A method for the preparation of CD437

Abstract

The application discloses a preparation method of CD437, and the CD437 is obtained by the following method: S1, compound A is converted under alkaline or acidic conditions to obtain a CD437 crude product; and S2, the CD437 crude product is purified through a paddle operation of a water-miscible organic solvent and water to obtain the CD437. The compound A selected by the application has a wide source, and the preparation cost of raw materials is reduced; the application further provides various alkaline and acidic reaction conditions, which can be flexibly selected according to the structural characteristics of the compound A and actual production conditions, the reaction conditions are mild, the harsh reaction conditions in the prior art are avoided, the production equipment requirements and safety risks are reduced; in addition, the application adopts the paddle operation of the water-miscible organic solvent and water for purification, the operation is simple and efficient, complex purification equipment is not needed, the product purity and yield (more than 80%) can be effectively improved, and the application is suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a method for preparing CD437. Background Technology

[0002] CD437, also known as AHPN, with the chemical name 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid and CAS number 125316-60-1, is a highly selective RARγ agonist with a Ki value of 77 nM. It is a highly selective probe for RARγ pathway research and holds promise for the treatment of retinoic acid-resistant tumors, or for use in combination with chemotherapy / immunotherapy. It also shows promise for skin diseases such as acne, offering both anti-inflammatory and antibacterial benefits while reducing the risk of antibiotic resistance, demonstrating significant medicinal value.

[0003] The current preparation route for CD437 is reported by Charpentier et al. (J. Med. Chem. 1995, 38, 4993), as follows:

[0004] The route begins with the Fokker alkylation of p-bromophenol 1 and adamantanol 2 to obtain compound 3. Compound 3 is then protected with a tert-butyldimethylsilyl group (TBDMS) of its phenolic hydroxyl group to obtain compound 4. Compound 4 is first converted into a corresponding Grignard reagent by magnesium powder and then into an organozinc reagent 5 by zinc chloride. Compounds 5 and 6 are coupled via Negishi under the action of a nickel catalyst to generate compound 7. Compound 7 is deprotected by the tert-butyldimethylsilyl group by tetrabutylammonium fluoride (TBAF) to generate compound 8. Compound 8 is then hydrolyzed under alkaline conditions with sodium hydroxide to generate CD437.

[0005] In summary, CD437 is an important retinoic acid receptor agonist with broad biological activity and potential applications in cancer treatment and dermatology. However, existing methods for preparing CD437 suffer from long synthetic routes and low yields, limiting its industrial production and application. Therefore, developing a simple, high-yield, and easy-to-purify method for preparing CD437 is of significant practical importance. Summary of the Invention

[0006] The purpose of this invention is to provide a CD437 synthesis method that solves the problems of complex operation processes and low product yield in the prior art, which make it unsuitable for industrial production.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows: a method for preparing CD437, wherein the CD437 is obtained by the following method: S1. Under alkaline or acidic conditions, the molecular formula is Compound A was converted to obtain crude product CD437; S2. The crude CD437 product is purified by a slurrying process with a water-miscible organic solvent and water to obtain a product with the molecular formula: CD437.

[0008] Preferably, in S1, compound A is 6-[3-(1-adamantyl)-4-alkoxyphenyl-2-naphthoic acid ester, 6-[3-(1-adamantyl)-4-alkoxyphenyl-2-naphthoic acid, or 6-[3-(1-adamantyl)-4-alkoxyphenyl-2-naphthoic acid salt.

[0009] Preferably, R in the molecular formula of compound A 2 It is at least one of alkyl, acyl, allyl, alkynyl, alkenyl, aryl, and heterocyclic.

[0010] Preferably, the compound represented by compound A includes a corresponding carboxylic ester, carboxylate, acyl chloride, or carboxylic anhydride.

[0011] Preferably, in S1, the alkali used under alkaline conditions is at least one of thiolates, thiophenolates, phenolates, or amines.

[0012] Preferably, in S1, the acid used in the acidic condition is at least one of Lewis acid, protic acid, silicon reagent, a mixture of silicon reagent and alcohol, or a mixture of silicon reagent and thiol.

[0013] Preferably, in S1, R in the molecular formula of compound A 2 When Me is α and R1 is H, compound A is adapalene.

[0014] Preferably, in S2, the organic solvent miscible with water includes at least one of ethanol, methanol, acetone, acetonitrile, isopropanol, and n-propanol.

[0015] Preferably, in step S2, the volume ratio of the water-miscible organic solvent to water is 2:1 to 1:4.

[0016] Preferably, in step S2, the temperature during paddle stirring is between room temperature and 70°C, and the stirring time is 1.5h to 6h.

[0017] Compared with existing technologies, the compound A used in this invention is widely available, especially when adapalene is used, it can be directly purchased commercially, reducing the cost of raw material preparation. This invention also provides a variety of basic and acidic reaction conditions, which can be flexibly selected according to the structural characteristics of compound A and actual production conditions. The reaction conditions are mild, avoiding the harsh reaction conditions in existing technologies, and reducing the requirements for production equipment and safety risks. In addition, this invention uses a water-miscible organic solvent and water for purification, which is simple and efficient, requires no complex purification equipment, and can effectively improve the purity and yield of the product (above 80%), making it suitable for large-scale industrial production. Attached Figure Description

[0018] Figure 1 The proton spectrum of CD437 obtained in Example 1 of this invention; Figure 2 The carbon spectrum of CD437 obtained in Example 1 of this invention is shown. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the present application will be further described in detail below with reference to the accompanying drawings. The described embodiments should not be regarded as limitations on the present invention. All other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0020] In the following description, references to "some embodiments" refer to a subset of all possible embodiments; however, it is understood that "some embodiments" may be the same or different subsets of all possible embodiments and may be combined with each other without conflict. Unless otherwise defined, all technical and scientific terms used in the embodiments of the invention have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments of the invention pertain. The terminology used in the embodiments of the invention is for the purpose of describing the embodiments of the invention only and is not intended to limit the invention.

[0021] Those skilled in the art should understand that, in the following description of the embodiments of the present invention, the sequence of numbers does not imply the order of execution. Some or all steps may be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present invention.

[0022] The terminology used in the embodiments of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention. The singular forms “a” and “the” as used in the embodiments of this invention and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0023] Those skilled in the art will understand that the numerical ranges in the embodiments of the present invention should be understood to specifically disclose each intermediate value between the upper and lower limits of the range. Each smaller range between any stated value and an intermediate value within the stated range, as well as any other stated value or an intermediate value within the stated range, is also included within the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0024] Unless otherwise stated, the technical / scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may be used in embodiments or test cases of the invention. All references to this specification are generally incorporated herein by reference to disclose and describe methods and / or materials associated with said references. In the event of any conflict with any incorporated reference, the contents of this application shall prevail.

[0025] It should be noted that all raw materials or reagents in the embodiments of the present invention were purchased on the market or prepared according to conventional methods known to those skilled in the art.

[0026] This invention provides a method for preparing CD437, which specifically includes the following steps: S1. Under alkaline or acidic conditions, the molecular formula is Compound A is converted to crude product CD437. Under alkaline conditions, thiolates such as sodium methanethiolate and sodium ethanethiolate, thiophenol salts such as sodium thiophene and potassium thiophene, alkoxides such as potassium tert-butoxide and sodium methoxide, phenol salts such as sodium phenolate and potassium phenolate, and amine salts such as sodium amino and potassium hexamethyldisilamide can be used. Under acidic conditions, Lewis acids such as BBr3, BCl3, BI3, TiCl4, SnCl4, and AlCl3, protic acids such as HI, HBr, HF, HCl, HOTf, and HN(Tf)2, silicon reagents such as TMSI, TBDMSI, TMSOTf, and TBDMSOTf, or mixtures of the above silicon reagents with alcohols or thiols can be used. The conversion reaction temperature can be adjusted from -10℃ to reflux temperature (maximum reflux temperature 140℃) depending on the reaction system, and the reaction time is 10h to 40h. By controlling the reaction temperature and time, the conversion rate can be effectively improved. Furthermore, compound A is 6-[3-(1-adamantyl)-4-alkoxyphenyl]-2-naphthoic acid ester or its acid or its salt; wherein, R in the molecular formula of compound A 2 Including common alkyl, acyl, allyl, alkynyl, alkenyl, aryl, and heterocyclic groups; compound A can be in the form of the corresponding carboxylic acid ester, carboxylate, acyl chloride, or carboxylic anhydride; when R in compound A... 2When =Me and R1=H, it is the known compound adapalene, which can be directly purchased commercially or prepared by conventional methods. It is widely available, which reduces the preparation cost. S2. The crude CD437 product is purified by slurry mixing with water and a water-miscible organic solvent to obtain high-purity CD437. The water-miscible organic solvent includes one or more of ethanol, methanol, acetone, acetonitrile, tetrahydrofuran, isopropanol, and n-propanol. The slurry mixing temperature is room temperature to 70°C, and the mixing time is 1.5 h to 6 h. The volume ratio of the water-miscible organic solvent to water is 2:1 to 1:4. This slurry purification method is simple to operate, does not require complex purification methods such as column chromatography, can effectively remove impurities from the crude product, significantly improve the purity of the product, and at the same time reduce purification costs and operational difficulty.

[0027] The specific reaction equation is as follows: .

[0028] The following are specific embodiments. Example 1 The CD437 provided in Example 1 is obtained through the following method: Compound A (where R) is added to the reaction vessel 2 =Me,R 1 =H, i.e., adapalene) 11.0 g, add anhydrous DMF (N,N-dimethylformamide) 200 mL, then add sodium methanethiol 11.0 g, the system is heated to 120 o The reaction was carried out at C for 16 h, and most of the solvent was recovered by vacuum distillation. Under ice bath conditions, 1M hydrochloric acid aqueous solution was added to adjust the pH to 1, and the mixture was extracted with ethyl acetate (100 mL each time, for a total of 5 times). The combined organic phases yielded crude CD437. The crude product was dissolved in 50 mL of ethanol and then subjected to 60... o The CD437 was slurried in 100 mL of water at room temperature for 2 hours, filtered, and the filter cake was dried under vacuum to obtain 9.26 g of purified CD437, with a yield of 87%.

[0029] The CD437 obtained in this embodiment was subjected to nuclear magnetic resonance (NMR) detection, and the detection data are as follows: 1H NMR: (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.60 (s, 1H), 8.59 (s, 1H), 8.18 –8.10 (m, 2H), 8.05 (d, J = 8.7 Hz, 1H), 7.97 (dd, J = 8.6, 1.7 Hz, 1H), 7.86 (dd, J = 8.6, 1.9 Hz, 1H), 7.54 – 7.47 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 2.17 (s, 6H), 2.06 (s, 3H), 1.75 (s, 6H) ppm. 13 C NMR: (101 MHz, DMSO-d6) δ 167.49, 156.49, 140.63, 136.08, 135.54, 130.75, 130.25, 130.02, 129.75, 128 .26, 127.44, 125.88, 125.44, 125.23, 123.65, 117.02, 36.65, 36.38, 28.43ppm. Example 2 The CD437 provided in this embodiment 2 is obtained through the following method: Compound A (where R) is added to the reaction vessel 2 =Me,R 1 =H, i.e., adapalene) 11.0 g, add anhydrous NMP (N-methylpyrrolidone) 200 mL, then add sodium methanethiol 11.0 g, the system is heated to 140 o The reaction was carried out at C for 22 h, and most of the solvent was recovered by vacuum distillation. Under ice bath conditions, 1M hydrochloric acid aqueous solution was added to adjust the pH to 1, and the mixture was extracted with ethyl acetate (100 mL each time, for a total of 5 times). The combined organic phases yielded crude CD437. The crude product was dissolved in 50 mL of ethanol and then subjected to 60... o The mixture was stirred in 100 mL of water at room temperature for 2 hours, filtered, and the filter cake was dried under vacuum to obtain 7.55 g of purified CD437, with a yield of 71%.

[0030] The CD437 obtained in this embodiment was subjected to nuclear magnetic resonance (NMR) detection, and the detection data are as follows: 1H NMR: (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.60 (s, 1H), 8.59 (s, 1H), 8.18 –8.10 (m, 2H), 8.05 (d, J = 8.7 Hz, 1H), 7.97 (dd, J = 8.6, 1.7 Hz, 1H), 7.86 (dd, J = 8.6, 1.9 Hz, 1H), 7.54 – 7.47 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 2.17 (s, 6H), 2.06 (s, 3H), 1.75 (s, 6H) ppm. 13 C NMR: (101 MHz, DMSO-d6) δ 167.49, 156.49, 140.63, 136.08, 135.54, 130.75, 130.25, 130.02, 129.75, 128 .26, 127.44, 125.88, 125.44, 125.23, 123.65, 117.02, 36.65, 36.38, 28.43ppm. Example 3 The CD437 provided in this embodiment 3 is obtained through the following method: Compound A (where R) is added to the reaction vessel 2 =Me,R 1 =H, i.e., adapalene) 11.0 g, add anhydrous DMF 200 mL, then add sodium ethanethiol 10.0 g, the system is heated to 120 o The reaction was carried out at C for 36 h, and most of the solvent was recovered by vacuum distillation. Under ice bath conditions, 1M hydrochloric acid aqueous solution was added to adjust the pH to 1, and the mixture was extracted with ethyl acetate (100 mL each time, for a total of 5 times). The combined organic phases yielded crude CD437. The crude product was dissolved in 50 mL of ethanol and then subjected to 60... o The mixture was stirred in 100 mL of water at room temperature for 2 hours, filtered, and the filter cake was dried under vacuum to obtain 7.13 g of purified CD437, with a yield of 67%.

[0031] The CD437 obtained in this embodiment was subjected to nuclear magnetic resonance (NMR) detection, and the detection data are as follows: 1H NMR: (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.60 (s, 1H), 8.59 (s, 1H), 8.18 –8.10 (m, 2H), 8.05 (d, J = 8.7 Hz, 1H), 7.97 (dd, J = 8.6, 1.7 Hz, 1H), 7.86 (dd, J = 8.6, 1.9 Hz, 1H), 7.54 – 7.47 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 2.17 (s, 6H), 2.06 (s, 3H), 1.75 (s, 6H) ppm. 113 C NMR: (101 MHz, DMSO-d6) δ 167.49, 156.49, 140.63, 136.08, 135.54, 130.75, 130.25, 130.02, 129.75, 128 .26, 127.44, 125.88, 125.44, 125.23, 123.65, 117.02, 36.65, 36.38, 28.43ppm. Example 4 The CD437 provided in Example 4 is obtained through the following method: Compound A (where R) is added to the reaction vessel 2 =Me,R 1 =H, i.e., adapalene) 11.5 g, add anhydrous DMF (N,N-dimethylformamide) 200 mL, then add sodium benzyl mercaptan 11.0 g, the system is heated to 120 o The reaction was carried out at C for 16 h, and most of the solvent was recovered by vacuum distillation. Under ice bath conditions, 1M hydrochloric acid aqueous solution was added to adjust the pH to 1, and the mixture was extracted with ethyl acetate (100 mL each time, for a total of 5 times). The combined organic phases yielded crude CD437. The crude product was dissolved in 50 mL of ethanol and then subjected to 60... o The mixture was stirred in 100 mL of water at room temperature for 2 hours, filtered, and the filter cake was dried under vacuum to obtain 4.79 g of purified CD437, with a yield of 45%.

[0032] The CD437 obtained in this embodiment was subjected to nuclear magnetic resonance (NMR) detection, and the detection data are as follows: 1H NMR: (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.60 (s, 1H), 8.59 (s, 1H), 8.18 –8.10 (m, 2H), 8.05 (d, J = 8.7 Hz, 1H), 7.97 (dd, J = 8.6, 1.7 Hz, 1H), 7.86 (dd, J = 8.6, 1.9 Hz, 1H), 7.54 – 7.47 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 2.17 (s, 6H), 2.06 (s, 3H), 1.75 (s, 6H) ppm. 13 C NMR: (101 MHz, DMSO-d6) δ 167.49, 156.49, 140.63, 136.08, 135.54, 130.75, 130.25, 130.02, 129.75, 128 .26, 127.44, 125.88, 125.44, 125.23, 123.65, 117.02, 36.65, 36.38, 28.43ppm. Example 5 The CD437 provided in Example 5 is obtained through the following method: Compound A (where R) is added to the reaction vessel 2 =Me,R 1 =H, i.e., adapalene) 11.0 g, added to anhydrous dichloromethane 200 mL, then added to boron tribromide 25.0 g, the system was heated to 70 o The reaction was carried out at C for 16 h, and most of the solvent was recovered by vacuum distillation. Under ice bath conditions, 1M hydrochloric acid aqueous solution was added to adjust the pH to 1, and the mixture was extracted with ethyl acetate (100 mL each time, for a total of 5 times). The combined organic phases yielded crude CD437. The crude product was dissolved in 50 mL of ethanol and then subjected to 60... o The mixture was stirred in 100 mL of water at room temperature for 2 hours, filtered, and the filter cake was dried under vacuum to obtain 3.71 g of purified CD437, with a yield of 34%.

[0033] The CD437 obtained in this embodiment was subjected to nuclear magnetic resonance (NMR) detection, and the detection data are as follows: 1H NMR: (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.60 (s, 1H), 8.59 (s, 1H), 8.18 –8.10 (m, 2H), 8.05 (d, J = 8.7 Hz, 1H), 7.97 (dd, J = 8.6, 1.7 Hz, 1H), 7.86 (dd, J = 8.6, 1.9 Hz, 1H), 7.54 – 7.47 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 2.17 (s, 6H), 2.06 (s, 3H), 1.75 (s, 6H) ppm. 13 C NMR: (101 MHz, DMSO-d6) δ 167.49, 156.49, 140.63, 136.08, 135.54, 130.75, 130.25, 130.02, 129.75, 128 .26, 127.44, 125.88, 125.44, 125.23, 123.65, 117.02, 36.65, 36.38, 28.43ppm. Example 6 The CD437 provided in this embodiment 6 is obtained through the following method: Compound A (where R) is added to the reaction vessel 2 =Me,R 1 =H, i.e., adapalene) 11.5 g, add anhydrous DMF (N,N-dimethylformamide) 200 mL, then add 20 g of a 1:1 molar mixture of TMSOTf and methanethiol, and the system is heated to 120 o The reaction was carried out at C for 16 h, and most of the solvent was recovered by vacuum distillation. Under ice bath conditions, 1M hydrochloric acid aqueous solution was added to adjust the pH to 1, and the mixture was extracted with ethyl acetate (100 mL each time, for a total of 5 times). The combined organic phases yielded crude CD437. The crude product was dissolved in 50 mL of ethanol and then subjected to 60... o The mixture was stirred in 100 mL of water at room temperature for 2 hours, filtered, and the filter cake was dried under vacuum to obtain 4.36 g of purified CD437, with a yield of 41%.

[0034] The CD437 obtained in this embodiment was subjected to nuclear magnetic resonance (NMR) detection, and the detection data are as follows: 1H NMR: (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.60 (s, 1H), 8.59 (s, 1H), 8.18 –8.10 (m, 2H), 8.05 (d, J = 8.7 Hz, 1H), 7.97 (dd, J = 8.6, 1.7 Hz, 1H), 7.86 (dd, J = 8.6, 1.9 Hz, 1H), 7.54 – 7.47 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 2.17 (s, 6H), 2.06 (s, 3H), 1.75 (s, 6H) ppm. 13 C NMR: (101 MHz, DMSO-d6) δ 167.49, 156.49, 140.63, 136.08, 135.54, 130.75, 130.25, 130.02, 129.75, 128.26, 127.44, 125.88, 125.44, 125.23, 123.65, 117.02, 36.65, 36.38, 28.43 ppm. Results Analysis The detection data of CD437 obtained from Examples 1-6 show that the H and C atoms in CD437 prepared by this method have stable elution positions in different chemical environments, no impurity peaks, high purity, good separation, and high yield.

[0035] In summary, the compound A selected in this invention is widely available, especially adapalene, which can be directly purchased commercially, reducing the cost of raw material preparation. This invention also provides various basic and acidic reaction conditions, which can be flexibly selected according to the structural characteristics of compound A and actual production conditions. The reaction conditions are mild, avoiding the harsh reaction conditions in existing technologies, and reducing the requirements for production equipment and safety risks. Furthermore, this invention uses a water-miscible organic solvent and water for purification, which is simple, efficient, and requires no complex purification equipment. It can effectively improve product purity and yield (over 80%), enabling large-scale industrial production and showing promising industrial application prospects.

[0036] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for preparing CD437, characterized in that, The CD437 is obtained through the following method: S1. Under alkaline or acidic conditions, the molecular formula is Compound A was converted to obtain crude product CD437; S2. The crude CD437 product is purified by a slurrying process with a water-miscible organic solvent and water to obtain a product with the molecular formula: CD437.

2. The CD437 synthesis method according to claim 1, characterized in that, In S1, compound A is 6-[3-(1-adamantyl)-4-alkoxyphenyl-2-naphthoic acid ester, 6-[3-(1-adamantyl)-4-alkoxyphenyl-2-naphthoic acid, or 6-[3-(1-adamantyl)-4-alkoxyphenyl-2-naphthoic acid salt.

3. A method for synthesizing CD437 according to claim 1 or 2, characterized in that, The R in the molecular formula of compound A 2 It is at least one of alkyl, acyl, allyl, alkynyl, alkenyl, aryl, and heterocyclic.

4. The method for preparing CD437 according to claim 3, characterized in that, In S1, R in the molecular formula of compound A 2 When Me is α and R1 is H, compound A is adapalene.

5. The CD437 synthesis method according to claim 3, characterized in that, The compounds represented by compound A include their corresponding carboxylic esters, carboxylic salts, acyl chlorides, or carboxylic anhydrides.

6. The method for synthesizing CD437 according to claim 1, characterized in that, In S1, the base used under alkaline conditions is at least one of thiolates, thiophenolates, phenolates, or amines.

7. The method for preparing CD437 according to claim 1, characterized in that, In S1, the acid used in the acidic conditions is at least one of Lewis acid, protic acid, silicon reagent, a mixture of silicon reagent and alcohol, or a mixture of silicon reagent and thiol.

8. A method for preparing CD437 according to claim 1, 2, 6 or 7, characterized in that, In S1, the conversion reaction temperature is -10℃ to reflux temperature, and the conversion reaction time is 10h to 40h.

9. A method for preparing CD437 according to claim 1, 2, 6 or 7, characterized in that, In S2, the volume ratio of the water-miscible organic solvent to water is 2:1 to 1:4; the temperature during paddle mixing is room temperature to 70°C; and the paddle mixing time is 1.5h to 6h.

10. A method for preparing CD437 according to claim 9, characterized in that, In S2, the organic solvent miscible with water includes at least one of ethanol, methanol, acetone, acetonitrile, isopropanol, and n-propanol.

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