WO2008107887A2 - (1r,1'r)-atracurium salts separation process - Google Patents
(1r,1'r)-atracurium salts separation process Download PDFInfo
- Publication number
- WO2008107887A2 WO2008107887A2 PCT/IL2008/000289 IL2008000289W WO2008107887A2 WO 2008107887 A2 WO2008107887 A2 WO 2008107887A2 IL 2008000289 W IL2008000289 W IL 2008000289W WO 2008107887 A2 WO2008107887 A2 WO 2008107887A2
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- Prior art keywords
- cis
- mixture
- isomer
- solvent
- acid
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Definitions
- Cisatracurium besylate has the chemical name (1R,1 I R,2R,2'R)-2,2 I -[1,5- pentanediylbis[oxy(3-oxo-3,l-propanediyl)]]bis[l-[(3,4-dimethoxyphenyl)methyl]- l,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-isoquinolinium dibenzenesulfonate and is represented by the structural formula (I) below:
- Cisatracurium besylate is the dibenzenesulfonate salt of lR-cis,l'R-cis isomer of atracurium (i.e., two molecules of benzenesulfonate per one diammonium molecule of cisatracurium).
- Cisatracurium besylate is one of the 10 possible isomers of atracurium besylate and constitutes approximately 15% of that mixture (atracurium has four chiral centers, two on each half of the molecule, one at each of the nitrogen atoms and the other at position 1 in each of the tetrahydroisoquinolinium rings so theoretically there are expected 16 possible isomers; however, due to the symmetry of the molecule, the number of atracurium isomers is reduced to 10).
- Cisatracurium besylate is a nondepolarizing neuromuscular blocking agent indicated for inpatients and outpatients as an adjunct to general anesthesia, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation in the Intensive Care Unit (ICU).
- Cisatracurium besylate possesses an activity that is superior to atracurium besylate, with significantly less side effects.
- Cisatracurium besylate is marketed in the United States and Europe by Glaxo (S)
- Nimbex is a sterile, non-pyrogenic aqueous solution that is adjusted to pH 3.25 to 3.65 with benzenesulfonic acid.
- the drug is provided in 2.5 ml, 5 ml and 10 ml ampules having a strength of 2 mg/ml cisatracurium besylate.
- a 30 ml vial containing 5 mg/ml cisatracuiium besylate is also available.
- Cisatracurium besylate slowly loses potency with time at a rate of approximately 5% per year under refrigeration (5°C).
- Nimbex should be refrigerated at 2° to 8° C (36° to 46°F) in the carton to preserve potency. The rate of loss in potency increases to approximately 5% per month at 25° C (77° F).
- Atracurium besylate is disclosed in U.S. Patent No. 4,179,507 (hereinafter U.S. '507), which describes a series of bis veratryl isoquinolinium quaternary ammonium salts, including atracurium besylate.
- Cisatracurium besylate is disclosed in U.S. Patents 5,453,510 (hereinafter U.S. '510), and 5,556,978 (hereinafter US '978), which describe forming (R)- tetrahydropapaverine from compound (II), and the conversion of compound (II) into a mixture of R and S diastereoisomer salts with the chiral amino acid, N-acetyl-L-leucinate, comprising 83% of the R and 17% of the S diastereoisomer.
- the (R)-tetrahydropapaverine is subsequently reacted with 1,5-pentamethylene diacrylate followed by oxalic acid to afford the di oxalate salt of the bis tertiary amine base, (IR, I 1 R)- 2,2'-(3 s ll-dioxo-4,10-dioxatridecamethylene)-bis-(l,2,3,4-tetrahydro-6,7- dimethoxyveratryl- isoquinoline.
- the (lR,l'R)-atracurium besylate isomer mixture is subjected to preparative HPLC column chromatography on silica using a mixture of dichloromethane, methanol and benzenesulfonic acid in the ratio of 4000:500:0.25 as the eluent.
- the fractions containing the required isomer are collected and washed with water.
- the dichloromethane solution is evaporated to dryness, the residue dissolved in water and the pH of the solution adjusted to 3.5-4.0 with an aqueous solution of benzenesulfonic acid.
- the aqueous solution is lyophilized to afford cisatracurium besylate possessing an isomeric purity of about 99%.
- U.S. '978 describe performing the high-performance liquid chromatography separation in the presence of a strong acid which include benzenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid or phosphoric acid.
- a strong acid which include benzenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid or phosphoric acid.
- an alcohol such as methanol, ethanol or n-propanol is required for the isomer separation.
- the present invention provides an improved chromatographic method of separating the isomers of (lR,l'R)-atracurium salts (e.g. the besylate salt), i.e., (IR- cis,l'R-cis), (lR-cis,l'R-trans), and (lR-trans,l'R-trans) isomers, which avoids the use of strong acids.
- Good separation as well as improved stability of the lR-cis,l'R-cis cisatracurium besylate isomer can be achieved in accordance with the present invention.
- the method of chromatographically separating the (lR,l'R)-atracurium salts e.g.
- the besylate salt) isomer mixture uses mixtures of an organic solvent, a polar aprotic co- solvent and a weak acid as eluent.
- the weak acid is an organic acid.
- the method of separating the isomers of (lR,l'R)-atracurium salts preferably includes the steps of:
- the present invention additionally provides a method for isolating lR-cis, I 1 R- cis isomer of atracurium besylate obtained in accordance with the separation process of the present invention.
- the method for isolating the lR-cis, l'R-cis isomer of atracurium besylate preferably includes the steps of:
- the method for isolating the lR-cis,l'R-cis isomer of cisatracurium besylate further optionally includes performing an ion exchange, e.g., via a strong anion exchange column or cartridge (hereinafter SAX).
- SAX strong anion exchange column or cartridge
- a particularly preferred embodiment includes performing high-performance liquid chromatography (HPLC) separation using a column packed with silica, eluting with a mobile phase, which includes a mixture of an organic solvent in combination with a polar aprotic co-solvent and a weak acid, e.g., dichloromethane, DMSO and formic acid.
- a mobile phase which includes a mixture of an organic solvent in combination with a polar aprotic co-solvent and a weak acid, e.g., dichloromethane, DMSO and formic acid.
- the dichloromethane;DMSO:formic acid ratio in the eluent mixture is about 70-85 (dichloromethane): 8-20 (DMSO):5-15 (formic acid).
- Exemplary eluent mixtures contain dichloromethane, DMSO and formic acid in ratios of e.g., 75:15:10, 78:13:9 and 80:10:10.
- Figure 1 depicts the stability of the lR-cis,l'R-cis isomer in the eluent mixture at 25 0 C as a function of time.
- Figure 3 depicts the chromatogram of (lR,l'R)-atracurium besylate isomer mixture using N-methyl-2-pyrrolidone as polar aprotic co-solvent in the eluent mixture.
- the present invention provides an improved chromatographic method of separating the (lR,rR)-atracurium salts (e.g., the besylate salt) isomer mixture, which avoids the use of strong acids in the eluent mixture.
- the method of the present invention allows for the separation of the lR-cis,l'R-cis isomer from an isomer mixture Of (IR 3 I 1 R)- atracurium salt (e.g., the besylate salt) and other compounds present.
- the inventors of the present invention have found that the lR-cis, l'R-cis isomer, obtained by HPLC separation as described in U.S. '510 and U.S.
- strong acids refers to acids that dissociate practically completely
- isomeric purity refers to the area percent of the peak corresponding to the lR-cis, 1'R-cis isomer relative to the total area percent of the
- the present invention provides a method of separating isomers of (lR,l'R)-atracurium salt (e.g., the besylate salt), which includes the steps of:
- the isomer separation is effected by using a suitable stationary phase (a solid support), which is capable of separating the lR-cis, l'R-cis isomer from an isomeric mixture of (lR,l'R)-atracurium salt (e.g., the besylate salt).
- a suitable stationary phase a solid support
- Suitable solid supports can include, for example, silica gel.
- the polar aprotic solvent includes DMSO.
- the weak acid of step (c) is preferably an organic acid, which includes formic acid, acetic acid, propionic acid or a mixture thereof.
- a particularly preferred weak organic acid includes formic acid.
- the inventors of the present invention have found that good separation can be obtained using mixtures of e.g., dichloromethane/DMSO/formic acid.
- the column is eluted with a mixture comprising dichloromethane, formic acid and DMSO.
- the dichloromethane:DMSO:formic acid ratio in the eluent mixture is about 70-85
- an ion exchange step can be performed to afford the desired besylate anion.
- the content of the lR-cis,l'R-cis isomer remains unchanged after 26 hours in an eluent mixture comprising dichloromethane, DMSO and formic acid.
- the content of the lR-cis,l'R-cis isomer decreases in the eluent mixture employed in U.S. '978 (dichloromethane, methanol, and benzenesulfonic acid) by more than 3% after 26 hours at room temperature
- the present invention provides a method of performing work-up procedure for isolating the lR-cis,l'R-cis isomer, which includes the steps of: (a) combining eluted fractions, which preferably contain at least 90% of the IR- cis,l'R-cis isomer;
- the solution used for washing the combined eluted fraction is 10% brine solution, which is acidified to pH 2 with a suitable acid, e.g., benzenesulfonic acid
- BSA aqueous solution of BSA.
- 10% brine refers to
- acidifying the combined eluted fraction is performed by using an aqueous BSA solution.
- Precipitation is preferably carried out at least once from a solvent or a solvent mixture selected from tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-Me-THF), diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), acetone, hexane, heptane, cyclohexane, and mixtures thereof.
- a solvent or a solvent mixture selected from tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-Me-THF), diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), acetone, hexane, heptane, cyclohexane, and mixtures thereof.
- the solvent or solvent mixture can contain formic acid or brine acidified to pH 2 with, e.g., about a 0.6 niM aqueous BSA solution (hereinafter the aqueous acidic solution).
- Table 6 illustrates how the amount of the lR-cis,l'R-cis isomer changes at room temperature as a function of time in 3 different eluent mixtures.
- the (1R,1'R)- atracurium besylate isomer mixture was dissolved in the eluent and the resulting solutions were allowed to stand at room temperature for a period of 26 hours. After certain time intervals, as specified in Table 6, samples were withdrawn from each one of the 3 solutions and assayed by HPLC to determine the amount of the lR-cis,l'R-cis isomer in the mixture.
- R,R'-atracurium besylate isomer mixture (consisting of about 58% lR-cis,l'R-cis, 36% lR-cis,l'R-trans and 6% lR-trans,l'R-trans isomers).
- This example demonstrates a method of performing work-up procedure for isolating the lR-cis, l'R-cis isomer of atracurium.
- This example demonstrates a method of performing work-up procedure for isolating the lR-cis, l'R-cis isomer of atracurium.
- the collected fractions mixture in an expected amount of 205 mg of the IR- cis,l'R-cis isomer and total volume of 97 ml was washed four times with 10% brine that was acidified to pH 2 with an aqueous BSA solution and then applied to a pretreated ion exchange SAX cartridge.
- the pretreatment consisted of passing 600 ml of 0.1M of an aqueous BSA solution through the cartridge in order to substitute chloride anions with benzenesulfonate anions.
- the cartridge was conditioned by passing 300 ml of methanol followed by 300 ml dichloromethane through the cartridge).
- the product was retained by the cartridge and eluted from the cartridge with methanol.
- the methanol solution was dried over magnesium sulfate and evaporated.
- the residual oil was dissolved in water and the pH was adjusted to about 3 with a BSA solution.
- the aqueous solution was lyophilized to afford 162 mg (79% yield) of a solid containing only the lR-cis,l'R-cis isomer.
- This example demonstrates a method of performing a work-up procedure for isolating the lR-cis,l'R-cis isomer of atracurium.
- This example demonstrates a method of performing a work-up procedure for isolating the lR-cis,l'R-cis isomer of atracurium.
- the oil was mixed with a mixture of 3 ml acetone, and 12 ml of 2:1 mixture of 2-methyl-tetrahydrofurane (2-Me-THF):hexane was added. The mixture was stirred for 10 minutes and then it was cooled for 15 minutes to a temperature of about 1O 0 C. The solvent was decanted and thick oil was obtained. The oil was dissolved in 2 ml of acetone, and 15 ml of a 1:2 mixture of 2-Me-THF: methyl tert- butyl ether (MTBE) was added and the mixture was cooled overnight at 4°C.
- 2-Me-THF 2-methyl-tetrahydrofurane
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Analytical Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002680277A CA2680277A1 (en) | 2007-03-08 | 2008-03-05 | (1r,1'r)-atracurium salts separation process |
US12/529,269 US8461338B2 (en) | 2007-03-08 | 2008-03-05 | (1R, 1′R)-atracurium salts separation process |
BRPI0808272-3A BRPI0808272A2 (en) | 2007-03-08 | 2008-03-05 | "METHOD FOR CHROMATOGRAPHICALLY SEPARATING THE 1R-CIS ISOMER, 1´R-CIS FROM A MIXTURE OF (1R-1'R) ISOMERS - ATTRACURIUM, CISATRACURY BESILATE, 1R-CIS ISOLOMUS OF THE CESATRUM " |
AU2008222298A AU2008222298A1 (en) | 2007-03-08 | 2008-03-05 | (1R,1'R)-atracurium salts separation process |
EP08719914A EP2125742A2 (en) | 2007-03-08 | 2008-03-05 | (1r,1'r)-atracurium salts separation process |
IL200785A IL200785A0 (en) | 2007-03-08 | 2009-09-07 | (1r,1'r)-atracurium salts separation process |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US89374907P | 2007-03-08 | 2007-03-08 | |
US60/893,749 | 2007-03-08 |
Publications (2)
Publication Number | Publication Date |
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WO2008107887A2 true WO2008107887A2 (en) | 2008-09-12 |
WO2008107887A3 WO2008107887A3 (en) | 2008-11-06 |
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ID=39689236
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PCT/IL2008/000289 WO2008107887A2 (en) | 2007-03-08 | 2008-03-05 | (1r,1'r)-atracurium salts separation process |
Country Status (6)
Country | Link |
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US (1) | US8461338B2 (en) |
EP (1) | EP2125742A2 (en) |
AU (1) | AU2008222298A1 (en) |
BR (1) | BRPI0808272A2 (en) |
CA (1) | CA2680277A1 (en) |
WO (1) | WO2008107887A2 (en) |
Cited By (6)
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EP2283005A2 (en) * | 2008-05-01 | 2011-02-16 | Chemagis Ltd. | Cisatracurium derivatives, preparation and uses thereof |
US8293912B2 (en) | 2007-05-01 | 2012-10-23 | Chemagis Ltd. | Process for producing cisatracurium compounds and associated intermediates |
US8354537B2 (en) | 2007-10-29 | 2013-01-15 | Chemagis Ltd. | R,R1-atracurium salts |
US8357805B2 (en) | 2007-06-18 | 2013-01-22 | Chemagis Ltd. | (1R,1′R)-atracurium salts separation process |
US8357807B2 (en) | 2007-05-01 | 2013-01-22 | Chemagis Ltd. | Isoquinolinium compounds useful in the preparation of cisatracurium and associated intermediates |
CN104557703A (en) * | 2015-01-27 | 2015-04-29 | 江苏嘉逸医药有限公司 | Cisatracurium besilate refining method |
Families Citing this family (3)
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---|---|---|---|---|
EP2125743A1 (en) * | 2007-03-26 | 2009-12-02 | Chemagis Ltd. | (1r,1'r)-atracurium salts separation process |
BRPI0812625A2 (en) * | 2007-07-09 | 2019-02-19 | Chemagis Ltd | process for preparing a cis-atracurium salt |
CN112979547B (en) * | 2021-03-15 | 2022-10-21 | 江苏诚信药业有限公司 | Purification method of cisatracurium besilate |
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2008
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- 2008-03-05 CA CA002680277A patent/CA2680277A1/en not_active Abandoned
- 2008-03-05 BR BRPI0808272-3A patent/BRPI0808272A2/en not_active IP Right Cessation
- 2008-03-05 AU AU2008222298A patent/AU2008222298A1/en not_active Abandoned
- 2008-03-05 WO PCT/IL2008/000289 patent/WO2008107887A2/en active Application Filing
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
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US8293912B2 (en) | 2007-05-01 | 2012-10-23 | Chemagis Ltd. | Process for producing cisatracurium compounds and associated intermediates |
US8357807B2 (en) | 2007-05-01 | 2013-01-22 | Chemagis Ltd. | Isoquinolinium compounds useful in the preparation of cisatracurium and associated intermediates |
US8357805B2 (en) | 2007-06-18 | 2013-01-22 | Chemagis Ltd. | (1R,1′R)-atracurium salts separation process |
US8354537B2 (en) | 2007-10-29 | 2013-01-15 | Chemagis Ltd. | R,R1-atracurium salts |
EP2283005A2 (en) * | 2008-05-01 | 2011-02-16 | Chemagis Ltd. | Cisatracurium derivatives, preparation and uses thereof |
EP2283005A4 (en) * | 2008-05-01 | 2011-08-31 | Chemagis Ltd | Cisatracurium derivatives, preparation and uses thereof |
CN104557703A (en) * | 2015-01-27 | 2015-04-29 | 江苏嘉逸医药有限公司 | Cisatracurium besilate refining method |
CN104557703B (en) * | 2015-01-27 | 2018-01-16 | 江苏嘉逸医药有限公司 | A kind of benzene sulphur is along atracurium process for purification |
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AU2008222298A1 (en) | 2008-09-12 |
WO2008107887A3 (en) | 2008-11-06 |
US8461338B2 (en) | 2013-06-11 |
CA2680277A1 (en) | 2008-09-12 |
EP2125742A2 (en) | 2009-12-02 |
US20100099878A1 (en) | 2010-04-22 |
BRPI0808272A2 (en) | 2014-07-08 |
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