CN101360727A - 药物中间体的制备方法 - Google Patents
药物中间体的制备方法 Download PDFInfo
- Publication number
- CN101360727A CN101360727A CNA2006800455299A CN200680045529A CN101360727A CN 101360727 A CN101360727 A CN 101360727A CN A2006800455299 A CNA2006800455299 A CN A2006800455299A CN 200680045529 A CN200680045529 A CN 200680045529A CN 101360727 A CN101360727 A CN 101360727A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- piperazine
- benzyl chloride
- chloride base
- oxyethyl group
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000012450 pharmaceutical intermediate Substances 0.000 title abstract description 3
- 239000002585 base Substances 0.000 claims description 46
- 229940073608 benzyl chloride Drugs 0.000 claims description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- -1 β-chloro oxyethyl Chemical group 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000009835 boiling Methods 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 235000007715 potassium iodide Nutrition 0.000 claims description 4
- 229960004839 potassium iodide Drugs 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000002191 fatty alcohols Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- 229910001513 alkali metal bromide Inorganic materials 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 229910001511 metal iodide Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 235000010755 mineral Nutrition 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 17
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 abstract description 15
- 229960001803 cetirizine Drugs 0.000 abstract description 15
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 abstract description 3
- 230000001387 anti-histamine Effects 0.000 abstract description 3
- 239000000739 antihistaminic agent Substances 0.000 abstract description 3
- 230000001624 sedative effect Effects 0.000 abstract description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract 2
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 abstract 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- 229960001508 levocetirizine Drugs 0.000 abstract 1
- 230000009466 transformation Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000007791 liquid phase Substances 0.000 description 9
- 230000003287 optical effect Effects 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000004611 spectroscopical analysis Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- IHTYTYHXCRAMAV-UHFFFAOYSA-N acetic acid;dihydrochloride Chemical compound Cl.Cl.CC(O)=O IHTYTYHXCRAMAV-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 235000009508 confectionery Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000010813 municipal solid waste Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 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 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Inorganic materials [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明涉及式(I)的{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺及其对映异构体的制备方法。式(I)的化合物或其对映异构体是适用于直接转化为非镇静性抗组胺型药物活性成分西替利嗪和左旋西替利嗪的重要药物中间体。
Description
本发明涉及式(I)的{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺
及其光学异构体的制备方法。式(I)的化合物是药物活性成分{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸的重要中间体,该药物活性成分公知的国际非专有名称为西替利嗪(cetirizine)。西替利嗪是一种非镇静性抗组胺型药物成分。
式(I)的化合物(-)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺是式(VI)的(-)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸
的制备方法中的原料,其也是药物活性成分,公知的国际非专有名称为左旋西替利嗪。左旋西替利嗪属于非镇静性抗组胺型药物成分。西替利嗪和左旋西替利嗪在US 5627083和5698558中已成为公知的。
EP58146中首次公开了西替利嗪的制备方法。通过式(VII)的{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酰胺
的水解获得西替利嗪。
所述式(VII)的{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酰胺是通过使式(II)的[1-(α-苯基-p-氯苄基)-哌嗪与式(VIII)的2-氯代乙氧基-乙酰胺
在二甲苯溶剂中在无水碳酸钠的存在下反应制得的。
上述方法的缺陷在于,在反应过程中2-氯代乙氧基-乙酰胺的氨基的烷基化也作为副反应发生。通过简单的过程不能将上述反应中形成的副产物从产物中除去。除去所述副产物和产物的纯化需要高成本的纯化过程,其也导致产率的显著损失。
国际公开文献WO01/40211公开了一种由式(IV)的化合物2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙醇
制备式(I)的{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺的方法,通过使所述取代的乙醇衍生物在不同溶剂中转化为其碱金属盐并使由此获得的盐与式(V)的氯代乙酸-N,N-二甲基酰胺反应。
以二盐酸盐的形式获得产物式(I)的{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺,将其直接用作制备西替利嗪中的原料。
上述方法的缺点在于如下事实,在无水和醇的溶液中,可以发生式(IV)化合物2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙醇的O-烷基化,其要求采用特定设备以及无水试剂。
我们研究工作的目的是开发出一种制备式(I)的{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺的方法,其适用于制备药典质量的最终产物西替利嗪,无需使用昂贵的试剂、复杂和高成本的设备且无需复杂的操作(例如,水和水分去除、从副产物中纯化产物)。
依据本发明的方法解决了上述目的。
本发明是基于如下令人吃惊的发现,如果通过使式(II)的1-(α-苯基-p-氯苄基)-哌嗪
和式(III)的(2-氯代乙氧基)-乙酸-N,N-二甲基酰胺
在不同溶剂中并在酸-结合剂与催化剂的存在下反应制备式(I)化合物{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺,可以消除上述缺陷。所述方法中获得的式(I)的{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺适用于直接转化为西替利嗪。该方法的另一优点在于如下事实,通过使用式(II)的单一对映异构体的起始化合物(-)-1-(α-苯基-p-氯苄基)-哌嗪,可以制得左旋西替利嗪。
在依据本发明的上述方法中,仅形成少量的副产物且无需无水操作条件。
该方法特别令人吃惊的特征在于如下事实,在(-)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺的碱水解期间,不会发生外消旋化,由此所述碱水解获得光学纯的(-)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸[左旋西替利嗪],无(+)异构体。
依据本发明,式(II)的1-(α-苯基-p-氯苄基)-哌嗪与式(III)的(2-氯代乙氧基)-乙酸-N,N-二甲基酰胺的烷基化在质子或非质子、极性或非极性溶剂,如包含1至4个碳原子的脂族醇、乙腈、甲苯、二氧杂环己烷、丙酮中进行,优选在甲苯中进行。
对于该反应中形成的酸的中和,可以使用弱的有机或无机碱,如碱金属或碱土金属碳酸盐或碳酸氢盐,优选碳酸钠,吡啶或其中烷基包含2至6个碳原子的脂族叔胺,优选三乙胺。
作为催化剂,可以使用碱金属卤化物,例如锂、钠或钾碘化物,优选碘化钾。
该反应在50℃至溶剂沸点温度之间、优选80℃至溶剂沸点温度之间的温度下、最有利地在溶剂的沸点温度下进行。
可以通过现有技术中本质上已知的方法来分离产物。特别有利的方法是获得其二盐酸盐形式的产物。
依据本发明的方法的起始物质,式(II)的1-(α-苯基-p-氯苄基)-哌嗪和其光学异构体是已知的化合物[Yakugaku Zasshi,74,1954,1049;Chem.Abstr.,1955,11666;GB 2225321]。
依据本发明的方法的第二种起始物质,2-氯代乙氧基-乙酸-N,N-二甲基酰胺在德国专利2150075中是已知的。
下列实施例中提供了本发明的进一步详细内容,但是并非将保护范围限定为所述实施例。
实施例1
(±)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺
将14.4g(0.05mol)的(±)-1-(α-苯基-p-氯苄基)-哌嗪溶解于120ml甲苯中,并加入15g无水碳酸钠和0.7g碘化钾。搅拌下将反应混合物加热到约110℃并在该温度下,在1小时内滴加8.8g(0.053mol)原料2-氯代乙氧基-乙酸-N,N-二甲基酰胺。滴加之后,使反应混合物在上述温度下加热和搅拌24小时。
使反应混合物冷却,将20g碎冰加到其中,并通过加入约1.5ml的浓盐酸将混合物的pH调节到6.4。分层,在甲苯层中加入25g碎冰并通过加入约3ml浓盐酸调节其pH到3.8。分层,将50ml二氯甲烷加到含水层中并通过加入约4.5ml的40wt%氢氧化钠溶液将其pH调节到7至8。将二氯甲烷层分离,在无水硫酸钠上干燥,过滤并在真空下使溶剂蒸发。
通过该过程,获得18.4g(88.2%)的粘性、油状产物(熔点183-190℃)。通过高效液相色谱测量产物的纯度为大于98wt%。该产物适合作为制备满足欧洲药典(European Pharmacopoeia)1997:1084中给出的规定的药典质量西替利嗪的原料。
依据上述规定,总杂质的含量必须不超过0.5wt%,且任意单一杂质的含量应小于0.1wt%。
如果期望的话,可以使用2-丙醇作为溶剂通过使游离碱与25wt%异丙醇盐酸溶液反应,将该游离碱转化为其二盐酸盐。
实施例2
(±)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸二盐酸盐
将48.9g(0.1mol)依据实施例1的方法制得的(±)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺二盐酸盐溶解于170ml水中,并将所获得的溶液与100ml的40wt%氢氧化钠水溶液混合物。在采用氮气连续鼓泡下使所获得的悬浮液沸腾3小时。使获得的反应混合物冷却到40℃,用250ml水稀释并用约60ml浓盐酸将其酸化到pH 3.8。分别用200ml和100ml二氯乙烷萃取该酸性溶液。将二氯甲烷层合并,使溶剂蒸发并将残留物溶解于25ml水中。使该水溶液与12ml浓盐酸混合并在真空下蒸发到干燥。将粘稠的油状残留物溶解于25ml丙酮中,将该溶液与另一部分的300ml丙酮混合并搅拌1小时。将沉淀的结晶产物过滤掉,用丙酮和二乙醚洗涤并在真空下干燥。由此获得39.4g(85.5%)纯的目标化合物,熔点225.5-228℃。由此获得的产物满足欧洲药典3,1997:1084的所有要求。
实施例3
(±)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸二盐酸盐
进行实施例2的方法,区别在于,使用41.7g(0.1mol)的(±)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺代替48.9g(0.1mol)的(±)-{2-[4-(α-苯基--氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺二盐酸盐。产生38.1g(82.1%)的纯的目标化合物(熔点226-228℃),其满足欧洲药典3,1997:1084的所有要求。
实施例4
(-)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺
采取实施例1的方法,区别在于,使用对映异构体纯度大于99%的(-)-1-(α-苯基-p-氯苄基)-哌嗪代替(±)-1-(α-苯基-p-氯苄基)-哌嗪。产生18.2g(87.3%)的粘性油状产物,高效液相色谱测量的纯度大于98%。手性高效液相色谱测量的产物的光学纯度高于99%。旋光性,[α]D 20=-6.4°(c=0.8g/10cm3乙醇)。
通过使用Chiralpak AD柱和包含2-丙醇-己烷25∶75(v/v)的流动相的高效液相色谱(HPLC)测量产物的纯度。
实施例5
(+)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸二盐酸盐
采用实施例2的方法,区别在于,使用光学纯度大于99%的(-)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺代替(±)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺二盐酸盐,并且在0.02mol规模上进行该反应。产生7.3g(79.4%)的目标化合物,旋光性[α]365 20=+12.2°。高效液相色谱测量的产物纯度大于98%。手性高效液相色谱测量的产物光学纯度大于99%。
通过使用Chiracell OD-R柱和包含2-丙醇-己烷32∶68(v/v)乙腈-0.5M高氯酸钠的流动相的HPLC测量产物的光学纯度。
实施例6
(+)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺
采取实施例1的方法,区别在于,使用对映异构体纯度大于99%的(+)-1-(α-苯基-p-氯苄基)-哌嗪代替(±)-1-(α-苯基-p-氯苄基)-哌嗪。产生17.5g(83.8%)的粘性油状产物,高效液相色谱测量的纯度大于98%。手性高效液相色谱测量的产物的光学纯度高于99%。旋光性,[α]D 20=+6.3°(c=0.8g/10cm3乙醇)。
实施例7
(-)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸二盐酸盐
依据实施例2的方法制备目标化合物,区别在于,使用光学纯度大于99%的(+)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺代替(±)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺二盐酸盐,并且在0.02mol规模上进行该反应。产生6.9g(75.0%)的目标化合物,旋光性[α]365 20=-12.4°。高效液相色谱测量的产物纯度大于98%。手性高效液相色谱测量的产物光学纯度大于99%。
实施例8
(±)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺
依据实施例1的方法制备目标化合物,区别在于,使用100ml乙腈代替120ml甲苯溶剂,且使反应在乙腈的沸点温度下进行24小时。产生10.2g(48.9%)粘性、蜜状产物,通过高效液相色谱测量的纯度大于98%且其适用于直接转化为满足欧洲药典中给出的规定的西替利嗪。
实施例9
(±)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺
依据实施例1的方法制备目标化合物,区别在于,使用150ml丙酮代替120ml甲苯溶剂,且通过使反应混合物在丙酮的沸点温度下沸腾48小时来进行该反应。产生9.4g(45.1%)蜜状产物,基于高效液相色谱分析的纯度大于95%且其适用于直接转化为满足欧洲药典中给出的规定的西替利嗪。
实施例10
(±)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺
依据实施例1的方法制备目标化合物,区别在于,使用120ml二氧杂环己烷代替120ml甲苯溶剂,且通过使反应混合物在二氧杂环己烷的沸点温度下沸腾24小时来进行该反应。产生10.8g(51.8%)粘性、蜜状产物,通过高效液相色谱测量的纯度大于98%且其适用于直接转化为药典质量的西替利嗪。
实施例11
(±)-{2-[4-(α-苯基-p-氯苄基)-哌嗪-1-基]-乙氧基}-乙酸-N,N-二甲基酰胺
依据实施例1的方法制备目标化合物,区别在于,使用100ml乙腈代替120ml甲苯溶剂和使用10ml三乙胺代替无水碳酸钠酸-结合剂,且通过使反应混合物在80℃下加热72小时来完成该反应。产生8.2g(39.3%)蜜状产物,通过高效液相色谱测量的纯度大于98%且其适用于直接转化为满足欧洲药典的要求的西替利嗪。
Claims (8)
2、权利要求1的方法,其特征在于,使用包含1至4个碳原子的脂族醇、乙腈、甲苯、二氧杂环己烷或丙酮或其混合物作为溶剂。
3、权利要求1的方法,其特征在于,使用无机或有机碱作为酸-结合剂。
4、权利要求3的方法,其特征在于,使用选自碱金属碳酸盐或碱土金属碳酸盐的无机碱作为酸-结合剂。
5、权利要求3的方法,其特征在于,使用选自三乙胺或吡啶的有机碱作为酸-结合剂。
6、权利要求1的方法,其特征在于,使用碱金属碘化物或碱金属溴化物、优选碘化钾作为催化剂。
7、权利要求1的方法,其特征在于,通过在50℃至溶剂沸点温度之间、优选80℃至溶剂沸点温度之间的温度下、最有利地在溶剂的沸点温度下加热反应混合物来进行反应。
8、权利要求1的方法,其特征在于,使用式(II)的(-)-{1-(α-苯基-p-氯苄基)-哌嗪}作为原料。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU0501138A HU227325B1 (en) | 2005-12-08 | 2005-12-08 | Process for the production of an intermediate of (dextro- and levo)- cetirizine |
HUP0501138 | 2005-12-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101360727A true CN101360727A (zh) | 2009-02-04 |
Family
ID=89986438
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2006800455299A Pending CN101360727A (zh) | 2005-12-08 | 2006-12-08 | 药物中间体的制备方法 |
Country Status (11)
Country | Link |
---|---|
US (1) | US20090018337A1 (zh) |
EP (1) | EP1971585B1 (zh) |
JP (1) | JP2009518378A (zh) |
CN (1) | CN101360727A (zh) |
AT (1) | ATE501131T1 (zh) |
DE (1) | DE602006020624D1 (zh) |
EA (1) | EA014530B1 (zh) |
HU (1) | HU227325B1 (zh) |
NO (1) | NO20083064L (zh) |
UA (1) | UA92770C2 (zh) |
WO (1) | WO2007066162A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103044355A (zh) * | 2011-10-13 | 2013-04-17 | 湖南九典制药有限公司 | 合成左西替利嗪的关键中间体及其制备方法 |
CN111205247A (zh) * | 2020-04-22 | 2020-05-29 | 湖南九典宏阳制药有限公司 | 左旋西替利嗪的制备方法 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7880761B2 (en) | 2005-07-20 | 2011-02-01 | Lab Partners Associates, Inc. | Wireless photographic communication system and method |
EP2162792A4 (en) | 2007-05-29 | 2011-08-24 | Lab Partners Associates Inc | SYSTEM AND METHOD FOR MAINTAINING FLASH CONTACT COMMUNICATIONS BETWEEN A CAMERA AND A WIRELESS DEVICE |
US20110230496A1 (en) * | 2007-08-15 | 2011-09-22 | Chemagis Ltd. | Novel process for preparing highly pure levocetirizine and salts thereof |
CN110988163B (zh) * | 2019-11-29 | 2022-04-19 | 重庆华邦胜凯制药有限公司 | 一种hplc法分离测定盐酸左西替利嗪及其基因毒性杂质e的方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK154078C (da) * | 1981-02-06 | 1989-05-22 | Ucb Sa | Analogifremgangsmaade til fremstilling af 2-(2-(4-(diphenyl-methyl)-1-piperazinyl)ethoxy)-acetamider eller syreadditionssalte heraf |
GB8827391D0 (en) * | 1988-11-23 | 1988-12-29 | Ucb Sa | Process for preparation of 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-pipera-zinyl)ethoxy)-acetic acid & its dihydrochloride |
US20030064995A1 (en) * | 2001-10-03 | 2003-04-03 | Merck Patent Gmbh | Amide and urea derivatives as 5-HT reuptake inhibitors and as5-HT1B/1D ligands |
IL124195A (en) * | 1998-04-23 | 2000-08-31 | Chemagis Ltd | Process for the preparation of esters of 2-¬4-¬4-chlorophenyl¾phenylmethyl¾-1-piperazinyl¬ethoxy¾acetic acid |
EP1233954B1 (en) * | 1999-11-30 | 2004-10-20 | Egis Gyogyszergyar Rt. | A process for the preparation of 2- 4-(alpha-phenyl-p-chlorobenzyl)piperazin-1-yl]ethoxy acetic acid and novel intermediates therefor |
-
2005
- 2005-12-08 HU HU0501138A patent/HU227325B1/hu not_active IP Right Cessation
-
2006
- 2006-08-12 UA UAA200808850A patent/UA92770C2/ru unknown
- 2006-12-08 CN CNA2006800455299A patent/CN101360727A/zh active Pending
- 2006-12-08 EP EP06842191A patent/EP1971585B1/en active Active
- 2006-12-08 DE DE602006020624T patent/DE602006020624D1/de active Active
- 2006-12-08 JP JP2008543922A patent/JP2009518378A/ja not_active Withdrawn
- 2006-12-08 AT AT06842191T patent/ATE501131T1/de not_active IP Right Cessation
- 2006-12-08 EA EA200801505A patent/EA014530B1/ru not_active IP Right Cessation
- 2006-12-08 WO PCT/HU2006/000108 patent/WO2007066162A1/en active Application Filing
- 2006-12-08 US US12/096,630 patent/US20090018337A1/en not_active Abandoned
-
2008
- 2008-07-08 NO NO20083064A patent/NO20083064L/no not_active Application Discontinuation
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103044355A (zh) * | 2011-10-13 | 2013-04-17 | 湖南九典制药有限公司 | 合成左西替利嗪的关键中间体及其制备方法 |
CN111205247A (zh) * | 2020-04-22 | 2020-05-29 | 湖南九典宏阳制药有限公司 | 左旋西替利嗪的制备方法 |
CN111205247B (zh) * | 2020-04-22 | 2020-08-14 | 湖南九典宏阳制药有限公司 | 左旋西替利嗪的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
HU0501138D0 (en) | 2006-02-28 |
EA014530B1 (ru) | 2010-12-30 |
EP1971585A1 (en) | 2008-09-24 |
UA92770C2 (ru) | 2010-12-10 |
US20090018337A1 (en) | 2009-01-15 |
JP2009518378A (ja) | 2009-05-07 |
WO2007066162A1 (en) | 2007-06-14 |
NO20083064L (no) | 2008-07-08 |
EP1971585B1 (en) | 2011-03-09 |
DE602006020624D1 (de) | 2011-04-21 |
HUP0501138A2 (en) | 2007-08-28 |
HU227325B1 (en) | 2011-03-28 |
EA200801505A1 (ru) | 2008-10-30 |
ATE501131T1 (de) | 2011-03-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5935958A (en) | Muscarinic antagonists | |
ES2367976T3 (es) | Procedimiento para la preparación de sildenafilo. | |
EP0912534B1 (en) | Muscarinic antagonists | |
CN101501000B (zh) | 孟鲁司特和其胺盐的纯化方法 | |
CN105283442A (zh) | 用于合成1-(2-((2,4-二甲基苯基)硫代)苯基)哌嗪的新方法 | |
US20080167479A1 (en) | Process for preparing vildagliptin | |
CN101360727A (zh) | 药物中间体的制备方法 | |
EP3386945A1 (en) | Solid forms of (2r,4s)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2- -methylpentanoic acid ethyl ester, its salts and a preparation method | |
CN104066719B (zh) | 用作mogat-2抑制剂的苄基磺酰胺衍生物 | |
WO1998000412A9 (en) | Muscarinic antagonists | |
WO2010038124A1 (en) | An improved process for preparing pyrimidine propenaldehyde | |
EP1781665A2 (en) | Olanzapine salts and their conversion to olanzapine free base | |
CN101657437B (zh) | 制备左西替利嗪及其中间体的新方法 | |
MXPA04008730A (es) | Proceso para preparacion de piperazinas quirales 1,4-disustituidas. | |
WO2013020672A1 (en) | Process for the preparation of aripiprazole | |
KR101304640B1 (ko) | 신규의 로수바스타틴 엔-메틸벤질아민 염 및 그의 제조방법 | |
CN112125889A (zh) | 一种7-溴-2-(1-甲基-1h-吡唑-4-基)喹喔啉的制备方法 | |
CN101128446B (zh) | 焦谷氨酸盐及其在用于合成右旋西替利嗪和左旋西替利嗪的中间体的光学拆分中的用途 | |
TW591025B (en) | Production of the piperazine derivative | |
EP2540717B1 (en) | Lamivudine oxalate and preparation method thereof | |
CN115286571A (zh) | 一种氯喹衍生物及其制备方法 | |
CN104592129A (zh) | 一种改进的制备安立生坦的方法 | |
CN103012261A (zh) | 一种孟鲁司特钠及其中间体的制备方法 | |
CN112125888A (zh) | 一种3-(1-甲基-1h-吡唑-4-基)-6-喹喔啉胺的制备方法 | |
HU195485B (en) | Process for producing aromatic carboxylic acid derivatives and -carboxamide derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20090204 |