WO2015062560A1 - An industrially applicable process for preparing high purity aclidinium bromide - Google Patents
An industrially applicable process for preparing high purity aclidinium bromide Download PDFInfo
- Publication number
- WO2015062560A1 WO2015062560A1 PCT/CZ2014/000123 CZ2014000123W WO2015062560A1 WO 2015062560 A1 WO2015062560 A1 WO 2015062560A1 CZ 2014000123 W CZ2014000123 W CZ 2014000123W WO 2015062560 A1 WO2015062560 A1 WO 2015062560A1
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- WO
- WIPO (PCT)
- Prior art keywords
- solvent
- process according
- formula
- bromide
- ester
- Prior art date
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- KBMJOSVLUSHAAQ-KBPBESRZSA-N NCC[C@H](CCCC1)[C@H]1OC(C(c1ccc[s]1)(c1ccc[s]1)O)=O Chemical compound NCC[C@H](CCCC1)[C@H]1OC(C(c1ccc[s]1)(c1ccc[s]1)O)=O KBMJOSVLUSHAAQ-KBPBESRZSA-N 0.000 description 1
- FVEJUHUCFCAYRP-UHFFFAOYSA-N OC(C(O)=O)(c1ccc[s]1)c1ccc[s]1 Chemical compound OC(C(O)=O)(c1ccc[s]1)c1ccc[s]1 FVEJUHUCFCAYRP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Definitions
- the invention relates to an efficient and industrially applicable process for preparing aclidinium bromide of formula I.
- the new process is focused on applicability of the process in industrial-scale synthesis.
- the newly developed process results in elimination of the formation of impurities and thus to preparation of the API with high purity, complying with high requirements for purity in pharmaceutical production.
- Aclidinium bromide of structure I is the name for (3R)-3- ⁇ [hydroxy ⁇ di-2- thienyl)acetyl]oxy ⁇ -1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]acetate bromide.
- Aclidinium bromide first described in document WO0104118 by Almirall, is a selective antagonist of cholinergic receptors with a long-term effect on M 3 receptors. It has significant bronchodilatory effects. It is used for treatment of the chronic obstructive pulmonary disease (COPD).
- COPD chronic obstructive pulmonary disease
- the therapeutic dosage of the active substance is low (400 pg), in the form of powder, which is applied by means of an inhalation device.
- Synthesis of aclidinium bromide described in document WO0104118 formally includes two steps: preparation of (3R)-1-azabicyclo[2.2.2]oct-3-yl ester of 2,2-dithienyl-glycolic acid of structure V (hereinafter the quinuclidinyi ester) and subsequent quaternization of the adduct V in the presence of an excess of 3-phenoxypropyl bromide.
- Patent application WO2004096800 describes a different procedure for preparing the quinuclidinyl ester V (Scheme 3). It consists in transesterification of the 2,2-dithienyl- glycolic acid methyl ester of formula VI with R-(-)-3-quinuclidinol of formula III in toluene in the presence of sodium in the stoichiometric amount as the base. The reaction mixture was agitated in an inert atmosphere of argon at 85°C for 4 hours, the solvent being systematically removed by distillation.
- the yield of the described preparation method of the quinuclidinyl ester V was 50%.
- the subsequent alkylation was carried out in accordance with the process of the document WO0104118.
- a similar method of preparing the quinuclidinyl ester V was also described in patent application WO2009139710.
- Patent application EP2130830 describes transesterification of the 2,2-dithienyl- glycolic acid ethyl ester with f?-(-)-3-quinuciidinol of formula III in an excess of sodium ethanolate (1.2 equivalents) as the base in a small scale (0.6 mmol).
- sodium ethanolate as specified in the application, must be fresh, prepared just before the reaction itself.
- the reaction was carried out in dry toluene and under the inert argon atmosphere. The reaction temperature starts at 70°C and is gradually increased to the internal temperature of up to 115°C.
- reaction mixture was cooled, diluted with an organic solvent, washed with water and then with a 1N solution of methanesulfonic acid. Then, the aqueous phase was alkalinized at 0°C using a saturated solution of potassium carbonate and extracted with ethyl acetate. The organic layer was washed again with water and brine, dried and concentrated at a reduced pressure, the result of which was the crude product with unknown purity in the yield of 60%.
- the invention relates to an efficient and industrially applicable process for preparing of aclidinium bromide of formula I, which comprises the following steps: a) preparation of the highly pure quinuclidinyl ester of formula V
- Di(2-thienyl)giycolic acid VII is subsequently a non-reactive partner in the esterification by the alcohol III under strongly basic conditions.
- Suitable solvents for the transestenfication reaction comprise toluene, xylene, THF, MeTHF and cyclopentyl methyl ether.
- 2-methyl tetrahydrofuran (MeTHF) was used as the solvent for the transestenfication.
- the optimum reaction temperature was 80°C (temperature of the reaction mixture 70°C), the sterically hindered base being fed as a 2M solution in MeTHF at 35°C.
- the side product of the reaction (methanol) is removed concurrently from the reaction mixture by azeotropic distillation at the atmospheric or reduced pressure (50 kPa to 30 kPa).
- azeotropic distillation at the atmospheric or reduced pressure (50 kPa to 30 kPa).
- an acid-base extraction was selected for processing of the reaction.
- the reaction mixture was cooled down and mixed with a 2M aqueous solution of HCI.
- the reaction mixture was diluted with ethyl acetate.
- the aqueous phase was alkalinized with a 2M aqueous solution of Na 2 C0 3 and the quinuclidinyl ester V was extracted with dichloromethane. After evaporation of the solvent the crude product was re-crystallized from acetonitrile.
- Suitable sterically hindered bases especially sodium and potassium fert-butoxides were investigated, which are relatively well soluble in organic solvents (e.g. THF, MeTHF, cyclopentyl methyl ether), are commercially available (also as a solution: 1M or 2M solutions of tert-butoxide in THF), and are also technologically acceptable due to good physical and chemical properties.
- organic solvents e.g. THF, MeTHF, cyclopentyl methyl ether
- Suitable solvents for the final extraction of the product comprise especially dichloromethane, chloroform, MeTHF, cyclopentyl methyl ether, ethyl acetate or isopropyl acetate.
- Experiments 1 and 2 (Table 1 ) describe the use of sodium and potassium ie/f-butoxides in the stoichiometric amounts, the yield of the reaction being 53% in both cases, but in using sodium iert-butoxide the crude product was isolated in higher purity. Then, we focused on the possibility of increasing the conversion of the reaction by extending the reaction time (experiments 3 and 4), wherein extension by one hour only resulted in a slightly better yield.
- the comparative experiment 5 where dichloromethane as the extraction solvent was replaced by the more internal chloroform (selected for excellent solubility of the product V in chlorinated solvents) illustrates the increase of purity and yield.
- the second step of the synthesis of aclidinium bromide was alkylation of the quinuclidinyl ester V by 3-phenoxypropyl bromide (Scheme 7).
- alkylation of the quinuclidinyl ester V (Scheme 2), described in document WO0104118, was carried out in a mixture of the solvents acetonitrile and chloroform, in the presence of a high excess of the alkylation agent (5 equivalents of 3- phenoxypropyl bromide).
- the use of a high excess of the alkylation agent as a potential genotoxic impurity in the final step is not a suitable solution.
- chloroform as the solvent in the final step.
- chloroform belongs to the group of solvents whose use in pharmaceutical products is limited and amounts strictly controlled (the concentration limit is 60ppm).
- the sterically hindered base means a sterically hindered alkoxide in the form of a salt with an alkali metal such as ferf-butoxide, ferf-pentoxide, amoxide and isopropoxide.
- an alkali metal such as ferf-butoxide, ferf-pentoxide, amoxide and isopropoxide.
- the sodium or potassium salt of terf-butoxide was used, most preferably sodium ferf-butoxide.
- the transesterifioation was carried out in an inert organic solvent such as aromatic hydrocarbons and cyclic ethers, especially toluene, xylene, tetrahydrofuran, 2- methyltetrahydrofuran (MeTHF), cyclopentyl methyl ether or their mixtures, in a preferable embodiment in 2-methyltetrahydrofuran.
- an inert organic solvent such as aromatic hydrocarbons and cyclic ethers, especially toluene, xylene, tetrahydrofuran, 2- methyltetrahydrofuran (MeTHF), cyclopentyl methyl ether or their mixtures, in a preferable embodiment in 2-methyltetrahydrofuran.
- the reaction was carried out by slow addition of the base to an agitated solution of the starting compounds III and IV in a suitable solvent.
- the base was added dropwise as a solution of the base in a suitable solvent; preferably a 1 M solution of sodium tert- butoxide in 2-methyltetrahydrofuran is used.
- the base was added at a temperature of 30 to 50°C, in a preferable embodiment at 35°C.
- the reaction itself was conducted in the temperature range of 55 to 90°C, preferably at 75°C and at the pressure range of 101 kPa to 40 kPa, methanol being periodically removed from the reaction mixture by distillation, for 1 to 4 hours, preferably for 2.5 hours or less.
- the isolation in step b) means admixing of an aqueous solution of an inorganic acid to the reaction mixture cooled to a temperature of 22 to 26°C.
- hydrochloric acid or its aqueous solution, was used as the inorganic acid.
- the reaction mixture can be diluted with a solvent suitable for washing of the reaction mixture and removal of undesired impurities.
- a suitable washing solvent was ethyl acetate, heptane or toluene.
- the aqueous layer containing the salt of the quinuclidinyl ester of formula V was alkalized with a suitable base to pH in the range of 8 to 11 , preferably 10.
- suitable bases comprise especially inorganic bases of the NaOH, KOH, LiOH, K2CO3, of sodium carbonate is used.
- the product was subsequently finally extracted with an extraction solvent (final/last extraction) from the group of ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether; in a preferable embodiment 2-methy!tetrahydrofuran was used as the solvent.
- the extraction was conducted in the temperature range of 45 to 70°C, in a preferable embodiment at 60°C.
- the product quinuclidinyl ester V was obtained with the high purity of 95.0 to 99.9% (determined by UPLC and GC), in a preferable embodiment with a purity higher than 98.5% (determined by UPLC and GC).
- the product may be further re-purified by crystallization from a suitable solvent as necessary. Crystallization of the quinuclidinyl ester of formula V was carried out either directly from the concentrated solution of the crude product V after extraction and re- drying, or the crude product V was obtained by evaporation at a reduced pressure, which was re-crystallized from the solution by dissolving the quinuclidinyl ester of formula V at an increased temperature in a suitable solvent.
- the crystallization was carried out by cooling of the saturated solution of the quinuclidinyl ester V in a suitable solvent to a temperature of 0 to 30°C.
- the crystalline product was isolated by filtration and dried at the atmospheric pressure or in vacuo at temperatures in the range of 23 to 50°C. After crystallization the product V was isolated in the purity of 99.5% to 99.9%, in a preferable embodiment in a purity higher than 99.5%.
- the second step of the synthesis of aclidinium bromide I was quaternization of the quinuclidinyl ester of formula V with the alkylation agent 3-phenoxypropyl bromide in a suitable solvent.
- Acetonitrile was selected as a suitable solvent.
- 3-Phenoxypropyl bromide was slowly added dropwise to a suspension of the slight excess of the alkylation agent in the range of 1.05 to 3 equivalents with regard to the quinuclidinyl ester of formula V; in a preferable embodiment 1.25 equivalents of the alkylation agent are used.
- the reaction was carried out at the boiling temperature of the solvent until the starting compounds have reacted, usually for 2 to 5 hours, preferably for 2.5 hours or less.
- the reaction mixture was cooled down, filtered and the fine crystalline product was washed with acetonitrile.
- the drying was done at the atmospheric pressure or in vacuo, at a temperature of 20 to 45°C, for 4 to 12 hours. This way, the final product aclidinium bromide I was obtained in high yield and purity of 99.95% to 99.99%, in a preferable embodiment with a purity higher than 99.95%.
- the melting points were measured using a Kofler block
- Mobile phase A: 2 ml of 70 % perchloric acid R are dissolved in 1000 ml of water for the chromatography R.
- Capillary column Rxi-5Sil MS (30 m; 0.32 mm ID; 0.5 ⁇ df) or equivalent Temperature program: 60°C - 0 min, gradient 10°C /min to 330°C - 5 min,
- Carrier gas helium for the chromatography R; 40 cm/s, constant flow
- Mobile phase A: 2 ml of 70% perchloric acid R are dissolved in 1000 ml of water for the chromatography R.
- a flat powder sample was used that was placed on a Si plate; the sample was not modified before the measurement.
- 0.02 rad Sol!er slits and a 1 ⁇ 4° anti-diffusion slit were used.
- 0.02 rad Sol!er slits and a 1 ⁇ 4° anti-diffusion slit For the setting of the secondary optical equipment an X ' Ceierator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.
- Example 1 (Reference example: procedure in accordance with the process the patent EP 2 130 830)
- the reaction mixture was heated up for 2.5 hours (at 70 to 80°C for 1 hour and at 80 to 95°C for 1.5 hours).
- the combined aqueous fractions were basified by gradual and careful addition of a 2M solution of sodium carbonate up to pH 10 and subsequently extracted with MeTHF (100 ml), or with ethy! acetate (150 ml) at the temperature of 50 to 60°C. After separation the aqueous phase was extracted with a selected solvent (50 ml) twice more.
- the combined organic fractions were dried with sodium sulphate and concentrated at a reduced pressure and temperature of 50°C to the volume of 50 ml in the case of using MeTHF or 100 ml in the case of using ethyl acetate (accompanied by product crystallization). Then the solution, or suspension, was cooled down to 23°C and then left to crystallize at -10°C. The crystalline product was filtered and dried in vacuum at 23°C.
- Table 1 Quaternization of the quinuclidinyl ester V with 3-phenoxypropyl bromide
- the quinuclidinyl ester V (0.70 g, 2 mmol, purity 99.6%) was suspended in a mixture of the solvents chloroform (20 ml) and acetonitrile (13 ml). 1.58 ml of 3-phenoxypropyl bromide (5 equivalents) was added dropwise to the agitated suspension and the mixture was stirred at 23°C for 72 hours in an inert nitrogen atmosphere. The reaction mixture was concentrated at a reduced pressure. 20 ml of ether was added to the evaporation product and the mixture was stirred for 30 minutes. Then, the product was filtered, washed with ether and dried under a nitrogen stream.
- the X-ray patterns of the crystalline forms are included in the Annex in Figs. 1 to 3.
- the quinuclidinyl ester V (0.5 g, 1.43 mmol, purity 99.99%) was suspended in acetonitrile (10 ml). 0.28 ml of 3-phenoxypropyl bromide (1.25 equivalents) was added to the agitated suspension dropwise at the temperature of 23°C. The reaction mixture was heated up to the boiling point of the solvent and agitated under reflux in an inert nitrogen atmosphere for 4 hours. Then, the reaction mixture was freely cooled down to 23°C and agitated at 23°C for another 48 hours. The resulting suspension was filtered and the white crystalline product was washed with a minimum amount of acetonitrile and dried in a vacuum drier at 23°C for 4 hours.
- reaction mixture was heated up to 75°C (70°C internal temperature of the reaction mixture) during 30 minutes and further stirred at this temperature for 2.5 hours.
- an azeotropic mixture consisting of MeTHF and the side product of the reaction, methanol, was concurrently removed by distillation at a reduced pressure (68 kPa).
- the total amount of 400 ml of the azeotropic mixture was removed by distillation.
- the reaction mixture was cooled down to 22°C During 25 minutes and 490 ml of a 2M solution of HCI was added dropwise during another 15 minutes so that the temperature of the reaction mixture does not exceed 26°C. For easier separation of the layers 200 ml of ethyl acetate was also poured into the mixture.
- the separated organic phase was washed with 150ml of a 2M HCI solution twice more.
- the combined aqueous fractions were basified by gradual dropwise addition of a 2M solution of sodium carbonate up to pH 10 (450 ml) at 23°C. Then, 700 ml of MeTHF was added to the mixture and the mixture was heated up to 58°C and stirred for 15 minutes.
- the separated aqueous layer was twice more extracted with MeTHF (350 ml) at the temperature of 50°C.
- the organic fractions were combined and 650 ml of a mixture of MeTHF and water was removed by azeotropic distillation at a reduced pressure (57 kPa) and the temperature of 58 to 61°C.
- the quinuclidinyl ester V (32 g, 0.0916 moi) was suspended in 500 ml of dry acetonitrile. 18 ml of 3-phenoxypropyl bromide (1.25 equivalents) was added dropwise to the agitated suspension at 23°C under an inert nitrogen atmosphere. The reaction mixture was heated up to the boiling point of the solvent and agitated under reflux in an inert nitrogen atmosphere for 2.5 hours. Then, the reaction mixture was left to freely cool down to 23°C and agitated at 23°C for another 12 hours. The crystalline product was filtered and washed with 200 ml of acetonitrile and dried in a vacuum drier at 45°C for 24 hours.
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CN201480058709.5A CN105683186A (zh) | 2013-10-29 | 2014-10-29 | 工业上适用的用于制备高纯度阿地溴铵的方法 |
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CZ2013-827A CZ306791B6 (cs) | 2013-10-29 | 2013-10-29 | Průmyslově využitelný způsob přípravy aklidinium bromidu o vysoké čistotě |
CZPV2013-827 | 2013-10-29 |
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CN (1) | CN105683186A (cs) |
CZ (1) | CZ306791B6 (cs) |
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WO (1) | WO2015062560A1 (cs) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016156836A1 (en) * | 2015-03-30 | 2016-10-06 | Hovione Scientia Limited | Process for the preparation of aclidinium bromide |
CN108059632A (zh) * | 2017-08-10 | 2018-05-22 | 扬州奥锐特药业有限公司 | 一种r-2,2-二(2-噻吩基)-2-羟基乙酸奎宁-3-基酯的制备方法 |
CN111018678A (zh) * | 2019-12-10 | 2020-04-17 | 山东省药学科学院 | 一种高纯度3-苯氧基溴丙烷的制备方法 |
Families Citing this family (1)
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CN108794464A (zh) * | 2018-04-03 | 2018-11-13 | 安徽赛诺制药有限公司 | 一种阿地溴铵合成及纯化的新方法 |
Citations (6)
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---|---|---|---|---|
WO2001004118A2 (en) | 1999-07-14 | 2001-01-18 | Almirall Prodesfarma S.A. | Quinuclidine derivatives and their use as muscarinic m3 receptor ligands |
WO2004096800A2 (en) | 2003-05-02 | 2004-11-11 | Novartis Ag | Quinuclidine derivatives binding to mucarinic m3 receptors |
WO2008009397A1 (en) * | 2006-07-21 | 2008-01-24 | Laboratorios Almirall, S.A. | Process for manufacturing 3(r)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide |
WO2009139710A1 (en) | 2008-05-13 | 2009-11-19 | Astrazeneca Ab | Quinuclidine derivatives and their use as muscarinic receptor antagonists |
EP2130830A1 (en) | 2008-06-03 | 2009-12-09 | Ranbaxy Laboratories Limited | Muscarinic receptor antagonists |
CN103755698A (zh) * | 2014-01-06 | 2014-04-30 | 万特制药(海南)有限公司 | 一锅法制备阿地溴铵的工艺 |
-
2013
- 2013-10-29 CZ CZ2013-827A patent/CZ306791B6/cs not_active IP Right Cessation
-
2014
- 2014-10-29 HU HU1600350A patent/HUP1600350A2/hu unknown
- 2014-10-29 CN CN201480058709.5A patent/CN105683186A/zh active Pending
- 2014-10-29 WO PCT/CZ2014/000123 patent/WO2015062560A1/en active Application Filing
Patent Citations (7)
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WO2001004118A2 (en) | 1999-07-14 | 2001-01-18 | Almirall Prodesfarma S.A. | Quinuclidine derivatives and their use as muscarinic m3 receptor ligands |
WO2004096800A2 (en) | 2003-05-02 | 2004-11-11 | Novartis Ag | Quinuclidine derivatives binding to mucarinic m3 receptors |
WO2008009397A1 (en) * | 2006-07-21 | 2008-01-24 | Laboratorios Almirall, S.A. | Process for manufacturing 3(r)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide |
EP2044067A1 (en) | 2006-07-21 | 2009-04-08 | Laboratorios Almirall, S.A. | Process for manufacturing 3(r)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3- phenoxypropyl)-1 -azoniabicyclo[2.2.2]octane bromide |
WO2009139710A1 (en) | 2008-05-13 | 2009-11-19 | Astrazeneca Ab | Quinuclidine derivatives and their use as muscarinic receptor antagonists |
EP2130830A1 (en) | 2008-06-03 | 2009-12-09 | Ranbaxy Laboratories Limited | Muscarinic receptor antagonists |
CN103755698A (zh) * | 2014-01-06 | 2014-04-30 | 万特制药(海南)有限公司 | 一锅法制备阿地溴铵的工艺 |
Non-Patent Citations (3)
Title |
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J. MED. CHEM., vol. 52, 2009, pages 5076 - 5092 |
J.ORG.CHEM., vol. 52, no. 9, 1987, pages 1857 - 1859 |
MARÍA PRAT ET AL: "Discovery of Novel Quaternary Ammonium Derivatives of (3 R )-Quinuclidinol Esters as Potent and Long-Acting Muscarinic Antagonists with Potential for Minimal Systemic Exposure after Inhaled Administration: Identification of (3 R )-3-{[Hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicy", JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 16, 27 August 2009 (2009-08-27), pages 5076 - 5092, XP055024812, ISSN: 0022-2623, DOI: 10.1021/jm900132z * |
Cited By (11)
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WO2016156836A1 (en) * | 2015-03-30 | 2016-10-06 | Hovione Scientia Limited | Process for the preparation of aclidinium bromide |
JP2018510189A (ja) * | 2015-03-30 | 2018-04-12 | ホビオネ サイエンティア リミテッド | アクリジニウム臭化物の製造方法 |
US10087177B2 (en) | 2015-03-30 | 2018-10-02 | Hovione Scientia Limited | Process for the preparation of aclidinium bromide |
US10590124B2 (en) | 2015-03-30 | 2020-03-17 | Hovione Scienta Limited | Process for the preparation of aclidinium bromide |
AU2016240289B2 (en) * | 2015-03-30 | 2020-08-27 | Hovione Scientia Limited | Process for the preparation of aclidinium bromide |
JP2020143160A (ja) * | 2015-03-30 | 2020-09-10 | ホビオネ サイエンティア リミテッド | アクリジニウム臭化物の製造方法 |
JP2021020965A (ja) * | 2015-03-30 | 2021-02-18 | ホビオネ サイエンティア リミテッド | アクリジニウム臭化物の製造方法 |
JP7124035B2 (ja) | 2015-03-30 | 2022-08-23 | ホビオネ サイエンティア リミテッド | アクリジニウム臭化物の製造方法 |
CN108059632A (zh) * | 2017-08-10 | 2018-05-22 | 扬州奥锐特药业有限公司 | 一种r-2,2-二(2-噻吩基)-2-羟基乙酸奎宁-3-基酯的制备方法 |
CN111018678A (zh) * | 2019-12-10 | 2020-04-17 | 山东省药学科学院 | 一种高纯度3-苯氧基溴丙烷的制备方法 |
CN111018678B (zh) * | 2019-12-10 | 2022-08-09 | 山东省药学科学院 | 一种高纯度3-苯氧基溴丙烷的制备方法 |
Also Published As
Publication number | Publication date |
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HUP1600350A2 (hu) | 2016-08-29 |
WO2015062560A9 (en) | 2016-04-28 |
CN105683186A (zh) | 2016-06-15 |
CZ306791B6 (cs) | 2017-07-12 |
CZ2013827A3 (cs) | 2015-05-06 |
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