CN101407517A - 氨溴索茶碱-7-乙酸盐的制备方法 - Google Patents
氨溴索茶碱-7-乙酸盐的制备方法 Download PDFInfo
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- 229940113035 ambroxol-theophylline-7-acetate Drugs 0.000 title abstract 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 36
- HCYFGRCYSCXKNQ-UHFFFAOYSA-M 2-(1,3-dimethyl-2,6-dioxopurin-7-yl)acetate Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC([O-])=O)C=N2 HCYFGRCYSCXKNQ-UHFFFAOYSA-M 0.000 claims abstract description 33
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Abstract
本发明提供了一种氨溴索茶碱－7－乙酸盐的制备方法，属于化学医药领域。该方法以水、乙醇或甲醇为溶剂，茶碱－7－乙酸与氨溴索碱以1∶1.49～1.69的重量比反应制得氨溴索茶碱－7－乙酸盐，以重量比计茶碱－7－乙酸：溶剂为1∶20～60。本发明方法步骤简便，制得的氨溴索茶碱－7－乙酸盐含量大于98％，重量收率以氨溴索碱计大于113.0％，以水作为反应溶剂成本低、易回收处理，减少了有机溶剂排放对环境的污染。
Description
技术领域
本发明涉及氨溴索茶碱-7-乙酸盐的制备方法，属于化学医药领域。
背景技术
氨溴索茶碱-7-乙酸盐结构如式I所示：
英文名：Acebrophylline；分子式：C22H28Br2N6O5；分子量：616.3。氨溴索茶碱七乙酸盐为白色至类白色粉末，略溶于水，溶于二甲基甲酰胺。
氨溴索茶碱-7-乙酸盐由祛痰成份氨溴索及抗哮喘成份茶碱组成，在体内分解成为茶碱与氨溴索而共同发挥作用，其中茶碱是磷酸二酯酶抑制剂类抗哮喘代表性药物，氨溴索的功能是祛痰镇咳。因而氨溴索茶碱-7-乙酸盐是用于治疗多痰性哮喘病的一种新药，具有化痰、止咳、平喘等多种功效，适用于带有异常分泌物的急性和慢性呼吸道疾病，尤其是恶化了的慢性支气管炎、气喘性支气管炎及支气管哮喘等疾病的治疗。
氨溴索茶碱-7-乙酸盐的现有制备方法(DE3425007)为以二甲基甲酰胺为溶剂，茶碱-7-乙酸与氨溴索碱在此溶剂中反应，并在乙酸乙酯中结晶制得成品。该方法引用了大量的化学溶剂，直接导制生产成本偏高，且大量的乙酸乙酯与二甲基甲酰胺的使用导致严重的环境污染，不符合可持续发展的理念。
发明内容
本发明所要解决的技术问题是提供一种氨溴索茶碱-7-乙酸盐的制备方法，该方法能降低生产成本，更重要的是避免使用乙酸乙酯与二甲基甲酰胺，大大减少了有机溶剂的排放，降低了对环境的污染与危害。
本发明解决上述术问题所采用的技术方案是以水、乙醇或甲醇为溶剂，茶碱-7-乙酸与氨溴索碱以1∶1.49～1.69的重量比反应制得氨溴索茶碱-7-乙酸盐；茶碱-7-乙酸与氨溴索碱的重量比优选为1∶1.59。
溶剂的用量为茶碱-7-乙酸的20～60重量倍，优选为40重量倍。
茶碱-7-乙酸 氨溴索碱
进一步的，由于氨溴索碱水溶性较差，可以将其溶于乙醇配制成氨溴索碱的乙醇溶液后，再将氨溴索碱的乙醇溶液与茶碱-7-乙酸的水溶液反应。其中氨溴索碱的乙醇溶液为1g溴索碱加6～9ml 95％乙醇配制而成；优选为1g氨溴索碱加7.2～7.8ml 95％乙醇配制而成。
反应溶剂为甲醇或乙醇时，分别将茶碱-7-乙酸和氨溴索碱溶于溶剂后进行反应。
反应时间为40～50min，反应温度60℃～65℃。反应完成后采用常规方法冷却析出粗品晶体，重结晶后即得成品。
本发明方法步骤简便，制得的氨溴索茶碱-7-乙酸盐含量大于98％，反应溶剂成本低、易回收处理，减少了有机溶剂排放对环境的污染。
具体实施方式
以下结合实施例对本发明作进一步的阐述。实施例仅用于说明本发明，而不是以任何方式来限制本发明。
实施例中采用的原料规格见表1：
表1
| 原料 | 产地 | 规格 |
| 盐酸 | 成都欣海化学试制厂 | AR |
| 乙醇 | 成都科龙 | 95％ |
| 纯化水 | \ | 中国药典标准 |
| 氯乙酸 | 成都金山化学制品厂 | AR |
| 溴素碱 | 浙江天台福达医药化工有限公司 | HPLC≥99％ |
| 茶碱 | 上海万代制药有限公司 | ≥99％ |
| 氢氧化钠 | 天津瑞金化学制品厂 | AR |
实施例1 茶碱-7-乙酸的制备
在250ml三口瓶中，加入5g茶碱，25ml纯化水，装置回流冷却系统，启动搅拌。快速搅拌下，升温至96～100℃，反应液溶解透明。加入氯乙酸3.0g，用50％NaOH溶液调pH值10～10.5，于100±2℃反应2～2.5小时，HPLC监测反应溶液中原料低于3.5％时停止反应。色谱条件：流动相：Buffer：ACN＝93∶7(Buffer：1.36g CH3COONa+5ml HAC用水溶解至1000ml)；流速：1.5ml/min；样品稀释剂：流动相；样品浓度：1mg/ml；进样量：10ul；波长：272nm；柱温：35℃。
将上述反应溶液温度降至74℃，滴加5N盐酸调pH＝2，即有晶体析出，于25℃继续搅拌2～4小时，抽滤，滤饼用20ml～30ml自来水洗涤2次，抽干，于60℃减压干燥4小时，得粗品重6.3g，重量收率126％。
粗品中加入纯化水(按重量百分比1∶12)升温至65～70℃，搅拌45～60分钟，热过滤，滤饼用20～30ml的50℃热水洗涤二次，抽干。过滤得到的固体60℃干燥4～6小时，得到精制产品5.67g，重量收率：113％。高效液相色谱检测精制产品纯度为99％，茶碱残留量0.5％以下。
H NMR(ppm)：3.20，3.43，5.07，8.04。
实施例2 氨溴索茶碱-7-乙酸盐的制备
在100ml三口瓶中，加入氨溴索碱7.93g和95％乙醇60ml，搅拌30min溶解透明配制成氨溴索碱溶液，加热至30～35℃待用。
在500ml三口瓶中加入实施例1制备的茶碱-7-乙酸5g、纯化水200ml，搅拌，升温至95℃回流30min使反应液溶解透明；控制温度60℃～65℃，将上述配制好的氨溴索碱溶液缓慢滴加入反应液中，滴加完毕后继续搅拌至反应液透明，控制反应时间为45min(从开始滴加氨溴索碱溶液起计算)。降温至50℃～60℃，减压蒸馏回收溶剂80ml。反应溶液降温至10℃搅拌析晶，2h～4h后抽滤，滤饼用少量乙醇洗涤两次后抽干，60℃干燥2～4h，105℃烘4h得粗产品10g，重量收率以氨溴索碱计为126％。
按粗产品∶纯化水＝1∶30(重量比)混匀并升温溶解透明，降温析晶，室温搅拌2～4h抽滤，60℃干燥2h，105℃烘4h得精制产品9g，重量收率以氨溴索碱计为113.5％。
制得的精制产品检测数据如下所示：
元素分析(意大利CARLO ERBA 1106元素分析仪，Br元素测定采用氧瓶燃烧法)：N％13.51，C％42.43，H％4.78，Br％26.28。
紫外光谱(nm)：吸收峰出现在209.00，243.00，273.00，307.00。
EI质谱(m/z)：364，308，284，274，261，238，194，183，137，128，114，109，96，81，77，67，56。
快原子轰击质谱(FAB+MS，m/z)：617，563，471，379、300、264、184、116。
红外图谱(KBr压片，cm-1)：3286，2945.5，2921.7，1700.6，1664.5，1547.0，1473.7，1390.3，1310.3，1226.1，1087.2，743.9，704.9。
H NMR(ppm)：1.49，2.18，3.33，3.55，4.23，4.91，7.39，7.70，7.95。
表2
| 1 | 茶碱-7-乙酸含量 | 22.68％ |
| 2 | 氨溴索碱含量 | 77.32％ |
| 3 | pH值 | 5.5 |
| 4 | 熔点 | 211.3～212.4℃ |
| 5 | 含量 | 98.8％ |
表2为精制产品的其余检测数据，第5项的检测方法为：0.4g精制产品用水溶解至40ml，用0.1M KOH滴定液滴定，以每消耗1mlKOH含61.63mg氨溴索茶碱-7-乙酸盐计算。
其中1、2项的检测方法为：精密称取约0.1g样品，用水稀释至100ml，作为供试品溶液。精密称取约0.1g氨溴索茶碱-7-乙酸盐对照品，用水稀释至100ml，作为对照品溶液。按照《韩国药典》中规定的HPLC法分别对20ml供试品溶液和对照品溶液进行检测，具体的色谱条件为：色谱柱：Lichrosorb RP 184mm×125mm，流速：1.2ml/min，流动相：乙腈∶0.1％四硼酸铵＝570∶430，检测器：UV 244nm，出峰顺序：茶碱-7-乙酸(约1.1分钟)，氨溴索(约5.9分钟)。
精制氨溴索茶碱-7-乙酸盐的X射线晶体衍射数据见表3：
表3
| 2-theta | d(A) | BG | Height | 1％ | Area | 1％ | FWHM | XS(A) | |
| 1 | 7.799 | 11.3260 | 59 | 223 | 7.6 | 721 | 7.4 | 0.220 | 435 |
| 2 | 8.443 | 10.4645 | 51 | 217 | 7.4 | 598 | 6.1 | 0.187 | 556 |
| 3 | 10.152 | 8.7057 | 49 | 199 | 6.7 | 442 | 4.5 | 0.151 | 848 |
| 4 | 11.821 | 7.4805 | 75 | 119 | 4.0 | 169 | 1.7 | 0.091 | ＞1000 |
| 5 | 12.522 | 7.0628 | 104 | 408 | 13.8 | 743 | 7.6 | 0.124 | ＞1000 |
| 6 | 13.121 | 6.7419 | 47 | 581 | 19.7 | 1561 | 15.9 | 0.183 | 560 |
| 7 | 13.583 | 6.5137 | 47 | 164 | 5.6 | 461 | 4.7 | 0.180 | 573 |
| 8 | 15.253 | 5.8041 | 77 | 2951 | 100.0 | 9792 | 100.0 | 0.226 | 408 |
| 9 | 15.481 | 5.7191 | 84 | 953 | 32.3 | 4664 | 47.6 | 0.313 | 274 |
| 10 | 16.462 | 5.3804 | 85 | 347 | 11.8 | 764 | 7.8 | 0.150 | 785 |
| 11 | 16.840 | 5.2604 | 73 | 171 | 5.8 | 361 | 3.7 | 0.135 | ＞1000 |
| 12 | 18.405 | 4.8165 | 77 | 511 | 17.3 | 1917 | 19.6 | 0.255 | 347 |
| 13 | 19.121 | 4.6377 | 87 | 1189 | 40.3 | 3347 | 34.2 | 0.191 | 505 |
| 14 | 19.982 | 4.4399 | 80 | 62 | 2.1 | 121 | 1.2 | 0.125 | ＞1000 |
| 15 | 20.355 | 4.3594 | 116 | 186 | 6.3 | 160 | 1.6 | 0.080 | ＞1000 |
| 16 | 21.280 | 4.1719 | 162 | 814 | 27.6 | 1673 | 17.1 | 0.140 | 859 |
| 17 | 22.004 | 4.0362 | 144 | 121 | 4.1 | 157 | 1.6 | 0.083 | ＞1000 |
续表3-1
| 2-theta | d(A) | BG | Height | 1％ | Area | 1％ | FWHM | XS(A) | |
| 18 | 22.762 | 3.9034 | 222 | 2370 | 80.3 | 7682 | 78.5 | 0.220 | 414 |
| 19 | 23.344 | 3.8075 | 441 | 501 | 17.0 | -291 | -3.0 | 0.080 | ＞1000 |
| 20 | 24.355 | 3.6517 | 472 | 790 | 26.8 | 912 | 9.3 | 0.080 | ＞1000 |
| 21 | 25.274 | 3.5208 | 314 | 1300 | 44.1 | 3142 | 32.1 | 0.164 | 620 |
| 22 | 26.366 | 3.3775 | 193 | 623 | 21.1 | 3293 | 33.6 | 0.359 | 236 |
| 23 | 27.840 | 3.2019 | 115 | 145 | 4.9 | 61 | 0.6 | 0.080 | ＞1000 |
| 24 | 29.679 | 3.0076 | 84 | 446 | 15.1 | 3185 | 32.5 | 0.486 | 173 |
| 25 | 30.663 | 2.9133 | 169 | 385 | 13.0 | 708 | 7.2 | 0.125 | 990 |
| 26 | 31.924 | 2.8010 | 184 | 494 | 16.7 | 1065 | 10.9 | 0.147 | 725 |
| 27 | 32.581 | 2.7460 | 213 | 171 | 5.8 | 78 | 0.8 | 0.080 | ＞1000 |
| 28 | 33.975 | 2.6365 | 271 | 489 | 16.6 | 1120 | 11.4 | 0.156 | 655 |
| 29 | 34.560 | 2.5932 | 366 | 18 | 0.6 | 36 | 0.4 | 0.100 | ＞1000 |
| 30 | 34.996 | 2.5619 | 288 | 269 | 9.1 | 67 | 0.7 | 0.080 | ＞1000 |
| 31 | 35.652 | 2.5162 | 132 | 501 | 17.0 | 2451 | 25.0 | 0.333 | 260 |
| 32 | 36.723 | 2.4453 | 145 | 31 | 1.1 | -85 | -0.9 | 0.080 | ＞1000 |
| 33 | 37.530 | 2.3945 | 144 | 139 | 4.7 | 221 | 2.3 | 0.108 | ＞1000 |
| 34 | 38.184 | 2.3550 | 153 | 134 | 4.5 | 226 | 2.3 | 0.108 | ＞1000 |
续表3-2
| 2-theta | d(A) | BG | Height | 1％ | Area | 1％ | FWHM | XS(A) | |
| 35 | 39.686 | 2.2693 | 138 | 166 | 5.6 | 1228 | 12.5 | 0.503 | 170 |
| 36 | 40.145 | 2.2444 | 142 | 284 | 9.6 | 1721 | 17.6 | 0.412 | 210 |
| 37 | 40.735 | 2.2132 | 133 | 31 | 1.1 | -10 | -0.1 | 0.080 | ＞1000 |
| 38 | 41.351 | 2.1816 | 128 | 197 | 6.7 | 483 | 4.9 | 0.167 | 591 |
| 39 | 42.178 | 2.1408 | 114 | 62 | 2.1 | -6 | -0.1 | 0.080 | ＞1000 |
| 40 | 43.031 | 2.1003 | 129 | 134 | 4.5 | 360 | 3.7 | 0.183 | 526 |
| 41 | 43.767 | 2.0666 | 125 | 50 | 1.7 | 58 | 0.6 | 0.080 | ＞1000 |
| 42 | 44.209 | 2.0470 | 140 | 39 | 1.3 | -146 | -1.5 | 0.080 | ＞1000 |
| 43 | 45.093 | 2.0089 | 157 | 280 | 9.5 | 1278 | 13.1 | 0.310 | 287 |
| 44 | 46.387 | 1.9558 | 164 | 89 | 3.0 | 34 | 0.3 | 0.080 | ＞1000 |
| 45 | 47.592 | 1.9091 | 157 | 67 | 2.3 | 610 | 6.2 | 0.583 | 150 |
| 46 | 48.105 | 1.8899 | 190 | 44 | 1.5 | 220 | 2.2 | 0.320 | 281 |
| 47 | 49.819 | 1.8288 | 125 | 102 | 3.5 | 589 | 6.0 | 0.393 | 228 |
| 48 | 52.100 | 1.7540 | 108 | 59 | 2.0 | 221 | 2.3 | 0.255 | 365 |
| 49 | 52.827 | 1.7316 | 120 | 59 | 2.0 | 133 | 1.4 | 0.153 | 674 |
| 50 | 53.936 | 1.6985 | 122 | 55 | 1.9 | 217 | 2.2 | 0.268 | 347 |
| 51 | 57.172 | 1.6098 | 113 | 101 | 3.4 | 453 | 4.6 | 0.305 | 307 |
实施例3 氨溴索茶碱-7-乙酸盐的制备
在100ml三口瓶中，加入氨溴索碱7.93g和95％乙醇60ml，搅拌30min溶解透明配制成氨溴索碱溶液，加热至30～35℃待用。
在500ml三口瓶中加入实施例1制备的茶碱-7-乙酸5g、乙醇180ml，搅拌，升温至80℃回流30min使反应液溶解透明。控制温度60℃～65℃，将上述配制好的氨溴索碱溶液缓慢滴加入反应液中，滴加完毕后继续搅拌15min至反应液透明。于45℃减压蒸馏回收溶剂70ml，降温至10℃搅拌析晶，2h～4h后抽滤，滤饼用少量乙醇洗涤两次后抽干，60℃干燥2～4h，105℃烘4h得粗产品10g，重量收率以氨溴索碱计为124％。
按粗产品∶乙醇＝1∶30(重量比)混匀并升温溶解透明，降温析晶，室温搅拌2～4h抽滤，60℃干燥2h，105℃烘4h得精制产品8.8g，重量收率以氨溴索碱计为110.0％。
制得的精制产品检测数据与实施例2相同。
本发明方法成本低、易回收处理，减少了有机溶剂排放对环境的污染，制得的氨溴索茶碱-7-乙酸盐符合药典的质量标准。
Claims (8)
1.氨溴索茶碱-7-乙酸盐的制备方法，其特征在于：以水、乙醇或甲醇为溶剂，茶碱-7-乙酸与氨溴索碱以1∶1.49～1.69的重量比反应制得氨溴索茶碱-7-乙酸盐。
2.根据权利要求1所述的氨溴索茶碱-7-乙酸盐的制备方法，其特征在于：茶碱-7-乙酸与氨溴索碱的重量比为1∶1.59。
3.根据权利要求1所述的氨溴索茶碱-7-乙酸盐的制备方法，其特征在于：溶剂的用量为茶碱-7-乙酸的20～60重量倍。
4.根据权利要求1所述的氨溴索茶碱-7-乙酸盐的制备方法，其特征在于：反应溶剂为水时，氨溴索碱溶于乙醇配制成氨溴索碱的乙醇溶液，氨溴索碱的乙醇溶液与茶碱-7-乙酸一起加入水中反应。
5.根据权利要求4所述的氨溴索茶碱-7-乙酸盐的制备方法，其特征在于：氨溴索碱的乙醇溶液为1g溴索碱加95％乙醇6～9ml配制而成。
6.根据权利要求5所述的氨溴索茶碱-7-乙酸盐的制备方法，其特征在于：氨溴索碱的乙醇溶液为1g氨溴索碱加95％乙醇7.2～7.8ml配制而成。
7.根据权利要求1所述的氨溴索茶碱-7-乙酸盐的制备方法，其特征在于：反应溶剂为甲醇或乙醇时，分别将茶碱-7-乙酸和氨溴索碱溶于溶剂后进行反应。
8.根据权利要求1～7任一项所述的氨溴索茶碱-7-乙酸盐的制备方法，其特征在于：反应时间为40～50min，反应温度60℃～65℃。
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| CN103360393A (zh) * | 2013-07-29 | 2013-10-23 | 上海万巷制药有限公司 | 茶碱乙酸的制备方法 |
| WO2014080413A1 (en) * | 2012-11-22 | 2014-05-30 | Ami Lifesciences Pvt. Ltd. | A process for the preparation of acebrophylline |
| CN105566325A (zh) * | 2016-01-04 | 2016-05-11 | 石家庄学院 | 一种茶碱乙酸氨溴索的制备工艺 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014080413A1 (en) * | 2012-11-22 | 2014-05-30 | Ami Lifesciences Pvt. Ltd. | A process for the preparation of acebrophylline |
| US9133196B2 (en) | 2012-11-22 | 2015-09-15 | Ami Lifesciences Pvt. Ltd. | Process for the preparation of acebrophylline |
| CN103360393A (zh) * | 2013-07-29 | 2013-10-23 | 上海万巷制药有限公司 | 茶碱乙酸的制备方法 |
| CN103360393B (zh) * | 2013-07-29 | 2016-01-06 | 上海万巷制药有限公司 | 茶碱乙酸的制备方法 |
| CN105566325A (zh) * | 2016-01-04 | 2016-05-11 | 石家庄学院 | 一种茶碱乙酸氨溴索的制备工艺 |
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