CN102936274B - Preparation method for [17alpha, 16alpha-d] methyl oxazoline - Google Patents

Preparation method for [17alpha, 16alpha-d] methyl oxazoline Download PDF

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CN102936274B
CN102936274B CN 201210446928 CN201210446928A CN102936274B CN 102936274 B CN102936274 B CN 102936274B CN 201210446928 CN201210446928 CN 201210446928 CN 201210446928 A CN201210446928 A CN 201210446928A CN 102936274 B CN102936274 B CN 102936274B
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anhydride
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CN102936274A (en )
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张峥斌
王锦凯
尹金玉
朱敦明
赵晓宝
叶海燕
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江西君业生物制药有限公司
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Abstract

本发明公开了一种地夫可特关键中间体[17α,16α-d]甲基噁唑啉甾体化合物的制备方法。 The present invention discloses a key intermediate deflazacort [17α, 16α-d] methyl steroid preparing oxazoline. 其步骤为:将[16,17α-环氧-孕甾-20-甲酸甲酯肼代乙酰基-1,4-二烯-3,11-二酮]用三氯甲烷溶解,与添加剂一并加入压力反应釜,搅拌下往反应釜通入氨气至一定压力,一定温度下反应;将反应制得的化合物粗品溶解于冰醋酸中,搅拌下加入一定量的酸酐,控制反应温度。 It comprises the following steps of: [16,17α- ethylene - pregn -20- methyl hydrazino-1,4-diene-3,11-acetimidoyl-dione] was dissolved with chloroform, together with additives pressure reactor was added, with stirring ammonia gas to the reaction vessel to a certain pressure at a certain temperature of the reaction; the reaction crude compound obtained was dissolved in glacial acetic acid anhydride was stirred under a certain amount of control of the reaction temperature. 反应毕,将反应液倒入冷的500mL10%氢氧化钠溶液中,搅拌1小时,抽滤得到地夫可特的关键中间体[17α,16α-d]甲基噁唑啉甾体化合物。 Completion of the reaction, the reaction solution was poured into cold 500mL10% sodium hydroxide solution, stirred for 1 hour, filtered off with suction to give the key intermediate of deflazacort [17α, 16α-d] oxazoline steroid. 本发明方法实现了地夫可特的安全清洁生产,有利于减少环境污染,缩短生产周期,降低企业生产成本,提高生产安全性,社会效益、环境效益和经济效益明显。 The method of the present invention achieves deflazacort of safe and clean production, help reduce environmental pollution, shorten the production cycle, reduce production costs and improve production safety, significant social, environmental and economic benefits.

Description

-种[1 7 α,16 a -d]甲基噁唑啉制备方法 - Species [1 7 α, 16 a -d] oxazoline prepared methyl

技术领域 FIELD

[0001] 本发明涉及一种留体化合物的制备方法,具体涉及一种地夫可特关键中间体[17 α,16 a -d]甲基噁唑啉甾体化合物的制备方法。 [0001] The present invention relates to a method for preparing a steroidal compound, in particular, to a key intermediate deflazacort [17 α, 16 a -d] oxazoline prepared methyl steroids.

背景技术 Background technique

[0002] 在此处键入背地夫可特(Deflazacort)化学名为[1,4-孕留二烯-21-乙酰氧基-11 β -羟基-[17,16-D]甲噁唑-3, 20二酮],是第三代糖皮质激素留体抗炎药,具有抗炎、抗过敏、增加糖原异生等作用,主要用于治疗肾上腺皮质机能减退、自身免疫性疾病、类风湿性关节炎、结节病等。 [0002] Type sly deflazacort (deflazacort) where the chemical name [1,4-diene-21-acetoxy progesterone stay -11 β - hydroxy - [17,16-D] -3 sulfamethoxazole , 20-dione], it is the third generation of glucocorticoid-steroidal anti-inflammatory drugs, anti-inflammatory, anti-allergic, increased gluconeogenesis action, mainly for the treatment of adrenocortical hypofunction, autoimmune diseases, rheumatoid arthritis, sarcoidosis and the like. 由于其具有副作用小,药效强和适应症广的优点,该药物自1985 年于意大利上市以来,取得了巨大的成功,销售量逐年递增。 Because of its side effects, efficacy and broad indications of the strong advantages of the drug on the market since 1985 in Italy, it was a huge success, sales increased year by year. 其结构式如(A)所示。 The structural formula (A) shown in FIG.

[0003] 目前,国内外文献报道主要以霉菌脱氢物[16,17α-环氧-Ila-羟基-孕甾-1,4-二烯-3, 20-二酮](B)为起始原料,通过氧化、上保护、开环、闭环、还原、脱保护、 碘代置换制备地夫可特。 [0003] Currently, mainly in the mold reported in the literature was dehydrogenated [16,17α- epoxy -Ila- hydroxy - pregna-1,4-diene -3, 20-dione] (B) as a starting material, by oxidation, protective, open loop, closed loop, reduction, deprotection, iodo substituted prepared deflazacort. 其中,[16, 17 α -环氧-孕甾-20-甲酸甲酯肼代乙酰基-1,4-二烯-3, 11-二酮](a) 16, 17位的开闭环(引入噁唑环)反应为关键步骤。 Wherein, [16, 17 α - epoxy - pregn -20- hydrazino carboxylate acetyl-1,4-diene -3-generation, 11-dione] (a) 16, 17-bit open loop (incorporated oxazole ring) as the key step of the reaction.

Figure CN102936274BD00031

[0005] 目前文献报道主要采用叠氮化钠开环,产生叠氮化合物中间体,后者在Raney-Ni 或PtO2催化下氢化还原闭环,制得[17a,16a-d]甲基噁唑啉甾体化合物。 [0005] It is mainly reported ring opening using sodium azide, the azide intermediate is generated, which in the hydrogenation loop PtO2 or Raney-Ni catalyst, to obtain [17a, 16a-d] methyl oxazoline steroids. 该方法用到叠氮化钠,为剧毒化学品,且与反应生成的叠氮化物中间体均为易燃易爆物质,工业生产过程存在较大安全隐患;同时,昂贵金属催化剂Raney-Ni、Pt0 2也限制了该方法在工业化生产中的应用。 This method uses sodium azide, to toxic chemicals, and the reaction of the azide intermediate materials are flammable, there is a big safety hazard industrial processes; Meanwhile, an expensive metal catalyst Raney-Ni , Pt0 2 also limits the application of this method in industrial production.

发明内容 SUMMARY

[0006] 本发明的目的是提供一种地夫可特关键中间体[17 α,16 a -d]甲基噁唑啉甾体化合物的制备方法,以克服该化合物现有技术中存在的生产工艺复杂,安全性差,成本高, 污染大等缺陷。 [0006] The object of the present invention is to provide a key intermediate deflazacort [17 α, 16 a -d] oxazoline prepared methyl steroid to overcome the prior art compounds present in the production complex process, poor security, high cost, pollution and other defects.

[0007] 本发明的反应方程式如下: [0007] The reaction of the present invention, the equation is as follows:

[0008] [0008]

Figure CN102936274BD00041

[0009] 本发明的方法包括如下步骤: [0009] The method of the present invention comprises the steps of:

[0010] (1)将化合物a用一定体积的三氯甲烷溶解,与一定质量的添加剂一并加入压力反应釜,搅拌下往反应釜通入氨气至一定压力。 [0010] (1) a compound with a volume of chloroform is dissolved, together with a mass of additive added to the pressure reactor, under stirring ammonia gas to the reaction vessel to a certain pressure. 一定温度下,保温反应,TLC跟踪反应进度。 Under certain temperature, holding the reaction, the progress of the reaction was followed TLC. 反应毕,将料液转移至玻璃反应瓶,待物料温度降至10 °C以下,加醋酸调节pH至5〜6,减压脱除溶剂,得化合物b,不经纯化直接用于下步反应。 Completion of the reaction, the reaction material was transferred to a glass vial, until batch temperature dropped below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure to give compound B, without purification was used directly in the next reaction step .

[0011] 所述添加剂为选自N,N-二甲基甲酰胺、四氢呋喃、吡啶或三乙胺,优选DMF和吡啶。 [0011] The additive is selected from N, N- dimethylformamide, tetrahydrofuran, pyridine or triethylamine, preferably pyridine and DMF.

[0012] 所述的通氨气压力为0· 1〜I MPa,优选0· 15〜0· 2 MPa。 [0012] The pressure of the ammonia gas 0 · 1~I MPa, preferably 0 · 15~0 · 2 MPa.

[0013] 式a所示的化合物与添加剂的质量比为I :0. 1〜3,优选1 :0. 5〜1。 Quality additive compound represented [0013] wherein a ratio of I:. 0 1~3, preferably 1: 5~1 0.

[0014] 所述反应温度为15〜60 °C,优选30〜40 °C。 [0014] The reaction temperature is 15~60 ° C, preferably 30~40 ° C.

[0015] (2)将上步反应制得的化合物粗品b溶解于冰醋酸中搅拌下加入一定量的酸酐, 控制反应温度,TLC跟踪反应进度。 [0015] (2) The compound obtained in the reaction step b crude was dissolved in glacial acetic acid anhydride was added under stirring a certain amount, reaction temperature, TLC tracking the progress of the reaction. 反应毕,将反应液倒入冷的500 mL10%氢氧化钠溶液中,搅拌1小时,抽滤得到产品c。 Completion of the reaction, the reaction solution was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtered off with suction to obtain a product c.

[0016] 所述酸酐选自醋酸酐、丙酸酐、顺丁烯二酸酐、苯甲酸酐或其中两者的混合物,优选醋酸酐和顺丁烯二酸酐。 [0016] The acid anhydride is selected from acetic anhydride, propionic anhydride mixture, maleic anhydride, benzoic anhydride or both wherein, preferably acetic anhydride and maleic anhydride.

[0017] 式b所示的化合物与所述醋酸摩尔比为1 :0. 2〜5,优选为1 :0. 5〜1。 The molar ratio of compound with acetic acid [0017] b as shown in Formula 1: 0 2 ~ 5, preferably 1: 5~1 0.

[0018] 式b所示的化合物与所述酸酐的摩尔比为1 :0. 5〜2,优选为I :1. 0〜1. 5。 The molar ratio of the acid anhydride with the compound represented by [0018] Formula b is 1: 5~2 0, preferably I:.. 1 0~1 5.

[0019] 所述反应温度可以根据其他反应参数在所述反应温度为10〜50 °C,优选为25〜 30。 [0019] The reaction temperature may be in the other reaction parameters according to the reaction temperature is 10~50 ° C, preferably 25~ 30. . .

[0020] 本发明以霉菌脱氢物保护产物(a)为起始原料生产地夫可特关键中间体[17α, 16 a -d]甲基噁唑啉留体化合物的步骤,与现有技术相比,其有益效果体现在: [0020] In the present invention dehydrogenation mold was protected product (a) as a starting material to produce a key step deflazacort left intermediate compound [17α, 16 a -d] methyl oxazoline, and prior art compared to its beneficial effects reflected in:

[0021] (1)采用氨气替代叠氮化钠开环,减少有毒有害辅料的使用,避免易燃易爆中间体一叠氮化物的产生,增加生产安全性; [0021] (1) using sodium azide ammonia alternative open loop, to reduce the use of hazardous materials, to avoid generating flammable intermediate nitride stack, increase production safety;

[0022] (2)采用廉价易得的酸酐和酸实现闭环反应,避免了昂贵重金属PtO2或Raney-Ni 的使用,大大降低了生产成本,有利于减少由重金属引起的环境污染; [0022] (2) using inexpensive, readily available acid anhydrides and closed-loop reaction, avoiding expensive or heavy metals using PtO2 Raney-Ni, greatly reducing the production cost, helps to reduce the environmental pollution caused by the heavy metals;

[0023] (3)在开闭环反应中,采用"一锅煮"法,即开环物(b)不需纯化可直接进行下步反应,简化操作步骤,缩短生产周期。 [0023] (3) in the open ring-closure reaction, the use of "one pot" method, i.e., the open loop (b) is carried out directly without purification in the next reaction, simplified operation, shorten the production cycle.

[0024] 综上所述,本发明方法实现了地夫可特的安全清洁生产,有利于减少环境污染,缩短生产周期,降低企业生产成本,提高生产安全性,社会效益、环境效益和经济效益明显。 [0024] In summary, the method of the present invention achieves deflazacort of safe and clean production, help reduce environmental pollution, shorten the production cycle, reduce production costs and improve production safety, social, environmental and economic benefits obvious.

[0025] (四)具体实施方式 [0025] (IV) DETAILED DESCRIPTION

[0026] 以下以具体实施例来说明本发明的技术方案,但本发明的保护范围不限于此。 [0026] In the following specific examples describe the technical solutions of the present invention, but the scope of the present invention is not limited thereto.

[0027] 实施例1 [0027] Example 1

[0028] 将30 g 16, 17 α-环氧-孕甾-20-甲酸甲酯肼代乙酰基-1,4-二烯-3, 11-二酮(a)与150 mL三氯甲烷和15 mLDMF混合,加入压力反应釜,搅拌下通入氨气至反应釜压力至0.15 MPa(通气过程控制反应温度在10-15 °C),30 °C保温反应,TLC跟踪反应进度。 [0028] A 30 g 16, 17 α- epoxy - pregn -20- hydrazino carboxylate acetyl-1,4-diene -3-generation, 11-dione (a) and 150 mL of chloroform and 15 mLDMF mixed, and the pressure reactor, under stirring ammonia gas to the reactor pressure to 0.15 MPa (reaction temperature control during ventilation 10-15 ° C), 30 ° C incubation the reaction, the progress of the reaction was followed TLC. 反应毕,将料液转移至玻璃反应瓶,待物料温度降至10 °C以下,加醋酸调节pH至5〜6,减压除去溶剂;在反应瓶中加30 mL醋酸、30 g醋酸酐,反应温度控制在30 °C,反应6小时,将反应液倒入冷的500 mL10%氢氧化钠溶液中,搅拌1小时,抽滤得到产品30.6 g,质量收率为102%,产品经HPLC检测,纯度为95. 2%。 Completion of the reaction, the reaction material was transferred to a glass vial, until batch temperature dropped below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; the reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, the reaction temperature was controlled at 30 ° C, reacted for 6 hours, the reaction solution was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtered off with suction to give product 30.6 g, 102% mass yield, product by HPLC purity of 95.2%.

[0029] 实施例2 [0029] Example 2

[0030] 将30 g 16, 17 α-环氧-孕甾-20-甲酸甲酯肼代乙酰基-1,4-二烯-3, 11-二酮(a)与150 mL三氯甲烷和30 mL吡啶混合,加入压力反应釜,搅拌下通入氨气至反应釜压力至0. 15 MPa (通气过程控制反应温度在10〜15 °C),15 °C保温反应,TLC跟踪反应进度。 [0030] A 30 g 16, 17 α- epoxy - pregn -20- hydrazino carboxylate acetyl-1,4-diene -3-generation, 11-dione (a) and 150 mL of chloroform and 30 mL of pyridine were mixed, charged to a pressure reactor, under stirring ammonia gas to a pressure reactor to 0. 15 MPa (reaction temperature control during ventilation 10~15 ° C), 15 ° C incubation the reaction, the progress of the reaction was followed TLC. 反应毕,将料液转移至玻璃反应瓶,待物料温度降至10 °C以下,加醋酸调节pH至5〜6,减压除去溶剂;在反应瓶中加30 mL醋酸、30 g醋酸酐,反应温度控制在30 °C,反应6小时, 将反应液倒入冷的500 mL10%氢氧化钠溶液中,搅拌1小时,抽滤得到产品28.6 g,质量收率为95%,产品经HPLC检测,纯度为94. 8%。 Completion of the reaction, the reaction material was transferred to a glass vial, until batch temperature dropped below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; the reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, the reaction temperature was controlled at 30 ° C, reacted for 6 hours, the reaction solution was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtered off with suction to give product 28.6 g, 95% yield, quality, product by HPLC purity of 94.8%.

[0031] 实施例3 [0031] Example 3

[0032] 将30 g 16, 17 α-环氧-孕甾-20-甲酸甲酯肼代乙酰基-1,4-二烯-3, 11-二酮(a)与150 mL三氯甲烷和30 mLDMF混合,加入压力反应釜,搅拌下通入氨气至反应釜压力至0.15 MPa (通气过程控制反应温度在10〜15 °C),40 °C保温反应,TLC跟踪反应进度。 [0032] A 30 g 16, 17 α- epoxy - pregn -20- hydrazino carboxylate acetyl-1,4-diene -3-generation, 11-dione (a) and 150 mL of chloroform and 30 mLDMF mixed, and the pressure reactor, under stirring ammonia gas to the reactor pressure to 0.15 MPa (reaction temperature control during ventilation 10~15 ° C), 40 ° C incubation the reaction, the progress of the reaction was followed TLC. 反应毕,将料液转移至玻璃反应瓶,待物料温度降至10 °C以下,加醋酸调节pH至5〜6,减压除去溶剂;在反应瓶中加30 mL醋酸、30 g醋酸酐,反应温度控制在30 °C,反应6小时, 将反应液倒入冷的500 mL10%氢氧化钠溶液中,搅拌1小时,抽滤得到产品31.2 g,质量收率为104%,产品经HPLC检测,纯度为95. 4%。 Completion of the reaction, the reaction material was transferred to a glass vial, until batch temperature dropped below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; the reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, the reaction temperature was controlled at 30 ° C, reacted for 6 hours, the reaction solution was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtered off with suction to give product 31.2 g, 104% mass yield, product by HPLC purity of 95.4%.

[0033] 实施例4 [0033] Example 4

[0034] 将30 g 16, 17 α-环氧-孕甾-20-甲酸甲酯肼代乙酰基-1,4-二烯-3, 11-二酮(a)与150 mL三氯甲烷和30 mLDMF混合,加入压力反应釜,搅拌下通入氨气至反应釜压力至0.5 MPa (通气过程控制反应温度在10〜15 °C),40 °C保温反应,TLC跟踪反应进度。 [0034] A 30 g 16, 17 α- epoxy - pregn -20- hydrazino carboxylate acetyl-1,4-diene -3-generation, 11-dione (a) and 150 mL of chloroform and 30 mLDMF mixed, and the pressure reactor, under stirring ammonia gas to the reactor pressure to 0.5 MPa (reaction temperature control during ventilation 10~15 ° C), 40 ° C incubation the reaction, the progress of the reaction was followed TLC. 反应毕,将料液转移至玻璃反应瓶,待物料温度降至10 °C以下,加醋酸调节pH至5〜6,减压除去溶剂;在反应瓶中加30 mL醋酸、30 g醋酸酐,反应温度控制在30 °C,反应6小时, 将反应液倒入冷的500 mL10%氢氧化钠溶液中,搅拌1小时,抽滤得到产品31. I g,质量收率为102%,产品经HPLC检测,纯度为95. 2%。 Completion of the reaction, the reaction material was transferred to a glass vial, until batch temperature dropped below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; the reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, the reaction temperature was controlled at 30 ° C, reacted for 6 hours, the reaction solution was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtered off with suction to give the product 31. I g, 102% mass yield, product by by HPLC, with a purity of 95.2%.

[0035] 实施例5 [0035] Example 5

[0036] 将30 g 16, 17 α-环氧-孕甾-20-甲酸甲酯肼代乙酰基-1,4-二烯-3, 11-二酮(a)与150 mL三氯甲烷和30 mLDMF混合,加入压力反应釜,搅拌下通入氨气至反应釜压力至0.15 MPa (通气过程控制反应温度在10〜15 °C),40 °C保温反应,TLC跟踪反应进度。 [0036] A 30 g 16, 17 α- epoxy - pregn -20- hydrazino carboxylate acetyl-1,4-diene -3-generation, 11-dione (a) and 150 mL of chloroform and 30 mLDMF mixed, and the pressure reactor, under stirring ammonia gas to the reactor pressure to 0.15 MPa (reaction temperature control during ventilation 10~15 ° C), 40 ° C incubation the reaction, the progress of the reaction was followed TLC. 反应毕,将料液转移至玻璃反应瓶,待物料温度降至10 °C以下,加醋酸调节pH至5〜6,减压除去溶剂;在反应瓶中加60 mL醋酸、15 g醋酸酐,反应温度控制在30 °C,反应6小时, 将反应液倒入冷的500 mL10%氢氧化钠溶液中,搅拌1小时,抽滤得到产品29. 5 g,质量收率为98%,产品经HPLC检测,纯度为95%。 Completion of the reaction, the reaction material was transferred to a glass vial, until batch temperature dropped below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; 60 mL of acetic acid was added to the reaction flask, 15 g of acetic anhydride, the reaction temperature was controlled at 30 ° C, reacted for 6 hours, the reaction solution was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtered off with suction to give the product 29. 5 g, yield 98% by mass, the product of by HPLC, 95% purity.

[0037] 实施例6 [0037] Example 6

[0038] 将30 g 16, 17 α-环氧-孕甾-20-甲酸甲酯肼代乙酰基-1,4-二烯-3, 11-二酮(a)与150 mL三氯甲烷和30 mLDMF混合,加入压力反应釜,搅拌下通入氨气至反应釜压力至0.15 MPa (通气过程控制反应温度在10〜15 °C),40 °C保温反应,TLC跟踪反应进度。 [0038] A 30 g 16, 17 α- epoxy - pregn -20- hydrazino carboxylate acetyl-1,4-diene -3-generation, 11-dione (a) and 150 mL of chloroform and 30 mLDMF mixed, and the pressure reactor, under stirring ammonia gas to the reactor pressure to 0.15 MPa (reaction temperature control during ventilation 10~15 ° C), 40 ° C incubation the reaction, the progress of the reaction was followed TLC. 反应毕,将料液转移至玻璃反应瓶,待物料温度降至10 °C以下,加醋酸调节pH至5〜6,减压除去溶剂;在反应瓶中加30 mL醋酸、30 g顺丁烯二酸酐,反应温度控制在30 °C,反应6 小时,将反应液倒入冷的500 mL10%氢氧化钠溶液中,搅拌1小时,抽滤得到产品30 g,质量收率为100 %,产品经HPLC检测,纯度为95. 2%。 Completion of the reaction, the reaction material was transferred to a glass vial, until batch temperature dropped below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; the reaction flask was added 30 mL of acetic acid, 30 g of maleic dianhydride, the reaction temperature was controlled at 30 ° C, reacted for 6 hours, the reaction solution was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtered off with suction to give the product 30 g, 100% mass yield, product by HPLC, with a purity of 95.2%.

[0039] 实施例7 [0039] Example 7

[0040] 将30 g 16, 17 α-环氧-孕甾-20-甲酸甲酯肼代乙酰基-1,4-二烯-3, 11-二酮(a)与150 mL三氯甲烷和30 mLDMF混合,加入压力反应釜,搅拌下通入氨气至反应釜压力至0.15 MPa (通气过程控制反应温度在10〜15 °C),40 °C保温反应,TLC跟踪反应进度。 [0040] A 30 g 16, 17 α- epoxy - pregn -20- hydrazino carboxylate acetyl-1,4-diene -3-generation, 11-dione (a) and 150 mL of chloroform and 30 mLDMF mixed, and the pressure reactor, under stirring ammonia gas to the reactor pressure to 0.15 MPa (reaction temperature control during ventilation 10~15 ° C), 40 ° C incubation the reaction, the progress of the reaction was followed TLC. 反应毕,将料液转移至玻璃反应瓶,待物料温度降至10 °C以下,加醋酸调节pH至5〜6,减压除去溶剂;在反应瓶中加30 mL醋酸、30 g丙酸酐,反应温度控制在30 °C,反应6小时, 将反应液倒入冷的500 mL10%氢氧化钠溶液中,搅拌1小时,抽滤得到产品27.6 g,质量收率为92%,产品经HPLC检测,纯度为93. 5%。 Completion of the reaction, the reaction material was transferred to a glass vial, until batch temperature dropped below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; the reaction flask was added 30 mL of acetic acid, 30 g propionic anhydride, the reaction temperature was controlled at 30 ° C, reacted for 6 hours, the reaction solution was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtered off with suction to give product 27.6 g, 92% mass yield, product by HPLC purity of 93.5%.

[0041] 实施例8 [0041] Example 8

[0042] 将30 g 16, 17 α-环氧-孕甾-20-甲酸甲酯肼代乙酰基-1,4-二烯-3, 11-二酮(a)与150 mL三氯甲烷和30 mLDMF混合,加入压力反应釜,搅拌下通入氨气至反应釜压力至0.15 MPa (通气过程控制反应温度在10〜15 °C),40 °C保温反应,TLC跟踪反应进度。 [0042] A 30 g 16, 17 α- epoxy - pregn -20- hydrazino carboxylate acetyl-1,4-diene -3-generation, 11-dione (a) and 150 mL of chloroform and 30 mLDMF mixed, and the pressure reactor, under stirring ammonia gas to the reactor pressure to 0.15 MPa (reaction temperature control during ventilation 10~15 ° C), 40 ° C incubation the reaction, the progress of the reaction was followed TLC. 反应毕,将料液转移至玻璃反应瓶,待物料温度降至10 °C以下,加醋酸调节pH至5〜6,减压除去溶剂;在反应瓶中加30 mL醋酸、30 g醋酸酐,反应温度控制在50 °C,反应6小时, 将反应液倒入冷的500 mL10%氢氧化钠溶液中,搅拌1小时,抽滤得到产品29.8 g,质量收率为99%,产品经HPLC检测,纯度为94. 8%。 Completion of the reaction, the reaction material was transferred to a glass vial, until batch temperature dropped below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; the reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, the reaction temperature was controlled at 50 ° C, reacted for 6 hours, the reaction solution was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtered off with suction to give product 29.8 g, 99% mass yield, product by HPLC purity of 94.8%.

Claims (9)

  1. 1. 地夫可特关键中间体[17a,16a-d]甲基噁唑啉留体化合物的制备方法,其特征在于,包括如下步骤: 1. deflazacort key intermediates [17a, 16a-d] Preparation of methyl left oxazoline compound, which is characterized by comprising the steps of:
    Figure CN102936274BC00021
    (1) 将化合物a用一定体积的三氯甲烷溶解,与一定质量的添加剂一并加入压力反应釜,搅拌下往反应釜通入氨气至一定压力;一定温度下,保温反应,TLC跟踪反应进度;反应毕,将料液转移至玻璃反应瓶,待物料温度降至l〇°C以下,加醋酸调节pH至5〜6,减压脱除溶剂,得化合物b,不经纯化直接用于下步反应;所述添加剂选自N,N-二甲基甲酰胺、四氢呋喃、吡啶或三乙胺。 (1) a compound with a volume of chloroform is dissolved, together with a mass of additive added to the pressure reactor, under stirring ammonia gas to the reaction vessel to a certain pressure; certain temperature, heat the reaction, the reaction is followed TLC progress; completion of the reaction, the reaction material was transferred to a glass vial, until batch temperature dropped l〇 ° C below, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure to give compound B, was used directly without purification next reaction; the additive is selected from N, N- dimethylformamide, tetrahydrofuran, pyridine or triethylamine. (2) 将步骤(1)制得的化合物粗品b溶解于冰醋酸中搅拌下加入一定量的酸酐,控制反应温度,TLC跟踪反应进度;反应毕,将反应液倒入冷的500mL10%氢氧化钠溶液中,搅拌1小时,抽滤得到产品。 (2) Step (1) Compound b obtained crude product was dissolved in glacial acetic acid was added under stirring a certain amount of acid anhydride, reaction temperature, TLC tracking the progress of the reaction; completion of the reaction, the reaction solution was poured into cold hydroxide 500mL10% soda solution, stirred for 1 hour, filtered off with suction to give the product.
  2. 2. 根据权利要求1所述的方法,其特征在于,步骤(1)所述添加剂优选DMF或吡啶。 2. The method according to claim 1, wherein the step (1) the additive is preferably pyridine or DMF.
  3. 3. 根据权利要求1所述的方法,其特征在于,步骤(1)所述的通氨气压力为0.1〜 IMPa。 3. The method according to claim 1, wherein the step (1) of the ammonia gas pressure was 0.1~ IMPa.
  4. 4. 根据权利要求1所述的方法,其特征在于,步骤⑴式a所示的化合物与添加剂的质量比为1 :〇. 1〜3。 4. The method according to claim 1, wherein the step of mass ⑴ additive compound represented by the formula is a ratio of 1: 1 ~ 3 billion.
  5. 5. 根据权利要求1所述的方法,其特征在于,步骤⑴所述反应温度为15〜60°C。 5. The method according to claim 1, wherein the step of ⑴ the reaction temperature is 15~60 ° C.
  6. 6. 根据权利要求1所述的方法,其特征在于,步骤(2)所述酸酐选自醋酸酐、丙酸酐、顺丁烯二酸酐、苯甲酸酐或其中两者的混合物。 6. The method according to claim 1, wherein the step (2) the acid anhydride is selected from acetic anhydride, propionic anhydride, maleic anhydride, benzoic anhydride or a mixture wherein the two.
  7. 7. 根据权利要求1所述的方法,其特征在于,步骤(2)式b所示的化合物与所述冰醋酸摩尔比为1 :〇. 2〜5。 7. The method according to claim 1, wherein the compound of step (2) of formula b with the glacial acetic acid molar ratio of 1: 2 ~ 5 billion.
  8. 8. 根据权利要求1所述的方法,其特征在于,步骤(2)式b所示的化合物与所述酸酐的摩尔比为1 :〇. 5〜2。 8. The method according to claim 1, wherein the compound of step (2) of formula b with a molar ratio of the acid anhydride is 1: 5~2 square.
  9. 9. 根据权利要求1所述的方法,其特征在于,步骤(2)所述反应温度可以根据其他反应参数设置所述反应温度为10〜50°C。 9. The method according to claim 1, wherein the step (2) the reaction temperature may be the reaction temperature is 10~50 ° C according to other reaction parameters.
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