CN102746358B - Pregn-21 A synthetic process bromide - Google Patents

Pregn-21 A synthetic process bromide Download PDF

Info

Publication number
CN102746358B
CN102746358B CN 201110101280 CN201110101280A CN102746358B CN 102746358 B CN102746358 B CN 102746358B CN 201110101280 CN201110101280 CN 201110101280 CN 201110101280 A CN201110101280 A CN 201110101280A CN 102746358 B CN102746358 B CN 102746358B
Authority
CN
Grant status
Grant
Patent type
Prior art keywords
compound
formula
preparing
method
nitrite
Prior art date
Application number
CN 201110101280
Other languages
Chinese (zh)
Other versions
CN102746358A (en )
Inventor
卢彦昌
孙亮
韩英
刘爱
Original Assignee
天津金耀集团有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Grant date

Links

Abstract

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 pregn-21 new technology bromide, a compound of Formula 2 in an organic solvent, NO donors, and HBr, NO can be oxidized to NO2 as oxidizing agent a compound of formula 1 under conditions.

Description

一种合成孕留21位溴化物的工艺 A synthetic progestin bromide 21 process left

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 21-bromo-pregna-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 remain pregnant is an important intermediate which can be obtained by replacing the corresponding esterified, then after alkaline hydrolysis of the 21-hydroxy, novel compounds can also be obtained by other nucleophiles attack, e.g. Taiwan University Master thesis movable Wei Chen published in 2006 "-3α- hydroxy-21-bromo intermediate -3β- Discussion methoxymethyl -5α- pregnan-20-one and the reaction of lithium imidazole."

[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] A common method of preparing compound 21-Bromo-pregnant left is obtained by the halogenation reaction of Br2, but often a hydroxyl group and the like, double bonds or epoxy groups due to the chemical structure of the compound megestrol, tend to produce direct halo impurities, and in order to complete the molar Br2 is used in an amount much larger than the reaction of 1: 1, resulting in environmental pollution on 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 have provided a new process 21 remain pregnant bromide, hydroxyl and the like are present, a double bond or an epoxy group at the 16 and 17-bit architecture, the bit configuration 9,11 presence of a hydroxy progesterone other, double bonds or epoxy groups remain compound (a 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 it N0 donor reaction, HBr, some oxidants are present insoluble non-polar organic the problem of the solvent, resulting in lower yields, a problem of a longer time 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 left bromide (compound 1) the presence 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 Acronym

[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, a compound of Formula 2 in an organic solvent, N0 donor, and HBr, N0 can be oxidized to compound N02 oxidizing agent under conditions 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 = ethylene or a single bond, S Jie between bits 16 and 17 are connected through an oxygen bridge or a double bond

[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 = a single bond or an epoxy, i.e. between position 9, 11 or a double bond linked through an oxygen bridge

[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 or 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 = ethylene or a single bond, S Jie between bits 16 and 17 are connected through an oxygen bridge or a double bond

[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 = a single bond or an epoxy, i.e. between position 9, 11 or a double bond linked through an oxygen bridge

[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 or 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. between 9,11 bits connected through an oxygen bridge

[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 or double bond.

[0038] 进一步优选 [0038] Further preferably

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

[0045] 更进一步优选 [0045] Still further preferably

[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] the 1,2-dotted line represents a single or 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 method for preparing 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0°C至100°C。 [0053] The preparation of Formula 1 compounds, the reaction temperature is from 0 ° C to 100 ° C. 优选20°C至90°C。 Preferably 20 ° C to 90 ° C. 更有选40°C至70°C。 40 ° C to more selected from the 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、20°C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、20°C下为液态的有机酸一种或几种。 [0054] The method of preparing the compound of formula 1, the reaction of the organic solvent is less than 6 carbon alcohols, at 20 ° C, a haloalkyl group having 1 to 4 halogens liquid, halogenated aromatic hydrocarbons, aromatic hydrocarbons, or under an ether, an ester, a nitrile, 20 ° C is one or more liquid organic acid. 优选为6个碳以内的醇、20°C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、20°C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 alcohols, at 20 ° C for the next liquid containing 2-4 chloroalkyl, less than 6 carbon ether, 4 or less carbon nitrile, 20 ° C for the liquid 4 carbon atoms within one or more of an organic acid. 更优选为3个碳以内的醇、20°C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、20°C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 alcohols containing 2-4 chloroalkyl liquid at 20 ° C, within the next six carbon ether, 4 or less carbon nitrile, 20 ° C for the liquid 4 carbon atoms within one or more of an organic acid. 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, iso-butyric acid in one or more. 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, dioxane 1,4_, one or more of ethanol, acetic acid, acetonitrile.

[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] The method for preparing a compound of formula, 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 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 method for preparing a compound of the formula, the donor is N0 nitrite ester within six carbon nitrite 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。 Alkali metal salt is selected from nitrous acid, it is further selected from sodium nitrite, potassium nitrite in one or several 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 further donor selected isoamyl nitrite, t-butyl nitrite, ethyl nitrite, methyl nitrite, propyl nitrite, butyl nitrite, amyl nitrite, isopropyl nitrite, ethylene isosorbide one or more of butyl.

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 Example embodiments [0057] only in the aspect of the invention further explanation, not to be construed as limiting the embodiments 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) yield, 21 bromine compound is a bromine compound and 21 bis unified computing, which is due to the 21-bromo compound 21 in the displacement reaction and bis-bromo compound may each be 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60°C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] /] Shang inch • B 'κ / mouthpiece "^ Shang Cheng, τ> Wu Chuan 7/15 & twenty four ,; qe" gate, Dan qe ^ /, £ ± Shang Shang Sin 11〇 ribR (concentration 42% aqueous solution) and finally 3mmolNaN02, warmed to 60 ° C under stirring, into oxygen, 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 added without over anhydrous sodium sulfate, filtered, and then rotary evaporated in vacuo to remove the organic solvent, to give the product recrystallized from methanol to give 1.1 5. 8_〇1 compound.

[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40°C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] 2.1 The compound 10mmol, 40ml acetonitrile was added to the reaction vessel, was added 13mmolHBr (concentration of 42% aqueous solution) and finally 2. 5mmolNaN02, warmed to 40 ° C under stirring, oxygen was 6 hours the reaction until no starting 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. 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20°C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 tetrahydrofuran was added to the reaction vessel, was added 13mmolHBr (concentration of 42% solution in water), and finally added 4mmolNaN02, warmed to 20 ° C under stirring, feeding oxygen to the reaction after 8 hours no starting 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30°C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, was added 13mmolHBr (concentration of 42% solution in water), and finally added 2mmolNaN02, warmed to 30 ° C under stirring, feeding oxygen to the reaction after 6 hours no starting 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40°C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 acetic acid added to the reaction vessel, was added 13mmolHBr (concentration of 42% solution in water), and finally added 2mmolNaN02, warmed to 40 ° C under stirring, oxygen was 6 hours until the reaction no starting material, diluted in 150ml of aqueous 5% Na2S03, filtered, washed to neutrality, dried and recrystallized from methanol to give the product 1.1 to give compound 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40°C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, was added 14mmolHBr (concentration of 42% solution in water), and finally added 4mmolNaN02, warmed to 40 ° C under stirring, feeding oxygen to the reaction after 10 hours no starting material, diluted in 150ml of aqueous 5% Na2S03, filtered, washed to neutrality, dried and recrystallized from methanol to give the product 1.1 to give compound 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25°C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。 Under [0074] The compound 2.2 10mmol, 20ml of ethanol, 10ml of tetrahydrofuran was added to the reaction vessel, was added 13 mmol of HBr (42% aqueous solution concentration) and finally 3mmolNaN02, warmed to 25 ° C with stirring, into oxygen, 8 after h the reaction until no starting material, diluted in 150ml of aqueous 5% Na2S03, filtered, washed to neutrality, dried and recrystallized from methanol to give the product, compound 9. 0_〇1 1.1.

[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25°C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。 Under [0076] The compound 2.2 10mmol, 20ml of ethanol, 5ml of acetonitrile was added to the reaction vessel, was added 13 mmol of HBr (42% aqueous solution concentration) and finally 3mmolNaN02, warmed to 25 ° C with stirring, into oxygen, 8 after h the reaction until no starting 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 9. 0_〇1 1.1.

[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45°C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, was added 13 mmol (42% concentration in water) of HBr, is added last 3mmolKN02, warmed to 45 ° C under stirring, into the air, 20 after h the reaction until no starting 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 9. 1_〇1 1.1.

[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35°C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 30ml of carbon tetrachloride was added 13.OmmolHBr (concentration of 42% solution in water), added last square. 8mmol tetrabutylammonium bromide, 3mmolNaN02, warmed to 35 ° C under stirring, into oxygen, 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 was added, filtered, and then vacuum rotary evaporator, the organic solvent was removed recrystallized from methanol to give the product 1.3 to give compound 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35°C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 30ml of carbon tetrachloride was added 13.OmmolHBr (concentration of 42% solution in water), polyethylene glycol added last lmmol, 3mmolNaN02, warmed to 35 ° C under stirring, through 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 was added, filtered, and then vacuum rotary evaporator, the organic solvent was removed and recrystallized from methanol to give the product 1.3 to give compound 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35°C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 30ml of carbon tetrachloride was added 13.OmmolHBr (concentration of 42% solution in water), and finally added 3mmolNaN02, warmed to 35 ° C under stirring, oxygen was, after 8 hours the reaction until no starting material, 10 percent of Na2S (VK was washed several times with the organic phase, to remove inorganic salts, the organic layer was dried over anhydrous sodium sulfate was added, filtered, and then vacuum rotary evaporator, the organic solvent was removed, and recrystallized from methanol to give the product, to give compound 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35°C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 lOmmol 2.3 50ml of carbon tetrachloride was added, followed by addition 13.OmmolHBr (concentration of 42% solution in water), and finally added 3mmolNaN02, warmed to 35 ° C under stirring, into the air, 25 hours the reaction until no starting 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 7 to give 1.3 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35°C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-thiopyran Misaki added to the reaction vessel, was added 14.OmmolHBr (concentration of 42% solution in water), 3. 5mmol finally added isoamyl nitrite was heated to 35 ° C under stirring, into oxygen, the reaction for 8 hours until no starting 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 7 to give 1.4 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35°C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-thiopyran Misaki added to the reaction vessel, was added 14.OmmolHBr (concentration of 42% solution in water), and finally 3mmol isoamyl nitrite was added, heated to 35 ° C with stirring , 13mmol slowly added dropwise a solution of H202 (30% aqueous solution), after 5 hours the reaction until no starting material, diluted in 5% Na2S (VK solution (150ml), 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55°C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, was added 14.OmmolHBr (concentration of 42% aqueous solution) and finally 2mmol methyl nitrite, warmed to 55 ° C for stirring, slowly added dropwise 13mmol of H202 (30% aqueous solution), after 5 hours the reaction until no starting material, diluted in 5% Na2S (VK solution (150ml), filtered, washed to neutrality and dried with methanol recrystallized to give the product, to give compound 8. 7_〇1 1.5.

[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55°C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, was added 14.OmmolHBr (concentration of 42% aqueous solution) and finally sodium nitrite 2mmol, warmed to 55 ° C under stirring slowly added dropwise 13mmol of H202 (30% aqueous solution), after 5 hours the reaction until no starting material, diluted in an aqueous solution of 5% to 2303 & 150ml, filtered, washed to neutrality, dried, and recrystallized from methanol to give the product, 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4·ummol HBr(浓度为42%的水溶液),最后加入2mmol亚硝酸钾,升温至55°C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] configuration · Si dagger a heart "day, was iummo Shang edge zum Shang B 0 word, Shang um Shang fat B 'edge qe, Chinese gall valley benefits | AJ, Dan edge Shang 4 · ummol HBr (concentration 42% aqueous solution) and finally 2mmol nitrite, warmed to 55 ° C under stirring, added dropwise slowly added dropwise 13mmol of H202 (30% aqueous solution), after 5 hours the reaction until no starting material, diluted in 5% Na2S (VK solution (150ml), filtered, washed to neutrality, dried and recrystallized from methanol to give the product 1.6 to give compound 8.Ommol.

Claims (23)

  1. 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、 20°C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、20°C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 of preparing a compound of formula 1, wherein a compound of Formula 2 in an organic solvent, and the dish for r NO vivo conditions, NO is oxidized W N02 as oxidizing agent a compound of formula 1, the organic solvent is 6 carbon in an alcohol W, face alkyl group having 1 to 4 under the liquid surface of the element 20 ° C, the surface generation aromatase control, control or aromatic acid, vinegar, wax, 20 ° C in a liquid organic acid one or more of the oxidizing agent is oxygen, air, & oriented, nitrite NO donor, one or more of vinegar within six carbon nitrite 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 = ethylene or a single bond, i.e. between 16, 17 is connected through an oxygen bridge or a double bond Ri = 0H, R4 = H, C1, F, Ri, R4 = a single bond or an epoxy, i.e. between 9 and 11 is a double bond linked through an oxygen bridge or R5 = H, methyl or pigment surface, the 1,2-dotted line represents a single bond or a double bond.
  2. 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. The preparation of compounds of formula according to claim 11, wherein wherein R2 = 0H R3 = Η or methyl, Rz, R3 = ethylene or a single bond, i.e. a double bond between the 16, 17 Ri = 0H or joined through an oxygen bridge, R4 = C1, Ri, R4 = a single bond or an epoxy, i.e. between 9, 11 are connected to through an oxygen bridge or a double bond R5 = H, methyl or surface element, 1, 2 the dotted line represents a single bond or a double bond.
  3. 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 preparation of compounds of formula according to claim 11, wherein wherein R2 = 0H R3 = Η or methyl, Ri = 0H, R4 = H, F or Cl, Ri, R4 = propylene, i.e., 9, between 11 connected through an oxygen bridge to R5 = H, F or methyl, the dotted line represents a single bond or the 1,2-double bond.
  4. 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。 4. The preparation of compounds of formula 1 according to claim 1, characterized in that wherein R2 = 0H R3 = Η or methyl, Ri = OH, R4 = H, F or Cl, Rs = H or methyl, 1 , 2 the dotted line represents a single bond or a double bond.
  5. 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. The preparation of compounds of formula according to claim 11, wherein wherein R2 = 0H R3 = η, Ri = OH, R4 = H, F or Cl, R5 = H, or methyl, 1,2 the dotted line represents a single bond or a double bond position.
  6. 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 preparing the compound of formula 1 as claimed in claim 1, wherein the oxidizing agent is oxygen.
  7. 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0°C至100°C。 7. The method of preparing the compound of formula 1 as claimed in claim 1, wherein the reaction temperature is from 0 ° C to 100 ° C.
  8. 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20°C至90°C。 8. The method of preparing the compound of formula 1 as claimed in claim 1, characterized in that the reaction temperature to 20 ° C and 90 ° C.
  9. 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40°C至70°C。 9. The method of preparing the compound of formula 1 as claimed in claim 1, wherein the reaction temperature at 40 ° C to 70 ° C.
  10. 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、20°C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、20°C下为液态的4个碳W内有机酸中的一种或几种。 10. The method of preparing the compound of formula 1 as claimed in claim 1, wherein the reaction of the organic solvent is an alcohol in 6 carbons W, at 20 ° C 2-4 chloroalkyl containing liquid, 6 carbon in the acid W, within the liquid W 4 carbon atoms one or more organic acids in the wax, 20 ° C in W 4 carbon atoms.
  11. 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、20°C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、20°C下为液态的4个碳W内有机酸中的一种或几种。 11. The method of preparing the compound of formula 1 as claimed in claim 1, wherein the reaction of the organic solvent is an alcohol over 3 carbons W, at 20 ° C 2-4 chloroalkyl containing liquid, 6 carbon in the acid W, within the liquid W 4 carbon atoms one or more organic acids in the wax, 20 ° C in W 4 carbon atoms.
  12. 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 preparing the compound of formula 1 as claimed in claim 1, wherein the reaction of the organic solvent is methanol, ethanol, propanol, dichloromethane burning, chloroform, 1,2-dichloroethane burning tetrachloride carbon, acetic acid, tetraammine clever thiopyran, 1,4-dioxane, acetic acid ethyl ester, wax acetate, formic acid, acetic acid, propionic acid, iso-propionic acid, iso-under one or more acids.
  13. 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 preparing the compound of formula 1 as claimed in claim 1, wherein the reaction of the organic solvent is carbon tetrachloride, acetic acid, tetraammine clever thiopyran, 1,4-dioxane, ethanol, acetic acid, ethyl one or more of wax.
  14. 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 preparing the compound of formula 1 as claimed in claim 1, characterized in that the phase transfer catalyst was added to the reaction.
  15. 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 of preparing a compound of the formula as claimed in claim 114, wherein the phase transfer catalyst is an ingot salts, acids or quaternary cyclodextrins.
  16. 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 of preparing a compound of the formula as claimed in claim 114, wherein the phase transfer catalyst is a quaternary salt ingot.
  17. 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 of preparing a compound of the formula as claimed in claim 114, wherein the phase transfer catalyst is acid.
  18. 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 of preparing a compound of the formula as claimed in claim 114, wherein the phase transfer catalyst is polyethylene glycol.
  19. 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 of preparing a compound of the formula as claimed in claim 114, wherein the phase transfer catalyst is looked yl desertification ingot, the ingot group looked chloride.
  20. 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 preparing the compound of formula 1 as claimed in claim 1, characterized in that the nitrite is an alkali metal salt of nitrous acid.
  21. 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 preparing the compound of formula 1 as claimed in claim 1, characterized in that the NO donor is one or more steel nitrite, the nitrite clock.
  22. 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 preparing the compound of formula 1 as claimed in claim 1, characterized in that the NO donor is nitrous steel.
  23. 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 preparing the compound of formula 1 as claimed in claim 1, characterized in that the NO donor is vinegar amyl nitrite, the nitrous acid tert vinegar, vinegar ethyl nitrite, nitrous acid methyl ester, nitrite, propyl acetate, ethylene vinegar, vinegar amyl nitrite, isopropyl nitrite, acetate, isobutyl nitrite under one or more of nitric acid in vinegar.
CN 201110101280 2011-04-22 2011-04-22 Pregn-21 A synthetic process bromide CN102746358B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 201110101280 CN102746358B (en) 2011-04-22 2011-04-22 Pregn-21 A synthetic process bromide

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 201110101280 CN102746358B (en) 2011-04-22 2011-04-22 Pregn-21 A synthetic process bromide

Publications (2)

Publication Number Publication Date
CN102746358A true CN102746358A (en) 2012-10-24
CN102746358B true CN102746358B (en) 2016-02-10

Family

ID=47026895

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 201110101280 CN102746358B (en) 2011-04-22 2011-04-22 Pregn-21 A synthetic process bromide

Country Status (1)

Country Link
CN (1) CN102746358B (en)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2684968A (en) * 1953-03-30 1954-07-27 Searle & Co 21-halo-11beta, 17alpha-dihydroxy-4-pregnene-3, 20-diones and their preparation
US5965548A (en) * 1993-10-27 1999-10-12 Merrel Pharmaceuticals, Inc. .increment.16 unsaturated C17 heterocyclic steroids useful as steroid C17-20 lyase inhibitors
WO2005105822A2 (en) * 2004-04-23 2005-11-10 Euro-Celtique S.A. 3-alpha-hydroxy 21-n- heteroaryl-pregnane derivatives for modulation of brain excitability and a process for the production thereof
CN1757649A (en) * 2004-11-19 2006-04-12 天津理工大学 Synthesis of intermediate 21 position halogenated compound for mometasone furate, and its application
CN101418029A (en) * 2008-11-13 2009-04-29 湖南甾体化学品有限公司 Method for synthesizing methylprednisolone
CN101417912A (en) * 2008-11-10 2009-04-29 湖南甾体化学品有限公司 Method for preparing becort acetate
CN101418032A (en) * 2008-11-13 2009-04-29 湖南甾体化学品有限公司 Method for synthesizing deflazacort

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2684968A (en) * 1953-03-30 1954-07-27 Searle & Co 21-halo-11beta, 17alpha-dihydroxy-4-pregnene-3, 20-diones and their preparation
US5965548A (en) * 1993-10-27 1999-10-12 Merrel Pharmaceuticals, Inc. .increment.16 unsaturated C17 heterocyclic steroids useful as steroid C17-20 lyase inhibitors
WO2005105822A2 (en) * 2004-04-23 2005-11-10 Euro-Celtique S.A. 3-alpha-hydroxy 21-n- heteroaryl-pregnane derivatives for modulation of brain excitability and a process for the production thereof
CN1757649A (en) * 2004-11-19 2006-04-12 天津理工大学 Synthesis of intermediate 21 position halogenated compound for mometasone furate, and its application
CN101417912A (en) * 2008-11-10 2009-04-29 湖南甾体化学品有限公司 Method for preparing becort acetate
CN101418029A (en) * 2008-11-13 2009-04-29 湖南甾体化学品有限公司 Method for synthesizing methylprednisolone
CN101418032A (en) * 2008-11-13 2009-04-29 湖南甾体化学品有限公司 Method for synthesizing deflazacort

Also Published As

Publication number Publication date Type
CN102746358A (en) 2012-10-24 application

Similar Documents

Publication Publication Date Title
Turner Heat of Hydrogenation of Bicyclo [2.2. 2] octa-2, 5, 7-triene
CN101481321A (en) Agomelatine halogen hydride complex and preparation thereof
CN101684139A (en) Synthesis process of vecuronium bromide
CN101177437A (en) Method for synthesizing environment-friendly sucralose
CN102146039A (en) Process for synthesizing gefarnate compound
CN101805327A (en) Rabeprazole sodium compound and novel preparation method thereof
CN101418029A (en) Method for synthesizing methylprednisolone
Klosterman et al. An Improved Synthesis of the Selenium Analogs of Methionine and Homocystine1
WO2003080643A1 (en) Process for producing triterpene derivative
CN101993447A (en) Method for synthesizing Prasugrel artificially
CN102141731A (en) Toluylene-containing meta-substituted sulfonium salt photoproduction acid agent and preparation method thereof
CN102050781A (en) Industrial preparation method of hydroxychloroquine sulfate
CN1594321A (en) Process for preparing cephazoline three-position intermediate
CN103539697A (en) Synthesis of reduced sensitive azo connection unit and application of azo connection unit in DNA (deoxyribonucleic acid) sequencing
CN102206151A (en) Synthetic method of royaljelly acid
CN1733674A (en) Preparation method of double(2-hydroxyl hexafluopropyl) phenol
CN101585769A (en) Microwave synthesis of gallate ester
CN101935324A (en) Method for preparing penicillanic acid sulfoxide diphenyl methyl ester
CN102850325A (en) Preparation method of Dabigatran etexilate key intermediate
CN101058552A (en) Double-functional group ionic liquid and preparation method
CN101693729A (en) Synthesis method of sucrose-6-acetate
CN101979396A (en) Method for synthesizing sucrose-6-ester and sucralose
CN102372702A (en) Preparation method for thiamethoxam
CN101648877A (en) Preparation method of quaternary ammonium carboxylate ion liquid with low halogen
CN101210015A (en) Method for preparing hepatitis B therapeutic medicament entecavir

Legal Events

Date Code Title Description
C06 Publication
C14 Grant of patent or utility model