MX2008004089A - Processes for the synthesis of o-desmethylvenlafaxine - Google Patents
Processes for the synthesis of o-desmethylvenlafaxineInfo
- Publication number
- MX2008004089A MX2008004089A MXMX/A/2008/004089A MX2008004089A MX2008004089A MX 2008004089 A MX2008004089 A MX 2008004089A MX 2008004089 A MX2008004089 A MX 2008004089A MX 2008004089 A MX2008004089 A MX 2008004089A
- Authority
- MX
- Mexico
- Prior art keywords
- process according
- oba
- coba
- solvent
- protected
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 79
- KYYIDSXMWOZKMP-UHFFFAOYSA-N Desvenlafaxine Chemical compound C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 title claims abstract description 4
- 238000003786 synthesis reaction Methods 0.000 title abstract description 13
- 230000015572 biosynthetic process Effects 0.000 title abstract description 12
- 230000002194 synthesizing Effects 0.000 title abstract description 12
- 239000002904 solvent Substances 0.000 claims description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 239000002585 base Substances 0.000 claims description 34
- 239000002253 acid Substances 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 33
- 239000011780 sodium chloride Substances 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000004519 manufacturing process Methods 0.000 claims description 22
- -1 amine salt Chemical class 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 17
- 230000003213 activating Effects 0.000 claims description 16
- 239000003638 reducing agent Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- JHIVVAPYMSGYDF-UHFFFAOYSA-N Cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000011084 recovery Methods 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- BUDQDWGNQVEFAC-UHFFFAOYSA-N 3,4-dihydro-2H-pyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 10
- 239000010410 layer Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- FGWUONPLLAJZPP-UHFFFAOYSA-N OC([N-]C)C1=CC=CC=C1 Chemical compound OC([N-]C)C1=CC=CC=C1 FGWUONPLLAJZPP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical group [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N Pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 150000001340 alkali metals Chemical class 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 229910052987 metal hydride Inorganic materials 0.000 claims description 5
- 150000004681 metal hydrides Chemical group 0.000 claims description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 5
- 239000003223 protective agent Substances 0.000 claims description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 4
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-Hydroxyphenylacetic acid Chemical class OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 claims description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Chemical compound [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 claims description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 claims description 3
- 101710024147 CYP716A53v2 Proteins 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 3
- 235000019439 ethyl acetate Nutrition 0.000 claims description 3
- 239000008079 hexane Substances 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 claims description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 2
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 claims description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N Aluminium hydride Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 2
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 claims description 2
- PBGGNZZGJIKBMJ-UHFFFAOYSA-N di(propan-2-yl)azanide Chemical compound CC(C)[N-]C(C)C PBGGNZZGJIKBMJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- BLUITXBEAKYQKE-UHFFFAOYSA-N 2-(4-hydroxyphenyl)-N,N-dimethylacetamide Chemical compound CN(C)C(=O)CC1=CC=C(O)C=C1 BLUITXBEAKYQKE-UHFFFAOYSA-N 0.000 claims 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N Diisopropylamine Chemical group CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims 2
- 125000003944 tolyl group Chemical group 0.000 claims 2
- FOBXCIWPAJUIQC-UHFFFAOYSA-N 2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)-N,N-dimethylacetamide Chemical compound C1CCCCC1(O)C(C(=O)N(C)C)C1=CC=C(O)C=C1 FOBXCIWPAJUIQC-UHFFFAOYSA-N 0.000 claims 1
- YCFXZVSXGXVNBC-UHFFFAOYSA-N 2-(2-hydroxyphenyl)-N,N-dimethylacetamide Chemical compound CN(C)C(=O)CC1=CC=CC=C1O YCFXZVSXGXVNBC-UHFFFAOYSA-N 0.000 claims 1
- IRXSLJNXXZKURP-UHFFFAOYSA-N Fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 claims 1
- GRKCZMCXXJZFCI-UHFFFAOYSA-N OC1=CC=C(C=C1)CC(=O)O.OC1=CC=C(C=C1)CC(=O)O Chemical class OC1=CC=C(C=C1)CC(=O)O.OC1=CC=C(C=C1)CC(=O)O GRKCZMCXXJZFCI-UHFFFAOYSA-N 0.000 claims 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- 125000005103 alkyl silyl group Chemical group 0.000 claims 1
- 229960005070 ascorbic acid Drugs 0.000 claims 1
- 235000010323 ascorbic acid Nutrition 0.000 claims 1
- 239000011668 ascorbic acid Substances 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 229940043279 diisopropylamine Drugs 0.000 claims 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 239000011814 protection agent Substances 0.000 claims 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims 1
- 125000005353 silylalkyl group Chemical group 0.000 claims 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical group CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims 1
- 150000003512 tertiary amines Chemical class 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 11
- 241000629719 Oat dwarf virus Species 0.000 description 42
- 238000003756 stirring Methods 0.000 description 16
- 230000002829 reduced Effects 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 13
- 229960004688 venlafaxine Drugs 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012047 saturated solution Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000017858 demethylation Effects 0.000 description 4
- 238000010520 demethylation reaction Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- 229940005513 ANTIDEPRESSANTS Drugs 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- JLGVMPWOBYLJRL-UHFFFAOYSA-N C1(CCCCC1)C([N-]C)(C1=CC=CC=C1)O Chemical compound C1(CCCCC1)C([N-]C)(C1=CC=CC=C1)O JLGVMPWOBYLJRL-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- SFLSHLFXELFNJZ-MRVPVSSYSA-N L-Noradrenaline Natural products NC[C@@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-MRVPVSSYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 229960002748 Norepinephrine Drugs 0.000 description 2
- 229940076279 Serotonin Drugs 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N Sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 230000001430 anti-depressive Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical group Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- MOHIYTLRUDZQDP-UHFFFAOYSA-N 2-cyclohexyl-2-phenylpropanenitrile Chemical compound C=1C=CC=CC=1C(C#N)(C)C1CCCCC1 MOHIYTLRUDZQDP-UHFFFAOYSA-N 0.000 description 1
- NVAOLENBKNECGF-UHFFFAOYSA-N 2-phenylpropanenitrile Chemical compound N#CC(C)C1=CC=CC=C1 NVAOLENBKNECGF-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N Acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 241001120493 Arene Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N N,N-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- CROBTXVXNQNKKO-UHFFFAOYSA-N borohydride Chemical compound [BH4-] CROBTXVXNQNKKO-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic Effects 0.000 description 1
- 230000005591 charge neutralization Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide DMF Chemical group CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000011874 heated mixture Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- FZTWZIMSKAGPSB-UHFFFAOYSA-N phosphide(3-) Chemical compound [P-3] FZTWZIMSKAGPSB-UHFFFAOYSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
Abstract
Provided are processes and intermediates for the synthesis of O- desmethylvenlafaxine.
Description
PROCESS FOR THE SYNTHESIS OF 0-DESMETILVENLAFAXINA
FIELD OF THE INVENTION The invention comprises a process for the synthesis of 0-desmethylvenlafaxine.
BACKGROUND OF THE INVENTION Venlafaxine, (±) -1- [2- (Dimethylamino) -1- (-methoxyphenyl) -ethyl] cyclohexanol, of the following formula:
It is the first of a class of antidepressants. Venlafaxine acts by inhibiting the reuptake of norepinephrine and serotonin and is an alternative for selective antidepressants and inhibitors of resorption.
It is reported that O-desmeilvenlafaxine, 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol, of the following formula:
is a metabolite of venlafaxine, which is also known as a
inhibitor of norepinephrine and serotonin absorption. See
Klamerus, K. J. et al, "Introduction of the Composite Paramter to
the Pharmcokinetics of Venlafaxine and its Active O-Desmethyl
Metabolite "and J. Clin. Pharmacol 32: 716-724 (1992).
The processes for the synthesis of O-demethylevenlafaxine by demethylation of the methoxy group of venlafaxine are described in
U.S. Patent Nos. 7,026,508 and 6,689,912.
The synthesis that is revealed in the preceding patents is carried out
according to the following scheme:
Venlafaxine V L wherein "MCB" refers to methyl benzyl cyanide, "CMBC" refers to cyclohexyl methylbenzyl cyanide, "DDMV" refers to didesmethyl venlafaxine, and "ODV" refers to 0-desmethylvenlafaxine.
The demethylation process disclosed in U.S. Patent No. 7,026,508 provides an ODV succinate salt using L-selectride, which is an alkali metal salt of trialkyl borohydride; wherein the hydrogen gas is formed during the reaction. Therefore, the process is not suitable for manufacturing on an industrial scale.
US Patent Application No. 2005/0197392 discloses a method for preparing the hydrochloride salt of (±) 0-desmethylvenlafaxine by the reaction of venlafaxine with lithium diphenyl phosphide.
U.S. Patent No. 6,689,912 discloses the demethylation process performed using a high molecular weight alkane, arene, or aryl alkyl thiolate anion salt in the presence of a protic or aprotic solvent. The salt can be prepared separately and therefore react with venlafaxine, or can react in situ with venlafaxine. When prepared separately, the solvent, methanol, must be removed. This operation is very complicated because the mixture containing the salt is highly viscous, therefore the operation requires a prolonged time even under high vacuum. When the reaction is carried out in situ through the removal of methanol in situ, this operation is still tedious and only partially successful, since it is difficult to reach the high temperature that the reaction needs to advance.
The processes for the synthesis of ODV described are all indirect, that is, carried out through Venlafaxine. The present invention provides a direct synthesis of 0-demethylvenlafaxine; that is, without going through venlafaxine as an intermediate compound.
Extract of the invention
In one embodiment, the invention comprises hydroxyphenyl dimethylamide (OBA), which has the following formula
OBA In another embodiment, the present invention provides a process for preparing hydroxyphenyl dimethylamide (OBA) which comprises combining hydroxyphenyl carboxy (OBCarboxi), a catalyst and an acid activating agent to obtain an activated acid; recover the activated acid and combine it with a dimethylamine to obtain OBA.
Preferably, the process for preparing OBA is carried out in the presence of an organic solvent.
In yet another embodiment, the present invention provides a process for preparing ODV by preparing OBA as described above, and converting it to ODV. OBA can be transformed into ODV through another intermediate product such as COBA.
In yet another embodiment, the present invention comprises hydroxy protected OBA (POBA), having the following formula
In another embodiment, the present invention comprises a process for preparing POBA comprising combining OBA with a hydroxyl protecting agent and a base.
In yet another embodiment, the present invention provides a process for preparing ODV by preparing POBA as described above, and converting it to ODV. POBA can be transformed into ODV through another intermediate compound such as PCOBA.
In yet another embodiment, the present invention comprises cyclohexyl OBA (COBA), which has the following formula:
In one embodiment the process for the preparation of cyclohexyl OBA (COBA) comprising: reacting OBA with cyclohexanone and a base which can form a carbanion; and recover the COBA obtained.
In yet another embodiment, the present invention provides a process for preparing ODV by preparing COBA as described above, and converting it to ODV, by any method known in the art, ie the method described above.
In yet another embodiment, the present invention comprises a hydroxyl-protected COBA (PCOBA) having the following formula:
PCOBA In another embodiment the process for preparing PCOBA comprising: combining POBA with cyclohexanone and a base which can form a carbanion; and recover the PCOBA obtained.
In yet another embodiment, the present invention provides a process for preparing ODV by preparing PCOBA as described above and converting it to ODV, by any method known in the art, ie the method described above.
In another embodiment, the present invention comprises a process for preparing ODV from COBA comprising: reacting COBA and a reducing agent to obtain ODV, where optionally, PCOBA can be used as an initial material.
In another embodiment, the present invention comprises a process for preparing ODV comprising the steps of: combining OBCarboxi, a catalyst and an acid activating agent to obtain an activated acid; recover the activated acid and combine it with an amine to obtain OBA; reacting activated OBA with cyclohexanone and a base that can form a carbanion; recover the COBA and react the obtained COBA; a reducing agent; and recovering the ODV obtained, wherein, optionally, a protected derivative of OBA (POBA) can be used as an initial material and PCOBA is obtained, which is then reacted with a reducing agent to obtain ODV.
Detailed Description of the Invention As used herein, the term "ambient temperature" refers to a temperature of 18 ° C to 25 ° C.
As used herein, the term "OBA" refers to hydroxyphenyl dimethylamide (IUPAC name: 2- (-hydroxyphenyl) N, N-dimethylacetamide) of the following structure: OBA
As used herein, the term "POBA" refers to protected hydroxyphenyl dimethylamide (IUPAC name: 2- (4-hydroxyphenyl) -N, -dimethylacetamide) of the following structure:
wherein x is a hydroxy protecting group.
As used herein, the term "COBA" refers to cyclohexyl hydroxyphenyl dimethylamide (IUPAC name: 2- (l-hydroxycyclohexyl) -2- (-hydroxyphenyl) -N, -dimethylacetamide) of the following structure:
COBA As used herein, the term "PCOBA" refers to protected cyclohexyl hydroxyphenyl dimethylamide (IUPAC name: 2- (1-hydroxycyclohexyl) -2- (4-hydroxyphenyl) -N, -dimethylacetamide) of the following structure :
wherein x is a hydroxy protecting group.
As used herein, the term "ODV" refers to 0-desmethylvenlafaxine.
The present invention provides a direct synthesis of ODV through novel intermediates. This process produces ODV and its intermediate compounds with high yields and purity. In the process of the present invention, ODV is synthesized without going through venlafaxine, which results in the elimination of a demethylation step.
In the process of the invention, the intermediate compound OBA is condensed with cyclohexanone to form the intermediate compound COBA. In addition, the carboxylic group of COBA is reduced, and the reduced product is converted to ODV. The process can be done through the intermediate compound POBA and PCOBA, to increase the yield, due to the avoidance of collateral reactions. The process is described in the following scheme:
OBCarboxi OBA COBA ODV
POBA PCOBA
In one embodiment, the invention comprises hydroxyphenyl dmethylamide (OBA) (IUPAC name: 2- (4-hiroxyphenyl) -N, N-dimethylacetamide). OBA is characterized by 1HNMR (Braker DPX-300 (DMS0-d6) with d: 2.80 (s, CH3-N), 2.96 (s, CH3N), 3.53 (s, CH2), 6.79 (m, H atom), 6.98 (m, H atom), 9.24 (s, OH), OBA has a mass of 180 (MS (CI +) = 180).
In one embodiment, the present invention provides isolated or purified OBA. Isolated refers to being separated from the reaction mixture where it is formed. Preferably, the OBA is at least 50% pure measured by HPLC.
OBA is prepared by a process comprising combining hydroxyphenyl carboxy OBCarboxi (IUPAC name: (4-hydroxyphenyl) acetic acid catalyst) and an acid activating agent to obtain an activated acid; recover the activated acid and combine it with an amine to obtain OBA.
Preferably, the catalyst is an organic catalyst. More preferably, the catalyst is dimethyl formamide DMF or p-toluene sulfonate pyridinium (PPTS).
Generally, the reaction is carried out in the presence of a solvent. The solvent is an organic solvent that does not react with the acid activating agent. More preferably, the solvent is selected from the group consisting of the aromatic hydrocarbon of C6-i2, preferably a halogenated hydrocarbon of C6 to Ce, of Ci_4, preferably chloroform, dichloromethane, an ether preferably a C4 to C6 ether, more preferably tetrahydrofuran, diethyl ether, methyl tert-butyl ether and mixtures thereof. Even more preferably, the solvent is selected from the group consisting of toluene, CH2C12 and THF. More preferably, the solvent is CH 2 Cl 2.
Usually, the reaction with the acid activating agent is exothermic, therefore the mixture is cooled before combining it with the acid activating agent. Preferably, the mixture is cooled to a temperature of -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C, more preferably to a temperature of 0 ° C.
To reduce the exothermic effect of the reaction, the acid activating agent is added dropwise, preferably for 30 minutes to 3 hours. Preferably, the acid activating agent is an agent that activates carboxylic acids, ie converts the "OH" into a suitable leaving group. The activating agent may be S0C12, C0C12, DCC (? '-dicyclohexyl carbodiimide) or the like, HOBT (N-hydroxybenzotriazole), FMOC (fluorenylmethoxycarbonyl) or the like (and other analogs used in the chemical composition of the peptides) or PC15 or (COCI) 2 · More preferably, the activating agent is S0C12.
After adding the activation agent, the obtained mixture is heated, preferably at a temperature of 0 ° C to 30 ° C, preferably 15 ° C to 28 ° C. More preferably, the heating is at room temperature.
The heated mixture is stirred for a sufficient time to obtain the activated acid, preferably for a period of 0.5 to 3 hours, preferably 1 to 2.5 hours. More preferably, the stirring is for 2 hours.
The activated acid is optionally recovered by any method known in the art. Preferably, it is recovered by removing the solvent and providing a residue comprising the activated acid. A person skilled in the art can also foresee a process of a container that skips the recovery of the intermediate compound in the synthesis scheme.
Preferably, the solvent is removed by evaporation under reduced pressure (pressure less than one atmosphere).
Then, the residue is optionally dissolved in another organic solvent, where the solvent is described above. Subsequently, the solution is combined with dimethylamine to provide a mixture. This reaction is easier if a dimethylamine salt is used, and then the salt is removed with another amine. Preferably, the amine salt is dimethylamine-HCl and the second amine is a C3-C9 trialkylamine, wherein each alkyl chain is independently selected from C1-C7 carbons. The example of said amine includes diisopropylethylamine. A gaseous amine can also be used. Preferably, the second amine is added dropwise, more preferably, for 1 hour.
The mixture is then stirred for a sufficient time to obtain OBA. Preferably, the stirring is carried out for a time of from 1 hour to 24 hours, more preferably from 4 hours to 16 hours. More preferably, the stirring is carried out overnight.
OBA can be recovered. The recovery is preferably carried out by cooling the new mixture providing a precipitate; washing, filtering and drying. Preferably, the cooling is performed by adding a saturated solution of a base. More preferably, the base is an inorganic base, such as an alkali metal or alkaline earth metal carbonate / bicarbonate. More preferably, the base is NaHCC > 3.
Preferably, the precipitate is filtered under a reduced pressure. Preferably, the washing is carried out with methylene chloride and drying, under vacuum (pressure less than 100 mmHg). Preferably, the drying is at a temperature of 20 ° C to 80 ° C. More preferably, the drying is carried out at room temperature.
The process for preparing OBA may also comprise a process for converting OBA into ODV. OBA can be transformed into ODV through another intermediate compound such as COBA.
In another embodiment, the present invention comprises OBA protected by hydroxy (POBA). Suitable hydroxy protected groups are listed in T.W. Greene, Protective Gropus in Organic Synthesis, (12nd ed.), Which is incorporated herein by reference. More preferably, POBA is a POBA protected with silyl, such as a POBA protected with tri (Ci_6 alkyl) silyl, wherein the alkyl groups may be the same or different, preferably OBA protected with t-butyldimethylsilyl ether (TBDMS) , or trimethylsilyl (TMS), where TBDMS is preferred, or OBA protected with DHP.
In one embodiment the present invention provides isolated or purified POBA, which includes TBDMS-OBA. Isolated refers to being separated from the reaction mixture in which it is formed. Preferably, the POBA is at least 50% pure measured by HPLC.
TBDMS-OBA is characterized by a 1HNMR (Bruker DPX-300 (DMSO-d6) with d: 0.20 (s, Me2Si), 0.99 (s, tBuSi), 2.85 (s, CH3-N), 2.99 (s, CH3N), 3.62 (s, CH2), 6.77 (m, H atom), 7.10 (m, H atom), POBA, which includes TBDMS-OBA, can be Prepare by combining OBA with a suitable hydroxyl protective agent and a base.An acid can also be used instead of a base.
Usually, the reaction is carried out in the presence of a solvent. Preferably, the solvent is an organic solvent. Preferably, the solvent is a non-protic solvent. The organic solvent can be an aromatic hydrocarbon of C6 to Ci2 or a chlorinated hydrocarbon of Ci-C6 or a C4_6 ether. More preferably, the solvent is selected from the group consisting of toluene, CH2C12 and THF. More preferably, the solvent is CH2C12.
Preferably, the hydroxyl protecting agent is a trialkylsilyl halide, preferably a tri (Ci_6) alkyl silyl halide, wherein the alkyl may be the same or different, preferably the trialkylsilyl halide is a trimethylsilyl halide or a halide of tert-butyldimethylsilyl, wherein the halide is chloride or bromide or DHP (dihydropyran). Preferably, the hydroxyl protecting agent is a silyl protecting group or DHP (dihydropyran). More preferably, the hydroxyl protecting group is TBDMS-C1, acetyl chloride or acetic anhydride.
Preferably, the base is imidazole. They can also be used after bases such as pyridine, triethylamine, lutidine, dimethylaminopyridine.
The obtained combination is stirred at a temperature of 0 ° C to 100 ° C, preferably 40 ° C to 70 ° C. Preferably, the stirring is carried out at a temperature of 55 ° C.
Preferably, the above combination is maintained, while stirring, for 0.5 hour to 24 hours, preferably 1 hour to 4 hours, more preferably for two hours, during which time POBA is formed.
The process to prepare POBA can also comprise a recovery process. Recovery is preferably carried out by cooling the combination providing a two-phase system; separating the two phases obtained, washing and drying the organic phase, followed by filtration and evaporation of the solvent under reduced pressure (pressure below one atmosphere.Preferably, the combination is cooled with saline and 10% aqueous solution of citric acid .
The process for preparing POBA may also comprise a process for converting POBA to ODV. POBA can be converted to ODV through COBA or PCOBA.
In another embodiment, the present invention comprises cyclohexyl OBA (COBA). COBA isolated or purified is also provided. "Isolated" refers to being separated from the reaction mixture in which it is formed. Preferably, the COBA is at least 50% pure measured by HPLC.
COBA can be prepared by reacting OBA with cyclohexanone and a base which can form a carbanion; and recovering the COBA obtained. Optionally, an OBA protected derivative can be used as the starting material to obtain PCOBA.
Usually, the reaction is carried out in the presence of a solvent. Preferably, the solvent is one of those described above. More preferably, the solvent is THF.
Initially, OBA or POBA is combined with the solvent to obtain a mixture. Then add a base that can form a carbanion, providing a new mixture.
Preferably, the base can form a carbanion. More preferably, the base is LDA; alkali metal diisopropylamide or an alkaline earth metal (such as lithium); or BuLi. The base can also be sodium hydride (NaH); or alkali metal or alkaline earth metal salts (such as sodium or potassium or lithium) of bis trimethylsilylamide. { MN (SiMe3) 2.}.; or a tert-butoxide metal salt (MOtBu).
The reaction of the base with the reagent is exothermic. Preferably, the base is added at a temperature of 80 ° C to 25 ° C. For example, when the base is LDA, the aggregate can be made at room temperature and when the base is BuLi, the aggregate can be made at a temperature of -80 ° C.
Usually, the base is added drop by drop. Preferably, the dropwise addition is carried out for a period of 30 minutes. Then the new mixture is stirred. Preferably, the stirring is for 10 minutes to 2 hours. More preferably, the new mixture is stirred for 30 minutes.
Cyclohexanone is then added to the mixture. Preferably the cyclohexanone is added dropwise, more preferably, for a period of time of 30 minutes.
Preferably, the obtained mixture is maintained, while stirring, for 30 minutes to 24 hours, more preferably, the stirring is carried out overnight.
The reaction mixture is then cooled, by reacting the reaction mixture with a proton donor, such as NH 4 Cl. The recovery provides COBA or PCOBA, which depends on the initial material.
PCOBA and COBA can then be recovered. Preferably, the recovery step includes: separating the layers obtained after cooling, washing the organic layer obtained after cooling, and evaporating the residual organic solvent under reduced pressure (pressure less than one atmosphere) to obtain COBA or PCOBA.
In another embodiment, the present invention comprises a hydroxyl-protected cyclohexyl OBA (PCOBA). Preferably, PCOBA is COBA protected with TBDMS.
The process to prepare COBA or PCOBA can also comprise a process to convert COBA or PCOBA into ODV. COBA and PCOBA can be converted to ODV by reacting COBA or PCOBA with a reducing agent, and recovering to obtain ODV.
Usually, COBA or PCOBA are combined with a solvent to obtain a solution. Solvents that are inert to the reducing agent can be used. Preferably, the solvent is THF. Subsequently, a reducing agent is added, preferably, the reducing agent is a metal hydride complex. More preferably, the metal hydride complex is selected from the group consisting of BH3 derivatives or aluminum hydride derivatives. More preferably, the resulting agent is LiAlH4, NaBH4, NaBH3CN; sodium cyanoborohydride. Instead of using the metal hydride complex, the hydrogenation can be carried out under H2 pressure in the presence of a catalyst such as N or Co.
Usually, the reducing agent is added dropwise to prevent the accumulation of heat. The aggregate can be done during a period of 30 minutes. The aggregate can preferably be made at a temperature of -50 ° C up to room temperature. Preferably, the temperature is the room temperature.
The aggregate of the reducing agent provides a mixture. Preferably, the mixture is stirred for 1 hour to 24 hours. More preferably, the stirring is carried out overnight.
Preferably, the recovery of ODV is carried out by cooling. More preferably, the cooling is carried out by acidifying the mixture. The acidification is carried out for example by adding an aqueous solution of HC1 or NH4C1. Cooling, generally, provides a two-phase system, comprising an aqueous phase and an organic phase. The phases are separated, and the aqueous phase is neutralized, adding a base. The neutralization is carried out by adding a base such as a carbonate / bicarbonate of alkali metal or alkaline earth metal. Preferably, the base is a saturated solution of NaHCO 3.
The process for preparing ODV may also comprise a recovery process. Recovery can be done by extracting ODV from the aqueous layer, for example by adding an organic solvent immiscible with water. Preferably, the organic solvent immiscible with water is CH 2 Cl 2, EtOAc, hexanes or toluene.
The extract can then be dried, filtered and evaporated under reduced pressure (pressure less than one atmosphere). The drying is preferably about a2S04.
One skilled in the art will appreciate that each of the processes described above can be combined in a continuous process for the synthesis of ODV. In said process ODV can be synthesized by combining OBCarboxi, a catalyst and an acid activating agent to obtain an activated acid; recover the activated acid, combine it with an amine to obtain OBA; reacting the obtained OBA with cyclohexanone and a base which can form a carbanion; recover the COBA obtained; reacting the obtained COBA and a reducing agent; and recover the obtained ODV. Optionally, a protected OBA derivative (POBA) can be used as the starting material for the process to prepare PCOBA, and where optionally, a COBA protected derivative (PCOBA) can be used as the starting material for the preparation of ODV.
Having described the invention with reference to certain preferred embodiments, other embodiments will be apparent to one skilled in the art upon consideration of the specification. The invention is also defined with reference to the following examples which describe in detail the synthesis of the OBA compound, COBA, its protected forms and also its conversion into O-demethylvenlafaxine. It will be apparent to those skilled in the art that many modifications can be made to both materials and methods, without departing from the scope of the invention.
EXAMPLES
Preparation of OBA
Example 1:
A 500 ml three neck flask equipped with a nitrogen inlet, a thermometer and a mechanical stir bar was loaded with OBcarboxi (10 g, 65, 72 mmol), DMF (1 mL) and CH2C12 (50 mL). The reaction mixture was stirred at 0 ° C and S0C12 was added dropwise.
The reaction was stirred at room temperature for 2 hours and then the solvent was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL) and dimethylamine-HCl (100 g, 1.22 mol) was added. Then diisopropylethylamine (150 ml, 0.882 mol) was added dropwise. The mixture was stirred at room temperature overnight and then washed with a saturated solution of NaHCO3; a precipitate appeared. The precipitate was filtered under reduced pressure and washed with methylene chloride. The solid thus obtained was dried in a vacuum oven at room temperature to obtain 5.55 g of OBA (purity 99.45%).
The organic layer was washed with saline and evaporated to dryness and gave 5.84 g of OBA crystals (purity 96.57%). Total yield: 97.85%.
Preparation of Protected OBA (POBA)
Example 2:
A 100 ml three neck flask equipped with a nitrogen inlet, a thermometer and a mechanical stir bar was charged with OBA (2.4 g, 13.39 mmol) of TBDMS-C1 (4.5 g, 29, 9 mmol), imidazole (5.5 g, 80.78 mmol) and CH2C12 (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saline and a 10% aqueous solution of citric acid. The organic phase was then washed with saline and dried over Na2SO4. After filtration the solvent was evaporated under reduced pressure to obtain 3.82 g of OBA-P (purity: 99.34%, yield: 97.45%).
Example 3:
In a 50 ml flask equipped with a mechanical stir bar, OBA (1.45 g, 8.09 mmol) was dissolved at room temperature in DHP (8 ml) under nitrogen. Pyridinium p-toluene sulfonate (PPTS, catalytic amount) was added and the reaction mixture was heated at 55 ° C for 5 hours. The reaction was monitored by HPLC. EtOAc was added and the organic layer was washed with saline, dried over MgSO4 and filtered under reduced pressure to obtain OBA-DHP.
Preparation of protected COBA (PCOBA) Example 4:
A 100 ml three neck flask equipped with a nitrogen inlet, a thermometer and a mechanical stir bar was loaded with OBA-TBDMS (3.8 g, 12.95 mmol) and THF (50 ml). The solution was cooled to -80 ° C and n-BuLi (1M in Hexane 8.5 ml, 13.6 mmol) was added dropwise. The reaction was stirred at -80 ° C for 45 minutes and cyclohexanone (1.7 g, 17.32 mmol) was added dropwise. This mixture was stirred for 3 hours at this temperature and poured into a saturated solution of NH 4 Cl. The layers separated.
The organic layer was washed with saline and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure to obtain 4.85 g of COBA-P (purity: 79.63%, yield: 95.65%).
Preparation of COBA through OBA Example 5:
A 100 ml three neck flask equipped with a nitrogen inlet, a thermometer and a mechanical stir bar was charged with OBA (1.2 g, 6.69 mmol) and THF (10 mL). The mixture was stirred at room temperature and LDA (2M in 7 mL THF, 14.02 mmol) was added dropwise. The mixture was stirred at this temperature for 30 minutes and cyclohexanone (1.4 g, 14.26 mmol) was added dropwise. This mixture was stirred overnight at room temperature and then poured into a saturated aqueous solution of NH4C1. The layers were separated and the organic phase was washed with saline and dried over Na2SO4 and evaporated under reduced pressure to obtain COBA.
Preparation of ODV through PCOBA Example 6:
A 100 ml three neck flask equipped with a nitrogen inlet, a thermometer and a mechanical stir bar was charged with PCOBA-TBDMS (2.3 g, 5.6 mmol) and THF (30 mL). This solution was stirred at room temperature and LiAlH4 (1M in 10 mL THF, 10 mmol) was added dropwise. The mixture was stirred at room temperature overnight. This mixture was then acidified with a 10% aqueous solution of HC1. The layers were separated and then the aqueous phase was basified with a saturated solution of NaHCO 3. The aqueous layer was extracted with CH2Cl2, dried over Na2SO4, filtered and evaporated under reduced pressure to obtain 0.43 g of ODV (purity = 100%).
Preparation of ODV through COBA Example 7:
A 100 ml three neck flask equipped with a nitrogen inlet, a thermometer and a mechanical stir bar is charged with COBA-TBDMS (2.2 g, 5.6 mmol) and THF (30 ml). This solution was stirred at room temperature and LiAlH4 (1M in 10 mL THF, 10 mmol) was added dropwise. The mixture was stirred at room temperature overnight. This mixture was then acidified with 10% aqueous HC1 solution. The layers are separated and the aqueous phase is basified with a saturated solution of NaHCO3. The aqueous layer is extracted with CH2C12, dried over Na2SO4, filtered and evaporated under reduced pressure to obtain ODV.
Claims (71)
1. 2- (-hydroxyphenyl) -N, N-dimethylacetamide having the structure:
2. The 2- (4-hydroxyphenyl) -N, N-dimethylacetamide according to claim 1, wherein the compound is characterized by an XHNMR (Bruker DPX-300 (DMS0-d6) with d: 2.80 (s, CH3) -N), 2.96 (s, CH3N), 3.53 (s, CH2), 6.70 (m, H atom), 6.98 (m, H atom), 9.24 (s, OH), and a mass of 180 (MS (Cl +) = 180).
3. The 2- (4-hydroxyphenyl) -N, -dimethylacetamide according to claim 1, which has a purity of 50% as measured by HPLC.
4. A process for preparing the 2- (4-hydroxyphenyl) -N, N-dimethylacetamide according to any of the preceding claims, which comprises forming an activated acid derivative of 4-hydroxyphenylacetic acid (4-hydroxyphenyl) acetic acid, and react the activated acid with dimethylamine.
5. A process according to claim 4, wherein the activated acid derivative of 4-hydroxyphenylacetic acid is prepared by combining 4-hydroxyphenylacetic acid with an acid activating agent and a catalyst and optionally recovering the activated acid.
6. A process according to claim 4 or claim 5, wherein the activated acid is combined with an amine to obtain OBA, and optionally the OBA is recovered.
7. The process according to claim 5, wherein the catalyst is an organic catalyst.
8. The process according to claim 5, wherein the catalyst is dimethyl formamide (DMF) or p-toluene sulfonate pyridinium (PPTS).
9. The process according to claim 4, 5 or 6, wherein the acid is activated in the presence of a solvent.
10. The process according to claim 9, wherein the solvent is selected from the group consisting of an aromatic hydrocarbon of C6-i2, a halogenated hydrocarbon of Ci_4, a C4-8 ether and mixtures thereof.
11. The process according to claim 9, wherein the solvent is selected from the group consisting of toluene, CH2C12 and THF.
12. The process according to claim 9, wherein the solvent is CH2C12.
13. The process according to claim 9, wherein the solvent is cooled to a temperature of -40 ° C to 70 ° C.
14. The process according to claim 13, wherein the solvent is cooled to a temperature of -10 ° C to 10 ° C.
15. The process according to claim 5, wherein the activating agent is S0C12, C0C12, DCC (N-dicyclohexyl carbodiimide) or the like, HOBT or the like, or FMOC or the like.
16. The process according to claim 15, wherein the activating agent is S0C12.
17. The process according to claim 5, wherein the activated acid is recovered by removing the solvent.
18. The process according to claim 5, wherein the dimethylamine is a salt, and after the reaction with the activated acid, a second amine is added.
19. The process according to claim 18, wherein the amine salt is HC1 of dimethylamine.
20. The process according to claim 19, wherein the second amine is a tertiary amine of C3-C9.
21. The process according to claim 20, wherein the second amine is diisopropylamine.
22. The process according to claim 17, wherein the recovery is carried out by cooling, washing, filtering and drying.
23. The process according to claim 6, which also comprises converting OBA to O-desmethylvenlafaxine or a salt thereof.
24. Hidroxyphenyl dimethylamide protected from the following structure: wherein x is a hydroxy protecting group.
25. The protected hydroxyphenyl dimethylamide according to claim 24, wherein x is a silyl group or DHP (dihydropyran), acetate, benzyl or benzoyl, preferably a tri (Ci-6) alkyl silyl group wherein the alkyl group may be the same or different, or THP (tetrahydropyranyl).
26. The protected hydroxyphenyl dimethylamide according to claim 24, wherein x is a tri (Ci-e) silyl alkyl group.
27. The protected hydroxyphenyl dimethylamide according to claim 26, wherein the compound is a t-butyldimethylsilyl ether (TBDMS) -OBA.
28. The protected hydroxyphenyl dimethylamide according to claim 24, wherein x is tetrahydropyranyl.
29. The protected hydroxyphenyl dimethylamide according to claim 24, which has a purity of 50% measured by HPLC.
30. The compound according to claims 24-29, wherein the compound is characterized by a 1HNMR with d: 0.20 (s, Me2Si), 0.99 (s, tBuSi), 2.85 (s, CH3-N) ), 2.99 (s, CH3N), 3.62 (s, CH2), 6.77 (m, H atom), 7.10 (m, H atom).
31. A process for preparing a compound according to claim 24 comprising combining ??? with a suitable hydroxyl protection agent and optionally a base.
32. The process according to claim 31, wherein the reaction is carried out in the presence of a solvent.
33. The process according to claim 32, wherein the solvent is an organic solvent, wherein the organic solvent is selected from the group consisting of an aromatic hydrocarbon of C6 to C12, a chlorinated hydrocarbon of Ci-C6 and an ether of ascorbic acid. 3. 4.
The process according to claim 33, wherein the organic solvent is toluene, CH2C12 or THF.
35. The process according to claim 33, wherein the organic solvent is CH2C12.
36. The process according to claim 31, wherein the activating agent is a silyl protecting group or DHP (dihydropyran).
37. The process according to claim 31, wherein the protective agent is TBDMS-Cl.
38. The process according to claim 31, wherein the base is imidazole, pyridine, triethylamine, lutidine or diemethylaminopyridine.
39. The process according to claim 31, which also comprises converting COBA to ODV (O-demethylvenlafaxine) or a salt thereof.
40. 2- (1-hydroxycyclohexyl) -2- (-hydroxyphenyl) -N, N-dimethylacetamide (COBA) having the following structure:
41. The 2- (1-hydroxycyclohexyl) -2- (-hydroxyphenyl) -N, N-dimethylacetamide according to claim 40, which has a purity of 50% as measured by HPLC.
42. A process for preparing the compound according to claim 40, comprising reacting OBA with cyclohexanone and a base which can form a carbanion and recover the obtained COBA.
43. The process according to claim 42, wherein an OBA protected with hydroxy is used to obtain a COBA protected with hydroxy.
44. The process according to claim 42, wherein the reaction is carried out in the presence of a solvent.
45. The process according to claim 44, wherein the solvent is an organic solvent, wherein the organic solvent is selected from the group consisting of an aromatic hydrocarbon of 6 to C12, a chlorinated hydrocarbon of C1-C6 and a C4_8 ether.
46. The process according to claim 45, wherein the organic solvent is toluene, CH2C12 or THF.
47. The process according to claim 46, wherein the organic solvent is CH2Cl2.
48. The process according to claim 46, wherein the solvent is THF.
49. The process according to claim 42, wherein OBA is combined with a solvent to obtain a mixture, then the base that is capable of forming a carbanion is added.
50. The process according to claim 42, wherein the base is an alkali metal or alkaline earth metal diisopropylamide or BuLi.
51. The process according to claim 49, wherein the base is lithium diisopropylamide.
52. The process according to claim 49, wherein the base is sodium hydride (NaH), alkali metal or alkaline earth metal salts (such as sodium or potassium or lithium) of bis trimethylsilylamide. { MN (SiMe3) 2.}. , a metal salt of tert-butoxide (MOtBu).
53. The process according to claim 42, wherein the recovery comprises cooling, separating the layers obtained after cooling, washing the obtained organic layer after cooling with saline, and further evaporating the residual organic solvent under a pressure of less than one atmosphere. to obtain COBA or COBA protected with hydroxy.
54. 2- (1-hydroxycyclohexyl) -2- (4-hydroxyphenyl) -N, N-dimethylacetamide protected with hydroxyl (PCOBA) having the following structure: wherein x is a hydroxy protecting group.
55. The hydroxyl-protected 2- (1-hydroxycyclohexyl) -2- (4-hydroxyphenyl) -N, -dimethylacetamide according to claim 54, wherein the compound is COBA protected with TBDMS.
56. A process for preparing hydroxyl-protected 2- (1-hydroxycyclohexyl) -2- (4-hydroxyphenyl) -, -dimethylacetamide according to claims 54-55, which comprises reacting a hydroxy-protected OBA (POBA) with cyclohexanone and a base capable of forming a carbanion and recovering the obtained PCOBA.
57. The process for preparing ODV (O-demethylvenlafaxine) which comprises converting the COBA according to claim 40 or the PCOBA according to claim 54 into ODV or a salt thereof.
58. The process according to claim 57, wherein the conversion is carried out by reacting COBA or PCOBA with a reducing agent, and recovering to obtain ODV or a salt thereof.
59. The process according to claim 58, wherein the conversion is carried out in tetrahydrofuran (THF).
60. The process according to claim 58, wherein the reducing agent is a metal hydride complex.
61. The process according to claim 58, wherein the reducing agent is hydrogen in the presence of a catalyst.
62. The process according to claim 60, wherein the metal hydride complex is a derivative of BH3 or an aluminum hydride derivative.
63. The process according to claim 60, wherein the reducing agent is LiAlH4 or NaBH4.
64. The process according to claim 60, wherein the recovery is carried out by extracting ODV from an aqueous layer by adding a solvent immiscible with water.
65. The process according to claim 64, wherein the solvent immiscible with water is CH2C12, EtOAc, hexanes or toluene.
66. The process according to claim 65, which also comprises drying, filtering and evaporating at a pressure of less than one atmosphere.
67. A process for preparing ODV (O-demethylvenlafaxine) or salts thereof, comprising the steps of: combining OBCarboxi, a catalyst and an acid activating agent to obtain an activated acid; recover the activated acid, combine it with dimethylamine or a salt of it and an amine to obtain OBA; reacting the obtained OBA with cyclohexanone and a base capable of forming a carbanion, recovering the obtained COBA; reacting the obtained COBA, and a reducing agent; and recover the ODV or a salt from it.
68. The process according to claim 67, wherein the protected OBA derivative (POBA) is used as an initial material for preparing PCOBA, and wherein, optionally, a protected COBA derivative (PCOBA) is used for the preparation of ODV or a salt of it.
69. A process for preparing ODV (O-demethylvenlafaxine) or salts thereof comprising the steps of: (i) preparing OBA from 4-hydroxyphenylacetic acid by a process according to any of claims 4 to 22, (ii) optionally prepare POBA from OBA by a process according to any of claims 27 to 35; (iii) preparing COBA from OBA by a process according to any of claims 42 to 53; (iv) optionally prepare PCOBA from POBA according to claim 56; (v) converting the COBA or PCOBA into ODV by a process according to any of claims 57 to 68.
70. The process according to claim 67, wherein a protected OBA derivative (POBA) is used as an initial material for preparing PCOBA, and wherein, optionally, a protected COBA derivative (PCOBA) is used for the preparation of ODV .
71. The use of a compound according to any of claims 1-3, 23-30, 40-41 and 50-51 in a process for the manufacture of O-demethylvenlafaxine.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/833,616 | 2006-07-26 | ||
| US60/837,879 | 2006-08-14 | ||
| US60/843,998 | 2006-09-11 | ||
| US60/849,255 | 2006-10-03 | ||
| US60/849,216 | 2006-10-03 | ||
| US60/906,639 | 2007-03-12 | ||
| US60/906,879 | 2007-03-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2008004089A true MX2008004089A (en) | 2008-10-03 |
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