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Publication numberCN102936274 A
Publication typeApplication
Application numberCN 201210446928
Publication dateFeb 20, 2013
Filing dateNov 12, 2012
Priority dateNov 12, 2012
Also published asCN102936274B
Publication number201210446928.3, CN 102936274 A, CN 102936274A, CN 201210446928, CN-A-102936274, CN102936274 A, CN102936274A, CN201210446928, CN201210446928.3
Inventors张峥斌, 王锦凯, 尹金玉, 朱敦明, 赵晓宝, 叶海燕
Applicant浙江仙居君业药业有限公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Preparation method for [17alpha, 16alpha-d] methyl oxazoline
CN 102936274 A
Abstract
The invention discloses a preparation method for a denazacort key intermediate [17alpha, 16alpha-d] methyl oxazoline steroids. The steps include: dissolving [16, 17alpha-epoxy-pregnane-20-methyl formate hydrazine acetyl-1,4-diene-3,11-diketone] in trichloromethane, adding [16, 17alpha-epoxy-pregnane-20-methyl formate hydrazine acetyl-1,4-diene-3,11-diketone] and additives into a pressure reaction kettle, leading ammonia to the reaction kettle to a certain pressure under the condition of stirring, and reacting at certain temperature; and dissolving the obtained compound crude products in glacial acetic acid, adding a certain amount of anhydride under the condition of stirring, and controlling reaction temperature. After the reaction, reaction liquid is poured into 500mL of cold 10% sodium hydroxide solution and stirred for 1 hours, and the denazacort key intermediate [17alpha, 16alpha-d] methyl oxazoline steroids is obtained after suction filtration. The method achieves safe and clean production of denazacort, is favorable for reducing environment pollution, shortens a production period, reduces production cost for enterprises, improves production safety, and is remarkable in social benefit, environment benefit and economical benefit.
Claims(9)  translated from Chinese
1.地夫可特关键中间体[17 α,16 α-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 [17 α, 16 α-d] methyleneoxazoline preparing steroidal compound, comprising the steps of:
Figure CN102936274AC00021
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;将化合物粗品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500 mL10%氢氧化钠溶液中,搅拌I小时,抽滤得到产品。 A compound with a volume of chloroform was dissolved, together with a certain quality of additives added pressure reactor, stirring ammonia gas into the reactor to a certain pressure; at a certain temperature, holding the reaction, TLC track the progress of the reaction; Reaction complete, the material was transferred to a glass reaction flask until the material temperature falls below 10 C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure to give compound b, without further purification was used directly in the next reaction; b The crude compound was dissolved in glacial acetic acid was added under stirring a certain amount of acid anhydride, reaction temperature, TLC tracking progress of the reaction; the reaction was completed, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution and stirred I hour, pumping filtered to obtain the product.
2.根据权利要求I所述的方法,其特征在于,步骤(I)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。 2. A method according to claim I, wherein the step (I) the additive is selected from N, N- dimethylformamide, tetrahydrofuran, pyridine or triethylamine, preferably pyridine and DMF.
3.根据权利要求I所述的方法,其特征在于,步骤(I)所述的通氨气压力为O. I〜IMPa,优选O. 15 〜O. 2 MPa。 3. The method according to claim I, characterized in that the ammonia pressure through step (I) according to O. I~IMPa, preferably O. 15 ~O. 2 MPa.
4.根据权利要求I所述的方法,其特征在于,步骤(I)式a所示的化合物与添加剂的质量比为I :0. I〜3,优选I :0. 5〜I。 4. The method according to claim I, characterized in that the mass of the additive compound in step (I) shown in the formula a ratio of I:. 0 I~3, preferably I:. 0 5~I.
5.根据权利要求I所述的方法,其特征在于,步骤(I)所述反应温度为15〜60 C,优选30 〜40 C。 5. The method according to claim I, wherein the step (I) the reaction temperature is 15~60 C, preferably 30 ~40 C.
6.根据权利要求2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,优选醋酸酐和顺丁烯二酸酐。 6. The method according to claim 2, characterized in that, in step (2) of the acid anhydride is selected from acetic anhydride, propionic anhydride mixture, maleic anhydride, benzoic anhydride or both wherein, preferably acetic anhydride and cis maleic anhydride.
7.根据权利要求2所述的方法,其特征在于,步骤(2)式b所示的化合物与所述醋酸摩尔比为I :0. 2〜5,优选为I :0. 5〜I。 7. The method according to claim 2, characterized in that the compound of step b shown in equation (2) the acetic acid with a molar ratio of I:. 0 2~5, preferably I:. 0 5~I.
8.根据权利要求2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I :0. 5〜2,优选为I :1. O〜I. 5。 8. The method according to claim 2, characterized in that the molar ratio as shown in step b (2) with the compound of formula anhydride was I:. 0 5~2, preferably I:. 1 O~I 5.
9.根据权利要求2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在所述反应温度为10〜50 C,优选为25〜30 C。 9. The method according to claim 2, characterized in that, in step (2) the reaction temperature may be in accordance with other reaction parameters in the reaction temperature is 10~50 C, preferably 25~30 C.
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] methyloxazoline 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 a ,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 a, 16 a -d] Preparation methyleneoxazoline steroids. 背景技术 Background

[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 behind deflazacort (Deflazacort) chemical name is in here [1,4_ pregnant stay-diene-21-acetoxy -11 β - hydroxy - [17,16-D] SMZ -3 20-dione], it is the third generation of glucocorticoid-steroidal anti-inflammatory drugs, anti-inflammatory, anti-allergy, increased gluconeogenesis and so on, mainly used for the treatment of adrenal dysfunction, autoimmune disease, 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) 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] At present, domestic and foreign literature was mainly mold dehydrogenation [16,17α_ epoxy -Ila- hydroxy - progesterone-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,[16,17α-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, [16,17α- epoxy - pregn -20- substituting methyl hydrazine acetyl-1,4-diene-3,11-dione] (a) 16,17 bits on closed loop (introduction of evil azole ring) reaction as a key step.

Figure CN102936274AD00031

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[17 a ,16 a -d]甲基噁唑啉甾体化合物。 At present the literature mainly sodium azide open loop, resulting azide intermediate compound, which at Raney-Ni or PtO2 closed-loop catalytic hydrogenation, to prepare [17 a, 16 a -d] methyloxazoline steroid donor compound. 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、Pt02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 the reaction of azide intermediates are flammable and explosive substances, industrial production process there is a big security risk; at the same time, an expensive metal catalyst Raney-Ni , Pt02 also limits the application of this method in industrial production.

发明内容 DISCLOSURE

[0005] 本发明的目的是提供一种地夫可特关键中间体[17 a ,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。 [0005] The object of the present invention is to provide a Deflazacort key intermediates [17 a, 16 a -d] Preparation methyleneoxazoline steroids in order to overcome the prior art compound production complex process, poor security, high cost, high pollution and other defects.

[0006] 本发明的反应方程式如下: [0006] The present reaction equation is as follows:

Figure CN102936274AD00041

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

(I)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。 (I) 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 V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 dropped to 10 V or less, add acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure to give compound b, without purification in the next step.

[0007] 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。 [0007] The additive is selected from N, N- dimethylformamide, tetrahydrofuran, pyridine or triethylamine, preferably pyridine and DMF.

[0008] 所述的通氨气压力为O. I〜I MPa,优选O. 15〜O. 2 MPa。 [0008] The ammonia pressure through O. I~I MPa, preferably O. 15~O. 2 MPa.

[0009] 式a所示的化合物与添加剂的质量比为I :0. I〜3,优选I :0. 5〜I。 The mass of the compound with additives [0009] wherein a ratio shown I:. 0 I~3, preferably I:. 0 5~I.

[0010] 所述反应温度为15〜60 C,优选30〜40 C。 [0010] The reaction temperature is 15~60 C, preferably 30~40 C.

[0011] (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。 [0011] (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I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 and stirred I hour, filtration to obtain product C.

[0012] 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。 [0012] 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.

[0013] 式b所示的化合物与所述醋酸摩尔比为I :0. 2〜5,优选为I :0. 5〜I。 Compound [0013] b shown in the formula and the molar ratio of acetic acid I:. 0 2~5, preferably I:. 0 5~I.

[0014] 式b所示的化合物与所述酸酐的摩尔比为I :0. 5〜2,优选为I :1. O〜I. 5。 Compound [0014] b shown in the formula and the acid anhydride molar ratio of I:. 0 5~2, preferably I:.. 1 O~I 5.

[0015] 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 V,优选为25〜30。 [0015] The reaction temperature in the reaction according to other reaction parameters temperature 10~50 V, preferably 25~30. . .

[0016] 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: [0016] The present invention dehydrogenation was mildew protection product (a) as a starting raw material production Deflazacort key step steroidal compound intermediates [17α, 16 a -d] methyleneoxazoline the prior art compared to its beneficial effects reflected in:

(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——叠氮化物的产生,增加生产安全性; (1) using ammonia replace sodium azide open loop, reducing the use of hazardous materials, to avoid explosive intermediates - produce azide, to increase production safety;

(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 *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; (2) the use of inexpensive and readily available acid anhydride and closed-loop response, avoiding costly heavy metal PtO2 * Raney-Ni of use, greatly reduce production costs, help reduce the environmental pollution caused by the heavy metal;

(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。 (3) in the open ring closure reaction, the use of "one-pot" method, open-loop material (b) can be carried out without further purification in the next step directly, simplify procedures and shorten the production cycle.

[0017] 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。 [0017] In summary, the method of the present invention achieves deflazacort safe and clean production, help reduce environmental pollution, shortening production cycle, reduce production costs and improve production safety, social, environmental and economic benefits obviously.

[0018](四)具体实施方式 [0018] (iv) Description of Embodiments

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。 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.

[0019] 实施例I [0019] Example I

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O. 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。 The 30 g 16,17 α- epoxy - pregn -20- substituting methyl hydrazine acetyl-1,4-diene-3,11-dione (a) and 150 mL of chloroform and 15 mLDMF mixing added pressure reactor, stirring ammonia gas to the reactor pressure to O. 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 V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I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 10 V or less, adding acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure; the reaction flask add 30 mL of acetic acid, 30 g of acetic anhydride, the reaction temperature controlled at 30 C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for I hour, filtration to give product 30. 6 g, 102% mass yield, product by HPLC detecting, with a purity of 95.2%.

[0020] 实施例2 [0020] Example 2

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 The 30 g 16,17 α- epoxy - pregn -20- substituting methyl hydrazine acetyl-1,4-diene-3,11-dione (a) and 150 mL of chloroform and 30 mL of pyridine mixed, pressure reactor, stirring ammonia gas to the reactor pressure to

O. 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。 O. 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 V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I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 10 V or less, adding acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure; the reaction flask add 30 mL of acetic acid, 30 g of acetic anhydride, the reaction temperature controlled at 30 C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for I hour, filtration to give product 28. 6 g, yield 95% by mass, the product was purified by HPLC detecting, with a purity of 94.8%.

[0021] 实施例3 [0021] Example 3

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 The 30 g 16,17 α- epoxy - pregn -20- substituting methyl hydrazine acetyl-1,4-diene-3,11-dione (a) and 150 mL of chloroform and 30 mLDMF mixing added pressure reactor, stirring ammonia gas to the reactor pressure to

O. 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。 O. 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 V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I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 10 V or less, adding acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure; the reaction flask add 30 mL of acetic acid, 30 g of acetic anhydride, the reaction Temperature control at 30 C, for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution and stirred I hour, filtration to give the product 31. 2 g, mass yield of 104%, the product was purified by HPLC detecting, with a purity of 95.4%.

[0022] 实施例4 [0022] Example 4

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 The 30 g 16,17 α- epoxy - pregn -20- substituting methyl hydrazine acetyl-1,4-diene-3,11-dione (a) and 150 mL of chloroform and 30 mLDMF mixing added pressure reactor, stirring ammonia gas to the reactor pressure to

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。 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 V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I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 10 V or less, adding acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure; the reaction flask add 30 mL of acetic acid, 30 g of acetic anhydride, the reaction temperature controlled at 30 C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for I hour, filtration to give product 31. I g, 102% mass yield, product by HPLC detecting, with a purity of 95.2%.

[0023] 实施例5 [0023] Example 5

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 The 30 g 16,17 α- epoxy - pregn -20- substituting methyl hydrazine acetyl-1,4-diene-3,11-dione (a) and 150 mL of chloroform and 30 mLDMF mixing added pressure reactor, stirring ammonia gas to the reactor pressure to

O. 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。 O. 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 V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I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 10 V or less, adding acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure; the reaction flask add 60 mL of acetic acid, 15 g of acetic anhydride, the reaction Temperature control at 30 C, for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution and stirred I hour, filtration to give the product 29. 5 g, mass yield was 98%, the product was purified by HPLC detection, 95% purity.

[0024] 实施例6 [0024] Example 6

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 The 30 g 16,17 α- epoxy - pregn -20- substituting methyl hydrazine acetyl-1,4-diene-3,11-dione (a) and 150 mL of chloroform and 30 mLDMF mixing added pressure reactor, stirring ammonia gas to the reactor pressure to

O. 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。 O. 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 V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I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 dropped to 10 V or less, add 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 acid 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 I hour, filtration to give the product 30 g, 100% mass yield, product by by HPLC, the purity was 95.2%.

[0025] 实施例7 [0025] Example 7

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 The 30 g 16,17 α- epoxy - pregn -20- substituting methyl hydrazine acetyl-1,4-diene-3,11-dione (a) and 150 mL of chloroform and 30 mLDMF mixing added pressure reactor, stirring ammonia gas to the reactor pressure to

O. 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。 O. 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 V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I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 10 V or less, adding acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure; the reaction flask add 30 mL of acetic acid, 30 g of propionic anhydride, the reaction Temperature control at 30 C, for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution and stirred I hour, filtration to give the product 27. 6 g, mass yield was 92%, the product was purified by HPLC detecting, with a purity of 93.5%.

[0026] 实施例8 [0026] Example 8

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 The 30 g 16,17 α- epoxy - pregn -20- substituting methyl hydrazine acetyl-1,4-diene-3,11-dione (a) and 150 mL of chloroform and 30 mLDMF mixing added pressure reactor, stirring ammonia gas to the reactor pressure to

O. 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。 O. 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 V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I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 10 V or less, adding acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure; the reaction flask add 30 mL of acetic acid, 30 g of acetic anhydride, the reaction Temperature control at 50 C, for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution and stirred I hour, filtration to give the product 29. 8 g, mass yield was 99%, the product was purified by HPLC detecting, with a purity of 94.8%.

Patent Citations
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International ClassificationC07J71/00
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