CN103159659A - Preparation method of muscarinic receptor antagonist glycopyrronium bromide - Google Patents

Preparation method of muscarinic receptor antagonist glycopyrronium bromide Download PDF

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CN103159659A
CN103159659A CN 201110426038 CN201110426038A CN103159659A CN 103159659 A CN103159659 A CN 103159659A CN 201110426038 CN201110426038 CN 201110426038 CN 201110426038 A CN201110426038 A CN 201110426038A CN 103159659 A CN103159659 A CN 103159659A
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cyclopentyl
glycopyrronium bromide
receptor antagonist
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王钝
于航
魏小飞
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沈阳药科大学
沈阳药科大学(本溪)医药科技有限公司
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Abstract

The invention belongs to the technical field of medicine and discloses a preparation method of muscarinic receptor antagonist glycopyrronium bromide. The preparation method of the muscarinic receptor antagonist glycopyrronium bromide is characterized in that Alpha-cyclopentyl mandelic acid methyl ester is obtained by aceptophenone ketonic acid Grignard reaction and esterification reaction, and then glycopyrronium bromide is obtained by N-methyl pyrrolidine-3-alcohol ester exchange and quaterisation.

Description

一种毒蕈碱受体拮抗剂格隆溴铵的制备方法 One kind muscarinic receptor antagonist preparation glycopyrrolate

[0001] 技术领域: [0001] Technical Field:

本发明属于医药技术领域,涉及一种格隆溴铵的制备方法。 The present invention belongs to the field of medical technology, it relates to a method for preparing glycopyrrolate.

[0002] 背景技术: [0002] BACKGROUND:

格隆溴铵(Glycopyrrolate, I),化学名为3_( α -环戍基轻基苯乙酰氧基)_1,1- 二甲基吡咯烷溴铵盐,由日本Shionogi公司开发,1982年在美国批准上市,目前在国内上市的制剂为片剂,商品名胃长宁。 Glycopyrronium bromide (Glycopyrrolate, I), chemical name 3_ (α - benzene ring pentyl light acetoxy) pyrrolidine-bromo _1,1- dimethyl ammonium salts, Shionogi developed by the Japanese, U.S. in 1982 approved for marketing, in the domestic market for the tablet formulation, trade name glycopyrrolate. 本品为毒蕈碱受体(Μ受体)拮抗剂,临床用于胃及十二指肠溃疡、慢性胃炎、胃液分泌过多等症。 This product muscarinic receptors ([mu] receptor) antagonists, clinically used for gastric and duodenal ulcers, chronic gastritis, gastric hypersecretion embolism.

[0003] 美国专利US2956062报道,格隆溴铵可以α -环戊基扁桃酸甲酯为原料,在强碱性条件下与甲基吡咯烷-3-醇进行酯交换反应,再与溴甲烷发生季铵化反应制得。 [0003] U.S. Patent No. US2956062 reported, glycopyrrolate can α - cyclopentyl mandelate as starting material, a transesterification reaction with methyl-3-ol under strongly basic conditions, and then with methyl bromide quaternary occur quaternization reaction. α-环戊基扁桃酸甲酯的制备主要有三种方法:(I)当代结构药物全集,1993,1151文中报道苯乙酮酸甲酯与环戊二烯基溴化二聚体状态存在,需高温裂解制得单体后参与反应;(2)美国专利US3381017报道苯乙酮酸甲酯与环戊基溴化镁经格氏反应直接制得α -环戊基扁桃酸甲酷;(3)文章Journal of pharmacy and pharmacology, 2005, 1427-1435报道以苯乙丽酸为原料,与环戊基溴化镁发生格氏反应,再在对甲苯磺酸催化下与甲醇成酯制得α-环戊基扁桃酸甲酯。 Preparation of methyl α- cyclopentyl mandelate There are three main methods: (I) Complete structure of the drug present, 1993,1151 reported herein acetophenone with methyl bromide, cyclopentadienyl dimer state exists, to be after pyrolysis reacted monomer was prepared; (2) U.S. Patent No. US3381017 reported acetophenone and methyl cyclopentyl magnesium bromide Grignard reaction was prepared directly from α - mandelic acid A cool cyclopentyl; (3) articles Journal of pharmacy and pharmacology, 2005, 1427-1435 are reported in Korea phenethyl acid as raw materials, a Grignard reaction with cyclopentyl bromide, and then of the methanol to catalytic p-toluenesulfonic acid ester prepared α- ring pentyl methyl mandelate. 本研究首先对方法一、方法二进行了研究,结果表明,苯乙酮酸甲酯与格氏试剂进行反应时,在酮羰基被亲核进攻的同时,酯羰基也会发生格氏反应,故得到目标中间体α -环戊基扁桃酸甲酯及双格氏化的副产物,两者极性相近,分离困难,本研究尝试通过对物料配比、反应温度、加料顺序的调整来避免双格氏化副产物的生成,但均未成功,由此推断,在苯乙酮酸甲酯的结构中酮羰基与酯羰基发生格氏反应的活性无明显差异。 This study was a first method, two methods were studied, the results show that methyl acetophenone is reacted with a Grignard reagent, while the ketone carbonyl group by a nucleophilic attack of the ester carbonyl group Grignard reaction also occurs, and therefore to give the title intermediate α - methyl mandelate byproduct cyclopentyl and double Grignard, both of similar polarity, separation difficulties, attempts by the present study, the ratio of the reaction temperature on the material, to avoid double addition sequences generating a Grignard byproducts, unsuccessfully, infer, the active ketone carbonyl ester carbonyl Grignard reaction occurs in the structure of the methyl acetophenone no significant difference.

[0004] 对方法三展开研究后,实验结果表明,虽然苯乙酮酸结构中羧基的存在会消耗一摩尔的格氏试剂,但有效避免了双格式化副反应的发生,反应具有良好的选择性;在中间体α-环戊基扁桃酸甲基吡咯烷-3-酯的制备中,文献中采用庚烷作为溶剂,金属钠作为催化剂,而按照此文献方法进行了操作,产物收率仅为32%。 [0004] After a study of the three methods, experimental results show that, although the presence of acetophenone carboxyl acid structure consumes a mole of the Grignard reagent, but avoid the occurrence of side reactions of the double format, the reaction with good selectivity sex; in the preparation of the intermediate mandelic acid α- cyclopentyl-3-methyl ester, the literature using heptane as the solvent, sodium metal as a catalyst, according to this document and an operation method, the product yield was only 32%.

[0005] 现有的格隆溴铵的制备方法均存在着不足,因此其制备方法有待于进一步研究。 [0005] The method of preparing the conventional glycopyrrolate there were insufficient, so the production method needs further study.

[0006] 发明内容: [0006] SUMMARY OF THE INVENTION:

本发明解决的技术问题是提供一种格隆溴铵的制备方法。 The present invention solves the technical problem is to provide a method for the preparation of glycopyrrolate.

[0007] 本发明通过如下方法制备: [0007] The present invention can be prepared by the following method:

US29560628的苯乙酮酸经格氏反应、酯化反应制得α -环戊基扁桃酸甲酯,再与甲基吡咯烷-3-醇经酯交换、季铵化反应制得格隆溴铵。 US29560628 phenethyl acid via Grignard reaction, an esterification reaction of α - methyl mandelate cyclopentyl, and then exchanged with the methyl ester-pyrrolidin-3-ol, quaternized reaction of glycopyrronium bromide . 反应式如下: The following reaction formula:

Figure CN103159659AD00041

苯乙酮酸2:溴代环戊烷3:镁为1:1 1:5:1条件下制备α -环戊基扁桃酸5,再经酯化反应制得目标中间体α-环戊基扁桃酸甲酯6。 Acid 2-phenylethyl: Bromocyclopentane 3: Mg is 1: 1 1: 5: 1 was prepared under the conditions α - mandelic acid cyclopentyl-5, and then an esterification reaction to obtain the objective Intermediate Cyclopentyl-α- mandelate 6.

[0008] 中间体6以正己烷作为溶剂,氢化钠催化,回流条件下反应,同时为促进可逆反应的正向移动,在反应中不断蒸出生成的甲醇。 [0008] Intermediate 6 to n-hexane as a reaction solvent, catalyzed by sodium hydride, at reflux conditions, and to facilitate the forward movement of the reversible reaction in the reaction was distilled off continuously generated methanol.

[0009] 所制备的格隆溴铵可用丁酮,丙酮,乙腈精制;α -环戊基扁桃酸5用二氯甲烷,二氯乙烷,丁酮精制。 [0009] glycopyrrolate prepared available methyl ethyl ketone, acetone, acetonitrile purification; α - 5-cyclopentyl-mandelic acid with dichloromethane, dichloroethane, butanone purification.

具体实施方式 Detailed ways

[0010] Ct-环戍基扁桃酸(5) [0010] Ct- cycloalkyl pentyl mandelic acid (5)

250mL三颈瓶中加入镁屑(1.5g,62mmol)、无水乙醚(20mL),少量碘粒。 250mL three-necked flask was added magnesium turnings (1.5g, 62mmol), anhydrous diethyl ether (20mL), a small amount of iodine tablets. 加热至30°C,向反应液中滴加少量溴代环戊烷(3)乙醚溶液,加热使反应引发,当碘色消失后,搅拌下滴加3(8.94g,60mmol)的乙醚(15mL)溶液,滴毕升温至37°C回流20min,降温冷却至(T5°C。分次加入2(3g,20mmol),加完补加40mL无水乙醚,升温至30°C,搅拌IOh,加入盐酸(30mL,4 mol/L)搅拌至固体全溶,分出乙醚层,水层用乙醚(20mL,20mL , IOmL)萃取三次。合并醚层,用10%碳酸钠水溶液(60mL,40mL)萃取两次,合并水层,用浓盐酸调至pH广2,有淡黄色固体析出,静置,抽滤,滤饼水洗、干燥得浅黄色固体粗品5(2.6g),mpl46〜15(TC。将粗品(2.6g)、二氯甲烧(7.8mL)加入50mL三颈瓶中,回流下打衆15 min,冷却,抽滤,滤饼用二氯甲烷洗涤,干燥,得白色固体5 (2g,45.5%)mp 153〜154 °C ;MS(m/z):219 (M-H+);1H NMR(CDCl3) δ: 1.31-1.72, (m,8H), 2.88-2.99 (m,1H),7.26-7.38,7.65-7.68 (m,5H)。 It was heated to 30 ° C, a small amount of added dropwise to the reaction mixture bromocyclopentane (3) ether solution was heated to initiate the reaction, after the iodine color disappeared, added dropwise with stirring 3 (8.94g, 60mmol) in diethyl ether (15mL ) was added dropwise at reflux temperature was raised to 37 ° C 20min, cooled down to (T5 ° C. was added in 2 (3g, 20mmol), plus complete additional 40mL anhydrous ether, warmed to 30 ° C, stirring IOH, was added hydrochloric acid (30mL, 4 mol / L) was stirred until all dissolved solids, the ether layer was separated, the aqueous layer with diethyl ether (20mL, 20mL, IOmL) and extracted three times. The combined ether layers were extracted with 10% aqueous sodium carbonate (60mL, 40mL) twice and the combined aqueous layers was adjusted with concentrated hydrochloric wide pH 2, has a light yellow solid precipitate was allowed to stand, filtered off with suction, the filter cake was washed with water, and dried to give the crude product as a pale yellow solid 5 (2.6g), mpl46~15 (TC. the crude product (2.6 g of), dichloromethane burning (7.8 mL) was added 50mL three-necked flask at reflux for playing all 15 min, cooled, filtered off with suction, the filter cake was washed with dichloromethane, and dried to give a white solid 5 (2g , 45.5%) mp 153~154 ° C; MS (m / z): 219 (m-H +); 1H NMR (CDCl3) δ: 1.31-1.72, (m, 8H), 2.88-2.99 (m, 1H) , 7.26-7.38,7.65-7.68 (m, 5H).

[0011] α -环戊基扁桃酸甲酯(6) [0011] α - cyclopentyl methyl mandelate (6)

50mL三颈瓶中加入5 (4g, 18mmol)、甲醇(20mL)、对甲苯磺酸(0.4g),搅拌至全溶,升温回流20h。 50mL three-necked flask was added 5 (4g, 18mmol), methanol (20 mL), p-toluenesulfonic acid (0.4 g of), to the whole solution was stirred and heated at reflux for 20h. 停止反应,反应液减压蒸干,加入水(IOmL),用10%碳酸钠水溶液调至pH 8、,用正己烷(10mLX2)萃取,有机相用无水硫酸钠干燥,减压浓缩,得淡黄色油状物6 (2.6g,61.7%)。 The reaction was stopped, the reaction solution was evaporated to dryness under reduced pressure, water (IOmL), 10% aqueous sodium carbonate solution was adjusted to pH 8 ,, and extracted with n-hexane (10 mLx2) and the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give as a pale yellow oil 6 (2.6g, 61.7%). MS (m/z):235 (M+H+)。 MS (m / z): 235 (M + H +).

[0012] 甲基-3-(环戊基羟基苯乙酰氧基)吡咯烷(8) [0012] methyl 3- (cyclopentyl-acetoxy-hydroxyphenyl) pyrrolidine (8)

安装有蒸馏装置的IOOmL三颈瓶中加入氢化钠(0.04g,1.7mmOl),正己烷(20mL),搅拌下加入6 (1.8g, 18mmol),升温蒸懼,待有懼分蒸出时,滴加7 (3.5g, 15mmol)的正己烧(20mL)溶液,滴毕加热至回流,反应过程中始终保持有馏份均匀馏出,并分三次加入氢化钠(0.1g, 4.3mmol),每次间隔lh,同时不断补加正己烷以保持溶剂量不变。 When a distillation apparatus attached IOOmL three-necked flask was added sodium hydride (0.04g, 1.7mmOl), hexane (20 mL), was added with stirring 6 (1.8g, 18mmol), heating steam fear, there is fear to be distilled off points, solution of 7 (3.5g, 15mmol) in n-burn (20mL) was dropwise was heated to reflux and kept there during the homogeneous fractions were distilled off, and added in three portions sodium hydride (0.1g, 4.3mmol), each time interval lh, while continuously supplemented with an amount of n-hexane solvent remains unchanged. TLC[展开剂:石油醚-丙酮(5:1)]监测至原料点消失,停止反应,降温至25°C,加入盐酸(20mL,4 mol/L)搅拌,抽滤,滤液分出水层,有机层再加盐酸(10mL,4 mol/L)萃取,合并水层,用10%碳酸钠水溶液调至pH 8〜9,析出油状物,用乙醚(20mL, IOmL)萃取,合并萃取液,无水硫酸钠干燥,减压蒸干溶剂得浅黄色油状物8 (3.4g,75%)。 TLC [developing solvent: petroleum ether - acetone (5: 1)] to monitor the disappearance of starting material point, the reaction was stopped, cooled to 25 ° C, was added hydrochloric acid (20mL, 4 mol / L) with stirring, filtered off with suction, the filtrate was separated and the aqueous layer, (10mL, 4 mol / L) hydrochloric acid plus organic layer was extracted, the aqueous layer were combined, washed with 10% aqueous sodium carbonate solution was adjusted to pH 8~9, the precipitated oil was extracted with diethyl ether (20mL, IOmL), the extracts combined, no over anhydrous sodium sulfate, and the solvent evaporated to dryness under reduced pressure to give a pale yellow oil 8 (3.4g, 75%). MS (m/z):304 (M+H+)。 MS (m / z): 304 (M + H +).

[0013] 格隆溴铵(I) [0013] glycopyrrolate (I)

IOOmL三颈瓶中加入8 (4.6g, 15mmol)的丁酮(20mL)溶液,于(Γ5°C下滴加溴甲烷(2.9g,30mmol)的丁酮(5 mL)溶液,滴加完毕,继续搅拌反应15min,有白色固体析出,室温静置36h,抽滤,滤饼充分干燥得粗品,经丁酮重结晶两次得白色粉末状结晶I (3.9g,66%) mp 191〜193 °C色谱纯度99.8% [HPLC法,流动相:lmol/L醋酸三乙胺-乙腈-水(1:150:49);检测波长:230nm,面积归一化法测定]。MS m/z: 318 (M-BrO !1HNMR(CD3OD)δ:1.33〜1.38 (m, 2H),1.55〜1.70 (m, 6H),2.11〜2.21 (m, 1H),2.67〜2.80 (m, 1H),3.02 (m, 1H), 3.06 (s, 3H),3.23 (s, 3H),3.59〜3.71 (m, 3H),3.90 (dd, /=13.8,1H), 5.47 (m, 1H),7.27 (t, 1H), 7.35 (t, 2H),7.62 (dd, 2H)。13C 匪R (DMSO)δ:27.0, 27.4, 28.0, 31.3, 47.8, 53.8, 54.3, 66.0, 71.3, 74.6, 81.1, 126.9,128.7,129.3, 143.2, 17 5.00 Methyl ethyl ketone (20mL) IOOmL three-necked flask was added 8 (4.6g, 15mmol) was, at (Γ5 ° C was added dropwise dibromomethane (2.9g, 30mmol) in butanone (5 mL) was added dropwise completed, continued The reaction was stirred for 15min, and a white solid precipitated, was allowed to stand 36h at room temperature, filtered off with suction, the filter cake was sufficiently dried to give crude ketone was recrystallized twice to give a white powdery crystals I (3.9g, 66%) mp 191~193 ° C chromatographic purity 99.8% [HPLC method, mobile phase: lmol / L triethylamine acetate - acetonitrile - water (1: 150: 49); detection wavelength: 230nm, a measurement of the area normalization method] .MS m / z: 318 ( m-BrO 1HNMR (CD3OD) δ:! 1.33~1.38 (m, 2H), 1.55~1.70 (m, 6H), 2.11~2.21 (m, 1H), 2.67~2.80 (m, 1H), 3.02 (m, 1H), 3.06 (s, 3H), 3.23 (s, 3H), 3.59~3.71 (m, 3H), 3.90 (dd, /=13.8,1H), 5.47 (m, 1H), 7.27 (t, 1H) , 7.35 (t, 2H), 7.62 (dd, 2H) .13C bandit R (DMSO) δ: 27.0, 27.4, 28.0, 31.3, 47.8, 53.8, 54.3, 66.0, 71.3, 74.6, 81.1, 126.9,128.7,129.3 , 143.2 17 5.00

Claims (5)

  1. 1.一种毒蕈碱受体拮抗剂格隆溴铵的制备方法,其特征在于:苯乙酮酸经格氏反应、酯化反应制得α-环戊基扁桃酸甲酯,再与甲基吡咯烷-3-醇经酯交换、季铵化反应制得格隆溴铵,其反应式如下: Preparation glycopyrrolate A muscarinic receptor antagonist, wherein: phenethyl acid via Grignard reaction, an esterification reaction of α- cyclopentyl mandelate, and then A pyrrolidin-3-ol-yl transesterification, quaternized reaction of glycopyrronium bromide, the reaction is as follows:
    Figure CN103159659AC00021
    O O
  2. 2.根据权利要求1所述的方法,其特征在于:苯乙酮酸(2):溴代环戊烷(3):镁为1:1:Γ1:5:1,制得化合物α-环戊基扁桃酸(5)。 The method according to claim 1, wherein: phenethyl acid (2): bromocyclopentane (3): Mg is 1: 1: Γ1: 5: 1, to prepare the compound α- ring pentyl mandelic acid (5).
  3. 3.根据权利要求1所述的方法,其特征在于:中间体(6)以正己烷作为溶剂,氢化钠为催化剂,回流条件下反应,在反应中不断蒸出生成的甲醇,反应。 3. The method according to claim 1, wherein: the intermediate (6) in n-hexane as the solvent, sodium hydride as a reaction catalyst, at reflux conditions, the reaction continuously generated methanol was distilled off, the reaction.
  4. 4.根据权利要求1所述的方法,其特征在于:所制备的格隆溴铵(I)用丁酮,丙酮,精制。 4. The method according to claim 1, wherein: glycopyrrolate (I) are prepared with methyl ethyl ketone, acetone, purified.
  5. 5.根据权利要求2所述的方法,其特征在于:所制备的α-环戊基扁桃酸(5)用二氯甲烷,二氯乙烷,丁酮精制。 5. The method according to claim 2, wherein: α- cyclopentyl-mandelic acid prepared in (5) with dichloromethane, dichloroethane, butanone purification.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105175304A (en) * 2013-11-13 2015-12-23 李兴惠 Cholinolytic drug glycopyrronium bromide and composition
CN103819384A (en) * 2013-12-05 2014-05-28 广东嘉博制药有限公司 Preparation method of glycopyrronium bromide
CN107129439A (en) * 2016-02-26 2017-09-05 中国科学院大连化学物理研究所 Compound, muscarine M receptor antagonist, composition and application

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