CN116143756A - 一种托匹司他的制备方法 - Google Patents
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- UBVZQGOVTLIHLH-UHFFFAOYSA-N 4-[5-pyridin-4-yl-1h-[1,2,4]triazol-3-yl]-pyridine-2-carbonitrile Chemical compound C1=NC(C#N)=CC(C=2N=C(NN=2)C=2C=CN=CC=2)=C1 UBVZQGOVTLIHLH-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 229950004176 topiroxostat Drugs 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000012535 impurity Substances 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000013078 crystal Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 17
- 238000004537 pulping Methods 0.000 claims abstract description 16
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 239000012043 crude product Substances 0.000 claims abstract description 10
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 9
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 9
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- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims abstract description 7
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 7
- 230000035772 mutation Effects 0.000 claims abstract description 7
- 239000000047 product Substances 0.000 claims abstract description 7
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- 238000003756 stirring Methods 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
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- 238000001035 drying Methods 0.000 claims description 19
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- 150000003839 salts Chemical class 0.000 claims description 9
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- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 6
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 5
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
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- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 8
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- 235000019441 ethanol Nutrition 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 231100000219 mutagenic Toxicity 0.000 description 5
- 230000003505 mutagenic effect Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- HCEPIFBYVFRGOI-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;4-(5-pyridin-4-yl-1h-1,2,4-triazol-3-yl)pyridine-2-carbonitrile Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.C1=NC(C#N)=CC(C=2NN=C(N=2)C=2C=CN=CC=2)=C1 HCEPIFBYVFRGOI-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 201000001431 Hyperuricemia Diseases 0.000 description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 2
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 108010093894 Xanthine oxidase Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 229940116269 uric acid Drugs 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 102100033220 Xanthine oxidase Human genes 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 238000006386 neutralization reaction Methods 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于托匹司他技术领域,其公开了一种托匹司他的制备方法,包括以下步骤:化合物IV先与水合肼缩合生成化合物III,然后与化合物V反应生成化合物II,化合物II环合为托匹司他I粗品,托匹司他I粗品与有机磺酸成盐,再通过碳酸钾解盐,解盐过程中添加一定量的金属离子络合剂以除去残余重金属离子,然后经过水打浆和与水混溶的溶剂打浆得到I晶型托匹司他。该制备方法既可有效地控制生产过程中生成的多个致突变警示结构杂质,又可显著降低氰基水解杂质的生成,提高了产品质量,生产过程简洁,收率高,成本低,适合工业化生产。
Description
技术领域
本发明属于托匹司他技术领域,具体涉及一种用于治疗高尿酸血症和痛风的托匹司他的制备方法。
背景技术
托匹司他(Topiroxostat,FYX-051,I)是由日本富士药品株式会社和三和化学共同研发的新一代抗高尿血酸和痛风的药物,为非嘌呤类黄嘌呤氧化酶抑制剂,对氧化型和还原型的黄嘌呤氧化酶均有抑制作用,抑制尿酸的生成,的抗痛风症药物秋水仙碱、非甾体类抗炎药等,本品具有降低尿酸作用强、不良反应少、安全性好等优点。
2013年6月23日,托匹司他片在日本获批上市,托匹司他化学名为5-(2-氰基-4-吡啶基)-3-(4-吡啶基)-1,2,4-三唑,结构式如下:
托匹司他制备主要采用如下两种方式:
方式一(化合物II不单离):
日本株式会社富士药品申请专利CN1561340B公开的制备方法中,化合物III和化合物V缩合后的中间体II未经分离,直接环合制备托匹司他,该方式的缺点是:氰基水解风险高,致突变警示结构杂质残留风险高,不利于工业化生产的质量控制。其中主要杂质II、III、A、B、C、D、E、F和G等是影响托匹司他质量的主要杂质,需要严格控制。
主要氰基水解杂质A产生途径如下:
主要致突变警示结构杂质II、III、B、C、D、E、F和G引入途径如下:
方式二(化合物II单离):
专利CN105294656公开的制备方法中,化合物II单离出来的滤饼用酸洗涤,明显降低了氰基水解杂质含量,对该步骤前生成的致突变杂质及其衍生杂质有一定的清除效果,但对后续步骤生成的其他致突变杂质的清除尚需采取进一步的措施。
托匹司他的精制主要有两种方式:
一是采用重结晶的方式,专利CN104411700B使用有机溶剂(包括多种醇类、酰胺类、醚类、酯类、烷烃和芳香烃等中的一种或多种组合)重结晶制备II晶型托匹司他,专利CN107778292使用乙酸乙酯和醇类的混合溶剂重结晶,虽然有较好的精制效果,但所得为II晶型托匹司他,不能直接获得药用I晶型,尚需进一步转晶。
二是采用成盐解盐的方式,专利CN104411700B使用托匹司他对甲苯磺酸盐,用碱处理,再用酸中和,此种方式所得为药用I晶型托匹司他,由于精制过程不可避免的使用了醇类溶剂,有可能生成对甲苯磺酸酯类致突变杂质,其后处理方式仅采用水淋洗滤饼,致突变警示结构杂质残余风险高,不利于杂质控制。
发明内容
发明目的
本发明提供一种既可有效地控制生产过程中生成的多个致突变杂质,又可显著降低氰基水解杂质生成的方法,提高了产品质量,生产过程简洁,收率较高,适合工业化生产。
技术方案
为了实现上述发明的目的,本发明采用如下的技术方案:
一种托匹司他的制备方法,其特征在于如下实现步骤:
(1)化合物IV在溶剂中,与水合肼发生反应,生成化合物III;
(2)化合物III与化合物V在甲醇钠作用下生成化合物II;
(3)化合物II发生环合反应得到托匹司他I粗品;
(4)托匹司他I粗品精制得到成品托匹司他。
所述步骤(1)中所用水合肼与化合物IV的摩尔比为2:1~7:1;向反应釜中搅拌下依次加入乙醇、化合物IV,控温20~30℃;滴加80%水合肼;滴毕,20~30℃搅拌反应1.5h,降温至-10~-5℃搅拌2h,离心,打浆,用乙醇洗涤。
所述步骤(2)中,化合物III、化合物V和甲醇钠的摩尔比为为1:1:0.05~1:1.2:0.1;依次加入甲醇和化合物V,控温25~30℃,搅拌下缓慢加入甲醇钠,0~10℃搅拌3h,加入化合物III;控温0~10℃保温搅拌6h,反应毕,加入无水甲醇与纯化水混合溶液,控温20~30℃,保温搅拌3h离心。
所述步骤(3)中,向反应釜中搅拌下依次加入甲醇、纯化水和化合物II,升温至85℃搅拌5h,降温至20~30℃,保温搅拌3h,离心干燥后得10kg托匹司他I粗品。
所述步骤(4)中,精制过程包括如下步骤实现:
a、托匹司他I粗品在溶剂中于一定温度下与有机磺酸成盐;
b、托匹司他有机磺酸盐在溶剂中于一定温度下用碳酸钾解盐,解盐过程中添加一定量的金属离子络合剂;
c、解盐后的滤饼分别用水和与水混溶的溶剂打浆,打浆后滤饼在一定温度下干燥得到I晶型托匹司他(化合物I)。
其中:
所述步骤a中,反应溶剂为水和异丙醇或2-丁醇,所述的有机磺酸包括但不限于萘磺酸、樟脑磺酸。有机磺酸与托匹司他I粗品的摩尔比为为1:1~3:1,优选2:1;反应温度为40~80℃。
所述步骤b中,反应溶剂为乙醇和水,金属离子络合剂为EDTA-2Na,所述的EDTA-2Na与托匹司他有机磺酸盐摩尔比为0.0005:1~0.005:1,优选0.001:1~0.002:1;反应温度为20~40℃,优选25~30℃。
所述步骤c中,与水混溶的溶剂为异丙醇;所述的干燥温度为70~90℃,优选75~80℃;干燥时间为10~50小时,优选15~25小时。
精制获得托匹司他的晶体为晶型I,致突变警示结构杂质单个杂质不超过9ppm,其他一般单个杂质不超过0.10%,纯度不低于99.8%。
有益效果
本发明所述的制备方法与现有工艺相比,具有如下优点:
1.通过单离出化合物II提高了对杂质的过程控制效率;
2.在精制过程中选择结构较大的萘磺酸、樟脑磺酸与托匹司他成盐,大位
阻的萘磺酸、樟脑磺酸更难以与位阻较大的异丙醇或2-丁醇反应生成致突变的磺酸酯杂质,可以有效地避免磺酸酯杂质的引入;
3.通过添加EDTA-2Na络合残余金属离子,既可避免重金属超限风险,又可避免金属离子催化而导致氰基水解杂质生成;
4.解盐之后的托匹司他分别采用水和异丙醇打浆,水可除去残余无机盐杂
质,异丙醇的使用既可提高对致突变警示结构杂质的精制效果,又可提高干燥效率,显著减少干燥时间,进一步降低了氰基水解风险,同时,所得产品没有发生转晶,仍为药用I晶型晶体;
5.本发明整个工艺过程可有效地控制生产过程中生成的多个致突变警示
结构杂质和氰基水解杂质,提高了产品质量,生产过程简洁,收率高,成本低,适合工业化生产。
附图说明
图1为实施例1托匹司他XRD图谱;
图2为实施例1托匹司他HPLC图谱;
图3为实施例3托匹司他HPLC图谱。
具体实施方式
下面对本发明的实施例作详细说明,本实施例在以本发明技术方案为前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施例。
实施例1
化合物III的制备:
向反应釜中搅拌下依次加入乙醇、13kg(80.2mol)化合物IV,控温20~30℃滴加80%水合肼12.4kg(308.4mol);滴毕,20~30℃搅拌反应1.5h,降温至-10~-5℃搅拌2h,离心,打浆,用乙醇洗涤、干燥后得8.01kg(49.4mol)黄色粉末状化合物III,收率61.6%。
化合物II的制备:
向反应釜中搅拌下依次加入甲醇和5.4kg(52.3mol)化合物V,控温25~30℃,搅拌下缓慢加入甲醇钠,0~10℃搅拌3h,加入8kg(49.3mol)化合物III;控温0~10℃保温搅拌6h,反应毕,加入无水甲醇2与纯化水1混合溶液,控温20~30℃,保温搅拌3h离心,滤饼纯化水淋洗,干燥后得11.9kg化合物II,收率90.3%。
化合物I粗品的制备:
向反应釜中搅拌下依次加入甲醇、纯化水和11.5kg(41.2mol)化合物II,升温至85℃搅拌5h,降温至20~30℃,保温搅拌3h,离心,滤饼用纯化水淋洗,干燥后得10kg托匹司他I粗品,收率93.7%。
托匹司他I的制备:
向反应釜中搅拌下依次加入异丙醇、纯化水、10kg(40.3mol)托匹司他I粗品和10.1kg(48.3mol)萘磺酸,回流,保温搅拌0.5h,缓慢降温至20~30℃,搅拌3h,离心,用异丙醇和水打浆,离心干燥后得16.1kg(35.3mol)托匹司他萘磺酸盐,收率87.6%。
向反应釜中搅拌下依次加入乙醇、纯化水、11.5kg(83.3mol)无水碳酸钾,控温20~30℃溶清,加入16kg(33.3mol)托匹司他萘磺酸盐,搅拌溶清,加入112g(0.333mol)EDTA-2Na和活性炭浆,搅拌脱色0.5h,压滤,控温20~30℃,滤液中快速滴加6M盐酸调节pH值至6.5~7.0,继续搅拌5h,离心,滤饼用纯化水打浆,滤饼用异丙醇打浆,于75~80℃干燥后得7.8kg(31.4mol)I晶型托匹司他I,收率94.4%。XRD图谱见图1,所得产品为I晶型托匹司他;HPLC图谱见图2,托匹司他纯度99.97%,杂质A未检出。所有致突变杂质均未检出。
实施例2
托匹司他I的制备:
向反应釜中搅拌下依次加入2-丁醇、纯化水、100g(0.403mol)托匹司他I粗品和102.2g(0.44mol)樟脑磺酸,于80℃保温搅拌1h,缓慢降温至25~30℃,搅拌3h,离心,滤饼中加入2-丁醇和水打浆,离心,80℃干燥后得159g(0.331mol)托匹司他樟脑磺酸盐,收率82.1%。
向反应釜中搅拌下依次加入乙醇、纯化水、114g(0.828mol)无水碳酸钾,控温20~30℃溶清,加入159g(0.331mol)托匹司他樟脑磺酸盐,搅拌溶清,加入1.1g(0.0033mol)EDTA-2Na和活性炭浆,搅拌脱色0.5h,压滤,控温20~30℃,滤液中加入6M盐酸调节pH值至6.5~7.0,继续搅拌5h,离心,滤饼用纯化水打浆,滤饼用异丙醇打浆,于80℃干燥后得76.7g(0.309mol)I晶型托匹司他I,收率93.3%。所有致突变杂质均未检出。
实施例3
发明人重复专利CN104411700工艺的对比实施例如下所述:
化合物III的制备:
10g(0.062mol)化合物IV中加入甲醇,再加入80%水合肼2.7g(0.068mol),氮气氛围下室温搅拌2h,减压蒸除溶剂,加入氯仿,室温搅拌1h,过滤,氯仿洗涤后真空干燥得4.17g(0.026mol)化合物III,收率41.7%。
化合物I粗品的制备:
2.77g(0.027mol)化合物V溶于甲醇中,加入0.86g(0.016mol)甲醇钠,室温下搅拌1h,加入4g(0.025mol)化合物III,回流反应40h,反应结束后,过滤,甲醇洗涤滤饼,真空干燥得3.68g(0.015mol)化合物I粗品,收率60%。
发明人重复专利CN104411700工艺的对比实施例如下所述:
托匹司他I的制备:
向反应釜中搅拌下依次加入2-丁醇、纯化水、100g(0.403mol)托匹司他I粗品和83.7g(0.44mol)对甲苯磺酸一水合物,于80℃保温搅拌1h,缓慢降温至25~30℃,离心,滤饼用2-丁醇和水淋洗,离心干燥后得145g(0.345mol)托匹司他对甲苯磺酸盐,收率85.6%。
向反应釜中搅拌下依次加入乙醇、纯化水、120g(0.87mol)无水碳酸钾,控温20~30℃溶清,加入145g(0.345mol)托匹司他对甲苯磺酸盐,搅拌溶清,加入活性炭浆,搅拌脱色0.5h,压滤,控温20~30℃,滤液中加入6M盐酸2.2L,继续搅拌5h,离心,滤饼用纯化水洗涤,于80℃干燥后得79.4g(0.32mol)I晶型托匹司他I,收率92.8%。HPLC图谱见图3,托匹司他I纯度99.769%,杂质A为0.071%,杂质II含量0.059%。
Claims (7)
2.根据根据权利要求1所述的一种托匹司他的制备方法,其特征在于所述步骤(1)中所用水合肼与化合物IV的摩尔比为2:1~7:1;向反应釜中搅拌下依次加入乙醇、化合物IV,控温20~30℃;滴加80%水合肼;滴毕,20~30℃搅拌反应1.5h,降温至-10~-5℃搅拌2h,离心,打浆,用乙醇洗涤。
3.根据权利要求1所述的托匹司他的制备方法,其特征在于所述步骤(2)中,化合物III、化合物V和甲醇钠的摩尔比为为1:1:0.05~1:1.2:0.1;依次加入甲醇和化合物V,控温25~30℃,搅拌下缓慢加入甲醇钠,0~10℃搅拌3h,加入化合物III;控温0~10℃保温搅拌6h,反应毕,加入无水甲醇与纯化水混合溶液,控温20~30℃,保温搅拌3h离心。
4.根据根据权利要求1所述的托匹司他的制备方法,其特征在于所述步骤(3)中,向反应釜中搅拌下依次加入甲醇、纯化水和化合物II,升温至85℃搅拌5h,降温至20~30℃,保温搅拌3h,离心干燥后得10kg托匹司他I粗品。
5.根据权利要求1所述的托匹司他的制备方法,其特征在于所述步骤(4)中,精制过程包括如下步骤实现:
a、托匹司他I粗品在溶剂中与有机磺酸成盐;
b、托匹司他有机磺酸盐在溶剂中于用碳酸钾解盐,解盐过程中添加金属离子络合剂;
c、解盐后的滤饼分别用水和与水混溶的溶剂打浆,打浆后滤饼在干燥得到I晶型托匹司他I。
6.根据权利要求5所述的托匹司他的制备方法,其特征在于:
所述步骤a中,反应溶剂为水和异丙醇或2-丁醇,所述的有机磺酸包括萘磺酸、樟脑磺酸;有机磺酸与托匹司他I粗品的摩尔比为为1:1~3:1;反应温度为40~80℃;
所述步骤b中,反应溶剂为乙醇和水,金属离子络合剂为EDTA-2Na,所述的EDTA-2Na与托匹司他有机磺酸盐摩尔比为0.0005:1~0.005:1;反应温度为20~40℃;
所述步骤c中,与水混溶的溶剂为异丙醇;所述的干燥温度为70~90℃;干燥时间为10~50小时。
7.如权利要求6所述的托匹司他的制备方法,其特征在于获得精制的托匹司他的晶体为晶型I,致突变警示结构单个杂质不超过9ppm,其他一般单个杂质不超过0.10%,纯度不低于99.8%。
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