CN101538257B - Method for preparing citalopram and S-citalopram - Google Patents
Method for preparing citalopram and S-citalopram Download PDFInfo
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- CN101538257B CN101538257B CN200810034958A CN200810034958A CN101538257B CN 101538257 B CN101538257 B CN 101538257B CN 200810034958 A CN200810034958 A CN 200810034958A CN 200810034958 A CN200810034958 A CN 200810034958A CN 101538257 B CN101538257 B CN 101538257B
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- Prior art keywords
- citalopram
- alkali
- water
- chloride
- fluorophenyl
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- 229960001653 citalopram Drugs 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 25
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 title claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000003513 alkali Substances 0.000 claims abstract description 16
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical class CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 110
- 238000006243 chemical reaction Methods 0.000 claims description 50
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 16
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- 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 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- -1 hydrated barta Chemical compound 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 235000010755 mineral Nutrition 0.000 claims description 4
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 claims description 3
- 229960000846 camphor Drugs 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 241000723346 Cinnamomum camphora Species 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical group 0.000 claims description 2
- UCVMQZHZWWEPRC-UHFFFAOYSA-L barium(2+);hydrogen carbonate Chemical compound [Ba+2].OC([O-])=O.OC([O-])=O UCVMQZHZWWEPRC-UHFFFAOYSA-L 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- 150000003818 basic metals Chemical class 0.000 claims description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 2
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 2
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 229930008380 camphor Natural products 0.000 claims description 2
- 125000005518 carboxamido group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims description 2
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 32
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- 239000010410 layer Substances 0.000 description 17
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 16
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000001816 cooling Methods 0.000 description 9
- 238000004821 distillation Methods 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 8
- 235000006408 oxalic acid Nutrition 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- OOXDCWTZWAELJT-UHFFFAOYSA-N C(C(=O)O)(=O)O.C=1OC=C2C=CC=CC12 Chemical compound C(C(=O)O)(=O)O.C=1OC=C2C=CC=CC12 OOXDCWTZWAELJT-UHFFFAOYSA-N 0.000 description 6
- 230000006340 racemization Effects 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- BRKADVNLTRCLOW-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=[C-]C=C1 BRKADVNLTRCLOW-UHFFFAOYSA-M 0.000 description 1
- RYEXTBOQKFUPOE-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].CC[CH2-] RYEXTBOQKFUPOE-UHFFFAOYSA-M 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 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 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention provides a method for preparing citalopram and S-citalopram. In the method, 1-[2-(hydroxymethyl)-5-substituting group-]phenyl-4-(dimethylamino)-1-(4-fluorophenyl)-1- butyl alcohol undergoes a cyclization reaction with halogenated acylate in water and an organic solvent immiscible with water under the alkali condition to form a citalopram product. The method has high yield and high purity and is suitable for industrialized production.
Description
Technical field:
The present invention relates to pharmaceutical chemistry, be specifically related to a kind of method for preparing citalopram and S-citalopram.
Background technology
Citalopram, chemistry 1-[3-(dimethylin) propyl group] by name-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran is a kind of novel medicine that is used to treat dysthymia disorders, it belongs to selective serotonin reuptake inhibitor.Concrete like structural formula I, its S-configuration structural formula II is a main active ingredient.
Citalopram is developed by Denmark LUNDBECK company; Be disclosed in patent DE2657013 first; Corresponding to patent US4136193, the synthetic of S-citalopram is disclosed in patent USRE34712 first, has a lot of patent reports that the synthetic of citalopram studied afterwards.
Patent US4136193, US4650884, WO9819512 and WO9819513 etc. have reported the method for preparing citalopram, and like reaction formula-1, wherein Z can be a cyanic acid; Perhaps any group that can change into cyanic acid through chemical reaction, as: halogen, carboxamido-group; Carboxyl, aldehyde radical etc.See reaction formula one:
In above-mentioned patented process; 5-replaces glycol such as the structural formula II I (abbreviation of 1-[2-(methylol)-5-substituting group-] phenyl-4-(dimethylin)-1-(4-fluorophenyl)-1-butanols; Chemical combination under the catalysis of excessive strong acid down together) has a large amount of impurity (like structure V) to generate, and has caused reaction yield on the low side like this; And because the consumption of acid is big, three-waste pollution is quite serious.In addition, in reaction process, the chiral carbon of structural formula I can be accompanied by the chirality racemization, changes the chirality of the finished product.
Adopt the S-enantiomorph of 5-cyanic acid glycol to form a kind of unstable ester with methylsulfonyl, p-toluenesulfonyl, 10-camphor sulfonyl, trifluoro acyl group or trifyl reaction among the patent USRE34712, this unstable ester closed loop under the organic bases action condition obtains the S-citalopram.Though this method condition is gentle, reaction is easier to, and the chirality after the closed loop can keep or have a spot of racemization, and this method severe reaction conditions needs anhydrous low temperature to carry out, and used a large amount of organic basess are difficult to recycle, and three-waste pollution is very serious.
Adopt compound III or its S enantiomorph among the patent WO2006037714, closed loop under DEAD, phosphorus hydrogen type compound and highly basic (like the alkali alkyl thing) condition, preparation citalopram or S-citalopram.There is the big problem of suitability for industrialized production environmental protection pressure in this method equally owing to used materials such as a large amount of DEAD and triphenyl phosphorus.
Summary of the invention
The technical problem that the present invention will solve is to overcome above-mentioned weak point, and research and design is suitable for the method for preparing citalopram and S-citalopram of suitability for industrialized production.
The invention provides a kind of preparation citalopram, 1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the method for 3-dihydro-5-cyanic acid isobenzofuran (structural formula I) or S-citalopram (structural formula II).
The present invention adopts the 5-of racemization or single configuration to replace glycol III or its salt, forms unsettled ester derivative, and closed loop under alkaline condition obtains citalopram or S-citalopram through conversion reaction again.The present invention makes the inert organic solvents that water and other a kind of and water can not be miscible, adopts K
2CO
3Replace organic bases Deng mineral alkali.Following reaction formula two.
Compound III or its salt (S-, R-or raceme) react under the base catalysis condition with RX, and RX is 0.5～5 with the molar ratio of compound III, are preferably 1.0～1.5 and form unstable ester derivative VII, and cyclization obtains compound IV again.This is reflected at the alkaline aqueous solution existence and directly carries out down; Reaction finishes after aftertreatment; Directly prepare citalopram or S-citalopram (when the Z of compound III is cyanic acid); Or further preparing citalopram or its enantiomorph (when the Z of compound III is other group except that cyanic acid) by the routine techniques conversion reaction, chirality does not take place or rare conversion in the reaction process.
Reacting used solvent is and the not miscible inert solvent of water, and promptly in reaction process, not dissolving each other fully with water forms the solvent of homogeneous reaction system.These solvents can be aromatic hydrocarbons, fat hydrocarbon, halogenated hydrocarbon, ethers, ester class, specifically include but are not limited to benzene,toluene,xylene, hexanaphthene, heptane, sherwood oil, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, THF, methyltetrahydrofuran, ETHYLE ACETATE, butylacetate etc.
The RX that uses in the reaction formula-2 is the halo acylate, shown in structural formula VI, forms the ester group that the ability of leaving away is stronger behind RX and the hydroxyl reaction.RX can be preferably 1～1.5 times at 1～5 times with respect to the mole dosage of glycol.R in structure VI
1Can be alkane, alkane substitute, aromatic nucleus or substituted aroma ring; X is halogens such as chlorine, bromine or iodine, is preferably chlorine.Corresponding acylating reagent is but is not limited only to methylsulfonyl chloride, third SULPHURYL CHLORIDE, benzene sulfonyl chloride, Tosyl chloride, p-nitrophenyl SULPHURYL CHLORIDE, 10-sulphur acyl chloride of camphor or the like.
The alkali that uses in the reaction can be organic bases and mineral alkali, and it partly or entirely is dissolved in the water uses; Be preferably mineral alkali; Optimization is selected the carbonate of basic metal and earth alkali metal for use.The consumption of alkali can be preferably 2～6 times at 1～20 times effective alkali equivalent with respect to the mole dosage of intermediate III.These alkali can be but be not limited only in Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, hydrated barta, calcium hydroxide, Quilonum Retard, yellow soda ash, salt of wormwood, lithium bicarbonate, sodium hydrogencarbonate, saleratus, Calcium hydrogen carbonate, barium bicarbonate, triethylamine, pyridine, the quinoline etc. one or more.
Through preparing with 4-fluorophenyl magnesium bromide and the addition of 3-dimethylamine propyl magnesium chloride, the III referenced patent USRE34712 of single configuration splits with (+) or (-) two pairs of toluyl tartrate and obtains the III referenced patent US4650884 that the present invention uses by the 5-substituted phthalide.When compound III is that the 5-of racemic modification replaces glycol, it is racemic modification that respective reaction obtains compound IV, and finally obtains racemization citalopram or S-citalopram through transforming.Replace glycol when compound III is the S enantiomeric ratio greater than 50% 5-, respective reaction obtain compound VI be the S ratio greater than 50% enantiomorph, and final the conversion obtains S-citalopram or racemization citalopram.Replace glycol when compound III is the R enantiomeric ratio greater than 50% 5-, respective reaction obtain compound IV be the R ratio greater than 50% enantiomorph, and final the conversion obtains S-citalopram or racemization citalopram.
Certainly, compound III 5-among the present invention replaces glycol and also can use with acid and combine salifiable form to use as raw material, and these acid of can salify using include but are not limited to hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid or oxalic acid etc.
The inventive method product yield is high, and purity is high, and it is few that material loss produces the three wastes, is suitable for suitability for industrialized production.
Embodiment:
Raw material that adopts among the embodiment and quality situation:
(1) .4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, the quality situation is: HPLC:99.9%;
(2). (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, the quality situation is: HPLC:99.9%, R isomer: 0.3%;
(3) .4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-bromobenzene, the quality situation is: HPLC:99.9%;
Embodiment 1 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 19.1g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 17.4gK
2CO
3, adding 200mL toluene, 80mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 8.4g methylsulfonyl chloride and 70mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.To doing, adding 100mL absolute ethyl alcohol, 10g oxalic acid stir and dissolve clear postcooling crystallization, filter with the toluene underpressure distillation, and oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 10g.Yield: 45.2%, HPLC: purity: 99.19%, R isomer: 1.72%.
Embodiment 2 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 28.8g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 20.8gNa
2CO
3, adding 200mL toluene, 80mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 17g Tosyl chloride and 150mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Filter, the filtrating layering, water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.To doing, adding 110mL absolute ethyl alcohol, 16g oxalic acid stir and dissolve clear postcooling crystallization, filter with the toluene underpressure distillation, and oven dry gets S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 22.5g.Yield: 73.9%, HPLC: purity: 99.62%, R isomer: 0.31%.
Embodiment 3 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 500mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 19.5g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile; 3.36gNaOH, add 80mL toluene, 20mL water; Open to stir, bathe cooling system to 0 ℃ with cryosel; The solution of 8.5g Tosyl chloride and 65mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 50mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.To doing, adding 60mL absolute ethyl alcohol, 6.9g oxalic acid stir and dissolve clear postcooling crystallization, filter with the toluene underpressure distillation, and oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 19.4g.Yield: 82.0%, HPLC: purity: 99.90%, R isomer: 0.58%.
Embodiment 4 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 19.1g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile; 11g KOH adds 200mL toluene, 80mL water; Open to stir, bathe cooling system to 0 ℃ with cryosel; The solution of 15g Tosyl chloride and 100mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.To doing, adding 100mL absolute ethyl alcohol, 10g oxalic acid stir and dissolve clear postcooling crystallization, filter with the toluene underpressure distillation, and oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 19.8g.Yield: 83.0%, HPLC: purity: 99.97%, R isomer: 0.48%.
Embodiment 5 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 19.1g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 17.4gK
2CO
3, adding 200mL toluene, 80mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 18.6g p-nitrophenyl SULPHURYL CHLORIDE and 190mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.The toluene underpressure distillation to doing, is added 100mL absolute ethyl alcohol, 10g oxalic acid, stir and dissolve clear postcooling crystallization, after crystal is separated out, put the crystallization that spends the night to the refrigerator.Next day, to filter, oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran. oxalate 18.6g.Yield: 80.3%, HPLC: purity: 99.46%, R isomer: 0.42%.
Embodiment 6 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 19.1g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 27gK
2CO
3, adding 200mL toluene, 100mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 15g Tosyl chloride and 150mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.To doing, adding 100mL absolute ethyl alcohol, 10g oxalic acid stir and dissolve clear postcooling crystallization, filter with the toluene underpressure distillation, and oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 20.6g.Yield: 85.8%, HPLC: purity: 99.48%, R isomer: 0.33%.
Embodiment 7 (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (formula II) oxalate
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 18.5g (S)-(-)-4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 26.2gK
2CO
3, adding 250mL ETHYLE ACETATE, 80mL water is opened and is stirred, cooling system to 0 ℃; The solution of 14.5g methylsulfonyl chloride and 150mL ETHYLE ACETATE is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL ethyl acetate extraction once again, merges organic layer, with twice of 100mL water washing.The ETHYLE ACETATE underpressure distillation to doing, is added 100mL absolute ethyl alcohol, 10g oxalic acid, stir and dissolve clear postcooling crystallization; Filter; Oven dry gets (S)-(+)-1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran oxalate 18.9g.Yield: 81.4%, HPLC: purity: 99.74%, R isomer: 0.54%.
Embodiment 8 1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the preparation of 3-dihydro-5-cyanic acid isobenzofuran (structure I) hydrobromate:
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 22.5g4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-benzene nitrile, 33.4gK
2CO
3, adding 200mL toluene, 90mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 18g Tosyl chloride and 180mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.The toluene underpressure distillation to dried, added 150mL ETHYLE ACETATE, drips the about 10mL of Hydrogen bromide, and stirring and crystallizing is filtered, and oven dry gets 1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran hydrobromate 18.8g.Yield: 71.0%, HPLC: purity: 99.48%
Embodiment 9 1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1, the 3-dihydro-phosphatic preparation of 5-bromine isobenzofuran
In the 1000mL there-necked flask that is equipped with powerful stirring and constant pressure funnel, add 20g 4-[4-(dimethylin)-1-(4-fluorophenyl)-1-hydroxyl butyl]-3-(methylol)-bromobenzene, 25gK
2CO
3, adding 200mL toluene, 80mL water is opened and is stirred, and bathes cooling system to 0 ℃ with cryosel; The solution of 14g Tosyl chloride and 140mL toluene is added dropwise to reaction solution through constant pressure funnel, and 0 ℃ of temperature in the control reaction flask dropwised and controlled through TLC (thin-layer chromatography) and reacts completely in 2 hours.Reaction finishes after-filtration, the filtrating layering, and water layer is used the 100mL methylbenzene extraction once again, and the combining methylbenzene layer is with twice of 100mL water washing.The toluene underpressure distillation to dried, is added 80mL acetone, drip the about 10mL of SPA, stirring and crystallizing is filtered, and oven dry gets 1-[3-(dimethylin) propyl group]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanic acid isobenzofuran. phosphoric acid salt 19g.Yield: 76.2%, HPLC: purity: 98.9%.
Claims (8)
1. a method for preparing citalopram or S-citalopram is characterized in that this method comprises the following steps:
(1) compound III or its salt water and with the immiscible inert solvent of water in, under the mineral alkali condition, obtain compound IV with RX reaction cyclization, RX is 0.5-5 with the molar ratio of compound III;
Z is cyanic acid, halogen, carboxamido-group, carboxyl or aldehyde radical in the formula;
RX is halo acylate VI:
Described halo acylate VI is methylsulfonyl chloride, third SULPHURYL CHLORIDE, benzene sulfonyl chloride, Tosyl chloride, p-nitrophenyl SULPHURYL CHLORIDE or 10-sulphur acyl chloride of camphor;
(2) preparation citalopram I or S-citalopram II;
, the Z of compound IV directly prepares citalopram or S-citalopram when being cyanic acid through the aftertreatment purifying; Or when the Z of compound IV is other group except that cyanic acid, need further press routine techniques conversion preparation citalopram or S-citalopram,
2. a kind of method for preparing citalopram or S-citalopram according to claim 1 is characterized in that said and the immiscible inert solvent of water is aromatic hydrocarbons, fat hydrocarbon, halogenated hydrocarbon, ethers or ester class.
3. method according to claim 2 is characterized in that said and the immiscible inert solvent of water is benzene,toluene,xylene, hexanaphthene, heptane, sherwood oil, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, THF, methyltetrahydrofuran, ETHYLE ACETATE or ethyl ester butyl ester.
4. a kind of method for preparing citalopram or S-citalopram according to claim 1, the consumption that it is characterized in that said alkali is the effective alkali equivalent with respect to 1～20 times of the mole dosage of intermediate III.
5. method according to claim 4 is characterized in that the consumption of said alkali is the mole dosage 2-6 effective alkali equivalent doubly with respect to intermediate III.
6. according to the said method of claim 4, it is characterized in that said alkali is the carbonate of basic metal or earth alkali metal.
7. according to the said method of claim 4, it is characterized in that said alkali is one or more in Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, hydrated barta, calcium hydroxide, Quilonum Retard, yellow soda ash, salt of wormwood, lithium bicarbonate, sodium hydrogencarbonate, saleratus, Calcium hydrogen carbonate or the barium bicarbonate.
8. according to the said method of claim 1, it is characterized in that RX is 1.0-1.5 with the molar ratio of compound III.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4943590A (en) * | 1988-06-14 | 1990-07-24 | H. Lundbeck A/S | Pharmaceutically useful (+)-1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydrosobenzofuran-5-carbonitrile and non-toxic acid addition salts thereof |
| CN1331685A (en) * | 1999-10-25 | 2002-01-16 | H·隆德贝克有限公司 | Method for preph. of citalopram |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4943590A (en) * | 1988-06-14 | 1990-07-24 | H. Lundbeck A/S | Pharmaceutically useful (+)-1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydrosobenzofuran-5-carbonitrile and non-toxic acid addition salts thereof |
| CN1331685A (en) * | 1999-10-25 | 2002-01-16 | H·隆德贝克有限公司 | Method for preph. of citalopram |
Non-Patent Citations (2)
| Title |
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| 余红霞等.西酞普兰合成路线图解.《中国医药工业杂志》.2003,第34卷(第10期),535-536. * |
| 吴秋业 等.氢溴酸西酞普兰的合成.《中国医药工业杂志》.2005,第36卷(第1期),6-8. * |
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