CN102070512B - Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof - Google Patents
Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof Download PDFInfo
- Publication number
- CN102070512B CN102070512B CN200910225972.XA CN200910225972A CN102070512B CN 102070512 B CN102070512 B CN 102070512B CN 200910225972 A CN200910225972 A CN 200910225972A CN 102070512 B CN102070512 B CN 102070512B
- Authority
- CN
- China
- Prior art keywords
- formula compound
- compound
- solvent
- reaction
- sodium
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 claims 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 14
- 239000002904 solvent Substances 0.000 claims 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 11
- -1 cyanogen methyl benzoic acid ester Chemical class 0.000 claims 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 10
- 239000003513 alkali Substances 0.000 claims 9
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims 9
- 229960003592 fexofenadine Drugs 0.000 claims 9
- 238000006243 chemical reaction Methods 0.000 claims 8
- 239000003960 organic solvent Substances 0.000 claims 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 7
- 239000003153 chemical reaction reagent Substances 0.000 claims 7
- 238000002360 preparation method Methods 0.000 claims 7
- 150000003839 salts Chemical class 0.000 claims 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 3
- 230000002378 acidificating effect Effects 0.000 claims 3
- 150000004820 halides Chemical class 0.000 claims 3
- 238000006460 hydrolysis reaction Methods 0.000 claims 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 3
- 235000015320 potassium carbonate Nutrition 0.000 claims 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 3
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical group CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical group Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- 239000002585 base Substances 0.000 claims 2
- 150000001555 benzenes Chemical class 0.000 claims 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 2
- 229910052794 bromium Inorganic materials 0.000 claims 2
- 229940043232 butyl acetate Drugs 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 239000000460 chlorine Substances 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 230000032050 esterification Effects 0.000 claims 2
- 238000005886 esterification reaction Methods 0.000 claims 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 2
- 230000007062 hydrolysis Effects 0.000 claims 2
- 125000005905 mesyloxy group Chemical group 0.000 claims 2
- 239000012046 mixed solvent Substances 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 239000001301 oxygen Substances 0.000 claims 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 2
- 230000002829 reductive effect Effects 0.000 claims 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims 2
- 239000012279 sodium borohydride Substances 0.000 claims 2
- 239000012312 sodium hydride Substances 0.000 claims 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims 2
- SDGKUVSVPIIUCF-UHFFFAOYSA-N 2,6-dimethylpiperidine Chemical compound CC1CCCC(C)N1 SDGKUVSVPIIUCF-UHFFFAOYSA-N 0.000 claims 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims 1
- GSGANNBJZYZKKY-UHFFFAOYSA-N [Li].N[Si]N Chemical compound [Li].N[Si]N GSGANNBJZYZKKY-UHFFFAOYSA-N 0.000 claims 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims 1
- 239000012346 acetyl chloride Substances 0.000 claims 1
- 229910000085 borane Inorganic materials 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 238000006114 decarboxylation reaction Methods 0.000 claims 1
- 230000026030 halogenation Effects 0.000 claims 1
- 238000005658 halogenation reaction Methods 0.000 claims 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims 1
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 claims 1
- 230000009467 reduction Effects 0.000 claims 1
- 238000006722 reduction reaction Methods 0.000 claims 1
- 238000010992 reflux Methods 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims 1
- 239000008096 xylene Substances 0.000 claims 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of high-purity fexofenadine (chemical name (+/-)-4-[1-hydroxyl-4-[4-(hydroxyldiphenylmethyl)-1-piperidyl]butyl]-alpha, alpha-dimethylphenylacetic acid) and an intermediate thereof and a novel synthesizing route. The method comprises the following steps of: with p-cyanomethylbenzoate (II) as a raw material, and with a new compound (Va) or salt (Vb) thereof as a key intermediate, hydrolyzing, esterifying or halogenating to obtain a compound (VII); and condensing, hydrolyzing and reducing with a piperdinol compound (VIII) to obtain a high-purity fexofenadine type compound (I) without para-position substitution. The invention has the advantages of simple reaction, convenience for postprocessing, higher yield and high purity of generated products and is a more ideal preparation method of fexofenadine.
Description
Technical field
The present invention relates to fexofenadine, chemical name: (±)-4-[1-hydroxyl-4-[4-(hydroxy benzophenone base)-piperidino] butyl] preparation method of-alpha-alpha-dimethyl phenyl acetic acid and intermediate thereof, belong to chemical pharmacy field.
Background technology
Fexofenadine, chemistry (±)-4-[1-hydroxyl-4-[4-(hydroxy benzophenone base)-piperidino by name] butyl]-α, alpha-alpha-dimethyl phenyl acetic acid is the activeconstituents at the non-sedating type antihistaminic of U.S.'s sale with trade(brand)name " Allegra ".This medical instrument has good antihistaminic activity, belongs to the third generation antihistamine drug without sedative effect, with like product astemizole, cetirizine, and Loratadine compare good drug action and extremely low toxic side effect.
US patent 4254129 discloses the synthetic method of fexofenadine first.In this route, by alpha-alpha-dimethyl phenyl acetic acid ethyl ester and fourth chloroacetyl chloride friedel-crafts acylation reaction, then obtain fexofenadine through condensation, hydrolysis, reduction.The problem of this route maximum is to produce, two kinds of positions isomer in reaction, and the ratio of contraposition and metacompaund is 85: 15, and is difficult to separate.Schroeder also reported and utilized Fu of Succinic anhydried and alpha-alpha-dimethyl phenyl acetic acid methyl esters-Ke reaction to build contraposition phenyl ring skeleton at patent WO 02102776, contraposition simultaneously and metacompaund can by with after aniline salify in Virahol recrystallization separate.The method is applicable to suitability for industrialized production, but reaction has nearly 67% metacompaund.Lv Binhua (Chinese pharmaceutical chemistry magazine 2004,14,96) has reported with cheap 2-methyl-2-phenylpropionic acid as the synthetic fexofenadine of raw material.First carry out chlorination with sulfur oxychloride, then amination, utilizes space steric effect, in the time carrying out one gram of acylation reaction of Fu with 4-chlorobutanoylchloride, only produces contraposition product, and yield is higher.This route has solved in the time carrying out one gram of acylation reaction of Fu the problem easily producing, metacompaund well.But and when piperidine carbinols condensation, due to use be that chloro thing reactive behavior is little, and easily self closes ring.
Kawai is at document J.Org.Chem.1994,59,2620. reported with cheap to bromo-acid as raw material through over-churning, methylate, coupling, oxidation, reduction and the synthetic fexofenadine of hydrolysis 6 steps.This route requires under strong acidic condition, to use red precipitate in the time that oxidation triple bond becomes ketone, due to the strong dehydration of red precipitate, can produce the impurity that is difficult to separation, and the toxicity of HgO is large, environmental pollution is also large.Fang is at document Tetrahedron Lett.1998, in 39,2701. with ethyl-2-[4-(chloroformyl) phenyl]-2 Methylpropionic acid ester is as raw material, obtains fexofenadine through steps such as peroxidation, addition, reduction aminations, overall yield is 33%.This process can be avoided metacompaund, but owing to using active grignard reagent, reaction may produce some by products, is difficult for separation and purification.
In a word, synthetic fexofenadine mainly contains two kinds of paths, and one is the benzene ring structure that builds para-orientation by Fu-Ke reaction, as: US Patent 5589487, US Patent 5663412, US Patent 5750703, US Patent 5581011, US patent 4254129.This method problem is unavoidable generation, two kinds of positions isomer in reaction, and reaction preference is poor, and by product is difficult to separate or separation costs is very high.Another kind method is exactly as raw material with the phenyl ring derivative of 4 replacements.Document Tetrahedron Lett.1998 as previously mentioned, 39,2701 and J.Org.Chem.1994,59,2620.Also just like document Synth.Commun.1996,26,4699 mention and using bromobenzylcyanide as raw material.First method can build the benzene ring structure of para-orientation more easily, but reaction preference is poor.Although the report of synthetic fexofenadine is more; but can be applicable to the actually rare of suitability for industrialized production; highly purified fexofenadine has patent protection (WO 102777); therefore, can low cost facilitate the synthetic method of the fexofenadine of synthesis of high purity to there is important industry and commercial value.
The present invention taking to cyanogen methyl benzoic acid ester as raw material, prepare fexofenadine and intermediate thereof through steps such as Hypermethylation, condensation hydrolysis, bromination or esterification, coupling and reductive hydrolysis.The method is from to cyanogen methyl benzoic acid ester, have to the target product of para-orientation, thoroughly overcome that the issuable reaction preference of Freidel-Crafts is poor, by product is difficult to separate or the very high shortcoming of separation costs, can obtain the fexofenadine of the ultra-high purity of only having para-orientation.Reaction involved in the present invention is simple in addition, convenient post-treatment, productive rate product purity higher and that generate are very high, is a kind of more satisfactory, preparation method with the fexofenadine of industrial applications prospect.
Summary of the invention
The invention provides that a kind of easy to operate, technique is simple, the preparation high purity of low cost product is suc as formula (I) (±)-4-[1-hydroxyl-4-[4-(hydroxy benzophenone base)-piperidino] butyl] new synthetic route and the preparation method of-alpha-alpha-dimethyl phenyl acetic acid (fexofenadine) and intermediate thereof.
The present invention be taking to cyanogen methyl benzoic acid ester (II) as raw material, taking new compound (Va) or its salt (Vb) as key intermediate, make formula compound (VII) through hydrolysis, esterification or halogenation again, then make Fexofenadine fixed pattern compound (I) with piperidine alcohols formula compound (VIII) condensation, reductive hydrolysis.The present invention sets out with the raw material of para-orientation, can high yield through conventional, simple reaction make highly purified target product fexofenadine (fexofenadine).
Technical scheme of the present invention, synthetic route and design schematic diagram be (following reaction scheme is only schematic diagram, and only representative reaction special case and part, can not be explained or be interpreted as limitation of the scope of the invention) as shown in scheme one.
The synthetic route schematic diagram of fexofenadine and intermediate thereof
Preparation method of the present invention comprises the steps: that Fexofenadine fixed pattern compound (I) can be reacted and obtains at 0-100 DEG C with reductive agent by formula compound (XI) in solvent, and formula compound (I) also can be obtained by catalytic hydrogenation by formula compound (XI) under catalyst action; Formula compound (XI) can be hydrolyzed by formula compound (X) and obtain under alkaline condition; Formula compound (X) can, by formula compound (VII) and lupetidine methyl alcohol formula compound (VIII) under alkaline condition, obtain in 0-100 DEG C of reaction in organic solvent; Formula compound (VII) can by formula compound (VI) and halide reagent in 0-40 DEG C in solvent, react and or by formula compound (VI) with esterifying reagent under alkaline condition, in organic solvent, carry out esterification and obtain in 0-100 DEG C; Formula compound (VI) can be obtained by formula compound (Va) or its salt (Vb) in decarboxylation under acidity or alkaline condition; Formula compound (Vb) can be reacted and obtain in 50-150 DEG C by compound (III) and gamma-butyrolactone (compound (IV)) under alkaline condition in organic solvent, and formula compound (Va) can be by formula compound (Vb) acidifying and obtaining under acidic conditions; Formula compound (III) can be by formula compound (II) and methyl-sulfate under alkaline condition, in solvent, obtains in-20-50 DEG C reaction.Formula compound (X) to formula compound (XI) again to formula compound (I) can without separation and purification, " one kettle way carries out; Formula compound (III) can carry out without separation and purification " one kettle way " to formula compound (VI) to formula compound (Va) or (Vb) again.
Fexofenadine fixed pattern compound of the present invention (I) can be reacted and obtain at 0-100 DEG C with reductive agent by formula compound (XI) in organic solvent;
Described reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, triethoxy sodium borohydride, borine etc., be preferably sodium borohydride, its consumption is 1～5 times of formula compound (XI) mole dosage, is preferably 1.5 times of formula compound (XI) mole dosage.
Described solvent is C
1～C
4alcohol as methyl alcohol, ethanol, Virahol, propyl carbinol etc., halogenated solvent is as methylene dichloride, ethylene dichloride, chloroform etc.; Tetrahydrofuran (THF) (THF), dioxane, acetonitrile etc. or their mixed solvent etc.; Be preferably ethanol, solvent load needs solvent 1～5ml by every 1g formula compound (XI).
Described temperature of reaction is 0-100 DEG C, is preferably 20-40 DEG C.
Formula compound (I) also can be obtained by catalytic hydrogenation in 20-150 DEG C by formula compound (XI) under catalyst action in solvent; Described catalyzer is Raney's nickel, Lei Nitong, the Lei Nitong of Raney's nickel that adulterated, palladium carbon, is preferably Raney's nickel, and its consumption is the 5%-8% of compound (XI) quality.
Described temperature of reaction is 20-150 DEG C, preferably 80-120 DEG C.
Described organic solvent is C
1～C
8alcohol as methyl alcohol, ethanol, Virahol, propyl carbinol etc., halogenated solvent is as methylene dichloride, ethylene dichloride, chloroform etc.; Tetrahydrofuran (THF) (THF), dioxane, acetonitrile etc. or their mixed solvent etc.; Be preferably methyl alcohol, solvent load calculates and is generally 1～5ml by every 1g formula compound (X).
Formula compound (XI) can be hydrolyzed by formula compound (X) and obtain under alkaline condition; Described alkali is lithium hydroxide, potassium hydroxide, and sodium hydroxide etc., are preferably potassium hydroxide, the mol ratio of the consumption of alkali and formula compound (X) 20: 1～80: 1, preferably 40: 1～60: 1.
Described hydrolysis reaction can carry out in as methyl alcohol, ethanol, Virahol, propyl carbinol etc. or their mixed solvent at the alcohol of water, C1～C8, is preferably water.Solvent load calculates and is generally 1～5ml by every 1g formula compound (X).
Described temperature of reaction according to the difference of solvent and difference, is preferably the reflux temperature of solvent.
Formula compound (X) arrives formula compound (I) again to formula compound (XI), can carry out without separation and purification " one kettle way ".
Formula compound (I) can, by formula compound (X) under alkaline condition, react and obtain at 0-100 DEG C with reductive agent in organic solvent;
Optional one of following or their arbitrary combination of described solvent: alcohol, acetonitrile, toluene, dimethylbenzene, halogeno-benzene, methane amide, the N of the C1-C4 such as water, methyl alcohol, ethanol, Virahol, propyl carbinol, dinethylformamide (DMF), 1,2-glycol dimethyl ether (DME), methyl-sulphoxide (DMSO), methylene dichloride, 1, halohydrocarbon, tetrahydrofuran (THF), the dioxane such as 2-ethylene dichloride, chloroform, be preferably water and ethanolic soln, solvent load calculates and is generally 1～5ml by every 1g formula (9) compound.
Described alkali is lithium hydroxide, potassium hydroxide, and sodium hydroxide etc., are preferably potassium hydroxide, the equivalence ratio of the consumption of alkali and formula compound (9) 20: 1～80: 1.Described reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE, triethoxy sodium borohydride, sodium cyanoborohydride, borine etc., be preferably sodium borohydride, its consumption is 1～5 times of formula compound (X) mole dosage, is preferably 2 times of formula compound (X) mole dosage.
Described temperature of reaction is preferably 80 DEG C.
Compound of the present invention (X) can, by formula compound (VII) and lupetidine methyl alcohol formula compound (VIII) under alkaline condition, obtain in 0-100 DEG C of reaction in organic solvent.
Optional one of following or their arbitrary combination of described solvent: ethyl acetate, butylacetate, acetone, butanone, hexone, toluene, dimethylbenzene, chlorinated benzene, methylene dichloride, ethylene dichloride, chloroform, DMF, DEF, DMSO, THF, DME, dioxane, acetonitrile, be preferably tetrahydrofuran solution, consumption calculates and is generally 1～5ml by every 1g formula compound (VII).
Described alkali is triethylamine, pyridine, and DMA, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, potassium hydroxide, sodium hydroxide etc., are preferably triethylamine, and the equivalence ratio of alkali and formula compound (VII) is 1: 1～2.5: 1.Be preferably 1.1: 1.
Described temperature of reaction is 0-100, preferably 25 DEG C.
Formula compound of the present invention (VII) can be reacted and obtain in 0-40 DEG C with halide reagent by formula compound (VI) in solvent.
Optional one of following or their arbitrary combination of described solvent: water, methyl alcohol, ethanol, Virahol, the alcohol of the C1-C4 such as propyl carbinol, acetonitrile, toluene, dimethylbenzene, halogeno-benzene, methane amide, N, dinethylformamide (DMF), 1, 2-glycol dimethyl ether (DME), methyl-sulphoxide (DMSO), methylene dichloride, 1, 2-ethylene dichloride, the halohydrocarbon such as chloroform, acetone, butanone, hexone, tetrahydrofuran (THF), dioxane, preferentially select water and methylene dichloride mixed solvent, consumption calculates and is generally 1～5ml by every 1g formula compound (VI).
Described halide reagent can be Hydrogen bromide or hydrochloric acid, and concentration is that percentage composition is 10-40%, and preferentially selecting Hydrogen bromide percentage composition is 40%, and hydrochloric acid percentage composition is 36%.
Described temperature of reaction can be 0-40 DEG C, is preferably 20 DEG C.Vigorous stirring is conducive to the abundant reaction of substrate.
In above-mentioned formula compound (VII), if X is ester group, formula compound (VII) carries out esterification in 0-100 DEG C with esterifying reagent by formula compound (VI) and obtains under alkaline condition in organic solvent.
Described esterifying reagent, as Tosyl chloride, methylsulfonyl chloride, acid anhydrides, acetic acid, Acetyl Chloride 98Min. etc., is preferably Tosyl chloride or methylsulfonyl chloride.The equivalence ratio of esterifying reagent and formula compound (VI) is preferably 1-1.2: 1.
Described organic solvent is as one of following or more than one arbitrary combination: ethyl acetate, butylacetate, acetone, butanone, hexone, toluene, dimethylbenzene, chlorinated benzene, methylene dichloride, ethylene dichloride, chloroform, DMF, N, N-diethyl acetamide (DEF), DMSO, THF, glycol dimethyl ether (DME), dioxane, acetonitrile, be preferably CH
2cl
2, consumption of organic solvent is calculated and is generally 1～5ml by every 1g formula compound (VI).
Described reaction is carried out under alkaline condition, can adopt one of following alkali or more than one arbitrary combination: sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, saleratus, salt of wormwood, triethylamine, pyridine, N, N-dialkyl aniline, preferably adopt one of following alkali or more than one arbitrary combination: sodium hydroxide, potassium hydroxide, triethylamine, DMA.The equivalence ratio of described alkali and formula compound (VI) is generally 1-5: 1.
Described esterification reaction temperature is preferably 0-30 DEG C.
Formula compound of the present invention (VI) can by formula compound (Va) or its salt formula compound (Vb) under acidity or alkaline condition in solvent decarboxylation obtain;
Optional one of following or their the arbitrary combination water of described solvent, methyl alcohol, ethanol, Virahol, the alcohol of the C1-C4 such as propyl carbinol, acetonitrile, toluene, dimethylbenzene, halogeno-benzene, methane amide, N, dinethylformamide (DMF), 1, 2-glycol dimethyl ether (DME), methyl-sulphoxide (DMSO), methylene dichloride, 1, 2-ethylene dichloride, the halohydrocarbon such as chloroform, acetone, butanone, hexone, tetrahydrofuran (THF), dioxane, preferentially elect water as, the consumption of water calculates and is generally 1～5ml by every 1g formula compound (Va) or formula compound (Vb).
Described temperature of reaction can be 40-100 DEG C, is preferably 50 DEG C.
Described alkaline condition, to control the initial system of reaction at pH=10-14, is preferentially selected pH=12.
Described acidic conditions can hydrochloric acid or sulfuric acid control reaction system PH be 1-4, be preferably 2-3.
Formula compound of the present invention (Vb) can be reacted and obtain in 50-150 DEG C by compound (III) and gamma-butyrolactone (compound (IV)) under alkaline condition in organic solvent, and formula compound (Va) can be by formula compound (Vb) acidifying and obtaining under acidic conditions;
Optional one of following or their arbitrary combination of described solvent: the halogeno-benzenes such as benzene,toluene,xylene, N, dinethylformamide (DMF), acetonitrile, 1,2-glycol dimethyl ether (DME), methyl-sulphoxide (DMSO), methylene dichloride, 1, the halohydrocarbon such as 2-ethylene dichloride, chloroform, tetrahydrofuran (THF), dioxane etc., be preferably dimethylbenzene and N, the mixing solutions of dinethylformamide (DMF), the consumption of organic solvent calculates and is generally 1～5ml by every 1g formula compound (III).
Described reaction is carried out under alkaline condition, can adopt one of following or their arbitrary combination: sodium alkylate, butyllithium, hexamethyl diamino silicon lithium (LiHDMS), the diisopropylamine lithium LDA such as sodium, sodium hydride, sodium amide, sodium methylate, sodium ethylate, be preferably sodium hydride.The equivalence ratio of described alkali and formula compound (III) is 1.2: 1～1.5: 1.
Described temperature of reaction can be 50-150 DEG C, is preferably 110 DEG C.
(Vb) is soluble in water for formula compound, is easy to separation and purification after reaction, and the complete raw material of unreacted easily reclaims.Formula compound (III), through formula compound (V), arrives formula compound (VI), can be without directly " treating different things alike " of separation and purification.
Formula compound of the present invention (III) can be by formula compound (II) and methyl-sulfate under alkaline condition, in solvent, obtains in-20-50 DEG C reaction.
Optional one of following or their arbitrary combination of described solvent: alcohol, acetonitrile, toluene, dimethylbenzene, halogeno-benzene, methane amide, the N of the C1-C4 such as water, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, dinethylformamide (DMF), 1,2-glycol dimethyl ether (DME), methyl-sulphoxide (DMSO), methylene dichloride, 1, the halohydrocarbon such as 2-ethylene dichloride, chloroform, acetone, butanone, hexone, tetrahydrofuran (THF), dioxane etc., be preferably water, the consumption of organic solvent calculates and is generally 1～5ml by every 1g formula compound (II).
Can be-20-50 DEG C of described temperature of reaction, is preferably 0 DEG C.
In reaction, also can add a small amount of phase-transfer catalyst as TEBA or Tetrabutyl amonium bromide, tetrabutylammonium chloride etc.
Described alkali is sodium hydroxide, potassium hydroxide, and sodium hydride, sodium carbonate, salt of wormwood, is preferably sodium hydroxide, and the equivalence ratio of described alkali and formula compound (II) is 10: 1～15: 1.
The invention provides syntheti c route and the method for preparing fexofenadine fixed pattern compound (I), the preparation method of its key intermediate formula compound (V) and formula compound (VI) is also provided simultaneously.Method provided by the invention has raw material and is easy to get, reacts simple, easy and simple to handle, harmful reagent and solvent species and consumption are few, technique is simple, separation and purification is easy, product purity is high, intermediate and pilot process can separately carry out, also can strictly not separate or separately, carry out " one pot " and react to obtain feature.
Embodiment:
In order to absolutely prove essence, preparation thinking and the design of patent of the present invention, verify in the following embodiments preparation method of the present invention, these embodiment only, for illustrating and special case representative, should not explained or be interpreted as the restriction to the present invention's protection.
Steps A
Embodiment 1
At 20 DEG C, the alkali lye that sodium hydroxide 30g (0.75mol) and 140 ml waters are made into adds 2 grams of tetra-n-butyl ammonium bromides and in cyanogen methyl-toluate 21g (0.12mol), drip 53 grams of methyl-sulfates (0.42mol), within approximately 1 hour, drip off.Continue reaction 4 hours.Add 100 milliliters of toluene to stir 20 minutes, leave standstill, layering, water liquid merges organic liquor with 30 × 2 milliliters of toluene extracting twice again, be washed to neutral reclaim under reduced pressure toluene, reclaim under reduced pressure toluene (the toluene that reclaims continue cover for this), gained solid recrystallization in Virahol, productive rate 85%.
Embodiment 2
At 20 DEG C, the alkali lye that potassium hydroxide 28g (0.5mol) and 120 ml waters are made into adds 2 grams of tetra-n-butyl ammonium bromides and in cyanogen tolyl acid ethyl ester 23g (0.12mol), drip the DMF of 53 grams of methyl-sulfates (0.42mol), within approximately 1 hour, drip off.Continue reaction 4 hours, pressure reducing and steaming DMF, add 100 milliliters of toluene to stir 20 minutes, leave standstill, layering, water liquid merges organic liquor with 30 × 2 milliliters of toluene extracting twice again, be washed to neutral reclaim under reduced pressure toluene, reclaim under reduced pressure toluene (the toluene that reclaims continue cover for this), gained solid recrystallization in Virahol, productive rate 88%.
Embodiment 3
At 5 DEG C, the alkali lye that sodium hydroxide 20g (0.5mol) and 120 ml waters are made into adds 2 grams of tetra-n-butyl ammonium bromides and in cyanogen methyl-toluate 21g (0.12mol), drip 53 grams of methyl-sulfates (0.42mol), within approximately 1 hour, drip off.Continue reaction 4 hours.Add 100 milliliters of toluene to stir 20 minutes (now still maintaining former temperature), leave standstill, layering, water liquid merges organic liquor with 30 × 2 milliliters of toluene extracting twice again, be washed to neutral reclaim under reduced pressure toluene, reclaim under reduced pressure toluene (the toluene that reclaims continue cover for this), gained solid recrystallization in Virahol, productive rate 90%.
Embodiment 4
At 5 DEG C, the alkali lye that sodium hydroxide 20g (0.5mol) and 120 ml waters are made into adds 2 grams of tetrabutylammonium chlorides and in cyanogen tolyl acid ethyl ester 23g (0.12mol), drip the dichloromethane solution of 53 grams of methyl-sulfates (0.42mol), within approximately 1 hour, drip off.Continue reaction 4 hours.Add 100 milliliters of toluene to stir 20 minutes (now still maintaining former temperature), leave standstill layering, water liquid merges organic liquor with 30 × 2 milliliters of toluene extracting twice again, is washed to neutral reclaim under reduced pressure toluene, decompression and solvent recovery, gained solid recrystallization in Virahol, productive rate 85%.
Embodiment 5
At 35 DEG C, the alkali lye that potassium hydroxide 28g (0.5mol) and 120 ml waters are made into adds 2 grams of TEBA (triethyl benzyl brometo de amonio) and in cyanogen methyl-toluate 21g (0.12mol), drip the 100ml acetonitrile solution of 53 grams of methyl-sulfates (0.42mol), within approximately 1 hour, drip off.Continue reaction 4 hours.Add 100 milliliters of toluene to stir 20 minutes (now still maintaining former temperature), leave standstill, layering, water liquid merges organic liquor with 30 × 2 milliliters of toluene extracting twice again, be washed to neutral reclaim under reduced pressure toluene, reclaim under reduced pressure toluene (the toluene that reclaims continue cover for this), gained solid recrystallization in Virahol, productive rate 86%.
Embodiment 6
At 15 DEG C, the alkali lye that sodium hydroxide 20g (0.5mol) and 120 ml waters are made into adds 2 grams of TEBA (triethyl benzyl brometo de amonio) and in cyanogen methylbenzene methyl ethyl ester 23g (0.12mol), drip the 100ml toluene solution of 53 grams of methyl-sulfates (0.42mol), within approximately 1 hour, drip off.Continue reaction 4 hours.Add 100 milliliters of toluene to stir 20 minutes (now still maintaining former temperature), leave standstill, layering, water liquid merges organic liquor with 30 × 2 milliliters of toluene extracting twice again, be washed to neutral reclaim under reduced pressure toluene, reclaim under reduced pressure toluene (the toluene that reclaims continue cover for this), gained solid recrystallization in Virahol, productive rate 88%.
Embodiment 7
At-5 DEG C, the alkali lye that sodium hydroxide 20g (0.5mol) and 120 ml waters are made into adds 2 grams of TEBA (triethyl benzyl brometo de amonio) and in cyanogen methylbenzene methyl ethyl ester 23g (0.12mol), drip 100 ml methanol solution of 53 grams of methyl-sulfates (0.42mol), within approximately 1 hour, drip off.Continue reaction 4 hours.Evaporated under reduced pressure methyl alcohol, add 100 milliliters of toluene to stir 20 minutes (now still maintaining former temperature), leave standstill, layering, water liquid merges organic liquor with 30 × 2 milliliters of toluene extracting twice again, is washed to neutral reclaim under reduced pressure toluene, reclaim under reduced pressure toluene (institute's toluene that reclaims continue to overlap be used for this), gained solid recrystallization in Virahol, productive rate 88%.
Embodiment 8
At 5 DEG C, the alkali lye that sodium hydroxide 20g (0.5mol) and 120 ml waters are made into adds 2 grams of TEBA (triethyl benzyl brometo de amonio) and in cyanogen methylbenzene methyl ethyl ester 23g (0.12mol), drip 100 milliliters of ethanolic solns of 65 grams of ethyl sulfates (0.42mol), within approximately 1 hour, drip off.Continue reaction 4 hours.Evaporated under reduced pressure ethanol, add 100 milliliters of toluene to stir 20 minutes (now still maintaining former temperature), leave standstill, layering, water liquid merges organic liquor with 30 × 2 milliliters of toluene extracting twice again, is washed to neutral reclaim under reduced pressure toluene, reclaim under reduced pressure toluene (institute's toluene that reclaims continue to overlap be used for this), gained solid recrystallization in Virahol, productive rate 72%.
Step B:
Embodiment 9
To adding 4-(2-cyano group sec.-propyl) methyl benzoate 20.0 grams (0.1mol), in advance dried dimethylbenzene 40ml and the mixed solvent of 4mlDMF, stirring and dissolving material in band thermometer, nitrogen inlet, dropping funnel, prolong and churned mechanically drying receptacle.Logical nitrogen displaced air, at 6 grams of NaH of situation lower-weighing (60wt% content, 0.15mol) of isolated as far as possible moisture.And be transferred to as early as possible in container, be warming up to 100 DEG C.Start to drip 10.0 grams of γ--the 70ml toluene solution of butyrolactone 20.0 grams (0.24mol), about 4h left and right dropwises, and then back flow reaction 2h.Be cooled near 0 DEG C with frozen water with being water-cooled to after room temperature, once add 200ml frozen water on rapid stirring, in controlling, temperature, lower than 10 DEG C, separates water, then uses 75ml × 2 water extraction, merges water, and the aqueous solution of gained compound Vb is directly used in next step reaction.
It is below 2 that the aqueous solution of Vb is adjusted to PH with 6NHCl, adds 50ml × 2 n-butyl acetate extraction, dry can obtain formula compound (Va)
1h NMR (300MHz, CDCl
3, TMS): δ 1.75 (s, 6H, CH
3), 2.54-2.93 (m, 2H, CH
2), 4.45-4.59 (m, 3H, COCHCO, OCH
2), 7.60-7.64 (d, 2H, J=12Hz, Ar), 8.09-8.13 (d, 2H, J=12Hz, Ar).
13c NMR (75MHz, CDCl
3) δ 25.6,28.6,37.2,47.9,67.64,125.2,125.5,130.0,130.6,147.2,172.7,192.2.IR (cm
-1): 3062,2990,2237,1749,1679,1604,1570,1481,1452,1409,1370,1016,950,857,812,683.HR-MS (ESI) Calcd for C
15h
15n
1na
1o
3: 280.0944.Found:280.0941.
Embodiment 10
To adding 4-(2-cyano group sec.-propyl) ethyl benzoate 21.7 grams (0.1mol), dried toluene 40ml in advance, stirring and dissolving material in band thermometer, nitrogen inlet, dropping funnel, prolong and churned mechanically drying receptacle.Logical nitrogen displaced air, at 6.5 grams of CH of situation lower-weighing of isolated as far as possible moisture
3oNa (0.12mol).And be transferred to as early as possible in container, be warming up to 100 DEG C.Start to drip the 70ml toluene solution of 10.0 grams of gamma-butyrolactones 20.0 grams (0.24mol), about 4h left and right dropwises, and then back flow reaction 2h.Be cooled near 0 DEG C with frozen water with being water-cooled to after room temperature, once add 200ml frozen water on rapid stirring, in controlling, temperature, lower than 10 DEG C, separates water, then uses 75ml × 2 water extraction, merges water, and the aqueous solution of gained compound Vb is directly used in next step reaction.
Embodiment 11
To adding 4-(2-cyano group sec.-propyl) methyl benzoate 20.0 grams (0.1mol), dried benzene 50ml in advance, stirring and dissolving material in band thermometer, nitrogen inlet, dropping funnel, prolong and churned mechanically drying receptacle.Logical nitrogen displaced air, at 6 grams of NaH of situation lower-weighing (60wt% content, 0.15mol) of isolated as far as possible moisture.And be transferred to as early as possible in container, be warming up to 100 DEG C.Start to drip the 60ml benzole soln of 10.0 grams of gamma-butyrolactones 20.0 grams (0.24mol), about 4h left and right dropwises, and then back flow reaction 2h.Be cooled near 0 DEG C with frozen water with being water-cooled to after room temperature, once add 200ml frozen water on rapid stirring, in controlling, temperature, lower than 10 DEG C, separates water, then uses 75ml × 2 water extraction, merges water, and the aqueous solution of gained compound Vb is directly used in next step reaction.
Embodiment 12
To adding 4-(2-cyano group sec.-propyl) methyl benzoate 20.0 grams (0.1mol), dried THF40ml in advance, stirring and dissolving material in band thermometer, nitrogen inlet, dropping funnel, prolong and churned mechanically drying receptacle.Logical nitrogen displaced air, at 7.8 grams of NaNH of situation lower-weighing of isolated as far as possible moisture
2(0.2mol).And be transferred to as early as possible in container, be warming up to 100 DEG C.Start to drip 10.0 grams of γ--the 70ml toluene solution of butyrolactone 20.0 grams (0.24mol), about 4h left and right dropwises, and then back flow reaction 2h.Be cooled near 0 DEG C with frozen water with being water-cooled to after room temperature, once add 200ml frozen water on rapid stirring, in controlling, temperature, lower than 10 DEG C, separates water, then uses 75ml × 2 water extraction, merges water, and the aqueous solution of gained compound Vb is directly used in next step reaction.
Embodiment 13
To adding 4-(2-cyano group sec.-propyl) ethyl benzoate 21.7 grams (0.1mol), dried methylene dichloride 40ml in advance, stirring and dissolving material in band thermometer, nitrogen inlet, dropping funnel, prolong and churned mechanically drying receptacle.Logical nitrogen displaced air, at 7.8 grams of NaNH of situation lower-weighing of isolated as far as possible moisture
2(0.2mol).And be transferred to as early as possible in container, be warming up to 100 DEG C.Start to drip the 70ml toluene solution of 10.0 grams of gamma-butyrolactones 20.0 grams (0.24mol), about 4h left and right dropwises, and then back flow reaction 2h.Be cooled near 0 DEG C with frozen water with being water-cooled to after room temperature, once add 200ml frozen water on rapid stirring, in controlling, temperature, lower than 10 DEG C, separates water, then uses 75ml × 2 water extraction, merges water, and the aqueous solution of gained compound Vb is directly used in next step reaction.
Embodiment 14
To adding 4-(2-cyano group sec.-propyl) t-butyl perbenzoate 24.5 grams (0.1mol), dried N in advance in band thermometer, nitrogen inlet, dropping funnel, prolong and churned mechanically drying receptacle, dinethylformamide 40ml, stirring and dissolving material.Logical nitrogen displaced air, at 7.8 grams of NaNH of situation lower-weighing of isolated as far as possible moisture
2(0.2mol).And be transferred to as early as possible in container, be warming up to 100 DEG C.Start to drip the 70ml toluene solution of 10.0 grams of gamma-butyrolactones 20.0 grams (0.24mol), about 4h left and right dropwises, and then back flow reaction 2h.Be cooled near 0 DEG C with frozen water with being water-cooled to after room temperature, once add 200ml frozen water on rapid stirring, in controlling, temperature, lower than 10 DEG C, separates water, then uses 75ml × 2 water extraction, merges water, and the aqueous solution of gained compound Vb is directly used in next step reaction.
Step C:
Embodiment 15
The aqueous solution of the Vb that step B is generated regulates pH to equal 11 with Glacial acetic acid, stirs 4 hours at 40 DEG C, and reaction finishes rear system and is adjusted to neutrality with Glacial acetic acid and 5% sodium hydroxide again.Add 50ml × 3 methylene dichloride fully to stir extraction, water discards, and merges organic phase, and organic layer look shallow, water reddish brown (reservation).The appropriate anhydrous magnesium sulfate drying of organic phase, except desolventizing obtains Melon yellow liquid.Be directly used in next step reaction.Productive rate 89%.
Embodiment 16
The aqueous solution of the Vb that step B is generated regulates pH to equal 11 with Glacial acetic acid, adds 30ml methyl alcohol, stirs 4 hours at 60 DEG C, and reaction finishes rear system and is adjusted to neutrality with Glacial acetic acid and 5% sodium hydroxide again.Evaporated under reduced pressure methyl alcohol, adds water 100ml and 50ml × 3 methylene dichloride fully to stir extraction, and water discards, and merges organic phase, and organic layer look shallow, water reddish brown (reservation).The appropriate anhydrous magnesium sulfate drying of organic phase, except desolventizing obtains Melon yellow liquid.Be directly used in next step reaction.Productive rate 86%.
Embodiment 17
The aqueous solution of the Vb that step B is generated regulates pH to equal 11 with Glacial acetic acid, adds 30ml acetonitrile.At 60 DEG C, stir 4 hours, reaction finishes rear system and is adjusted to neutrality with Glacial acetic acid and 5% sodium hydroxide again.Evaporated under reduced pressure acetonitrile, adds water 100ml and 50ml × 3 methylene dichloride fully to stir extraction, and water discards, and merges organic phase, and organic layer look shallow, water reddish brown (reservation).The appropriate anhydrous magnesium sulfate drying of organic phase, except desolventizing obtains Melon yellow liquid.Be directly used in next step reaction.Productive rate 89%.
Embodiment 18
The aqueous solution of the Vb that step B is generated regulates pH to equal 11 with Glacial acetic acid, adds 30ml ethyl acetate.At 60 DEG C, stir 4 hours, reaction finishes rear system and is adjusted to neutrality with Glacial acetic acid and 5% sodium hydroxide again.Evaporated under reduced pressure solvent, adds water 100ml and 50ml × 3 methylene dichloride fully to stir extraction, and water discards, and merges organic phase, and organic layer look shallow, water reddish brown (reservation).The appropriate anhydrous magnesium sulfate drying of organic phase, except desolventizing obtains Melon yellow liquid.Be directly used in next step reaction.Productive rate 80%.
Embodiment 19
The aqueous solution of the Vb that step B is generated regulates pH to equal 11 with Glacial acetic acid, adds 30ml toluene.At 60 DEG C, stir 4 hours, reaction finishes rear system and is adjusted to neutrality with Glacial acetic acid and 5% sodium hydroxide again.Separate organic phase, add water 100ml and 50ml × 3 methylene dichloride fully to stir extraction, water discards, and merges organic phase, and organic layer look shallow, water reddish brown (reservation).The appropriate anhydrous magnesium sulfate drying of organic phase, except desolventizing obtains Melon yellow liquid.Be directly used in next step reaction.Productive rate 87%.
Embodiment 20
The aqueous solution of the Vb that step B is generated regulates pH to equal 11 with Glacial acetic acid, adds 30ml1,2-ethylene dichloride.At 60 DEG C, stir 4 hours, reaction finishes rear system and is adjusted to neutrality with Glacial acetic acid and 5% sodium hydroxide again.Separate organic phase, add water 100ml and 50ml × 3 methylene dichloride fully to stir extraction, water discards, and merges organic phase, and organic layer look shallow, water reddish brown (reservation).The appropriate anhydrous magnesium sulfate drying of organic phase, except desolventizing obtains Melon yellow liquid.Be directly used in next step reaction.Productive rate 85%.
Embodiment 21
The aqueous solution of the Vb that step B is generated equals 2-3 with hydrochloric acid acid for adjusting pH, at 60 DEG C, stir 4 hours, stopped reaction, add butylacetate, separate organic phase, 50ml × 3 butylacetate fully stirs extraction, water discards, merge organic phase, the appropriate anhydrous magnesium sulfate drying of organic phase, except desolventizing obtains Melon yellow liquid.Be directly used in next step reaction, productive rate 80%.
Embodiment 22
To adding 4-(2-cyano group sec.-propyl) methyl benzoate 20.0 grams (0.1mol), in advance dried dimethylbenzene 40ml and the mixed solvent of 4mlDMF, stirring and dissolving material in band thermometer, nitrogen inlet, dropping funnel, prolong and churned mechanically drying receptacle.Logical nitrogen displaced air, at 6 grams of NaH of situation lower-weighing (60wt% content, 0.15mol) of isolated as far as possible moisture.And be transferred to as early as possible in container, be warming up to 100 DEG C.Start to drip 10.0 grams of γ--the 70ml toluene solution of butyrolactone 20.0 grams (0.24mol), about 4h left and right dropwises, and then back flow reaction 2h.Be cooled near 0 DEG C with frozen water with being water-cooled to after room temperature, on rapid stirring, once add 100ml frozen water, then be heated to 50 DEG C of decarboxylic reactions after 5 hours, separate organic phase, use again 75ml × 2 n-butyl acetate extraction, merge organic phase, dry, filter, decompression desolventizes and obtains product and can be directly used in the next step.
Embodiment 23
To adding 4-(2-cyano group sec.-propyl) methyl benzoate 20.0 grams (0.1mol), in advance dried dimethylbenzene 40ml and the mixed solvent of 4mlDMF, stirring and dissolving material in band thermometer, nitrogen inlet, dropping funnel, prolong and churned mechanically drying receptacle.Logical nitrogen displaced air, at 6 grams of NaH of situation lower-weighing (60wt% content, 0.15mol) of isolated as far as possible moisture.And be transferred to as early as possible in container, be warming up to 100 DEG C.Start to drip 10.0 grams of γ--the 70ml toluene solution of butyrolactone 20.0 grams (0.24mol), about 4h left and right dropwises, and then back flow reaction 2h.Be cooled near 0 DEG C with frozen water with being water-cooled to after room temperature, on rapid stirring, once add 100ml frozen water, then adding sulfuric acid tune PH is 2-3, be heated to 50 DEG C of decarboxylic reactions after 5 hours, separate organic phase, use again 75ml × 2 n-butyl acetate extraction, merge organic phase, dry, filter, decompression desolventizes and obtains product and can be directly used in the next step.
Step D:
Embodiment 24
In reactor, add crude product VI 10g, 30ml methylene dichloride and 15 milliliter of 40% Hydrogen bromide, 20 DEG C of reactions of room temperature 6 hours under rapid stirring.Add phase-splitting after 50ml methylene dichloride and 50ml water rapid stirring, after water is used the extraction of methylene dichloride 30ml × 2 again, water discards.The saturated NaHCO of organic phase
3and saturated common salt water washing, separate appropriate anhydrous MgSO for organic phase
4dry, removal of solvent under reduced pressure, gained solid obtains sterling VII with ethyl alcohol recrystallization, productive rate 82%.
Embodiment 25
In reactor, add crude product VI 10g, 30ml1.2-ethylene dichloride and 15 milliliters of concentrated hydrochloric acids, 20 DEG C of reactions of room temperature 6 hours under rapid stirring.Add phase-splitting after 50ml methylene dichloride and 50ml water rapid stirring, after water is used the extraction of methylene dichloride 30ml × 2 again, water discards.The saturated NaHCO of organic phase
3and saturated common salt water washing, separate the appropriate anhydrous MgSO4 of organic phase dry, removal of solvent under reduced pressure, gained solid obtains sterling VII with ethyl alcohol recrystallization, productive rate 70%.
Embodiment 26
In reactor, add crude product VI 10g, 20ml acetonitrile and 25 milliliter of 20% Hydrogen bromide, 20 DEG C of reactions of room temperature 6 hours under rapid stirring.Add phase-splitting after 50ml methylene dichloride and 50ml water rapid stirring, after water is used the extraction of methylene dichloride 30ml × 2 again, water discards.The saturated NaHCO of organic phase
3and saturated common salt water washing, separate appropriate anhydrous MgSO for organic phase
4dry, removal of solvent under reduced pressure, gained solid obtains sterling VII with ethyl alcohol recrystallization.Productive rate 54%.
Embodiment 27
In reactor, add crude product VI (9.2g, 0.04mol) 40ml tetrahydrofuran (THF) and triethylamine 6g (0.06mol), Tosyl chloride 11.4g (0.06mol), stirs 8 hours.After reaction finishes, solvent evaporated.After adding 50ml methylene dichloride and 50ml water rapid stirring, separate organic phase, washing, steaming desolventizes, and gained crude product re-crystallizing in ethyl acetate, obtains white solid yield 63%.
Embodiment 28
In reactor, add crude product VI (9.2g, 0.04mol) 40ml methylene dichloride and triethylamine 6g (0.06mol), methylsulfonyl chloride 6.9g (0.06mol), stirs 8 hours.After reaction finishes, solvent evaporated.After adding 50ml methylene dichloride and 50ml water rapid stirring, separate organic phase, washing, steaming desolventizes, and gained crude product re-crystallizing in ethyl acetate, obtains white solid yield 65%.
Step e:
Embodiment 29
At 20 DEG C, compound 2-(4-(4-methyl bromoethyl ketone) phenyl)-2-methyl isopropyl eyeball 2.94g (10mmol) is dissolved in 20mL tetrahydrofuran (THF) in agent, add Difrm methyl alcohol (compounds X) 2.94g (11mmol), triethylamine 2g (20mmol), stirs 8 hours.After reaction finishes, solvent evaporated.After adding 20ml methylene dichloride and 20ml water rapid stirring, separate organic phase, washing, steaming desolventizes, and gained crude product re-crystallizing in ethyl acetate, obtains white solid yield 63%.
Embodiment 30
At 20 DEG C, compound 2-(4-(4-neoprene ketone) phenyl)-2-methyl isopropyl eyeball 2.5g (10mmol) is dissolved in 20mL ethanol, add Difrm methyl alcohol (compounds X) 2.94g (11mmol), triethylamine 2g (20mmol).Stir 8 hours.After reaction finishes, solvent evaporated.After adding 20ml methylene dichloride and 20ml water rapid stirring, separate organic phase, washing, steaming desolventizes, and gained crude product re-crystallizing in ethyl acetate, obtains white solid yield 54%.
Embodiment 31
At 20 DEG C, compound 2-(4-(4-neoprene ketone) phenyl)-2-methyl isopropyl eyeball 2.94g (10mmol) is dissolved in 20mL acetonitrile, add Difrm methyl alcohol (compounds X) 2.94g (11mmol), pyridine 1.6g (20mmol).Stir 8 hours.After reaction finishes, solvent evaporated.After adding 20ml methylene dichloride and 20ml water rapid stirring, separate organic phase, washing, steaming desolventizes, and gained crude product re-crystallizing in ethyl acetate, obtains white solid yield 43%.
Embodiment 32
At 20 DEG C, compound VI I (X=OTs) 3.85g (10mmol) is dissolved in 20mL methylene dichloride, add Difrm methyl alcohol (compound 8) 2.94g (11mmol), pyridine 1.6g (20mmol).Stir 8 hours.After reaction finishes.After adding 20ml methylene dichloride and 20ml water rapid stirring, separate organic phase, washing, steaming desolventizes, and gained crude product re-crystallizing in ethyl acetate, obtains white solid yield 45%.
Embodiment 33
At 20 DEG C, compound VI I (X=OMs) 3.10g (10mmol) is dissolved in 20mL toluene, adds Difrm methyl alcohol (compound 8) 2.94g (11mmol), pyridine 1.6g (20mmol).Stir 8 hours.After reaction finishes, solvent evaporated.After adding 20ml methylene dichloride and 20ml water rapid stirring, separate organic phase, washing, steaming desolventizes, and gained crude product re-crystallizing in ethyl acetate, obtains white solid yield 56%.
Step F:
Example 34
At 20 DEG C, compounds X 9.6g (20mmol) is dissolved in 30mL ethanol, adds the 200mL ethanol of potassium hydroxide 56g (1mol) and the solution of 10mL water, reflux 8 hours.Be chilled to room temperature, solvent evaporated, is adjusted to pH 5～6 with glacial acetic acid, and 4 DEG C of following crystallizatioies that leave standstill, filter, and filter cake washs with a small amount of frozen water, obtains white solid after oven dry, productive rate 80%.
Example 35
At 20 DEG C, compounds X 9.6g (20mmol) is dissolved in 30mL methyl alcohol, adds the 200mL methyl alcohol of sodium hydroxide 44g (1.1mol) and the solution of 10mL water, reflux 8 hours.Be chilled to room temperature, solvent evaporated, is adjusted to pH 5～6 with glacial acetic acid, and 4 DEG C of following crystallizatioies that leave standstill, filter, and filter cake washs with a small amount of frozen water, obtains white solid after oven dry, productive rate 71%.
Example 36
At 20 DEG C, compounds X 9.6g (20mmol) is dissolved in 30mL methyl alcohol, adds the 200mL Virahol of potassium hydroxide 56g (1mol) and the solution of 10mL water, reflux 8 hours.Be chilled to room temperature, solvent evaporated, is adjusted to pH 5～6 with glacial acetic acid, and 4 DEG C of following crystallizatioies that leave standstill, filter, and filter cake washs with a small amount of frozen water, obtains white solid after oven dry, productive rate 71%.
Step G:
Example 37
At 20 DEG C, compounds X I 9.6g (20mmol) is dissolved in 30mL ethanol, adds sodium borohydride 1.14g (30mmol).React 30 minutes, be adjusted to pH 5～6 with glacial acetic acid.After adding 50ml methylene dichloride and 50ml water rapid stirring, separate organic phase, washing, steaming desolventizes, and gained crude product Virahol recrystallization, obtains white solid yield 87%.
Example 38
At 20 DEG C, compounds X I 9.6g (20mmol) is dissolved in 30mL methyl alcohol, adds POTASSIUM BOROHYDRIDE 1.35g (25mmol).React 30 minutes, be adjusted to pH 5～6 with glacial acetic acid.After adding 50ml methylene dichloride and 50ml water rapid stirring, separate organic phase, washing, steaming desolventizes, and gained crude product Virahol recrystallization, obtains white solid yield 90%.
Example 39
At 20 DEG C, compounds X I 9.6g (20mmol) is dissolved in 40mLTHF, adds sodium cyanoborohydride 1.88g (30mmol), react 30 minutes, be adjusted to pH 5～6 with glacial acetic acid.After adding 50ml methylene dichloride and 50ml water rapid stirring, separate organic phase, washing, steaming desolventizes, and gained crude product Virahol recrystallization, obtains white solid yield 92%.
Example 40
At 20 DEG C, compounds X I 9.6g (20mmol) is dissolved in 40mL toluene, adds sodium cyanoborohydride 1.88g (30mmol), react 30 minutes, be adjusted to pH 5～6 with glacial acetic acid.After adding 50ml methylene dichloride and 50ml water rapid stirring, separate organic phase, washing, steaming desolventizes, and gained crude product Virahol recrystallization, obtains white solid yield 92%.
Example 41
Compounds X I 28.8g (60mmol) is added in people 500mL autoclave, add people 70mL methyl alcohol, add Raney-Ni 1.5g, respectively replace 3 times with nitrogen, hydrogen successively in confined conditions, be filled with 1MPa hydrogen, 40 DEG C of reaction 6h, drive still, filter, reclaim catalyzer (treating to apply mechanically next time), filtrate Distillation recovery methyl alcohol, gained crude product Virahol recrystallization, obtains white solid yield 92%.
Example 42
Compounds X I 28.8g (60mmol) is added in people 500mL autoclave, add people 70mL ethanol, add Pd/C1.5g, respectively replace 3 times with nitrogen, hydrogen successively in confined conditions, be filled with 1MPa hydrogen, 40 DEG C of reaction 6h, drive still, filter, reclaim catalyzer (treating to apply mechanically next time), filtrate Distillation recovery methyl alcohol, gained crude product Virahol recrystallization, obtains white solid yield 93%.
Example 43
Compounds X I28.8g (60mmol) is added in people 500mL autoclave, add people 70mLTHF, add thunder Buddhist nun copper 1.5g, respectively replace 3 times with nitrogen, hydrogen successively in confined conditions, be filled with 1MPa hydrogen, 40 DEG C of reaction 6h, drive still, filter, reclaim catalyzer (treating to apply mechanically next time), filtrate Distillation recovery methyl alcohol, gained crude product Virahol recrystallization, obtains white solid yield 83%.
Example 44
Compounds X I28.8g (60mmol) is added in people 500mL autoclave, add people 70mL ethylene dichloride, add Raney's nickel 1.5g, respectively replace 3 times with nitrogen, hydrogen successively in confined conditions, be filled with 1MPa hydrogen, 40 DEG C of reaction 6h, drive still, filter, reclaim catalyzer (treating to apply mechanically next time), filtrate Distillation recovery methyl alcohol, gained crude product Virahol recrystallization, obtains white solid yield 89%.
Example 45
Compounds X I 28.8g (60mmol) is added in people 500mL autoclave, add people 40mL methyl alcohol and 30ml tert.-butyl acetate, add Raney's nickel 1.5g, respectively replace 3 times with nitrogen, hydrogen successively in confined conditions, be filled with 1MPa hydrogen, 40 DEG C of reaction 6h, drive still, filter, reclaim catalyzer (treating to apply mechanically next time), filtrate Distillation recovery methyl alcohol, gained crude product Virahol recrystallization, obtains white solid yield 90%.
Compound (X) arrives formula compound (I) again to formula compound (XI), can be without the embodiment of separation and purification " one kettle way "
Embodiment 46
At 20 DEG C, compounds X 9.6g (20mmol) is dissolved in 30mL ethanol, add sodium borohydride 1.5g (40mmol), react after 20 minutes and add the 10mL ethanol of potassium hydroxide 56g (1mol) and the solution of 1mL water, reflux 8 hours.Be chilled to room temperature, be adjusted to pH 5～6 with glacial acetic acid, 4 DEG C of following crystallizatioies that leave standstill, filter, and filter cake washs with a small amount of frozen water, obtains white solid after oven dry, productive rate 80%.
Example 47
At 20 DEG C, compounds X 9.6g (20mmol) is dissolved in 30mL acetonitrile, add triethoxy sodium borohydride 6.3g (30mmol), react after 20 minutes and add the 10mL ethanol of sodium hydroxide 16g (0.4mol) and the solution of 1mL water, reflux 8 hours.Be chilled to room temperature, be adjusted to pH 5～6 with glacial acetic acid, pressure reducing and steaming organic solvent, with ethyl alcohol recrystallization, filtration, the dry white solid, productive rate 73% of obtaining.
Example 48
At 20 DEG C, compounds X 9.6g (20mmol) is dissolved in 30mL toluene, add POTASSIUM BOROHYDRIDE 1.7g (30mmol), react after 20 minutes and add the 10mL ethanol of sodium hydroxide 48g (1.2mol) and the solution of 1mL water, reflux 8 hours.Be chilled to room temperature, be adjusted to pH 5～6 with glacial acetic acid, pressure reducing and steaming organic solvent, with ethyl alcohol recrystallization, filtration, the dry white solid, productive rate 61% of obtaining.
Example 49
At 20 DEG C, compounds X 9.6g (20mmol) is dissolved in 30mLDMF, add sodium cyanoborohydride 1.8g (30mmol), react after 20 minutes and add the 10mL ethanol of sodium hydroxide 8g (200mmol) and the solution of 1mL water, reflux 8 hours.Be chilled to room temperature, be adjusted to pH 5～6 with glacial acetic acid,, pressure reducing and steaming organic solvent, with ethyl alcohol recrystallization, filtration, the dry white solid, productive rate 68% of obtaining.
Example 50
At 20 DEG C, compounds X 9.6g (20mmol) is dissolved in 30mLTHF, add the THF solution 30ml (C=1mol/L) of borine (30mmol), react after 20 minutes and add the 10mL ethanol of sodium hydroxide 8g (200mmol) and the solution of 1mL water, reflux 8 hours.Pressure reducing and steaming organic solvent, with ethyl alcohol recrystallization, filtration, the dry white solid, productive rate 68% of obtaining.
Claims (7)
1. the preparation method of a high purity fexofenadine and intermediate thereof, it is characterized in that the method taking to cyanogen methyl benzoic acid ester (II) as raw material, taking compound (Va) or its salt (Vb) as key intermediate, make formula compound (VII) through hydrolysis, esterification or halogenation again, then with piperidine alcohols formula compound (VIII) condensation, hydrolysis, reduction make only have para-orientation, highly purified Fexofenadine fixed pattern compound (I);
Specifically comprise the steps:
1) Fexofenadine fixed pattern compound (I) is reacted and obtains at 20-40 DEG C with reductive agent in organic solvent by formula compound (XI), or formula compound (I) is obtained by catalytic hydrogenation under catalyst action by formula compound (XI); Described reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, triethoxy sodium borohydride, borine, and its consumption is 1～5 times of formula compound (XI) mole dosage; Described organic solvent is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, ethylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, acetonitrile or their mixed solvent, and it is 1～5ml that solvent load needs to use the amount of solvent by every 1g formula compound (XI) calculating; Described catalyzer is Raney's nickel, Lei Nitong, the Lei Nitong of Raney's nickel that adulterated, palladium carbon, and its consumption is the 5%-8% of compound (XI) quality;
2) formula compound (XI) is hydrolyzed under alkaline condition by formula compound (X) and obtains; Described alkali is lithium hydroxide, potassium hydroxide, sodium hydroxide, the equivalence ratio of the consumption of alkali and formula compound (X) 20: 1～80: 1; Described hydrolysis reaction is at water, C
1～C
8alcohol or their mixed solvent in carry out, solvent load is calculated as 1～5ml by every 1g formula compound (X);
3) formula compound (X) by formula compound (VII) and lupetidine methyl alcohol formula compound (VIII) under alkaline condition, in organic solvent, obtain in 0-100 DEG C of reaction, wherein X is chlorine, bromine or mesyloxy, tolysulfonyl oxygen base, acetoxyl group; Described solvent is selected from: ethyl acetate, butylacetate, acetone, butanone, hexone, toluene, dimethylbenzene, chlorinated benzene, methylene dichloride, ethylene dichloride, chloroform, DMF, DEF, DMSO, THF, DME, dioxane, acetonitrile, and consumption is calculated as 1～5ml by every 1g formula compound (VII); Described alkali is triethylamine, pyridine, and DMA, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, potassium hydroxide, sodium hydroxide, the equivalence ratio of alkali and formula compound (VII) is 1: 1～2.5: 1;
4) formula compound (VII) by formula compound (VI) and halide reagent in 0-40 DEG C in solvent, react and or by formula compound (VI) with esterifying reagent under alkaline condition, in organic solvent, carry out esterification and obtain in 0-30 DEG C; Wherein X is chlorine, bromine or mesyloxy, tolysulfonyl oxygen base, acetoxyl group; The solvent reacting with halide reagent is selected from one of following or their arbitrary combination: water, methyl alcohol, ethanol, Virahol, propyl carbinol, acetonitrile, toluene, dimethylbenzene, halogeno-benzene, methane amide, N, dinethylformamide, 1,2-glycol dimethyl ether, methyl-sulphoxide, methylene dichloride, 1,2-ethylene dichloride, chloroform, acetone, butanone, hexone, tetrahydrofuran (THF), dioxane, consumption is calculated as 1～5ml by every 1g formula compound (VI); Described halide reagent is Hydrogen bromide or hydrochloric acid, and concentration is that percentage composition is 10-40%; Described esterifying reagent is Tosyl chloride, methylsulfonyl chloride, acetic acid, Acetyl Chloride 98Min.; The equivalence ratio of esterifying reagent and formula compound (VI) is 1-1.2: 1; The solvent reacting with esterifying reagent is ethyl acetate, butylacetate, acetone, butanone, hexone, toluene, dimethylbenzene, chlorinated benzene, methylene dichloride, ethylene dichloride, chloroform, DMF, N, N-diethyl acetamide, DMSO, THF, dioxane, acetonitrile, consumption of organic solvent is calculated as 1～5ml by every 1g formula compound (VI); Described alkaline condition is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, saleratus, salt of wormwood, triethylamine, pyridine; The equivalence ratio of described alkali and formula compound (VI) is 1-5: 1;
5) formula compound (VI), by compound (Va) or its salt (Vb) under alkalescence or acidic conditions, obtains in 40-100 DEG C of decarboxylation in solvent; Described organic solvent is selected from water, methyl alcohol, ethanol, Virahol, propyl carbinol, acetonitrile, toluene, dimethylbenzene, halogeno-benzene, methane amide, N, dinethylformamide, 1,2-glycol dimethyl ether, methyl-sulphoxide, methylene dichloride, 1,2-ethylene dichloride, chloroform, acetone, butanone, hexone, tetrahydrofuran (THF), dioxane; Alkaline condition reacts initial system alkalescence and is controlled at pH=12; Acidic conditions system PH is 2-3;
6) formula compound (Vb) is reacted and obtains in 50-150 DEG C under alkaline condition by compound (III) and compound (IV) gamma-butyrolactone in organic solvent, and formula compound (Va) is by formula compound (Vb) acidifying and obtaining under acidic conditions; Described solvent is selected from one of following or their arbitrary combination: benzene,toluene,xylene, DMF, acetonitrile, 1,2-glycol dimethyl ether, methyl-sulphoxide, methylene dichloride, 1,2-ethylene dichloride, chloroform, tetrahydrofuran (THF), dioxane; The consumption of organic solvent is calculated as 1～5ml by every 1g formula compound (III); Described reaction is carried out under alkaline condition, and alkali is selected from: sodium, sodium hydride, sodium amide, sodium methylate, sodium ethylate, butyllithium, hexamethyl diamino silicon lithium, diisopropylamine lithium; The equivalence ratio of described alkali and formula compound (III) is 1.2: 1～1.5: 1;
7) formula compound (III), by formula compound (II) and methyl-sulfate under alkaline condition, obtains in-20-50 DEG C reaction in solvent; Described solvent selects one of following or their arbitrary combination: water, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, acetonitrile, toluene, dimethylbenzene, halogeno-benzene, methane amide, N, dinethylformamide, 1,2-glycol dimethyl ether, methyl-sulphoxide, methylene dichloride, 1,2-ethylene dichloride, chloroform, acetone, butanone, hexone, tetrahydrofuran (THF), dioxane; The consumption of solvent is calculated as 1～5ml by every 1g formula compound (II); Described alkali is sodium hydroxide, potassium hydroxide, and sodium hydride, sodium carbonate, salt of wormwood, the equivalence ratio of described alkali and formula compound (II) is 10: 1～15: 1.
2. the preparation method of high purity fexofenadine and intermediate thereof according to claim 1, is characterized in that step 1) Chinese style compound (I) obtains by catalytic hydrogenation in 80-120 DEG C under catalyst action by formula compound (XI) in solvent.
3. the preparation method of high purity fexofenadine and intermediate thereof according to claim 1, is characterized in that step 2) described prepare the reflux temperature that compound (XI) temperature of reaction is solvent.
4. the preparation method of high purity fexofenadine and intermediate thereof according to claim 1, is characterized in that step 3) temperature of reaction of preparing compound (X) is 25 DEG C.
5. the preparation method of high purity fexofenadine and intermediate thereof according to claim 1, is characterized in that step 5) in prepare compound (VI) temperature of reaction be 50 DEG C.
6. the preparation method of high purity fexofenadine and intermediate thereof according to claim 1, is characterized in that step 6) in prepare compound (Vb) temperature of reaction be 110 DEG C.
7. the preparation method of high purity fexofenadine and intermediate thereof according to claim 1, is characterized in that step 7) in the temperature of reaction of compound be 0 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910225972.XA CN102070512B (en) | 2009-11-21 | 2009-11-21 | Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910225972.XA CN102070512B (en) | 2009-11-21 | 2009-11-21 | Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102070512A CN102070512A (en) | 2011-05-25 |
| CN102070512B true CN102070512B (en) | 2014-11-19 |
Family
ID=44029293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910225972.XA Active CN102070512B (en) | 2009-11-21 | 2009-11-21 | Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102070512B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116143686A (en) * | 2022-12-30 | 2023-05-23 | 深圳市江川医药技术有限公司 | Preparation method of haloperidol impurity D |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995000482A1 (en) * | 1993-06-24 | 1995-01-05 | Albany Molecular Research, Inc. | Piperidine derivatives and process for their production |
| CN1128987A (en) * | 1993-06-25 | 1996-08-14 | 默里尔多药物公司 | New intermediates for the preparation of antihistamine piperidine derivatives |
| WO2002010115A1 (en) * | 2000-07-28 | 2002-02-07 | Texcontor Etablissement | New processes for the production of fexofenadine |
| US20060063808A1 (en) * | 2004-09-17 | 2006-03-23 | Amr Technology, Inc. | Process for production of piperidine derivatives |
| WO2007007347A1 (en) * | 2005-07-07 | 2007-01-18 | Wockhardt Limited | Industrial process of fexofenadine hydrochloride with controlled side products |
| CN101182306A (en) * | 2007-12-14 | 2008-05-21 | 重庆大学 | The synthetic method of the intermediate of fexofenadine |
-
2009
- 2009-11-21 CN CN200910225972.XA patent/CN102070512B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995000482A1 (en) * | 1993-06-24 | 1995-01-05 | Albany Molecular Research, Inc. | Piperidine derivatives and process for their production |
| CN1128987A (en) * | 1993-06-25 | 1996-08-14 | 默里尔多药物公司 | New intermediates for the preparation of antihistamine piperidine derivatives |
| WO2002010115A1 (en) * | 2000-07-28 | 2002-02-07 | Texcontor Etablissement | New processes for the production of fexofenadine |
| US20060063808A1 (en) * | 2004-09-17 | 2006-03-23 | Amr Technology, Inc. | Process for production of piperidine derivatives |
| WO2007007347A1 (en) * | 2005-07-07 | 2007-01-18 | Wockhardt Limited | Industrial process of fexofenadine hydrochloride with controlled side products |
| CN101182306A (en) * | 2007-12-14 | 2008-05-21 | 重庆大学 | The synthetic method of the intermediate of fexofenadine |
Non-Patent Citations (6)
| Title |
|---|
| A new synthesis of carboxyterfenadine (fexofenadine) and its bioisosteric tetrazole analogs;Barbara Di Giacomo,等;《IL Farmaco》;19990930;第54卷(第9期);第600–610页 * |
| Amane El Ouarradi,等.Biooxidation of methyl group: application to the preparation of alcohol and acid metabolites of terfenadine, ebastine and analogues.《Tetrahedron》.2008,第64卷(第51期),第11738–11744页. * |
| Barbara Di Giacomo,等.A new synthesis of carboxyterfenadine (fexofenadine) and its bioisosteric tetrazole analogs.《IL Farmaco》.1999,第54卷(第9期),第600-610页. * |
| Biooxidation of methyl group: application to the preparation of alcohol and acid metabolites of terfenadine, ebastine and analogues;Amane El Ouarradi,等;《Tetrahedron》;20081008;第64卷(第51期);第11738–11744页 * |
| 特非它唑的合成;罗成,等;《华西药学杂志》;20031030;第18卷(第05期);第346-347页 * |
| 罗成,等.特非它唑的合成.《华西药学杂志》.2003,第18卷(第05期),第346-347页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102070512A (en) | 2011-05-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101429115B (en) | Process for producing trifluoro benzene acetic acid and sitagliptin | |
| CN110396054A (en) | A kind of green synthesis method of kresoxim-methyl | |
| CN101495444A (en) | A process for the preparation of optically active cyclopropylamines | |
| CN101412670A (en) | Method for synthesizing loxoprofen sodium | |
| CN102276559B (en) | Method for synthesizing 3-hydroxymethyl tetrahydrofuran | |
| CN113735701B (en) | Preparation method of 8-hydroxy-2,2,14,14-tetramethyl pentadecane diacid | |
| CN112479856A (en) | Synthesis method of piparidic acid | |
| CN115108904A (en) | The synthetic method of beipedox acid raw material medicine | |
| CN103613498B (en) | The synthetic method of Win-35833 | |
| CN103420855A (en) | Trans-4-amino cyclohexylmethanol hydrochloride and preparation method thereof | |
| CN102070512B (en) | Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof | |
| CN105175346B (en) | A kind of method of synthesizing rosuvastatin spit of fland calcium intermediate | |
| CN114539048A (en) | Caronic anhydride intermediate and preparation method of caronic anhydride | |
| CN102267934B (en) | Method for preparing 6-carbomethoxy indolone | |
| CN115819408B (en) | Method for synthesizing rosuvastatin key intermediate with high selectivity | |
| CN105032473B (en) | A kind of method using the sulfuric acid modified catalyst preparation dialkoxy methanes for the treatment of nanoscale HZSM 5 | |
| US20010034459A1 (en) | Process for preparing 4'-trifluoromethyl-2-methylbiphenyl and 4'-trifluoromethyl-biphenyl-2-carboxylic acid from o-tolylmetallates | |
| CN110734368A (en) | Preparation method of buparvaquone | |
| CN104909994A (en) | Method for synthesizing ciprofibrate intermediate and the intermediate | |
| CN104496899A (en) | Synthesis method of midbody of Montelukast sodium | |
| CN112552299B (en) | Preparation method of linagliptin for treating type II diabetes | |
| CN101270048B (en) | The synthetic method of 1-chloro-2-methyl-4-acetoxy-2-butene | |
| CN102070490B (en) | Method for preparing fexofenadine intermediate 2-(4-(4-maloyl) phenyl)-2-methylpropionitrile | |
| CN110240561B (en) | Low-cost preparation method of 3-hydroxypyridine | |
| CN107880011B (en) | The synthetic method of Lu Makatuo key intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |