CN101012147A - Method of preparing R-(+)-3-chlorophenylpropanol - Google Patents
Method of preparing R-(+)-3-chlorophenylpropanol Download PDFInfo
- Publication number
- CN101012147A CN101012147A CN 200710061510 CN200710061510A CN101012147A CN 101012147 A CN101012147 A CN 101012147A CN 200710061510 CN200710061510 CN 200710061510 CN 200710061510 A CN200710061510 A CN 200710061510A CN 101012147 A CN101012147 A CN 101012147A
- Authority
- CN
- China
- Prior art keywords
- propyl alcohol
- derivative
- preparation
- chlorobenzene propyl
- dimethyl
- 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
- 238000000034 method Methods 0.000 title abstract description 17
- APYGJPRINQKIQF-SECBINFHSA-N (1r)-1-(3-chlorophenyl)propan-1-ol Chemical compound CC[C@@H](O)C1=CC=CC(Cl)=C1 APYGJPRINQKIQF-SECBINFHSA-N 0.000 title 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 170
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 68
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 61
- 239000002904 solvent Substances 0.000 claims description 52
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 39
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 28
- VCNYPJMEQHTAHS-UHFFFAOYSA-N 1-(3-chlorophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=CC(Cl)=C1 VCNYPJMEQHTAHS-UHFFFAOYSA-N 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000011592 zinc chloride Substances 0.000 claims description 16
- 235000005074 zinc chloride Nutrition 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 6
- 125000003944 tolyl group Chemical group 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical class OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 5
- 150000002519 isoleucine derivatives Chemical class 0.000 claims description 5
- 229960001701 chloroform Drugs 0.000 claims description 4
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical class OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 claims 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 abstract description 4
- 229930182817 methionine Natural products 0.000 abstract description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 abstract description 2
- 229940024606 amino acid Drugs 0.000 abstract description 2
- 150000001413 amino acids Chemical class 0.000 abstract description 2
- 241001597008 Nomeidae Species 0.000 abstract 7
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 abstract 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 abstract 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 abstract 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 abstract 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 abstract 1
- 235000001014 amino acid Nutrition 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 235000018417 cysteine Nutrition 0.000 abstract 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 abstract 1
- 229960000310 isoleucine Drugs 0.000 abstract 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 abstract 1
- 239000012279 sodium borohydride Substances 0.000 abstract 1
- 229910000033 sodium borohydride Inorganic materials 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- 238000003756 stirring Methods 0.000 description 40
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 36
- 239000012043 crude product Substances 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 238000001953 recrystallisation Methods 0.000 description 21
- 150000001412 amines Chemical class 0.000 description 20
- 229910021529 ammonia Inorganic materials 0.000 description 18
- 235000015177 dried meat Nutrition 0.000 description 18
- RGJOLSWGURYBNM-UHFFFAOYSA-N [Cl-].C[NH3+].C1=CC=CC=C1 Chemical compound [Cl-].C[NH3+].C1=CC=CC=C1 RGJOLSWGURYBNM-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 12
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 11
- -1 alkali metal salt Chemical class 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 230000003252 repetitive effect Effects 0.000 description 10
- 238000005201 scrubbing Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 7
- LRCYAJZPDFSJPQ-UHFFFAOYSA-N 3-azaniumyl-2-phenylpropanoate Chemical compound NCC(C(O)=O)C1=CC=CC=C1 LRCYAJZPDFSJPQ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000005194 fractionation Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000009413 insulation Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- SRJCJJKWVSSELL-UHFFFAOYSA-N 2-methylnaphthalen-1-ol Chemical compound C1=CC=CC2=C(O)C(C)=CC=C21 SRJCJJKWVSSELL-UHFFFAOYSA-N 0.000 description 3
- LLJKLSASLJIYAO-UHFFFAOYSA-N 3-naphthalen-1-yloxy-1-phenylpropan-1-amine Chemical class C=1C=CC2=CC=CC=C2C=1OCCC(N)C1=CC=CC=C1 LLJKLSASLJIYAO-UHFFFAOYSA-N 0.000 description 3
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical class [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 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 description 3
- 229960005217 dapoxetine Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 229960003067 cystine Drugs 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 208000000044 Amnesia Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- UQXKXGWGFRWILX-UHFFFAOYSA-N ethylene glycol dinitrate Chemical compound O=N(=O)OCCON(=O)=O UQXKXGWGFRWILX-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000002440 industrial waste Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 201000003995 melancholia Diseases 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 229940049547 paraxin Drugs 0.000 description 1
- 206010036067 polydipsia Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- RPLOPBHEZLFENN-HTMVYDOJSA-M sodium;4-[(2r,3r)-2-[(2,2-dichloroacetyl)amino]-3-hydroxy-3-(4-nitrophenyl)propoxy]-4-oxobutanoate Chemical compound [Na+].[O-]C(=O)CCC(=O)OC[C@@H](NC(=O)C(Cl)Cl)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 RPLOPBHEZLFENN-HTMVYDOJSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a making method of R-(+)-3-chlophenicol, which is characterized by the following: adopting left-handed bulk of chiral amino acid derivant as catalyst; synthesizing 3-chlophenicol and NaBH4 or KBH4 directly to produce R-(+)-3-chlophenicol; selecting the left-handed bulk from one of left-handed isoleucine derivant, left-handed proline derivant, left-handed tryptophan derivant, left-handed cysteine derivant, left-handed histidine derivant and left-handed methionine derivant.
Description
Technical field
The present invention relates to a kind of preparation method who can be used as the useful intermediates 3-chlorobenzene propyl alcohol of treatment dysthymia disorders medicine, particularly relate to the preparation method of its single rotator R-(+)-3-chlorobenzene propyl alcohol.
Background technology
Dapoxetine (Dapoxetine), chemical name S-(+)-N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride (N, N-dimethyl-α-[2-(naphthalenyloxy) ethyl] benyenemethanamine hydrochloride), it is a kind of selectivity serotonin reuptake inhibithors, can be used for treating diseases such as melancholia and excessive drinking, fat-reducing, memory loss, to forgetful, irritability, depressed, unsociable and eccentric effective, also be that first is used for the treatment of the oral pharmaceutical of prospermia of males in the world simultaneously.This medicine is a kind of optionally seronine uptake inhibitor, and to not directly effect of neuronal acceptor.Because such medicine can not suppress other monoamine effectively, so the expection side effect is smaller after dispenser.
1988, U.S. Eli Lilly Company applied for the pharmaceutical patent (EP288188) of α-[2-(naphthyloxy) ethyl] benzene methanamine and derivative thereof, the DL body that is actually α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives that this patent relates to.Among the target compound preparation method who in this patent, provides, a kind of effective means is by with benzaldehyde derivative and propanedioic acid and ammonium acetate reaction, generate corresponding beta-amino phenylpropionic acid, and further be converted into the corresponding carboxylic acid ester, restore and be alcohol, at last the hydroxy intermediate of gained is handled with alkalimetal hydride and generated corresponding alkali metal salt, with the suitable compound reaction that contains good leavings group, make target compound again.
200510012624 of Chinese patents further provide a kind of method for preparing dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives, specifically be to make phenyl aldehyde and propanedioic acid and ammonium acetate reaction obtain the beta-amino phenylpropionic acid earlier, re-using the anhydrous tartrate of dextrorotation splits the beta-amino phenylpropionic acid, obtain dextrorotation beta-amino phenylpropionic acid, make the compound reaction of dextrorotation beta-amino phenylpropionic acid and general formula (c) expression then
Obtain the compound of general formula (d) expression,
Again the compound reduction of general formula (d) expression is converted into the compound of general formula (b) expression,
At last, compound and the α-Xiu Dainai reaction with general formula (b) expression obtains dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives that general formula (a) is represented.
What this patent was different with other preparation feedback is that promptly DL beta-amino phenylpropionic acid begins, and just optically-active compound is split, rather than splits to the finished product again from a generation optically-active compound.This technology can be saved the raw material consumption of each step reaction subsequently greatly, also greatly reduces the discarded levorotatory amount of generation.
Chinese patent 200610024697 discloses a kind of synthetic method of dapoxetine, and is specific as follows:
1. with 3-chlorophenyl acetone and NaBH
4In the glycol dinitrate ether solvents, obtain the 3-chlorobenzene propyl alcohol behind the reaction 1h;
2. 3-chlorobenzene propyl alcohol and methyl naphthol are carried out condensation reaction in KOH/DMF solution, obtain condensation product 3-(1-naphthyloxy)-1-phenyl-1-propyl alcohol;
3. the condenses with step 2 adds in Dimethylamino pyridine/tetrahydrofuran (THF)/triethylamine solution, stir ice bath and drip methane sulfonyl chloride down, feed dimethylamine gas behind the 6h, after stirring 30h under the room temperature, decompression and solvent recovery, obtain N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride crude product;
4. with Ltartaric acid splitting step 3 crude products, obtain its Ltartaric acid salt, behind recrystallization, change into S-(+)-N again, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride.
Obtaining to have the most current way of single rotator character compound now in the world is to adopt the method that splits that single rotator character compound is separated from the DL body, behind the single rotator that needing to obtain, another part single rotator then discards as waste material or racemization becomes the DL body, is reused for fractionation again.Its racemization becomes the technology of DL body, and regardless of expense carries out in order to solve environmental issue sometimes, the intermediate dextrorotation amido thing of for example making paraxin is the waste material after a kind of the fractionation, in order to solve these a large amount of discarded discharging solids, its racemization have to be made DL amido thing, and its preparation cost is to be higher than DL amido thing that usual way makes far away.Equally, the synthetic method of patent 200610024697 can produce R-(-)-N with the target product same amount inevitably, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride waste.
It is starting raw material that 5292962 of U.S. Pat provide a kind of single rotator with the 3-chlorobenzene propyl alcohol, directly synthetic N, the method of N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride single rotator, specifically be with the synthetic S-(+) of R-(+)-3-chlorobenzene propyl alcohol-N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride, with the synthetic R-(-) of S-(-)-3-chlorobenzene propyl alcohol-N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride.Similar with Chinese patent 200510012624, this method can be saved the raw material consumption of subsequent step, reduces the discarded thing amount of singly revolving.
Yet the single rotator of 3-chlorobenzene propyl alcohol still needs to obtain by splitting in the aforesaid method, still can produce the discarded thing that singly revolves of 3-chlorobenzene propyl alcohol.So how many in the world people can go out to have the compound of our required opticity by one-step synthesis in research, and avoid resolution process.But the compound that has required opticity that only a few also only arranged up to now, in the world is one-step synthesis without fractionation.
Summary of the invention
The purpose of this invention is to provide a kind of fractionation that do not need, is starting raw material with the 3-chlorophenyl acetone, the preparation method of directly synthetic R-(+)-3-chlorobenzene propyl alcohol single rotator after reducing.
We find in research process, when the derivative that uses the amino acid single rotator during as catalyzer, can be unexpectedly by the 3-chlorophenyl acetone directly reduction obtain the single rotator of 3-chlorobenzene propyl alcohol, find that based on this we have developed a kind of preparation method of brand-new R-(+)-3-chlorobenzene propyl alcohol.
The preparation method of R-of the present invention (+)-3-chlorobenzene propyl alcohol is that the levo form with chiral amino acid derivative is a catalyzer, by 3-chlorophenyl acetone and NaBH
4Or KBH
4The directly synthetic R-(+) of reaction-3-chlorobenzene propyl alcohol.
Wherein, the levo form of described chiral amino acid derivative is meant a kind of in left-handed Isoleucine derivative, levoproline derivative, Try derivative, left-handed cystine derivatives, l-histidine derivative, the L-Methioine derivative.
Particularly, described left-handed Isoleucine derivative is meant the compound of general formula (I) expression:
In the formula:
R1 and R2 are H, C independently of one another
1～C
4Alkyl, phenyl or tolyl;
R3 and R4 are H or C independently of one another
1～C
4Straight chained alkyl.
Typical left-handed Isoleucine derivative can have:
S-(-)-, the different bright amine alcohol of alpha-alpha-dimethyl; The bright amine alcohol of S-(-)-α-isopropyl; S-(-)-N, N-dimethyl-α, the different bright amine alcohol of alpha-alpha-dimethyl; S-(-)-N, N-dimethyl-α, the different bright amine alcohol of α-di-isopropyl; S-(-)-N, the different bright amine alcohol of N-dimethyl-Alpha-Methyl-α-ethyl; S-(-)-N-methyl-N-ethyl-α, the different bright amine alcohol of alpha-alpha-dimethyl; S-(-)-N-methyl-N-ethyl-α, the different bright amine alcohol of α-di-isopropyl; S-(-)-N, the different bright amine alcohol of N-dimethyl-α-p-methylphenyl; S-(-)-N, N-diethyl-α, the different bright amine alcohol of alpha-alpha-dimethyl; S-(-)-N, the different bright amine alcohol of N-diethyl-α-p-methylphenyl; S-(-)-N, the different bright amine alcohol of N-dimethyl; S-(-)-N, N-diethyl-α, the different bright amine alcohol of α-di-t-butyl; S-(-)-N, the different bright amine alcohol of N-dimethyl-Alpha-Methyl; S-(-)-N-methyl-α, the different bright amine alcohol of α-di-isopropyl; The different bright amine alcohol of S-(-)-N-methyl-α-p-methylphenyl; S-(-)-N, the different bright amine alcohol of N-dimethyl-α-phenyl; The different bright amine alcohol of S-(-)-α-phenyl; Or the like.
Described levoproline derivative is meant the compound of general formula (II) expression:
In the formula:
R1 and R2 are H, C independently of one another
1～C
4Alkyl, phenyl or tolyl;
R3 is H or C
1～C
4Straight chained alkyl.
Typical levoproline derivative can have:
S-(-)-N-methyl-α, α-di-p-tolyl dried meat ammonia alcohol; S-(-)-N-methyl-α, α-diphenylprolinol; S-(-)-N-methyl-α, alpha-alpha-dimethyl dried meat ammonia alcohol; S-(-)-N-methyl-α, α-diethyl dried meat ammonia alcohol; S-(-)-N-methyl-α, α-di-isopropyl dried meat ammonia alcohol; S-(-)-N-methyl-Alpha-Methyl-α-ethyl dried meat ammonia alcohol; S-(-)-N-methyl-α-p-methylphenyl dried meat ammonia alcohol; S-(-)-N-methyl-α-phenyl dried meat ammonia alcohol; S-(-)-N-methyl-Alpha-Methyl dried meat ammonia alcohol; S-(-)-N-methyl dried meat ammonia alcohol; S-(-)-α, α-di-p-tolyl dried meat ammonia alcohol; S-(-)-α, alpha-alpha-dimethyl dried meat ammonia alcohol; S-(-)-N-ethyl-α, alpha-alpha-dimethyl dried meat ammonia alcohol; S-(-)-N-ethyl-α, α-di-p-tolyl dried meat ammonia alcohol; S-(-)-N-propyl group-α, α-diethyl dried meat ammonia alcohol; S-(-)-N-ethyl-α, α-di-isopropyl dried meat ammonia alcohol; S-(-)-N-propyl group-Alpha-Methyl-α-ethyl dried meat ammonia alcohol; S-(-)-N-ethyl-Alpha-Methyl dried meat ammonia alcohol; S-(-)-N-ethyl dried meat ammonia alcohol; Or the like.
Described Try derivative is meant the compound of general formula (III) expression:
In the formula:
R1, R2, R3 and R4 are H, C independently of one another
1～C
4Alkyl, phenyl or tolyl;
R5 is H or C
1～C
4Straight chained alkyl.
Typical Try derivative can have:
S-(-)-α, the alpha-alpha-dimethyl tryptosol; S-(-)-α, α-di-isopropyl tryptosol; S-(-)-α, α-di-p-tolyl tryptosol; S-(-)-α-phenyl tryptosol; S-(-)-N, N-dimethyl-α-p-methylphenyl tryptosol; S-(-)-indoles N-ethyl-Alpha-Methyl-α-ethyl tryptosol; S-(-)-indoles N-ethyl-N, N-dimethyl-α, α-di-isopropyl tryptosol; S-(-)-Alpha-Methyl-α-ethyl tryptosol; S-(-)-indoles N-methyl-α, the alpha-alpha-dimethyl tryptosol; S-(-)-indoles N-methyl-N, N-dimethyl-α, alpha-alpha-dimethyl tryptosol; S-(-)-N, N-dimethyl-α-phenyl tryptosol; S-(-)-N-methyl-N-ethyl-α, α-di-isopropyl tryptosol; S-(-)-N, N-dimethyl-α, alpha-alpha-dimethyl tryptosol; S-(-)-N, N-dimethyl-Alpha-Methyl-α-ethyl tryptosol; S-(-)-N, N-dimethyl tryptosol; S-(-)-N-methyl-N-isopropyl propyl group-α, α-phenylbenzene tryptosol; S-(-)-N-methyl-N-ethyl-α-p-methylphenyl tryptosol; S-(-)-N, N-diethyl-α-p-methylphenyl tryptosol; S-(-)-N-methyl-α, α-di-isopropyl tryptosol; S-(-)-N, N-diethyl-α, α-di-t-butyl tryptosol; S-(-)-indoles N-propyl group-α-p-methylphenyl tryptosol; S-(-)-indoles N-methyl tryptosol; Or the like.
Described left-handed cystine derivatives is meant the compound of general formula (IV) expression:
In the formula:
R1 is methyl, ethyl or phenyl;
R2 is H or C
1～C
4Alkyl.
Typical left-handed cystine derivatives can have:
S-(-)-N, N-dimethyl-N ', N '-dimethyl-cystine dimethyl; S-(-)-N, N-diethyl-N ', N '-diethyl-cystine dimethyl; S-(-)-N, N-di-isopropyl-N ', N '-di-isopropyl-cystine dimethyl; S-(-)-N, N-dimethyl-N ', N '-dimethyl-Gelucystine diphenyl ester; S-(-)-N, N-di-isopropyl-N ', N '-di-isopropyl-Gelucystine diphenyl ester; S-(-)-N, N-dimethyl-N ', N '-dimethyl-Gelucystine diethyl ester; S-(-)-Gelucystine diethyl ester; S-(-)-cystine dimethyl; S-(-)-Gelucystine diphenyl ester; Or the like.
Described l-histidine derivative is meant the compound that logical formula V is represented:
In the formula:
R1 is methyl, ethyl or phenyl;
R2 and R3 are H or C independently of one another
1～C
4Straight chained alkyl;
Typical l-histidine derivative can have:
S-(-)-N, N-dimethyl Histidine ethyl ester; S-(-)-N, N-dimethyl Histidine phenyl ester; S-(-)-N, N-dipropyl Histidine methyl esters; S-(-)-N, N-diethyl Histidine phenyl ester; S-(-)-N-methyl-N-ethyl Histidine ethyl ester; S-(-)-N-methyl-N-ethyl Histidine phenyl ester; S-(-)-Histidine phenyl ester; S-(-)-Histidine methyl esters; Or the like.
Described L-Methioine derivative is meant the compound of general formula (VI) expression:
In the formula:
R1 is methyl, ethyl or phenyl;
R2 and R3 are H or C independently of one another
1～C
4Straight chained alkyl;
Typical L-Methioine derivative can have:
S-(-)-N-methyl-N-ethyl methionine(Met) phenyl ester; S-(-)-N, N-dimethyl methionine(Met) ethyl ester; S-(-)-N, N-diethyl methionine(Met) phenyl ester; S-(-)-methionine(Met) ethyl ester; S-(-)-methionine(Met) phenyl ester; S-(-)-N-methyl-N-ethyl methyl methionine; S-(-)-N-methylmethionine methyl esters; S-(-)-N-propyl group methionine(Met) phenyl ester; S-(-)-N-ethyl methyl methionine; S-(-)-N, N-dimethyl methyl methionine; S-(-)-N, N-diethyl methionine(Met) ethyl ester; S-(-)-N-methyl-N-ethyl methyl methionine; S-(-)-N-methylmethionine phenyl ester; Or the like.
Among the preparation method of the present invention, be that the levo form with above-mentioned a kind of chiral amino acid derivative is a catalyzer, by 3-chlorophenyl acetone and NaBH
4Or KBH
4Mol ratio according to 1: 0.5～5, reaction in the presence of Zinc Chloride Anhydrous or anhydrous stannic chloride is with preparation R (+)-3-chlorobenzene propyl alcohol.Reaction of the present invention is carried out in such as anhydrous solvents such as dimethyl sulfoxide (DMSO), dimethyl formamide, tetrahydrofuran (THF), ethylene dichloride, trichloromethanes.In reaction of the present invention, the suitable 3-chlorophenyl acetone and the mol ratio of chiral amino acid derivative catalyzer are 1: 0.6～3.
Usually the way of preparation R-(+)-3-chlorobenzene propyl alcohol is earlier synthetic 3-chlorobenzene propyl alcohol DL body, through splitting, makes R-(+)-3-chlorobenzene propyl alcohol again.R-(+)-3-chlorobenzene propyl alcohol by this method production, because the instability of operation and the restriction that is subjected to disassemble technique, the dextrorotatory form content of the 3-chlorobenzene propyl alcohol that obtains can not reach 100%, usually, only can obtain content by disassemble technique is 97～98% dextrorotatory, and the specific rotation of product is+24 °.And adopt the present invention with the levo form of chiral amino acid derivative catalysis directional synthesising technology as catalyzer, and can obtain dextrorotatory form content 100%, the product specific rotation reaches+R-(+)-3-chlorobenzene propyl alcohol product of 25 °.
Adopt method of the present invention to prepare R-(+)-3-chlorobenzene propyl alcohol, can not produce 50% levo form, thereby yield is enhanced about more than once, product cost descends greatly than resolution process.Because 50% levorotatory that resolution process produces is otiose industrial waste, very bad processing, and directional synthesising technology of the present invention does not produce levo form, therefore can deserve to be called an environmental protection project.
Equally, with R-of the present invention (+)-3-chlorobenzene propyl alcohol is starting raw material, can directly synthesize compound S-(+)-N of our required opticity, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride, thereby avoided resolution process, greatly reduced production cost.General S-(+)-N that adopts Split Method technology to obtain, the specific rotation (1% chloroform soln) of N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride is up to+and 128 °, the content of single rotator also only is 97～98%, and S-(+)-N that adopts R-of the present invention (+)-3-chlorobenzene propyl alcohol to prepare, the specific rotation of N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride can reach+and 129.1 °, single rotator purity can reach 100%.
Embodiment
Embodiment 1:
Get dimethyl sulfoxide (DMSO) 200mL, S-(-)-N, N-dimethyl-α, the different bright amine alcohol 30g of α-di-isopropyl, NaBH
49g adds in the three-necked bottle, add the dimethyl sulfoxide (DMSO) 100mL that contains the 28g Zinc Chloride Anhydrous again, stir, get 3-chlorophenyl acetone 34g under 25～30 ℃ of conditions adds in batches, be warming up to backflow, reaction 14h is cooled to room temperature, removes by filter filter residue, with filtrate heat up evaporate to dryness and reclaim solvent after, add the 300mL ethylene dichloride again, be cooled to 0 ℃, insulation crystallization 8h, filter, obtain R-(+)-about 18g of 3-chlorobenzene propyl alcohol solid crude product, crude product with 250mL ethylene dichloride recrystallization, is obtained R-(+)-3-chlorobenzene propyl alcohol solid 11g.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 56～57 ℃, specific rotation α
19=+25 °.
Embodiment 2:
With dimethyl sulfoxide (DMSO) 350mL, S-(-)-N, the different bright amine alcohol 35g of N-dimethyl-α-p-methylphenyl, NaBH
410g, Zinc Chloride Anhydrous 15g, 3-chlorophenyl acetone 35g adds in the three-necked bottle together, stir, be warming up to backflow, reaction 24h, be cooled to room temperature, remove by filter filter residue, add NaOH solution 100mL and the water 300mL of 5mol/L in the filtrate, in 40 ℃ of following stirring reaction 1h, standing demix, branch vibration layer with the solvent layer evaporate to dryness and after reclaiming solvent, is emitted resistates while hot, obtain R-(+)-about 30g of 3-chlorobenzene propyl alcohol crude product after the cooling, with crude product anhydrous isopropyl alcohol recrystallization, obtain R-(+)-about 23g of 3-chlorobenzene propyl alcohol elaboration, yield is about 68%～73%.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 57～59 ℃, specific rotation α
19=+25 °.
Embodiment 3:
Earlier the 18g anhydrous stannic chloride is joined in the 200mL tetrahydrofuran (THF), it is standby to make suspension liquid A.Get tetrahydrofuran (THF) 150mL respectively, the different bright amine alcohol 37.8g of S-(-)-N-methyl-N-ethyl-Alpha-Methyl-α-ethyl, KBH
415g, 3-chlorophenyl acetone 21g-rise and add in the three-necked bottle, stir, and are warming up to 40 ℃, add suspension liquid A, stir temperature rising reflux reaction 18h down, and reaction finishes, and is cooled to 40 ℃, removes by filter filter residue.Filtrate intensification evaporate to dryness and reclaim solvents tetrahydrofurane after, add the 400mL normal hexane, be heated to transparent, be cooled to 5 ℃ again, insulation crystallization 3h filters, and obtains R-(+)-3-chlorobenzene propyl alcohol solid crude product, behind crude product usefulness 250mL Virahol recrystallization, obtain R-(+)-about 8g of 3-chlorobenzene propyl alcohol white solid.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 58～60 ℃, specific rotation α
19=+25 °, molecular weight is 170.64 after testing.
Embodiment 4:
With 9g Zinc Chloride Anhydrous and 100mL dimethyl formamide mixing, it is standby to make suspension liquid A earlier.Get dimethyl formamide 250mL again, S-(-)-N-methyl-α, α-di-p-tolyl Prolinol 23.2g, NaBH
49g, 3-chlorophenyl acetone 21g adds in the three-necked bottle together, divides to add above-mentioned suspension liquid A 2 times, slowly is warming up to 95～98 ℃, under agitation reacts 12h, and reaction finishes, and removes by filter filter residue.Intensification evaporate to dryness and reclaim the solvent dimethyl formamide under vacuum, add the 200mL ethyl acetate in the resistates, heating for dissolving is to as clear as crystal, be cooled to 0 ℃ again, insulation crystallization 0.5h filters, and obtains R-(+)-3-chlorobenzene propyl alcohol solid crude product, crude product with 300mL hexanaphthene recrystallization, is obtained R-(+)-about 3.5g of 3-chlorobenzene propyl alcohol white solid.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 56～59 ℃, specific rotation α
19=+25 °.
Embodiment 5:
With dimethyl formamide 350mL, S-(-)-N-sec.-propyl-α-p-methylphenyl Prolinol 26.1g, KBH
411g, Zinc Chloride Anhydrous 10g, borax 0.8g, 3-chlorophenyl acetone 20g adds in the three-necked bottle together, is heated to backflow under stirring, and reaction 12h is cooled to room temperature, removes by filter filter residue.Under vacuum the intensification evaporate to dryness and reclaim the solvent dimethyl formamide after, the NaOH solution 150mL and the water 100mL that add 3mol/L in the resistates, hexanaphthene 200mL, room temperature reaction 1h under violent stirring, standing demix, branch vibration layer, solvent layer are repeatedly with the clear water washing, until water layer pH=7～7.2 of telling.Solvent layer is concentrated into volume is about 50mL, be cooled to room temperature, obtain R-(+)-3-chlorobenzene propyl alcohol crude product, crude product is filtered out,, obtain R-(+)-about 5.5g of 3-chlorobenzene propyl alcohol elaboration with 100mL hexanaphthene recrystallization.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 55～57 ℃, specific rotation α
19=+25 °.
Embodiment 6:
Get tetrahydrofuran (THF) 300mL, S-(-)-α, alpha-alpha-dimethyl Prolinol 12g, KBH
411g, Zinc Chloride Anhydrous 12g, 3-chlorophenyl acetone 15g adds in the three-necked bottle together, is heated to backflow under stirring, reaction 8h, reaction finishes, and is cooled to room temperature, removes by filter filter residue.Add the NaOH solution 300mL of 2mol/L in the filtrate, stir 1h under the room temperature, standing demix, branch vibration layer, solvent layer washs 0.5h, standing demix with the acetum 200mL of 1mol/L, branch vibration layer, solvent layer are used the clear water repetitive scrubbing again, are neutrality until the water layer of telling.With the solvent layer evaporate to dryness and after reclaiming solvents tetrahydrofurane, emit the resistates of melting while hot, obtain R-(+)-3-chlorobenzene propyl alcohol crude product after the cooling, crude product with 100mL hexanaphthene recrystallization, is obtained R-(+)-about 3g of 3-chlorobenzene propyl alcohol elaboration.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 57～59 ℃, specific rotation α
19=+25 °.
Embodiment 7
With tetrahydrofuran (THF) 300mL, S-(-)-indoles N-methyl-α, α-phenylbenzene tryptamines alcohol 33g, KBH
48g, anhydrous stannic chloride 5g, 3-chlorophenyl acetone 13g adds in the three-necked bottle together, stirs heating reflux reaction 12h down, after finishing, is cooled to room temperature, removes by filter filter residue.Add the HCl solution 200mL of 3mol/L in the filtrate, stir 0.5h under the room temperature, standing demix, branch vibration layer, solvent layer is with 0.5% NaHCO
3Solution 100mL washing, standing demix, branch vibration layer, solvent layer are used the clear water repetitive scrubbing again, are neutrality until the water layer of telling.With the solvent layer evaporate to dryness and after reclaiming solvents tetrahydrofurane, emit the resistates of melting while hot, obtain R-(+)-3-chlorobenzene propyl alcohol crude product after the cooling, with crude product 150mL acetone recrystallization, obtain R-(+)-about 6.8g of 3-chlorobenzene propyl alcohol elaboration.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 57～59 ℃, specific rotation α
19=+25 °.
Embodiment 8
With dimethyl formamide 300mL, S-(-)-N, N-dimethyl-α, α-di-p-tolyl tryptamines alcohol 36.3g, NaBH
48g, anhydrous stannic chloride 5g, 3-chlorophenyl acetone 13g adds in the three-necked bottle together, is heated to backflow under stirring, and reaction 24h after reaction finishes, is cooled to room temperature, removes by filter filter residue.Add the acetum 200mL of 3mol/L in the filtrate, at room temperature stir 0.5h, standing demix, branch vibration layer, solvent layer is with 0.5% Na
2CO
3Solution 100mL washing, standing demix, branch vibration layer, solvent layer are used the clear water repetitive scrubbing again, are neutrality until the water layer of telling.With the solvent layer evaporate to dryness and after reclaiming the solvent dimethyl formamide, emit the resistates of melting while hot, obtain R-(+)-3-chlorobenzene propyl alcohol crude product after the cooling, with crude product 300mL acetone recrystallization, obtain R-(+)-about 5.1g of 3-chlorobenzene propyl alcohol elaboration.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 57～59 ℃, specific rotation α
19=+25 °.
Embodiment 9:
Get dimethyl formamide 300mL respectively, S-(-)-indoles N-propyl group-N, N-dimethyl-α-sec.-propyl tryptamines alcohol 21.5g, KBH
410g, Zinc Chloride Anhydrous 7g, 3-chlorophenyl acetone 12g add in the three-necked bottle, stir heating reflux reaction 14h down, after reaction finishes, are cooled to room temperature, remove by filter filter residue.Add the NaOH solution 150mL of 3mol/L in the filtrate, stir 1h under the room temperature, standing demix, branch vibration layer, solvent layer washs 0.5h, standing demix with the acetum 100mL of 1mol/L, branch vibration layer, solvent layer are used the clear water repetitive scrubbing again, are neutrality until the water layer of telling.With the solvent layer evaporate to dryness and after reclaiming the solvent dimethyl formamide, emit the resistates of melting while hot, obtain R-(+)-3-chlorobenzene propyl alcohol crude product after the cooling, crude product with 100mL pimelinketone recrystallization, is obtained R-(+)-about 4.2g of 3-chlorobenzene propyl alcohol elaboration.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 56～58 ℃, specific rotation α
19=+25 °.
Embodiment 10:
With dimethyl formamide 200mL, S-(-)-N, N-dimethyl-N ', N '-dimethyl cystine dimethyl 20g, NaBH
410g, Zinc Chloride Anhydrous 7g, 3-chlorophenyl acetone 12g adds in the three-necked bottle together, is heated to backflow under stirring, and reaction 12h after reaction finishes, is cooled to room temperature, removes by filter filter residue.The NaOH solution 150mL that adds 3mol/L in the filtrate, stirring reaction 0.5h, standing demix, branch vibration layer, behind the acetum 200mL washing 0.5h of solvent layer with 0.5mol/L, standing demix, branch vibration layer, solvent layer are used the clear water repetitive scrubbing again, are neutrality until the water layer of telling.With the solvent layer evaporate to dryness and after reclaiming the solvent dimethyl formamide, add the 300mL hexanaphthene in the resistates, reflux is limpid transparent to solution, is cooled to 5 ℃ again, and insulation crystallization 10h filters, and obtains R-(+)-3-chlorobenzene propyl alcohol elaboration 9g, yield about 75%.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 56～58 ℃, specific rotation α
19=+25 °.
Embodiment 11
With dimethyl formamide 500mL, the two ethyl ester 23g of S-(-)-Gelucystine, KBH
46g, Zinc Chloride Anhydrous 7g, 3-chlorophenyl acetone 9.7g adds in the three-necked bottle together, is heated to backflow under stirring, and reaction 10h after reaction finishes, is cooled to room temperature, removes by filter filter residue.The HCl solution 400mL that adds 1mol/L in the filtrate, stirring reaction 0.5h leaves standstill the back branch vibration layer, the solvent layer NaHCO of 1mol/L
3Solution 300mL washs 0.5h, standing demix, and branch vibration layer, solvent layer are used the clear water repetitive scrubbing again, are neutrality until the water layer of telling.With the solvent layer evaporate to dryness and after reclaiming the solvent dimethyl formamide, add the 600mL hexanaphthene in the resistates, reflux is limpid transparent to solution, continues to stir 1h again, is cooled to room temperature, filters and obtains R-(+)-3-chlorobenzene propyl alcohol elaboration 13g, yield about 78%.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 56～58 ℃, specific rotation α
19=+25 °, molecular weight is 170.64 after testing.
Embodiment 12:
Get trichloromethane 300mL, S-(-)-N, N-dimethyl-N ', the two phenyl ester 36g of N '-dimethyl Gelucystine, KBH
46g, Zinc Chloride Anhydrous 2g, 3-chlorophenyl acetone 17g add in the three-necked bottle, are heated to backflow under stirring, and reaction 4h is cooled to 10 ℃, removes by filter filter residue.The filtrate evaporate to dryness and reclaim the solvent trichloromethane after, add the HCl solution 500mL of 2mol/L in the resistates, in 40 ℃ of stirring reaction 0.5h, filter, a little washing with alcohol of filter cake is after the drying, with 300mL hexanaphthene recrystallization, obtain R-(+)-3-chlorobenzene propyl alcohol elaboration 6g.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 57～59 ℃, specific rotation α
19=+25 °, molecular weight is 170.64 after testing.。
Embodiment 13:
With ethylene dichloride 350mL, S-(-)-N-methylhistidine ethyl ester 15g, KBH
44.5g, Zinc Chloride Anhydrous 3.5g, 3-chlorophenyl acetone 12g adds in the three-necked bottle together, is heated to backflow under stirring, and reaction 8h after reaction finishes, is cooled to room temperature, removes by filter filter residue.The filtrate evaporate to dryness and reclaim solvent after, add the HCl solution 300mL of 3mol/L in the resistates, stirring reaction 1h filters, till filter cake was washed till pH and is neutrality with clear water, drying with 300mL hexalin recrystallization, obtained R-(+)-about 7g of 3-chlorobenzene propyl alcohol elaboration.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 56～58 ℃, specific rotation α
19=+25 °.
Embodiment 14
With dimethyl formamide 300mL, S-(-)-Histidine methyl esters 18g, NaBH
411g, Zinc Chloride Anhydrous 2g, 3-chlorophenyl acetone 12g adds in the three-necked bottle together, is heated to backflow under stirring, and reaction 14h is cooled to room temperature, removes by filter filter residue.The HCl solution 100mL that adds 3mol/L in the filtrate, in 10 ℃ of stirring reaction 0.5h, standing demix, branch vibration layer, solvent layer is with 2% NaHCO
3Solution 200mL washing 2 times, difference standing demix and branch vibration layer, solvent layer is used the clear water repetitive scrubbing again, is neutrality until the water layer of telling.With the solvent layer evaporate to dryness and after reclaiming the solvent dimethyl formamide, add the 200mL pimelinketone in the resistates, obtain R-(+)-about 7g of 3-chlorobenzene propyl alcohol elaboration behind the recrystallization.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 56～58 ℃, specific rotation α
19=+25 °.
Embodiment 15:
With tetrahydrofuran (THF) 300mL, S-(-)-N, N-dimethyl Histidine phenyl ester 21.2g, KBH
46g, Zinc Chloride Anhydrous 1.5g, 3-chlorophenyl acetone 13g adds in the three-necked bottle together, is heated to backflow under stirring, and reaction 8h is cooled to room temperature, removes by filter filter residue.The HCl solution 100mL that adds 3mol/L in the filtrate, in 5 ℃ of stirring reaction 0.5h, standing demix, branch vibration layer, solvent layer clear water repetitive scrubbing is neutrality until the water layer of telling.With the solvent layer evaporate to dryness and after reclaiming solvents tetrahydrofurane, add 200mL acetone in the resistates, recrystallization obtains R-(+)-about 3.2g of 3-chlorobenzene propyl alcohol elaboration.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 56～58 ℃, specific rotation α
19=+25 °.
Embodiment 16:
With tetrahydrofuran (THF) 200mL, S-(-)-N-methyl-N-ethyl methyl methionine 14g, KBH
44g, Zinc Chloride Anhydrous 1.2g, 3-chlorophenyl acetone 12g adds in the three-necked bottle together, is heated to backflow under stirring, and reaction 10h is cooled to room temperature, removes by filter filter residue.The NaOH solution 200mL that adds 2mol/L in the filtrate, violent stirring 0.5h, standing demix, branch vibration layer, solvent layer clear water repetitive scrubbing is neutrality until the water layer of telling.With the solvent layer evaporate to dryness and after reclaiming solvents tetrahydrofurane, add the 360mL hexanaphthene in the resistates, recrystallization obtains R-(+)-about 2.5g of 3-chlorobenzene propyl alcohol elaboration.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 57～58 ℃, specific rotation α
19=+25 °.
Embodiment 17
Get dimethyl formamide 200mL, S-(-)-methionine(Met) phenyl ester 20g, KBH
44g, anhydrous stannic chloride 2g, 3-chlorophenyl acetone 13g adds in the three-necked bottle together, is heated to backflow under stirring, and reaction 8h is cooled to room temperature, removes by filter filter residue.The HCl solution 300mL that adds 2mol/L in the filtrate, violent stirring 0.5h, standing demix, branch vibration layer, solvent layer clear water repetitive scrubbing is neutrality until the water layer of telling.With the solvent layer evaporate to dryness and after reclaiming the solvent dimethyl formamide, add the 400mL hexanaphthene in the resistates, recrystallization obtains R-(+)-about 1.5g of 3-chlorobenzene propyl alcohol elaboration.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 56～58 ℃, specific rotation α
19=+25 °.
Embodiment 18
With dimethyl formamide 150mL, S-(-)-N-methyl-methionine(Met) phenyl ester 22.5g, NaBH
45g, Zinc Chloride Anhydrous 0.8g, 3-chlorophenyl acetone 17g adds in the three-necked bottle together, is heated to backflow under stirring, and behind the reaction 8h, is cooled to room temperature, removes by filter filter residue.Add the HCl solution 200mL of 2mol/L in the filtrate, be heated to 40 ℃ slightly, stir 0.5h, filter, filter cake is washed till neutrality with clear water, after the drying, with 400mL methylene dichloride recrystallization, obtains R-(+)-about 7g of 3-chlorobenzene propyl alcohol elaboration.
The fusing point mp of the R-(+) that obtains-3-chlorobenzene propyl alcohol is 56～58 ℃, specific rotation α
19=+25 °.
Embodiment 19
Prepare R-(-)-3-(1-naphthyloxy)-1-phenyl-1-propyl alcohol by R-(+)-3-chlorobenzene propyl alcohol
Get the 32g methyl naphthol and be dissolved in the 100mL tetrahydrofuran (THF), make solution A, 34gR-(+)-3-chlorobenzene propyl alcohol is dissolved in the 100mL tetrahydrofuran (THF), makes solution B; 9g solid NaOH and 300mL tetrahydrofuran (THF) are added in the three-necked bottle, heating reflux reaction 2h is cooled to 5 ℃, adds solution A, be warming up to 10 ℃ of reaction 10h, add solution B then, be heated to backflow, reaction 50h, be cooled to and do not reflux, reaction solution is poured in the 600mL frozen water, slowly stirred 1h, separate out crystallization.Filter, filter cake is washed till neutrality with clear water, gets crude product after the drying, with crude product hexanaphthene recrystallization, obtains R-(-)-3-(1-naphthyloxy)-1-phenyl-1-propyl alcohol white solid 20g, and recording product fusing point mp is 76～78 ℃.
Prepare S-(+)-N by R-(-)-3-(1-naphthyloxy)-1-phenyl-1-propyl alcohol, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride
Get R-(-)-3-(1-naphthyloxy)-1-phenyl-1-propyl alcohol 42g, triethylamine 30g, 40% dimethylamine solution 150mL, dimethyl formamide 300mL adds in the three-necked bottle together, in 40 ℃ of reaction 40h, after reaction finishes, reclaim solvent, add the NaOH solution 270mL of 1mol/L in the resistates, make pH, stir 1h in 3 ℃ to strong basicity, separate out solid, filtration obtains S-(+)-N, and N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine crude product adds crude product in the 300ml ethyl acetate, stir and drip the about 120ml of ethyl acetate/hydrogenchloride (saturated) solution down, react 2h down at 5 ℃, filter and obtain S-(+)-N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride crude product, crude product is used again the Virahol recrystallization of 10 times of amounts, obtain S-(+)-N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride elaboration, yield is about 35%.
Embodiment 20
Prepare R-(-)-3-(1-naphthyloxy)-1-phenyl-1-propyl alcohol by R-(+)-3-chlorobenzene propyl alcohol
In the 500mL three-necked bottle, add the 300mL dimethyl formamide successively, 70gR-(+)-3-chlorobenzene propyl alcohol, 26g solid KOH and 64g methyl naphthol, under the backflow situation, react 14h, after reaction finishes, be cooled to 80 ℃, reactant is slowly poured in the 1500mL frozen water, under 2 ℃, stir 0.5h, separate out solid, filter and obtain crude product, according to crude product: the ratio ether recrystallization of ether=1: 20, obtain R-(-)-3-(1-naphthyloxy)-1-phenyl-1-propyl alcohol elaboration 75g, yield is 67%, and product fusing point mp is 76～78 ℃.
Prepare S-(+)-N by R-(-)-3-(1-naphthyloxy)-1-phenyl-1-propyl alcohol, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride
The product 40g of step reaction in three-necked bottle, adding respectively, pyridine 15g, triethylamine 20g, tetrahydrofuran (THF) 360mL, at the dimethylamine gas of 0 ℃ of feeding through the dry mistake of Calcium Chloride Powder Anhydrous, the 1h that ventilates approximately is in 40 ℃ of reaction 12h, reclaim under reduced pressure tetrahydrofuran (THF), the NaOH solution 170mL that adds 1mol/L in the resistates, regulate pH=13, normal temperature stirs 0.5h down, obtains yellow crystal, obtain S-(+)-N after the filtration, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine crude product is dissolved in crude product in the 300mL hexanaphthene, feeds dry hydrogen chloride gas, till not absorbing, in 0 ℃ of following reaction 2h, filtering and obtaining fusing point mp is S-(+)-N of 175～178 ℃, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride crude product, crude product is used again the Virahol recrystallization of 10 times of amounts, obtain S-(+)-N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride elaboration, yield is about 57%.
Claims (11)
1, the preparation method of R-(+)-3-chlorobenzene propyl alcohol is that the levo form with chiral amino acid derivative is a catalyzer, by 3-chlorophenyl acetone and NaBH
4Or KBH
4The directly synthetic R-(+) of reaction-3-chlorobenzene propyl alcohol.
2, the preparation method of R-according to claim 1 (+)-3-chlorobenzene propyl alcohol, the levo form that it is characterized in that described chiral amino acid derivative is meant a kind of in left-handed Isoleucine derivative, levoproline derivative, Try derivative, left-handed cystine derivatives, l-histidine derivative, the L-Methioine derivative.
3, the preparation method of R-according to claim 2 (+)-3-chlorobenzene propyl alcohol is characterized in that described left-handed Isoleucine derivative is meant the compound of general formula (I) expression:
In the formula:
R1 and R2 are H, C independently of one another
1～C
4Alkyl, phenyl or tolyl;
R3 and R4 are H or C independently of one another
1～C
4Straight chained alkyl.
4, the preparation method of R-according to claim 2 (+)-3-chlorobenzene propyl alcohol is characterized in that described levoproline derivative is meant the compound of general formula (II) expression:
In the formula:
R1 and R2 are H, C independently of one another
1～C
4Alkyl, phenyl or tolyl;
R3 is H or C
1～C
4Straight chained alkyl.
5, the preparation method of R-according to claim 2 (+)-3-chlorobenzene propyl alcohol is characterized in that described Try derivative is meant the compound of general formula (III) expression:
In the formula:
R1, R2, R3 and R4 are H, C independently of one another
1～C
4Alkyl, phenyl or tolyl;
R5 is H or C
1～C
4Straight chained alkyl.
6, the preparation method of R-according to claim 2 (+)-3-chlorobenzene propyl alcohol is characterized in that described left-handed cystine derivatives is meant the compound of general formula (IV) expression:
In the formula:
R1 is methyl, ethyl or phenyl;
R2 is H or C
1～C
4Alkyl.
7, the preparation method of R-according to claim 2 (+)-3-chlorobenzene propyl alcohol is characterized in that described l-histidine derivative is meant the compound that logical formula V is represented:
In the formula:
R1 is methyl, ethyl or phenyl;
R2 and R3 are H or C independently of one another
1～C
4Straight chained alkyl;
8, the preparation method of R-according to claim 2 (+)-3-chlorobenzene propyl alcohol is characterized in that described L-Methioine derivative is meant the compound of general formula (VI) expression:
In the formula:
R1 is methyl, ethyl or phenyl;
R2 and R3 are H or C independently of one another
1～C
4Straight chained alkyl;
9, the preparation method of R-according to claim 1 (+)-3-chlorobenzene propyl alcohol is characterized in that the levo form with chiral amino acid derivative is a catalyzer, by 3-chlorophenyl acetone and NaBH
4Or KBH
4Mol ratio according to 1: 0.5～5 is reacted in the anhydrous solvent of Zinc Chloride Anhydrous or anhydrous stannic chloride, preparation R-(+)-3-chlorobenzene propyl alcohol.
10, the preparation method of R-according to claim 9 (+)-3-chlorobenzene propyl alcohol is characterized in that described anhydrous solvent is a kind of in dimethyl sulfoxide (DMSO), dimethyl formamide, tetrahydrofuran (THF), ethylene dichloride, the trichloromethane.
11, the preparation method of R-according to claim 1 (+)-3-chlorobenzene propyl alcohol, the mol ratio that it is characterized in that 3-chlorophenyl acetone and chiral amino acid derivative is 1: 0.6～3.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101844966A (en) * | 2009-03-23 | 2010-09-29 | 上海中康伟业生物科技有限公司 | Preparation method of 3-chlorobenzene propyl alcohol |
| CN102584536A (en) * | 2012-01-18 | 2012-07-18 | 广西新晶科技有限公司 | Method for asymmetrically catalyzing and synthesizing (R)-(+)-3-chlorine-phenylpropanol |
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| CN108383703A (en) * | 2018-03-30 | 2018-08-10 | 南京哈柏医药科技有限公司 | A kind of 3 '-chlorobenzene propyl alcohol synthesis technologies |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101844966A (en) * | 2009-03-23 | 2010-09-29 | 上海中康伟业生物科技有限公司 | Preparation method of 3-chlorobenzene propyl alcohol |
| US8546615B2 (en) | 2009-11-13 | 2013-10-01 | Symed Labs Limited | Solid dapoxetine |
| CN102584536A (en) * | 2012-01-18 | 2012-07-18 | 广西新晶科技有限公司 | Method for asymmetrically catalyzing and synthesizing (R)-(+)-3-chlorine-phenylpropanol |
| CN102584536B (en) * | 2012-01-18 | 2014-06-11 | 广西新晶科技有限公司 | Method for asymmetrically catalyzing and synthesizing (R)-(+)-3-chlorine-phenylpropanol |
| CN104496830A (en) * | 2015-01-15 | 2015-04-08 | 安润医药科技（苏州）有限公司 | Dapoxetine hydrochloride synthetic method |
| CN106317024A (en) * | 2016-08-19 | 2017-01-11 | 上海艾康睿医药科技有限公司 | Crizotinib intermediate, preparation method and crizotinib preparation method |
| CN108383703A (en) * | 2018-03-30 | 2018-08-10 | 南京哈柏医药科技有限公司 | A kind of 3 '-chlorobenzene propyl alcohol synthesis technologies |
| CN108383703B (en) * | 2018-03-30 | 2021-08-03 | 兰州紫东药业有限公司 | 3' -chlorophenylpropanol synthesis process |
| CN112194558A (en) * | 2020-11-26 | 2021-01-08 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride |
| CN112194558B (en) * | 2020-11-26 | 2022-05-10 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2-fluoro-3-methyl-4- (trifluoromethyl) benzylamine hydrochloride |
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