solution is heated to reflux temperature and diphenylphosphorylazide (2.2 g; 18 mmol) is added in about 2-3 h; at the end of the addition it is left to boil for about 1 h. It is cooled to room temperature and the reaction mixture is poured into a 10% w / w sodium hydroxide solution (30 ml), extracted with toluene (3 x 25 ml) and the combined organic phases are washed with water ( 2 x 25 mi). The washed organic phase is concentrated under reduced pressure, obtaining 3.5 g of a light yellow oil; yield 80%.
1H-NMR (300 MHz, CDC13, 28°C): δ 3,6 (s, 6H); 3,2 (m, IH); 3,0 (m, 1H); 2,3 (m, 2H); 2,1 (m, 1H); 1,6 (m, 1H); 1,2 (m, 2H); 0,9 (m, 6H). GC-MS (M+): 231 1H-NMR (300 MHz, CDC13, 28 ° C): δ 3.6 (s, 6H); 3.2 (m, 1H); 3.0 (m, 1H); 2.3 (m, 2H); 2.1 (m, 1H); 1.6 (m, 1H); 1.2 (m, 2H); 0.9 (m, 6H). GC-MS (M +): 231
Esempio 4 - SINTESI DI {4-METIL-2-[(1-CARBOSSI)-METIL-]-PENTIL-}-CARBAMMATO DI ISOPROPILE (V) Example 4 - SYNTHESIS OF {4-METHYL-2 - [(1-CARBOSS) -METHYL -] - PENTYL -} - ISOPROPYL CARBAMATE (V)
In un pallone a tre colli da 50 mi sotto atmosfera di azoto si aggiunge { 4-metil-2- [( 1 -metossicarbonil-)-metil-] -pentii- } -carbammato di isopropile (62,0 g; 0,237 mmol) ad una soluzione di sodio idrossido (16,0 g; 0,400 mol) in acqua (300 mi) e si mantiene sotto agitazione ad temperatura ambiente per 18 h. Si aggiunge una soluzione di acido cloridrico 37% p/p fino a pH acido (60 mi); si estrae la fase acquosa con toluene (3 x 300 mi). La fase organica viene concentrata a piccolo volume, si ottiene un olio di colore giallo chiaro (56,9 g; resa: 97%). {4-methyl-2- [(1-methoxycarbonyl -) - methyl-] -pentii-} -carbamate of isopropyl (62.0 g; 0.237 mmol) is added to a 50 ml three-necked flask under nitrogen atmosphere. to a solution of sodium hydroxide (16.0 g; 0.400 mol) in water (300 ml) and kept under stirring at room temperature for 18 h. A 37% w / w hydrochloric acid solution is added up to an acid pH (60 ml); the aqueous phase is extracted with toluene (3 x 300 ml). The organic phase is concentrated to a small volume, a light yellow oil is obtained (56.9 g; yield: 97%).
1H-NMR (300 MHz, CDC13, 28°C): δ 7,00 (broad, 1H scambiabile con D2O); 4, 70 (m, 1H); 3,00 (m, 1H); 2,80 (m, 1H); 2,10 (m,2H); 1,95 (m, 1H); 1,60 (m, 1H); 1,20-1,00 (m, 8H); 0,80 (d, 6H). 1H-NMR (300 MHz, CDC13, 28 ° C): δ 7.00 (broad, 1H exchangeable with D2O); 4.70 (m, 1H); 3.00 (m, 1H); 2.80 (m, 1H); 2.10 (m, 2H); 1.95 (m, 1H); 1.60 (m, 1H); 1.20-1.00 (m, 8H); 0.80 (d, 6H).
Procedendo in modo analogo si ottengono: Proceeding in the same way we obtain:
{ 4-metil-2- [( 1 -metossicarbonil)-metil] -pentii } -carbammato di metile, { 4-metil-2- [( 1 -etossicarbonil)-metil] -pentii } -carbammato di metile, { 4-metil-2- [( 1 -propossicarbonil)-metil] -pentii } -carbammato di metile, {4-metil-2-[(l-butossicarbonil)-metil-]-pentil}-carbammato di metile, {4-metil-2-[(l-isobutilossicarbonil)-metil] -pentii} -carbammato di metile, {4-metil-2-[(l-ottilossicarbonil)-metil]-pentil}-carbammato di metile, { 4-metil-2- [( 1 -metossicarbonil)-metil] -pentii } -carbammato di etile, { 4-metil-2- [( 1 -etossicarbonil)-metil] -pentii } -carbammato di etile, { 4-metil-2- [( 1 -propossicarbonil)-metil] -pentii } -carbammato di etile, { 4-metil-2- [( 1 -butossicarbonil)-metil] -pentii } -carbammato di etile, { 4-metil-2- [(1 -isobutilossicarbonil)-metil] -pentii } -carbammato di etile, { 4-metil-2- [( 1 -ottilossicarbonil)-metil] -pentii } -carbammato di etile, { 4-metil-2- [( 1 -etossicarbonil)-metil] -pentii } -carbammato di isopropile, {4-metil-2-[(1-propossicarbonil)-metil]-pentil}-carbammato di isopropile, {4-metil-2-[(1-butossicarbonil)-metil]-pentil}-carbammato di isopropile, {4-metil-2-[(1-isobutilossicarbonil)-metil]-pentil} -carbammato di isopropile, e {4-methyl-2- [(1-methoxycarbonyl) -methyl] -pentii} -methyl carbamate, {4-methyl-2- [(1-ethoxycarbonyl) -methyl] -pentii} -methyl carbamate, {4 -methyl-2- [(1-propoxycarbonyl) -methyl] -pentii} -methyl carbamate, {4-methyl-2 - [(1-butoxycarbonyl) -methyl -] - pentyl} -methylcarbamate, {4- methyl-2 - [(1-isobutyloxycarbonyl) -methyl] -pentii} -methyl carbamate, {4-methyl-2 - [(1-octyloxycarbonyl) -methyl] -pentyl} -methylcarbamate, {4-methyl- 2- [(1-methoxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1-ethoxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1-propoxycarbonyl) -methyl] -pentii} -ethylcarbamate, {4-methyl-2- [(1 -butoxycarbonyl) -methyl] -pentii} -ethylcarbamate, {4-methyl-2- [( 1-isobutyloxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1-octyloxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1 - ethoxycarbonyl) -methyl] -pentii} -isopropyl carbamate, {4-methyl-2 - [(1-propo ssicarbonyl) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2 - [(1-butoxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2 - [(1-isobutyloxycarbonyl) -methyl] -pentyl} -carbamate of isopropyl, e
{ 4-metil-2- [( 1 -ottilossicarbonil)-metil] -pentii } -carbammato di isopropile. {4-methyl-2- [(1-octyloxycarbonyl) -methyl] -pentii} -carbamate of isopropyl.
Esempio 5 - RISOLUZIONE OTTICA DI (S)-{4-METIL-2-[(1-CARBOSSI)-METIL-]-PENTIL-}-CARBAMMATO DI ISOPROPILE (V) In un pallone a tre colli da 100 ml sotto atmosfera di azoto sono aggiunti {4-metil-2-[(1-carbossi-)-metil-]-pentil-}-carbammato di isopropile (13,0 g, 53,0 mmol), trietilammina (2,70 g; 26,5 mmol) e (S)-(-)-Feniletilammina (3,2 g, 26,5 mmol) in una miscela acqua/isopropanolo 95:5 (50 mi). La soluzione viene scaldata alla temperatura di circa 60-65°C e si raffredda lentamente fino circa 35°C, quindi si riscalda a 50°C e si lascia raffreddare spontaneamente a temperatura ambiente. Si raffredda a 0-5 °C per almeno 1 h e si filtra il solido lavando con acqua fredda (2 x 10 mi), poi con toluene (3 x 10 mi). Si essicca il prodotto in stufa a 50°C sotto vuoto per 18 ore, si ottiene 8,9 g di prodotto avente un rapporto enantiomerico 98(S):2(R) ed una resa del 92%. Example 5 - OPTICAL RESOLUTION OF (S) - {4-METHYL-2 - [(1-CARBOSS) -METHYL -] - PENTYL -} - ISOPROPYL CARBAMATE (V) In a 100 ml three-necked flask under the atmosphere of nitrogen are added {4-methyl-2 - [(1-carboxy -) - methyl -] - pentyl -} - isopropyl carbamate (13.0 g, 53.0 mmol), triethylamine (2.70 g; 26, 5 mmol) and (S) - (-) - Phenylethylamine (3.2 g, 26.5 mmol) in a 95: 5 water / isopropanol mixture (50 ml). The solution is heated to a temperature of about 60-65 ° C and slowly cooled to about 35 ° C, then it is heated to 50 ° C and allowed to cool spontaneously to room temperature. It is cooled to 0-5 ° C for at least 1 h and the solid is filtered by washing with cold water (2 x 10 ml), then with toluene (3 x 10 ml). The product is dried in an oven at 50 ° C under vacuum for 18 hours, giving 8.9 g of product having an enantiomeric ratio 98 (S): 2 (R) and a yield of 92%.
Procedendo in modo analogo si ottengono: Proceeding in the same way we obtain:
{4-metil-2-[(1-carbossi)-metil]-pentil}-carbammato di metile, e Methyl {4-methyl-2 - [(1-carboxy) -methyl] -pentyl} -carbamate, and
{4-metil-2-[(1-carbossi)-metil]-pentil}-carbammato di etile. {4-methyl-2 - [(1-carboxy) -methyl] -pentyl} -carbamate of ethyl.
Esempio 6 - SINTESI DELL’ACIDO (S)-(+)-3-AMMINOMETIL-5-METILESANOICO (I) Example 6 - SYNTHESIS OF THE ACID (S) - (+) - 3-AMINOMETHYL-5-METHYLESANOIC (I)
In un pallone a tre colli da 50 mi sotto atmosfera di azoto sono aggiunti (S)-{4-metil-2-[(l-carbossi-)-metil-]-pentil-}-carbammato di isopropile sale di (S)-(-)-feniletilammina (60,0 g, 164 mmol) avente un rapporto enantiomerico 98(S):2(R) ed una soluzione di acido cloridrico al 37% p/p (17,8 g, 180,4 mmol) in acqua (200 mi), e si estrae con toluene (2 x 200 mi). Si concentra la fase organica a piccolo volume, si riprende con acido cloridrico 30% p/p (59,6 g, 490 mmol) e si scalda la miscela a 90-95°C per 24 h. Si raffredda la soluzione a 0-5°C, si aggiunge idrossido di sodio (18,0 g, 450 mmol) e si mantiene sotto agitazione a freddo per almeno 1 h. Si filtra il solido lavando con una soluzione di acqua/isopropanolo 8:2 raffreddata a 0-5°C (2 x 15 mi) e si essicca in stufa. Si ottiene un solido bianco, 21,1 g, con rapporto enantiomerico 99,96(S):0,04(R); resa 82%. (S) - {4-methyl-2 - [(1-carboxy -) - methyl -] - pentyl -} - carbamate of isopropyl salt of (S) are added to a 50 ml three-necked flask under nitrogen atmosphere - (-) - phenylethylamine (60.0 g, 164 mmol) having an enantiomeric ratio 98 (S): 2 (R) and a 37% w / w hydrochloric acid solution (17.8 g, 180.4 mmol ) in water (200 ml), and extracted with toluene (2 x 200 ml). The organic phase is concentrated to a small volume, taken up with hydrochloric acid 30% w / w (59.6 g, 490 mmol) and the mixture is heated at 90-95 ° C for 24 h. The solution is cooled to 0-5 ° C, sodium hydroxide (18.0 g, 450 mmol) is added and it is kept under cold stirring for at least 1 h. The solid is filtered by washing with an 8: 2 water / isopropanol solution cooled to 0-5 ° C (2 x 15 ml) and dried in an oven. A white solid is obtained, 21.1 g, with an enantiomeric ratio 99.96 (S): 0.04 (R); yield 82%.
1H-NMR (300 MHz, CDC13, 28°C): δ 2,95 (m, 2H); 2,30-2,05 (m, 3H); 1,60 (m, 1 H); 1,2 (m, 2H); 0,80 (dd, 6H). 1H-NMR (300 MHz, CDC13, 28 ° C): δ 2.95 (m, 2H); 2.30-2.05 (m, 3H); 1.60 (m, 1H); 1.2 (m, 2H); 0.80 (dd, 6H).
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ITMI20071722 ITMI20071722A1 (en) | 2007-09-05 | 2007-09-05 | PROCEDURE FOR THE PREPARATION OF ACID (S) (+) - 3- (AMINOMETHYL) -5-METHYLESANOIC |
EP08008415A EP1992609A1 (en) | 2007-05-14 | 2008-05-05 | A process for the preparation of a (S)(+)-3-(aminomethyl)-5-methylhexanoic acid |
US12/119,967 US20080311635A1 (en) | 2007-05-14 | 2008-05-13 | Process for the preparation of (s)(+)-3-(aminomethyl)-5-methylhexanoic acid |
CA002631110A CA2631110A1 (en) | 2007-05-14 | 2008-05-13 | A process for the preparation of (s)(+)-3-(aminomethyl)-5-methylhexanoic acid |
JP2008125408A JP2009046467A (en) | 2007-05-14 | 2008-05-13 | Method for preparing (s)(+)-3-(aminomethyl)-5-methylhexanoic acid |
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ITMI20071722 ITMI20071722A1 (en) | 2007-09-05 | 2007-09-05 | PROCEDURE FOR THE PREPARATION OF ACID (S) (+) - 3- (AMINOMETHYL) -5-METHYLESANOIC |
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ITMI20071722A1 true ITMI20071722A1 (en) | 2009-03-06 |
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ITMI20071722 ITMI20071722A1 (en) | 2007-05-14 | 2007-09-05 | PROCEDURE FOR THE PREPARATION OF ACID (S) (+) - 3- (AMINOMETHYL) -5-METHYLESANOIC |
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