KR102453655B1 - Improved process for preparing acotiamide - Google Patents

Abstract

The present invention provides a method for preparing acotiamide or acotiaamide hydrochloride trihydrate using a novel intermediate, ie, 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester. The manufacturing method of the present invention can avoid the use of 2,4,5-trimethoxybenzoyl chloride, which is an intermediate prepared using thionyl chloride, used in the conventional manufacturing method, so the earth due to the production of sulfur dioxide It is possible to effectively avoid the warming problem and the risk of explosion at the manufacturing site. In addition, the preparation method according to the present invention can prepare acotiamide or acotiaamide hydrochloride trihydrate in high yield and high purity.

Description

Improved process for preparing acotiamide

The present invention relates to an improved process for the preparation of acotiamide. More particularly, it relates to a method for preparing acotiamide or acotiaamide hydrochloride trihydrate using a novel intermediate 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester. The present invention also relates to said novel intermediates and methods for their preparation.

Acotiamide (Acotiamide) is known as a compound having an irritable bowel syndrome, constipation, intestinal motility improvement, such as atony. The chemical name of acotiamide is N-[2-(diisopropylamino)ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-car It has the structure of the following formula (1) as a moxamide (WO96/36619).

<Formula 1>

Acotiamide is being used clinically in the form of hydrochloride trihydrate having the structure of the following Chemical Formula 1'.

<Formula 1'>

A representative method for preparing acotiamide is disclosed in WO96/36619, and is shown in Scheme 1 below.

<Scheme 1>

The preparation method according to Scheme 1 is to react 2,4,5-trimethoxybenzoic acid (compound of Formula 6) with thionyl chloride to obtain 2,4,5-trimethoxybenzoyl chloride (compound of Formula 5') manufacturing; 2-[(2,4,5-trimethoxybenzoyl)amino by reacting the compound of formula 5' with 2-amino-1,3-thiazole-4-carboxylic acid ethyl ester (compound of formula 4) ] preparing -1,3-thiazole-4-carboxylic acid ethyl ester (compound of formula 3); 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester (of Formula 2) by performing a demethylation reaction of the compound of Formula 3 compound); and reacting the compound of Formula 2 with N,N-diisopropylethylenediamine to prepare acotiamide (compound of Formula 1).

That is, in the conventional method for preparing acotiamide, 2,4,5-trimethoxybenzoyl chloride (compound of Formula 5') is used as an intermediate, and the compound of Formula 5' is a compound of Formula 6 and thionyl chloride includes the reaction of The reaction between the compound of Formula 6 and thionyl chloride produces sulfur dioxide (SO ₂ ) gas and hydrochloric acid (HCl) gas during the reaction process. However, sulfur dioxide gas is designated as a substance causing global warming in the Convention on Climate Change (UNFCCC), so there is a need in the art to avoid its generation. In addition, since the reaction of the compound of Formula 6 and thionyl chloride is performed through a heating reaction at about 80° C., the generation of hydrochloric acid gas has a risk of explosion at the manufacturing site, so it is not suitable for mass production on an industrial scale. . In addition, there is a problem in that the reaction between the compound of Formula 5' and the compound of Formula 4 shows a low yield of 73 to 83%.

The present inventors conducted various studies to develop an improved method for preparing acotiamide that can effectively avoid the global warming problem and the risk of explosion at the manufacturing site due to the use of thionyl chloride. As a result, the present inventors have discovered a novel intermediate that can avoid the use of thionyl chloride, i.e., 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (compound of formula 5) via When an intermediate of acotiamide (that is, the compound of Formula 3) is prepared and converted to acotiamide, the problems caused by the generation of sulfur dioxide/hydrochloric acid gas can be fundamentally avoided, and the acortic acid in high yield and high purity It has been discovered that thiamides can be prepared.

Accordingly, the present invention provides a novel intermediate acotiamide or acotiaamide hydrochloride trihydrate comprising the use of 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (compound of formula 5) An object of the present invention is to provide a method for manufacturing

Another object of the present invention is to provide the novel intermediate 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (compound of Formula 5) and a method for preparing the same.

According to one aspect of the present invention, (a) 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (compound of formula 5) 2-amino-1,3-thiazol-4 2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester by reaction with a carboxylic acid ethyl ester (compound of formula 4) in the presence of a base preparing (a compound of Formula 3); (b) performing the demethylation reaction of 2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester (compound of formula 3) to 2 preparing -[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester (compound of formula 2); and (c) the 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester (compound of formula 2) with N,N- There is provided a method for preparing acotiamide or acotiaamide hydrochloride trihydrate, comprising the step of preparing acotiamide (compound of formula 1) by reacting with diisopropylethylenediamine.

According to another aspect of the present invention, there is provided 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (compound of formula 5).

According to another aspect of the present invention, it comprises reacting 2,4,5-trimethoxybenzoic acid (compound of formula 6) with 2,2'-dithiobis(benzothiazole) in the presence of triphenylphosphine. A method for preparing 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (compound of Formula 5) is provided.

The method for preparing acotiamide or acotiaamide hydrochloride trihydrate of the present invention uses a novel intermediate 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (compound of formula 5) include Therefore, it is possible to avoid the use of 2,4,5-trimethoxybenzoyl chloride, which is an intermediate prepared using thionyl chloride, so that it is possible to effectively avoid the global warming problem and the risk of explosion at the manufacturing site due to the generation of sulfur dioxide. can In addition, the preparation method according to the present invention can prepare acotiamide or acotiaamide hydrochloride trihydrate in high yield and high purity.

The present invention provides a process for the preparation of acotiamide or acotiaamide hydrochloride trihydrate comprising the steps of:

(a) 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (compound of formula 5) with 2-amino-1,3-thiazole-4-carboxylic acid ethyl ester (formula 5) 4) and reacted in the presence of a base to prepare 2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester (compound of formula 3) to do;

(b) performing the demethylation reaction of 2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester (compound of formula 3) to 2 preparing -[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester (compound of formula 2); and

(c) the 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester (compound of formula 2) with N,N-di Preparing acotiamide (compound of formula 1) by reacting with isopropylethylenediamine.

If the preparation method of the present invention is shown as an overall reaction scheme, it is shown in Scheme 2 below.

<Scheme 2>

As shown in Scheme 2, preferably, the 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (compound of Formula 5) is 2,4,5-trimethoxybenzoic acid ( It can be obtained by reacting the compound of Formula 6) with 2,2'-dithiobis(benzothiazole) in the presence of triphenylphosphine. In the above reaction, triphenylphosphine is reacted with 2,2'-dithiobis(benzothiazole) to form a condensate of triphenylphosphine and 2,2'-dithiobis(benzothiazole), followed by 2, It can be preferably carried out by reacting 4,5-trimethoxybenzoic acid (compound of formula 6). Triphenylphosphine and 2,2'-dithiobis(benzothiazole) in a ratio of 1.0 to 2.0 equivalents, preferably 1.1 to 1.5 equivalents, more preferably 1.1 to 1.2 equivalents, based on 1 equivalent of the compound of Formula 6 can be used The reaction may be carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran, benzene, toluene, xylene, acetone, and acetonitrile, preferably in dichloromethane. In addition, the reaction may be carried out at 0 to 20 ℃, preferably 5 to 10 ℃. The reaction is different depending on the solvent used, the reaction temperature, etc., but may be carried out for about 1 to 3 hours.

In the preparation method of the present invention, the base used in the reaction of step (a) may be an alkali metal carbonate selected from the group consisting of K ₂ CO ₃ , Na ₂ CO ₃ , and Li ₂ CO ₃ , preferably K ₂ CO ₃ can be In addition, the reaction of step (a) may be carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran, benzene, toluene, xylene, acetone, and acetonitrile, preferably in toluene can be In addition, the reaction of step (a) may be carried out at the reflux temperature of the solvent used, for example, it may be carried out at 80 to 150 ℃, preferably about 110 ℃. The reaction is different depending on the solvent used, the reaction temperature, etc., but may be carried out for about 4 hours.

In the preparation method of the present invention, the demethylation of step (b) may be performed according to the demethylation method used in the conventional method for preparing acotiamide. For example, the demethylation of step (b) is performed by reacting pyridine hydrochloride with 2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester. It can be done by The demethylation of step (b) may be performed in an organic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide, preferably using N,N-dimethylformamide. it is preferable The demethylation reaction of step (b) may be performed at the reflux temperature of the solvent used, for example, at 80 to 180°C, preferably at about 150°C.

In the preparation method of the present invention, the conversion of the compound of Formula 2 to acotiamide in step (c) may be performed according to a conversion method used in a conventional method for preparing acotiamide. For example, the reaction of step (c) can be, without the use of a solvent, 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester (Compound of Formula 2) may be carried out by reacting N,N-diisopropylethylenediamine in excess (eg, 2 to 5 equivalents) with respect to 1 equivalent. The reaction of step (c) may be carried out at 80 to 120°C, preferably at about 120°C. The reaction of step (c) is different depending on the solvent used, the reaction temperature, etc., but may be carried out for about 0.5 to 3 hours.

The preparation method of the present invention may further comprise converting the hydrochloride trihydrate form of acotiamide. That is, the preparation method of the present invention may further include the step of converting the acotiamide prepared in step (c) into its hydrochloride trihydrate. The conversion to the hydrochloride trihydrate may be carried out according to a conventional method. For example, the conversion to the hydrochloride trihydrate is performed by mixing an aqueous hydrochloric acid solution in water, a C ₁ to C ₃ alcohol, or a mixed solvent of water and C ₁ to C ₃ alcohol, preferably a mixed solvent of water and isopropyl alcohol. It can be carried out by reacting with thiamide.

The present invention also provides a novel intermediate for the preparation of acotiamide, namely 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (compound of formula 5).

The present invention also provides a process for the preparation of the novel intermediate. That is, the present invention is 2,4 comprising reacting 2,4,5-trimethoxybenzoic acid (compound of formula 6) with 2,2'-dithiobis(benzothiazole) in the presence of triphenylphosphine It provides a method for preparing ,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (compound of Formula 5).

In the method for preparing the compound of Formula 5, triphenylphosphine is reacted with 2,2'-dithiobis(benzothiazole) to obtain a condensate of triphenylphosphine and 2,2'-dithiobis(benzothiazole). After formation, it can be preferably carried out by reacting 2,4,5-trimethoxybenzoic acid (compound of Formula 6). Triphenylphosphine and 2,2'-dithiobis(benzothiazole) in a ratio of 1.0 to 2.0 equivalents, preferably 1.1 to 1.5 equivalents, more preferably 1.1 to 1.2 equivalents, based on 1 equivalent of the compound of Formula 6 can be used The reaction may be carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran, benzene, toluene, xylene, acetone, and acetonitrile, preferably in dichloromethane. In addition, the reaction may be carried out at 0 to 20 ℃, preferably 5 to 10 ℃. The reaction is different depending on the solvent used, the reaction temperature, etc., but may be carried out for about 1 to 3 hours.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

Example 1. 2,4,5- trimethoxybenzoic acid S- benzothiazole Preparation of -2-yl ester (Compound 5)

While stirring a mixture of triphenylphosphine (68 g, 0.26 mol) and dichloromethane (500 mL) at 5 ° C under a nitrogen atmosphere, 2,2'-dithiobis (benzothiazole) (86.2 g, 0.26 mol) was prepared was put in. After the reaction mixture was stirred at the same temperature of 5°C for 1 hour, 2,4,5-trimethoxybenzoic acid (50 g, 0.24 mol) was added thereto. The reaction mixture was stirred at 5°C for 1 hour, and then concentrated under reduced pressure at about 30°C. Methanol (300 mL) was added and stirred at room temperature for about 3 hours to form a precipitate. The reaction mixture was filtered to obtain a precipitate, washed with cold methanol (50 mL), and vacuum dried at 40° C. for 18 hours to obtain 80.4 g of the title compound. (Yield: 94.4%)

HPLC purity: 99.3%

Melting Point: 125-129℃

IR(ATR)cm ^{- 1} : 3717, 3238, 1718

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.91 (3H, s), 3.98 (3H, s), 4.05 (3H, s), 6.55 (1H, s), 7.42 (1H, td, J=7.6, 1.0 Hz), 7.49 (2H, td, J=8, 1.4Hz), 7.94 (2H, d, J=8Hz), 8.04 (2H, d, J=7.6Hz)

Example 2. 2-[(2,4,5- trimethoxybenzoyl )amino]-1,3-thiazole-4- carboxylic acid Preparation of ethyl ester (compound 3)

2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester (80.4 g, 0.22 mol) under a nitrogen atmosphere, 2-amino-1,3-thiazole-4-carboxylic acid ethyl ester ( A mixture of 38.3 g, 0.22 mol), potassium carbonate (30.8 g, 0.24 mol), and toluene (1.2 L) was refluxed for 4 hours. The reaction mixture was stirred at about 5° C. for 3 hours to form a precipitate. The reaction mixture was filtered to obtain a precipitate, washed with toluene (80 mL), and blow-dried at 50° C. for 20 hours to obtain 143.5 g of a crude product. A mixture of the obtained crude product and distilled water (800 mL) was stirred at 20-25 ° C. for 5 hours at room temperature, filtered to obtain a precipitate, washed with distilled water, and blow-dried at 50 ° C. for 20 hours to obtain the title compound 74.1 g were obtained. (Yield: 90.9%)

HPLC purity: 99.3%

Melting Point: 241-247℃

IR(ATR)cm ^{- 1} : 3300, 3131, 1721, 1659

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.35 (3H, t, J=4Hz), 3.84 (3H, s), 3.91 (3H, s), 4.02 (3H, s), 4.35 (2H, q, J) =4Hz), 6.50 (1H, s), 7.69 (1H, s), 7.78 (1H, s), 11.05 (1H, s)

Example 3. 2-[(2-hydroxy-4,5- dimethoxybenzoyl )amino]-1,3-thiazole-4- carboxy Preparation of Silic Acid Ethyl Ester (Compound 2)

2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester (12 g, 32.8 mmol), pyridine hydrochloride (11.6 g, 98.3) under nitrogen atmosphere mmol), pyridine (2.6 mL, 32.8 mmol), and N,N-dimethylformamide (36 mL) was refluxed for 8 hours. The reaction mixture was cooled to about 50 °C, distilled water (100 mL) was added, and the mixture was stirred at room temperature for 20 hours to form a precipitate. The reaction mixture was filtered to obtain a precipitate, washed with distilled water (3 mL), and vacuum dried at 60° C. for 20 hours to obtain 10.5 g of the title compound. (Yield: 91%)

HPLC purity: 97.4%

Melting Point: 220-228℃

IR(ATR)cm ^{- 1} : 3129, 1722, 1635

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.32 (3H, t, J=4Hz), 3.77 (3H, s), 3.81 (3H, s), 4.28 (2H, q, J=4Hz), 6.58 (1H, s), 7.62 (1H, s), 8.08 (1H, s), 12.37 (1H, br)

Example 4. N-[2-( diisopropylamino )ethyl]-2-[(2-hydroxy-4,5- dimethoxybenzoyl )amino]-1,3-thiazole-4-carboxamide (acotiamide, compound 1) of Produce

2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester (10 g, 28.4 mmol) and N,N-di under a nitrogen atmosphere A mixture of isopropylethylenediamine (10 mL, 56.8 mmol) was stirred at 120° C. for 3 hours. The reaction mixture was cooled to about 50° C. and extracted with saturated aqueous sodium chloride solution (30 mL) and dichloromethane (50 mL). The organic layer was washed twice with distilled water (5 mL), dried over magnesium sulfate (5 g), washed with dichloromethane (10 mL), and dried under reduced pressure to obtain 11.4 g of the title compound. (Yield: 89.1%)

HPLC purity: 98.9%

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.15 (12H, d, J=6.4Hz), 2.93 (2H, m), 3.4 (4H, m), 3.71 (3H, s), 3.73 (3H, s), 6.44 (1H, s), 7.40 (1H, s), 7.60 (1H, s), 8.36 (1H, br)

Example 5. N-[2-( diisopropylamino )ethyl]-2-[(2-hydroxy-4,5- dimethoxybene Preparation of crude) amino]-1,3-thiazole-4-carboxamide hydrochloride trihydrate (Compound 1')

A mixture of acotiamide (11 g, 24.4 mmol), isopropyl alcohol (30 mL), and 35% aqueous hydrochloric acid solution (2.2 mL) prepared in Example 4 was dissolved under heating and stirring. The resulting solution was cooled to about 5° C. and stirred for 1 hour to form a precipitate. The reaction mixture was filtered to obtain a precipitate, which was washed with isopropyl alcohol (6 mL) and dried in vacuo to obtain 11 g (23 mmol) of a crude product. A mixture of the obtained crude product, isopropyl alcohol (9 mL), and distilled water (35 mL) was dissolved by heating and stirring, then cooled to about 5° C. and stirred for 1 hour to form a precipitate. The reaction mixture was filtered to give a precipitate, which was washed with 30% isopropyl alcohol (10 mL) to give 10.3 g of the title compound. (Yield: 78%)

HPLC purity: 99.8%

K/F : 10.01 ~ 10.23%

Melting Point: 190~196℃

IR(ATR)cm ^{- 1} : 3396, 1658, 1518, 1267

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.31 (12H, m), 3.15 (2H, m), 3.40 (9H, s), 3.62 (4H, m), 3.76 (3H, s), 3.80 ( 3H, s), 6.86 (1H, s), 7.48 (1H, s), 7.89 (1H, s), 8.72 (1H, t, J=6Hz), 9.64 (1H, br), 11.78 (1H, s) , 12.08 (1H, br)

Claims (15)

(a) 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester is reacted with 2-amino-1,3-thiazole-4-carboxylic acid ethyl ester in the presence of a base to give 2- preparing [(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester;
(b) demethylation of 2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester to 2-[(2-hydro preparing hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester; and
(c) reaction of 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester with N,N-diisopropylethylenediamine A method for preparing acotiamide or acotiaamide hydrochloride trihydrate, comprising the step of preparing acotiamide. The method of claim 1, wherein the 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester is 2,4,5-trimethoxybenzoic acid 2,2'-dithiobis(benzothiazole ) and triphenylphosphine in the presence of a production method, characterized in that obtained by reacting. 3. The method of claim 2, wherein the reaction reacts triphenylphosphine with 2,2'-dithiobis(benzothiazole) to form a condensate of triphenylphosphine and 2,2'-dithiobis(benzothiazole). After the formation, a method characterized in that it is carried out by reacting 2,4,5-trimethoxybenzoic acid. The method according to claim 2, wherein the reaction is carried out at 0 to 20 °C. The method according to claim 2, wherein the reaction is carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran, benzene, toluene, xylene, acetone, and acetonitrile. The method according to claim 1, wherein the base used in the reaction of step (a) is an alkali metal carbonate selected from the group consisting of K ₂ CO ₃ , Na ₂ CO ₃ , and Li ₂ CO ₃ . The preparation according to claim 1, wherein the reaction of step (a) is carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran, benzene, toluene, xylene, acetone, and acetonitrile. Way. The method according to claim 1, wherein the demethylation of step (b) is pyridine hydrochloride to the 2-[(2,4,5-trimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid ethyl ester. A manufacturing method, characterized in that it is carried out by reacting. The method of claim 1, wherein the reaction of step (c) is 2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid without the use of a solvent A production method, characterized in that it is carried out by reacting 2 to 5 equivalents of N,N-diisopropylethylenediamine with respect to 1 equivalent of ethyl ester. 10. The process according to any one of claims 1 to 9, further comprising the step of converting the acotiamide prepared in step (c) to its hydrochloride trihydrate. 2,4,5-trimethoxybenzoic acid S-benzothiazol-2-yl ester. 2,4,5-trimethoxybenzoic acid S-benzothia comprising reacting 2,4,5-trimethoxybenzoic acid with 2,2'-dithiobis(benzothiazole) in the presence of triphenylphosphine A process for the preparation of zol-2-yl esters. 13. The method of claim 12, wherein the reaction reacts triphenylphosphine with 2,2'-dithiobis(benzothiazole) to form a condensate of triphenylphosphine and 2,2'-dithiobis(benzothiazole). After the formation, a method characterized in that it is carried out by reacting 2,4,5-trimethoxybenzoic acid. The method according to claim 12, wherein the reaction is carried out at 0-20 °C. The method according to claim 12, wherein the reaction is carried out in an organic solvent selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran, benzene, toluene, xylene, acetone, and acetonitrile.