CN101407517B - 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
- Publication number
- CN101407517B CN101407517B CN200810305735XA CN200810305735A CN101407517B CN 101407517 B CN101407517 B CN 101407517B CN 200810305735X A CN200810305735X A CN 200810305735XA CN 200810305735 A CN200810305735 A CN 200810305735A CN 101407517 B CN101407517 B CN 101407517B
- Authority
- CN
- China
- Prior art keywords
- theophylline
- acetate
- transbroncho
- alkali
- ambroxol
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims description 16
- IPUHJDQWESJTGD-PFWPSKEQSA-N Cn1c2ncn(CC(O)=O)c2c(=O)n(C)c1=O.Nc1c(Br)cc(Br)cc1CN[C@H]1CC[C@H](O)CC1 Chemical compound Cn1c2ncn(CC(O)=O)c2c(=O)n(C)c1=O.Nc1c(Br)cc(Br)cc1CN[C@H]1CC[C@H](O)CC1 IPUHJDQWESJTGD-PFWPSKEQSA-N 0.000 title abstract description 5
- 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 32
- 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 30
- 239000003513 alkali Substances 0.000 claims abstract description 29
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 229960000278 theophylline Drugs 0.000 claims description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 9
- 239000002904 solvent Substances 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 4
- HCYFGRCYSCXKNQ-UHFFFAOYSA-N 2-(1,3-dimethyl-2,6-dioxo-7-purinyl)acetic acid Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC(O)=O)C=N2 HCYFGRCYSCXKNQ-UHFFFAOYSA-N 0.000 abstract description 3
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 3
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 abstract 2
- 229960005174 ambroxol Drugs 0.000 abstract 2
- 238000011084 recovery Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000012264 purified product Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012670 alkaline solution Substances 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010062717 Increased upper airway secretion Diseases 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 208000026435 phlegm Diseases 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 0 CCN(C(*O)N(C)CN=CN(CC(O)=O)C1)C1=O Chemical compound CCN(C(*O)N(C)CN=CN(CC(O)=O)C1)C1=O 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 239000000924 antiasthmatic agent Substances 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- XDVOLDOITVSJGL-UHFFFAOYSA-N 3,7-dihydroxy-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane Chemical compound O1B(O)OB2OB(O)OB1O2 XDVOLDOITVSJGL-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 241000360771 Coreana Species 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 101000837626 Homo sapiens Thyroid hormone receptor alpha Proteins 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- 102100028702 Thyroid hormone receptor alpha Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000010265 fast atom bombardment Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000009840 oxygen flask method Methods 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
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 (4)
1.氨溴索茶碱-7-乙酸盐的制备方法，其特征在于：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为1∶1.49～1.69；反应时间为40～50min，反应温度60℃～65℃。
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或2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。
4.根据权利要求3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。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810305735XA CN101407517B (zh) | 2008-11-26 | 2008-11-26 | 氨溴索茶碱-7-乙酸盐的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810305735XA CN101407517B (zh) | 2008-11-26 | 2008-11-26 | 氨溴索茶碱-7-乙酸盐的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101407517A CN101407517A (zh) | 2009-04-15 |
| CN101407517B true CN101407517B (zh) | 2011-05-18 |
Family
ID=40570748
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810305735XA Active CN101407517B (zh) | 2008-11-26 | 2008-11-26 | 氨溴索茶碱-7-乙酸盐的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101407517B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9133196B2 (en) | 2012-11-22 | 2015-09-15 | Ami Lifesciences Pvt. Ltd. | Process for the preparation of acebrophylline |
| 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 |
-
2008
- 2008-11-26 CN CN200810305735XA patent/CN101407517B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN101407517A (zh) | 2009-04-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101407517B (zh) | 氨溴索茶碱-7-乙酸盐的制备方法 | |
| CN102351778A (zh) | 一种盐酸阿比朵尔的制备方法 | |
| CN101735023B (zh) | 一种3-溴-5-氯苯酚的制备方法 | |
| CN103396318B (zh) | 一种2,4-二硝基苯甲醚的合成工艺 | |
| CN105503842A (zh) | 盐酸奈必洛尔环氧中间体6-氟-2-环氧乙基色满的制备方法 | |
| CN103012290B (zh) | 一种高纯度吉非替尼的制备方法 | |
| CN108147977B (zh) | N-对氨基苯甲酰-l-谷氨酸的制备方法 | |
| CN104557576B (zh) | 一种高纯度普瑞巴林的制备方法 | |
| CN101362732A (zh) | 一种头孢克肟侧链酸的制备方法 | |
| CN103755648A (zh) | 一种吉非替尼的新杂质及其制备方法 | |
| CN102212035A (zh) | 磺胺甲氧吡嗪的制备方法 | |
| CN103113294B (zh) | 瑞巴派特的合成方法 | |
| CN104788429B (zh) | 一种通过脱除三苯甲基保护基制备沙坦类药物的方法 | |
| CN102718662A (zh) | 一种制备盐酸西那卡塞的方法 | |
| CN107188888A (zh) | 一种制备甲磺酸迈瑞替尼的方法 | |
| CN109810066A (zh) | 一种盐酸氨溴索有关物质的合成方法 | |
| CN110183446B (zh) | 一种莫西沙星新杂质及其合成方法和用途 | |
| CN103254156A (zh) | 阿法替尼中间体的制备方法 | |
| CN114031560A (zh) | 一种来特莫韦钠盐的制备方法 | |
| CN102010325A (zh) | 一种对羟基苯乙酸的合成方法 | |
| CN105732547A (zh) | 一种脱水穿心莲内酯二酸半酯碱式盐的制备方法 | |
| CN102898401B (zh) | 一种普拉克索的制备方法 | |
| CN108707146A (zh) | 一种硝呋太尔的合成方法 | |
| CN103755706A (zh) | 一种合成叶酸的环保制备方法 | |
| CN115057846B (zh) | 一种曲格列汀二聚体的制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of ambroxol theophylline-7-acetate Effective date of registration: 20180105 Granted publication date: 20110518 Pledgee: Bank of Chengdu science and technology branch of Limited by Share Ltd. Pledgor: CHENGDU MOL BIOPHARMACEUTICAL Co.,Ltd. Registration number: 2017510000096 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20190917 Granted publication date: 20110518 Pledgee: Bank of Chengdu science and technology branch of Limited by Share Ltd. Pledgor: CHENGDU MOL BIOPHARMACEUTICAL Co.,Ltd. Registration number: 2017510000096 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of ambroxol theophylline-7-acetate Effective date of registration: 20210802 Granted publication date: 20110518 Pledgee: Bank of Chengdu science and technology branch of Limited by Share Ltd. Pledgor: CHENGDU MOL BIOPHARMACEUTICAL Co.,Ltd. Registration number: Y2021510000166 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20220510 Granted publication date: 20110518 Pledgee: Bank of Chengdu science and technology branch of Limited by Share Ltd. Pledgor: CHENGDU MOL BIOPHARMACEUTICAL Co.,Ltd. Registration number: Y2021510000166 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of ambroxol theophylline-7-acetate Effective date of registration: 20221027 Granted publication date: 20110518 Pledgee: Chengdu SME financing Company Limited by Guarantee Pledgor: CHENGDU MOL BIOPHARMACEUTICAL Co.,Ltd. Registration number: Y2022980019842 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20230620 Granted publication date: 20110518 Pledgee: Chengdu SME financing Company Limited by Guarantee Pledgor: CHENGDU MOL BIOPHARMACEUTICAL Co.,Ltd. Registration number: Y2022980019842 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation method of ambroxol theophylline 7-acetate Effective date of registration: 20230814 Granted publication date: 20110518 Pledgee: Chengdu SME financing Company Limited by Guarantee Pledgor: CHENGDU MOL BIOPHARMACEUTICAL Co.,Ltd. Registration number: Y2023980052022 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |