CN105461710A - Preparation method of umeclidinium bromide - Google Patents

Preparation method of umeclidinium bromide Download PDF

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CN105461710A
CN105461710A CN 201510701851 CN201510701851A CN105461710A CN 105461710 A CN105461710 A CN 105461710A CN 201510701851 CN201510701851 CN 201510701851 CN 201510701851 A CN201510701851 A CN 201510701851A CN 105461710 A CN105461710 A CN 105461710A
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water
reaction
filtered
hours
washed
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李学坤
许坤
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安徽德信佳生物医药有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D453/00Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Abstract

The invention discloses a preparation method of umeclidinium bromide. The method is suitable for industrial routine reactions, and industrial production schemes exist at present. A technical scheme adopted in the invention is characterized in that a Grignard reagent is adopted to substitute a lithium reagent, bromobenzene, chlorobenzene and other benzene halides are adopted as raw materials, and ether and tetrahydrofuran can be used as a solvent. Compared with the prior art, the method disclosed in the invention has the following advantages: 1, the lithium reagent with high price is substituted by magneson; 2, reaction conditions are mild, too low temperature is not needed, and the reaction temperature is about 0-5DEG C, so the refrigeration cost is reduced; and 3, a routine device can be used, and the Grignard reaction is a classic reaction and industrially exists for a hundred years or above, so people can be simply trained, and the device is mature and has high operating stability.

Description

一种芜地溴铵的制备方法 One kind umeclidinium bromide preparation

技术领域 FIELD

[0001 ]本发明涉及一种制备方法,尤其涉及一种芜地溴铵的制备方法。 [0001] The present invention relates to a method for preparing, in particular, it relates to a method for preparing ammonium umeclidinium.

背景技术 Background technique

[0002]芜地溴铵的制备专利US7439393、US RE44874、US 7488827、US 7498440、US7361787等采用苯基锂反应制备中间体4-[(二苯基)羟甲基]氮杂双环[2.2.2]辛烷。 [0002] umeclidinium bromide prepared patent US7439393, US RE44874, US 7488827, US 7498440, US7361787 and the like using phenyllithium prepared by reaction of intermediate 4 - [(diphenyl) hydroxymethyl] azabicyclo [2.2.2 ] octane. 具体方法为:氮杂双环[2.2.2]辛烷-4-羧酸乙酯与2.02-2.5倍量的苯基锂发生亲核加成反应,反应温度控制为-78°0_15°C ο锂试剂价格高、难储存、使用条件苛刻、成本相对较高。 Specific methods: azabicyclo [2.2.2] octane-nucleophilic addition reaction with 4-carboxylate-fold amount of 2.02-2.5 phenyllithium occurs, the reaction temperature is controlled to -78 ° 0_15 ° C ο lithium Reagents expensive, difficult to store, use of harsh conditions, relatively high cost.

发明内容 SUMMARY

[0003]为了克服上述现有技术的不足,本发明改进了反应类型,将原反应变更为一种适于工业化的常规反应,该类别的反应有现成的工业化生产方案。 [0003] In order to overcome the disadvantages of the prior art, the present invention improves the type of the reaction, the reaction changed to the original conventional reaction suitable for industrialization, the reaction of this category are ready for industrial production scheme.

[0004]本发明是通过以下技术方案实现的: [0004] The present invention is achieved by the following technical solutions:

一种芜地溴铵的制备方法,包括以下步骤: One kind umeclidinium ammonium production method, comprising the steps of:

(1)配料:原料包括物质的量比值为2.5-3.0:1的格式试剂、氮杂双环[2.2.2]辛烷-4-羧酸乙酯和适量的溶剂; (1) Ingredients: feed molar ratio of the value of 2.5-3.0 comprising: a Grignard reagent 1-azabicyclo [2.2.2] octane-4-carboxylate and the appropriate amount of solvent;

(2)粗品的制备:将氮杂双环[2.2.2]辛烷-4-羧酸乙酯溶于适量的四氢呋喃中,在氮气保护下,溶液降温到_5-25°C,滴加格氏试剂,_5-25°C下保温搅拌1-1.2小时,加入水淬灭,分液,水相用四氢呋喃萃取两次,合并有机相水洗,干燥过滤;减压脱除部分溶剂,将剩余物在20-25°C下搅拌过夜析晶,过滤,用石油醚洗涤,将滤饼于40-45°C下真空干燥,得粗品; Preparation of crude product (2): A-azabicyclo [2.2.2] octane-4-carboxylate was dissolved in an appropriate amount of tetrahydrofuran, under nitrogen, was cooled to _5-25 ° C, dropwise Gag 's reagent and incubated under stirring _5-25 ° C 1-1.2 hours, quenched with addition of water, separated, the aqueous phase was extracted twice with tetrahydrofuran, and the combined organic phases were washed with water, filtered and dried; part of the solvent removed under reduced pressure, the residue was was stirred overnight at 20-25 ° C crystallization, filtered, washed with petroleum ether, the filter cake was dried under vacuum at 40-45 ° C, to obtain a crude product;

(3)精制:将上述粗品用体积比为1:0.5-1:5的水、丙酮的混合物溶解,加活性炭脱色,过滤,将滤液降温到10_45°C,保温1-1.5小时,在1-2小时内降温到0-10°〇并保温2-4小时,过滤,将滤饼用冷冻的体积比为1:5-20的丙酮、水洗涤2-3次,将滤饼真空干燥,既得。 (3) purified: The above crude product was a volume ratio of 1: 5 water, a mixture of acetone is dissolved, add decolorizing charcoal, filtered, and the filtrate was cooled to 10_45 ° C, incubated for 1-1.5 hours, in 1: 0.5-1 over 2 hours and cooled to 0-10 ° square incubated for 2-4 hours, filtered, the filter cake with chilled volume ratio of 1: 5-20 acetone, washed with water 2-3 times, and the filter cake was dried in vacuo vested .

[0005]与现有技术相比,本发明的优点是: [0005] Compared with the prior art, advantages of the present invention are:

(1)替代了价格昂贵的锂试剂,代之以镁试剂; (1) instead of the expensive lithium reagent, magnesium reagent instead;

(2)反应条件温和,不需要太低的温度,反应温度约0-5°C,降低了制冷成本; Mild conditions (2) The reaction does not require low temperatures, the reaction temperature of about 0-5 ° C, reducing the cooling costs;

(3)可使用常规的设备,格式反应为经典反应,已有一百年以上的工业化历史,对人员培训简单,设备成熟,操作稳定性高。 (3) using conventional equipment, the format of classic reaction to reaction, has more than a hundred years of industrial history, staff training simple, sophisticated equipment, high operational stability.

附图说明 BRIEF DESCRIPTION

[0006]图1为;葛兰素史克制备芜地溴铵的反应步骤图; [0006] FIG. 1 is a; GlaxoSmithKline prepared umeclidinium bromide FIG reaction step;

图2为改进后的反应图:其中是将图一中的1(葛兰素史克以苯基锂为试剂)改为II(grinard试剂)。 FIG 2 is a view of improving the reaction: wherein a is FIG. 1 (GSK to phenyl lithium reagent) to II (grinard reagent).

具体实施方式 detailed description

[0007]下面结合实施例对本发明作进一步详细描述: 实施例1 [0007] The following embodiments in conjunction with embodiments of the present invention is described in further detail: Example 1

制备苯基氯化镁:氮气保护下将55g(2.3mol)砂纸打亮的金属镁带加入3升四氢呋喃,滴加215g( 1.91mol)氯苯,微热反应进行,控制滴加速度,使反应保持沸腾,约1.5小时滴完,滴完后加热轻微回流30min。 Phenyl magnesium chloride: Under nitrogen atmosphere to 55g (2.3mol) of metallic magnesium sandpaper lit with 3 L of tetrahydrofuran was added dropwise 215g (1.91mol) chlorobenzene, micro-thermal reaction proceeds, controlled dropping, the reaction was kept boiling, dropwise for about 1.5 hours, after the dropping was heated slightly under reflux for 30min. 冷却备用。 Cool reserve.

[0008] 实施例2 [0008] Example 2

制备苯基溴化镁:氩气保护下将50.4g(2.lmol)砂纸打亮的金属镁带加入4.2升无水乙醚,滴加300g( 1.91mol)溴苯,加入一粒碘引发,电吹风微热反应进行,控制滴加速度,使反应保持沸腾,约1.5小时滴完,滴完后加热轻微回流30min。 Phenyl magnesium bromide: The under argon 50.4g (2.lmol) sandpaper lit magnesium metal with 4.2 liters of anhydrous ethyl ether was added a solution of 300g (1.91mol) of bromobenzene, was added an iodine initiator, electrical hair fever reaction proceeds, controlled dropping, the reaction was kept boiling, about 1.5 hours dropwise was added dropwise to a gentle reflux heated 30min. 冷却备用。 Cool reserve.

[0009] 实施例3 [0009] Example 3

粗品制备:氮杂双环[2.2.2]辛烷-4-羧酸乙酯(135g,0.736mo 1)溶于3L四氢呋喃,在氮气保护下,溶液降温到-5〜0°C,滴加300g溴化苯制备的格氏试剂。 Preparation of crude product: azabicyclo [2.2.2] octane-4-carboxylate (135g, 0.736mo 1) was dissolved in 3L of tetrahydrofuran, under nitrogen, was cooled to -5~0 ° C, was added dropwise 300g preparation of benzyl bromide Grignard reagent. -5〜0°C保温搅拌1小时后(取样TLC监控反应进度)。 After incubation -5~0 ° C stirred for 1 hour (progress of the reaction was monitored by TLC sample). 加入50ml水淬灭。 Adding 50ml of water quenching. 分液,水相用500ml四氢呋喃萃取两次,合并有机相水洗,干燥过滤。 Liquid separation, the aqueous phase was extracted twice with 500ml of tetrahydrofuran, and the combined organic phases were washed with water, dried and filtered. 减压脱除部分溶剂,余量保持约1L,剩余物20°C搅拌过夜析晶。 The solvent was partially removed under reduced pressure, the balance maintaining approximately 1L, the residue was stirred overnight at 20 ° C crystallization. 过滤,洗涤(石油醚2 X 200 ml),滤饼于40°C真空干燥,得黄白色晶体121.2 g,收率54.2%。 Filtered, washed (petroleum ether 2 X 200 ml), the filter cake was dried at 40 ° C in vacuo to give a yellowish white crystals 121.2 g, yield 54.2%.

[0010] 实施例4 [0010] Example 4

粗品制备:氮杂双环[2.2.2]辛烷-4-羧酸乙酯(18.3g,0.lOmo 1)溶于3L四氢呋喃,在氮气保护下,溶液降温到0〜5°C,滴加0.25 mol苯基氯化镁。 Preparation of crude product: azabicyclo [2.2.2] octane-4-carboxylate (18.3g, 0.lOmo 1) was dissolved in 3L of tetrahydrofuran, under nitrogen, was cooled to 0~5 ° C, was added dropwise 0.25 mol phenyl magnesium chloride. 0〜5°C保温搅拌1小时后(取样TLC监控反应进度)ο加入10ml水淬灭。 After incubation 0~5 ° C stirred for 1 hour (progress of the reaction was monitored by TLC sample) o quenched with 10ml of water was added. 分液,水相用100ml四氢呋喃萃取两次,合并有机相水洗,干燥过滤。 Liquid separation, the aqueous phase was extracted twice with 100ml of tetrahydrofuran, and the combined organic phases were washed with water, dried and filtered. 减压脱除部分溶剂,余量保持约50mL,剩余物20°C搅拌过夜析晶。 The solvent was partially removed under reduced pressure, the balance maintaining approximately 50mL, the residue was stirred overnight at 20 ° C crystallization. 过滤,洗涤(石油醚2X20 ml),滤饼于40°C真空干燥,得黄白色晶体14.63 g,收率48.1%。 Filtered, washed (petroleum ether 2X20 ml), the filter cake was dried at 40 ° C in vacuo to give a yellowish white crystals 14.63 g, yield 48.1%.

[0011] 实施例5 [0011] Example 5

粗品制备:氮杂双环[2.2.2]辛烷-4-羧酸乙酯(18.38,0.1011101)溶于31^四氢呋喃,在氮气保护下,溶液降温到5〜15°C,滴加0.30 mol苯基溴化镁。 Preparation of crude product: azabicyclo [2.2.2] octane-4-carboxylate (18.38,0.1011101) ^ 31 was dissolved in tetrahydrofuran, under nitrogen, was cooled to 5~15 ° C, was added dropwise 0.30 mol of benzene bromide. 5〜15°C保温搅拌1小时后(取样TLC监控反应进度)ο加入10ml水淬灭。 After incubation 5~15 ° C stirred for 1 hour (progress of the reaction was monitored by TLC sample) o quenched with 10ml of water was added. 分液,水相用100ml四氢呋喃萃取两次,合并有机相水洗,干燥过滤。 Liquid separation, the aqueous phase was extracted twice with 100ml of tetrahydrofuran, and the combined organic phases were washed with water, dried and filtered. 减压脱除部分溶剂,余量保持约50mL,剩余物20°C搅拌过夜析晶。 The solvent was partially removed under reduced pressure, the balance maintaining approximately 50mL, the residue was stirred overnight at 20 ° C crystallization. 过滤,洗涤(石油醚2 X 20 ml),滤饼于40°C真空干燥,得黄白色晶体13.80g,收率47.1%。 Filtered, washed (petroleum ether 2 X 20 ml), the filter cake was dried at 40 ° C in vacuo to yield 13.80 g of yellow-white crystals, yield 47.1%.

[0012] 实施例6 [0012] Example 6

芜地溴铵精制:粗品100g溶于80°C的320ml水一丙酮640ml混合物,加5g活性炭脱色,过滤。 Umeclidinium bromide purification: 100g crude product was dissolved in 320ml of water to 80 ° C a mixture of 640ml of acetone, add 5g active carbon, and filtered. 滤液降温到25°C,保温1小时。 The filtrate was cooled to 25 ° C, for 1 hour. 1〜2小时内降温到0〜5°C并保温3小时。 Within 1 to 2 hours and cooled to 0~5 ° C for 3 hours. 过滤,滤饼用冷冻的1:2丙酮-水洗涤两次(2x20ml)。 The filter cake with chilled 1: 2 acetone - washed twice with water (2x20ml). 滤饼于60°C真空干燥,得类白色结晶性固体(92g,收率92%)。 The filter cake was dried in vacuo at 60 ° C to give white crystalline solid (92 g, yield 92%). 纯度(HPLC 归一化法)99.25%。 Purity (HPLC normalization method) 99.25%.

[0013] 实施例7 [0013] Example 7

芜地溴铵精制:粗品100g溶于50°C的180ml水一丙酮360ml混合物,加5g活性炭脱色,过滤。 Umeclidinium bromide purification: 100g crude product was dissolved in 180ml water at 50 ° C a mixture of 360ml of acetone, add 5g active carbon, and filtered. 滤液1〜2小时到25°C,保温1小时。 The filtrate was ~ 2 hours to 25 ° C, for 1 hour. 1〜2小时内降温到0°C并保放置过夜。 Within 1 to 2 hours cooled to 0 ° C and left overnight protection. 过滤,滤饼用冷冻的1: 2丙酮-水洗涤两次(2x20ml)。 The filter cake with chilled 1: 2 acetone - washed twice with water (2x20ml). 滤饼于60°C真空干燥,得精品(98.3g,收率98.3%)。 The filter cake was dried at 60 ° C in vacuo to give fine (98.3 g, yield 98.3%). 纯度(HPLC 归一化法)97.75%。 Purity (HPLC normalization method) 97.75%.

Claims (1)

  1. 1.一种芜地溴铵的制备方法,其特征在于:包括以下步骤: (1)配料:原料包括物质的量比值为2.5-3.0:1的格式试剂、氮杂双环[2.2.2]辛烷-4_羧酸乙酯和适量的溶剂; (2)粗品的制备:将氮杂双环[2.2.2]辛烷-4-羧酸乙酯溶于适量的四氢呋喃中,在氮气保护下,溶液降温到_5-25°C,滴加格氏试剂,_5-25°C下保温搅拌1-1.2小时,加入水淬灭,分液,水相用四氢呋喃萃取两次,合并有机相水洗,干燥过滤;减压脱除部分溶剂,将剩余物在20-25°C下搅拌过夜析晶,过滤,用石油醚洗涤,将滤饼于40-45°C下真空干燥,得粗品; (3)精制:将上述粗品用体积比为1:0.5-1:5的水、丙酮的混合物溶解,加活性炭脱色,过滤,将滤液降温到10_45°C,保温1-1.5小时,在1-2小时内降温到0-10°〇并保温2-4小时,过滤,将滤饼用冷冻的体积比为1:5-20的丙酮、水洗涤2-3次,将滤饼真空干燥,既得。 1. A method for preparing umeclidinium bromide, characterized in that: comprising the steps of: (1) Ingredients: feed molar ratio of the value of 2.5-3.0 comprising: a Grignard reagent 1-azabicyclo [2.2.2] octan -4_ alkyl carboxylate and an appropriate amount of a solvent; (2) preparation of crude product: a-azabicyclo [2.2.2] octane-4-carboxylate was dissolved in an appropriate amount of tetrahydrofuran, under nitrogen protection, solution was cooled to _5-25 ° C, a dropping Grignard reagent, incubated under stirring _5-25 ° C 1-1.2 hours, quenched with addition of water, separated, the aqueous phase was extracted twice with tetrahydrofuran, and the combined organic phases were washed with water, sulfate was filtered; the solvent partially removed under reduced pressure, the residue was stirred overnight crystallization at 20-25 ° C, filtered, washed with petroleum ether, the filter cake was dried in vacuo at 40-45 ° C, to obtain a crude product; (3 ) was purified: the above crude product was a volume ratio of 1: 5 water, a mixture of acetone is dissolved, add decolorizing charcoal, filtered, and the filtrate was cooled to 10_45 ° C, incubated for 1-1.5 hours, 1-2 hours: 0.5 the square cooled to 0-10 ° and incubated for 2-4 hours, filtered, the filter cake with chilled volume ratio of 1: 5-20 acetone, washed with water 2-3 times, and the filter cake was dried in vacuo acquired.
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WO2005112644A2 (en) * 2004-05-13 2005-12-01 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
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CN103561731A (en) * 2011-06-08 2014-02-05 葛兰素集团有限公司 Dry powder inhaler compositions comprising umeclidinium

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CN1976701A (en) * 2004-04-27 2007-06-06 葛兰素集团有限公司 Muscarinic acetylcholine receptor antagonist
WO2005112644A2 (en) * 2004-05-13 2005-12-01 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
CN103561731A (en) * 2011-06-08 2014-02-05 葛兰素集团有限公司 Dry powder inhaler compositions comprising umeclidinium

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