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WO2018229796A2 - A process for betrixaban hydrochloride and betrixaban maleate salt - Google Patents

A process for betrixaban hydrochloride and betrixaban maleate salt Download PDF

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WO2018229796A2
WO2018229796A2 PCT/IN2018/050387 IN2018050387W WO2018229796A2 WO 2018229796 A2 WO2018229796 A2 WO 2018229796A2 IN 2018050387 W IN2018050387 W IN 2018050387W WO 2018229796 A2 WO2018229796 A2 WO 2018229796A2
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ether
process according
methyl
mixtures
solvent
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WO2018229796A3 (en
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Sureshbabu JAYACHANDRA
Vipin Kumar Kaushik
Bhaskar Kumar TELAGAMSETTY
Pudi Giri Jagannadham NAIDU
Madhuresh Sethi
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Mylan Laboratories Ltd
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Mylan Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the present disclosure relates to a process for the preparation of betrixaban hydrochloride and a process for the preparation of betrixaban maleate from betrixaban hydrochloride.
  • Betrixaban maleate is chemically known as N-(5-chloropyridin-2-yl)-2-[4-(N,N- dimethylcarbamimidoyl)-benzoylamino]-5-methoxybenzamide maleate and has the structure shown in Formula I.
  • Betrixaban is a factor Xa inhibitor, marketed in the US under the brand name BEVYXXA .
  • BEVYXXA ® contains betrixaban in the form of its maleate salt.
  • BEVYXXA® is indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE.
  • VTE venous thromboembolism
  • Betrixaban and pharmaceutically acceptable salts thereof are disclosed in the U.S. Patent No. 6,376,515.
  • U.S. Patent No. 7,598,276 discloses betrixaban maleate crystalline form-I and processes for the preparation thereof.
  • the present invention provides a process for the preparation of betrixaban hydrochloride.
  • betrixaban hydrochloride may be prepared by a process that includes the steps of: a) providing a suspension of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5- methoxybenzamide;
  • dimethylamine and isopropylmagnesium chloride may be in an ether solvent.
  • Suitable ethers include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran and mixtures thereof.
  • the suspension of N-(5-chloropyridin-2-yl)-2- (4-cyanobenzoylamino)-5-methoxybenzamide may be prepared by N-(5-chloropyridin-2-yl)- 2-(4-cyanobenzoylamino)-5-methoxybenzamide in an organic solvent.
  • the organic solvent may be, for example (but not limited to) ether, hydrocarbon solvent, or any mixtures thereof.
  • Suitable ethers include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • hydrocarbon solvents examples include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • dimethylamine and isopropylmagnesium chloride may be added to the suspension at a reduced temperature, for example, at a temperature of between -5 °C and 10 °C.
  • betrixaban hydrochloride may be crystalized in a solvent.
  • the solvent may be, for example (but not limited to), an amide, a chlorinated solvent, or mixtures thereof.
  • Suitable amides include, but are not limited to, formamide, dimethylformamide, ⁇ , ⁇ -dimethylacetamide, and mixtures thereof.
  • Suitable chlorinated solvents include, but are not limited to, chloroform, dichloromethane, dichloroethane, and mixtures thereof.
  • betrixaban maleate may be prepared by a process that includes the steps of: a) dissolving maleic acid in a solvent to form a solution;
  • the solvent may be, for example (but not limited to) an alcohol, ketones, ether, hydrocarbon solvent, or mixtures thereof.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-,3-pentanol, 2-methyl- 1-propanol, 2-methyl- 1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l- propanol, and mixtures thereof.
  • ketones include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • Suitable ethers include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
  • hydrocarbon solvents examples include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • betrixaban hydrochloride may be added to the maleic acid solution at ambient temperature.
  • betrixaban maleate may be prepared by a process that includes the steps of: a) adding betrixaban hydrochloride to a solvent to form a solution;
  • d) isolating betrixaban maleate salt examples include, but are not limited to, alcohols, ketones, ethers, hydrocarbon solvents, and mixtures thereof.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-,3-pentanol, 2-methyl- 1-propanol, 2-methyl- 1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l- propanol, and mixtures thereof.
  • ketones include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof,
  • Suitable ethers include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
  • hydrocarbon solvents examples include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • the base may be an organic base or an inorganic base.
  • Suitable organic bases include, but are not limited to, pyridine, imidazole, methylamine, and mixtures thereof.
  • suitable inorganic bases include, but are not limited to, sodium carbonate, sodium bicarbonate, sodium hydroxide, and mixtures thereof.
  • the term "about” when modifying a temperature measurement is meant to mean the recited temperature plus or minus five degrees.
  • the term “about” when modifying an absolute measurement, such as time, mass, or volume means the recited value plus or minus 10% of that value.
  • the present invention relates to a process for the preparation of betrixaban hydrochloride.
  • the present invention also relates to a process for the preparation of betrixaban maleate from betrixaban hydrochloride salt.
  • the present invention provides a process for the preparation of betrixaban hydrochloride salt of formula II)
  • betrixaban hydrochloride may be prepared by a process that includes the steps of:
  • a suspension of N-(5-chloropyridin-2-yl)-2-(4- cyanobenzoylamino)-5-methoxybenzamide may be prepared by suspending N-(5- chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide in an organic solvent.
  • the organic solvent for example (but not limited to), an ether, a hydrocarbon solvent, or mixtures thereof.
  • the suspension may be provided at a reduced temperature.
  • the temperature of the suspension is about 5 °C to about 10 °C.
  • this includes any temperature between about -5 °C and about 10 °C as well as -5 °C and 10 °C, including any temperature in the range of -5 °C - 8 °C, -5 °C - 6 °C, -5°C - 4 °C, -5 °C - 2 °C, -5 °C - 0 °C, -5 °C - -3 °C, -3 °C - 10 °C, -3 °C - 8 °C, -3 °C - 6 °C, -3 °C - 4 °C, -3 °C - 2 °C, -3 °C - 0 °C, 0 °C - 10 °C, 0 °C - 8 °C, 0 °C - 6 °C, 0 °C - 4 °C, 0 °C - 2 °C, 2 °C
  • Suitable ethers include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
  • suitable hydrocarbons include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide is suspended in ether liquid.
  • the ether is THF.
  • dimethylamine and isopropylmagnesium chloride may be sequentially added to the suspension of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide.
  • this may be performed at a reduced temperature.
  • dimethylamine and isopropylmagnesium chloride may be each added to the suspension while maintaining the temperature between about -5 °C and about 10 °C.
  • the solution of dimethylamine and the solution of isopropylmagnesium chloride are each added at temperature of about 0 °C to about 5 °C.
  • this includes any temperature between about -5 °C and about 10 °C as well as -5 and 10, including any temperature in the range of -5 °C - 8 °C, -5 °C - 6 °C, -5°C - 4 °C, -5 °C - 2 °C, -5 °C - 0 °C, -5 °C - -3 °C, -3 °C - 10 °C, -3 °C - 8 °C, -3 °C - 6 °C, -3 °C - 4 °C, -3 °C - 2 °C, -3 °C - 0 °C, 0 °C - 10 °C, 0 °C - 8 °C, 0 °C - 6 °C, 0 °C - 4 °C, 0 °C - 2 °C, 2 °C - 10 °C,
  • Suitable ether solvents include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert- butyl ether, tetrahydrofuran and mixtures thereof.
  • the ether solvent is tetrahydrofuran (THF).
  • isopropylmagnesium chloride is dissolved in an ether solvent.
  • the temperature of the resulting mixture may be raised to about 12 °C to about 25 °C.
  • this temperature range includes 12 °C and 25 °C as well as any temperature between, including 12 °C - 22 °C, 12 °C - 20 °C, 12 °C - 18 °C, 12 °C - 16 °C, 12 °C - 14 °C, 14 °C - 25 °C, 14 °C - 22 °C, 14 °C - 20 °C, 14 °C - 18 °C, 14 °C - 16 °C, 16 °C - 25 °C, 16 °C - 22 °C, 16 °C - 20 °C, 16 °C - 18 °C, 18 °C - 25 °C, 18 °C - 22 °C, 16 °C - 20 °C, 16 °C - 18 °C, 18 °C - 25 °C
  • Hydrochloric acid may then be added. While not wishing to be bound by theory, in addition to facilitating the formation of betrixaban hydrochloride, addition of the aqueous acid may also quench reactions occurring within the reaction mixture.
  • betrixaban hydrochloride may be isolated by methods well known in the art, for example, concentration, filtration, and the like.
  • the isolated solid may be further processed, for example, by drying, to obtain crude betrixaban hydrochloride. Crude betrixaban hydrochloride may then be crystallized.
  • suitable methods for crystalizing crude betrixaban hydrochloride For example, betrixaban hydrochloride may be crystalized from a solvent. Examples of suitable crystallization solvents include, but are not limited to, amides, chlorinated solvents, and mixtures thereof.
  • Suitable amides include, but are not limited to, formamide, dimethyl formamide, ⁇ , ⁇ -dimethylacetamide, and mixtures thereof.
  • suitable chlorinated solvents include, but are not limited to, chloroform, dichloromethane, dichloroethane, and mixtures thereof.
  • the conversion to betrixaban hydrochloride from N-(5-chloropyridin-2- yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide may take place in a single reaction vessel without isolating any intermediates (i.e., a "one -pot process").
  • Inventors have found that the processes disclosed herein may possess advantages of prior art processes, for example those disclosed in CN ' 114.
  • some prior art processes require multiple steps and multiple reaction vessels.
  • a separate step for the Grignard complexation is carried out, thus, the synthesis uses at two reaction vessels.
  • Some processes require multiple purifications and, when used, a high temperature during addition of toluene to ⁇ , ⁇ -dimethylacetamide (for crystallization). Further, removal of ⁇ , ⁇ -dimethylacetamide from the product is tedious and the formation of a common impurity, "N-Des methyl impurity" (shown below), is inconsistent (disclosed to vary from 0.2 to 0.8%.)
  • the processes disclosed herein are simple, preparing the Grignard complexation in situ. Multiple purifications are not required and, if used, the addition of dichloromethane to ⁇ , ⁇ -dimethylacetamide may be carried out at room temperature. Using processes disclosed herein, ⁇ , ⁇ -dimethylacetamide may be removed from the product efficiently resulting in consistent and significantly lower formation of N-Des methyl impurity (impurity levels are consistently below 0.05%).
  • betrixaban hydrochloride prepared by processes disclosed herein may be further converted to betrixaban maleate.
  • betrixaban maleate salt may be prepared by a process that includes the steps of: a) dissolving maleic acid in a solvent to form a solution;
  • maleic acid may be dissolved in a solvent to form a solution.
  • the solvent may be an organic solvent, an inorganic solvent, or a mixture thereof.
  • a suitable inorganic solvent is water.
  • suitable organic solvents include, but are not limited to, alcohols, ketones, ethers, hydrocarbon solvents, and mixtures thereof. In some embodiments, water is used.
  • betrixaban hydrochloride may be added to the maleic acid solution.
  • this resulting solution is stirred for 2 hours to 4 hours under ambient temperature to form a solid.
  • the obtained solid may then be filtered to isolate betrixaban maleate.
  • the solid may be processed further, for example, by drying.
  • betrixaban maleate may be prepared by a process that includes the steps of: a) adding betrixaban hydrochloride to a solvent to form a solution;
  • betrixaban hydrochloride may be added to a solvent to form a solution.
  • Maleic acid may then be added to the solution.
  • the solvent may be an organic solvent, an inorganic solvent, or a mixture thereof.
  • suitable organic solvents include, but are not limited to, alcohols, ketones, ethers, hydrocarbon solvents, and mixtures thereof.
  • a suitable inorganic solvent is water.
  • suitable alcohol solvent examples include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-,3-pentanol, 2-methyl-l -propanol, 2-methyl- 1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2- dimethyl- 1-propanol, and mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • Suitable ether solvents include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert- butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
  • suitable hydrocarbon solvents include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • a mixture of water and methanol is used as the solvent.
  • a 1: 1 mixture of water and methanol is used.
  • the reaction mixture may be maintained under stirring for an extended period of time, for example, from about 2 to about 5 hours, at ambient temperature.
  • a base may be added.
  • the base may be an organic base or an inorganic base.
  • suitable organic bases include, but are not limited to, pyridine, imidazole, and methylamine.
  • suitable inorganic bases include, but are not limited to, sodium carbonate, sodium bicarbonate, and sodium hydroxide. In some embodiments, an aqueous sodium carbonate solution is used.
  • reaction solution is stirred for about 1 to 2 hours after addition of the base.
  • Betrixaban maleate may then be isolated by methods well known in the art. For example, in some embodiments, the reaction solution is concentrated then filtered to obtain a solid. The solid may then be dried to obtain betrixaban maleate.
  • N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide which is used in the present invention, may be prepared per the method disclosed in U.S. Patent No. 6,376,515 or otherwise obtained commercially.
  • U.S. Patent No. 6,376,515 or otherwise obtained commercially.
  • Example 1 Preparation of betrixaban hydrochloride A solution of dimethylamine in tetrahydrofuran (29% w/w, 228 g) and a solution of isopropylmagnesium chloride (190 mL, 20% w/w) were added sequentially to a suspension of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide (25 g, 0.061 moles) in tetrahydrofuran (250 mL) at 0-5 °C. The reaction mass temperature was raised to 15-20 °C and stirred for 1-2 hours. The reaction mass was quenched into aqueous hydrochloric acid, concentrated and filtered.
  • the obtained solid product was dried and purified from a mixture of ⁇ , ⁇ -dimethylacetamide/dichloromethane to yield betrixaban hydrochloride.
  • the product obtained was crystalline in nature and the PXRD pattern obtained from its analysis is shown in FIG. 1
  • Example 2 Preparation of betrixaban maleate
  • Betrixaban hydrochloride (5 g, 0.01 moles) and maleic acid (2.4 g, 0.02 moles) were sequentially added to a 1: 1 mixture of water and methanol (50 mL). The reaction mass was stirred for 3-4 hours at ambient temperature. Aqueous sodium carbonate (1.09 g, 0.01 moles) was added and the solution was stirred for another hour. After concentrating the reaction mass under reduced pressure to remove the methanol, the solution was filtered to yield a solid product, which was washed with water (5 mL). Finally, the solid was dried under reduced pressure to yield betrixaban maleate.
  • reaction mass was then cooled to 0- 10 °C and quenched with 20% hydrochloric acid (thereby adjusting the pH to 1.5.) Thereafter, the reaction mass was concentrated under reduced pressure to remove THF solvent. The resulted concentrate was then filtered to isolate a solid product, which was dried then dissolved in methanol (500 mL). The solution was filtered to remove undissolved matter and the obtained filtrate was concentrated under reduced pressure. Acetone (500 mL), followed by triethylamine (18.7 g), was added. The reaction mixture was stirred for 2 hours and filtered to obtain a solid product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed herein is a process for the preparation of betrixaban hydrochloride and a process for the preparation of betrixaban maleate from betrixaban hydrochloride salt.

Description

A PROCESS FOR BETRIXABAN HYDROCHLORIDE AND BETRIXABAN
MALEATE SALT
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application IN 201741020808 filed on June 14, 2017 and Indian provisional patent application IN 201741035801 filed on October 09, 2017 which are hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION The present disclosure relates to a process for the preparation of betrixaban hydrochloride and a process for the preparation of betrixaban maleate from betrixaban hydrochloride.
DESCRIPTION OF RELATED ART
Betrixaban maleate is chemically known as N-(5-chloropyridin-2-yl)-2-[4-(N,N- dimethylcarbamimidoyl)-benzoylamino]-5-methoxybenzamide maleate and has the structure shown in Formula I.
Figure imgf000003_0001
I
Betrixaban is a factor Xa inhibitor, marketed in the US under the brand name BEVYXXA . BEVYXXA® contains betrixaban in the form of its maleate salt. BEVYXXA® is indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE.
Betrixaban and pharmaceutically acceptable salts thereof are disclosed in the U.S. Patent No. 6,376,515.
U.S. Patent No. 7,598,276 discloses betrixaban maleate crystalline form-I and processes for the preparation thereof.
Chinese patent application CN 104693114 ("CN ' 114") discloses a process for the preparation of betrixaban maleate. This patent application also discloses a process for the preparation of betrixaban hydrochloride.
Prior art processes known to date are operationally inconvenient, often requiring multiple steps, multiple purifications, and multiple reaction vessels. Hence, there is a need to develop an improved process for the preparation of betrixaban maleic acid. In addition, the improved process must be economical, high yielding, and provide betrixaban hydrochloride with a high degree of chemical purity that may be further converted to betrixaban maleate.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of betrixaban hydrochloride.
In one embodiment, betrixaban hydrochloride may be prepared by a process that includes the steps of: a) providing a suspension of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5- methoxybenzamide;
b) adding dimethylamine to the suspension;
c) adding isopropylmagnesium chloride to the suspension;
d) isolating the betrixaban hydrochloride; and
e) crystallizing betrixaban hydrochloride. Within the context of this embodiment, dimethylamine and isopropylmagnesium chloride may be in an ether solvent.
Examples of suitable ethers include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran and mixtures thereof.
Within the context of the present embodiment, the suspension of N-(5-chloropyridin-2-yl)-2- (4-cyanobenzoylamino)-5-methoxybenzamide may be prepared by N-(5-chloropyridin-2-yl)- 2-(4-cyanobenzoylamino)-5-methoxybenzamide in an organic solvent.
The organic solvent may be, for example (but not limited to) ether, hydrocarbon solvent, or any mixtures thereof.
Examples of suitable ethers include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
Examples of suitable hydrocarbon solvents include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
Within the context of this embodiment, dimethylamine and isopropylmagnesium chloride may be added to the suspension at a reduced temperature, for example, at a temperature of between -5 °C and 10 °C.
Within the context of this embodiment, betrixaban hydrochloride may be crystalized in a solvent. The solvent may be, for example (but not limited to), an amide, a chlorinated solvent, or mixtures thereof. Suitable amides include, but are not limited to, formamide, dimethylformamide, Ν,Ν-dimethylacetamide, and mixtures thereof. Suitable chlorinated solvents include, but are not limited to, chloroform, dichloromethane, dichloroethane, and mixtures thereof.
In another aspect, the present invention provides a process for the preparation of betrixaban maleate. In one embodiment, betrixaban maleate may be prepared by a process that includes the steps of: a) dissolving maleic acid in a solvent to form a solution;
b) adding betrixaban hydrochloride to the solution; and
c) isolating betrixaban maleate salt.
Within the context of this embodiment, the solvent may be, for example (but not limited to) an alcohol, ketones, ether, hydrocarbon solvent, or mixtures thereof.
Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-,3-pentanol, 2-methyl- 1-propanol, 2-methyl- 1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l- propanol, and mixtures thereof.
Examples of suitable ketones include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
Examples of suitable ethers include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
Examples of suitable hydrocarbon solvents include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
Within the context of this embodiment, betrixaban hydrochloride may be added to the maleic acid solution at ambient temperature.
In another embodiment, betrixaban maleate may be prepared by a process that includes the steps of: a) adding betrixaban hydrochloride to a solvent to form a solution;
b) adding maleic acid to the solution;
c) adding a base to the solution; and
d) isolating betrixaban maleate salt. Examples of suitable solvents include, but are not limited to, alcohols, ketones, ethers, hydrocarbon solvents, and mixtures thereof.
Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-,3-pentanol, 2-methyl- 1-propanol, 2-methyl- 1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l- propanol, and mixtures thereof.
Examples of suitable ketones include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof,
Examples of suitable ethers include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
Examples of suitable hydrocarbon solvents include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
Within the context of this embodiment, the base may be an organic base or an inorganic base.
Examples of suitable organic bases include, but are not limited to, pyridine, imidazole, methylamine, and mixtures thereof.
Examples of suitable inorganic bases include, but are not limited to, sodium carbonate, sodium bicarbonate, sodium hydroxide, and mixtures thereof.
DETAILED DESCRIPTION OF THE INVENTION
Within the context of the present disclosure, the term "about" when modifying a temperature measurement is meant to mean the recited temperature plus or minus five degrees. Within the context of the present disclosure, the term "about" when modifying an absolute measurement, such as time, mass, or volume, means the recited value plus or minus 10% of that value. The present invention relates to a process for the preparation of betrixaban hydrochloride. The present invention also relates to a process for the preparation of betrixaban maleate from betrixaban hydrochloride salt.
In one aspect, the present invention provides a process for the preparation of betrixaban hydrochloride salt of formula II)
Figure imgf000008_0001
In one embodiment, betrixaban hydrochloride may be prepared by a process that includes the steps of:
a) providing a suspension of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5- methox benzamide (Formula III);
Figure imgf000008_0002
(III)
b) adding dimethylamine to the suspension;
c) adding isopropylmagnesium chloride to the suspension;
d) isolating the betrixaban hydrochloride of formula (II); and
e) crystallizing betrixaban hydrochloride of formula (II).
Within the context the present embodiment, a suspension of N-(5-chloropyridin-2-yl)-2-(4- cyanobenzoylamino)-5-methoxybenzamide may be prepared by suspending N-(5- chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide in an organic solvent. The organic solvent, for example (but not limited to), an ether, a hydrocarbon solvent, or mixtures thereof. Within the context of this embodiment, the suspension may be provided at a reduced temperature. For example, in some embodiments, the temperature of the suspension is about 5 °C to about 10 °C. Within the context of this embodiment, this includes any temperature between about -5 °C and about 10 °C as well as -5 °C and 10 °C, including any temperature in the range of -5 °C - 8 °C, -5 °C - 6 °C, -5°C - 4 °C, -5 °C - 2 °C, -5 °C - 0 °C, -5 °C - -3 °C, -3 °C - 10 °C, -3 °C - 8 °C, -3 °C - 6 °C, -3 °C - 4 °C, -3 °C - 2 °C, -3 °C - 0 °C, 0 °C - 10 °C, 0 °C - 8 °C, 0 °C - 6 °C, 0 °C - 4 °C, 0 °C - 2 °C, 2 °C - 10 °C, 2 °C - 8 °C, 2 °C - 6 °C, 2 °C - 4 °C, 4 °C - 10 °C, 4 °C - 8 °C, 4 °C - 6 °C, 6 °C - 8 °C, and 8 °C - 10 °C.
Examples of suitable ethers include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof. Examples of suitable hydrocarbons include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof. In some embodiments, N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide is suspended in ether liquid. In some embodiments, the ether is THF.
Next, dimethylamine and isopropylmagnesium chloride may be sequentially added to the suspension of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide. Within the context of this embodiment, this may be performed at a reduced temperature. For example, dimethylamine and isopropylmagnesium chloride may be each added to the suspension while maintaining the temperature between about -5 °C and about 10 °C. In some embodiments, the solution of dimethylamine and the solution of isopropylmagnesium chloride are each added at temperature of about 0 °C to about 5 °C.
Within the context of this embodiment, this includes any temperature between about -5 °C and about 10 °C as well as -5 and 10, including any temperature in the range of -5 °C - 8 °C, -5 °C - 6 °C, -5°C - 4 °C, -5 °C - 2 °C, -5 °C - 0 °C, -5 °C - -3 °C, -3 °C - 10 °C, -3 °C - 8 °C, -3 °C - 6 °C, -3 °C - 4 °C, -3 °C - 2 °C, -3 °C - 0 °C, 0 °C - 10 °C, 0 °C - 8 °C, 0 °C - 6 °C, 0 °C - 4 °C, 0 °C - 2 °C, 2 °C - 10 °C, 2 °C - 8, 2 °C - 6 °C, 2 °C - 4 °C, 4 °C - 10 °C, 4 °C - 8 °C, 4 °C - 6 °C, 6 °C - 8 °C, and 8 °C - 10 °C. Within the context of this embodiment, dimethylamine and isopropylmagnesium chloride may be in an ether solvent.
Examples of suitable ether solvents include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert- butyl ether, tetrahydrofuran and mixtures thereof. In some embodiments, the ether solvent is tetrahydrofuran (THF). In some embodiments, isopropylmagnesium chloride is dissolved in an ether solvent.
In some embodiments, after adding dimethylamine and isopropylmagnesium chloride, the temperature of the resulting mixture may be raised to about 12 °C to about 25 °C. Within the context of this embodiment, this temperature range includes 12 °C and 25 °C as well as any temperature between, including 12 °C - 22 °C, 12 °C - 20 °C, 12 °C - 18 °C, 12 °C - 16 °C, 12 °C - 14 °C, 14 °C - 25 °C, 14 °C - 22 °C, 14 °C - 20 °C, 14 °C - 18 °C, 14 °C - 16 °C, 16 °C - 25 °C, 16 °C - 22 °C, 16 °C - 20 °C, 16 °C - 18 °C, 18 °C - 25 °C, 18 °C - 22 °C, 18 °C - 20 °C, 20 °C - 25 °C, 20 °C - 22 °C, and 22 °C - 25 °C. In some embodiments, the temperature is raised to about 15 °C to about 20 °C. In some embodiments, the mixture is maintained at this temperature while being stirred for an extended period of time, for example, for about 2 to 4 hours.
Hydrochloric acid may then be added. While not wishing to be bound by theory, in addition to facilitating the formation of betrixaban hydrochloride, addition of the aqueous acid may also quench reactions occurring within the reaction mixture.
According to the present embodiment, betrixaban hydrochloride may be isolated by methods well known in the art, for example, concentration, filtration, and the like. In some embodiments, the isolated solid may be further processed, for example, by drying, to obtain crude betrixaban hydrochloride. Crude betrixaban hydrochloride may then be crystallized. One of skill in the art will readily recognize suitable methods for crystalizing crude betrixaban hydrochloride. For example, betrixaban hydrochloride may be crystalized from a solvent. Examples of suitable crystallization solvents include, but are not limited to, amides, chlorinated solvents, and mixtures thereof. Examples of suitable amides include, but are not limited to, formamide, dimethyl formamide, Ν,Ν-dimethylacetamide, and mixtures thereof. Examples of suitable chlorinated solvents include, but are not limited to, chloroform, dichloromethane, dichloroethane, and mixtures thereof.
In some embodiments, the conversion to betrixaban hydrochloride from N-(5-chloropyridin-2- yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide may take place in a single reaction vessel without isolating any intermediates (i.e., a "one -pot process").
Inventors have found that the processes disclosed herein may possess advantages of prior art processes, for example those disclosed in CN ' 114. For example, some prior art processes require multiple steps and multiple reaction vessels. In some prior art processes, a separate step for the Grignard complexation is carried out, thus, the synthesis uses at two reaction vessels. Some processes require multiple purifications and, when used, a high temperature during addition of toluene to Ν,Ν-dimethylacetamide (for crystallization). Further, removal of Ν,Ν-dimethylacetamide from the product is tedious and the formation of a common impurity, "N-Des methyl impurity" (shown below), is inconsistent (disclosed to vary from 0.2 to 0.8%.)
Figure imgf000011_0001
N-Des methyl impurity
In contrast, the processes disclosed herein are simple, preparing the Grignard complexation in situ. Multiple purifications are not required and, if used, the addition of dichloromethane to Ν,Ν-dimethylacetamide may be carried out at room temperature. Using processes disclosed herein, Ν,Ν-dimethylacetamide may be removed from the product efficiently resulting in consistent and significantly lower formation of N-Des methyl impurity (impurity levels are consistently below 0.05%).
It is contemplated as within the scope of the present invention that betrixaban hydrochloride prepared by processes disclosed herein may be further converted to betrixaban maleate. Thus, in another embodiment, betrixaban maleate salt may be prepared by a process that includes the steps of: a) dissolving maleic acid in a solvent to form a solution;
b) adding betrixaban hydrochloride to the solution; and
c) isolating betrixaban maleate.
According to this embodiment, maleic acid may be dissolved in a solvent to form a solution. Within the context of this embodiment, the solvent may be an organic solvent, an inorganic solvent, or a mixture thereof. One example of a suitable inorganic solvent is water. Examples of suitable organic solvents include, but are not limited to, alcohols, ketones, ethers, hydrocarbon solvents, and mixtures thereof. In some embodiments, water is used.
Next, betrixaban hydrochloride may be added to the maleic acid solution. In some embodiments, this resulting solution is stirred for 2 hours to 4 hours under ambient temperature to form a solid.
The obtained solid may then be filtered to isolate betrixaban maleate. In some embodiments, the solid may be processed further, for example, by drying.
In another embodiment, betrixaban maleate may be prepared by a process that includes the steps of: a) adding betrixaban hydrochloride to a solvent to form a solution;
b) adding maleic acid to the solution;
c) adding a base to the solution; and
d) isolating betrixaban maleate.
According to this embodiment, betrixaban hydrochloride may be added to a solvent to form a solution. Maleic acid may then be added to the solution. Within the context of this embodiment, the solvent may be an organic solvent, an inorganic solvent, or a mixture thereof. Examples of suitable organic solvents include, but are not limited to, alcohols, ketones, ethers, hydrocarbon solvents, and mixtures thereof. One example of a suitable inorganic solvent is water. Examples of suitable alcohol solvent include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-,3-pentanol, 2-methyl-l -propanol, 2-methyl- 1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2- dimethyl- 1-propanol, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert- butyl ether, tetrahydrofuran, anisole, and mixtures thereof. Examples of suitable hydrocarbon solvents include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
In some embodiments, a mixture of water and methanol is used as the solvent. In particular embodiments, a 1: 1 mixture of water and methanol is used. In some embodiments, the reaction mixture may be maintained under stirring for an extended period of time, for example, from about 2 to about 5 hours, at ambient temperature.
Next, a base may be added. Within the context of the present embodiment, the base may be an organic base or an inorganic base. Examples of suitable organic bases include, but are not limited to, pyridine, imidazole, and methylamine. Examples of suitable inorganic bases include, but are not limited to, sodium carbonate, sodium bicarbonate, and sodium hydroxide. In some embodiments, an aqueous sodium carbonate solution is used.
In some embodiments, the reaction solution is stirred for about 1 to 2 hours after addition of the base.
Betrixaban maleate may then be isolated by methods well known in the art. For example, in some embodiments, the reaction solution is concentrated then filtered to obtain a solid. The solid may then be dried to obtain betrixaban maleate.
N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide, which is used in the present invention, may be prepared per the method disclosed in U.S. Patent No. 6,376,515 or otherwise obtained commercially. In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
EXAMPLE
Example 1: Preparation of betrixaban hydrochloride A solution of dimethylamine in tetrahydrofuran (29% w/w, 228 g) and a solution of isopropylmagnesium chloride (190 mL, 20% w/w) were added sequentially to a suspension of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide (25 g, 0.061 moles) in tetrahydrofuran (250 mL) at 0-5 °C. The reaction mass temperature was raised to 15-20 °C and stirred for 1-2 hours. The reaction mass was quenched into aqueous hydrochloric acid, concentrated and filtered. The obtained solid product was dried and purified from a mixture of Ν,Ν-dimethylacetamide/dichloromethane to yield betrixaban hydrochloride. The product obtained was crystalline in nature and the PXRD pattern obtained from its analysis is shown in FIG. 1
Example 2: Preparation of betrixaban maleate Betrixaban hydrochloride (5 g, 0.01 moles) and maleic acid (2.4 g, 0.02 moles) were sequentially added to a 1: 1 mixture of water and methanol (50 mL). The reaction mass was stirred for 3-4 hours at ambient temperature. Aqueous sodium carbonate (1.09 g, 0.01 moles) was added and the solution was stirred for another hour. After concentrating the reaction mass under reduced pressure to remove the methanol, the solution was filtered to yield a solid product, which was washed with water (5 mL). Finally, the solid was dried under reduced pressure to yield betrixaban maleate.
Example 3: Preparation of betrixaban hydrochloride
A solution of dimethylamine in THF (17% w/w, 228 g) was added to a solution of isopropylmagnesium chloride (446 mL, 17% w/w) at 0-5 °C. The reaction mixture was stirred for 2 hours. The obtained complex was added to a suspension of N-(5-chloropyridin-2-yl)-2- (4-cyanobenzoylamino)-5-methoxybenzamide (50 g) in THF (500 mL) at 15 + 3 °C. The suspension was stirred for 3 hours then cooled to 0-10 °C before quenching with 20% hydrochloric acid (which also adjusted the pH to 1.5). Thereafter, the reaction mass was concentrated under reduced pressures to remove THF, and then filtered. The obtained solid product was dried then dissolved in methanol (500 mL). The solution was again filtered to remove undissolved matter. The obtained filtrate was concentrated under reduced pressure and acetone (500 mL) was added. The reaction mixture was stirred for 2 hours then filtered. The obtained compound is added to a mixture of N-N-dimethylacetamide and toluene, and the resulting slurry is washed with acetone to yield betrixaban monohydrochloride. The product obtained was crystalline in nature and the PXRD pattern obtained from its analysis is shown in FIG. 1.
Example 4: Preparation of betrixaban hydrochloride
A solution of dimethylamine (17% w/w) in THF (228 g) was added to a solution of isopropylmagnesium chloride (17% w/w, 446 mL) at 0-5 °C. The mixture was stirred for 2 hours. The obtained complex was added to a suspension of N-(5-chloropyridin-2-yl)-2-(4- cyanobenzoylamino)-5-methoxybenzamide (50 g) in THF (500 mL) at 15 + 3 °C. The resulting suspension was stirred for 3 hours. The reaction mass was then cooled to 0- 10 °C and quenched with 20% hydrochloric acid (thereby adjusting the pH to 1.5.) Thereafter, the reaction mass was concentrated under reduced pressure to remove THF solvent. The resulted concentrate was then filtered to isolate a solid product, which was dried then dissolved in methanol (500 mL). The solution was filtered to remove undissolved matter and the obtained filtrate was concentrated under reduced pressure. Acetone (500 mL), followed by triethylamine (18.7 g), was added. The reaction mixture was stirred for 2 hours and filtered to obtain a solid product. The solid is then is purified in N-N-dimethylacetamide and toluene to yield a slurry which is washed with acetone to yield betrixaban monohydrochloride. The product obtained was crystalline in nature and the PXRD pattern obtained from its analysis is shown in FIG. 1
Example 5: Preparation of betrixaban maleate
Maleic acid (11.9 g (0.102 moles)) was dissolved in purified/milli-Q water (375 mL). Betrixaban hydrochloride (25 g) was added into the aqueous maleic acid solution. The reaction mass was stirred for 2-3 hours at ambient temperature, filtered, and the obtained solid product was washed with an additional amount of water (25 mL). The obtained solid product was dried under reduced pressure to get substantially pure betrixaban maleate salt.

Claims

We claim:
1. A process for the preparation of betrixaban hydrochloride salt comprising the steps of: a. providing a suspension of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)- 5 -methoxybenzamide ;
b. adding dimethylamine to the suspension;
c. adding isopropylmagnesium chloride to the suspension; and
d. isolating the betrixaban hydrochloride.
2. The process according to claim 1 , wherein the dimethylamine and isopropylmagnesium chloride are in ether solvents.
3. The process according to claim 2, where the ether is selected from the group consisting of isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
4. The process according to claim 1, wherein the suspension of N-(5-chloropyridin-2-yl)- 2-(4-cyanobenzoylamino)-5-methoxybenzamide comprises N-(5-chloropyridin-2-yl)- 2-(4-cyanobenzoylamino)-5-methoxybenzamide is prepared by suspending in an organic solvent.
5. The process according to claim 4, wherein the organic solvent is selected from the group consisting of ethers, hydrocarbon solvent, and mixtures thereof.
6. The process according to claim 5, wherein the ether is selected from the group consisting of isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
7. The process according to claim 5, wherein the hydrocarbon solvent is selected from the group consisting of toluene, heptane, hexane, cyclohexane, and mixtures thereof.
8. The process according to claim 1, wherein the adding of dimethylamine and the adding of isopropylmagnesium chloride is carried out a temperature of between -5 °C and 10 °C.
9. The process according to claim 1, wherein betrixaban hydrochloride is further purified by crystalizing in a solvent.
10. The process according to claim 9, wherein the solvent is selected from the group consisting of amides, chlorinated solvents, and mixtures thereof.
11. The process according to claim 10, wherein the amide is selected from the group consisting of formamide, dimethylformamide and Ν,Ν-dimethylacetamide, and mixtures thereof.
12. The process according to claim 10, wherein the chlorinated solvent is selected from the group consisting of chloroform, dichloromethane, dichloroethane, and mixtures thereof.
13. A process for the preparation of betrixaban maleate salt comprising the steps of:
a. dissolving maleic acid in a solvent to form a solution;
b. adding betrixaban hydrochloride to the solution; and
c. isolating betrixaban maleate salt.
14. The process according to claim 13, wherein the solvent is selected from the group consisting of alcohols, ketones, ethers, hydrocarbon solvents, and mixtures thereof.
15. The process according to claim 14, wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl- 2-propanol, 1-pentanol, 2-,3-pentanol, 2-methyl-l -propanol, 2-methyl- 1-butanol, 2- methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l -propanol, and mixtures thereof.
16. The process according to claim 14, wherein the ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
17. The process according to claim 14, wherein ether solvent is selected from the group consisting of isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
18. The process according to claim 14, wherein the hydrocarbon solvent is selected from the group consisting of toluene, heptane, hexane, cyclohexane, and mixtures thereof.
19. The process according to claim 13, wherein the adding step is carried out at ambient temperature.
20. A process for the preparation of betrixaban maleate salt comprising the steps of: a. adding betrixaban hydrochloride to a solvent to form a solution;
b. adding maleic acid to the solution;
c. adding a base to the solution; and d. isolating betrixaban maleate salt.
21. The process according to claim 20, wherein the solvent is selected from the group consisting of alcohols, ketones, ethers, hydrocarbon solvents, and mixtures thereof.
22. The process according to claim 21, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2- methyl-2-propanol, 1-pentanol, 2-,3-pentanol, 2-methyl-l -propanol, 2-methyl-l- butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, and mixtures thereof.
23. The process according to claim 21, wherein the ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
24. The process according to claim 21, wherein ether solvent is selected from the group consisting of isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
25. The process according to claim 21, wherein hydrocarbon solvent is selected from the group consisting of toluene, heptane, hexane, cyclohexane, and mixtures thereof.
26. The process according to claim 20, wherein the base is an organic base or an
inorganic base.
27. The process according to claim 26, wherein the organic base is selected from the
group consisting of pyridine, imidazole, methylamine, and mixtures thereof.
28. The process according to claim 26, wherein the inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium hydroxide and mixtures thereof.
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