CN1037905C - 生产9－氨基－6－脱甲基－6－脱氧四环素的新方法 - Google Patents

生产9－氨基－6－脱甲基－6－脱氧四环素的新方法 Download PDF

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CN1037905C
CN1037905C CN93106625A CN93106625A CN1037905C CN 1037905 C CN1037905 C CN 1037905C CN 93106625 A CN93106625 A CN 93106625A CN 93106625 A CN93106625 A CN 93106625A CN 1037905 C CN1037905 C CN 1037905C
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费尔克-恩格·萨姆
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Abstract

本发明涉及一种生产(4S-(4α，12aα))-9-氨基-4-(二甲基氨基)-1，4，4a，5，5a，6，11，12a-八氢，-3，10，12，12a-四羟基-1，11-二氧代-2-并四苯羧基酰胺(以下简称9-氨基-6-脱甲基-6-脱氧四环素)的新方法，该化合物是合成四环素的有价值的中间体。

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生产9-氨基-6-脱甲基-6-脱氧四环素的新方法
本发明涉及生产〔4S-(4α，12aα)〕-9-氨基-4-(二甲基氨基)-1，4，4a，5，5a，6，11，12a-八氢-3，10，12，12a-四羟基-1，11-二氧代-2-并四苯羧基酸胺(以下简称9-氨基-6-脱甲基-6-脱氧四环素)，该化合物是合成四环素有价值的中间体。
众所周知，9-氨基-6-脱甲基-6-脱氧四环素，不论作为最终产物，还是作为合成取代的四环素的中间体，都是很有用的。〔USPatent 3，219，671 and 3，226，436；Journal of the American Chemi-cal Society，82，1253(1960)〕。
在本发明之前，9-氨基-6-脱甲基-6-脱氧四环素的制造是通过硝化6-脱甲基-6-脱氧四环素，然后催化还原，得到所需产物(Boothe，J.H.et al.，Journal of the American Chemical Society，82，1253(1960))。然而，这个方法产生1∶1.5的7-和9-硝基-6-脱甲基-6-脱氧四环素的混合物，而这两者是很难分离的。使用传统的提纯技术时，例如使用结晶法或柱色谱层析法，9-硝基-6-脱甲基-6-脱氧四环素的得率为39％。然而，甚至那些传统的提纯技术也不能提供纯度100％的9-硝基-6-脱甲基-6-脱氧四环素。一些7-硝基-6-脱甲基-6-脱氧四环素仍作为杂质存在。
如此得到的9-硝基产物随后被还原，生成9-氨基-6-脱甲基-6-脱氧四环素。然而，因为正如前面提及的，很难将7-硝基-6-脱甲基-6-脱氧四环素从9-硝基-6-脱甲基-6-脱氧四环素中分开，所以也产生了部分7-氨基-6-脱甲基-6-脱氧四环素。
现在已发现，能高纯度地和高得率地制造9-氨基-6-脱甲基-6-脱氧四环素无机酸盐4，即通过将6-脱甲基-6-脱氧四环素1与卤化试剂在一定浓度的无机酸中反应(US.专利3,036,129)，得到7-卤-6-脱甲基-6-脱氧四环素无机酸盐2，而只有少量的7，9-二卤-6-脱甲基-6-脱氧四环素杂质。至少，用结晶的方法，7，9-二卤-6-脱甲基-6-脱氧四环素是易于从所期望的7-卤-6-脱甲基-6-脱氧四环素无机酸盐2中分离出去的。
接着7-卤-6-脱甲基-6-脱氧四环素无机酸盐2，硝化形成7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐3。因为7-位被卤素原子占据，所以，硝化反应以极高的纯度和产率提供7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐。
最好地，卤化反应和硝化反应在一步中进行，即将6-脱甲基-6-脱氧四环素无机酸盐1与卤化试剂，在一定浓度的无机酸中反应，接着，加入硝化试剂，从而提供基本上纯净的7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐3。
7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐3，随后被还原，以高产率形成极高纯度的9-氨基-6-脱甲基-6-脱氧四环素无机酸盐4。此还原反应在一步中既脱除了卤原子又将NO2还原，从而提供所期望的9-氨基-6-脱甲基-6-脱氧四环素无机酸盐4。图解I
Figure C9310662500051
参见图解I，通过前面文献所提及的方法而得到的6-脱甲基-6-脱氧四环素1，在诸如浓无机酸之类的溶剂中，用卤化试剂，例如溴，N-溴丁二酰亚胺，N-氯丁二酰亚胺，一氯化碘或苯基三甲基铵二氯碘酸盐(benzyltrimethylammonium dichloriodate)(用ShojiKajigaeshi et al.，Chem Lett，2109-2112(1987)的方法制备)。反应在温度范围0°-20℃之间进行，直至反应完成。反应混合物滴加于冷的***中然后收集。粗产品经重结晶以去除所有形成的7，9-二卤-6-脱甲基-6-脱氧四环素，从而得到纯净的7-卤-6-脱甲基-6-脱氧四环素无机酸盐2。
纯的7-卤-6-脱甲基-6-脱氧四环素无机酸盐2，溶于冷的浓无机酸中，例如硫酸，接着在约-15℃-+15℃温度范围下，用稍过量的硝化试剂，例如“混合酸”或金属硫酸盐，处理1-2小时。反应产物滴加于冷的***中，并收集得到7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐3。
最好地，6-脱甲基-6-脱氧四环素1经一步直接转化成7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐3。将6-脱甲基-6-脱氧四环素1溶于冷的溶剂中，例如浓无机酸中，然后用诸如溴，N-溴丁二酰亚胺，N-氯丁二酰亚胺或苯基三甲基铵基二氯碘酸盐(用Shojo Kaji-gaeshi et al.的方法制备)之类的硝化试剂处理。反应在0℃-20℃搅拌45分钟。加入稍过量的固体金属硝酸盐或“混合酸”，并在-15℃-+15℃继续搅拌30分钟至2小时。反应产物滴加于冷的***中。收集所得到的固体，用乙醇研磨，过滤，滤液加入到***中。收集黄色固体，得到纯净的7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐3，产率93％。
7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐3，溶于一混合溶剂，例如2-甲氧基乙醇，甲醇或乙醇与1N硫酸或1N盐酸组成的混合溶剂，用10-30％重量比的VIII族金属催化剂，它们的盐或稀有金属氧化物，在1-40磅/平方英寸压力的氢气氛中催化还原。反应产物经过滤，缓慢加于异丙醇中，收集，得到纯净的9-氨基-6-脱甲基-6-脱氧四环素无机酸盐4。
结合下列实施例，更详尽地阐述本发明。
                  实施例1
〔4S-(4α，12aα)〕-7-溴-4-(二甲基氨基)-1，4，4a，5，5a，6，11，12a-八氢-3，10，12，12a-四羟基-1，11-二氧代-2-并四苯羧基酰胺硫酸盐。
用文献提及的方法制得的4.14克6-脱甲基-6-脱氧四环素和1.99克N-溴丁二酰亚胺溶于50ml浓硫酸中，在0℃搅拌45分钟，或者直至形成溶液。反应混合物滴加于2升冷的***中。收集得到的沉淀并干燥。固体溶于2-甲氧基乙醇，用甲醇研磨，收集，用甲醇和***洗涤，然后干燥，得到6.22g粗产品。固体从2-甲氧基乙醇和甲醇中重结晶出，得到3.1g纯产品。
MS(FAB)：m/z493(M+H).
1H NMR(CD3SOCD3)：d4.3(s，1H，4-H)，6.8(d，1H，9-H)和7.75(d，1H，8-H).
                        实施例2
〔4S-(4α，12aa)〕-7-溴-4-(二甲基氨基)-1，4，4a，5，5a，6，11，12a-八氢-3，10，12，12a-四羟基-9-硝基-1，11-二氧代-2-并四苯羧基酰胺硫酸盐。
将由实施例1制得的产物1.1g溶于10ml冷的浓硫酸中，加入1.2ml含10％硝酸的浓硫酸。反应在0℃搅拌1.5小时，然后滴加于500ml冰冷的***中，收集得到的固体，用***洗三次，真空干燥，得到1.06g所期望的产物(90％)。
MS(FAB)：m/z538(M+H).
1H NMR(CD3SOCD3)：d4.3(s，1H，4-H)和8.48(s，1H，8-H).
                         实施例3
〔4S-(4α，12aα)〕-7-溴-4-(二甲基氨基)-1，4，4a，5，5a，6，11，12a-八氢-3，10，12，12a-四羟基-9-硝基-1，11-二氧代-2-并四苯羧基酰胺硫酸盐
将0.196克N-溴丁二酰亚胺加到0℃的由0.414g 6-脱甲基-6-脱氧四环素和10ml浓硫酸组成的溶液中。反应在0℃搅拌45分钟。随后加入0.11g固体硝酸钾。混合物在0℃搅拌30分钟，然后倒入到500ml冷的***中。收集固体，用***洗涤，干燥，得到0.72g粗产品。产品用甲醇和异丙醇研磨以纯化，过滤，滤液加入冷的***中，收集黄色固体，得到0.59g所期望的产物(93％)。
MS(FAB)：m/z538(M+H).
1H NMR(CD3SOCD3)：d4.3(s，1H，4-H)和8.48(s，1H，8-H)。
                        实施例4
〔4S-(4α，12aα)〕-9-氨基-4-(二甲基氨基)-1，4，4a，5，5a，6，11，12a-八氢-3，10，12，12a-四羟基-1，11-二氧代-2-并四苯羧基酰胺硫酸盐
得自实施例2或3的1.272g产物(溶于50ml 2-甲氧基乙醇和10ml 1N硫酸)与0.30g 10％钯/碳组成的混合物，在帕尔还原器中在40磅/平方英寸压力下氢化还原1小时。反应产物用硅藻土垫板过滤，滤液缓慢倒入500ml异丙醇和***(1∶4)中。收集黄色固体，用***洗涤，干燥，得到1.02g所期望的产物(97％)。
MS(FAB)：m/z430(M+H).
1H NMR(CD3SOCD3)：d4.3(s，1H，4-H)，6.8(d，1H，7-H)和7.45(d，1H，8-H)。

Claims (10)

1.一种制备9-氨基-6-脱甲基-6-脱氧四环素无机酸盐的方法，其特征在于，包括：
(a)将溶于冷的、浓无机酸中的6-脱甲基-6-脱氧四环素与卤化试剂，在0℃至约20℃下反应，并回收7-卤-6-脱甲基-6-脱氧四环素无机酸盐；和
(b)将溶于冷的、浓无机酸中的7-卤-6-脱甲基-6-脱氧四环素无机酸盐与稍过量的硝化试剂，在-15℃-+15℃下反应，并回收7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐；和
(c)在室温下，将溶于溶剂中的7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐，在1-40磅/平方英寸压力下，被VIII族金属催化剂，它们的盐或稀有金属氧化物还原，通过在醇中稀释而分离产品，并回收9-氨基-6-脱甲基-6-脱氧四环素无机酸盐。
2.如权利要求1所述的方法，其特征在于，将步骤(a)和(b)合并为：
将溶于冷的、浓无机酸中的6-脱甲基-6-脱氧四环素与卤化试剂，在0℃至约20℃温度下反应，随后在-15℃-+15℃加入稍过量的固体金属硝酸盐或“混合酸”，用溶剂稀释，并回收7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐。
3.如权利要求1或2所述的方法，其特征在于，所述的卤化试剂包括溴，N-氯丁二酰亚胺，N-溴丁二酰亚胺，一氯化碘或苯基三甲基铵基二氯碘酸盐。
4.如权利要求1或2所述的方法，其特征在于：所述的浓无机酸包括浓硫酸。
5.如权利要求1或2所述的方法，其特征在于：所述的7-卤-6-脱甲基-6-脱氧四环素无机酸盐，7-卤-9-硝基-6-脱甲基-6-脱氧四环素无机酸盐或者9-氨基-6-脱甲基-6-脱氧四环素无机酸盐是用过滤回收的。
6.如权利要求1所述的方法，其特征在于，所述的硝化试剂包括“混合酸”或金属硝酸盐。
7.如权利要求6所述的方法，其特征在于，所述的“混合酸”是稍过量的溶于浓硫酸的10％硝酸。
8.如权利要求1或2所述的方法，其特征在于，所述的VIII族的金属催化剂，它们的盐或稀土金属氧化物包括10-30％重量比的铂/活性炭，钯/活性炭，铑/活性炭，钌/活性炭或铱/活性炭。
9.如权利要求2所述的方法，其特征在于，所述的硝酸盐包括过量10％的硝酸钾。
10.如权利要求2所述的方法，其特征在于，所述的“混合酸”是稍过量的溶于浓硫酸的10％硝酸。
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