EA041945B1 - METHOD FOR PRODUCING ANTICOAGULANT N-(5-CHLOROPYRIDIN-2-YL)-2-({4-[ETANIMIDOIL(METHYL)AMINO]BENZOYL}AMINO)-5-METHYLBENZAMIDE HYDROCHLOROIDE - Google Patents

Description

Technical field

The invention relates to the field of organic chemistry, and in particular to a method for producing N-(5chloropyridin-2-yl)-2-({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride, which can be used in as an inhibitor of factor Xa for the control of blood clotting in humans and other mammals, as well as for the treatment of diseases associated with blood clotting.

State of the art

Blood clotting can be controlled with anticoagulants, which are protein (factor) Xa inhibitors. Factor Xa belongs to the family of serine proteases. Unlike thrombin, which acts on multiple substrate proteins and specific receptors, factor Xa appears to only act on a single substrate, namely prothrombin. Direct factor Xa inhibitors, such as thrombin formation inhibitors, can be used as an effective way to control blood clotting. Therefore, it is clear that substances that inhibit factor Xa can be used as drugs for diseases associated with blood clotting.

Patent EA015918 describes the compound N-(5-chloropyridin-2-yl)-2-({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide, which is highly active against factor Xa

Proposed in the patent EA 015918 method for obtaining the specified connection includes the following steps:

1) interaction of 5-methyl-2-nitrobenzoic acid with thionyl chloride and 2-amino-5-chloropyridine to obtain N-(5-chloropyridin-2-yl)-5-methyl-2-nitrobenzamide;

2) reduction of N-(5-chloropyridin-2-yl)-5-methyl-2-nitrobenzamide with tin chloride to give 2-amino-N-(5-chloropyridin-2-yl)-5-methylbenzαmide;

3) reaction of 2-amino-N-(5-chloropyridin-2-yl)-5-methylbenzamide with 4-methylaminobenzoic acid trifluoroacetate and amide coupling agent EDCI to give N-(5-chloropyridin-2yl)-2-[(4-methyl (trifluoroacetyl)aminophenylcarbonyl)amino]-5-methylbenzamide;

4) removal of the trifluoroacetyl protective group by alkaline hydrolysis to give N-(5chloropyridin-2-yl)-2-[(4-methylaminophenylcarbonyl)amino]-5-methylbenzamide;

5) Synthesis of amidine from N-(5-chloropyridin-2-yl)-2-[(4-methylaminophenylcarbonyl)amino]-5methylbenzamide by reacting with acetonitrile and passing gaseous HCl, followed by treatment with sodium bicarbonate to obtain N-(5-chloropyridine -2-yl)-2-({4[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide.

The disadvantages of the method disclosed in the patent EA 015918 include a large number of stages, the need to use tin(II) chloride to reduce the nitro group, which leads to a long procedure for separating side compounds of tin, the need to use hydrochloric acid to reduce the nitro group, inefficient use of protective groups , as well as the need to isolate and purify the products by column chromatography after each step.

Another patent RU2698202C2 proposes a method for obtaining the compound N-(5-chloropyridin-2-yl)2-({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride, which includes the following steps:

a) interaction of 5-methylanthranilic acid with thionyl chloride in toluene; reacting the product of the previous reaction with 2-amino-5-chloropyridine in tetrahydrofuran to give 2-aminoN-(5-chloropyridin-2-yl)-5-methylbenzamide;

b) reaction of 2-amino-N-(5-chloropyridin-2-yl)-5-methylbenzamide with 4-[(tert-butoxycarbonyl)-N-methyl]aminobenzoic acid;

c) removing the tert-butoxycarbonyl protecting group from the reaction product of step (b) to give N-(5-chloropyridin-2-yl)-5-methyl-2-(4-(methylamino)benzamido)benzamide;

d) interaction of N-(5-chloropyridin-2-yl)-5-methyl-2-(4-(methylamino)benzamido)benzamide with imidoacetic acid chloride to obtain N-(5-chloropyridin-2-yl)-2- ({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride.

The disadvantages of the method disclosed in patent RU2698202C2 include inefficient use of protective groups, a large number of stages and a linear synthesis strategy.

Thus, there is a need to develop a new method for the preparation of compound N- 1 041945 (5-chloropyridin-2-yl)-2-({4-[ethanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride, which would be devoid of these shortcomings.

Disclosure of invention

The objective of the present invention is to develop and create a new method for producing the anticoagulant N-(5-chloropyridin-2-yl)-2-({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride.

The technical result of the present invention is to create a new and effective method for producing the anticoagulant N-(5-chloropyridin-2-yl)-2-({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride (compound of the formula I), which allows to obtain a product with a high degree of purity (>99%) and high yield; the technical result of the present invention also lies in the simplification of the synthesis of the compound of formula I, the reduction of risks in industrial implementation and the scaling of the synthesis.

The specified technical result is achieved through the implementation of a method for obtaining a compound of formula I

where n=1, including the following steps:

a) interaction of 5-methylanthranilic acid and 5-chloropyridine-2-amine to obtain 2-aminoN-(5-chloropyridin-2-yl)-5-methylbenzamide II

b) interaction of 4-(methylamino)benzoic acid, acetonitrile and hydrogen chloride to obtain 4-(N-methylacetimidamido)benzoic acid hydrochloride III

c) reaction of 4-(N-methylacetimidamido)benzoic acid hydrochloride III and acid chloride to obtain 4-(N-methylacetimidamido)benzoyl chloride hydrochloride IV

d) interaction of 4-(N-methylacetimidamido)benzoyl chloride hydrochloride IV and 2-amino-N-(5chloropyridin-2-yl)-5-methylbenzamide II to obtain N-(5-chloropyridin-2-yl)-2-({ 4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide dihydrochloride I', where n=2

- 2 041945

e) reaction of N-(5-chloropyridin-2-yl)-2-({4-[ethα-imidoyl(methyl)-α-mino]-benzoyl}-amino)-5-methylbenzamide dihydrochloride and a base to give N-(5-chloropyridin-2-yl) -2-({4[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride I

In particular embodiments of the invention in step a), the interaction is the interaction of 5-methylanthranilic acid with thionyl chloride in an aromatic solvent, an organochlorine solvent, a solvent containing an ether moiety or without a solvent; reaction of the product of the previous reaction with 5-chloropyridine-2-amine in dialkyl ether of mono-, di- or polyethylene glycol or in another solvent containing a structural fragment of a simple ether in the presence of a base to obtain 2-amino-N-(5-chloropyridine-2 -yl)-5methylbenzamide.

In some embodiments, the aromatic solvent in step a) is benzene.

In some embodiments, in step a), the organochlorine solvent is methylene chloride, chloroform, carbon tetrachloride, or dichloroethane.

In some embodiments, in step a), the solvent containing the ether moiety is independently diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di-, or polyethylene glycol dialkyl ether.

In some embodiments, in step a), the diethylene glycol dialkyl ether is diethylene glycol dimethyl ether.

In particular embodiments of the invention in step a), the base is independently pyridine, substituted pyridine, dialkylaniline, or trialkylamine. In some embodiments, the substituted pyridine is independently selected and is an alkyl pyridine or a dialkylamino pyridine.

In particular embodiments of the invention, the interaction in step b) of 4(methylamino)benzoic acid, acetonitrile and hydrogen chloride is carried out with the participation of dry gaseous hydrogen chloride and / or its solution in an organic solvent and / or with the participation of reagents capable of generating hydrogen chloride directly in the reaction system. In some embodiments, the organic solvent is acetonitrile.

In particular embodiments of the invention in step b), hydrogen chloride can be generated in the reaction system by reacting an acid chloride with an equivalent amount of water or alcohol, and the acid chloride can be an organic or inorganic acid chloride, the alcohol can be primary, secondary and tertiary aliphatic alcohols.

In particular embodiments of the invention in step b), the organic or inorganic acid chloride is independently thionyl chloride, sulfuryl chloride, phosphorus oxychloride, boron chloride, oxalyl chloride, acetyl chloride, alkyl carboxylic acid chlorides, benzoyl chloride, benzoic acid chloride, or cyanuric chloride.

In particular embodiments of the invention in step b), the alcohol is independently selected and is methanol, ethanol, 2-propanol or tert-butanol.

In particular embodiments of the invention at stage c) the interaction of 4-(N-methylacetimidamido)benzoic acid hydrochloride III and the acid chloride is carried out in an aromatic solvent, an organochlorine solvent, in a solvent containing a structural fragment of a simple ether or without a solvent in the presence of a catalyst to obtain hydrochloride 4-( N-methylacetimidamido)benzoyl chloride.

In particular embodiments of the invention in step c), the acid chloride is independently selected and is thionyl chloride, oxalyl chloride, cyanuric chloride, phosgene, phosphorus trichloride, or phosphorus pentachloride.

In particular embodiments of the invention in step c), the aromatic solvent is independently selected and is benzene or toluene.

In particular embodiments of the invention in step c) the organochlorine solvent is independently selected and is methylene chloride, chloroform, carbon tetrachloride or dichloroethane.

In particular embodiments of the invention in step c), the solvent containing the ether moiety is independently selected and is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di- or polyethylene glycol dialkyl ether.

In particular embodiments of the invention in step c), the catalyst is independently selected and is dimethylformamide or N,N-disubstituted carboxylic acid amide.

In particular embodiments of the invention in step c), the N-disubstituted carboxylic acid amide is dimethiacetamide, N-methylformanilide.

In particular embodiments of the invention, the interaction at stage d) of 4-(N-methylacetimidamido)benzoyl chloride IV hydrochloride and 2-amino-M-(5-chloropyridin-2-yl)-5-methylbenzamide II is carried out in tetrahydrofuran or in another solvent containing a structural fragment an ether such as diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, dialkyl ether of mono-, dior polyethylene glycol or alkyl carboxylate.

In particular embodiments of the invention in step d), the alkyl carboxylate is ethyl acetate.

In particular embodiments of the invention, the reaction in step e) N-(5-chloropyridin-2yl)-2-({4-[ethanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide dihydrochloride I' is carried out with an organic or inorganic base in an organic solvent or in water.

In particular embodiments of the invention in step e), the organic or inorganic base is independently ammonia, mono-, di- or trialkylamine, pyridine, alkylpyridine, dialkylaminopyridine, alkali or alkaline earth metal hydroxide.

In particular embodiments of the invention in step e) the solvent is independently a primary, secondary or tertiary aliphatic alcohol, an alkyl carboxylate, a solvent containing an ether structural moiety.

In particular embodiments of the invention in step e), the aliphatic alcohol is methanol, ethanol, 2-propanol or tert-butanol, the alkyl carboxylate is ethyl acetate, the solvent containing the ether structural fragment is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, dialkyl ether of mono-, di- or polyethylene glycol.

Detailed disclosure of the invention

Definitions (terms).

For a better understanding of the present invention, below are some of the terms used in the present description of the invention. In addition, unless otherwise indicated, all occurrences of functional groups are chosen independently, two occurrences can be either the same or different.

In the description of this invention, the terms includes and including are interpreted as meaning includes, among other things. These terms are not intended to be construed as consisting solely of.

The term alkyl as used herein means both straight and branched. In addition, alkyl may be either substituted or unsubstituted. The term alkyl as used herein refers to groups typically having one to five carbon atoms.

Brief description of the drawings

Fig. 1 - 1H-NMR spectrum of compound II.

Fig. 2 - 13С-NMR spectrum of compound II.

Fig. 3 - 1H-NMR spectrum of compound III.

Fig. 4 - 1H NMR spectra of compound IV in D ₂ O at 25°C compared to the starting acid (compound III), presented as 2 rotamers.

Fig. 5 - 1H NMR spectrum of compound I' (n=2).

Fig. 6 - 1H NMR spectrum of compound I (n=1).

Fig. 7 - ¹³ C NMR spectrum of I (n=1).

- 4 041945

Implementation of the invention

Below, in order to explain the essential differences of the proposed invention, a general scheme for the synthesis of the invention is presented.

Scheme 1

General synthesis scheme according to the invention

Within the framework of this synthesis scheme, the following stages can be distinguished.

Step 1. Reaction of 5-methylanthranilic acid with 2-amino-5-chloropyridine to give 2-amino-N-(5-chloropyridin-2-yl)-5-methylbenzamide (compound II).

Step 2. Reaction of 4-(methylamino)benzoic acid, acetonitrile and hydrogen chloride to obtain 4-(N-methylacetimidamido)benzoic acid(III) hydrochloride. The reaction proceeds through the formation of an intermediate product of the interaction of hydrogen chloride with acetonitrile, acetimidoyl chloride hydrochloride, which further reacts with 4-(methylamino)benzoic acid.

Stage 3. Reaction of 4-(N-methylacetimidamido)benzoic acid(III) hydrochloride and acid chloride, in particular thionyl chloride, in particular, in toluene in the presence of dimethylformamide to obtain 4-(N-methylacetimidamido)benzoyl chloride(IV) hydrochloride.

Step 4. Reaction of 4-(N-methylacetimidamido)benzoyl chloride(IV) hydrochloride and 2-aminoN-(5-chloropyridin-2-yl)-5-methylbenzamide(II) to give N-(5-chloropyridin-2-yl) -2-({4[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide dihydrochloride (I', n=2).

Step 5. Reaction of N-(5-chloropyridin-2-yl)-2-({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide dihydrochloride (I', n=2) and a base, in in particular ammonia, to give N-(5-chloropyridin-2-yl)-2-({4-[ethanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide dihydrochloride (I, n=1).

Preparation of 2-amino-N-(5-chloropyridin-2-yl)-5-methylbenzamide, II

Ί? $ gt ^C| o $ gg ^C|

Α/ΌΗ SOCI2 1 η ₂ ν Ν ' ^Ν

IJ * I \ II J h \4^NH ₂ ^{2 Na0H} XX ⁴ nh ₂ '%

II

In a 250 ml flat-bottomed flask equipped with a magnetic anchor and a reflux condenser, 100 ml of benzene, 20 ml (~280 mmol) of thionyl chloride and 10 g (66 mmol) of 5-methylanthranilic acid were mixed. The mixture was stirred at room temperature for 15-30 min, then gradually heated to boiling, and boiled for 2-4 h. The reaction mixture was evaporated on a rotary evaporator, 30 ml of benzene was added and evaporated again, which gave an oily residue of the intermediate acid chloride in an amount of 15-16 g The intermediate was used further without further purification.

75 ml of dry diglyme was added to the resulting acid chloride, the mixture was stirred until dissolved, and the system was cooled to 10°C. A solution of 8.5 g (66 mmol) of 5-chloropyridine-2-amine and 5.2 g (66 mmol) of pyridine in 25 ml of diglyme was added dropwise to the cooled stirred solution of the acid chloride (a precipitate formed). The cooling was removed and the orange suspension was stirred for 1-2 hours at room temperature. Then a solution of 8.5 g (212.5 mmol) of NaOH in 200 ml of water was added to the reaction mixture and stirred for 1–2 h. The resulting yellow suspension was filtered, the precipitate was washed with water and dried in an oil pump vacuum, which gave 12.8 g of a light yellow product. Yield: 74% based on 5-methylanthranilic acid, ~95% purity ( ¹ H NMR, ¹³ C NMR).

Preparation of 4-(N-methylacetimidamido)benzoic acid hydrochloride, III

100 ml of dry acetonitrile was placed in a 250 ml flat-bottomed flask equipped with a magnetic anchor, cooled to 10°C, and dry hydrogen chloride was bubbled through it until an HCl concentration of ~3 mol/l was reached (determined by the increase in the mass of the flask) (Note 1 below ). 10.6 g (0.07 mol) of 4-(methylamino)benzoic acid was added to the resulting solution without removing the cooling. The flask was hermetically sealed and the resulting suspension was stirred at room temperature (2030°C) for 5-10 days. The precipitate was filtered off, washed with 20 ml of acetonitrile and dried in an oil vacuum.

- 5 041945 pump, which gave 11.2 g of a white crystalline product. Yield - 70%, purity - 98% (1H NMR).

Note 1. For this reaction, hydrogen chloride can be produced directly in the reaction system by reacting an organic or inorganic acid chloride with an equivalent amount of water or alcohol. For example, if 17.9 g (0.15 mol) of thionyl chloride is added to 100 ml of dry acetonitrile, the mixture is cooled to 10°C, and 2.7 g (0.15 mol) of distilled water is added, then an HCl solution in acetonitrile with a concentration of ~3 mol/L is obtained.

Preparation of 4-(N-methylacetimidamido)benzoyl chloride hydrochloride IV

O^OH O^C1

LA

-V-V

NH HCl NH HCI

IIIIV

In a 250 ml flat-bottomed flask equipped with a magnetic anchor and a reflux condenser, 13.0 g (57 mmol) of acid III, 10 ml of toluene, 13 ml (~180 mmol) of thionyl chloride were mixed and 150 μl of dimethylformamide were added. The reaction mixture was heated at 50-60°C for 4-6 hours with stirring. After cooling, 80 ml of toluene was added to the mixture and stirred until a crystalline precipitate appeared, which was filtered off, washed with 15 ml of toluene and dried in an oil pump vacuum, which gave 12.4 g white crystalline substance. Yield - 88%.

Preparation of N-(5-chloropyridin-2-yl)-5-methyl-2-(4-(N-methylacetimidamido)benzamido)benzamide dihydrochloride, I' (n=2)

In a 500 ml flat-bottom flask equipped with a magnetic anchor, 150 ml of dry tetrahydrofuran and 13.1 g (50 mmol) of compound II were mixed and stirred at room temperature until the precipitate dissolved. Then 12.4 g (50 mmol) of acid chloride IV were added in portions. The resulting suspension was stirred at room temperature for 10-30 hours. The precipitate was filtered off, washed with 70 ml of tetrahydrofuran and dried in an oil pump vacuum to give 24.5 g of light yellow product I' (n=2). Yield: 96%, purity -96% (1H NMR).

Preparation of N-(5-chloropyridin-2-yl)-5-methyl-2-(4-(N-methylacetimidamido)benzamido)benzamide hydrochloride, I (n=1)

In a beaker equipped with a magnetic anchor, 15 g (29.5 mmol) of product I (n=2) and 150 ml of distilled water were mixed. 3.2 g (30 mmol) of a solution of ammonia (16%) in 30 ml of water was added to the resulting mixture, which led to the separation of a thick precipitate. The reaction mixture was heated with stirring until dissolved and allowed to crystallize, the precipitate was filtered off, washed with 10 ml of water and dried in an oil pump vacuum to give 10.7 g of a white product. Yield 77%, purity >99% (1H NMR, ¹³ C NMR).

While the invention has been described with reference to the disclosed embodiments, it should be apparent to those skilled in the art that the specific experiments described in detail are for the purpose of illustrating the present invention only and should not be construed as limiting the scope of the invention in any way. It should be clear that various modifications are possible without departing from the essence of the present invention.

-

Claims (19)

CLAIM 1. Process for the preparation of a compound of formula I where n=1, including the following steps: a) interaction of 5-methylanthranilic acid and 5-chloropyridine-2-amine to obtain 2-aminoN-(5-chloropyridin-2-yl)-5-methylbenzamide II b) interaction of 4-(methylamino)benzoic acid, acetonitrile and hydrogen chloride to obtain 4-(N-methylacetimidamido)benzoic acid hydrochloride III c) reaction of 4-(N-methylacetimidamido)benzoic acid hydrochloride III and acid chloride to obtain 4-(N-methylacetimidamido)benzoyl chloride hydrochloride IV d) interaction of 4-(N-methylacetimidamido)benzoyl chloride hydrochloride IV and 2-amino-N-(5chloropyridin-2-yl)-5-methylbenzamide II to obtain N-(5-chloropyridin-2-yl)-2-({ 4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide dihydrochloride I', where n=2 - 7 041945 e) reaction of N-(5-chloropyridin-2-yl)-2-({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5methylbenzamide dihydrochloride and base to give N-(5-chloropyridin-2-yl) -2-({4[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride I 1' (11=2) 1(11=1) 2. The method according to claim 1, in which stage a) the interaction is the interaction of 5methylanthranilic acid with thionyl chloride in an aromatic solvent, an organochlorine solvent, in a solvent containing a structural fragment of a simple ether or without a solvent; interaction of the product of the previous reaction with 5-chloropyridine-2-amine in dialkyl ether of mono-, di- or polyethylene glycol or in another solvent containing a structural fragment of a simple ether, in the presence of a base to obtain 2-amino-N-(5-chloropyridine-2 -yl)-5-methylbenzamide. 3. The method of claim 2 wherein the aromatic solvent is benzene. 4. The method of claim 2, wherein the organochlorine solvent is methylene chloride, chloroform, carbon tetrachloride, or dichloroethane. 5. The method of claim 2, wherein the ether-containing solvent is independently diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di-, or polyethylene glycol dialkyl ether. 6. The method of claim 2 wherein the diethylene glycol dialkyl ether is diethylene glycol dimethyl ether. 7. The method of claim 2 wherein the base is independently pyridine, substituted pyridine, dialkylaniline, or trialkylamine. 8. The method of claim 7 wherein the substituted pyridine is independently an alkyl pyridine or a dialkylamino pyridine. 9. The method according to claim 1, where the interaction in stage b) of 4-(methylamino)benzoic acid, acetonitrile and hydrogen chloride is carried out with the participation of dry gaseous hydrogen chloride and / or its solution in an organic solvent and / or with the participation of reagents capable of generating hydrogen chloride directly in the reaction system. 10. The method of claim 9 wherein the organic solvent is acetonitrile. 11. The method according to claim 9, in which hydrogen chloride can be generated in the reaction system by reacting the acid chloride with an equivalent amount of water or alcohol, and the acid chloride can be an organic or inorganic acid chloride, the alcohol can be primary, secondary and tertiary aliphatic alcohols. 12. The method of claim 11, wherein the organic or inorganic acid chloride is independently thionyl chloride, sulfuryl chloride, phosphorus oxychloride, boron chloride, oxalyl chloride, acetyl chloride, alkyl carboxylic acid chlorides, benzoyl chloride, benzoic acid chloride, or cyanuric chloride. 13. The method of claim 11 wherein the alcohol is independently selected and is methanol, ethanol, 2-propanol, or tert-butanol. 14. The method according to claim 1, in which at stage c) the interaction of 4-(N-methylacetimidamido)benzoic acid hydrochloride III and the acid chloride is carried out in an aromatic solvent, an organochlorine solvent, in a solvent containing an ether structural fragment or without a solvent in the presence of a catalyst with obtaining 4-(N-methylacetimidamido)benzoyl chloride hydrochloride. 15. The method according to claim 1, wherein in step c) the acid chloride is independently selected and is thionyl chloride, oxalyl chloride, cyanuric chloride, phosgene, phosphorus trichloride or phosphorus pentachloride. 16. The method of claim 14 wherein the aromatic solvent is independently selected and is benzene or toluene. 17. The method of claim 14 wherein the organochlorine solvent is independently selected and is methylene chloride, chloroform, carbon tetrachloride or dichloroethane. 18. The method of claim 14, wherein the ether-containing solvent is independently selected and is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di-, or polyethylene glycol dialkyl ether. 19. The method of claim 14, wherein the catalyst is independently selected and is dimethylformamide or N,N-disubstituted carboxylic acid amide. -