CN113912510A - 一种甲氧氯普胺双氯新杂质和用途 - Google Patents
一种甲氧氯普胺双氯新杂质和用途 Download PDFInfo
- Publication number
- CN113912510A CN113912510A CN202111156246.4A CN202111156246A CN113912510A CN 113912510 A CN113912510 A CN 113912510A CN 202111156246 A CN202111156246 A CN 202111156246A CN 113912510 A CN113912510 A CN 113912510A
- Authority
- CN
- China
- Prior art keywords
- metoclopramide
- impurity
- new
- dichlorine
- formula
- 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.)
- Granted
Links
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229960004503 metoclopramide Drugs 0.000 title claims abstract description 43
- 239000012535 impurity Substances 0.000 title claims abstract description 42
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 15
- 239000000126 substance Substances 0.000 claims abstract description 6
- 239000013558 reference substance Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000001514 detection method Methods 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 7
- 238000010828 elution Methods 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 claims description 2
- 239000008055 phosphate buffer solution Substances 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000003908 quality control method Methods 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000007787 solid Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000012071 phase Substances 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- YTNLUMMYZOKSNG-UHFFFAOYSA-N 4-amino-3,5-dichloro-2-methoxybenzoic acid Chemical compound COC1=C(Cl)C(N)=C(Cl)C=C1C(O)=O YTNLUMMYZOKSNG-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 4
- SEHADVWVUBOTQB-UHFFFAOYSA-N 4-amino-3,5-dichloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide Chemical compound CCN(CC)CCNC(C(C=C(C(N)=C1Cl)Cl)=C1OC)=O SEHADVWVUBOTQB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- YJSYOVSDBWOVAD-UHFFFAOYSA-N methyl 4-acetamido-3,5-dichloro-2-methoxybenzoate Chemical compound COC(=O)C1=CC(Cl)=C(NC(C)=O)C(Cl)=C1OC YJSYOVSDBWOVAD-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229910052788 barium Inorganic materials 0.000 description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- UQKAOOAFEFCDGT-UHFFFAOYSA-N n,n-dimethyloctan-1-amine Chemical compound CCCCCCCCN(C)C UQKAOOAFEFCDGT-UHFFFAOYSA-N 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- DEWLEGDTCGBNGU-UHFFFAOYSA-N 1,3-dichloropropan-2-ol Chemical compound ClCC(O)CCl DEWLEGDTCGBNGU-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000015163 Biliary Tract disease Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 1
- 206010015137 Eructation Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033649 Pancreatitis chronic Diseases 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 208000027687 belching Diseases 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 201000003152 motion sickness Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/047—Standards external
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Library & Information Science (AREA)
- Engineering & Computer Science (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明首次公开了一种甲氧氯普胺双氯新杂质,且制备得到的甲氧氯普胺双氯新杂质纯度大于99%,可以作为对照品用于甲氧氯普胺的质量研究,该杂质在甲氧氯普胺或其盐的原料药、制剂有关物质检测时作为杂质对照品,实现了对甲氧氯普胺更为严格的质量控制。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种甲氧氯普胺双氯新杂质和用途。
背景技术
甲氧氯普胺,又名氯普胺,英文名为metoclopramide,分子式是C14H22ClN3O2,分子量为299.7964,CAS登记号为364-62-5,白色至淡黄色结晶性粉末,有强大的中枢性镇吐作用。
甲氧氯普胺可用于因脑部肿瘤手术、肿瘤的放疗及化疗、脑外伤后遗症、急性颅脑损伤以及药物所引起的呕吐。对于胃胀气性消化不良、食欲不振、嗳气、恶心、呕吐也有较好的疗效,也可用于海空作业引起的呕吐及晕车(船)。除此之外,甲氧氯普胺亦可减轻钡餐检查时的恶心、呕吐反应,促进钡剂通过;或十二指肠插管前服用,有助于顺利插管;或用于胆道疾病和慢性胰腺炎的辅助治疗。
申请人采用的甲氧氯普胺原料药合成路线如下:
在合成过程中发现有未知的杂质,通过对IM2物料的结晶和母液分离富集,得到一个全新的杂质,如式I所示。
在新药研发过程中,药物的杂质含量将直接影响到药物的疗效和毒副作用,因此控制杂质限度、提高纯度对于保证药物的安全性、有效性和质量可控性至关重要。故本发明对甲氧氯普胺的新杂质作了进一步的结构确证,也开发了合适的检测方法并制定杂质限度,以便实现对药物更严格的质量控制。
发明内容
本发明要解决的技术问题是:提供一种甲氧氯普胺双氯新杂质,其结构如式Ⅰ所示:
发明人推测,上述杂质应当是在原料药合成路线中,通过氯代反应制备化合物SM1步骤中,发生了双氯代反应;后续又继续发生酯水解、缩合酰化反应得到;
本发明的第二方面提供了一种式I化合物在甲氧氯普胺或其盐的原料药、制剂有关物质检测时作为杂质对照品的用途。
本发明的第三方面提供了一种上述甲氧氯普胺双氯新杂质的检测方法,其色谱条件为:用辛烷基硅烷键合硅胶为填充剂;用磷酸盐缓冲液为流动相A,用乙腈为流动相B,优选用 0.050mol/L磷酸二氢钾溶液(加入0.2ml N,N-二甲基辛胺,用磷酸调节pH至4.0)为流动相 A;梯度洗脱;流速1ml/min;检测波长275nm;柱温为35℃。
进一步的,所述梯度洗脱程序如下:
时间(min) | 流动相A(%) | 流动相B(%) |
0 | 92 | 8 |
10 | 92 | 8 |
15 | 90 | 10 |
40 | 70 | 30 |
45 | 70 | 30 |
46 | 92 | 8 |
55 | 92 | 8 |
本发明中化合物的中文命名与结构式有冲突的,以结构式为准;结构式有明显错误的除外。
本发明首次公开了一种甲氧氯普胺双氯新杂质,制备得到的新杂质纯度大于99%,可作为甲氧氯普胺有关物质检测时的杂质对照品,有效监控甲氧氯普胺中的杂质含量,从而保证了甲氧氯普胺的安全性和有效性;
另外,常规HPLC检测方法不利于区分该杂质和甲氧氯普胺,从而易忽视该新杂质,因此即使甲氧氯普胺中的未知杂质均降至0.1%以下,也不能说明合成甲氧氯普胺的过程中未生成该杂质,更不可认为甲氧氯普胺与该杂质已完全分离,因此本发明开发的检测方法对于甲氧氯普胺双氯新杂质的检测具有明显优势。
附图:
图1:甲氧氯普胺双氯新杂质式I化合物的质谱图;
图2:甲氧氯普胺双氯新杂质式I化合物的氢谱图。
具体实施方式
以下结合实例说明本发明,但不限制本发明。在本领域内,技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案内。
实施例1:
(1)4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)
向三颈瓶中加入式II化合物(36g,0.14mol),DMF100mL,NCS(37.4g,0.28mol)加热至内温85℃,保温反应5小时,后处理将反应液倒入冰水中,用EA萃取100mL×3次,合并有机相用水洗100mL×2次,分液,无水硫酸钠干燥,浓缩得黄色固体30.2g,用THF/PE 5:16 重结晶,得23.6g类白色固体,收率57.9%,mp:137-139℃,ESI-MS(m/z):291.98[M+H]+。
(2)2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)
向250ml四颈瓶中加入4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)(20.0g, 0.069mol),乙醇20mL,水100ml,氢氧化钠(8.7g,0.22mol),升温至回流,反应3小时。停止加热,反应液转移至500ml瓶中,搅拌下开始滴加1M盐酸,调节pH至5左右,降温至12℃以下搅拌30min,抽滤,滤饼重新加100ml水,20℃以下打浆30min,抽滤,用20mL 水洗涤容器和滤饼,80℃烘干得15g粗品,粗品收率92.9%。
上述固体加242mL无水乙醇和45mL水加热直至溶清,关闭加热缓慢降温析晶,降温至 20℃以下搅拌3小时,抽滤,滤饼用20mL85%乙醇洗涤,80℃烘干得白色晶体12g,收率74.3%,HPLC纯度为99.8%。m.p.255℃分解,ESI-MS(m/z):258.01[M+Na]+。
(3)N-(2-二乙氨基乙基)-2-甲氧基-3,5-二氯-4-氨基苯甲酰胺(式I)
向250mL三颈瓶中加入2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)(9.6g,40.85mmol),CDI (7.23g,44.63mmol),DCM 100mL,加热至内温35℃,保温反应1.5小时,加入N,N-二乙基乙二胺(5.18g,44.63mmol),回流1.5小时。后处理向瓶内补加100mL DCM稀释反应液,另加水20mL×3洗涤有机相,分液,无水硫酸钠干燥,浓缩得淡黄色油状物10.1g,收率 74.5%,HPLC纯度为99.8%。ESI-MS(m/z):334.13[M+H]+。
1H-NMR(CDCl3,400MHz)δ:8.148(s,1H),8.006(s,1H),4.781(s,2H),3.862(s,3H),3.470~3.518( m,2H),2.543~2.643(m,6H),1.006~1.042(t,6H)。
实施例2:
(1)4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)
向三颈瓶中加入式II化合物(36g,0.14mol),DMF100mL,t-BuOCl(30.4g,0.28mol)加热至内温85℃,保温反应5小时,后处理将反应液倒入冰水中,用EA萃取100mL×3次,合并有机相用水洗100mL×2次,分液,无水硫酸钠干燥,浓缩得黄色固体30.2g,用THF/PE 5:16重结晶,得20.1g类白色固体,收率49.3%,mp:137-139℃,ESI-MS(m/z):291.98[M+H]+。
(2)2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)
向250ml四颈瓶中加入4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)(20.0g,0.069mol),乙醇20mL,水100ml,氢氧化钠(8.7g,0.22mol),升温至回流,反应3小时。停止加热,反应液转移至500ml瓶中,搅拌下开始滴加1M盐酸,调节pH至4左右,降温至12℃以下搅拌30min,抽滤,滤饼重新加100ml水,20℃以下打浆30min,抽滤,用20mL 水洗涤容器和滤饼,80℃烘干得14g粗品,粗品收率86.7%。
上述固体加242mL无水乙醇和45mL水加热直至溶清,关闭加热缓慢降温析晶,降温至 20℃以下搅拌3小时,抽滤,滤饼用20mL 85%乙醇洗涤,80℃烘干得白色晶体11g,收率68.1%, HPLC纯度为99.6%。m.p.255℃分解,ESI-MS(m/z):258.01[M+Na]+。
(3)N-(2-二乙氨基乙基)-2-甲氧基-3,5-二氯-4-氨基苯甲酰胺(式I)
向250mL三颈瓶中加入2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)(9.6g,40.85mmol),CDI (7.23g,44.63mmol),DCM 100mL,加热至内温35℃,保温反应1.5小时,加入N,N-二乙基乙二胺(5.18g,44.63mmol),回流1.5小时。后处理向瓶内补加100mL DCM稀释反应液,另加水20mL×3洗涤有机相,分液,无水硫酸钠干燥,浓缩得淡黄色油状物10g,收率73.7%,HPLC纯度为99.5%。ESI-MS(m/z):334.13[M+H]+。核磁数据见实施例1。
实施例3:
(1)4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)
向三颈瓶中加入式II化合物(36g,0.14mol),DMF100mL,NCS(37.4g,0.28mol)加热至内温85℃,保温反应5小时,后处理将反应液倒入冰水中,用EA萃取100mL×3次,合并有机相用水洗100mL×2次,分液,无水硫酸钠干燥,浓缩得黄色固体30.2g,用THF/PE 5:20 重结晶,得21.3g类白色固体,收率52.3%,mp:137-139℃,ESI-MS(m/z):291.98[M+H]+。
(2)2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)
向250ml四颈瓶中加入4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)(20.0g, 0.069mol),乙醇20mL,水100ml,氢氧化钠(8.7g,0.22mol),升温至回流,反应3小时。停止加热,反应液转移至500ml瓶中,搅拌下开始滴加1M盐酸,调节pH至5左右,降温至12℃以下搅拌30min,抽滤,滤饼重新加100ml水,20℃以下打浆30min,抽滤,用20mL 水洗涤容器和滤饼,80℃烘干得15.1g粗品,粗品收率93.5%。
上述固体加242mL无水乙醇和45mL水加热直至溶清,关闭加热缓慢降温析晶,降温至 20℃以下搅拌3小时,抽滤,滤饼用20mL 85%乙醇洗涤,80℃烘干得白色晶体12g,收率74.3%,HPLC纯度为99.8%。m.p.255℃分解,ESI-MS(m/z):258.01[M+Na]+。
(3)N-(2-二乙氨基乙基)-2-甲氧基-3,5-二氯-4-氨基苯甲酰胺(式I)
向250mL三颈瓶中加入2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)(9.6g,40.85mmol),TsCl (8.51g,44.63mmol),DCM 100mL,加热至内温35℃,保温反应1.5小时,加入N,N-二乙基乙二胺(5.18g,44.63mmol),回流1.5小时。后处理向瓶内补加100mL DCM稀释反应液,另加水20mL×3洗涤有机相,分液,无水硫酸钠干燥,浓缩得淡黄色油状物8g,收率59%, HPLC纯度为99.0%。ESI-MS(m/z):334.13[M+H]+。核磁数据见实施例1。
实施例4:甲氧氯普胺双氯新杂质的检测方法
供试品溶液取甲氧氯普胺原料药约10mg,精密称定,置10ml量瓶中,加甲醇:水(1:2) 10ml使溶解并稀释至刻度,摇匀,作为供试品溶液。
对照溶液精密量取供试品溶液,用流动相定量稀释制成每1ml中约含1μg的溶液,作为对照溶液。
色谱条件色谱柱为Welch Xtimate-C8(5μm,4.6×250mm);以0.050mol/L磷酸二氢钾溶液 (加入0.2ml N,N-二甲基辛胺,用磷酸调节pH至4.0)为流动相A,乙腈为流动相B;流速1ml/min;检测波长275nm;柱温为35℃,按表1进行线性梯度洗脱。
系统适用性要求理论塔板数按甲氧氯普胺峰计算不得少于4000。
测定法精密量取供试品溶液与对照溶液,分别注入液相色谱仪,记录色谱图至主成分色谱峰保留时间的2倍。
表1有关物质的梯度洗脱程序
时间(min) | A(%) | B(%) |
0 | 92 | 8 |
10 | 92 | 8 |
15 | 90 | 10 |
40 | 70 | 30 |
45 | 70 | 30 |
46 | 92 | 8 |
55 | 92 | 8 |
表2甲氧氯普胺双氯新杂质的相对保留时间及限度
在上述色谱条件下,甲氧氯普胺双氯新杂质所示的相对保留时间为1.1,能与甲氧氯普胺原料药实现有效分离。该杂质分析方法的建立,为监控甲氧氯普胺的有关物质含量提供了一种行之有效的手段,更加有利于保障甲氧氯普胺的产品质量以及患者的用药安全。
试验例:
以TA97、TA98、TA100和TA102为测试菌株,以甲氧氯普胺双氯新杂质为样品进行平板掺入试验,结果表明致突比MR值为2.1,且有剂量-反应关系,可判定该杂质致突变阳性。
以上所述的仅是本发明的优选实施方式,应当指出,对于本领域的普通技术人员来说,在不脱离本发明创造构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。
Claims (4)
2.式I化合物在甲氧氯普胺或其盐的原料药、制剂有关物质检测时作为杂质对照品的用途。
3.一种根据权利要求1所述的甲氧氯普胺双氯新杂质的检测方法,其色谱条件为:用辛烷基硅烷键合硅胶为填充剂;用磷酸盐缓冲液为流动相A,用乙腈为流动相B;梯度洗脱;流速1ml/min;检测波长275nm;柱温为35℃。
4.根据权利要求3所述的甲氧氯普胺双氯新杂质的检测方法,其特征在于,所述梯度洗脱的程序如下:
。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111156246.4A CN113912510B (zh) | 2021-09-30 | 2021-09-30 | 一种甲氧氯普胺双氯新杂质和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111156246.4A CN113912510B (zh) | 2021-09-30 | 2021-09-30 | 一种甲氧氯普胺双氯新杂质和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113912510A true CN113912510A (zh) | 2022-01-11 |
CN113912510B CN113912510B (zh) | 2024-05-07 |
Family
ID=79237208
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111156246.4A Active CN113912510B (zh) | 2021-09-30 | 2021-09-30 | 一种甲氧氯普胺双氯新杂质和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113912510B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4413497Y1 (zh) * | 1966-11-10 | 1969-06-05 | ||
DE4131276A1 (de) * | 1990-09-28 | 1992-04-02 | Kali Chemie Pharma Gmbh | Peroral applizierbare metoclopramidloesungen |
CN105486776A (zh) * | 2016-01-14 | 2016-04-13 | 吉林师范大学 | 甲氧氯普胺的气相色谱分析方法 |
-
2021
- 2021-09-30 CN CN202111156246.4A patent/CN113912510B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4413497Y1 (zh) * | 1966-11-10 | 1969-06-05 | ||
DE4131276A1 (de) * | 1990-09-28 | 1992-04-02 | Kali Chemie Pharma Gmbh | Peroral applizierbare metoclopramidloesungen |
CN105486776A (zh) * | 2016-01-14 | 2016-04-13 | 吉林师范大学 | 甲氧氯普胺的气相色谱分析方法 |
Non-Patent Citations (2)
Title |
---|
田兰;赵秀红;封淑华;郭毅;刘红莉;曹凤习;: "HPLC法测定甲氧氯普胺中有关物质的含量", 中国药房, no. 13, pages 54 - 56 * |
臧金鹏: "甲氧氯普胺合成工艺及有关物质研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技》, no. 02, 16 January 2023 (2023-01-16), pages 1 - 74 * |
Also Published As
Publication number | Publication date |
---|---|
CN113912510B (zh) | 2024-05-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2014292888B2 (en) | Inhibitors of transcription factors and uses thereof | |
CN102702008A (zh) | 阿戈美拉汀硫酸复合物及其制备方法 | |
KR101545068B1 (ko) | Cddo 에틸 에스테르의 다형체 및 이의 용도 | |
CN112521371B (zh) | 杂环酰胺类化合物、其可药用的盐及其制备方法和用途 | |
CN113372315B (zh) | 一种c-糖苷类衍生物的杂质的合成方法 | |
CN108017619B (zh) | 一种托匹司他杂质及其制备方法 | |
CN113387957A (zh) | 螺环吲哚酮-吡咯烷碳酸酯化合物和其组合物、制备方法及用途 | |
CN113912510A (zh) | 一种甲氧氯普胺双氯新杂质和用途 | |
CN110156735B (zh) | 芒柄花黄素衍生物及其制备方法和应用 | |
CN109400577B (zh) | 利伐沙班有关化合物及其制备方法和用途 | |
US20210346367A1 (en) | O-glcnac transferase inhibitors and uses thereof | |
CN113773219A (zh) | 一种甲氧氯普胺双氯新杂质的制备方法 | |
CN113582864B (zh) | Prmti型甲基转移酶抑制活性化合物及其制备与应用 | |
CN113698321B (zh) | 一种甲氧氯普胺双胺新杂质和用途 | |
CN109810115B (zh) | 异黄酮类化合物及其制备方法与应用 | |
CN113717079B (zh) | 一种甲氧氯普胺双胺新杂质的制备方法 | |
CN110577501A (zh) | 吲哚胺2,3-双加氧酶调节剂,其制备方法及用途 | |
CN113861255B (zh) | 一种别孕烷醇酮有关物质的制备方法 | |
CN114478509B (zh) | 五元杂环取代的苯甲酰胺类化合物及其制备方法与应用 | |
JPS6183163A (ja) | 抗腫瘍剤 | |
CN116217611B (zh) | 一种环丁酮衍生物及制备方法、用途 | |
CN112409338B (zh) | 一种盐酸咪达唑仑糖浆杂质c和杂质d及其用途 | |
CN112824426B (zh) | 一种别孕烯醇酮膦酰胺衍生物、其制备方法及其在医药上的用途 | |
RU2768824C1 (ru) | 2-(фенил(фенилимино)метил)изоиндолин-1,3-дион и способ его получения | |
CN112110862B (zh) | 一种1,4,5,6-四氢-5-羟基嘧啶化合物及其盐酸盐的制备方法及应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |