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Description: This patent application claims the benefit of priority under 35 U.S.C. §119 of German Patent Application No. 199 55 190.1, filed Nov. 16, 1999. German Patent Application No. 199 55 190.1 is incorporated herein in its entirety by reference. The present invention concerns highly pure, crystalline, stable compounds of novel derivatives of 3,3-diphenylpropylamines in the form of their salts, a method for manufacturing these and highly pure, stable, intermediate products. From document PCT/EP99/03212 novel derivatives of 3,3-diphenylproprylamines are known. These are valuable prodrugn for the treatment of urinary incontinence and other spasmodic complaints, which overcome the disadvantage of the active substances available to date, namely inadequate absorption of the active substance by biological membranes or the unfavourale metabolism of these. Furthermore these novel prodrugs have improved pharmacokinetic characteristics compared with Oxybutynin and Tolterodin. Preferred compounds from the group of these novel derivatives of 3,3-diphenylpropylarines are esters of aliphatic or aromatic carboxylic acids with the general formula A referred to below in which R denotes C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl or unsubstituted or substituted phenyl. These can occur in their optical isomers form as racemic mixtures and in the form of their individual enantiomers. Compounds with the structure of formula A do, however, have low solubility in water. This restricts their oral bioavailability. Finally, monoesters of the structure, as shown in formula A, have a tendency towards intermolecular transesterification. During long periods of storage, therefore, as the content of the compounds with the structure of general formula A drops an increase in diesters and free diol can be detected. Basically salts of the compounds of general formula A can be obtained if solutions of the compounds of formula A (base component) are purified with solutions of acids in suitable solvents, but the salts obtained in the form of solid matter can prove to be altogether amorphous and/or hygroscopic and cannot be directly crystallized from the normal solvents either. Such salts have inadequate chemical stability to be galenically processed as valuable pharmaceutically active substances. Surprisingly, it has now been found that the abovementioned disadvantages can be avoided if compounds with the structure of general formula A, once they have been prepared under a special reaction process, are converted with a physiologically compatible inorganic or organic acid with general formula H-X, in which − X represents the respective acid residue, into their respective salt with general formula I. The problem for the present invention is therefore to provide highly pure, crystalline, stable compounds of novel derivatives of 3,3-diphenylpropylamines in the form of their salts, that avoid the stated disadvantages and are well suited to use in pharmaceutical-technical formulations and can be processed into these. A further problem for the present invention is to provide a method for manufacturing such highly pure, crystalline, stable compounds in the form of their salts, as well as highly pure, stable intermediate products. The final problem for the invention is to provide a method for manufacturing the abovementioned compounds with which a high yield of the products of the process and the respective intermediate products can be obtained chemo- or regioselectively. This problem is solved in that highly pure, crystalline, stable compounds of the 3,3-diphenylpropylamines in the form of their salts with general formula I are provided, in which R denotes C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, substituted or unsubstituted phenyl and X − is the acid residue of a physiologically compatible inorganic or organic acid. In accordance with a design of the invention the salts of general formula I can contain the respective acid residue X − of the acids mentioned below: • o hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(−  -malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric acid, D-(−-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid. In accordance with a further design form of the invention R-configured compounds with general formula 2 are provided in which R denotes C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, substituted or unsubstituted phenyl and X − is the acid residue of a physiologically compatible inorganic or organic acid. In accordance with an advantageous design form of the invention the compounds in the form of their salts of general formula 2 can contain the respective acid residue X − of the acids mentioned below: • o hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(− -malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric acid, D-(−-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid. Preferred compounds of the present invention are the salts • o R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hy droxymethylphenylisobutyrate ester hydrogen fumarate and o R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hy droxymethylphenylisobutyrate ester hydrochloride hydrate. Furthermore, compounds are preferred in which R stands for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-(1-cyclo-propyl-methanoyloxy)-phenyl, 4-(1-cyclobutyl-methanoyloxy)-phenyl, 4-(1-cyclohexyl-methanoyloxy)-phenyl or 4-(2,2-dimethyl-propanoyloxy)-phenyl and X denotes chloride. Particular preference is for [(R)-3-(2-{1-[4-(1-cyclopropyl-methanoyloxy)-phenyl]-methano yloxy}-5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl- ammonium chloride, [(R)-3-(2-{1-[4-(1-cyclobutyl-methanoyloxy)-phenyl]-methanoy loxy}-5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl-a mmonium chloride, [(R)-3-(2-{1-[4-(1-cyclohexyl-methanoyloxy)-phenyl]-methanoy loxy}-5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl-a mmonium chloride, [(R)-3-(2-{1-[4-(2,2-dimethyl-propanoyloxy)-phenyl]-methanoy loxy}-5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl-a mmonium chloride, {(R)-3-[2-(1-cyclopropyl-methanoyloxy)-5-hydroxymethyl-pheny l]-3-phenyl-propyl}-diisopropyl-ammonium chloride, {(R)-3-[2-(1-cyclobutyl-methanoyloxy)-5-hydroxymethyl-phenyl ]-3-phenyl-propyl}-diisopropyl-ammonium chloride, {(R)-3-[2-(1-cyclopentyl-methanoyloxy)-5-hydroxymethyl-pheny l]-3-phenyl-propyl}-diisopropyl-ammonium chloride and {(R)-3-[2-(1-cyclohexyl-methanoyloxy)-5-hydroxymethyl-phenyl ]-3-phenyl-propyl}-diisopropyl-ammonium chloride. In the compounds of the present invention the expression “alkyl” preferably stands for a straight-chain or branched-chain hydrogen group with between 1 and 6 C-atoms. Special preference is for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl. The expression “cycloalkyl” designates cyclical hydrogen groups, that have between 3 and 10 hydrogen atoms, that may also contain suitable substitutes in place of the hydrogen atoms. The expression “phenyl” designates a —C 6 H 5 -group that may be substituted or unsubstituted. Suitable substitutes can be, for example, alkyl, alkoxy, halogen, nitro and amine. The expression “alkoxy” has, with respect to the alkyl component, the same meaning as already given above for “alkyl”. Suitable halogens are fluorine, chlorine, bromine and iodine atoms The present invention also includes methods for manufacturing the compounds in accordance with the invention of general formula I as well as valuable intermediate products. The method is characterised by chemo- and regioselectivity. Compounds of General Formula I in which R denotes C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, substituted or unsubstituted phenyl and X − is the acid residue of a physiologically compatible inorganic or organic acid, are that • o a) a compound of formula III is split with a hydrogenation agent to form a compound of formula V whereupon o b) the compound of formula V so obtained is converted with agent, in order to give a compound of formula VI which o c) is converted with an acylation agent, in order to obtain of formula A in which R has the significance stated above, which d) is converted with a physiologically compatible inorganic or organic acid to form a compound of formula I in which R denotes C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, unsubstituted or substituted phenyl and X− is the acid residue of a physiologically compatible inorganic or organic acid. In accordance with the invention, for the manufacture of the compounds of general formula I hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(− -malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric acid, D-(−-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid are used. In accordance with an advantageous further development of the invention a method for the manufacture of R-configured compounds of the general formula 2 is described, in which R denotes C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, substituted or unsubstituted phenyl and X − is the acid residue of a physiologically compatible inorganic or organic acid, in that • o a) a compound of formula 3 is split with a hydrogenation agent to form a compound of formula 5 whereupon o b) the compound of formula 5 so obtained is converted with a reducing agent, in order to give a compound of formula 6 which o c) is converted with an acylation agent, in order to obtain a compound of formula 1 in which R has the significance stated above, which o d) is converted with a physiologically compatible inorganic or organic acid to form a compound of formula 2 in which R denotes C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, unsubstituted or substituted phenyl and X− is the acid residue of a physiologically compatible inorganic or organic acid. Advantageously in order to obtain compounds of general formula 2, in accordance with the method hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(− -malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric acid, D-(−-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+) -glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid are used. Particular advantageously, on the basis of the crystalline R-(− -4-benzyloxy-3-(3-diisopropylamino-1-phenyl-propyl)be nzoic acid methyl ester, the highly pure, crystalline intermediate product R-(−-3-(3-diisopropylamino-phenyl-propyl)-4-hydroxy-benzo ic acid methyl ester is prepared, which is reduced to R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylp henol, is finally acylated in a suitable manner and is then converted with a physiologically compatible inorganic or organic acid under spontaneous crystallization to the respective highly pure, crystalline, stable salt. Depending on the acid chloride used, compounds of general formula 1 are obtained, in which R denotes C 1 -C 6 -alkyl, in particular isopropyl, C 3 -C 10 -cycloalkyl or unsubstituted or substituted phenyl. |
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wypward(金币+3):这是谷歌翻译的吧！但还是谢谢参与 2010-05-24 09:22:36
wypward(金币+3):这是谷歌翻译的吧！但还是谢谢参与 2010-05-24 09:22:36
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描述: 该专利申请要求优先权的35岁以下的编119德国中华民国专利申请案号(55 190.1、归档。199年11月16日。德国的专利申请号190.1 199 55一同被整合,以供参考。 本发明关切的高纯度、水晶、稳定的混合物,3-diphenylpropylamines小说的衍生3的形式的一种方法,他们的盐、高纯度,生产这些、稳定、中间产品。 从文件EP99/03212 PCT / 3,3-diphenylproprylamines衍生物的小说是众所周知的。 这些都是珍贵的prodrugn治疗性尿失禁和其他船上投诉,克服不利的活性物质可到目前为止,即不足的活性物质的吸收由生物膜或unfavourale代谢。 而且这些小说已经改善代谢特点热点和Tolterodin Oxybutynin相比。 优先化合物的这些小说中有3个,3-diphenylpropylarines衍生的脂肪或芳香羧酸酯酸与一般公式是指以下 在R代表C 1 -C 6 -alkyl、C 3 -C 10 -cycloalkyl或unsubstituted或取代苯。这些可以发生在他们的光学异构体用表格的形式混合物和个人对映体。 化合物的结构,然而,一个做公式水溶性较低。这种限制他们的口腔生物利用度。 最后,使结构,如图配方,有一间以倾向。在长期贮存,因此,为内容的化合物的结构,增加的一般表达式,在其中一个滴醇能被探测到,免费。 基本上盐的通用公式的化合物是可以解决的公式的化合物(组件基)的纯化解酸在适当的溶剂,但是盐的形式获得固体物质不能证明是共晶和/或吸湿性,不能直接从正常的溶剂结晶。这样的盐不足的化学稳定性是galenically处理为价值”活性物质。 令人惊讶的是,它现在已经发现上述缺点可以避免的化合物的结构一般公式,一旦他们已经准备下一个特别的反应过程,为有生理兼容的无机或有机酸和一般公式,H-X−X代表各自的酸性渣,为各自的盐与一般的公式。 本发明的问题,因此提供的高纯度、水晶、稳定的混合物,3-diphenylpropylamines小说的衍生3的形式,避免了他们的盐陈述弊端,非常适合用于pharmaceutical-technical配方,可加工成这些。 进一步的问题,本发明提供一种高纯度为制造这样,水晶,稳定化合物的形式的盐,以及高纯度、稳定的中间体。 最后的问题是提供了一种方法发明制造上述化合物和高产的产品的工艺及各自的中间产品可以获得——或者可以化疗。 这个问题已经解决,高纯度、水晶、稳定化合物的三、3-diphenylpropylamines的盐的形式与一般公式我, 在R代表C 1 -C 6 -alkyl、C 3 -C 10 -cycloalkyl取代苯、unsubstituted,或者是酸性渣X−的生理兼容的无机或有机酸。 按照设计的一般公式,发明了盐,我可以包含了各自的酸性渣X−以下的氨基酸。 • 啊,hydrobromic盐酸酸、磷酸、硫酸、硝酸、醋酸、丙酸、酸、硬脂酸、马来酸、富马酸、草酸琥珀酸、DL-malic酸、L -(−-malic酸、D -(+)-malic酸、DL-tartaric酸、L -(+)-tartaric酸、D -(−-tartaric酸、柠檬酸、天冬氨酸、L -(+)-ascorbic酸、D -(+)-glucuronic酸、2-oxopropionic酸(丙酮酸),furan-2-carboxylic酸(mucic酸)、苯甲酸、4-hydroxybenzoic酸、salicyclic酸、vanillic酸、4-hydroxycinammic酸、没食子酸、马尿酸(N-benzoyl-glycine),aceturic酸(N-aectylglycine),phloretinic酸(3 -(4-hydroxyphenyl)-propionic酸)、邻苯二甲酸、四种羧酸或orotic酸。 依照进一步设计的一般公式R-configured发明和2个被提供 在R代表C 1 -C 6 -alkyl、C 3 -C 10 -cycloalkyl取代苯、unsubstituted,或者是酸性渣X−的生理兼容的无机或有机酸。 依照一个有利的设计形式的发明的形式的化合物的一般公式的盐可容纳2×−各自的酸性渣酸下面提到: • 啊,hydrobromic盐酸酸、磷酸、硫酸、硝酸、醋酸、丙酸、酸、硬脂酸、马来酸、富马酸、草酸琥珀酸、DL-malic酸、L -(−-malic酸、D -(+)-malic酸、DL-tartaric酸、L -(+)-tartaric酸、D -(−-tartaric酸、柠檬酸、天冬氨酸、L -(+)-ascorbic酸、D -(+)-glucuronic酸、2-oxopropionic酸(丙酮酸),furan-2-carboxylic酸(mucic酸)、苯甲酸、4-hydroxybenzoic酸、salicyclic酸、vanillic酸、4-hydroxycinammic酸、没食子酸、马尿酸(N-benzoyl-glycine),aceturic酸(N-aectylglycine),phloretinic酸(3 -(4-hydroxyphenyl)-propionic酸)、邻苯二甲酸、四种羧酸或orotic酸。 本发明的优先化合物的盐 • o R -(+)- 2 -(3-diisopropylamino-1-phenylpropyl)-4-hy droxymethylphenylisobutyrate富氢酯和 o R -(+)- 2 -(3-diisopropylamino-1-phenylpropyl)-4-hy droxymethylphenylisobutyrate酯盐酸盐保湿。 再者,化合物的首选,cyclobutyl R代表cyclopropyl,cyclopentyl,cyclohexyl、4 -(2)-phenyl 1-cyclo-propyl-methanoyloxy,4 -(2)-phenyl 1-cyclobutyl-methanoyloxy,4 -(2)-phenyl 1-cyclohexyl-methanoyloxy或4 -(2)-phenyl 2-dimethyl-propanoyloxy和X表示。 特别偏爱是[(R)- 3 -(2 - { 1 - 4 -(1-cyclopropyl-methanoyloxy)-phenyl]-methano yloxy } -5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl -氯化铵,[(R)- 3 -(2 - { 1 - 4 -(1-cyclobutyl-methanoyloxy)-phenyl]-methanoy loxy } -5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl-a mmonium氯、[(R)- 3 -(2 - { 1 - 4 -(1-cyclohexyl-methanoyloxy)-phenyl]-methanoy loxy } -5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl-a mmonium氯、[(R)- 3 -(2 - { 1 - 4 -(2)-phenyl]-methanoy 2-dimethyl-propanoyloxy loxy } -5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl-a mmonium氯、{(R)- 3 -(2 -(1-cyclopropyl-methanoyloxy)-5-hydroxymethyl-pheny]-3-phenyl-propyl } -diisopropyl-ammonium氯、{(R)- 3 -(2 -(1-cyclobutyl-methanoyloxy)-5-hydroxymethyl-phenyl]-3-phenyl-propyl } -diisopropyl-ammonium氯、{(R)- 3 -(2 -(1-cyclopentyl-methanoyloxy)-5-hydroxymethyl-pheny]-3-phenyl-propyl } -diisopropyl-ammonium氯和{(R)- 3 -(2 -(1-cyclohexyl-methanoyloxy)-5-hydroxymethyl-phenyl]-3-phenyl-propyl } -diisopropyl-ammonium氯。 在这个化合物的本发明表达"烷基“最好是代表了一种straight-chain或branched-chain氢集团在1到6 C-atoms。特殊偏好、乙酸乙酯、醋酸丙对甲基异丙酯、醋酸异丁,,,pentyl和hexyl。表达" cycloalkyl”指明周期性氢团体,有3 - 10个氢原子,也可能包含了合适的替代品代替氢原子。 表达"苯基”指明了-C 6小时5 -group可替代或unsubstituted。合适的替代品,例如、醇酸、氧、卤素,硝基和三聚氰胺。表达"中",就烷基的组成部分,已给以上含义相同的“烷基”。适合有氟、氯离子、卤素溴碘原子 本发明也包括方法生产化合物的发明,按照一般公式我以及宝贵的中间体。 这个方法的特点是化学-和区域选择性。 我的一般公式 在R代表C 1 -C 6 -alkyl、C 3 -C 10 -cycloalkyl取代苯、unsubstituted,或者是酸性渣X−的生理兼容的无机或有机酸,是那样 • 一)的化合物啊。配方 用一个分裂形成一种化合物加氢剂的配方V吗 于是 o b)的转换公式,用了V的代理人,以给一组配方VI , o c)转换为原料,经酰化剂,以为了得到的公式 在上述的意义[j]. d),与生理兼容无机物转化为酸或有机化合物的形成 在R代表C 1 -C 6 -alkyl、C 3 -C 10 -cycloalkyl,unsubstituted或取代苯和X−是酸性渣的生理兼容的无机或有机酸。 依照这项发明,为制造的化合物的通用公式我盐酸、hydrobromic酸、磷酸、硫酸、硝酸、醋酸、丙酸、酸、硬脂酸、马来酸、富马酸、草酸琥珀酸、DL-malic酸、L -(−-malic酸、D -(+)-malic酸、DL-tartaric酸、L -(+)-tartaric酸、D -(−-tartaric酸、柠檬酸、天冬氨酸、L -(+)-ascorbic酸、D -(+)-glucuronic酸、2-oxopropionic酸(丙酮酸),furan-2-carboxylic酸(mucic酸)、苯甲酸、4-hydroxybenzoic酸、salicyclic酸、vanillic酸、4-hydroxycinammic酸、没食子酸、马尿酸(N-benzoyl-glycine),aceturic酸(N-aectylglycine),phloretinic酸(3 -(4-hydroxyphenyl)-propionic酸)、邻苯二甲酸、四种羧酸或orotic酸。 依照一个有利的进一步发展的发明了一种化合物,R-configured制造的一般公式,二是描述, 在R代表C 1 -C 6 -alkyl、C 3 -C 10 -cycloalkyl取代苯、unsubstituted,或者是酸性渣X−的生理兼容的无机或有机酸,在那 • 一个复合的阿三级方程式 用一个分裂形成一种化合物加氢剂的配方 于是 o b)的转换公式5所以取得与还原剂,为了给一个公式 , o c)转换为原料,经酰化剂,以为了获得了一级方程式 在上述的意义[j],它 阿d)转化为有生理兼容的无机或有机酸形成化合物的配方2 在R代表C 1 -C 6 -alkyl、C 3 -C 10 -cycloalkyl,unsubstituted或取代苯和X−是酸性渣的生理兼容的无机或有机酸。 为了获得成分资料库的通用公式,依照《中华人民共和国hydrobromic盐酸、酸法、磷酸、硫酸、硝酸、醋酸、丙酸、酸、硬脂酸、马来酸、富马酸、草酸琥珀酸、DL-malic酸、L -(−-malic酸、D -(+)-malic酸、DL-tartaric酸、L -(+)-tartaric酸、D -(−-tartaric酸、柠檬酸、天冬氨酸、L -(+)-ascorbic酸、D -(+)-glucuronic酸、2-oxopropionic酸(丙酮酸),furan-2-carboxylic酸(mucic酸)、苯甲酸、4-hydroxybenzoic酸、salicyclic酸、vanillic酸、4-hydroxycinammic酸、没食子酸、马尿酸(N-benzoyl-glycine),aceturic酸(N-aectylglycine),phloretinic酸(3 -(4-hydroxyphenyl)-propionic酸)、邻苯二甲酸、四种羧酸或orotic酸。 特定资料库的基础上,-4-benzyloxy-3水晶R -(− 是nzoic——(3-diisopropylamino-1-phenyl-propyl酸甲酯、高纯度、中间产品的R -(3 -(3-diisopropylamino-phenyl-propyl−-4-hydroxy-benzo ic酸甲酯制备,降至R -(+)- 2 -(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylp henol,终于在一个合适的方式、酰化和生理上然后转换兼容无机或有机酸下结晶的自发的高纯度、水晶、稳定的盐。根据酸氯化合物的一般公式,1, 在R代表C 1 -C 6 -alkyl,尤其是异丙醇、丙三-C 10 -cycloalkyl或unsubstituted或取代苯。 |
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