CN111518052A - 一种阿考替胺盐酸盐杂质的制备方法 - Google Patents
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- TWHZNAUBXFZMCA-UHFFFAOYSA-N Acotiamide Chemical compound C1=C(OC)C(OC)=CC(O)=C1C(=O)NC1=NC(C(=O)NCCN(C(C)C)C(C)C)=CS1 TWHZNAUBXFZMCA-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229950005462 acotiamide Drugs 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000012535 impurity Substances 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 21
- 238000007112 amidation reaction Methods 0.000 claims abstract description 15
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 15
- 125000002252 acyl group Chemical group 0.000 claims abstract description 14
- XHFUVBWCMLLKOZ-UHFFFAOYSA-N ethyl 2-amino-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC(N)=N1 XHFUVBWCMLLKOZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- KVZUCOGWKYOPID-UHFFFAOYSA-N 2,4,5-Trimethoxybenzoic acid Chemical compound COC1=CC(OC)=C(C(O)=O)C=C1OC KVZUCOGWKYOPID-UHFFFAOYSA-N 0.000 claims abstract description 10
- CURJNMSGPBXOGK-UHFFFAOYSA-N n',n'-di(propan-2-yl)ethane-1,2-diamine Chemical compound CC(C)N(C(C)C)CCN CURJNMSGPBXOGK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 6
- NJPNBZKMVUGMAU-UHFFFAOYSA-N 2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid Chemical compound C1=C(OC)C(OC)=CC(OC)=C1C(=O)NC1=NC(C(O)=O)=CS1 NJPNBZKMVUGMAU-UHFFFAOYSA-N 0.000 claims abstract description 5
- JEPXZNXBEFYVOZ-UHFFFAOYSA-N 2,4,5-trimethoxybenzoyl chloride Chemical compound COC1=CC(OC)=C(C(Cl)=O)C=C1OC JEPXZNXBEFYVOZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical class ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
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- 238000010992 reflux Methods 0.000 claims description 6
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- 238000010438 heat treatment Methods 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
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- PUOIEIREOKNEIS-UHFFFAOYSA-N n-[2-[di(propan-2-yl)amino]ethyl]-2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxamide Chemical compound C1=C(OC)C(OC)=CC(OC)=C1C(=O)NC1=NC(C(=O)NCCN(C(C)C)C(C)C)=CS1 PUOIEIREOKNEIS-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229920006395 saturated elastomer Chemical class 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims 1
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- 238000001291 vacuum drying Methods 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 6
- -1 di-isopropylamino Chemical group 0.000 abstract description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
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- RUBXSZYVSFYJQR-UHFFFAOYSA-N 2-hydroxy-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(O)=C(C(O)=O)C=C1OC RUBXSZYVSFYJQR-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 2
- 229950003102 efonidipine Drugs 0.000 description 2
- UXEGJHFOZNPWPB-UHFFFAOYSA-N ethyl 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC(NC(=O)C=2C(=CC(OC)=C(OC)C=2)O)=N1 UXEGJHFOZNPWPB-UHFFFAOYSA-N 0.000 description 2
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- MDCWDBMBZLORER-UHFFFAOYSA-N triphenyl borate Chemical compound C=1C=CC=CC=1OB(OC=1C=CC=CC=1)OC1=CC=CC=C1 MDCWDBMBZLORER-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NSVFSAJIGAJDMR-UHFFFAOYSA-N 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate Chemical compound CC=1NC(C)=C(C(=O)OCCN(CC=2C=CC=CC=2)C=2C=CC=CC=2)C(C=2C=C(C=CC=2)[N+]([O-])=O)C=1P1(=O)OCC(C)(C)CO1 NSVFSAJIGAJDMR-UHFFFAOYSA-N 0.000 description 1
- 208000028048 Accommodation disease Diseases 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- JOQPDTLREDYNCG-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)OC1=C(C=C(C(=C1)OC)OC)O Chemical compound C(C1=CC=CC=C1)(=O)OC1=C(C=C(C(=C1)OC)OC)O JOQPDTLREDYNCG-UHFFFAOYSA-N 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000002599 gastric fundus Anatomy 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
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- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种阿考替胺盐酸盐杂质的制备方法,将原料2,4,5‑三甲氧基苯甲酸经酰氯化制得2,4,5‑三甲氧基苯甲酰氯,再与2‑氨基‑4‑乙氧基羰基‑1,3‑噻唑经酰胺化反应制得2‑氨基‑4‑乙氧基羰基‑1,3‑噻唑(中间体1);中间体1经氢氧化钠水解得2‑[N‑(2,4,5‑三甲氧基苯甲酰基)氨基]‑4‑羧基‑1,3‑噻唑(中间体2);中间体2先进行酰氯化反应得到酰氯基,然后再与N,N‑二异丙基乙二胺酰胺化反应得到N‑[2‑(双异丙基氨基)乙基]‑2‑[(2,4,5‑三甲氧基苯甲酰)氨基]‑4‑噻唑甲酰胺(阿考替胺),阿考替胺经成盐反应得盐酸阿考替胺。本发明采用上述一种阿考替胺盐酸盐杂质的制备方法,反应条件温和、操作简单、成本低、收率高、适合工业化生产。
Description
技术领域
本发明涉及化合物制备的技术领域,特别是涉及一种阿考替胺盐酸盐杂质的制备方法。
背景技术
盐酸阿考替胺Acotiamide hydrochloride,化学名称为:N-[2-(二异丙基氨基)乙基]-2-[(2-羟基-4,5-二甲氧基苯甲酰)氨基]-1,3-噻唑-4-羧酰胺盐酸盐。结构式如下:
阿考替胺是世界上首个获批的功能性消化不良治疗药,消化不良症状较为普遍并显著降低了患者的生活质量,其中大多数患者具有功能性消化不良(FD)。最新数据显示,西方国家普通人群消化不良症状已接近40%,并显著降低了生活质量。其中小部分人群由胃溃疡引起,可通过根治幽门螺杆菌进行治疗,约20%的有症状人群属于胃食道逆流疾病,可通过质子泵抑制剂有效治疗,但大多数消化不良人群属于FD,对于FD的治疗目前仍具有挑战性。盐酸阿考替胺口服片剂在消化道主要是通过抑制乙酰胆碱酯酶的机制起作用,可促进胃动力、改善胃容纳障碍、增强胃底扩张。最早由日本Zeria新药工业柱式会社研发,后由Astellas制药与Zeria药业在日本共同推出。
目前盐酸阿考替胺的制备方法及类似方法可总结为以下路线:
方案1,采用2,4,5-三甲氧基苯甲酸作为原料与路易斯酸再酯系或酰胺系溶剂中反应得到2-羟基-4,5-二甲氧基苯甲酸。然后以甲苯为溶剂,以浓硫酸作为催化剂回流反应,得到中间体2-羟基-4,5-二甲氧基苯甲酸苯酯。之后将上述中间体与2-氨基4乙氧羰基-1,3-噻唑在硼酸三苯酯存在下,使用甲苯作溶剂,加热反应生成2-[N-(4,5-二甲氧基-2-羟基苯甲酰基)氨基]4(乙氧羰基)-1,3-噻唑,最后与N,N二异丙基乙二胺在甲苯中加热发生酯的胺解生成2-[N-(4,5-二甲氧基-2-羟基苯甲酰基)氨基]-4-[(2-二异丙基氨基乙基)氨基羰基]-1,3-噻唑,再经成盐酸盐操作得到目标化合物。该方法操作较烦,且需要加入三苯基硼酸酯作为反应助剂,此试剂价格贵,不利于工业化生产。
方案2,以2-羟基-4,5-二甲氧基苯甲酸为原料与光气、双光气或三光气在非极性溶剂中反应,生成环状的酸酐中间体。该中间体可不经分离直接与2-氨基4-乙氧羰基-1,3-噻唑反应得到2-[N-(4,5-二甲氧基-2-羟基苯甲酰基)氨基]4(乙氧羰基)-1,3-噻唑。然后与N,N-二异丙基乙二胺在1,4-二氧六环中反应再经过与HCI成盐酸盐反应,可以得到目标产物盐酸阿考替胺。该方法步骤1中采用的光气、双光气剧毒,在工业使用中具有较大的危险性,并且反应时低温控制较为严格,不利于工业化生产。
发明内容
本发明的目的是提供一种阿考替胺盐酸盐杂质的制备方法,反应条件温和、操作简单、成本低、收率高、适合工业化生产。
为实现上述目的,本发明提供了一种阿考替胺盐酸盐杂质的制备方法,包括下述步骤:
(1)将原料2,4,5-三甲氧基苯甲酸经酰氯化制得2,4,5-三甲氧基苯甲酰氯,再与2-氨基-4-乙氧基羰基-1,3-噻唑经酰胺化反应制得2-氨基-4-乙氧基羰基-1,3-噻唑(中间体1);
(2)中间体1经氢氧化钠水解得2-[N-(2,4,5-三甲氧基苯甲酰基)氨基]-4-羧基-1,3-噻唑(中间体2);
(3)中间体2先进行酰氯化反应得到酰氯基,然后再与N,N-二异丙基乙二胺酰胺化反应得到N-[2-(双异丙基氨基)乙基]-2-[(2,4,5-三甲氧基苯甲酰)氨基]-4-噻唑甲酰胺(阿考替胺),阿考替胺经成盐反应得盐酸阿考替胺;
反应路线为:
优选的,步骤(1)的酰氯化反应的氯化试剂是氯化亚砜,催化剂为N,N-二甲基甲酰胺,溶剂为无水甲苯,反应温度为80℃,在搅拌的条件下反应1.5小时,然后降温到40~50℃时减压蒸出溶剂;酰胺化反应是在1,2-二氯乙烷溶剂中进行的,酰胺化反应在搅拌条件下升温,酰胺化反应温度为回流反应,反应时间为6小时,反应完毕后搅拌析晶,析晶的温度为15~25℃,晶体用1,2-二氯乙烷洗涤后晾干,所得晾干后的固体在碱性条件下,用去离子水洗涤,然后真空干燥。
优选的,步骤(2)反应是在甲醇溶剂中进行的,控制温度为0~5℃时滴加氢氧化钠,滴加完毕后升温至室温,反应时间为4~5小时,然后在反应温度为-10~-5℃时滴加盐酸,控制温度为0~5℃调节pH为4左右,搅拌析晶,所得固体用水和乙醇洗涤,在温度为35~45℃的条件下减压干燥12小时以上。
优选的,步骤(3)中酰氯化反应的酰氯化剂为氯化亚砜,所述酰化反应在有机溶剂二氯乙烷溶液中进行,所述酰氯化反应温度为回流反应,反应完毕后减压蒸干二氯乙烷,然后再用乙腈加压带干;酰胺化反应在乙腈溶剂中进行,N,N-二异丙基乙二胺在温度为0℃时滴加,反应温度为室温,所述酰胺化反应时间为5~6小时,反应产物用二氯甲烷和饱和食盐水洗涤,分液后有机相用无水硫酸钠干燥;成盐反应是将所得的阿考替胺溶解到乙腈中,滴加盐酸反应,反应温度控制为10~20℃,盐酸滴加到pH为1~2时为滴加完毕,反应时间为4~5小时,用异丙醚析晶,在温度为40~50℃的条件下减压干燥12小时。
因此,本发明采用上述一种阿考替胺盐酸盐杂质的制备方法反应条件温和、操作简单、成本低、收率高、适合工业化生产。
具体实施方式
下面结合实施例,对本发明进一步描述。实施例中所用各种化学品和试剂如无特别说明均为市售购买。
(1)2-氨基-4-乙氧基羰基-1,3-噻唑(中间体1)的合成
在反应瓶中,将600g 2,4,5-三甲氧基苯甲酸加入到3L无水甲苯中,并在室温下加入250mL氯化亚砜和1.2mL N,N-二甲基甲酰胺,在温度为80℃条件下搅拌反应1.5小时。然后降温到40~50℃,减压蒸出溶剂,在起始阶段,真空度要缓慢上升,预防冲料。然后再用无水甲苯蒸馏两次,每次用量为580mL,蒸馏过程带出多余的氯化亚砜及氯化氢、二氧化硫。
向所得产物中加入5.4L 1,2-二氯乙烷,448g 2-氨基-4-乙氧基羰基-1,3-噻唑,开启搅拌并回流反应6小时。反应完毕后降温到15~25℃,搅拌析晶2~3小时,过滤后用1,2-二氯乙烷洗涤两次,每次用量580mL,所得固体在室温下晾干。晾干后的固体溶解到9.6L的去离子水及2.4L的冰水混合液中,控制温度为0~8℃滴加氢氧化钠溶液,调节pH为7.5。然后在15~25℃搅拌析晶4~5小时,过滤后用2.2L去离子水分两次洗涤。所得固体在真空(-0.1MPa),温度40~50℃条件下干燥6~8小时,得到固体即2-氨基-4-乙氧基羰基-1,3-噻唑(中间体1)910g,收率90%。
(2)2-[N-(2,4,5-三甲氧基苯甲酰基)氨基]-4-羧基-1,3-噻唑的合成(中间体2)
在反应瓶中,加入50g中间体1、100mL甲醇,控制温度为0~5℃时滴加氢氧化钠溶液,滴加完毕后升温至室温反应4~5小时。当HPLC监控原料残留小于0.3%后,降温至-10~-5℃,滴加预先降温的盐酸。然后控温到0~5℃,调节PH为4左右,搅拌析出固体。析晶2~3小时后抽滤,滤饼用5L水和2L乙醇洗涤,在温度为35~45℃条件下减压干燥12小时以上,得到约40g产品即2-[N-(2,4,5-三甲氧基苯甲酰基)氨基]-4-羧基-1,3-噻唑。
(3)盐酸阿考替胺的合成
在氮气氛围下,在三口反应瓶中,加入20g中间体2,8.44g氯化亚砜及200mL的二氯乙烷,搅拌加热升温至弱回流状态,反应完毕后减压蒸干二氯乙烷,再分别加入50mL乙腈加压带干2次,尽量将氯化亚砜全部除去。
然后加入100mL的乙腈,冷却到0℃,滴加9.38g的N,N-二异丙基乙二胺,滴加完毕升至室温反应5~6小时,直至反应完毕。搅拌下加入100mL二氯甲烷,用3L饱和食盐水分两次洗涤,分液,有机相用10g无水硫酸钠干燥12小时。抽滤后滤液减压浓缩干,所得产物加入50mL的乙腈,搅拌溶解,控制温度为10~20℃,滴加盐酸调pH为1~2,滴加完毕后继续搅拌4~5小时,加入100mL异丙醚析晶,在温度为40~50℃的条件下减压干燥12小时以上,得到约18g淡黄色粉末固体即盐酸阿考替胺。
因此,本发明采用上述一种阿考替胺盐酸盐杂质的制备方法,反应条件温和、操作简单、成本低、产品稳定性好、纯度高、收率高、适合工业化生产等特点。
最后应说明的是:以上实施例仅用以说明本发明的技术方案而非对其进行限制,尽管参照较佳实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对本发明的技术方案进行修改或者等同替换,而这些修改或者等同替换亦不能使修改后的技术方案脱离本发明技术方案的精神和范围。
Claims (7)
1.一种阿考替胺盐酸盐杂质的制备方法,其特征在于,包括下述步骤:
(1)将原料2,4,5-三甲氧基苯甲酸经酰氯化制得2,4,5-三甲氧基苯甲酰氯,再与2-氨基-4-乙氧基羰基-1,3-噻唑经酰胺化反应制得2-氨基-4-乙氧基羰基-1,3-噻唑(中间体1);
(2)中间体1经氢氧化钠水解得2-[N-(2,4,5-三甲氧基苯甲酰基)氨基]-4-羧基-1,3-噻唑(中间体2);
(3)中间体2先进行酰氯化反应得到酰氯基,然后再与N,N-二异丙基乙二胺酰胺化反应得到N-[2-(双异丙基氨基)乙基]-2-[(2,4,5-三甲氧基苯甲酰)氨基]-4-噻唑甲酰胺(阿考替胺),阿考替胺经成盐反应得盐酸阿考替胺;
反应路线为:
2.根据权利要求1的一种阿考替胺盐酸盐杂质的制备方法,其特征在于:步骤(1)的酰氯化反应的氯化试剂是氯化亚砜,催化剂为N,N-二甲基甲酰胺,酰氯化反应的溶剂为无水甲苯,反应温度为80℃,在搅拌的条件下反应1.5小时,然后降温到40~50℃时减压蒸出溶剂。
3.根据权利要求2的一种阿考替胺盐酸盐杂质的制备方法,其特征在于:步骤(1)的酰胺化反应在1,2-二氯乙烷溶剂中进行,酰胺化反应在搅拌条件下升温,反应温度为回流反应,反应时间为6小时,反应完毕后搅拌析晶,析晶的温度为15~25℃,晶体用1,2-二氯乙烷洗涤后晾干,所得晾干后的固体在碱性条件下,用去离子水洗涤,然后真空干燥。
4.根据权利要求1的一种阿考替胺盐酸盐杂质的制备方法,其特征在于:步骤(2)反应是在甲醇溶剂中进行的,控制温度为0~5℃时滴加氢氧化钠,滴加完毕后升温至室温,反应时间为4~5小时,然后在反应温度为-10~-5℃时滴加盐酸,控制温度为0~5℃调节pH为4左右,搅拌析晶,所得固体用水和乙醇洗涤,在温度为35~45℃的条件下减压干燥12小时以上。
5.根据权利要求1的一种阿考替胺盐酸盐杂质的制备方法,其特征在于:步骤(3)中酰氯化反应的酰氯化剂为氯化亚砜,酰化反应在有机溶剂二氯乙烷溶液中进行,反应温度为回流反应,反应完毕后减压蒸干二氯乙烷,然后再用乙腈加压带干。
6.根据权利要求5的一种阿考替胺盐酸盐杂质的制备方法,其特征在于:步骤(3)中酰胺化反应在乙腈溶剂中进行,N,N-二异丙基乙二胺在温度为0℃时滴加,反应温度为室温,酰胺化反应时间为5~6小时,反应产物用二氯甲烷和饱和食盐水洗涤,分液后有机相用无水硫酸钠干燥。
7.根据权利要求6的一种阿考替胺盐酸盐杂质的制备方法,其特征在于:步骤(3)成盐反应为将所得的阿考替胺溶解到乙腈中,滴加盐酸反应,反应温度控制为10~20℃,盐酸滴加到pH为1~2时为滴加完毕,反应时间为4~5小时,用异丙醚析晶,在温度为40~50℃的条件下减压干燥12小时。
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