CN101418032A - Method for synthesizing deflazacort - Google Patents

Method for synthesizing deflazacort Download PDF

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CN101418032A
CN101418032A CN 200810202742 CN200810202742A CN101418032A CN 101418032 A CN101418032 A CN 101418032A CN 200810202742 CN200810202742 CN 200810202742 CN 200810202742 A CN200810202742 A CN 200810202742A CN 101418032 A CN101418032 A CN 101418032A
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solvent
reaction
formula
acetate
compound
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CN 200810202742
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刘喜荣
胡爱国
谢来宾
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湖南甾体化学品有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J71/00Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0036Nitrogen-containing hetero ring
    • C07J71/0057Nitrogen and oxygen
    • C07J71/0068Nitrogen and oxygen at position 16(17)

Abstract

The invention provides a method for synthesizing deflazacort. The method comprises the following steps: dissolving 11 belta-hydroxy-pregna-1, 4-diene-3 and 20-diketone[17 alpha, 16 alpha-d]-2'-methyl oxazoline in solvent, reacting the solvent with a bromization reagent under the catalysis of ammonium salt, performing solid-liquid separation, collecting liquid phase, volatilizing the solvent, obtaining 21-bromization-11 belta-hydroxy-pregna-1, 4-diene-3 and 20-diketone[17 alpha, 16 alpha-d]-2'-methyl oxazoline, reacting the 21-bromization-11 belta-hydroxy-pregna-1, 4-diene-3 and 20-diketone[17 alpha, 16 alpha-d]-2'-methyl oxazoline in the solvent in the presence of acetate and catalytic amount phase-transfer catalyst, and collecting target products from reaction products. The method has the advantages of using the low-priced bromization reagent, lowering production cost, simultaneously solving the problems that the used reagent and intermediate products are unstable and have high toxicity, and the by-products can cause serious environmental pollution, and the like, having high reaction yield and mild reaction conditions, reclaiming the solvent and facilitating the industrialized production.

Description

地夫可特的合成方法 Deflazacort synthetic method

技术领域 FIELD

本发明涉及制备地夫可特的方法。 The present invention relates to a process for the preparation of deflazacort. 背景技术 Background technique

地夫可特,英文名为Deflazacort。 Deflazacort, the English called Deflazacort. 为一种白色结晶性粉末。 As a white crystalline powder. 属于肾上腺皮质激素及促肾上腺皮质激素药。 Belong to adrenocorticotropic hormone and adrenocorticotropic hormone drugs. 本品具有抗炎、抗过敏作用,其效果相当于泼尼松龙10〜20倍。 This product has anti-inflammatory, anti-allergic effects, the effect is equivalent prednisolone 10-20 times. 适用于肾上腺皮质机能减退、自身免疫性疾病、过敏性疾病及血液系统疾病等。 Adrenocortical hypofunction applicable to, autoimmune diseases, allergic diseases and hematological diseases. 其结构式如(1): Its structural formula (1):

<formula>formula see original document page 4</formula>(1) <Formula> formula see original document page 4 </ formula> (1)

目前,己有的技术中,关键步骤为11卩-羟基-孕甾-1,4-二烯-3, 20-二酮[17o, 16o-d]-2'-甲基噁唑啉(2)经21位碘代,醋酸钾置换得到最终产物地夫可特的过程。 At present, some techniques already, the key step is Jie 11 - hydroxy - pregna-1,4-diene -3, 20-dione [17o, 16o-d] -2'- methyl-oxazoline (2 ) via the iodo-21, substitution of potassium acetate to give a final process of the product deflazacort. 其反应式如下:如US Patent 3413286,提供了一种制备地夫可特的方法,在其关键步骤1lp-羟基-孕甾-l,4-二烯-3, 20-二酮[17《16a-d]-2'-甲基噁唑啉(2)经21 Reaction is as follows: The US Patent 3413286, a method is provided of preparing deflazacort, in which the key step 1lp- hydroxy - pregna--l, 4- diene -3, 20-dione [17 "16a -d] -2'- methyl-oxazoline (2) through 21

位碘代时使用了价格昂贵的单质碘,同时需要两分子的单质碘得到二碘代物(3),随后经醋酸钾置换得到最终产物。 When using the bit-iodo expensive elemental iodine, and elemental iodine required to give two molecules of diiodo (3), the final product was subsequently replaced with potassium acetate. 碘单质由于其原子不经济所以用量较大造成成本高昂,二碘代物(3)必须避光氮气下保存,不能长期放置,否则该化合物容易分解,同时单质碘对设备的腐蚀及存储及运输等问题限制了其在工业化生产中的使用。 Iodine substance because of their atoms uneconomical so a larger amount caused by the high cost of diiodo (3) must be protected from light and stored under nitrogen, is not long-term placement, or easy to decompose the compound, while elemental iodine to equipment corrosion and storage and transportation problems limited their use in industrial production. 发明内容 SUMMARY

本发明的目的是提供一种地夫可特的合成方法,以克服现有技术存在的上述缺陷。 Object of the present invention is to provide a method for synthesizing the deflazacort, to overcome the above drawbacks of the prior art.

本方法的方法包括如下步骤: (1)将如式(2)所示的化合物在铵盐催化下,于溶剂中与溴代试剂反应0.5〜24h,反应温度为20〜100。 The method of the present method comprises the following steps: (1) the formula (2) shown in ammonium compound catalyst in a solvent, the reaction with bromo 0.5~24h reagent, the reaction temperature is 20-100. C,然后液固分离,收集液相,挥去溶剂,得式(4)所示的化合物,不经纯化直接用于下步反应,收率为80〜99.5 %,反应方程式如下: C, then the liquid-solid separation, the liquid phase was collected, the solvent evaporated, to give a compound of formula (4) is used without purification in the next reaction, 80~99.5% yield, the reaction equation is as follows:

如式(2)所示的化合物的化学名称为lip-羟基-孕甾-l, 4-二烯-3, 20-二酮[17a, 16o-d]-2'-甲基噁唑啉(2),可采用US Patent 3413286文献报道的方法进行制备; The formula (2) compound represented by the chemical name is lip- hydroxy - pregna--l, 4- diene -3, 20-dione [17a, 16o-d] -2'- methyl-oxazoline ( 2), US Patent 3413286 may be employed a method reported in the literature were prepared;

所述铵盐选自醋酸铵、甲酸铵、丙酸铵、氯化铵、溴化铵或氟化铵等,优选的铵盐为甲酸铵或醋酸铵; The ammonium salt selected from ammonium acetate, ammonium formate, ammonium propionate, ammonium chloride, ammonium bromide, ammonium fluoride, or the like, preferably the ammonium salt is ammonium formate or ammonium acetate;

所述溴代试剂选自N-溴代琥珀酰亚胺或1,3-二溴5,5-二甲基海因等; 所述的溶剂没有特别要求,优选四氢呋喃、乙醚、2-甲基呋喃、异丙醚、 The reagent is selected from bromo-N- bromosuccinimide or 1,3-dibromo-5,5-dimethyl hydantoin and the like; the solvent is not particularly required, preferably tetrahydrofuran, diethyl ether, methyl furan, diisopropyl ether,

1, 4-二氧六环、乙二醇二甲醚、 一縮二乙二醇二甲醚、二氯甲烷、1, 2- 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, dichloromethane, 1, 2-

二氯乙垸、正戊烷、正己烷、乙腈、二甲基亚砜、甲苯或二甲苯的一种以 One kind of embankment dichloroacetyl, n-pentane, n-hexane, acetonitrile, dimethyl sulfoxide, toluene or xylene to

上; on;

式(2)所示的化合物与溴代试剂的摩尔比为1: 1〜2.5; (2) the molar ratio of the compound of formula bromo reagent is 1: 1~2.5;

式(2)所示的化合物与铵盐的摩尔比为1:0.001〜0.1; The molar ratio of the compound with an ammonium salt represented by formula (2) is 1: 0.001~0.1;

溶剂中,式(2)所示的化合物的含量为0.1〜1.0mol/L; (2)将式(4)所示的化合物在溶剂中,醋酸盐和催化量的相转移催化剂存在下,反应2〜48小时,反应温度为50〜120 。 The solvent content of the compound represented by formula (2) is 0.1~1.0mol / L; (2) the formula (4) in a solvent in the presence of a phase transfer catalyst and a catalytic amount of acetate compound represented by the following, The reaction 2~48 hours, the reaction temperature is 50~120. C,然后从反应产物中收集目标产物,收率为75〜99%,反应方程式如下: C, and then collecting the desired product from the reaction product, a yield of 75~99%, the reaction equation is as follows:

所述醋酸盐选自醋酸钾、醋酸钠或醋酸锂; 所述溶剂选自甲醇、乙醇、N, N-二甲基甲酰胺、二甲亚砜、丙酮、 乙腈、二氯甲烷或l, 2-二氯乙垸中的一种以上; 所述的相转移催化剂的结构通式为R4N"X、 其中R为d〜C8的直链烷基、d〜Q的支链烷基或苯基等; X为氟、氯、溴或碘; 所述催化剂均为市售化学品。化合物(4)与醋酸盐的摩尔比为1 : 1〜4; The acetate salt is selected from potassium acetate, sodium acetate or lithium acetate; the solvent is selected from methanol, ethanol, N, N- dimethylformamide, dimethylsulfoxide, acetone, acetonitrile, methylene chloride, or L, 2- dichloroacetyl one or more of the embankment; according to the general structural formula for the phase transfer catalyst R4N "X, wherein R is a linear alkyl group d~C8, branched-chain alkyl group or a phenyl group d~Q and the like; X is fluorine, chlorine, bromine or iodine; the catalyst are commercially available chemicals molar ratio of compound (4) with the acetate of 1: 1 ~ 4;

化合物(4)与相转移催化剂的摩尔比为1 :0.01〜0.1; Compound (4) with a molar ratio of phase transfer catalyst is 1: 0.01~0.1;

溶剂中,式(4)所示的化合物的含量为0.1〜1.0mol/L。 The solvent content of the compound represented by formula (4) is 0.1~1.0mol / L.

本发明的方法,使用了价格便宜的溴代试剂代替了单质碘,无论从原子经济角度和价格成本角度还是从储存运输角度都大大优于使用单质碘的传统工艺。 The method of the present invention, using inexpensive reagent in place of the bromo elemental iodine, atoms both from an economic point of view or from prices for the storage and transportation costs are much better than the traditional process angle using elemental iodine. 另人惊奇的是催化剂铵盐的使用,在未使用催化剂铵盐的时候, 化合物(2)与溴代试剂无任何反应或者副产物较多,但加入催化量的铵盐后,产物收率及反应选择性大大提高,得到的化合物(4)比传统工艺制备得到的化合物(3)更稳定,可长时间保存。 Surprisingly another catalyst is an ammonium salt, an ammonium salt when the catalyst is not used, the compound (2) with a bromo-reagent without any reaction or more by-products, but a catalytic amount of an ammonium salt, and the product yields greatly improve the selectivity of the reaction, the compound (3) to give compound (4) prepared by conventional processes to obtain more stable than can be stored for long periods. 随后在化合物(4)与醋酸盐的反应中,加入少量价廉易得的相转移催化剂其得到目标产物(1)的收率也比使用传统工艺毫不逊色。 Followed by reaction of the compound (4) and the acetate was added the yield of a small amount of readily available and inexpensive phase transfer catalysts which give the object product (1) is also compared favorably using conventional processes. 本方明所报道的方法避免了该类化合物传统合成工艺中所遇到的中间产物纯化困难、使用大量昂贵且具腐蚀性的单质碘等问题、用本方明制备得到的中间产物(4)结构稳定,大大降低了生产成本。 This method avoids the reported side out of the intermediate synthesis of these compounds in traditional purification difficulties encountered, and having a large amount of expensive corrosion problems elemental iodine, with the intermediate product obtained in the preparation of the present Masaaki (4) structural stability, greatly reducing the cost of production. 同时避免了所使用试剂及中间产物毒性大、不稳定、副产物对环境污染严重等问题。 While avoiding the big reagents and intermediates toxicity, instability, a byproduct of serious environmental pollution problems use. 其生产工艺中"三废"排放大幅度降低。 The production process of "three wastes" emissions significantly reduced. 这是其他方法无法达到的。 This can not be achieved by other methods. 以本发明所述及的方法制备得到的地夫可特由于其反应条件温和, 反应比较完全,经简单纯化后其纯度可达到99%以上。 In the present invention, and a method of preparing deflazacort is obtained due to the mild reaction conditions, the reaction is more complete, after which was purified by simple purity over 99%. 在整个反应中所使用的试剂都是较为易得的,同时反应收率高,反应条件温和,溶剂能回收利用,因而便于工业化实施。 Throughout the reagents used in the reaction it is relatively readily available, while high reaction yield, mild reaction conditions, the solvent can be recycled, thus facilitating industrial embodiment. 具体实施方式 detailed description

通过以下具体实施方法将有助于理解本发明,但并不限制本发明的内容。 By the following specific embodiment of the method will help to understand the present invention, but do not limit the present invention. 实施例1 Example 1

21-溴代-ll(3-羟基-孕甾-l,4-二烯-3, 20-二酮[170, 16o-d]-2'-甲基噁唑啉(4)的制备: 21-bromo -ll (3- hydroxy - pregna--l, 4- diene -3, 20-dione [170, 16o-d] -2'- methyl-oxazoline (4) Preparation of:

在一干燥的装配有温度计、回流冷凝管、磁力搅拌的250mL三口瓶中加入化合物(2) (19.17 g; Fw: 383.48; 50 mmol), N-溴代琥珀酰亚胺(9.79 g; Fw: 178.00; 55 mmol),乙醚150毫升;随后将醋酸铵(0.39 g; Fw: 77.08; 0.005 mmol)加入体系。 A dry equipped with a thermometer, a reflux condenser, magnetic stirring 250mL three-necked flask was added compound (2) (19.17 g; Fw: 383.48; 50 mmol), N- bromosuccinimide (9.79 g; Fw: 178.00; 55 mmol), 150 ml of diethyl ether; then ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. 体系在20 °C继续搅拌0.5 h,反应完毕。 System Stirring was continued at 20 ° C 0.5 h, the reaction is complete. 反应完毕后过滤除去白色沉淀后用二氯甲烷50 mL洗涤滤饼,合并有机相得淡黄色清液,减压浓縮除去溶剂,得淡黄色固体21.27 g,收率:92%, HPLC含量大于95 %。 After completion of the reaction a white precipitate was removed by filtration The filter cake was washed with 50 mL dichloromethane and the combined organic Xiangde pale yellow clear liquid, solvent was concentrated under reduced pressure to give a light yellow solid 21.27 g, yield: 92%, HPLC content of more than 95%.

实施例2 Example 2

21-溴代-lip-羟基-孕甾-l,4-二烯-3, 20-二酮[17《16o-d]-2'-甲基噁唑啉(4)的制备: 21-Bromo -lip- hydroxy - pregna--l, 4- diene -3, 20-dione [17 "16o-d] -2'- methyl-oxazoline (4) Preparation of:

在一干燥的装配有温度计、回流冷凝管、磁力搅拌的250mL三口瓶中依次加入化合物(2) (19.17 g; Fw: 383.48; 50 mmol), N-溴代琥珀酰亚胺(9.79 g;Fw: 178.00; 55 mmol),甲苯150毫升;随后将醋酸铵(0.39 g; Fw: 77.08; 0.005 mmol)加入体系。 A dry equipped with a thermometer, a reflux condenser, magnetic stirring 250mL three-neck flask were added the compound (2) (19.17 g; Fw: 383.48; 50 mmol), N- bromosuccinimide (9.79 g; Fw : 178.00; 55 mmol), 150 ml of toluene; followed by ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. 体系在110 °C继续搅拌5 h,反应完毕。 System Stirring was continued at 110 ° C 5 h, the reaction is complete. 反应完毕后冷却至室温,过滤除去白色沉淀后用二氯甲烷50 mL洗涤滤饼,合并有机相得淡黄色清液,减压浓縮除去溶剂得淡黄色固体19.65 g,收率:85 %, HPLC含量大于95%。 After the reaction was cooled to room temperature, the white precipitate was removed by filtration The filter cake was washed with 50 mL dichloromethane and the combined organic Xiangde pale yellow clear liquid, and concentrated under reduced pressure to remove the solvent to give a light yellow solid 19.65 g, yield: 85% HPLC titre greater than 95%.

实施例3 Example 3

21國溴代-11卩-羟基-孕甾-1,4-二烯-3, 20-二酮[17a, 16o-d]-2'-甲基噁唑啉(4)的制备: Of 21-bromo-Jie -11 - hydroxy - pregna-1,4-diene -3, 20-dione [17a, 16o-d] -2'- methyl-oxazoline (4) Preparation of:

在一干燥的装配有温度计、回流冷凝管、磁力搅拌的250mL三口瓶中依次加入化合物(2) (19.17 g;Fw: 383.48; 50 mmol), 1,3-二溴5,5-二甲基海因(35.74 g;Fw: 285.94; 125 mmol),乙醚150毫升;随后将醋酸铵(0.39 g; Fw: 77.08; 0.005 mmol)加入体系。 A dry equipped with a thermometer, a reflux condenser, magnetic stirring 250mL three-neck flask were added the compound (2) (19.17 g; Fw: 383.48; 50 mmol), 1,3- dibromo-5,5-dimethylhydantoin hydantoin (35.74 g; Fw: 285.94; 125 mmol), 150 ml of diethyl ether; then ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. 体系在回流下继续搅拌3 h,反应完毕。 Stirring was continued at reflux system 3 h, the reaction is complete. 反应完毕后过滤除去白色沉淀后用乙醚50 mL洗涤滤饼,合并有机相得淡黄色清液,减压浓縮除去溶剂得淡黄色固体16.18 g,收率:70 %, HPLC 含量大于92%。 After the white precipitate was removed by filtration after the completion of the reaction cake was washed with 50 mL of ether and the combined organic Xiangde pale yellow clear liquid, and concentrated under reduced pressure to remove the solvent to give a light yellow solid 16.18 g, yield: 70%, HPLC content of more than 92%.

实施例4 Example 4

21-溴代-11卩-羟基-孕甾-1,4-二烯-3, 20-二酮[17c, 16o-d]-2'-甲基噁唑啉(4)的制备: 21 -11 Jie bromo - hydroxy - pregna-1,4-diene -3, 20-dione [17c, 16o-d] -2'- methyl-oxazoline (4) Preparation of:

在一干燥的装配有温度计、回流冷凝管、磁力搅拌的250mL三口瓶中依次加入化合物(2) (19.17 g; Fw: 383.48; 50 mmol), 1,3-二溴5,5-二甲基海因(35.74 g; Fw: 285.94; 125 mmol), 二氯甲垸150毫升;随后将醋酸铵(0.039 g; Fw: 77.08; 0.0005 mmol)加入体系。 A dry equipped with a thermometer, a reflux condenser, magnetic stirring 250mL three-neck flask were added the compound (2) (19.17 g; Fw: 383.48; 50 mmol), 1,3- dibromo-5,5-dimethylhydantoin hydantoin (35.74 g; Fw: 285.94; 125 mmol), 150 ml of dichloromethane; subsequently ammonium acetate (0.039 g; Fw: 77.08; 0.0005 mmol) added to the system. 体系在回流下继续搅拌24 h, 反应完毕。 Stirring was continued at reflux for system 24 h, the reaction is complete. 反应完毕后过滤除去白色沉淀后用乙醚50 mL洗涤滤饼,合并有机相得淡黄色清液,减压浓縮除去溶剂得淡黄色固体16.41 g,收率:71 %, HPLC含量大于92。 After the white precipitate was removed by filtration after the completion of the reaction cake was washed with 50 mL of ether and the combined organic Xiangde pale yellow clear liquid, and concentrated under reduced pressure to remove the solvent to give a light yellow solid 16.41 g, yield: 71%, HPLC content of greater than 92. /0。 / 0.

实施例5 Example 5

地夫可特的制备: Deflazacort prepared:

在一干燥的充满氮气的装配有温度计、磁力搅拌以及回流冷凝管的100 mL三口烧瓶中加入化合物(4) (11.56 g;Fw: 462.38; 25 mmol),随后加入醋酸钠(8.20g;Fw: 82.03; lOOmmol),将甲醇50 mL加入体系中。 In a nitrogen-filled dry fitted with a thermometer, magnetic stirrer and reflux condenser, 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by sodium acetate (8.20g; Fw: 82.03; lOOmmol), 50 mL methanol was added to the system.

随后将四丁基溴化铵(O. 81g; Fw: 322.38; 2.5 mmol)。 Subsequently tetrabutylammonium bromide (O. 81g; Fw: 322.38; 2.5 mmol). 升温到50 °C搅拌 Warmed to 50 ° C with stirring

48 h。 48 h. 待反应完毕之后冷却至室温。 After completion of the reaction was cooled to room temperature. 反应完毕之后,体系温度冷却至室温后向体系中补加氯仿50mL,过滤,滤饼再用少量氯仿洗涤溶物以确证无产物、 合并有机相,有机相再用10%碳酸钠水溶液洗漆3次,饱和氯化钠洗涤一次。 After completion of the reaction, the system was cooled to room temperature after the system was supplemented with chloroform to 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm no product was dissolved, and the combined organic phases, the organic phase washed with 10% aqueous sodium carbonate paint 3 times, washed once with saturated sodium chloride. 有机相用无水硫酸钠干燥、除去无机盐得淡黄色液体,浓縮至干,乙酸乙酯精制得产物9.93g,收率90%, HPLC含量〉990/0。 The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, ethyl acetate to give purified product was 9.93 g, yield 90%, HPLC content> 990/0.

实施例6 Example 6

地夫可特的制备- Preparation of deflazacort -

在一干燥的充满氮气的装配有温度计、磁力搅拌以及回流冷凝管的100 mL三口烧瓶中加入化合物(4) (11.56 g; Fw: 462.38; 25 mmol),随后加入无水醋酸钾(3.68g;Fw: 98.14; 37.5 mmol),将丙酮50 mL加入体系中。 In a nitrogen-filled dry fitted with a thermometer, magnetic stirrer and reflux condenser, 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (3.68 g of; Fw: 98.14; 37.5 mmol), 50 mL acetone was added to the system. 随后将四丁基碘化铵(0.10g;Fw: 369.37; 0.25 mmol)。 Followed by tetrabutylammonium iodide (0.10g; Fw: 369.37; 0.25 mmol). 升温到回流搅拌2h。 Heated to reflux stirred for 2h. 待反应完毕之后冷却至室温。 After completion of the reaction was cooled to room temperature. 反应完毕之后,体系温度冷却至室温后向体系中补加氯仿50mL,过滤,滤饼再用少量氯仿洗涤溶物以确证无产物、合并有机相,有机相再用10%碳酸钠水溶液洗涤3次,饱和氯化钠洗涤一次。 After completion of the reaction, the system was cooled to room temperature after the system was supplemented with chloroform to 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm no product was dissolved, and the combined organic phases, the organic phase washed three times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. 有机相用无水硫酸钠干燥、除去无机盐得淡黄色液体,浓縮至干,乙酸乙酯精制得产物10.93 g,收率99 %, HPLC含量> 99%。 The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, it was concentrated to dryness, purified ethyl acetate to give the product 10.93 g, yield 99%, HPLC content> 99%.

实施例7 Example 7

地夫可特的制备: Deflazacort prepared:

在一干燥的充满氮气的装配有温度计、磁力搅拌以及回流冷凝管的100 mL三口烧瓶中加入化合物(4) (11.56 g;Fw: 462.38; 25 mmol),随后加入无水醋酸钾(3.68g;Fw: 98.14; 37.5 mmol),将乙腈50 mL加入体系中。 In a nitrogen-filled dry fitted with a thermometer, magnetic stirrer and reflux condenser, 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (3.68 g of; Fw: 98.14; 37.5 mmol), 50 mL of acetonitrile was added to the system. 随后将四丁基碘化铵(0.10g;Fw: 369.37; 0.25 mmol)。 Followed by tetrabutylammonium iodide (0.10g; Fw: 369.37; 0.25 mmol). 升温到回流搅拌2h。 Heated to reflux stirred for 2h. 待反应完毕之后冷却至室温。 After completion of the reaction was cooled to room temperature. 反应完毕之后,体系温度冷却至室温后向体系中补加氯仿50mL,过滤,滤饼再用少量氯仿洗涤溶物以确证无产物、合并有机相,有机相再用10%碳酸钠水溶液洗涤3次,饱和氯化钠洗涤一次。 After completion of the reaction, the system was cooled to room temperature after the system was supplemented with chloroform to 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm no product was dissolved, and the combined organic phases, the organic phase washed three times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. 有机相用无水硫酸钠干燥、除去无机盐得淡黄色液体,浓縮至干,乙酸乙酯精制得产物10.93 g,收率99 %, HPLC含量> 99%。 The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, it was concentrated to dryness, purified ethyl acetate to give the product 10.93 g, yield 99%, HPLC content> 99%.

实施例8 Example 8

地夫可特的制备: Deflazacort prepared:

在一干燥的充满氮气的装配有温度计、磁力搅拌以及回流冷凝管的100 mL三口烧瓶中加入化合物(4) (11.56 g; Fw: 462.38; 25 mmol),随后加入无水醋酸钾(2.45g;Fw: 98.14; 25 mmol),将N, N-二甲基甲酰胺50 mL加入体系中。 In a nitrogen-filled dry fitted with a thermometer, magnetic stirrer and reflux condenser, 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (2.45 g of; Fw: 98.14; 25 mmol), the N, N- dimethylformamide was added 50 mL system. 随后将四丁基碘化铵(O.IO g; Fw: 369.37; 0.25 mmol)。 Followed by tetrabutylammonium iodide (O.IO g; Fw: 369.37; 0.25 mmol). 升温到120 。 Warmed to 120. C搅拌2h。 C stirred for 2h. 待反应完毕之后冷却至室温。 After completion of the reaction was cooled to room temperature. 反应完毕之后,体系温度冷却至室温后向体系中补加氯仿50mL,过滤,滤饼再用少量氯仿洗涤溶物以确证无产物、合并有机相,有机相再用10%碳酸钠水溶液洗涤3次,饱和氯化钠洗涤一次。 After completion of the reaction, the system was cooled to room temperature after the system was supplemented with chloroform to 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm no product was dissolved, and the combined organic phases, the organic phase washed three times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. 有机相用无水硫酸钠干燥、除去无机盐得淡黄色液体,浓縮至干,乙酸乙酯精制得产物10.93 g,收率99%, HPLC含量〉99o/q。 The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, purified ethyl acetate to give the product 10.93 g, yield 99%, HPLC content> 99o / q.

Claims (10)

  1. 1. 地夫可特的合成方法,其特征在于,包括如下步骤:(1)将如式(2)所示的化合物在铵盐催化下,于溶剂中与溴代试剂反应,然后液固分离,收集液相,挥去溶剂,得式(4)所示的化合物,反应方程式如下:(2)将式(4)所示的化合物在溶剂中,醋酸盐和催化量的相转移催化剂存在下,反应,然后从反应产物中收集目标产物。 1. deflazacort synthesis method comprising the steps of: separating (1) the formula (2) ammonium salt compounds represented by catalysis, in a solvent is reacted with bromo-reagent, then the liquid-solid collecting the liquid phase, the solvent evaporated, to give the formula (4) compound represented by the reaction equation is as follows: in a solvent in the presence of a phase transfer catalyst and a catalytic amount of acetate compound (2) represented by the formula (4) , the reaction, the desired product is then collected from the reaction product. 所述的相转移催化剂的结构通式为R4N+X-;其中R为C1~C8的直链烷基、C1~C8的支链烷基或苯基等;X为氟、氯、溴或碘。 The structural formula of the phase transfer catalyst is R4N + X-; wherein R is a linear alkyl group of C1 ~ C8, like C1 ~ C8 branched alkyl group or a phenyl group; X is fluorine, chlorine, bromine or iodine .
  2. 2. 根据权利要求1所述的方法,其特征在于,步骤(1)的反应时间为0.5〜24h,反应温度为20〜100。 2. The method according to claim 1, characterized in that the reaction time in step (1) is 0.5~24h, the reaction temperature is 20-100. C。 C.
  3. 3. 根据权利要求1所述的方法,其特征在于,所述铵盐选自醋酸铵、 甲酸铵、丙酸铵、氯化铵、溴化铵或氟化铵。 3. The method according to claim 1, wherein the ammonium salt is selected from ammonium acetate, ammonium formate, ammonium propionate, ammonium chloride, ammonium bromide or ammonium fluoride.
  4. 4. 根据权利要求1所述的方法,其特征在于,所述溴代试剂选自N-溴代琥珀酰亚胺或1,3-二溴5,5-二甲基海因。 4. The method according to claim 1, wherein said agent is selected from bromo-N- bromosuccinimide or 1,3-dibromo-5,5-dimethyl hydantoin.
  5. 5. 根据权利要求1所述的方法,其特征在于,步骤(1)的溶剂为四氢呋喃、乙醚、2-甲基呋喃、异丙醚、1, 4-二氧六环、乙二醇二甲醚、一縮二乙二醇二甲醚、二氯甲烷、1, 2-二氯乙院、正戊烷、正己烷、乙腈、二甲基亚砜、甲苯或二甲苯的一种以上。 The method according to claim 1, wherein the solvent of step (a) is tetrahydrofuran, diethyl ether, 2-methylfuran, isopropyl ether, 1,4-dioxane, ethylene glycol dimethyl one or more ether, diethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane hospital, n-pentane, n-hexane, acetonitrile, dimethyl sulfoxide, toluene or xylene.
  6. 6. 根据权利要求1所述的方法,其特征在于,式(2)所示的化合物与溴代试剂的摩尔比为1: 1〜2.5;式(2)所示的化合物与铵盐的摩尔比为1:0.001〜0.1;溶剂中,式(2)所示的化合物的含量为0.1〜1.0mol/L。 Mole of the compound with an ammonium salt of formula (2); 1~2.5: 6. The method of claim 1, wherein (2) the molar ratio of the compound of formula bromo reagent is 1 ratio of 1: 0.001~0.1; solvent, the content of the compound represented by formula (2) is 0.1~1.0mol / L.
  7. 7. 根据权利要求1所述的方法,其特征在于,步骤(2)中,反应时间为2〜48小时,反应温度为50〜120 °C。 7. The method according to claim 1, wherein the step (2), the reaction time of 2~48 hours, the reaction temperature is 50~120 ° C.
  8. 8. 根据权利要求1所述的方法,其特征在于,所述醋酸盐选自醋酸钾、 醋酸钠或醋酸锂。 8. The method according to claim 1, wherein said salt is selected from acetate, potassium acetate, sodium acetate or lithium acetate.
  9. 9. 根据权利要求1所述的方法,其特征在于,步骤(2)中,所述溶剂选自甲醇、乙醇、N, N-二甲基甲酰胺、二甲亚砜、丙酮、乙腈、二氯甲烷或l, 2-二氯乙垸中的一种以上。 9. The method according to claim 1, wherein the step (2), the solvent is selected from methanol, ethanol, N, N- dimethylformamide, dimethylsulfoxide, acetone, acetonitrile, dimethylformamide methylene chloride or l, 2- dichloroethane one or more of the embankment.
  10. 10. 根据权利要求1所述的方法,其特征在于,化合物(4)与醋酸盐的摩尔比为1 : 1〜4;化合物(4)与相转移催化剂的摩尔比为1 : 0.01〜0.1; 溶剂中,式(4)所示的化合物的含量为0.1〜1.0mol/L。 10. The method according to claim 1, wherein the molar ratio of the compound (4) with the acetate of 1: 1 ~ 4; Compound (4) with a molar ratio of phase transfer catalyst is 1: 0.01~0.1 ; solvent, the content of the compound represented by formula (4) is 0.1~1.0mol / L.
CN 200810202742 2008-11-13 2008-11-13 Method for synthesizing deflazacort CN101418032A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102746358A (en) * 2011-04-22 2012-10-24 天津金耀集团有限公司 Novel technology for synthesis of pregnane 21-bit bromide
CN102936274A (en) * 2012-11-12 2013-02-20 浙江仙居君业药业有限公司 Preparation method for [17alpha, 16alpha-d] methyl oxazoline
JP2015509493A (en) * 2012-02-23 2015-03-30 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel process for the preparation of ciclesonide
CN106397532A (en) * 2016-08-30 2017-02-15 江西宇能制药有限公司 Preparation method of deflazacort

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102746358A (en) * 2011-04-22 2012-10-24 天津金耀集团有限公司 Novel technology for synthesis of pregnane 21-bit bromide
CN102746358B (en) * 2011-04-22 2016-02-10 天津金耀集团有限公司 Pregn-21 A synthetic process bromide
JP2015509493A (en) * 2012-02-23 2015-03-30 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel process for the preparation of ciclesonide
CN102936274A (en) * 2012-11-12 2013-02-20 浙江仙居君业药业有限公司 Preparation method for [17alpha, 16alpha-d] methyl oxazoline
CN102936274B (en) * 2012-11-12 2015-04-01 江西君业生物制药有限公司 Preparation method for [17alpha, 16alpha-d] methyl oxazoline
CN106397532A (en) * 2016-08-30 2017-02-15 江西宇能制药有限公司 Preparation method of deflazacort

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