CN116891420A - 一种碘普罗胺杂质d的合成方法 - Google Patents
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- DGAIEPBNLOQYER-UHFFFAOYSA-N iopromide Chemical compound COCC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I DGAIEPBNLOQYER-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 229960002603 iopromide Drugs 0.000 title claims abstract description 40
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000001308 synthesis method Methods 0.000 title claims description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 239000011347 resin Substances 0.000 claims abstract description 9
- 229920005989 resin Polymers 0.000 claims abstract description 9
- -1 N-methyl-N- (2, 3-dihydroxypropyl) -5-chloroformyl-3- (2-methoxyacetamido) -2,4, 6-triiodobenzamide Chemical compound 0.000 claims abstract description 8
- 239000012043 crude product Substances 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 5
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000001099 ammonium carbonate Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 3
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims 1
- 150000008041 alkali metal carbonates Chemical class 0.000 claims 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
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- 238000002360 preparation method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000007142 ring opening reaction Methods 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/27—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms
- C07D301/30—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms by reaction with carboxyl radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
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Abstract
一种碘普罗胺杂质D的合成方法,通过将碘普罗胺与环氧氯丙烷进行烃化反应得到杂质D中间体1,然后杂质D中间体1与氨水反应得到碘普罗胺杂质D中间体2,再用N‑甲基‑N‑(2,3‑二羟基丙基)‑5‑氯甲酰基‑3‑(2‑甲氧基乙酰胺基)‑2,4,6‑三碘苯甲酰胺酰化杂质D中间体2得到碘普罗胺杂质D粗品,经大孔树脂纯化、溶剂结晶得到碘普罗胺杂质D。
Description
技术领域
本发明涉及一种碘普罗胺杂质D的合成方法,属于医药化学领域。
背景技术
碘普罗胺(Iopromide),商品名为优维显(Ultravist),是由德国先灵(Schering)公司开发,于1985年首次在德国上市,临床用作X-射线造影剂,包含2,4,6-三碘-5-酰氨基-1,3-间苯二酰胺的母体结构,为中性、非离子型化合物。碘普罗胺具有水溶性大、造影增强效果好、毒性较低、耐受性较好等优点,广泛用于数字减影血管造影、尿路、肾动脉、心室、胃肠等造影以及CT扫描等。碘普罗胺具有良好的安全性,在全球造影剂市场中销售额位于前列,但是严重的不良反应仍时有发生。不良反应除与碘普罗胺自身的药理活性有关外,与碘普罗胺中存在的杂质也有密切关系。因此药物研究人员不仅要开发高效的合成工艺以获得高质量的原料药,同时也要研究原料药中杂质的结构来源并控制工艺杂质的产生。制备足够的杂质对照品,以保证每批原料药质量检测工作的开展(如杂质HPLC定性分析、定量分析等)也是必须且重要的工作。
目前文献中报道的碘普罗胺杂质(如欧洲药典EP9.0版p2798-2801)主要有杂质A-G,其中杂质D的获得方法主要是通过制备液相色谱富集并提纯碘普罗胺粗品中的杂质D。由于杂质D在碘普罗胺粗品含量很少,通常只有0.2-0.3%,因此需要大量的碘普罗胺粗品,制备过程中使用的有机溶剂量巨大,操作繁琐,需要消耗很多人工时间,使得杂质D的制备成本很高。
发明内容
为解决现有碘普罗胺杂质D制备方法的不足,本公司开发了一种碘普罗胺杂质D的合成方法,即将碘普罗胺与环氧氯丙烷进行烃化反应,再与氨发生开环反应得到碘普罗胺杂质D中间体2,最后酰化杂质D中间体2,得到碘普罗胺杂质D。合成路线如下:
步骤1:碘普罗胺与环氧氯丙烷在碱性条件下进行烃化反应得到中间体1。所述碱性条件使用的碱包括氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、甲醇钠、乙醇钠、叔丁醇钠和叔丁醇钾,可以单独使用其中一种作为碱性试剂,也可以组合使用。溶剂为极性溶剂,包括水、甲醇、乙醇、二甲基甲酰胺和二甲基乙酰胺,可以使用单一溶剂或上述溶剂的混合溶剂。
步骤2:中间体1与氨进行开环反应,得到中间体2。氨的来源包括氨水、碳酸铵和碳酸氢铵。
步骤3:中间体2与N-甲基-N-(2,3-二羟基丙基)-5-氯甲酰基-3-(2-甲氧基乙酰胺基)-2,4,6-三碘苯甲酰胺进行酰化反应,得到碘普罗胺杂质D,粗品经大孔树脂柱纯化,溶剂结晶得到碘普罗胺杂质D。
在步骤1中杂质D中间体1在碱性条件下稳定性较差,会产生一定量的开环副产物,如下式:
该开环副产物不与氨反应,与N-甲基-N-(2,3-二羟基丙基)-5-氯甲酰基-3-(2-甲氧基乙酰胺基)-2,4,6-三碘苯甲酰胺进行反应的可能性也较低,因此在反应过程中未与杂质D中间体进行分离,在步骤3大孔树脂纯化过程中去除。
大孔树脂选用苯乙烯型非离子大孔树脂,如XAD-1600、三菱HP-825等型号。杂质D结晶采用醇类溶剂,如甲醇、乙醇和异丙醇。
通过实施例对本发明作进一步说明,除以下实施例外,根据本领域普通技术知识和惯用手段做出的各种替换或变更,均包括在本发明的范围内。
具体实施例
实施例1:
步骤1:在反应瓶中,加入碘普罗胺20g、2mol/L氢氧化钾水溶液50ml,环氧氯丙烷4.2ml,保温30-40℃搅拌反应8小时。加入水50ml,二氯甲烷50ml,搅拌分层,将二氯甲烷层用水50ml提取1次,合并水层,直接投下一步反应。
步骤2:向步骤1得到的水溶液中,加入氨水20ml,20-30℃反应2小时,将反应液浓缩至干,加入甲醇150ml,加热50-60℃搅拌溶解,趁热过滤,滤液浓缩至干直接投下一步反应。
步骤3:用二甲基乙酰胺100ml溶解剩余物,加入碳酸钾4.5g,N-甲基-N-(2,3-二羟基丙基)-5-氯甲酰基-3-(2-甲氧基乙酰胺基)-2,4,6-三碘苯甲酰胺18.2g,20-30℃反应4小时,过滤,滤液用高真空浓缩,剩余物用水100ml溶解,加入活性炭1.0g室温脱色半小时,过滤,滤液通过装有XAD1600型的大孔树脂柱纯化,用水→10%甲醇水溶液→50%甲醇水溶液梯度洗脱,收集含有杂质D的馏分,浓缩后依次用阳离子树脂和阴离子树脂脱盐,脱盐后的溶液浓缩至干,加入无水乙醇50ml共沸,剩余物再加入无水乙醇100ml,回流4小时,10-20℃结晶2小时,得到碘普罗胺杂质D 6.8g,纯度96.86%。
实施例2:
步骤1:在反应瓶中,加入甲醇100ml和甲醇钠1.5g,搅拌溶解后再加入碘普罗胺20g和环氧氯丙烷2.6ml、保温30-40℃搅拌反应5小时。加入水50ml,二氯甲烷50ml,搅拌分层,将二氯甲烷层用水50ml提取1次,合并水层,直接投下一步反应。
步骤2:向步骤1得到的水溶液中,加入碳酸铵19.3g,20-30℃反应5小时,将反应液浓缩至干,加入甲醇150ml,加热50-60℃搅拌溶解,趁热过滤,滤液浓缩至干直接投下一步反应。
步骤3:用二甲基乙酰胺100ml溶解剩余物,加入碳酸钾4.5g,N-甲基-N-(2,3-二羟基丙基)-5-氯甲酰基-3-(2-甲氧基乙酰胺基)-2,4,6-三碘苯甲酰胺18.2g,20-30℃反应4小时,过滤,滤液用高真空浓缩,后续纯化过程与实施例1步骤3相同,得到碘普罗胺杂质D4.6g,纯度95.32%。
实施例3:
步骤1:在反应瓶中,加入碘普罗胺20g、碳酸钾7.0g和二甲基乙酰胺50ml,保温20-30℃搅拌反应20小时。过滤,将滤液减压浓缩至干,剩余物加水50ml溶解后直接投下一步反应。
步骤2:向步骤1得到的水溶液中,加入碳酸氢铵17.0g,20-30℃反应2小时,将反应液浓缩至干,加入甲醇150ml,加热50-60℃搅拌溶解,趁热过滤,滤液浓缩至干直接投下一步反应。
步骤3:用二甲基乙酰胺100ml溶解剩余物,加入碳酸钾4.5g,N-甲基-N-(2,3-二羟基丙基)-5-氯甲酰基-3-(2-甲氧基乙酰胺基)-2,4,6-三碘苯甲酰胺18.2g,20-30℃反应4小时,过滤,滤液用高真空浓缩,后续纯化过程与实施例1步骤3相同,得到碘普罗胺杂质D7.5g,纯度96.22%。
本发明通过定向合成杂质D,可以简便地得到杂质对照品,制备相同数量杂质D所需要的碘普罗胺原料药用量相比制备色谱降低99%以上,有机溶剂消耗量和人工时间也极大降低,为碘普罗胺质量分析和控制提供了保障。
Claims (4)
1.一种碘普罗胺杂质D的合成方法,其特征是通过如下化学反应合成制得:
步骤1:将碘普罗胺与环氧氯丙烷进行烃化反应得到杂质D中间体1;步骤2:杂质D中间体1与氨水反应得到碘普罗胺杂质D中间体2;
步骤3:用N-甲基-N-(2,3-二羟基丙基)-5-氯甲酰基-3-(2-甲氧基乙酰胺基)-2,4,6-三碘苯甲酰胺酰化杂质D中间体2得到碘普罗胺杂质D粗品,经大孔树脂纯化、溶剂结晶得到碘普罗胺杂质D;
合成路线如下:
2.如权利要求1所述,步骤1中所述碱性条件使用的碱为碱金属氢氧化物、碱金属碳酸盐和碱金属醇化物,包括氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、甲醇钠、乙醇钠、叔丁醇钠和叔丁醇钾,可以单独使用其中一种作为碱性试剂,也可以组合使用。
3.如权利要求1所述,步骤1中溶剂为极性溶剂,包括水、甲醇、乙醇、二甲基甲酰胺和二甲基乙酰胺。
4.如权利要求1所述,步骤2中氨的来源包括氨水、碳酸铵和碳酸氢铵。
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