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Publication numberCN102746358 A
Publication typeApplication
Application numberCN 201110101280
Publication dateOct 24, 2012
Filing dateApr 22, 2011
Priority dateApr 22, 2011
Also published asCN102746358B
Publication number201110101280.1, CN 102746358 A, CN 102746358A, CN 201110101280, CN-A-102746358, CN102746358 A, CN102746358A, CN201110101280, CN201110101280.1
Inventors刘爱, 卢彦昌, 孙亮, 韩英
Applicant天津金耀集团有限公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Novel technology for synthesis of pregnane 21-bit bromide
CN 102746358 A
Abstract
The invention relates to a novel technology for synthesis of a pregnane 21-bit bromide, which comprises the following steps: a compound in a formula 2 is reacted with HBr and an oxidant capable of oxidizing NO to NO2 under the conditions of an organic solvent and a NO donor to react to generate a compound in a formula 1.
Claims(10)  translated from Chinese
1. 一种式I化合物的制备方法,其特征在于由式2化合物在有机溶媒、NO供体、条件下与HBr、可以将NO氧化为NO2的氧化剂反应生成式I化合物, A method for preparing a compound of formula I, wherein the compound of formula 2 in an organic solvent, NO donor, under conditions and HBr, may be the NO oxidation reaction of the oxidant compound of formula I is NO2,
Figure CN102746358AC00021
式2化合物 式I化合物其中R2 = H,OH R3 = H或甲基, R2,R3 =单键或环氧,即16,17位之间为双键或通过氧桥相连Rl = OH, R4 = H,Cl, F, Rl,R4 =单键或环氧,即9,11位之间为双键或通过氧桥相连R5 = H,卤素或甲基, .1,2位虚线代表单键或双键。 Formula 2 compound of formula I wherein R2 = H, OH R3 = H or methyl, R2, R3 = a single bond or an epoxy, i.e., a double bond between positions 16 and 17 are connected through an oxygen bridge or Rl = OH, R4 = H, Cl, F, Rl, R4 = a single bond or an epoxy, i.e., a double bond between positions 9 and 11 are connected through an oxygen bridge or R5 = H, halogen or methyl, the dotted line represents a single bond or a bit .1,2 double bond.
2.如权利要求I所述式I化合物的制备方法,其特征在于氧化剂为氧气、空气、H202。 2. The preparation of the compounds of the formula I according to claim I, wherein the oxidizing agent is oxygen, air, H202.
3.如权利要求I所述式I化合物的制备方法,其特征在于反应温度在0C至100C。 Preparation of the compounds of the formula I as claimed in claim I 3., wherein the reaction temperature is from 0 C to 100 C.
4.如权利要求I所述式I化合物的制备方法,其特征在于反应中的有机溶媒为6个碳以内的醇、20C下为液态的含有1-4个卤素的卤代烷基、卤代芳香烃、芳香烃或醚、酯、腈、.20C下为液态的有机酸一种或几种。 The preparation of the compounds of the formula I according to claim I, wherein the reaction in organic solvent is less than 6 carbon alcohol, 20 C which is liquid under the halogen containing 1-4 haloalkyl, halo aromatic hydrocarbons, aromatic hydrocarbons or ethers, esters, nitriles, .20 C under one or more of an organic acid liquid.
5.如权利要求I所述式I化合物的制备方法,其特征在于反应中的有机溶媒为甲醇、乙醇、、丙醇、二氯甲烷、氯仿、1,2-二氯乙烷、四氯化碳、乙醚、四氢呋喃、1,4_ 二氧六环、乙酸乙酯、乙腈、甲酸、乙酸、丙酸、丁酸、异丙酸、异丁酸中的一种或几种。 5. A process for producing a compound of the formula I according to claim I, wherein the reaction of the organic solvent is methanol, ethanol ,, propanol, dichloromethane, chloroform, 1,2-dichloroethane, tetrachloride carbon, diethyl ether, tetrahydrofuran, 1,4_ dioxane, ethyl acetate, acetonitrile, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, isobutyric acid in one or several.
6.如权利要求I所述式I化合物的制备方法,其特征在于反应中还可以加入相转移催化剂。 6. The method for preparing the compounds of the formula I according to claim I, wherein the reaction may also be added a phase transfer catalyst.
7.如权利要求21所述式I化合物的制备方法,其特征在于相转移催化剂为季铵盐类、醚类、环糊精类。 7. The method of claim 21 for preparing a compound of formula I according to claim, characterized in that the phase transfer catalyst is a quaternary ammonium salts, ethers, cyclodextrins.
8.如权利要求21所述式I化合物的制备方法,其特征在于相转移催化剂为季铵盐类。 8. The method of claim 21 for preparing a compound of formula I according to claim, characterized in that the phase transfer catalyst is a quaternary ammonium salt.
9.如权利要求21所述式I化合物的制备方法,其特征在于相转移催化剂为醚类优选聚乙二醇。 9. The method of claim 21 for preparing a compound of formula I according to claim, characterized in that the phase transfer catalyst is preferably a polyethylene glycol ether.
10.如权利要求I所述式I化合物的制备方法,其特征在于NO供体为亚硝酸盐、亚硝酸的6个碳以内的酯中的一种或几种。 10. A process for producing a compound of the formula I according to claim I, characterized in that the NO donor is nitrite, 6 carbon within the ester of nitrous acid in one or several.
Description  translated from Chinese

一种合成孕留21位溴化物的新工艺 A synthetic progestin stay bromide 21 new process

技术领域: Technology areas:

[0001] 本发明涉及孕甾21-溴合成的新工艺。 [0001] The present invention relates to the synthesis of 21-bromo-pregna-new process.

背景技术: BACKGROUND:

[0002] 21-溴孕留化合物是一种重要的中间体,它可以通过置换得到相应的酯化物,再经过碱水解得到21位羟基,也可以通过与其他的亲核试剂进攻得到新化合物,例如台湾成功大学陳韋動2006年发表的硕士论文“21-溴-3 a -羥基-3 P -甲氧甲基_5 a -孕烷_20_酮與咪唑化鋰反應之中間產物探討”。 [0002] 21-bromo compound is a progesterone remain important intermediate which can be obtained by substituting the corresponding ester thereof, and then after alkaline hydrolysis to give 21-hydroxy, may be by other nucleophiles attack give the novel compound, Chen Wei Cheng Kung University in Taiwan such as moving master's thesis published in 2006, "21-bromo -3 a - hydroxy -3 P - methoxymethyl _5 a - pregnane _20_ one with imidazole intermediate reaction of lithium to explore" .

[0003] 21-溴孕甾化合物的制备常见方法是通过Br2进行卤代反应得到,但是由于孕甾化合物的化学结构上经常出现羟基、双键或环氧等基团,直接卤代往往会产生杂质,同时为了是反应完成Br2的摩尔使用量远大于I : 1,从而造成Br2对于环境的污染。 [0003] 21- common methods for preparing the compounds of bromine megestrol halogenation reaction is carried out by Br2 obtained, but due to the chemical structure of pregnane compounds often a hydroxyl group, a double bond or epoxy group, halogenated often produce directly using molar amount of impurities, and in order to complete the reaction of Br2 is much greater than I: 1, resulting in environmental pollution Br2.

发明内容 SUMMARY

[0004] 我们通过不断的研究,我们提供了一种孕留21位溴化的新工艺,是在16、17位结构上存在羟基、双键或环氧等基团,9,11位结构上存在羟基、双键或环氧等基团的孕留化合物(式2化合物)使用通过一次反应得到孕留21位溴化物(式I化合物)的新合成工艺。 [0004] Through continuous research, we provide a pregnant 21 new technology to stay bromide is the presence of a hydroxyl group, a double bond or epoxy groups on the 16 and 17-bit architecture, the 9,11-bit architecture pregnant presence of a hydroxy, a double bond or epoxy group leaving the compound (formula 2 compound) by using a reaction stay 21 pregnant bromide (compound of formula I) of the new synthesis.

[0005] 由于式(II)化合物本身脂溶性较强,一般均溶解在非极性较强的有机溶媒中,但是反应中的NO供体、HBr、氧化剂均存在不溶于某些非极性有机溶剂的问题,造成反应过程中出现收率较低、时间较长的问题,于是我们在反应中加入相转移催化剂,反应结果的收率有所提闻、时间有所缩短。 [0005] Since the fat-soluble compound itself strong formula (II), generally dissolved in a non-polar organic solvent, but the reaction of the NO donor, HBr, the presence of an oxidizing agent are not soluble in some non-polar organic problem of the solvent, resulting in a lower yield, longer a problem during the reaction, so we added a phase transfer catalyst in the reaction, the reaction yield results have mentioned smell, time has been shortened.

[0006] 孕甾21位溴化物(式I化合物)存在两种结构,即 [0006] pregn-21 bromide (compound of formula I) the presence of two structures, i.e.,

[0007] [0007]

Figure CN102746358AD00031

[0008] 所以孕甾21位溴化物(式I化合物)的结构被确定为 [0008] Therefore, megestrol 21 bromide (compound of formula I) is determined to be a structure

[0009] [0009]

Figure CN102746358AD00041

[0010] NBS为N-溴代琥珀酰亚胺的缩写 [0010] NBS is N- bromosuccinimide Abbreviation

[0011] 本发明提供了一种式I化合物的制备方法,由式2化合物在有机溶媒、NO供体、条件下与HBr、可以将NO氧化为NO2的氧化剂反应生成式I化合物, [0011] The present invention provides a process for preparing a compound of formula I, from compounds of formula 2 in an organic solvent, NO donor, under conditions and HBr, an oxidizing agent can be the NO oxidation reaction of a compound of formula I is NO2,

[0012] [0012]

Figure CN102746358AD00042

式2化合物 式I化合物 Formula 2 compound of formula I

[0013] R2 = H, OH [0013] R2 = H, OH

[0014] R3 = H 或甲基, [0014] R3 = H or methyl,

[0015] R2,R3 =单键或环氧,即16,17位之间为双键或通过氧桥相连 [0015] R2, R3 = a single bond or an epoxy, or a double bond that is attached through an oxygen bridge between positions 16 and 17

[0016] Rl = 0H, [0016] Rl = 0H,

[0017] R4 = H, Cl, F, [0017] R4 = H, Cl, F,

[0018] Rl, R4 =单键或环氧,即9,11位之间为双键或通过氧桥相连 [0018] Rl, R4 = a single bond or an epoxy, or a double bond that is attached through an oxygen bridge between positions 9,11

[0019] R5 = H,卤素或甲基, [0019] R5 = H, halogen or methyl,

[0020] 1,2位虚线代表单键或双键。 [0020] the 1,2-dotted line represents a single bond or a double bond.

[0021] 优选 [0021] Preferred

[0022] R2 = OH [0022] R2 = OH

[0023] R3 = H 或甲基, [0023] R3 = H or methyl,

[0024] R2, R3 =单键或环氧,即16,17位之间为双键或通过氧桥相连 [0024] R2, R3 = a single bond or an epoxy, or a double bond that is attached through an oxygen bridge between positions 16 and 17

[0025] Rl = 0H, [0025] Rl = 0H,

[0026] R4 = Cl, [0026] R4 = Cl,

[0027] Rl, R4 =单键或环氧,即9,11位之间为双键或通过氧桥相连 [0027] Rl, R4 = a single bond or an epoxy, or a double bond that is attached through an oxygen bridge between positions 9,11

[0028] R5 = H,卤素或甲基, [0028] R5 = H, halogen or methyl,

[0029] 1,2位虚线代表单键或双键。 [0029] the 1,2-dotted line represents a single bond or a double bond.

[0030] 更优选 [0030] More preferably

[0031] R2 = OH [0031] R2 = OH

[0032] R3 = H 或甲基,[0033] Rl = OH, [0032] R3 = H or methyl, [0033] Rl = OH,

[0034] R4 = H,F 或Cl, [0034] R4 = H, F or Cl,

[0035] Rl,R4 =环氧,SP 9,11位之间为通过氧桥相连 [0035] is connected to through an oxygen bridge between Rl, R4 = ethylene, SP 9,11 bits

[0036] R5 = H,F 或甲基, [0036] R5 = H, F, or methyl,

[0037] 1,2位虚线代表单键或双键。 [0037] the 1,2-dotted line represents a single bond or a double bond.

[0038] 进一步优选 [0038] Further preferred

[0039] R2 = OH [0039] R2 = OH

[0040] R3 = H 或甲基, [0041] Rl = 0H, [0040] R3 = H or methyl, [0041] Rl = 0H,

[0042] R4 = H,F 或Cl, [0042] R4 = H, F or Cl,

[0043] R5 = H 或甲基, [0043] R5 = H or methyl,

[0044] 1,2位虚线代表单键或双键。 [0044] the 1,2-dotted line represents a single bond or a double bond.

[0045] 更进一步优选 [0045] Further preferred

[0046] R2 = OH [0046] R2 = OH

[0047] R3 = H, [0047] R3 = H,

[0048] Rl = 0H, [0048] Rl = 0H,

[0049] R4 = H,F 或Cl, [0049] R4 = H, F or Cl,

[0050] R5 = H,或甲基, [0050] R5 = H, or methyl,

[0051] 1,2位虚线代表单键或双键。 [0051] the 1,2-dotted line represents a single bond or a double bond.

[0052] 所述式I化合物的制备方法,其特征在于氧化剂为氧气、空气、H202。 [0052] The method for preparing the compounds of the formula I, wherein the oxidizing agent is oxygen, air, H202. 优选为氧气。 Preferably oxygen.

[0053] 所述式I化合物的制备方法,反应温度在0C至100C。 Preparation Method [0053] The compound of the formula I, the reaction temperature is from 0 C to 100 C. 优选20C至90C。 Preferably from 20 C to 90 C. 更有选40C至70C。 More election 40 C to 70 C.

[0054] 所述式I化合物的制备方法,反应中的有机溶媒为6个碳以内的醇、20C下为液态的含有1-4个卤素的卤代烷基、卤代芳香烃、芳香烃或醚、酯、腈、20C下为液态的有机酸一种或几种。 [0054] The method for preparing the compounds of the formula I, the reaction of the organic solvent is less than 6 carbon alcohol, 20 C under 1-4 halogen containing halogenated alkyl, halogenated aromatic hydrocarbon liquid, an aromatic hydrocarbon or ethers, esters, nitriles, 20 C is liquid at one or more organic acids. 优选为6个碳以内的醇、20C下为液态的含有2-4个氯代烷基、6个碳以内的醚、4个碳以内的腈、20C下为液态的4个碳以内有机酸中的一种或几种。 Preferably 6 carbons or less alcohol, 20 C which is liquid under containing 2-4 chloroalkyl, less than 6 carbon ether, 4 or less carbon nitrile, 20 C which is liquid under four carbon within one or more organic acids. 更优选为3个碳以内的醇、20C下液态的含有2-4个氯代烷基、6个碳以内的醚、4个碳以内的腈、20C下为液态的4个碳以内有机酸中的一种或几种。 More preferably less than three carbon alcohol, 20 C in the liquid state containing 2-4 chloroalkyl, less than 6 carbon ether, 4 or less carbon nitrile, 20 C which is liquid under four carbon within one or more organic acids. 进一步优选为甲醇、乙醇、、丙醇、二氯甲烷、氯仿、1, More preferably methanol, ethanol ,, propanol, dichloromethane, chloroform, 1,

2-二氯乙烷、四氯化碳、乙醚、四氢呋喃、1,4_ 二氧六环、乙酸乙酯、乙腈、甲酸、乙酸、丙酸、丁酸、异丙酸、异丁酸中的一种或几种。 2- dichloroethane, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4_ dioxane, ethyl acetate, acetonitrile, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, isobutyric acid in a species or several. 更进一步优选为四氯化碳、乙醚、四氢呋喃、1,4_ 二氧六环、乙醇、乙酸、乙腈中的一种或几种。 Still more preferably carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4_ dioxane, ethanol, acetic acid, acetonitrile and combinations thereof.

[0055] 所述式I化合物的制备方法,在于反应中还可以加入相转移催化剂。 [0055] The method for preparing the compounds of the formula I, wherein the reaction may be added a phase transfer catalyst. 所述相转移催化剂为季铵盐类、醚类、环糊精类。 The phase transfer catalyst is a quaternary ammonium salts, ethers, cyclodextrins. 醚类优选聚乙二醇。 Ethers, preferably polyethylene glycol. 优选为季铵盐类;如四丁基溴化铵、四丁基氯化铵。 Preferably quaternary ammonium salts; as tetrabutylammonium bromide, tetrabutylammonium chloride.

[0056] 所述式I化合物的制备方法,所述NO供体为亚硝酸盐、亚硝酸的6个碳以内的酯中的一种或几种。 [0056] The method for preparing the compounds of the formula I, the NO donor is nitrite, 6 carbon within the ester of nitrous acid in one or several. 选自为亚硝酸的碱金属盐,进一步选自亚硝酸钠、亚硝酸钾中的一种或几种,更进一步选自为亚硝酸钠。 Is selected from alkali metal nitrite, is further selected from sodium nitrite, potassium nitrite in one or more, further selected from sodium nitrite. NO供体还选自亚硝酸异戊酯、亚硝酸叔丁酯、亚硝酸乙酯、亚硝酸甲酯、亚硝酸丙酯、亚硝酸丁酯、亚硝酸戊酯、亚硝酸异丙酯、亚硝酸异丁酯中的一种或几种。 NO donor also is selected from isoamyl nitrite, t-butyl nitrite, ethyl nitrite, methyl nitrite, propyl nitrite, butyl nitrite, amyl nitrite, isopropyl nitrite, Asia nitrate, isobutyl one or several. 具体实施方式: DETAILED DESCRIPTION:

[0057] 具体实施方式中的实施例仅为更进一步说明发明的技术方案,不能解释为对本发明实施方式的限制。 [0057] Example embodiment further describing the technical solutions of the invention only, and not to be construed as limiting the embodiments of the present invention.

[0058] 在计算孕甾21位溴化物(式I化合物)的收率时,是将21-溴化合物和21-双溴化合物统一计算,这是由于在置换反应中21-溴化合物和21-双溴化合物均可以被置换成单酯物如21-醋酸酯。 [0058] When calculating pregn 21 bromide (compound of formula I) yield, is a bromine compound and unified computing 21- 21- bis bromine compound, which is due to the 21-bromo compound in a displacement reaction, and 21- bis-bromo compound can be replaced with 21- monoesters thereof such as acetate.

[0059] 实施例I [0059] Example I

[0060] [0060]

Figure CN102746358AD00061

[0061] 将2. I化合物10mmol、30ml 二氯甲烧加入反应容器内,再加入14mmol HBr (浓度为42%的水溶液),最后加入3mmol NaN02,升温至60C搅拌下,通入氧气,8小时后反应至无原料,加入10 %的Na2SO3水溶液洗涤有机相数次,除去无机盐,有机层加入无水硫酸钠干燥,过滤,然后真空旋转蒸发,除去有机溶剂,甲醇重结晶即得产物,得I. I化合物5. Smmol。 [0061] The compound 2. I 10mmol, 30ml dichloromethane was added to the reaction vessel to burn, then add 14mmol HBr (at a concentration of 42% solution in water), and finally adding 3mmol NaN02, warmed to 60 C with stirring, which leads to oxygen, After 8 hours the reaction until no starting material, was added a 10% Na2SO3 aqueous solution was washed with the organic phase several times to remove inorganic salts, the organic layer was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated in vacuo to remove the organic solvent, the product was recrystallized from methanol to obtain , was I. I compound 5. Smmol.

[0062] 实施例I. I [0062] EXAMPLE I. I

[0063] 将2. I化合物10mmol、40ml乙腈加入反应容器内,再加入13mmol HBr (浓度为42%的水溶液),最后加入2. 5mmol NaN02,升温至40C搅拌下,通入氧气,6小时后反应至无原料,加入稀释于5% Na2SO3水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. I化合物8. 6mmol。 [0063] The compound 2. I 10mmol, 40ml acetonitrile was added to the reaction vessel, then add 13mmol HBr (at a concentration of 42% solution in water), and finally adding 2. 5mmol NaN02, warmed to 40 C under stirring, which leads to oxygen, 6 hours the reaction until no starting material, diluted in 150ml of 5% Na2SO3 solution, filtered, washed to neutrality, dried, and recrystallized from methanol to obtain the product, Compound I. I 8. 6mmol.

[0064] 实施例I. 2 [0064] EXAMPLE I. 2

[0065] 将2. I化合物10mmol、25ml四氢呋喃加入反应容器内,再加入13mmol HBr (浓度为42%的水溶液),最后加入4mmol NaN02,升温至20C搅拌下,通入氧气,8小时后反应至无原料,加入稀释于5% Na2SO3水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. I化合物8. 5mmol。 After [0065] The compound 2. I 10mmol, 25ml of tetrahydrofuran was added to the reaction vessel, then add 13mmol HBr (at a concentration of 42% solution in water), and finally adding 4mmol NaN02, warmed to 20 C under stirring, which leads to oxygen, 8 hours The reaction until no starting material, diluted in 150ml of 5% Na2SO3 solution, filtered, washed to neutrality, dried, and recrystallized from methanol to obtain the product, Compound I. I 8. 5mmol.

[0066] 实施例I. 3 [0066] EXAMPLE I. 3

[0067] 将2. I化合物10mmol、40ml乙醇加入反应容器内,再加入13mmol HBr(浓度为42%的水溶液),最后加入2mmol NaN02,升温至30C搅拌下,通入氧气,6小时后反应至无原料,加入稀释于5% Na2SO3水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. I化合物9. 4mmol0 After [0067] The compound 2. I 10mmol, 40ml of ethanol was added to the reaction vessel, then add 13mmol HBr (at a concentration of 42% solution in water), and finally adding 2mmol NaN02, warmed to 30 C under stirring, which leads to oxygen, 6 hours The reaction until no starting material, diluted in 150ml of 5% Na2SO3 solution, filtered, washed to neutrality, dried, and recrystallized from methanol to obtain the product, to give I. I compound 9. 4mmol0

[0068] 实施例I. 4 [0068] EXAMPLE I. 4

[0069] 将2. I化合物10mmol、25ml乙酸加入反应容器内,再加入13mmol HBr (浓度为42%的水溶液),最后加入2mmol NaN02,升温至40C搅拌下,通入氧气,6小时后反应至无原料,加入稀释于5% Na2SO3水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. I化合物7. 7mmolo[0070] 实施例I. 5 After [0069] The compound 2. I 10mmol, 25ml of acetic acid was added to the reaction vessel, then add 13mmol HBr (at a concentration of 42% solution in water), and finally adding 2mmol NaN02, warmed to 40 C under stirring, which leads to oxygen, 6 hours The reaction until no starting material, diluted in 150ml of 5% Na2SO3 solution, filtered, washed to neutrality, dried, and recrystallized from methanol to obtain the product, Compound I. I 7. 7mmolo [0070] Example I. 5

[0071] 将2. I化合物IOmmol、100ml甲醇加入反应容器内,再加入14mmol HBr (浓度为42%的水溶液),最后加入4mmol NaN02,升温至40C搅拌下,通入氧气,10小时后反应至无原料,加入稀释于5% Na2SO3水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. I化合物7. 3mmolo After [0071] The compound 2. I IOmmol, 100ml methanol was added to the reaction vessel, then add 14mmol HBr (at a concentration of 42% solution in water), and finally adding 4mmol NaN02, warmed to 40 C under stirring, which leads to oxygen, 10 hours The reaction until no starting material, diluted in 150ml of 5% Na2SO3 solution, filtered, washed to neutrality, dried, and recrystallized from methanol to obtain the product, to give I. I compound 7. 3mmolo

[0072] 实施例2 [0072] Example 2

[0073] [0073]

Figure CN102746358AD00071

[0074] 将2. 2化合物10mmol、20ml乙醇,IOml四氢呋喃加入反应容器内,再加入13mmolHBr (浓度为42%的水溶液),最后加入3mmol NaN02,升温至25C搅拌下,通入氧气,8小时后反应至无原料,加入稀释于5% Na2SO3水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. I化合物9. OmmoI。 [0074] A 2.2 Compound 10mmol, 20ml ethanol, IOml tetrahydrofuran was added to the reaction vessel, then add 13mmolHBr (at a concentration of 42% solution in water), and finally adding 3mmol NaN02, warmed to 25 C under stirring, which leads to oxygen, 8 hours the reaction until no starting material, diluted in 150ml of 5% Na2SO3 solution, filtered, washed to neutrality, dried, and recrystallized from methanol to obtain the product, to give I. I compound 9. OmmoI.

[0075] 实施例2. I [0075] EXAMPLE 2. I

[0076] 将2. 2化合物10mmol、20ml乙醇,5ml乙腈加入反应容器内,再加入13mmolHBr (浓度为42%的水溶液),最后加入3mmol NaN02,升温至25C搅拌下,通入氧气,8小时后反应至无原料,加入稀释于2% Na2SO3水溶液IOOml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. I化合物9. OmmoI。 [0076] A 2.2 Compound 10mmol, 20ml of ethanol, 5ml of acetonitrile was added to the reaction vessel, then add 13mmolHBr (at a concentration of 42% solution in water), and finally adding 3mmol NaN02, warmed to 25 C under stirring, which leads to oxygen, 8 hours the reaction until no starting material, diluted in 2% Na2SO3 aqueous solution IOOml, filtered, washed until neutral, dried and recrystallized from methanol to obtain the product, to give I. I compound 9. OmmoI.

[0077] 实施例2. 2 [0077] Example 2.2

[0078] 将2. 2化合物10mmol、20ml乙醇,5ml乙腈加入反应容器内,再加入13mmolHBr (浓度为42%的水溶液),最后加入3mmol KN02,升温至45C搅拌下,通入空气,20小时后反应至无原料,加入稀释于2% Na2SO3水溶液IOOml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. I化合物9. lmmol。 [0078] A 2.2 Compound 10mmol, 20ml of ethanol, 5ml of acetonitrile was added to the reaction vessel, then add 13mmolHBr (at a concentration of 42% solution in water), and finally adding 3mmol KN02, warmed to 45 C under stirring, passing air, 20 hours the reaction until no starting material, diluted in 2% Na2SO3 aqueous solution IOOml, filtered, washed until neutral, dried and recrystallized from methanol to obtain the product, to give I. I compound 9. lmmol.

[0079] 实施例3 [0079] Example 3

[0080] [0080]

Figure CN102746358AD00072

[0081] 将2. 3化合物IOmmol加入30ml四氯化碳中,再加入13. Ommol HBr(浓度为42%的水溶液),最后加入0. 8mmol四丁基溴化铵、3mmol NaN02,升温至35C搅拌下,通入氧气,8小时后反应至无原料,加入10%的Na2SO3水溶液洗涤有机相数次,除去无机盐,有机层加入无水硫酸钠干燥,过滤,然后真空旋转蒸发,除去有机溶剂,甲醇重结晶即得产物,得I. 3化合物8. lmmol o [0081] The compound IOmmol 2.3 30ml of carbon tetrachloride was added, then add 13. Ommol HBr (at a concentration of 42% solution in water), and finally adding 0. 8mmol tetrabutylammonium bromide, 3mmol NaN02, warmed to 35 C with stirring, which leads to oxygen, the reaction for 8 hours until no starting material, a 10% Na2SO3 aqueous solution was added the organic phase was washed several times to remove inorganic salts, the organic layer was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated in vacuo to remove organic solvent, and recrystallized from methanol to obtain the product, have I. 3 compound 8. lmmol o

[0082] 实施例3. I [0082] EXAMPLE 3. I

[0083] 将2. 3化合物IOmmol加入30ml四氯化碳中,再加入13. Ommol HBr(浓度为42%的水溶液),最后加入Immol聚乙二醇、3mmol NaN02,升温至35C搅拌下,通入氧气,8小时后反应至无原料,加入10%的Na2SO3水溶液洗涤有机相数次,除去无机盐,有机层加入无水硫酸钠干燥,过滤,然后真空旋转蒸发,除去有机溶剂,甲醇重结晶即得产物,得I. 3化合物8. Ommolo [0083] The compound IOmmol 2.3 30ml of carbon tetrachloride was added, then add 13. Ommol HBr (at a concentration of 42% solution in water), and finally adding Immol polyethylene glycol, 3mmol NaN02, warmed to 35 C with stirring , which leads to oxygen, after 8 hours the reaction until no starting material, was added a 10% Na2SO3 aqueous solution was washed organic phase several times to remove inorganic salts, the organic layer was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated in vacuo to remove the organic solvent, methanol recrystallization derived products, have I. 3 compound 8. Ommolo

[0084] 实施例3. 2 [0084] Example 3.2

[0085] 将2. 3化合物IOmmol加入30ml四氯化碳中,再加入13. Ommol HBr (浓度为42%的水溶液),最后加入3mmol NaN02,升温至35C搅拌下,通入氧气,8小时后反应至无原料,加入10 %的Na2SO3水溶液洗涤有机相数次,除去无机盐,有机层加入无水硫酸钠干燥,过滤,然后真空旋转蒸发,除去有机溶剂,甲醇重结晶即得产物,得I. 3化合物7. lmmol。 [0085] The compound IOmmol 2.3 30ml of carbon tetrachloride was added, then add 13. Ommol HBr (at a concentration of 42% solution in water), and finally adding 3mmol NaN02, warmed to 35 C under stirring, which leads to oxygen, 8 hours the reaction until no starting material, was added a 10% Na2SO3 aqueous solution was washed with the organic phase several times to remove inorganic salts, the organic layer was dried over anhydrous sodium sulfate, filtered, and then a vacuum rotary evaporator, the organic solvent was removed, and recrystallized from methanol to obtain the product, I. 3 compound was 7. lmmol. .

[0086] 实施例3. 3 [0086] EXAMPLE 3.3

[0087] 将2. 3化合物IOmmol加入50ml四氯化碳中,再加入13. Ommol HBr (浓度为42%的水溶液),最后加入3mmol NaN02,升温至35C搅拌下,通入空气,25小时后反应至无原料,加入稀释于2% Na2SO3水溶液IOOml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. 3化合物7. 3mmol o [0087] The compound IOmmol 2.3 50ml of carbon tetrachloride was added, then add 13. Ommol HBr (at a concentration of 42% solution in water), and finally adding 3mmol NaN02, warmed to 35 C with stirring, passing air, 25 hours the reaction until no starting material, diluted in 2% Na2SO3 aqueous solution IOOml, filtered, washed until neutral, dried and recrystallized from methanol to obtain the product, to give compound 7. 3mmol o I. 3

[0088] 实施例4 [0088] Example 4

[0089] [0089]

Figure CN102746358AD00081

[0090] 将2. 4化合物10mmol、30ml四氢呋喃加入反应容器内,再加入14. Ommol HBr (浓度为42%的水溶液),最后加入3. 5mmol亚硝酸异戍酯,升温至35C搅拌下,通入氧气,8小时后反应至无原料,加入稀释于2% Na2SO3水溶液IOOml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. 4化合物7. 7mmol。 [0090] A 2.4 Compound 10mmol, 30ml of tetrahydrofuran was added to the reaction vessel, then add 14. Ommol HBr (at a concentration of 42% solution in water), and finally adding 3. 5mmol isoamyl nitrite ester, warmed to 35 C with stirring , which leads to oxygen, after 8 hours the reaction until no starting material, diluted in 2% Na2SO3 aqueous solution IOOml, filtered, washed until neutral, dried and recrystallized from methanol to obtain the product, to give I. 4 compound 7. 7mmol.

[0091] 实施例4. I [0091] EXAMPLE 4. I

[0092] 将2. 4化合物10mmol、30ml四氢呋喃加入反应容器内,再加入14. Ommol HBr (浓度为42%的水溶液),最后加入3mmol亚硝酸异戊酯,升温至35C搅拌下,滴加缓慢滴加13mmol的H202 (30%7jC溶液),5小时后反应至无原料,加入稀释于5% Na2SO3水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. 4化合物7. OmmoI。 [0092] A 2.4 Compound 10mmol, 30ml of tetrahydrofuran was added to the reaction vessel, then add 14. Ommol HBr (at a concentration of 42% solution in water), and finally adding 3mmol isoamyl nitrite, warmed to 35 C under stirring, dropwise was slowly added dropwise 13mmol of H202 (30% 7jC solution), After 5 hours the reaction until no starting material, diluted in 150ml of 5% Na2SO3 solution, filtered, washed to neutrality, dried, and recrystallized from methanol to obtain the product as a I 4. Compound 7. OmmoI.

[0093] 实施例5 [0093] Example 5

[0094] [0094]

Figure CN102746358AD00091

[0095] 将2. 5化合物IOmmol、20ml 1,4_ 二氧六环、20ml乙醇加入反应容器内,再加入14. OmmolHBr (浓度为42%的水溶液),最后加入2mmol亚硝酸甲酯,升温至55C搅拌下,滴加缓慢滴加13mmol的H2O2 (30%水溶液),5小时后反应至无原料,加入稀释于5% Na2SO3水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. 5化合物8. 7mmol0 [0095] A 2.5 Compound IOmmol, 20ml 1,4_ dioxane, 20ml of ethanol was added to the reaction vessel, then add 14. OmmolHBr (concentration of 42% solution in water), and finally adding 2mmol methyl nitrite, warmed to at 55 C with stirring, a solution was slowly added dropwise 13mmol of H2O2 (30% aqueous solution), 5 hours after the reaction until no starting material, diluted in 150ml of 5% Na2SO3 solution, filtered, washed to neutrality, dried, and recrystallized from methanol That product was obtained, was I. 5 compound 8. 7mmol0

[0096] 实施例5. I [0096] Example 5. I

[0097] 将2. 5化合物IOmmol、20ml 1,4_ 二氧六环、20ml乙醇加入反应容器内,再加入14. OmmolHBr (浓度为42%的水溶液),最后加入2mmol亚硝酸钠,升温至55C搅拌下,滴加缓慢滴加13mmol的H2O2 (30%水溶液),5小时后反应至无原料,加入稀释于5% Na2SO3水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得化合物I. 58. 3mmol0 [0097] A 2.5 Compound IOmmol, 20ml 1,4_ dioxane, 20ml of ethanol was added to the reaction vessel, then add 14. OmmolHBr (concentration of 42% solution in water), and finally adding 2mmol sodium nitrite, warmed to 55 Under C with stirring, a solution was slowly added dropwise 13mmol of H2O2 (30% aqueous solution), 5 hours after the reaction until no starting material, diluted in 150ml of 5% Na2SO3 solution, filtered, washed until neutral, dried, and recrystallized from methanol i.e. The product was obtained Compound I. 58. 3mmol0

[0098] 实施例6 [0098] Example 6

[0099] [0099]

Figure CN102746358AD00092

[0100] 将2. 6化合物IOmmol加入20ml乙醇、IOml乙腈加入反应容器内,再加入14. OmmolHBr (浓度为42%的水溶液),最后加入2mmol亚硝酸钾,升温至55C搅拌下,滴加缓慢滴加13mmol的H202 (30%7jC溶液),5小时后反应至无原料,加入稀释于5% Na2SO3水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得I. 6化合物8. OmmoI。 [0100] A 2.6 Compound IOmmol added 20ml of ethanol, IOml acetonitrile was added to the reaction vessel, then add 14. OmmolHBr (concentration of 42% solution in water), and finally adding 2mmol potassium nitrite, warmed to 55 C under stirring, dropwise was slowly added dropwise 13mmol of H202 (30% 7jC solution), After 5 hours the reaction until no starting material, diluted in 150ml of 5% Na2SO3 solution, filtered, washed to neutrality, dried, and recrystallized from methanol to obtain the product as a I 6. Compound 8. OmmoI.

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