CN100355771C - 合成高纯度D-(17α)-13-乙基-17-羟基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟的方法 - Google Patents
合成高纯度D-(17α)-13-乙基-17-羟基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟的方法 Download PDFInfo
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Abstract
本发明涉及经由乙酰化d-炔诺孕酮的17位,肟化所得17-乙酸基衍生物的3位桥氧基,最后水解所得3-肟衍生物的17位乙酸基来合成高纯度d-(17α)-13-乙基-17-羟基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟(也称为norelgestromine)的方法。根据本发明所述方法如下:在乙酸中,在氯化锌和氯化氢或70%高氯酸的存在下,在惰性气体中,用乙酸酐乙酰化纯度至少为93-94%的起始原料d-(17α)-17-羟基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮(d-炔诺孕酮),在反应完成后用盐酸水溶液分解副产物即过量的乙酸酐和“乙酸烯醇酯”,随后通过添加冰水从反应混合物中分离所形成的d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮,滤出沉淀产物,用水洗涤,干燥,溶于二氯甲烷或丙酮中,并用硅胶或氧化铝和活性炭澄清,在滤掉澄清剂后浓缩最终溶液并重结晶残渣,在乙酸钠的存在下,在乙酸中,在氮气下并伴随剧烈的搅拌,将所得的d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮与乙酸羟铵或羟基氯化铵反应约1小时,在反应完成后添加水,滤出沉淀产物,用水洗涤,干燥并重结晶,在C1-C4烷基醇溶液中,在氮气下,在温度约5-38℃之间并伴随剧烈的搅拌下,用等量碱金属的氢氧化物水解所得到的d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟,在反应完成后用水稀释反应混合物,并用乙酸调最终混悬液的pH值至7.5-9,滤出沉淀产物,用水洗涤,干燥,将粗产物溶于乙醇中,用活性炭澄清,滤出澄清剂后在所得溶液中添加水,滤出沉淀的高纯度d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟,用水洗涤并在给定条件下从乙醇中重结晶。
Description
本发明涉及经由乙酰化d-炔诺孕酮的17位,肟化所得17-乙酸基衍生物的3位桥氧基,最后水解所得3-肟衍生物的17位乙酸基来合成高纯度d-(17α)-13-乙基-17-羟基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟(也称为norelgestromine)的方法。
说明书中所用术语″高纯度″是指产物/原料/化合物中指定化合物的含量至少为99.5%,以及其他甾类杂质的总量不超过0.1%。
有关诺孕酯代谢的研究记载于如下出版物中:Am.J.ObstetGynecol.
163,2127-31.(1990)。该作者发现d-诺孕酯的口服代谢产物为norelgestromine、d-(17α)-13-乙基-17-乙酸基-18,19-二去甲孕-4-烯-20-炔-3-酮(乙酸炔诺孕酮酯),以及d-(17α)-13-乙基-17-羟基-18,19-二去甲孕-4-烯-20-炔-3-酮(d-炔诺孕酮),它们是造成生物活性的首要原因。
作为第三代避孕药使用的诺孕酯/乙炔基***的有效性和安全性记载于如下出版物中:Am.J.Obstet Gynecol.,166,1969-77.(1992)。他们也证明了诺孕酯的主要代谢产物为norelgestromine,其与诺孕酯具有相似的药理学性质,并且在口服后的较短时间后就能在血清中被检测到。
在美国专利5,876,746中,作者建议使用norelgestromine本身或与经皮贴剂中的***成分结合使用norelgestromine以抑制生育。
在匈牙利专利165356中公开了dl-以及d-炔诺孕酮的合成。合成的起始原料为消旋性或旋光性的3-甲氧基-甾-2,5(10)-二烯-17β-醇,其在100℃下在吡啶中与羟基氯化铵反应,随后氧化所得13-乙基-[3-(羟基-亚胺基)]-甾-4-烯-17β-醇的17位,接着乙炔化17位的桥氧基得到d1-(17α)-13-乙基-17-羟基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟或norelgestromine。尽管该文中描述了中间产物d1-(17α)-13-乙基-17-羟基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟和norelgestromine的合成,但该专利中并没给出这些化合物的鉴定和纯度(质量要求)以及生物活性。
在美国专利4,027,019中主要从大体上描述了norelgestromine的17-乙酸基和其酯衍生物的合成,以及它们的生物学试验。
考虑到为了达到药典对于治疗中所用每种活性成分,尤其是具有生物活性的甾类越来越高的要求,我们努力研究生产所述高纯度产品的既经济又能达到甚至是最高要求的方法。
所需化合物的纯度还由起始原料的纯度来决定。这点尤其重要,因为如果最终产物的纯化仅能通过大量消耗原料实现的话,在这种情况下实现反应的经济化就会限制要求达到的纯度。然而在很多情况下,提供足够纯的起始原料还是会消耗掉大量的原料。在这种情况下,应该尽量利用最后或之前任何中间产物的更多有利的物理性质以生产纯化的最终产物。
令人惊奇的发现,可以通过如下的本发明制备比药典中通常规定的纯度界限(杂质最大量小于1%)更纯数量级的norelgestromine:
在乙酸中,在氯化锌和氯化氢或70%高氯酸中的存在下,在惰性气体中,用乙酸酐乙酰化纯度为93-94%的起始原料d-(17α)-17-羟基-13-以及-18,19-二去甲孕-4-烯-20-炔-3-酮(d-炔诺孕酮),在反应完成后用盐酸水溶液分解副产物即过量的乙酸酐和″乙酸烯醇酯″,
随后通过添加冰水从反应混合物中分离所形成的d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮,滤出沉淀产物,用水洗涤,干燥,溶于二氯甲烷或丙酮中,用硅胶或氧化铝和活性炭澄清,在滤出澄清剂后浓缩最终溶液,并优选从二异丙醚/乙腈或二异丙基醚/乙醇为9∶1的混合物中重结晶残渣,
在乙酸钠的存在下,在乙酸中,在氮气下并伴随剧烈的搅拌,将所得到的d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮与乙酸羟铵或羟基氯化铵反应约1小时,在反应完成后添加水,滤出沉淀产物,用水洗涤,干燥,并优选从乙醇中重结晶,
在C1-C4烷基醇溶液中,在氮气下,在温度约5-38℃之间并伴随剧烈的搅拌下,用等量碱金属的氢氧化物水解所得到的d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟,在反应完成后用水稀释混合物,并用乙酸调最终混悬液的PH值至7.5-9,滤出沉淀产物,用水洗涤,干燥,将粗产物溶于乙醇中,用活性炭澄清,滤出澄清剂后在所得溶液中添加水,滤出沉淀的高纯度d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟,用水洗涤并在给定条件下从乙醇中重结晶。
上述提及的″乙酸烯醇酯″是指具有3-乙酸基-3,5-二烯结构的不稳定化合物。该结构是在第一步乙酰化步骤下形成的少量平衡副反应产物,在形成d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮下用盐酸水溶液分解。
根据本发明可能的是,在水解之前通过已知方法例如色谱法分离肟化步骤中所形成的反式/顺式异构混合物中的几何异构体,随后水解所得到的化合物。因此,根据本发明的水解不会影响肟中氮原子的几何位置,水解之后得到合适的纯的反式和顺式norelgestromine异构体。
本发明通过如下非限制性的实施例进行说明。
实施例1
d-(17α)-13-乙基-17-乙酸基-18,19-二去甲孕-4-烯-20-炔-3-
酮(乙酸炔诺孕酮酯)
在氮气下,边剧烈搅拌边向150g(约0.45mol)d-炔诺孕酮(纯度94%)和1500ml乙酸的混悬液中,加入135ml(1.428mol)乙酸酐和3ml 70%的高氯酸水溶液。数分钟后混悬液变得澄清。搅拌持续20分钟,随后向反应混合物中加入135ml水和75ml 10%的盐酸水溶液。搅拌1小时后,将反应混合物倒入14L冰水中。滤出沉淀物,用水洗涤并干燥。将所得粗产物溶于1500ml二氯甲烷中,并与150g硅胶搅拌30分钟以澄清。滤出硅胶,蒸发溶剂。用异丙醚/乙腈为9∶1的混合物回流残渣15分钟,随后将溶液冷却至0℃。滤出沉淀物并干燥,收得137g纯目标化合物。通过重复上述纯化步骤从母液中获得另外的19g目标化合物。总收率:152g(89.3%)。Mp.:204-205℃。[α]D=-25°(c=1%氯仿)
根据薄层色谱法该产物含有小于1%的杂质(以乙酸左炔诺孕酮酯计算)。(使用TLC 25 DC-Alufolien硅胶60F254板和甲苯/丙酮为4∶1的混合物作为洗脱液。用乙醇-硫酸混合物对板喷雾进行检测。)
实施例2
d-(17α)-13-乙基-17-乙酸基-18,19-二去甲孕-4-烯-20-炔-3-
酮(乙酸炔诺孕酮酯)
在氮气下,边搅拌边向10g(约0.03mol)d-炔诺孕酮(纯度93%)和100ml乙酸的混悬液中,加入6ml(0.063mol)乙酸酐、2g无水氯化锌和乙酸中的1.6ml 6.7%的盐酸溶液。数分钟后混悬液变得澄清。搅拌持续20分钟,随后加入5ml水并进一步搅拌15分钟后,向反应混合物中加入3ml 18%的盐酸水溶液,并继续搅拌45分钟。随后将反应混合物倒入600ml冰水中,滤出沉淀物,用水洗涤并干燥。根据实施例1所述的方法纯化粗目标化合物。
收率:15.4g(90.47%)。Mp.:204-205℃。[α]D=-25°(c=1%氯仿)。根据实施例1所述的分析法得出最大杂质量为1%。
实施例3
d-(17α)-13-乙基-17-乙酸基-18,19-二去甲孕-4-烯-20-炔-3-
酮-肟(诺孕酯)
在氮气下,边搅拌边向根据实施例1或2所得的12g(0.033mol)d-乙酸炔诺孕酮酯和120ml乙酸的溶液中,加入9.44g(0.1mol)乙酸羟铵。在室温下搅拌反应混合物45分钟,随后倒入1L水中。滤出沉淀的结晶,用水洗涤并在40℃下真空干燥。将所得的12.2g粗产物溶于250ml沸腾乙醇中,用1.2g活性炭澄清,在滤出活性炭后将溶液浓缩至约最初体积的20%。将所得到的含结晶产物的溶液冷却至0℃,并在该温度下保持12小时。滤出沉淀的结晶,用乙醇洗涤,在40℃下干燥,收得11.0g(88%)目标化合物。Mp.:224-226℃。
根据USP 26th药典1335页所述的试验1和试验2得出产物的杂质量小于0.5%。
实施例4
d-(17α)-13-乙基-17-乙酸基-18,19-二去甲孕-4-烯-20-炔-3-
酮-肟(诺孕酯)
在氮气下,边剧烈搅拌边向根据实施例1或2所得的120g(0.33mol)乙酸炔诺孕酮酯和1259g(1200ml)乙酸的溶液中,加入90.2g(1.1mol)无水乙酸钠和76g(1.93mol)盐酸羟铵。反应混合物的温度需低于30℃。反应在1小时内完成。随后将所得到的白色混悬液倒入10L水中,并搅拌所得混合物30分钟。滤出沉淀产物,用水洗涤并在40℃干燥。
将所得的粗产物(122g)溶于197.3g(2500ml)的沸腾乙醇中,用12g活性炭澄清,在40℃以下减压浓缩滤液至400ml,随后冷却至0-5℃,并在该温度下保持3小时。滤出沉淀的白色结晶,用197g(250ml)乙醇分两次洗涤,并在40℃下干燥,收得102g(81.6%)目标化合物。Mp.:224-226℃。
根据USP 26th药典1335页所述的试验1和试验2得出产物的杂质量小于0.5%。
实施例5
d-(17α)-13-乙基-17-羟基-18,19-二去甲孕-4-烯-20-炔-3-酮
-肟(Norelgestromine)
在氮气下,在20-28℃,边搅拌边向根据实施例3或4所得的50.0g(135.3mmol)诺孕酯和500ml甲醇的混悬液中,加入17.04g(0.406mol)氢氧化锂一水合物。在搅拌约30分钟后,得到一均匀溶液,同时温度升高10℃。将反应混合物在25-35℃搅拌3小时,通过薄层色谱法检测反应是否完成。随后在10-25℃,将反应混合物倒入5L水中(混悬液pH值约为13),并用14.7ml(0.25mol)乙酸调混悬液PH值至7.5-9。搅拌所得混悬液20分钟,滤出结晶产物,并用2×200ml水洗涤。测滤液PH值,并重复洗涤直至滤液PH值为7-7.5。在50℃干燥滤出的粗产物。在25-30℃时将所得的45g粗产物溶于440ml乙醇中,随后加入2.2g活性炭。搅拌20分钟后,滤出澄清剂并用乙醇洗涤。随后在10-25℃时并伴随剧烈的搅拌,将滤液倒入4.4L水中。滤出所得产物,用水洗涤,并在50℃干燥,收得42.0g(94.8%)目标化合物。Mp.:110-130℃,含水量0.4%。
实施例6
d-(17α)-13-乙基-17-羟基-18,19-二去甲孕-4-烯-20-炔-3-酮
-肟(Norelgestromine)
在氮气下,在22℃时,边剧烈搅拌边向根据实施例3或4所得的10.0g(0.027mol)诺孕酯(左炔诺孕酮-乙酸酯-肟)和100ml甲醇的混悬液中,加入3.25g(0.081mol)氢氧化钠。搅拌约10分钟后得到一均匀溶液,同时温度上升至32℃。在25℃,搅拌反应混合物3小时,通过薄层色谱法检测反应是否完成。在10-20℃,边搅拌边将反应混合物倒入1000ml水中,用3ml乙酸调混悬液的PH值至7-7.5。随后搅拌所得混悬液20分钟,滤出沉淀产物,用水洗涤,并用五氧化磷在40℃真空干燥,收得8.4g(94.8%)为3E和3Z异构体混合物的目标化合物。Mp.:110-130℃。根据HPLC测得杂质量为0.09%。
Example 7
d-(17α)-13-乙基-17-羟基-18,19-二去甲孕-4-烯-20-炔-3-酮
-肟(Norelgestromine)
在氮气下,在22℃时,边搅拌边向根据实施例3或4所得的10.0g(0.027mol)诺孕酯(左炔诺孕酮-乙酸酯-肟)和100ml甲醇的混悬液中,加入4.56g(0.081mol)氢氧化钾。搅拌约10分钟后得到一均匀溶液,同时温度上升至32℃。在25℃,搅拌反应混合物3小时,通过薄层色谱法检测反应是否完成。在10-20℃,边搅拌边将反应混合物倒入1000ml水中,用2.7ml乙酸调混悬液的PH值至7-7.5。随后搅拌所得混悬液20分钟,滤出沉淀产物,用水洗涤,并用五氧化磷在40℃真空干燥,收得8.6g(96.9%)为3E和3Z异构体混合物的目标化合物。Mp.:110-130℃。根据HPLC测得杂质总量为0.1%。
使用Shimadzu UV检测仪和Shimadzu积分仪通过HPLC测定所得norelgestromine样品的纯度。在244nm进行检测。使用150×4.6mm柱,填充物为5μm大小的Supelcosil LC-18-DB。洗脱液为乙腈∶四氢呋喃∶水为7∶25∶68的混合物。在室温下进行测定,流速为1cm3/分钟。
通过如下制备样品溶液:称量25mg化合物至50ml容量瓶中,加入5ml甲醇,并使样品溶解,随后向瓶中加入洗脱液直至校准线。按同样的方法用含E/Z异构体比例为1.3-1.6的分析纯norelgestromine制备标准溶液(STD)。
通过如下公式计算杂质%(S%)量:
S%=(CSTD×A杂质)/(ASTDcalc.×C样品)×rf×100
在该式中:
A=下标中成分的曲线下面积
CSTD=标准曲线的浓度[mg/ml]
ASTDcalc.=ASTD,E×0.72+ASTD,Z(下标E是指E异构体,下标Z是指Z异构体)
C样品=样品溶液的浓度[mg/ml]
已知成分的响应因子(rf)如下所示:
左炔诺孕酮=0.78
norelgestromine Z异构体=1.00
norelgestromine E异构体=0.72
诺孕酯Z异构体=1.08
诺孕酯E异构体=0.81
关于不明杂质=1.00
上述HPLC测定结果为杂质总量为0.1%。
NMR测定结果:
1H NMR{500MHz,DMSO-d6(TMS),δ(ppm)Z/E异构体):0.92/0.92(3H,t,-CH2-CH3),1.40/1.40(2H,m,-CH2-CH3),2.05 & 2.24/1.87 &2.87(2H,m,H-2),3.28/3.28(1H,s,≡CH),5.23/5.23(1H,s,17-OH),6.40/5.78(1H,m,H-4),10.12/10.38(1H,s,=N-OH)
13C NMR{125MHz,DMSO-d6(TMS),δ(ppm)Z/E异构体}:9.4/9.4(-CH2-CH3),18.3/18.3(-CH2-CH3),26.9/20.6(C-2),79.6/79.6(C-17),89.1/89.1(-C≡),74.9/74.9(≡CH),111.6/118.6(C-4),151.2/154.3(C-3),152.0/148.1(C-5)
Claims (4)
1.经由乙酰化d-炔诺孕酮的17位,肟化所得17-乙酸基衍生物的3位桥氧基,最后水解所得3-肟衍生物的17位乙酸基来合成高纯度d-(17α)-13-乙基-17-羟基-18,1 -二去甲孕-4-烯-20-炔-3-酮-肟的方法,其特征在于:
在乙酸中,在氯化锌和氯化氢或70%高氯酸的存在下,在惰性气体中,用乙酸酐乙酰化纯度至少为93-94%的起始原料d-(17α)-17-羟基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮(d-炔诺孕酮),在反应完成后用盐酸水溶液分解过量的乙酸酐和副产物″乙酸烯醇酯″,
随后通过添加冰水从反应混合物中分离所形成的d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮,滤出沉淀产物,用水洗涤,干燥,溶于二氯甲烷或丙酮中,并用硅胶或氧化铝和活性炭澄清,在滤出澄清剂后浓缩最终溶液并重结晶残渣,
在乙酸钠的存在下,在乙酸中,在氮气下并伴随剧烈的搅拌,将所得的d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮与乙酸羟铵或羟基氯化铵反应约1小时,在反应完成后添加水,滤出沉淀产物,用水洗涤,干燥并重结晶,
在C1-C4烷基醇溶液中,在氮气下,在温度约5-38℃之间并伴随剧烈的搅拌下,用等量碱金属的氢氧化物水解所得到的d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟,在反应完成后用水稀释反应混合物,并用乙酸调最终混悬液的PH值至7.5-9,滤出沉淀产物,用水洗涤,干燥,将粗产物溶于乙醇中,用活性炭澄清,滤出澄清剂后在所得溶液中添加水,滤出沉淀的高纯度d-(17α)-17-羟基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟,用水洗涤并在给定条件下从乙醇中重结晶。
2.根据权利要求1的方法,其特征在于用氢氧化锂一水合物在甲醇中水解d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟。
3.根据权利要求1的方法,其特征在于从二异丙基醚/乙腈或二异丙基醚/乙醇为9∶1的混合物中使所得到的d-(17α)-17-乙酸基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮重结晶。
4.根据权利要求1的方法:其特征在于从乙醇中使所得到的d-(17α)-17-羟基-13-乙基-18,19-二去甲孕-4-烯-20-炔-3-酮-肟重结晶。
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- 2004-04-29 RS YUP-2005/0897A patent/RS20050897A/sr unknown
- 2004-04-29 EP EP04730316A patent/EP1638988B1/en not_active Expired - Lifetime
- 2004-04-29 MX MXPA05013948A patent/MXPA05013948A/es active IP Right Grant
- 2004-04-29 AT AT04730316T patent/ATE462712T1/de not_active IP Right Cessation
- 2004-04-29 EA EA200600119A patent/EA008411B1/ru not_active IP Right Cessation
- 2004-04-29 CN CNB2004800165780A patent/CN100355771C/zh not_active Expired - Fee Related
-
2006
- 2006-01-27 NO NO20060455A patent/NO20060455L/no not_active Application Discontinuation
- 2006-01-27 HR HR20060038A patent/HRP20060038A2/xx not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1190351A (zh) * | 1995-06-07 | 1998-08-12 | 西格纳斯公司 | 把17-脱乙酰基诺孕酯单独或与***结合给药的经皮贴片和方法 |
Also Published As
Publication number | Publication date |
---|---|
CA2528952A1 (en) | 2005-01-06 |
DE602004026306D1 (de) | 2010-05-12 |
WO2005000868A1 (en) | 2005-01-06 |
RS20050897A (sr) | 2007-08-03 |
NO20060455L (no) | 2006-03-29 |
EP1638988A1 (en) | 2006-03-29 |
UA80059C2 (en) | 2007-08-10 |
BRPI0412186A (pt) | 2006-08-22 |
HUP0301982D0 (en) | 2003-09-29 |
HRP20060038A2 (en) | 2006-11-30 |
EA008411B1 (ru) | 2007-04-27 |
CN1805970A (zh) | 2006-07-19 |
AU2004251118A1 (en) | 2005-01-06 |
NZ544378A (en) | 2008-02-29 |
EP1638988B1 (en) | 2010-03-31 |
ATE462712T1 (de) | 2010-04-15 |
EA200600119A1 (ru) | 2006-06-30 |
JP2007516946A (ja) | 2007-06-28 |
MXPA05013948A (es) | 2006-03-09 |
HUP0301982A2 (hu) | 2005-04-28 |
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