CN101875666A - Optical pure 1,3-alkamine compound as well as preparation method and application thereof in preparing Dapoxetine and analogues thereof - Google Patents
Optical pure 1,3-alkamine compound as well as preparation method and application thereof in preparing Dapoxetine and analogues thereof Download PDFInfo
- Publication number
- CN101875666A CN101875666A CN2010102394226A CN201010239422A CN101875666A CN 101875666 A CN101875666 A CN 101875666A CN 2010102394226 A CN2010102394226 A CN 2010102394226A CN 201010239422 A CN201010239422 A CN 201010239422A CN 101875666 A CN101875666 A CN 101875666A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- analogue
- dapoxetine
- tertiary butyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 91
- USRHYDPUVLEVMC-FQEVSTJZSA-N dapoxetine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)N(C)C)=CC=CC=C1 USRHYDPUVLEVMC-FQEVSTJZSA-N 0.000 title claims abstract description 37
- 229960005217 dapoxetine Drugs 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 230000003287 optical effect Effects 0.000 title claims abstract description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 59
- 238000006243 chemical reaction Methods 0.000 claims description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 239000002585 base Substances 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 31
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- -1 amino alcohol compounds Chemical class 0.000 claims description 23
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 claims description 20
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000007810 chemical reaction solvent Substances 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- LGXAANYJEHLUEM-UHFFFAOYSA-N 1,2,3-tri(propan-2-yl)benzene Chemical compound CC(C)C1=CC=CC(C(C)C)=C1C(C)C LGXAANYJEHLUEM-UHFFFAOYSA-N 0.000 claims description 16
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical group CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 16
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 14
- 125000006239 protecting group Chemical group 0.000 claims description 13
- SEQXIQNPMQTBGN-VIFPVBQESA-N (3s)-3-amino-3-phenylpropan-1-ol Chemical compound OCC[C@H](N)C1=CC=CC=C1 SEQXIQNPMQTBGN-VIFPVBQESA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 9
- 230000002829 reductive effect Effects 0.000 claims description 9
- 230000002378 acidificating effect Effects 0.000 claims description 8
- 238000005902 aminomethylation reaction Methods 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 230000006103 sulfonylation Effects 0.000 claims description 8
- 238000005694 sulfonylation reaction Methods 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 7
- 229960001701 chloroform Drugs 0.000 claims description 6
- 150000002460 imidazoles Chemical class 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 5
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 5
- 150000003053 piperidines Chemical class 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical group [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 5
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 238000006751 Mitsunobu reaction Methods 0.000 claims description 4
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 4
- 230000000903 blocking effect Effects 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 230000001035 methylating effect Effects 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 229920002866 paraformaldehyde Polymers 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 125000002524 organometallic group Chemical group 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 claims description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 13
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000002994 raw material Substances 0.000 description 9
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- LPTVKPNWVGBWSU-NSHDSACASA-N (3s)-3-(dimethylamino)-3-phenylpropan-1-ol Chemical compound OCC[C@H](N(C)C)C1=CC=CC=C1 LPTVKPNWVGBWSU-NSHDSACASA-N 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical group [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001414 amino alcohols Chemical class 0.000 description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 3
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- 150000004782 1-naphthols Chemical class 0.000 description 2
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 2
- SEQXIQNPMQTBGN-UHFFFAOYSA-N 3-amino-3-phenylpropan-1-ol Chemical compound OCCC(N)C1=CC=CC=C1 SEQXIQNPMQTBGN-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- QAZLUNIWYYOJPC-UHFFFAOYSA-M sulfenamide Chemical compound [Cl-].COC1=C(C)C=[N+]2C3=NC4=CC=C(OC)C=C4N3SCC2=C1C QAZLUNIWYYOJPC-UHFFFAOYSA-M 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- SMEMODSNLZWKBF-LBPRGKRZSA-N tert-butyl n-[(1s)-3-hydroxy-1-phenylpropyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](CCO)C1=CC=CC=C1 SMEMODSNLZWKBF-LBPRGKRZSA-N 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- JZFUHAGLMZWKTF-SECBINFHSA-N (1r)-3-chloro-1-phenylpropan-1-ol Chemical compound ClCC[C@@H](O)C1=CC=CC=C1 JZFUHAGLMZWKTF-SECBINFHSA-N 0.000 description 1
- SEQXIQNPMQTBGN-SECBINFHSA-N (3r)-3-amino-3-phenylpropan-1-ol Chemical class OCC[C@@H](N)C1=CC=CC=C1 SEQXIQNPMQTBGN-SECBINFHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- GSNZFWSMLXFMKP-UHFFFAOYSA-N 1,3-diamino-3-phenylpropan-1-ol Chemical compound NC(O)CC(N)C1=CC=CC=C1 GSNZFWSMLXFMKP-UHFFFAOYSA-N 0.000 description 1
- LPTVKPNWVGBWSU-UHFFFAOYSA-N 3-(dimethylamino)-3-phenylpropan-1-ol Chemical compound OCCC(N(C)C)C1=CC=CC=C1 LPTVKPNWVGBWSU-UHFFFAOYSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- 244000248349 Citrus limon Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 101710098556 Lipase A Proteins 0.000 description 1
- 101710099648 Lysosomal acid lipase/cholesteryl ester hydrolase Proteins 0.000 description 1
- 102100026001 Lysosomal acid lipase/cholesteryl ester hydrolase Human genes 0.000 description 1
- 241001661345 Moesziomyces antarcticus Species 0.000 description 1
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 1
- 108010073038 Penicillin Amidase Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- YSAVZVORKRDODB-PHDIDXHHSA-N diethyl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC YSAVZVORKRDODB-PHDIDXHHSA-N 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000002366 lipolytic effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001519 thymoleptic effect Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention specifically relates to an optical pure 1,3-alkamine compound as well as a preparation method and application thereof in preparing corresponding optical pure 1,3-alkamine and further preparing Dapoxetine and analogues thereof, belonging to the technical field of organic chemistry. The 1,3-alkamine compound is as shown in a formula I.
Description
Technical field
The invention belongs to technical field of organic chemistry, particularly optical purity 1,3-alkamine compound, preparation method and the purposes in preparation dapoxetine and analogue thereof.
Background technology
Dapoxetine ((S)-(+)-N, N-Dimethyl-3-(1-naphthyloxy)-1-phenylpropylamine, 1) is former to be a kind of thymoleptic of Eli Lilly company development in 1992, is a kind of selectivity serotonin reuptake inhibithors (SSRI).In February, 2009 is as the medicine (Prilig of treatment prospermia of males (PE)
TM) at first in the listing of Finland and Sweden, this is first kind of oral therapeutic drug that is used for this indication in the world.Classified as one of five tool prospect medicines that gone on the market or examined by Thomson Reuters (Thomson Reuters) first quarter in 2009 whole world medicament research and development major progress quarterly report.
The optical purity dapoxetine mainly obtains adopting the method for chiral separation to obtain behind the raceme by different synthetic routes, the chiral selectors that uses has L-(+)-tartrate of Lilly company, and (EP 0288188, US 5135947, AU 8814335, JP 1988258837), the D-(+)-two of Dave pair toluyl tartrate (WO 2008035358).These method for splitting need repeatedly recrystallization usually in order to obtain higher ee value, and owing to be to split in the final stage of reacting, can waste a large amount of raw materials, and are both uneconomical, cause environmental pollution again.Another kind of method is to be synthesis material with the optically active compound, and Liily company is at synthetic C
14Set out by obtaining key intermediate (S)-3-amino-3-phenyl propanol ((S)-3-Amino-3-phenylpropanol) after the sodium cyanide introducing itrile group prolongation carbochain with N-Boc-(R)-phenylglycocoll during marker, further synthetic optical purity dapoxetine (the J.Labelled Comp.Radiopharm that obtains, 1992,31,305-315).Livni, E. etc. are at synthetic N-methyl C
11During the dapoxetine of mark with (R)-1-phenyl-1, ammediol or (R)-3-chloro-1-phenyl propanol (Nucl.Med.Biol., 1994,21,4,669-675) be raw material.Poisonous reagent or optical purity raw material itself are synthetic to be difficult for these class methods owing to using, and it is limited to originate, and costs an arm and a leg to make its application be very limited.Shafi A.Siddiqui etc. are raw material with the trans-cinnamic acid ester, method synthesis of optically active dapoxetine by asymmetric synthesis, this route reaction complexity, expensive, poisonous, the dangerous reagent of a large amount of uses, and there is not ee value report (Tetrahedron:Asymmetry, 2007,18,2099-2103).
Structure and synthetic route analysis from dapoxetine, dapoxetine synthetic key intermediate is such one 1 of (S)-3-amino-3-phenyl propanol, the 3-amino alcohol compound, if can be economical, easily and effectively obtain high optically pure (S)-3-aminophenylpropyl alcohol, will provide better solution to dapoxetine synthetic.Carrying out catalysis with lipolytic enzyme (Candidaantarctica lipase A (CAL-A)) in the acylation process of the 3-amino-3-phenyl propanol of TBS protection hydroxyl splits; can obtain (the S)-3-amino-3-phenyl propanol (Tetrahedron:Asymmetry of 93%ee value; 2006; 17,860-866).The penicillin G acylase of Resins, epoxy appendix splits the amino 3-amino-3-phenyl propanol of phenylacetyl protection, obtained the ee value greater than 99% 1,3-amino alcohol product (Tetrahedron:Asymmetry, 2006,17,240-244).Man Kin Tse etc. split 3-phenyl-beta-amino acids with tartrate and obtain S respectively, and the amino acid product of R configuration, ee value just obtain 1 all greater than 98% after latter's reduction, and 3-amino alcohol product (Chem.Eur.J.2006,12,1855-1874).But these method for splitting efficient are low, waste big defective and still exist.Synthetic (the S)-3-amino of utilization method of asymmetric synthesis-3-phenyl propanol also has some researchs, as with L-diethyl tartrate (Tetrahedron, 2009,65,2605-2609) or 1,4-glycol (US 6207862) is a raw material, finally can synthesis of optically active 1, and the 3-amino alcohol, but reaction is complicated, step is many, and total recovery is low, and does not have the ee Value Data.The method of in general synthetic at present (S)-3-amino-3-phenyl propanol is all unsatisfactory, or the cost height, and waste is big, or optical purity is not enough, also is necessary the route that further exploiting economy is suitable for.
Chiral sulfenamide is new chiral reagent (Tetrahedron, 2005,61 of a class that development in recent years is got up; 6386-6408); it not only has extraordinary chiral induction effect, and is a kind of very superior amido protecting group, can be in the protection of going down of very gentle condition.By of the asymmetric addition of different nucleophilic reagents to the chirality sulfenimide, thereby can height Stereoselective synthesis of chiral aminated compounds (Acc.Chem.Res., 2002,35,984-995).
Summary of the invention
First technical problem to be solved by this invention provides the new compound of a class, and this compound is suc as formula the chirality shown in the I 1, the 3-alkamine compound:
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～8, n=1～5.
Preferably, the chirality 1 shown in the formula I, 3-alkamine compound R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～4, n=1～5.
Optimum, the chirality 1 shown in the formula I, 3-alkamine compound R
1Be the tertiary butyl;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
4For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
5For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
6For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
7For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
Further, described chirality 1, the 3-alkamine compound is suc as formula shown in the II:
Ⅱ
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～8, n=1～5.
Preferably, the chirality 1 shown in the formula II, 3-alkamine compound R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～4, n=1～5.
Optimum, the chirality 1 shown in the formula II, 3-alkamine compound R
1Be the tertiary butyl;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
4For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
5For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
6For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
7For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
Second technical problem to be solved by this invention provides chirality 1 shown in the formula I, the enantiomer of 3-alkamine compound, structure is suc as formula I ' shown in:
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～8, n=1～5.
Preferably, formula I ' shown in chirality 1,3-alkamine compound R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～4, n=1～5.
Optimum, formula I ' shown in chirality 1,3-alkamine compound R
1Be the tertiary butyl;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
4For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
5For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
6For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
7For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
Further, described chirality 1, the 3-alkamine compound is suc as formula II ' shown in:
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～8, n=1～5.
Preferably, formula II ' shown in chirality 1,3-alkamine compound R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～4, n=1～5.
Optimum, formula II ' shown in chirality 1,3-alkamine compound R
1Be the tertiary butyl;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
4For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
5For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
6For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
R
7For-H ,-F ,-Cl ,-Br ,-CH
3Or-OCH
3
The 3rd technical problem to be solved by this invention provides the chirality 1 shown in the formula I, the preparation method of 3-alkamine compound, and synthetic route is as follows:
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
M is Li or MgX, X=Cl or Br; Wherein, m=1～8, n=1～5.
Described synthetic method may further comprise the steps:
A: with 3-(tertiary butyl dimethyl Si base)-propionic aldehyde and (R)-R
1Replacement-sulfinyl amine generates chirality sulfenimide compound III under the dewatering agent effect;
B: compound III and organometallic reagent IV (M-R
2) reaction, stereoselectively obtain 1,3-alkamine compound I.
The described dewatering agent of steps A is anhydrous cupric sulfate, anhydrous magnesium sulfate, titanium isopropylate or tetraethyl titanate; Reaction solvent is methylene dichloride or tetrahydrofuran (THF).
The described reaction solvent of step B is for having electrophilic solvent, for example toluene, methylene dichloride, tetrahydrofuran (THF) or ether etc.; Described temperature of reaction is-78～-25 ℃; Blanketing with inert gas during reaction.
The 4th technical problem to be solved by this invention provides the formula I ' shown in chirality 1, the preparation method of 3-alkamine compound, synthetic route is as follows:
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
M is Li or MgX, X=Cl or Br; Wherein, m=1～8, n=1～5.
Described synthetic method may further comprise the steps:
A ': with 3-(tertiary butyl dimethyl Si base)-propionic aldehyde and (S)-R
1Replacement-sulfinyl amine generates chirality sulfenimide compound III under the dewatering agent effect ';
B ': compound III ' and organometallic reagent IV (M-R
2) reaction, stereoselectively obtain 1,3-alkamine compound I '.
Steps A ' described dewatering agent is anhydrous cupric sulfate, anhydrous magnesium sulfate, titanium isopropylate or tetraethyl titanate; Reaction solvent is methylene dichloride or tetrahydrofuran (THF).
The described reaction solvent of step B ' is for having electrophilic solvent, for example toluene, methylene dichloride, tetrahydrofuran (THF) or ether etc.; Described temperature of reaction is-78～-25 ℃; Blanketing with inert gas during reaction.
The 5th technical problem to be solved by this invention provides the chirality 1 shown in the formula I, the purposes of 3-alkamine compound.
Chirality 1 shown in the formula I, 3-alkamine compound can be used for preparing the optical purity 1 of S configuration, and the dapoxetine and the analogue thereof of 3-amino alcohol and further preparation S configuration are expressed as follows with reaction formula:
XI is
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
8For H or-CH
3R
9For H or-CH
3R
10Be methylsulfonyl or p-toluenesulfonyl;
R
11For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
12For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
13For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
14For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
15For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
16For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
17For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
Wherein, m=1～8, n=1～5.
Specifically may further comprise the steps:
C: the chirality 1 shown in the formula I, 3-amino alcohol compound and tert-Butyl dicarbonate reaction obtain the chiral amino alcohol compounds VI that Boc protects, and slough blocking group then and obtain the amino of (S)-3-shown in the VII-3-phenyl propanol and analogue thereof;
The perhaps chirality shown in the formula I 1, the 3-amino alcohol compound is sloughed N-tertiary butyl sulfinyl and TBS protecting group under acidic conditions, obtain the amino of (S)-3-shown in the formula VII-3-phenyl propanol and analogue thereof;
D: the amino of (S)-3-shown in the formula VII-3-phenyl propanol and analogue thereof obtain the compound IX with the aminomethylation reaction;
E: compound IX and compound XI are reacted under the Mitsunobu reaction conditions and are obtained dapoxetine and analogue thereof;
Perhaps, the esterification under alkali and sulfonylation agent effect of compound IX obtains the compound X, and compound X and compound XI obtain dapoxetine and analogue thereof with alkali reaction in DMF.
When step C directly sloughed N-tertiary butyl sulfinyl and TBS protecting group, described acidic conditions was for adding HCl, CF
3Reagent such as COOH; Described reaction solvent is at least a in methylene dichloride, ethyl acetate, methyl alcohol, acetonitrile or the water, and temperature of reaction is-25～50 ℃.
The methylating reagent of step D aminomethylation reaction is Paraformaldehyde 96 or formalin; Reductive agent is sodium cyanoborohydride, sodium borohydride or formic acid; Described reaction solvent is at least a in water, acetonitrile, tetrahydrofuran (THF) or the methyl alcohol.
When step e prepared dapoxetine and analogue thereof by the compound X, sulfonylation agent was Tosyl chloride or methylsulfonyl chloride; Described alkali is imidazoles, triethylamine, pyridine, piperidines, diisopropylethylamine, yellow soda ash, sodium bicarbonate, salt of wormwood or saleratus; Described reaction solvent is methylene dichloride, trichloromethane or tetrahydrofuran (THF); Temperature of reaction is-25～50 ℃.
The 6th technical problem to be solved by this invention provides the formula I ' shown in chirality 1, the purposes of 3-alkamine compound.
The formula I ' shown in chirality 1, the 3-alkamine compound can be used for preparing the optical purity 1 of R configuration, 3-amino alcohol and the further dapoxetine and the analogue thereof of preparation R configuration are expressed as follows with reaction formula:
XI is
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
8For H or-CH
3R
9For H or-CH
3R
10Be methylsulfonyl or p-toluenesulfonyl;
R
11For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
12For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
13For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
14For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
15For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
16For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
17For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
Wherein, m=1～8, n=1～5.
Specifically may further comprise the steps:
(S)-3-amino-3-phenyl propanol and analogue thereof shown in chirality 1 shown in the C ': formula I ', the reaction of 3-amino alcohol compound and tert-Butyl dicarbonate obtains the chiral amino alcohol compounds VI of Boc protection ', slough blocking group then and obtain VII ';
(S)-3-amino-3-phenyl propanol and analogue thereof shown in the perhaps formula I ' shown in chirality 1, the 3-amino alcohol compound is sloughed N-tertiary butyl sulfinyl and TBS protecting group under acidic conditions, obtain the formula VII ';
(S)-3-amino-3-phenyl propanol and analogue thereof shown in the D: formula VII ' obtain the compound IX with the aminomethylation reaction ';
E: compound IX ' reacts under the Mitsunobu reaction conditions with the compound XI and obtains dapoxetine and analogue thereof;
Perhaps, compound IX ' under alkali and sulfonylation agent effect esterification obtain the compound X ', the compound X ' in DMF, obtain dapoxetine and analogue thereof with the compound XI with alkali reaction.
When step C ' directly sloughed N-tertiary butyl sulfinyl and TBS protecting group, described acidic conditions was for adding HCl, CF
3Reagent such as COOH; Described reaction solvent is at least a in methylene dichloride, ethyl acetate, methyl alcohol, acetonitrile or the water, and temperature of reaction is-25～50 ℃.
The methylating reagent of step D ' aminomethylation reaction is Paraformaldehyde 96 or formalin; Reductive agent is sodium cyanoborohydride, sodium borohydride or formic acid; Described reaction solvent is at least a in water, acetonitrile, tetrahydrofuran (THF) or the methyl alcohol.
Step e ' when preparing dapoxetine and analogue thereof by the compound X, sulfonylation agent is Tosyl chloride or methylsulfonyl chloride; Described alkali is imidazoles, triethylamine, pyridine, piperidines, diisopropylethylamine, yellow soda ash, sodium bicarbonate, salt of wormwood or saleratus; Described reaction solvent is methylene dichloride, trichloromethane or tetrahydrofuran (THF); Temperature of reaction is-25～50 ℃.
The present invention is by introducing the chiral sulfenamide auxiliary reagent, control metal arylide reagent is to the stereoselectivity addition of 3-hydroxy aldehyde imines, highly stereoselective (the S)-3-amino-3-phenyl propanol class 1 of having synthesized, the 3-amino alcohol reaches (R)-3-amino-3-phenyl propanol class 1, the 3-amino alcohol can further synthesize dapoxetine and analogue thereof.Relatively have reaction briefly with the method for existing preparation dapoxetine, the stereoselectivity height does not have the enantiomer waste, is easy to characteristics such as large-scale production, has good application prospects.
Embodiment
3-(tertiary butyl-two silyloxy)-propionic aldehyde can be bought and obtain, also can prepare by the following method:
F: under the effect of alkali, glycerol and TERT-BUTYL DIMETHYL CHLORO SILANE (TBSCl) reaction generates 3-(tertiary butyl-dimethyl-the siloxy)-1-propyl alcohol of monohydroxy protection.
Described alkali is at least a in imidazoles, triethylamine, pyridine, piperidines, diisopropylethylamine, yellow soda ash, sodium bicarbonate, salt of wormwood or the saleratus; Reaction solvent is methylene dichloride, chloroform, tetrahydrofuran (THF), toluene, normal hexane, N, at least a in dinethylformamide or the dimethyl sulfoxide (DMSO).Temperature of reaction is below-18 ℃.
G: the hydroxyl oxidize with 3-(tertiary butyl-dimethyl-siloxy)-1-propyl alcohol under the oxygenant effect is 3-(tertiary butyl-two silyloxy)-propionic aldehyde.
Described oxygenant is pyridinium chlorochromate drone salt (PCC), 2-iodoxy phenylformic acid (IBX), Manganse Dioxide or swern oxygenant; Reaction solvent is methylene dichloride, trichloromethane, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or N, at least a in the dinethylformamide; Temperature of reaction is-78 ℃～50 ℃.
(tertiary butyl-two silyloxy)-the propyl alcohol charging capacity is bigger as 3-, can select 2-iodoxy phenylformic acid oxygenants such as (IBX) for use.
Below in conjunction with specific embodiment, the invention will be further described, helps better to understand the present invention, but do not limit content of the present invention.
The preparation of embodiment 13-(tertiary butyl two silyloxies)-propyl alcohol
1, (40g, 526mmol), (43g 632mmol) is dissolved in methylene dichloride and N to imidazoles to ammediol, (400ml, V in the mixed solvent of dinethylformamide
DCM: V
DMF=3: 1), be cooled to after-18 ℃, (79.4g 526mmol) is dissolved in the 200ml methylene dichloride and slowly is added drop-wise to above-mentioned solution with TERT-BUTYL DIMETHYL CHLORO SILANE.After reaction finishes, water, saturated common salt washing successively, anhydrous magnesium sulfate drying.Underpressure distillation behind the concentrating under reduced pressure steaming vibrating dichloromethane gets product 80g, productive rate 80%.
The preparation of embodiment 23-(tertiary butyl two silyloxies)-propionic aldehyde
3-(tertiary butyl two silyloxies)-propyl alcohol (4g, 21mmol) be dissolved in the 50ml methylene dichloride (4A molecular sieve drying), add pyridinium chlorochromate drone salt (5.4g in batches, 25mmol), stirring at normal temperature reaction 3 hours, the TLC detection reaction is complete, filtered through silica gel, and anhydrous magnesium sulfate drying is directly used in the next step after filtering.
The preparation of embodiment 33-(tertiary butyl-two silyloxy)-propionic aldehyde
3-(tertiary butyl two silyloxies)-propyl alcohol (10g; 52.5mmol) be dissolved in the mixed solvent of 185mml methylene dichloride (4A molecular sieve drying) and 75mml dimethyl sulfoxide (DMSO) (4A molecular sieve drying); adding 2-iodoxy phenylformic acid (18g, 64.3mmol), normal-temperature reaction is after 5 hours; the TLC monitoring reaction is the back diatomite filtration fully; methylene dichloride is washed, and merges organic phase, washes with water successively; the saturated common salt washing, anhydrous magnesium sulfate drying is directly used in the next step after filtering.
The preparation of embodiment 4 compound III a
(4g adds R-tertiary butyl sulfinyl amine (R-TBSA, 2.5g in dichloromethane solution 21mmol) at 3-(tertiary butyl two silyloxies)-propionic aldehyde, 21mmol), and anhydrous cupric sulfate (8.5g, 53mmol), after the stirring at normal temperature reaction 24 hours, TLC monitoring reaction fully, diatomite filtration.Quick purification by silica gel column chromatography obtains compound III a (3.8g, productive rate 63%) behind the concentrating under reduced pressure.
The preparation of embodiment 5 chemical compounds I a and I b, I c, I d, I e and diastereomer thereof
(2g 6.9mmol) is dissolved in the toluene of 20ml molecular sieve drying, is chilled to-78 ℃ under the nitrogen protection with compound III a; (1mol/L 10.5ml), is incubated-78 ℃ of reactions 2 hours to the diethyl ether solution of dropping phenyl-magnesium-bromide; after the TLC monitoring reaction is complete; drip saturated aqueous ammonium chloride cancellation reaction, organic phase is collected in first layering; the water layer ethyl acetate extraction; merge organic phase, with saturated common salt washing, anhydrous magnesium sulfate drying.After the filtration, concentrating under reduced pressure, purification by silica gel column chromatography (ethyl acetate/petroleum ether=10/1) gets chemical compounds I a (2.3g, productive rate 90%).
Chemical compounds I a measures when big, can be by sherwood oil and re-crystallizing in ethyl acetate purifying, and purity detects with HPLC.
The preparation method of compounds-I e is with compound I a, and part of compounds structure appraising datum is as follows:
ESI-MS?369.92(M+H)
+，391.86(M+Na)
+，760.93(2M+Na)
+.
1HNMR(300M，CDCl
3)δ0.014(s，3H)，0.023(s，3H)，0.89(s，9H)，1.22(s，9H)，1.92-2.03(m，1H)，2.14-2.25(m，1H)，3.49-3.64(m，2H)，3.77(d，J＝4.5Hz，1H)，4.59(dd，J＝6.6and?9.15Hz，1H)，7.28-7.30(m，5H).
1HNMR(300M，CDCl
3)δ0.014(s，3H)，0.023(s，3H)，0.89(s，9H)，1.22(s，9H)，1.92-2.03(m，1H)，2.14-2.25(m，1H)，3.49-3.64(m，2H)，3.77(d，J＝4.8Hz，1H)，4.59(dd，J＝6.6and?9.15Hz，1H)，7.28-7.30(m，5H).
ESI-MS?384.71(M+H)
+.
1HNMR(300M，CDCl
3)δ0.0000(s，3H)，0.010(s，3H)，0.88(s，9H)，1.20(s，9H)，1.86-1.97(m，1H)，2.11-2.22(m，1H)，2.33(s，3H)，3.46-3.62(m，2H)，3.65(d，J＝4.8Hz，1H)，4.51(dd，J＝6.6and?9.1Hz，1H)，7.13-7.20(m，4H).
1HNMR(300M，CDCl
3)δ0.0000(s，3H)，0.010(s，3H)，0.88(s，9H)，1.20(s，9H)，1.86-1.97(m，1H)，2.11-2.22(m，1H)，2.33(s，3H)，3.46-3.62(m，2H)，3.64(d，J＝4.2Hz，1H)，4.51(dd，J＝6.3and?9.0Hz，1H)，7.13-7.20(m，4H).
ESI-MS?425.74and?427.28(3∶1?M+H)
+.
1HNMR(300M，CDCl
3)δ-0.011(s，3H)，0.0000(s，3H)，0.86(s，9H)，1.18(s，9H)，1.86-1.97(m，1H)，2.06-2.17(m，1H)，3.45-3.62(m，2H)，3.80(d，J＝5.4Hz，1H)，4.54(dd，J＝6.6and?9.6Hz，1H)，7.24-7.31(m，4H).
1HNMR(300M，CDCl
3)δ0.0000(s，3H)，0.011(s，3H)，0.87(s，9H)，1.19(s，9H)，1.87-1.98(m，1H)，2.07-2.17(m，1H)，3.46-3.63(m，2H)，3.82(d，J＝5.4Hz，1H)，4.55(dd，J＝6.0and?9.0Hz，1H)，7.26-7.32(m，1H).
1HNMR(300M，CDCl
3)δ0.0000(s，3H)，0.010(s，3H)，0.88(s，9H)，1.20(s，9H)，1.86-1.97(m，1H)，2.11-2.22(m，1H)，3.46-3.62(m，2H)，3.65(d，J＝4.8Hz，1H)，3.80(s，3H)，4.51(dd，J＝6.6and?9.1Hz，1H)，6.87(d，J＝8.7Hz，2H)，7.25(d，J＝8.4Hz，2H).
ESI-MS?399.81(M+H)
+，421.92(M+Na)
+，437.95(M+K)
+，821.22(2M+Na)
+.
1HNMR(300M，CDCl
3)δ0.0000(s，3H)，0.010(s，3H)，0.88(s，9H)，1.20(s，9H)，1.86-1.97(m，1H)，2.11-2.22(m，1H)，3.46-3.62(m，2H)，3.64(d，J＝4.2Hz，1H)，3.80(s，3H)，4.51(dd，J＝6.3and?9.0Hz，1H)，6.87(d，J＝8.4Hz，2H)，7.26(d，J＝8.4Hz，2H).
ESI-MS?371.21(M+H)
+.
1HNMR(300M，CDCl
3)δ0.0000(s，3H)，0.010(s，3H)，0.88(s，9H)，1.20(s，9H)，1.86-1.97(m，1H)，2.11-2.22(m，1H)，3.46-3.62(m，2H)，3.65(d，J＝4.8Hz，1H)，4.51(dd，J＝6.6and?9.1Hz，1H)，7.23(d，J＝5.7Hz，2H)，8.55(J＝5.4Hz，2H).
1HNMR(300M，CDCl
3)δ0.0000(s，3H)，0.010(s，3H)，0.88(s，9H)，1.20(s，9H)，1.86-1.97(m，1H)，2.11-2.22(m，1H)，3.46-3.62(m，2H)，3.64(d，J＝4.2Hz，1H)，4.51(dd，J＝6.3and?9.0Hz，1H)，7.23(d，J＝5.7Hz，2H)，8.56(J＝5.7Hz，2H).
The preparation of embodiment 6 amino alcohol compound N-Boc-(S)-3-amino-3-phenyl propanol VI a and VI b-VI g and enantiomer thereof
(2g 5.4mmol) is dissolved in 20ml methyl alcohol, and normal temperature drips 4N hydrochloric acid (13.5ml down with chemical compounds I a, 54mmol), normal-temperature reaction 10 hours, after having reacted, pressure reducing and steaming methyl alcohol, add the 15ml tetrahydrofuran (THF), add sodium bicarbonate (6g 71mmol) regulates the pH value to alkalescence, adds tert-Butyl dicarbonate (1.5g in batches in batches, 6.9mmol), normal-temperature reaction is spent the night.After having reacted, ethyl acetate extraction merges organic phase, saturated common salt washing, anhydrous magnesium sulfate drying.Silica gel column chromatography behind the concentrating under reduced pressure (petrol ether/ethyl acetate=10/1) gets compound VI a (1.2g, productive rate 89%).
The preparation of VI b-VI e and enantiomer thereof is with compound VI a.After product ee value is handled all greater than 99%.The analytical data of part of compounds is as follows.
ESI-MS?251.80(M+H)
+，503.03(2M+H)
+，(M+K)
+，524.85(2M+Na)
+.
1HNMR(300M，CDCl
3)δ1.43(s，9H)，1.79-1.86(m，1H)，2.03-2.09(m，1H)，3.17(s，0.8H)，3.66-3.72(m，2H)，4.89(s，1H)，5.05(m，1H)，7.24-7.37(m，5H).
1HNMR(300M，CDCl
3)δ1.43(s，9H)，1.79-1.87(m，1H)，2.03-2.09(m，1H)，3.17(s，0.8H)，3.68(br，2H)，4.88(br，1H)，5.05(br，1H)，7.24-7.37(m，5H).
ESI-MS?287.87(M+Na)
+.
1HNMR(300M，CDCl
3)δ1.43(s，9H)，1.77-1.85(m，1H)，1.99-2.12(m，1H)，2.33(s，3H)，3.14(s，0.8H)，3.66-3.72(m，2H)，4.85-4.95(m，2H)，7.13-7.20(m，4H).
1HNMR(300M，CDCl
3)δ1.43(s，9H)，1.77-1.85(m，1H)，2.00-2.10(m，1H)，2.33(s，3H)，3.13(s，0.8H)，3.66-3.72(m，2H)，4.85-4.95(m，2H)，7.13-7.20(m，4H).
ESI-MS?304.64(M+Na)
+，585.39(2M+Na)
+.
1HNMR(300M，CDCl
3)δ1.43(s，9H)，1.77-1.85(m，1H)，1.99-2.09(m，1H)，3.17(s，0.8H)，3.66-3.71(m，2H)，3.79(s，3H)，4.83-4.94(m，2H)，6.87(d，J＝8.7Hz，2H)，7.22(d，J＝8.4Hz，2H).
1HNMR(300M，CDCl
3)δ1.43(s，9H)，1.77-1.85(m，1H)，2.01-2.07(m，1H)，3.17(s，0.8H)，3.65-3.71(m，2H)，3.79(s，3H)，4.84(br，1H)，4.93-4.95(m，1H)，6.87(d，J＝8.7Hz，2H)，7.22(d，J＝8.7Hz，2H).
ESI-MS?229.72and?231.80(3∶1，M-t-Bu+H)
+.
1HNMR(300M，CDCl
3)δ1.43(s，9H)，1.76-1.85(m，1H)，1.99-2.07(m，1H)，2.80(s，0.8H)，3.68-3.70(br，2H)，4.88(br，1H)，5.04-5.06(m，1H)，7.23(d，J＝8.7Hz，2H)，7.31(d，J＝8.4Hz，2H).
HNMR(300M，CDCl
3)δ1.43(s，9H)，1.76-1.84(m，1H)，2.01-2.06(m，1H)，2.88(s，0.8H)，3.67-3.69(m，2H)，4.87(br，1H)，5.08-5.10(br，1H)，7.23(d，J＝8.4Hz，2H)，7.31(d，J＝8.4Hz，2H).
ESI-MS?253.14(M+H)
+.
1HNMR(300M，CDCl
3)δ1.44(s，9H)，1.76-1.85(m，1H)，2.04-2.08(m，1H)，2.87(br，0.8H)，3.66-3.71(m，2H)，4.91(br，1H)，5.47-5.48(br，1H)，7.23(d，J＝5.7Hz，2H)，8.55(J＝5.4Hz，2H).
1HNMR(300M，CDCl
3)δ1.44(s，9H)，1.77-1.85(m，1H)，2.04-2.12(m，1H)，3.66-3.72(m，2H)，4.91(br，1H)，5.37-5.39(br，1H)，7.23(d，J＝5.7Hz，2H)，8.56(J＝5.7Hz，2H).
The preparation of embodiment 7 amino alcohol compounds (S)-3-amino-3-phenyl propanol VII a
With chemical compounds I a (2g, 5.4mmol) be dissolved in 20ml methyl alcohol, and dropping 4N hydrochloric acid under the normal temperature (13.5ml, 54mmol), normal-temperature reaction 10 hours, after having reacted, pressure reducing and steaming methyl alcohol, water is regulated about pH value to 10 with 4N NaOH solution, use dichloromethane extraction, merge organic phase, get compound VII a (0.74g, productive rate 90%) with chloroform-normal hexane recrystallization after the solvent evaporated.
ESI-MS?152.03(M+H)
+.
1HNMR(300M，CDCl
3)δ1.63-1.72(m，1H)，2.32-2.46(m，1H)，3.73-3.78(m，1H)，3.78-3.85(m，2H)，4.38(br，1H)，5.05(br，2H)，7.17-7.37(m，5H).
The preparation of embodiment 8 amino alcohol compounds (S)-3-amino-3-phenyl propanol VII a
(S)-preparation of 3-amino-3-phenyl propanol VII a can compound VI a be a raw material also, at HCl/EA or CF
3Slough the Boc protecting group under the COOH/DCM condition, solvent evaporated, the silicagel column purifying, first ethyl acetate rinse, again with methyl alcohol can wash product.
The preparation of embodiment 9 compounds (S)-3-dimethylamino-3-phenyl propanol
With chemical compounds I a is raw material: (3g 8.1mmol) is dissolved in 30ml methyl alcohol, and normal temperature drips 4N hydrochloric acid 20ml stirring reaction greater than 99% V a with HPLC purity; after deprotection reaction was finished, the pressure reducing and steaming solvent added water 10ml dissolving; ethyl acetate extraction, extraction liquid 10ml washing merges water.Add sodium bicarbonate and regulate pH value to 7, add the 10ml acetonitrile, (810mg 12.9mmol), regulates pH value about 7, normal-temperature reaction 2 hours with Glacial acetic acid to add 37～40% formaldehyde solution 2.6ml and sodium cyanoborohydride after the stirring successively.It is saturated to add salt after the TLC detection reaction is finished, and does not have product with ethyl acetate extraction to water, merges organic phase, anhydrous magnesium sulfate drying.Silica gel column chromatography (CHCl behind the evaporated under reduced pressure solvent
3/ CH
3OH=10/1) get compound (S)-3-dimethylamino-3-phenyl propanol (1.3g, productive rate 86%).
The preparation of embodiment 10 compounds (S)-3-dimethylamino-3-phenyl propanol
With compound N-Boc-(S)-3-amino-3-phenyl propanol is raw material: it is dissolved in the ethyl acetate solution that is added with HCl; after the Boc protecting group is sloughed in reaction; obtain (S)-3-amino-3-phenyl propanol, back operation makes compound IX a referring to the operation that embodiment 9 sloughs after the protecting group.
The preparation of embodiment 11 compounds (S)-3-dimethylamino-3-phenyl propanol
With compound (S)-3-amino-3-phenyl propanol is raw material, and the operation of sloughing after the protecting group referring to embodiment 9 can make (S)-3-dimethylamino-3-phenyl propanol.
The structure calibrating data of product are: ESI-MS 180.04 (M+H)
+.
1HNMR(300M，CDCl
3)δ1.63-1.71(m，1H)，2.18(s，6H)，2.34-2.47(m，1H)，3.73-3.78(m，1H)，3.78-3.85(m，2H)，4.38(br，1H)，7.17-7.37(m，5H).
The preparation of embodiment 12 (S)-tosic acid (3-dimethylin-3-phenyl) propyl alcohol ester
Compound (S)-3-dimethylamino-3-phenyl propanol (2g, 11.2mmol) be dissolved in 10ml methylene dichloride and the 1ml triethylamine solution, add p-methyl benzene sulfonic chloride (2.23g in batches, 11.7mmol), the stirring at normal temperature reaction is spent the night, and adds suitable quantity of water after reaction is finished, dichloromethane extraction, merge organic phase, with 20% lemon pickling, anhydrous magnesium sulfate drying.Silica gel column chromatography (ethyl acetate/petroleum ether=1/1) purifying gets compound 11a (3.14g, productive rate 84%).
The structure calibrating data of product are: ESI-Ms 334.16 (M+H)
+.
1HNMR(300M，CDCl
3)δ1.63-1.71(m，1H)，2.18(s，6H)，2.26(s，3H)，2.34-2.47(m，1H)，3.72-3.78(m，1H)，3.79-3.88(m，2H)，7.12-7.37(m，5H)，7.51-7.74(m，4H).
The preparation of embodiment 13 dapoxetines
(S)-(3g 16.8mmol) is dissolved in 240ml dry tetrahydrofuran, nitrogen protection to 3-dimethylamino-3-phenyl propanol; (4.8g 33.5mmol), adds triphenylphosphine (8.8g after being chilled to 0 ℃ successively to add the 1-naphthols; 33.5mmol) and diethyl azodiformate (5.8ml, 33.5mmol).Naturally rise to room temperature, stirring reaction spends the night, the back solvent evaporated that reacts completely, and silica gel column chromatography (ethyl acetate/petroleum ether=1/1) purifying gets dapoxetine product (3.6g, productive rate 70%).
The preparation of embodiment 14 dapoxetines
Under the normal temperature nitrogen protection DMF of 10ml molecular sieve drying inject sodium hydride (208mg, 8.7mmol) in, stir and inject 1-naphthols (1.14g down; 7.9mmol) the dry DMF solution of 5ml; behind the stirring reaction 15 minutes, inject (S)-3-dimethylamino-3-phenyl propanol (2.5g, the dry DMF solution of 5ml 7.5mmol); stirring at normal temperature reaction 4 hours; after the TLC monitoring reaction is finished, add the shrend reaction of going out, dichloromethane extraction; merge organic phase, anhydrous magnesium sulfate drying.Purification by silica gel column chromatography gets dapoxetine (1.8g, yield 80%).
The structure calibrating data of product are: ESI-MS 306.19 (M+H)
+.
1HNMR(300M，CDCl
3)δ2.21(s，6H)，2.34-2.47(m，1H)，2.58-2.73(m，1H)，3.63-3.70(m，1H)，3.94-4.13(m，2H)，7.17-7.57(m，9H)，7.69-7.76(m，1H)，7.91-8.25(m，2H).
[α]
D 25(1％MeOH)112.7°.
ee＞99％.
Claims (10)
1. the chirality shown in the formula I 1, the 3-alkamine compound:
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～8, n=1～5.
2. formula I ' shown in chirality 1, the 3-alkamine compound:
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～8, n=1～5.
3. the chirality shown in the formula I 1, the preparation method of 3-alkamine compound, synthetic route is as follows:
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
M is Li or MgX, X=Cl or Br; Wherein, m=1～8, n=1～5;
Described synthetic method may further comprise the steps:
A: with 3-(tertiary butyl dimethyl Si base)-propionic aldehyde and (R)-R
1Replacement-sulfinyl amine generates chirality sulfenimide compound III under the dewatering agent effect;
B: the reaction of compound III and organometallic reagent IV stereoselectively obtains 1,3-alkamine compound I.
4. I ' shown in chirality 1, the preparation method of 3-alkamine compound, identical with the method for claim 3, just the R-sulfinyl amine is replaced with the S-sulfinyl amine,
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～8, n=1～5.
5. the chirality shown in the formula I 1,3-alkamine compound be at preparation S configuration optical purity 1, the purposes in 3-amino alcohol, S configuration dapoxetine and the analogue thereof,
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～8, n=1～5.
6. formula I ' shown in chirality 1, the 3-alkamine compound is at preparation R configuration optical purity 1, the purposes in 3-amino alcohol, R configuration dapoxetine and the analogue thereof,
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)Wherein, m=1～8, n=1～5.
7.S the dapoxetine of configuration and the preparation method of analogue thereof is characterized in that: may further comprise the steps:
C: the chirality 1 shown in the formula I, 3-amino alcohol compound and tert-Butyl dicarbonate reaction obtain the chiral amino alcohol compounds VI that Boc protects, and slough blocking group then and obtain the amino of (S)-3-shown in the VII-3-phenyl propanol and analogue thereof;
The perhaps chirality shown in the formula I 1, the 3-amino alcohol compound is sloughed N-tertiary butyl sulfinyl and TBS protecting group under acidic conditions, obtain the amino of (S)-3-shown in the formula VII-3-phenyl propanol and analogue thereof;
D: the amino of (S)-3-shown in the formula VII-3-phenyl propanol and analogue thereof obtain the compound IX with the aminomethylation reaction;
E: compound IX and compound XI are reacted under the Mitsunobu reaction conditions and are obtained dapoxetine and analogue thereof;
Perhaps, the esterification under alkali and sulfonylation agent effect of compound IX obtains the compound X, and compound X and compound XI obtain dapoxetine and analogue thereof with alkali reaction in DMF;
XI is
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
8For H or-CH
3R
9For H or-CH
3R
10Be methylsulfonyl or p-toluenesulfonyl;
R
11For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
12For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
13For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
14For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
15For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
16For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
17For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
Wherein, m=1～8, n=1～5.
8. the dapoxetine of S configuration according to claim 7 and the preparation method of analogue thereof is characterized in that:
When step C directly sloughed N-tertiary butyl sulfinyl and TBS protecting group, described acidic conditions was for adding HCl, CF
3Reagent such as COOH; Described reaction solvent is at least a in methylene dichloride, ethyl acetate, methyl alcohol, acetonitrile or the water, and temperature of reaction is-25～50 ℃;
The methylating reagent of step D aminomethylation reaction is Paraformaldehyde 96 or formalin; Reductive agent is sodium cyanoborohydride, sodium borohydride or formic acid; Described reaction solvent is at least a in water, acetonitrile, tetrahydrofuran (THF) or the methyl alcohol;
When step e prepared dapoxetine and analogue thereof by the compound X, sulfonylation agent was Tosyl chloride or methylsulfonyl chloride; Described alkali is imidazoles, triethylamine, pyridine, piperidines, diisopropylethylamine, yellow soda ash, sodium bicarbonate, salt of wormwood or saleratus; Described reaction solvent is methylene dichloride, trichloromethane or tetrahydrofuran (THF); Temperature of reaction is-25～50 ℃.
9.R the dapoxetine of configuration and the preparation method of analogue thereof is characterized in that: may further comprise the steps:
XI is
R
1Be the tertiary butyl, 2-methyl-2-butyl, tert-pentyl, p-methylphenyl, sym-trimethylbenzene base or equal tri-isopropyl benzene base;
R
2For
R
3For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
4For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
5For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
6For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
7For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
8For H or-CH
3R
9For H or-CH
3R
10Be methylsulfonyl or p-toluenesulfonyl;
R
11For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
12For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
13For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
14For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
15For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
16For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
R
17For-H ,-F ,-Cl ,-Br ,-CF
3,-C
mH
(2m+1)Or-OC
mH
(2m+1)
Wherein, m=1～8, n=1～5;
May further comprise the steps:
(S)-3-amino-3-phenyl propanol and analogue thereof shown in chirality 1 shown in the C ': formula I ', the reaction of 3-amino alcohol compound and tert-Butyl dicarbonate obtains the chiral amino alcohol compounds VI of Boc protection ', slough blocking group then and obtain VII ';
(S)-3-amino-3-phenyl propanol and analogue thereof shown in the perhaps formula I ' shown in chirality 1, the 3-amino alcohol compound is sloughed N-tertiary butyl sulfinyl and TBS protecting group under acidic conditions, obtain the formula VII ';
(S)-3-amino-3-phenyl propanol and analogue thereof shown in the D: formula VII ' obtain the compound IX with the aminomethylation reaction ';
E: compound IX ' reacts under the Mitsunobu reaction conditions with the compound XI and obtains dapoxetine and analogue thereof;
Perhaps, compound IX ' under alkali and sulfonylation agent effect esterification obtain the compound X ', the compound X ' in DMF, obtain dapoxetine and analogue thereof with the compound XI with alkali reaction.
10. the dapoxetine of S configuration according to claim 9 and the preparation method of analogue thereof is characterized in that:
When step C ' directly sloughed N-tertiary butyl sulfinyl and TBS protecting group, described acidic conditions was for adding HCl, CF
3Reagent such as COOH; Described reaction solvent is at least a in methylene dichloride, ethyl acetate, methyl alcohol, acetonitrile or the water, and temperature of reaction is-25～50 ℃;
The methylating reagent of step D ' aminomethylation reaction is Paraformaldehyde 96 or formalin; Reductive agent is sodium cyanoborohydride, sodium borohydride or formic acid; Described reaction solvent is at least a in water, acetonitrile, tetrahydrofuran (THF) or the methyl alcohol;
Step e ' when preparing dapoxetine and analogue thereof by the compound X, sulfonylation agent is Tosyl chloride or methylsulfonyl chloride; Described alkali is imidazoles, triethylamine, pyridine, piperidines, diisopropylethylamine, yellow soda ash, sodium bicarbonate, salt of wormwood or saleratus; Described reaction solvent is methylene dichloride, trichloromethane or tetrahydrofuran (THF); Temperature of reaction is-25～50 ℃.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102976953A (en) * | 2011-09-05 | 2013-03-20 | 上海药明康德新药开发有限公司 | Preparation method of chiral alpha-difluoromethyl phenyl ethylamine |
| CN104177277A (en) * | 2013-03-14 | 2014-12-03 | 南京大学 | Chiral 2-arylpropyl-2-sulfinamide and chiral n-2-arylpropyl-2-sulfinylimines and synthesis thereof |
| CN106397227A (en) * | 2016-08-19 | 2017-02-15 | 山东省药学科学院 | Preparation method of dapoxetine hydrochloride |
| CN111825708A (en) * | 2019-04-18 | 2020-10-27 | 复旦大学 | Sulfoxide group-containing ortho-amino alcohol compound and preparation method thereof |
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| CN1709859A (en) * | 2005-06-22 | 2005-12-21 | 曹丽 | Method for preparing dextroa-[2-(naphthoxy, ethyl] phenyl methylamine derivatives |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102976953A (en) * | 2011-09-05 | 2013-03-20 | 上海药明康德新药开发有限公司 | Preparation method of chiral alpha-difluoromethyl phenyl ethylamine |
| CN104177277A (en) * | 2013-03-14 | 2014-12-03 | 南京大学 | Chiral 2-arylpropyl-2-sulfinamide and chiral n-2-arylpropyl-2-sulfinylimines and synthesis thereof |
| CN106397227A (en) * | 2016-08-19 | 2017-02-15 | 山东省药学科学院 | Preparation method of dapoxetine hydrochloride |
| CN106397227B (en) * | 2016-08-19 | 2018-07-06 | 山东省药学科学院 | A kind of preparation method of Dapoxetine hydrochloride hydrochloride |
| CN111825708A (en) * | 2019-04-18 | 2020-10-27 | 复旦大学 | Sulfoxide group-containing ortho-amino alcohol compound and preparation method thereof |
| CN111825708B (en) * | 2019-04-18 | 2023-02-07 | 复旦大学 | Sulfoxide group-containing ortho-amino alcohol compound and preparation method thereof |
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