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Publication numberCN102746358 B
Publication typeGrant
Application numberCN 201110101280
Publication dateFeb 10, 2016
Filing dateApr 22, 2011
Priority dateApr 22, 2011
Also published asCN102746358A
Publication number201110101280.1, CN 102746358 B, CN 102746358B, CN 201110101280, CN-B-102746358, CN102746358 B, CN102746358B, CN201110101280, CN201110101280.1
Inventors卢彦昌, 孙亮, 韩英, 刘爱
Applicant天津金耀集团有限公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
一种合成孕甾21位溴化物的工艺 A synthetic steroid progesterone 21 bromide process translated from Chinese
CN 102746358 B
Abstract  translated from Chinese
一种合成孕甾21位溴化物的新工艺,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1化合物。 A synthetic steroid progesterone 21 new technology bromide, a compound of formula 2 in an organic solvent, NO donor, under conditions HBr, may be NO oxidizing a compound of formula 1 as an oxidizing agent NO2.
Claims(23)  translated from Chinese
1. 一种式1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供体条件下与皿r、可W将NO氧化为N02的氧化剂反应生成式1化合物,有机溶媒为6个碳W内的醇、 20C下液态的含有1-4个面素的面代烷基、面代芳香控、芳香控或酸、醋、腊、20C下为液态的有机酸中的一种或几种,氧化剂为氧气、空气、&化,NO供体为亚硝酸盐、亚硝酸的6个碳W内的醋中的一种或几种, 1. A method for preparing a compound of formula 1, wherein the compound of Formula 2 in an organic solvent, NO Vivo and the dish for r, W may be a compound of formula 1 of an oxidizing agent oxidizes NO to N02, the organic solvent is 6 alcohol carbon within the W, 20 C at the surface pigment containing 1-4 alkyl group liquid surface, surface generation aromatase control, control or aromatic acid, vinegar, wax, 20 C under an organic acid in a liquid state one or more of the oxidizing agent is oxygen, air, & technology, NO donor nitrite, vinegar in one or more of six carbon nitrite within the W,
Figure CN102746358BC00021
其中R2=H,oh R3=Η或甲基, Rz,R3=单键或环氧,即16, 17位之间为双键或通过氧桥相连Ri=0H, R4=H,C1,F, Ri,R4=单键或环氧,即9, 11位之间为双键或通过氧桥相连R5=H,面素或甲基, 1,2位虚线代表单键或双键。 Wherein R2 = H, oh R3 = Η or methyl, Rz, R3 = single bond or ethylene, i.e. 16, 17 or a double bond between attached through an oxygen bridge Ri = 0H, R4 = H, C1, F, Ri, R4 = a single bond or ethylene, i.e. 9, 11 is a double bond between attached through an oxygen bridge or R5 = H, methyl, or surface elements, the dotted line represents a single bond or 1,2 position double bond.
2. 如权利要求1所述的式1化合物的制备方法,其特征在于其中R2=0H R3=Η或甲基, Rz,R3=单键或环氧,即16, 17位之间为双键或通过氧桥相连Ri=0H, R4=C1, Ri,R4=单键或环氧,即9, 11位之间为双键或通过氧桥相连R5=H,面素或甲基, 1,2位虚线代表单键或双键。 2. A method for preparing a compound of formula 1 according to claim 1, wherein R2 = 0H R3 = Η or methyl, Rz, R3 = single bond or an epoxy, i.e. 16, 17 is a double bond between or attached through an oxygen bridge Ri = 0H, R4 = C1, Ri, R4 = a single bond or an epoxy, i.e. 9, 11 is connected between a double bond or through an oxygen bridge R5 = H, methyl, or surface elements, 1, two dotted line represents a single bond or a double bond.
3. 如权利要求1所述的式1化合物的制备方法,其特征在于其中R2=0H R3=Η或甲基, Ri=0H, R4=H,F或Cl, Ri,R4=环氧,即9, 11位之间为通过氧桥相连R5=H,F或甲基, 1,2位虚线代表单键或双键。 3. The method of preparing the compounds of formula 1 according to claim 1, wherein R2 = 0H R3 = Η or methyl, Ri = 0H, R4 = H, F or Cl, Ri, R4 = propylene, i.e., 9, 11 is connected through an oxygen bridge between R5 = H, F or methyl, the dotted line represents a single bond or 1,2 position double bond.
4. 如权利要求1所述的式1化合物的制备方法,其特征在于其中R2=0H R3=Η或甲基, Ri=OH, R4=H,F或Cl, Rs=H或甲基, 1,2位虚线代表单键或双键。 The method for producing a compound of formula 1 according to claim 1, wherein R2 = 0H R3 = Η or methyl, Ri = OH, R4 = H, F or Cl, Rs = H or methyl, 1 , 2 the dashed line represents a single bond or a double bond.
5. 如权利要求1所述的式1化合物的制备方法,其特征在于其中R2=0H R3=η, Ri=OH, R4=H,F或Cl, R5=H,或甲基, 1,2位虚线代表单键或双键。 5. A method of preparing a compound of formula 1 according to claim 1, wherein R2 = 0H R3 = η, Ri = OH, R4 = H, F or Cl, R5 = H, or methyl, 1,2 bit dashed line represents a single bond or a double bond.
6. 如权利要求1所述式1化合物的制备方法,其特征在于氧化剂为氧气。 6. The method of claim 1 for preparing a compound of formula as claimed in claim 1, wherein the oxidizing agent is oxygen.
7. 如权利要求1所述式1化合物的制备方法,其特征在于反应溫度在0C至100C。 7. The method of claim 1 for preparing a compound of formula as claimed in claim 1, wherein the reaction temperature is from 0 C to 100 C.
8. 如权利要求1所述式1化合物的制备方法,其特征在于反应溫度在20C至90C。 8. The method of claim 1 for preparing a compound of formula as claimed in claim 1, characterized in that the reaction temperature to 20 C and 90 C.
9. 如权利要求1所述式1化合物的制备方法,其特征在于反应溫度在40C至70C。 9. The method of claim 1 for preparing a compound of formula as claimed in claim 1, wherein the reaction temperature is 40 C to 70 C.
10. 如权利要求1所述式1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W内的醇、20C下为液态的含有2-4个氯代烷基、6个碳W内的酸、4个碳W内的腊、20C下为液态的4个碳W内有机酸中的一种或几种。 10. The method of claim 1 for preparing a compound of formula as claimed in claim 1, characterized in that the reaction in organic solvent is an alcohol within six carbon W, 20 C is liquid at chloroalkyl containing 2-4, 6 acid carbons W within four carbon within the wax W, 20 C within the next four carbon W liquid organic acids in one or several.
11. 如权利要求1所述式1化合物的制备方法,其特征在于反应中的有机溶媒为3个碳W内的醇、20C下为液态的含有2-4个氯代烷基、6个碳W内的酸、4个碳W内的腊、20C下为液态的4个碳W内有机酸中的一种或几种。 11. The method of claim 1 for preparing a compound of formula as claimed in claim 1, characterized in that the reaction in organic solvent is an alcohol within three carbon W, 20 C is liquid at chloroalkyl containing 2-4, 6 acid carbons W within four carbon within the wax W, 20 C within the next four carbon W liquid organic acids in one or several.
12. 如权利要求1所述式1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、二氯甲烧、氯仿、1,2-二氯乙烧、四氯化碳、乙酸、四氨巧喃、1,4-二氧六环、乙酸乙醋、乙腊、甲酸、乙酸、丙酸、下酸、异丙酸、异下酸中的一种或几种。 12. The method of claim 1 for preparing a compound of formula as claimed in claim 1, characterized in that the reaction of the organic solvent is methanol, ethanol, propanol, dichloromethane burning, chloroform, 1,2-dichloroethane burn tetrachloride carbon, acetic acid, tetraamine clever furans, 1,4-dioxane, ethyl acetate, acetic wax, formic acid, acetic acid, propionic acid, an acid, iso-propionic acid, iso-acid one or several.
13. 如权利要求1所述式1化合物的制备方法,其特征在于反应中的有机溶媒为四氯化碳、乙酸、四氨巧喃、1,4-二氧六环、乙醇、乙酸、乙腊中的一种或几种。 13. The method of claim 1 for preparing a compound of formula as claimed in claim 1, characterized in that the reaction in organic solvent is carbon tetrachloride, acetic acid, furans clever tetraamine, 1,4-dioxane, ethanol, acetic acid, ethyl wax in one or several.
14. 如权利要求1所述式1化合物的制备方法,其特征在于反应中加入相转移催化剂。 14. The method of claim 1 for preparing a compound of formula as claimed in claim 1, characterized in that the reaction is added a phase transfer catalyst.
15. 如权利要求14所述式1化合物的制备方法,其特征在于相转移催化剂为季锭盐类、 酸类或环糊精类。 15. A method for preparing the compound of formula 1 of claim 14, wherein the phase transfer catalyst is a quaternary ingot salts, acids or cyclodextrins.
16. 如权利要求14所述式1化合物的制备方法,其特征在于相转移催化剂为季锭盐类。 16. A method for preparing the compound of formula 1 of claim 14, wherein the phase transfer catalyst is a quaternary salt ingot.
17. 如权利要求14所述式1化合物的制备方法,其特征在于相转移催化剂为酸类,。 17. A method for preparing the compound of formula 1 of claim 14, wherein the phase transfer catalyst acids.
18. 如权利要求14所述式1化合物的制备方法,其特征在于相转移催化剂为聚乙二醇。 18. A method for preparing the compound of formula 1 of claim 14, wherein the phase transfer catalyst is polyethylene glycol.
19. 如权利要求14所述式1化合物的制备方法,其特征在于相转移催化剂为四下基漠化锭、四下基氯化锭。 19. A method for preparing a compound of the formula 14 to claim 1, wherein the phase transfer catalyst is a base looked desertification ingot, ingot looked trichloride.
20. 如权利要求1所述式1化合物的制备方法,其特征在于亚硝酸盐为亚硝酸的碱金属盐。 20. The method of claim 1 for preparing a compound of formula as claimed in claim 1, characterized in that the nitrite is an alkali metal nitrite.
21. 如权利要求1所述式1化合物的制备方法,其特征在于NO供体为亚硝酸钢、亚硝酸钟中的一种或几种。 21. The method of claim 1 for preparing a compound of formula as claimed in claim 1, characterized in that the NO donor is steel nitrite, nitrous acid in one or more of the clock.
22. 如权利要求1所述式1化合物的制备方法,其特征在于NO供体为亚硝酸钢。 22. The method of claim 1 for preparing a compound of formula as claimed in claim 1, characterized in that the NO donor is nitrous steel.
23. 如权利要求1所述式1化合物的制备方法,其特征在于NO供体为亚硝酸异戊醋、亚硝酸叔下醋、亚硝酸乙醋、亚硝酸甲醋、亚硝酸丙醋、亚硝酸下醋、亚硝酸戊醋、亚硝酸异丙醋、亚硝酸异下醋中的一种或几种。 23. The method of claim 1 for preparing a compound of Formula according to claim 1, characterized in that the NO donor is vinegar amyl nitrite, nitrite, t-under vinegar, vinegar ethyl nitrite, nitrite, methyl ester, propyl nitrite vinegar, Asia under nitric acid vinegar, vinegar amyl nitrite, isopropyl nitrite, vinegar, isobutyl nitrite under one or more of the vinegar.
Description  translated from Chinese
一种合成孕留21位溴化物的工艺 A synthetic progestin left 21 bromide process

技术领域: FIELD:

[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 progesterone steroid 21-bromo new technology.

背景技术: Background technique:

[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-3α-羥基-3β-甲氧甲基-5α-孕烷-20-酮與咪唑化鋰反應之中間產物探討"。 [0002] 21-bromo compound to remain pregnant is an important intermediate which can be obtained by substituting the corresponding ester compound, then after alkaline hydrolysis to give 21-hydroxy, or by other nucleophiles attack to give the novel compound, for example Taiwan University Chen Wei dynamic master's thesis published in 2006, "21-bromo -3α- hydroxy -3β- intermediate methoxymethyl -5α- pregnane-20-one and lithium imidazole reaction of Discussion."

[0003] 21-溴孕留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1 : 1,从而造成Br2对于环境的污染。 [0003] 21-bromo common method for preparing a compound is left pregnant by Br2 be halogenated reaction, but due to the chemical structure of the compound megestrol often a hydroxyl group, a double bond or epoxy and other groups often have direct halo impurities, and in order to be used in an amount much greater than the molar Br2 completion of the reaction 1: 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1化合物)的新合成工艺。 [0004] Through continuous research, we provide a pregnancy leave 21 brominated new technology, is the presence of a hydroxyl group, a double bond or epoxy and other groups on the 16 and 17-bit architecture, the 9,11-bit architecture pregnant presence of a hydroxy, a double bond or epoxy group or leaving compound (the compound of formula 2) by using a reaction stay 21 pregnant bromide (compound of formula 1) 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N0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高、时间有所缩短。 [0005] Since the compounds per se of formula liposoluble strong (II), generally dissolved in a non-polar organic solvent, but the reaction in the donor N0, HBr, is insoluble in the presence of an oxidizing agent are certain non-polar organic problems 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 improved results, the time has been shortened.

[0006] 孕留21位溴化物(式1化合物)存在两种结构,即 [0006] 21 pregnant leaving the bromide (compound of formula 1) the existence of two structures, i.e.,

[0007] [0007]

Figure CN102746358BD00051

[0008] 所以孕留21位溴化物(式1化合物)的结构被确定为 [0008] 21 therefore remain pregnant bromide (compound of Formula 1) is determined to be a structure

[0009] [0009]

Figure CN102746358BD00061

[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1化合物的制备方法,由式2化合物在有机溶媒、N0供体、条件下与HBr、可以将N0氧化为N02的氧化剂反应生成式1化合物, [0011] The present invention provides a process for preparing a compound of formula 1, the compound of Formula 2 in an organic solvent, N0 donor, under conditions as HBr, can be N02 N0 oxidizing agent in the oxidizing compound of formula 1,

[0012] [0012]

Figure CN102746358BD00062

[0013] R2 = H,0H [0013] R2 = H, 0H

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

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

[0016] R1 = 0H, [0016] R1 = 0H,

[0017] R4 = H,C1,F, [0017] R4 = H, C1, 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 = single bond or epoxy, or a double bond that is connected through an oxygen bridge between positions 9,11

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

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

[0021] 优选 [0021] Preferably

[0022] R2 = 0H [0022] R2 = 0H

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

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

[0025] R1 = 0H, [0025] R1 = 0H,

[0026] R4 = C1, [0026] R4 = C1,

[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 = single bond or epoxy, or a double bond that is connected through an oxygen bridge between positions 9,11

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

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

[0030] 更优选 [0030] More preferably

[0031] R2 = 0H [0031] R2 = 0H

[0032] R3 = H或甲基, [0032] R3 = H or methyl,

[0033] R1 = 0H, [0033] R1 = 0H,

[0034] R4 = H,FSC1, [0034] R4 = H, FSC1,

[0035] Rl,R4 =环氧,即9,11位之间为通过氧桥相连 [0035] Rl, R4 = propylene, i.e., is connected through an oxygen bridge between positions 9,11

[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] 1,2-bit dotted line represents a single bond or a double bond.

[0038] 进一步优选 [0038] Further preferred

[0039] R2 = 0H [0039] R2 = 0H

[0040] R3 = H或甲基, [0040] R3 = H or methyl,

[0041] R1 = 0H, [0041] R1 = 0H,

[0042] R4 = H,FSC1, [0042] R4 = H, FSC1,

[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] 1,2-bit dotted line represents a single bond or a double bond.

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

[0046] R2 = 0H [0046] R2 = 0H

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

[0048] R1 = 0H, [0048] R1 = 0H,

[0049] R4 = H,FSC1, [0049] R4 = H, FSC1,

[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] 1,2-bit dotted line represents a single bond or a double bond.

[0052] 所述式1化合物的制备方法,其特征在于氧化剂为氧气、空气、H202。 [0052] The preparation of a compound of formula, wherein the oxidizing agent is oxygen, air, H202. 优选为氧气。 Preferably oxygen.

[0053] 所述式1化合物的制备方法,反应温度在0C至100C。 [0053] A method for preparing a compound of the formula, the reaction temperature is 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1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 compound of formula 1, the reaction of the organic solvent is an alcohol of 6 or less carbon, 20 C under 1-4 halogen containing liquid is a haloalkyl group, halogenated aromatic hydrocarbons, aromatic hydrocarbons, or ether, ester, nitrile, 20 C in a liquid state under 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 or less carbon alcohol, 20 C is liquid at 2-4 chloroalkyl containing, within six carbon ethers, nitriles within four carbon, 20 C is liquid at the 4 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 is liquid at the 4 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, 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。 More preferably methanol, ethanol ,, propanol, dichloromethane, chloroform, 1,2-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 one 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。 Even more preferably carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4_ dioxane, ethanol, acetic acid, acetonitrile and combinations thereof.

[0055] 所述式1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] A method for preparing a compound of the formula, and that the reaction may also be 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; such as tetrabutylammonium bromide, tetrabutylammonium chloride.

[0056] 所述式1化合物的制备方法,所述N0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 preparation of a compound of the formula, the donor N0 nitrite, less than 6 carbon 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。 Selected from alkali metal salts, nitrites, further selected from sodium nitrite, potassium nitrate in one or more, further selected from sodium nitrite. N0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。 N0 donor also be selected from amyl nitrite, butyl nitrite, ethyl nitrite, methyl nitrite, propyl, butyl nitrite, amyl nitrite, isopropyl nitrite, Asia isobutyl nitrate in one or several.

具体实施方式: detailed description:

具体实施方式[0057] 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。 DETAILED DESCRIPTION OF EXAMPLES [0057] The only aspect of the invention further explanation, can not be interpreted as limiting embodiment of the present invention.

[0058] 在计算孕留21位溴化物(式1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] In calculating the remaining 21 pregnant bromide (compound of formula 1) the yield is unified computing 21- bis 21-bromo compound and the bromine compound, which is due to the 21-bromo compound in a displacement reaction and 21- bis-bromo compound can be is replaced monoesters thereof such as 21- acetate.

[0059] 实施例1 [0059] Example 1

Figure CN102746358BD00081

[0060] [0060]

[0061] /]寸乙•丄'κ/口狀」丄^承、τ>兀7川/、;乂四廿15&"門,丹乂^/、丄仙11〇丄riBr(浓度为42%的水溶液),最后加入3mmolNaN02,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Na2S0yK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1. 1化合物5. 8_〇1。 [0061] /] inch B • Shang 'κ / mouthpiece "^ Shang Cheng, τ> Wu Chuan 7/15 & ,; Yi in twenty four" doors, Dan qe ^ / Shang Shang Xian 11〇 riBr (concentration 42% aqueous solution) and finally 3mmolNaN02, warmed to 60 C as stirring, which leads to oxygen, after 8 hours no starting material to the reaction, washing was added a 10% solution of Na2S0yK organic phase several times to remove inorganic salts, the organic layer was added without over anhydrous sodium sulfate, filtered, and then rotary evaporated in vacuo to remove the organic solvent, the product was recrystallized from methanol to give compound 5. 1.1 8_〇1.

[0062] 实施例1. 1 [0062] Example 1.1

[0063] 将2. 1化合物10mmol、40ml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2. 5mmolNaN02,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%Na2S03水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 1化合物8. 6mmol。 After [0063] The compound 2.1 10mmol, 40ml acetonitrile was added to the reaction vessel, then added 13mmolHBr (concentration of 42% aqueous solution) and finally 2. 5mmolNaN02, warmed to 40 C under stirring, which leads to oxygen, 6 hours no reaction to the raw material, diluted to 5% Na2S03 solution 150ml, filtered, washed to neutrality, dried and recrystallized from methanol to obtain the product, compound 1. 1 8. 6mmol.

[0064] 实施例1. 2 [0064] Example 1.2

[0065] 将2. 1化合物10mmol、25ml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4mmolNaN02,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%Na2S03水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 1化合物8. 5mmol。 [0065] The compound 2.1 10mmol, 25ml of tetrahydrofuran was added to the reaction vessel, then added 13mmolHBr (concentration of 42% aqueous solution) and finally 4mmolNaN02, warmed to 20 C under stirring, which leads to oxygen, to the reaction after 8 hours no raw material, diluted in 150ml of aqueous 5% Na2S03, filtered, washed to neutrality, dried and recrystallized from methanol to give the product, compound 1. 1 8. 5mmol.

[0066] 实施例1. 3 [0066] Example 1.3

[0067] 将2. 1化合物10mmol、40ml乙醇加入反应容器内,再加入13mmolHBr(浓度为42%的水溶液),最后加入2mmolNaN02,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%Na2S03水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 1化合物9. 4mmol。 [0067] The compound 2.1 10mmol, 40ml of ethanol was added to the reaction vessel, then added 13mmolHBr (concentration of 42% aqueous solution) and finally 2mmolNaN02, warmed to 30 C under stirring, which leads to oxygen, to the reaction after 6 hours no raw material, diluted in 150ml of aqueous 5% Na2S03, filtered, washed to neutrality, dried and recrystallized from methanol to give the product, compound 1. 1 9. 4mmol.

[0068] 实施例1. 4 [0068] Example 1.4

[0069] 将2. 1化合物10mmol、25ml乙酸加入反应容器内,再加入13mmolHBr(浓度为42%的水溶液),最后加入2mmolNaN02,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%Na2S03水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 1化合物7. 7mmol。 [0069] After 2.1 Compound 10mmol, 25ml of acetic acid was added to the reaction vessel, then added 13mmolHBr (concentration of 42% aqueous solution) and finally 2mmolNaN02, warmed to 40 C under stirring, which leads to oxygen, to the reaction 6 hours no raw material, diluted in 150ml of aqueous 5% Na2S03, filtered, washed to neutrality, dried and recrystallized from methanol to give the product compound was 1.1 7. 7mmol.

[0070] 实施例1. 5 [0070] Example 1.5

[0071] 将2. 1化合物10mmol、100ml甲醇加入反应容器内,再加入14mmolHBr(浓度为42%的水溶液),最后加入4mmolNaN02,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%Na2S03水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 1化合物7. 3mmol。 [0071] The compound 2.1 10mmol, 100ml methanol was added to the reaction vessel, then added 14mmolHBr (concentration of 42% aqueous solution) and finally 4mmolNaN02, warmed to 40 C under stirring, which leads to oxygen, to the reaction after 10 hours no raw material, diluted in 150ml of aqueous 5% Na2S03, filtered, washed to neutrality, dried and recrystallized from methanol to give the product compound was 1.1 7. 3mmol.

[0072] 实施例2 [0072] Example 2

[0073] [0073]

Figure CN102746358BD00091

[0074] 将2. 2化合物10mmol、20ml乙醇,10ml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3mmolNaN02,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%Na2S03水溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 1化合物9. 0_〇1。 [0074] The compound 2.2 10mmol, 20ml of ethanol, 10ml of tetrahydrofuran was added to the reaction vessel, then added 13mmol HBr (42% aqueous solution concentration) and finally 3mmolNaN02, warmed to 25 C under stirring, which leads to oxygen, 8 h no reaction to the raw material, diluted to 5% Na2S03 solution 150ml, filtered, washed to neutrality, dried and recrystallized from methanol to give the product compound 1.1 9. 0_〇1.

[0075] 实施例2. 1 [0075] Example 2.1

[0076] 将2. 2化合物10mmol、20ml乙醇,5ml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3mmolNaN02,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%Na2S03水溶液100ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 1化合物9. 0_〇1。 [0076] The compound 2.2 10mmol, 20ml of ethanol, 5ml of acetonitrile was added to the reaction vessel, then added 13mmol HBr (42% aqueous solution concentration) and finally 3mmolNaN02, warmed to 25 C under stirring, which leads to oxygen, 8 h no reaction to the raw material, diluted in 100ml of an aqueous solution of 2% Na2S03, filtered, washed to neutrality, dried and recrystallized from methanol to give the product compound 1.1 9. 0_〇1.

[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13mmol HBr(浓度为42%的水溶液),最后加入3mmolKN02,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%Na2S03水溶液100ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 1化合物9. 1_〇1。 [0078] The compound 2.2 10mmol, 20ml of ethanol, 5ml of acetonitrile was added to the reaction vessel, then added 13mmol HBr (42% aqueous solution concentration) and finally 3mmolKN02, warmed to 45 C under stirring, air was fed at 20 h no reaction to the raw material, diluted in 100ml of an aqueous solution of 2% Na2S03, filtered, washed to neutrality, dried and recrystallized from methanol to give the product compound 1.1 9. 1_〇1.

[0079] 实施例3 [0079] Example 3

[0080] [0080]

Figure CN102746358BD00092

[0081] 将2. 3化合物lOmmol加入30ml四氯化碳中,再加入13.OmmolHBr(浓度为42% 的水溶液),最后加入〇. 8mmol四丁基溴化铵、3mmolNaN02,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Na2S0yK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1. 3 化合物8.lmmol〇 [0081] The compound 2.3 lOmmol added 30ml of carbon tetrachloride was added 13.OmmolHBr (concentration of 42% aqueous solution) and finally square. 8mmol tetrabutylammonium bromide, 3mmolNaN02, heated to 35 C under stirring, and the oxygen, after 8 hours no starting material to the reaction, washing was added a 10% solution of Na2S0yK 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 recrystallized from methanol to give the product compound was 1.3 8.lmmol〇

[0082] 实施例3. 1 [0082] Example 3.1

[0083] 将2. 3化合物lOmmol加入30ml四氯化碳中,再加入13.OmmolHBr(浓度为42% 的水溶液),最后加入lmmol聚乙二醇、3mmolNaN02,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Na2S0yK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1. 3化合物8.Ommolo [0083] The compound 2.3 lOmmol added 30ml of carbon tetrachloride was added 13.OmmolHBr (concentration of 42% aqueous solution) and finally lmmol polyethylene glycol, 3mmolNaN02, warmed to 35 C under stirring, by oxygen gas, the reaction for 8 hours until no starting material, was added with 10% of the organic phase Na2S0yK solution 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 solvents, recrystallized from methanol That product was to give compound 1.3 8.Ommolo

[0084] 实施例3. 2 [0084] Example 3.2

[0085] 将2. 3化合物lOmmol加入30ml四氯化碳中,再加入13.OmmolHBr(浓度为42% 的水溶液),最后加入3mmolNaN02,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Na2S(VK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1. 3化合物7.lmmol。。 [0085] The compound 2.3 lOmmol added 30ml of carbon tetrachloride was added 13.OmmolHBr (concentration of 42% aqueous solution) and finally 3mmolNaN02, heated to 35 C under stirring, and the oxygen, after 8 hours the reaction until no starting material, 10% of Na2S (VK solution, 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, the organic solvent was removed, and recrystallized from methanol to obtain the product, the compound was 1.3 7.lmmol ..

[0086] 实施例3. 3 [0086] Example 3.3

[0087] 将2. 3化合物lOmmol加入50ml四氯化碳中,再加入13.OmmolHBr(浓度为42% 的水溶液),最后加入3mmolNaN02,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%Na2S03水溶液100ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物, 得1. 3化合物7. 3mmol〇 After [0087] The compound 2.3 lOmmol 50ml of carbon tetrachloride was added, then add 13.OmmolHBr (concentration of 42% aqueous solution) and finally 3mmolNaN02, warmed to 35 C under stirring, air was fed at 25 hours no reaction to the raw material, diluted in 100ml of an aqueous solution of 2% Na2S03, filtered, washed to neutrality, dried and recrystallized from methanol to give the product compound was 1.3 7. 3mmol〇

[0088] 实施例4 [0088] Example 4

[0089] [0089]

Figure CN102746358BD00101

[0090] 将2. 4化合物10mmol、30ml四氢咲喃加入反应容器内,再加入14.OmmolHBr(浓度为42%的水溶液),最后加入3. 5mmol亚硝酸异戊酯,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 %Na2S03水溶液100ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 4化合物7. 7_〇1。 [0090] The compound 2.4 10mmol, 30ml tetrahydro Misaki Nom reaction vessel was added, then add 14.OmmolHBr (at a concentration of 42% aqueous solution) and finally 3. 5mmol amyl nitrite, warmed to 35 C With stirring, which leads to oxygen, after 8 hours no reaction to the raw material, diluted in 100ml of an aqueous solution of 2% Na2S03, filtered, washed to neutrality, dried and recrystallized from methanol to give the product compound was 1.4 7. 7_ 〇1.

[0091] 实施例4.1 [0091] Example 4.1

[0092] 将2. 4化合物lOmmol、30ml四氢咲喃加入反应容器内,再加入14.OmmolHBr(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%水溶液),5小时后反应至无原料,加入稀释于5%Na2S(VK溶液150ml 中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 4化合物7.Ommol。 [0092] The compound 2.4 lOmmol, 30ml tetrahydro Kou Nan added to the reaction vessel, then add 14.OmmolHBr (at a concentration of 42% aqueous solution) and finally 3mmol amyl nitrite, warmed to 35 C with stirring , 13mmol slowly added dropwise a solution of H202 (30% aqueous solution) to the reaction after 5 hours no starting material, diluted in 5% Na2S (VK 150ml solution, filtered, washed to neutrality, dried and recrystallized from methanol to give the product to give compound 1.4 7.Ommol.

[0093]实施例5 [0093] Example 5

[0094] [0094]

Figure CN102746358BD00111

[0095] 将2. 5化合物10mmol、20ml1,4-二氧六环、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H202 (30 %水溶液),5小时后反应至无原料,加入稀释于5 %Na2S(VK 溶液150ml中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 5化合物8. 7_〇1。 [0095] The compound 2.5 10mmol, 20ml1,4- dioxane, 20ml of ethanol was added to the reaction vessel, then added 14.OmmolHBr (concentration of 42% aqueous solution) and finally 2mmol methyl nitrite, warmed to at 55 C with stirring, was slowly added dropwise a solution of 13mmol H202 (30% aqueous solution) to the reaction after 5 hours no starting material, diluted in 5% Na2S (VK 150ml solution, filtered, washed until neutral, dried and methanol The product was recrystallized to give 1.5 8. 7_〇1 compound.

[0096] 实施例5. 1 [0096] Example 5.1

[0097] 将2. 5化合物10mmol、20ml1,4_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H202 (30 %水溶液),5小时后反应至无原料,加入稀释于5 % ~&2303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1. 58. 3mmol。 [0097] The compound 2.5 10mmol, 20ml1,4_ dioxane, 20ml of ethanol was added to the reaction vessel, then added 14.OmmolHBr (concentration of 42% aqueous solution) and finally sodium nitrite 2mmol, warmed to 55 C under stirring, was slowly added dropwise a solution of 13mmol H202 (30% aqueous solution) to the reaction after 5 hours no starting material, diluted in 5% aqueous solution of ~ 2303 & 150ml, filtered, washed to neutrality, dried and recrystallized from methanol That product was obtained, the compound 1. 58. 3mmol.

[0098] 实施例6 [0098] Example 6

Figure CN102746358BD00112

[0099] [0099]

[0100] 构厶匕1心"日、物iummo丄刀口zum丄乙0字、丄um丄乙脂'刀口乂、汉胆谷益|aj,丹刀口丄4ummol HBr(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%水溶液),5小时后反应至无原料,加入稀释于5%Na2S(VK溶液150ml 中,过滤、洗涤至中性,干燥,甲醇重结晶即得产物,得1. 6化合物8.Ommol。 [0100] 1 structure Si dagger heart "day, was iummo Shang Shang edge zum B 0 word, um Shang Shang acetate 'cut qe, Han Yi gall Valley | aj, Dan Shang blade 4 ummol HBr (at a concentration of 42% aqueous solution) and finally 2mmol potassium nitrite, warmed to 55 C with stirring, was slowly added dropwise a solution of 13mmol H202 (30% aqueous solution) to the reaction after 5 hours no starting material, diluted in 5% Na2S (VK solution 150ml, filtered, washed to neutrality, dried and recrystallized from methanol to give the product compound was 1.6 8.Ommol.

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Classifications
International ClassificationC07J71/00, C07J7/00
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