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Publication numberCN102936274 B
Publication typeGrant
Application numberCN 201210446928
Publication dateApr 1, 2015
Filing dateNov 12, 2012
Priority dateNov 12, 2012
Also published asCN102936274A
Publication number201210446928.3, CN 102936274 B, CN 102936274B, CN 201210446928, CN-B-102936274, CN102936274 B, CN102936274B, CN201210446928, CN201210446928.3
Inventors张峥斌, 王锦凯, 尹金玉, 朱敦明, 赵晓宝, 叶海燕
Applicant江西君业生物制药有限公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Preparation method for [17alpha, 16alpha-d] methyl oxazoline
CN 102936274 B
Abstract  translated from Chinese
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 deflazacort key intermediates [17α, 16α-d] methyleneoxazoline preparation of steroids. 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。 The steps are as follows: The [16,17α- epoxy - pregn -20- methyl hydrazine-acetyl-1,4-diene-3,11-generation dione] was dissolved in chloroform, together with an additive pressure reactor was added under stirring ammonia gas fed to the reactor to a certain pressure at a certain temperature of the reaction; the compound obtained crude product was dissolved in glacial acetic acid was stirred under a certain amount of acid anhydride, to control 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 mixture was poured into cold 500mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the key intermediate deflazacort of [17α, 16α-d] oxazole steroid methyl morpholine. 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 to achieve a deflazacort safe and clean production, help reduce environmental pollution, shortening the production cycle, reduce production costs, improve production safety, social, environmental and economic benefits significantly.
Claims(9)  translated from Chinese
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] methyleneoxazoline preparing steroidal compound, 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 was dissolved, together with a certain quality of additives added pressure reactor, stirring ammonia gas to the reaction vessel to a certain pressure; at a certain temperature, holding the reaction, TLC tracking reaction progress; completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced l〇 C or less, adding acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure to give compound b, it was used directly without purification the next step; said 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) the step (1) obtained crude compound b was dissolved in glacial acetic acid was added under stirring a certain amount of acid anhydride, reaction temperature, TLC track the progress of the reaction; the reaction was completed, the reaction mixture was poured into cold 500mL10% hydroxide soda solution, stirred for 1 hour, filtration to give the product.
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. A method according to claim 1, characterized in that, in step (1) the additive is preferably DMF or pyridine.
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, characterized in that, in step (1) through the pressure of the ammonia gas is 0.1~ IMPa.
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 of claim 1, wherein the step ⑴ quality additive compound represented by the formula with a ratio of 1: 1~3 billion.
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15〜60C。 5. The method according to claim 1, wherein the step ⑴ the reaction temperature is 15~60 C.
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 of claim 1, wherein, in step (2) of the acid anhydride is selected from acetic anhydride, propionic anhydride, maleic anhydride, benzoic anhydride, or wherein a mixture of both.
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 in step b as shown in equation (2) the acetic acid with a molar ratio of 1: 2~5 billion.
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 in step b as shown in formula (2) with a molar ratio of the acid anhydride is 1: 5~2 billion.
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10〜50C。 9. The method according to claim 1, characterized in that, in step (2) the reaction temperature may be the reaction temperature is 10~50 C in accordance with other reaction parameters.
Description  translated from Chinese
-种[1 7 α,16 a -d]甲基噁唑啉制备方法 - Species [1 7 α, 16 a -d] methyleneoxazoline preparation

技术领域 TECHNICAL 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 deflazacort key intermediates [17 α, 16 a -d] Preparation methyleneoxazoline 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) chemical name in here [1,4-diene-21-acetoxy stay pregnant -11 β - hydroxy - [17,16-D] SMZ -3 20-dione], is the third generation of glucocorticoid-steroidal anti-inflammatory drugs, anti-inflammatory, anti-allergy, increased gluconeogenesis role, primarily for the treatment of adrenal 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 strong and broad indications of the advantages of the drug since 1985 in Italy the market, and achieved great success, sales annually. 其结构式如(A)所示。 Its structural formula (A) 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] At present, domestic and foreign literature was mainly mold dehydrogenation [16,17α- epoxy -Ila- hydroxy - pregn-1,4-diene -3, 20-dione] (B) as a starting raw materials, through oxidation, the protection, open-loop, closed loop, reduction, deprotection, iodide displacement was 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 - pregna--20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11-dione] (a) 16, 17 bits on the closed-loop (incorporated oxazole ring) reaction as a key step.

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] The present literature mainly uses sodium azide open loop, resulting azide intermediate compound, which under Raney-Ni or PtO2 closed-loop catalytic hydrogenation, to prepare [17a, 16a-d] methyleneoxazoline 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, a highly toxic chemicals, and with the reaction of azide intermediates are flammable and explosive substances, industrial production process there is a big security risk; the same time, expensive metal catalyst Raney-Ni , Pt0 2 also limits the application of this method in industrial production.

发明内容 SUMMARY OF THE INVENTION

[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 deflazacort key intermediates [17 α, 16 a -d] Preparation methyleneoxazoline steroids in order to overcome the prior art compound production complex process, poor security, high costs, heavy 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 was dissolved, together with a certain quality of additive added to the pressure reactor, under stirring ammonia gas fed to the reactor 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, TLC tracking progress of the reaction. 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。 The reaction was complete, the material was transferred to a glass reaction flask until the material temperature drops below 10 C, plus acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure to give compound b, without purification for the next 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 DMF and pyridine.

[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 through 0 1~I MPa, preferably from 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。 The mass of the compound with additives [0013] wherein a ratio shown 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 reaction of the compound prepared in step crude b was dissolved in glacial acetic acid was added under stirring a certain amount of acid anhydride, reaction temperature, TLC track 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 mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the 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, a mixture of propionic anhydride, maleic anhydride, benzoic anhydride or one of the two, 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。 Compound with acetic acid the molar ratio of [0017] b 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 compound [0018] b shown in the formula is 1: 0 5~2, 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 accordance with other reaction parameters in 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, the dehydrogenation was mold protection product (a) as a starting raw material production deflazacort key steps left of the compounds of intermediates [17α, 16 a -d] methyleneoxazoline the 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) The replacement of ammonia, sodium azide open loop, reducing the use of hazardous materials, to avoid generating explosive intermediate stack nitrides, increase in 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) the use of inexpensive and readily available acid anhydride and closed loop response, avoiding costly heavy metal PtO2 or Raney-Ni of use, greatly reduce production costs, help reduce environmental pollution caused by the heavy metal;

[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, that is, open-loop material (b) without further purification can be carried out directly in the next step, to simplify procedures and 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 safe and clean production, help reduce environmental pollution, shortening the production cycle, reduce production costs, improve production safety, social, environmental and economic benefits obvious.

[0025] (四)具体实施方式 [0025] (iv) Description of Embodiments

[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 to illustrate the technical solution 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- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 15 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10-15 C), 30 C heat reaction, TLC track the progress of the reaction. 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 material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give product 30.6 g, 102% mass yield, product by HPLC , a 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- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mL of pyridine were mixed, added pressure reactor, stirring ammonia gas to the reactor pressure to 0. 15 MPa (during ventilation control the reaction temperature at 10~15 C), 15 C heat reaction, TLC track the progress of the reaction. 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 material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give product 28.6 g, yield 95% by mass, product by HPLC , a 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- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 C), 40 C heat reaction, TLC track the progress of the reaction. 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 material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 31.2 g, yield 104% quality products by HPLC , a 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- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.5 MPa (during ventilation control the reaction temperature at 10~15 C), 40 C heat reaction, TLC track the progress of the reaction. 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 material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 31. I g, 102% mass yield, product by by HPLC, the purity was 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- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 C), 40 C heat reaction, TLC track the progress of the reaction. 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 material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 60 mL of acetic acid, 15 g of acetic anhydride, The reaction temperature was controlled at 30 C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 29. 5 g, yield 98% by mass, the product of by HPLC, purity of 95%.

[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- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 C), 40 C heat reaction, TLC track the progress of the reaction. 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%。 The reaction was complete, the material was transferred to a glass reaction flask until the material temperature drops below 10 C, plus acetic acid to adjust the pH to 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, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 30 g, 100% mass yield, product by HPLC 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- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 C), 40 C heat reaction, TLC track the progress of the reaction. 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 material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of propionic anhydride, The reaction temperature was controlled at 30 C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 27.6 g, 92% yield of quality products by HPLC , a 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- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 C), 40 C heat reaction, TLC track the progress of the reaction. 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 material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature is controlled at 50 C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 29.8 g, 99% yield of quality products by HPLC , a purity of 94.8%.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
CN101418032A *Nov 13, 2008Apr 29, 2009湖南甾体化学品有限公司Method for synthesizing deflazacort
*EP322630A1 Title not available
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