Synthesis method of tazobactam

Abstract

The invention discloses a method for synthesizing tazobactam, which comprises the following steps: taking sulbactam as a starting material, and carrying out one-step coupling reaction on sulbactam and 1R-1, 2, 3-triazole under the action of a palladium catalyst, a proline ligand, alkali, an oxidizing agent and a corresponding solvent to obtain the tazobactam. The synthesis method is high in yield, low in cost and environment-friendly, and the synthesis process of tazobactam is greatly simplified.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis and relates to a method for synthesizing tazobactam. Background Art

[0002] Tazobactam, with the chemical name of (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide, is an irreversible competitive β-lactamase inhibitor developed by Dainippon Pharmaceutical Co., Ltd. in Japan. It has strong inhibitory effects on penicillinase produced by Staphylococcus aureus, plasmid-mediated β-lactamase produced by Gram-negative bacilli, and chromosomally-mediated β-lactamase produced by bacteria such as Proteus, Bacteroides, and Klebsiella. Tazobactam is a third-generation antibacterial synergist. When combined with piperacillin or cefoperazone, it can enhance their drug efficacy and prolong the action time. When tazobactam is used in combination with sodium piperacillin, an obvious synergistic effect is produced. It is used to treat systemic and local infections, has a broad antibacterial spectrum and indications, and has great advantages in overcoming drug resistance. It is one of the most promising β-lactamase inhibitors.

[0003] The industrial synthesis route of tazobactam is shown in Synthetic Route 1. This route uses 6-APA as the starting material, and successively undergoes diazotization to introduce bromine, carboxyl protection, sulfur atom oxidation, and reduction with zinc powder to remove bromine to obtain Intermediate 4; then, after the high-temperature ring-opening of 2-mercaptobenzothiazole, bromination to close the ring, and introduction of triazole, Intermediate 7 is obtained; and then, through oxidation with potassium permanganate and decarboxylation to remove the carboxyl protecting group with m-cresol, tazobactam is obtained. This route is the most common commercial synthesis route of tazobactam reported at present, and has disadvantages such as a long synthesis route, many intermediates involved, complex operations, and high environmental protection pressure. Although the yield of each step is very high, the overall yield of the route to the final product is between 20% and 30%, and the overall yield is still relatively low.

[0004]

[0005] Patent CN102020663B discloses a method for synthesizing tazobactam. This method directly reacts the debrominated product with triazole protected by silane, and then obtains tazobactam through oxidation and deprotection (the synthetic route is shown in Route 2). This synthetic method has problems such as high raw material cost and harsh operations, and it is difficult to industrialize.

[0006]

[0007] Patent CN102643292B discloses a method for synthesizing tazobactam, specifically: 6,6-dihydropenicillane sulfoxide diphenylmethyl ester is subjected to thermal cracking, chloromethylation, azidation, potassium permanganate oxidation, acetylene cyclization, and deprotection under the action of m-cresol to obtain tazobactam (synthetic route three). This synthetic method has the disadvantages of a long synthetic route, involving many intermediates, and complicated operation.

[0008]

[0009] Comparing the chemical structures of tazobactam and sulbactam, it can be concluded that tazobactam only has one more triazole than sulbactam. However, the introduction of this triazole functional group using 6-APA as the starting material requires a series of reaction steps such as carboxyl protection, oxidation of sulfur atoms to sulfoxides, sulfoxide ring opening, bromination ring closure, triazole addition and deprotection, making the entire preparation process cumbersome and inefficient. If sulbactam is used as a raw material, the development of a production process for synthesizing tazobactam by introducing a triazole functional group in one step is of great practical significance.

[0010] Lu Ya et al. reported eight methods for synthesizing tazobactam (Lu Ya, Chen Hansong, Liang Gangfeng, et al. Illustrated Synthesis Route of Tazobactam [J]. Fine Chemical Intermediates, Issue 01, 2020). Among them, 2.2 disclosed that the sulbactam obtained in Route 8 was protected by esterification reaction with the carboxyl group of penicillin G (19) as the raw material to obtain compound 18, and compound 18 was diazotized and then attached to the 3-substitution position with a diazo group to obtain compound 11, and compound 11 was reacted with ethylene to generate triazole compound 12, and compound 12 was reacted with o-hydroxytoluene to obtain the target product tazobactam (Synthesis Route 4). This synthetic route is short and the raw materials are easy to obtain, but the metal catalyst and reaction conditions required for hydrogenolysis are harsh and not suitable for industrial production.

[0011] Summary of the invention

[0012] In view of the deficiencies of the above-mentioned prior art, the present invention provides a method for synthesizing tazobactam. In the present invention, sulbactam is used as a starting material, and a one-step coupling reaction is carried out with 1R-1,2,3-triazole under the action of a palladium catalyst, a proline ligand, a base, an oxidant and a corresponding solvent to obtain tazobactam. The synthesis method has high yield, low cost and is environmentally friendly, and greatly simplifies the synthesis process of tazobactam.

[0013] The technical scheme of the present invention is: a synthesis method of tazobactam, which is characterized in that sulbactam is used as a starting material, and a one-step coupling reaction is carried out with 1R-1,2,3-triazole under the joint action of a palladium catalyst, a proline ligand, an oxidant, a base and a corresponding solvent, and then tazobactam is obtained through post-treatment (quenching, extraction, palladium removal, liquid phase purification or crystallization process).

[0014] The reaction equation is as follows:

[0015]

[0016] According to the present invention, R is an atom or group connected to triazole, and can be a silane protecting group, a lithium atom, a sodium atom, a potassium atom or a cesium atom; the silane protecting group can be a trimethylsilyl group, a triethylsilyl group, a tri-n-propylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group or a triphenylsilyl group, and preferably a trimethylsilyl group is used as the group connected to triazole.

[0017] According to the present invention, the palladium catalyst can be one or a combination of palladium catalysts such as bis(acetonitrile)palladium(II) dichloride, palladium(II) bis(acetylacetonate), bis(benzonitrile)palladium(II) dichloride, bis(dibenzylideneacetone)palladium(0), allylpalladium(II) dichloride dimer, palladium(II) acetate, palladium(II) trifluoroacetate, palladium(II) dichloride, palladium(II) dibromide, palladium(II) tetrafluoroborate tetrakis(acetonitrile), tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, [1,2-bis(diphenylphosphino)ethane]palladium(II) dichloride, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct, bis(tricyclohexylphosphine)palladium(0), bis(triethylphosphine)palladium(II) dichloride, bis(triphenylphosphine)palladium(II) acetate, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium(0), bis[1,2-bis(diphenylphosphino)ethane]palladium(0), bis[tris(o-tolyl)phosphine]palladium(II) dichloride, dichloro-bis(tricyclohexylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0) and trans-benzyl(chloro)bis(triphenylphosphine)palladium(II), and preferably bis(acetonitrile)palladium(II) dichloride is used as the palladium catalyst for the reaction.

[0018] According to the present invention, the proline ligand is an L-proline derivative, where PG is the abbreviation of a protecting group and can be a phenyl group, a heteroaryl group, a heterocyclic group and a C1-C6 alkyl group; the phenyl group, heteroaryl group, heterocyclic group and C1-C6 alkyl group are optionally substituted by one or more of a halogen, a C1-C6 alkyl group and a C1-C6 alkoxy group; and the phenyl group and heteroaryl group are optionally further substituted by a fused C3-C6 cycloalkyl group or a C3-C6 heterocyclic group; it can also be an acetyl group, a propionyl group, a trifluoroacetyl group, a pivaloyl group, a benzoyl group, a benzoyl group and a substituted benzoyl group; it can also be a tert-butoxycarbonyl group, a fluorenylmethoxycarbonyl group, an allyloxycarbonyl group, a trimethylsilylethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group and a substituted benzyloxycarbonyl group, and preferably an acetoxy group or a tert-butoxycarbonyl group.

[0019] According to the present invention, the oxidant used in the reaction is one or a combination of oxidants such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, cumene hydroperoxide, tert-butyl hydroperoxide, lauroyl peroxide, benzoyl peroxide, di-tert-butyl peroxide, tert-butyl perbenzoate, tert-butyl peracetate, 2,2,6,6-tetramethylpiperidine-N-oxyl radical, iodobenzene diacetate, [bis(trifluoroacetoxy)iodo]benzene, [bis(tert-butylcarbonyloxy)iodo]benzene, N-fluorobis(phenylsulfonamide), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), ammonium persulfate, sodium persulfate, potassium persulfate, potassium monopersulfate, silver carbonate, and copper acetate, etc., and preferably tert-butyl hydroperoxide.

[0020] According to the present invention, the base used in the reaction can be an inorganic base such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, cesium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, cesium acetate, sodium trifluoroacetate, potassium trifluoroacetate, or an organic base such as trimethylamine, triethylamine, tetramethylguanidine, dimethylamine, diethylamine, pyridine, piperidine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), proton (1,8-bis(dimethylamino)naphthalene), or a composition of one or more bases, and preferably cesium carbonate.

[0021] According to the present invention, the reaction temperature range is 0 to 120 °C, preferably 40 to 80 °C, and more preferably 60 °C.

[0022] According to the present invention, the solvent used in the reaction is a composition of one or more solvents such as dichloromethane, 1,2-dichloroethane, ethyl acetate, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, methyl tert-butyl ether, toluene, isopropanol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, hexafluoroisopropanol, and tert-butanol, and preferably hexafluoroisopropanol.

[0023] According to the present invention, the molar ratio of sulbactam, triazole, proline ligand, palladium catalyst, oxidant, and base is 1:1.4 - 1.6:0.05 - 0.2:0.01 - 0.1:0.5 - 2.5:1.0 - 1.5, and preferably 1:1.5:0.1:0.05:1.5:1.2.

[0024] Technical features and beneficial effects of the present invention:

[0025] 1. Using commercial sulbactam as the starting material, both the supplier and the raw material quality can be effectively guaranteed;

[0026] 2. Adopting a more direct and effective C-H activation reaction mode to introduce triazole in one step, avoiding cumbersome synthesis and post-treatment operation procedures;

[0027] 3. The reaction operation process and post-treatment of this scheme adopt crystallization or liquid-phase purification and separation processes, which are simple in operation, high in yield, low in cost, without dangerous operations, environmentally friendly in process, with less generation of three wastes, and convenient for industrial production. Description of the Drawings

[0028] Figure 1 It is the liquid-phase spectrum of tazobactam obtained in Example 2. Detailed Embodiments

[0029] The present invention is further described by the following examples, which do not limit the present invention in any way. Any modification or change that is easily achieved by those of ordinary skill in the art to the present invention will fall within the scope of the present invention.

[0030] Example 1: Synthesis of tazobactam by reacting sulbactam acid with 1-trimethylsilyl-1H-1,2,3-triazole (liquid-phase purification and separation process)

[0031]

[0032] Under nitrogen protection, 40.00 g of sulbactam, 36.33 g of 1-trimethylsilyl-1H-1,2,3-triazole (1.5 eq.), 2.20 g of Pd(CH3CN)2Cl2 (5 mol%), 2.61 g of L-proline ligand (10 mol%), 67.02 g of cesium carbonate (1.2 eq.) and 400 ml of hexafluoroisopropanol (10 Vol.) were added to a reaction flask with magnetic stirring. After replacing the nitrogen system three times, 52 ml of a decane solution of tert-butyl hydroperoxide (concentration 5 mol / L, 1.5 eq.) was added dropwise to the reaction system using a syringe, which took about 30 min. After the addition was completed, the reaction system was heated to 55 - 65 °C and stirred for 12 h.

[0033] Cool the reaction solution to 0 - 5°C, add 400 ml of dichloromethane; control the temperature at 0 - 5°C, and dropwise add 400 ml of 5% (w / w) sodium thiosulfate solution. After the addition is complete, stir at 0 - 5°C for 25 - 30 min until the starch potassium iodide test paper no longer shows color. Let it stand for liquid separation, and wash the aqueous phase with 400 ml of dichloromethane. Separate it out, add 400 ml of dichloromethane to the AP phase, adjust the pH to 1.0 - 1.5 with 5% hydrochloric acid, stir for 15 min, and then let it stand for layer separation. Store the OP phase at 0 - 5°C, add 400 ml of dichloromethane to the AP phase for back extraction, let it stand for layer separation, combine the two OP phases, concentrate at 20 - 25°C, and purify the residual liquid by preparative liquid chromatography to collect 30.85 g of tazobactam, with a yield of 59.9% and a purity of 99.4%.

[0034] Example 2: Synthesis of tazobactam (crystallization process) by the reaction of sulbactam acid with 1 - trimethylsilyl - 1H - 1,2,3 - triazole

[0035]

[0036] Under nitrogen protection, add 40.00 g of sulbactam, 36.33 g of 1 - trimethylsilyl - 1H - 1,2,3 - triazole (1.5 eq.), 2.20 g of Pd(CH3CN)2Cl2 (5 mol%), 2.61 g of L - proline ligand (10 mol%), 67.02 g of cesium carbonate (1.2 eq.) and 400 ml of hexafluoroisopropanol (10 Vol.) into a reaction flask equipped with magnetic stirring. After replacing the nitrogen system three times, use a syringe to dropwise add 52 ml of a decane solution of tert - butyl hydroperoxide (concentration 5 mol / L, 1.5 eq.) to the reaction system, which takes about 30 min. After the addition is complete, heat the reaction system to 55 - 65°C and stir for 12 h.

[0037] Cool the reaction solution to 0 - 5 °C, add 400 ml of dichloromethane; control the temperature at 0 - 5 °C, and dropwise add 400 ml of 5% (w / w) sodium thiosulfate solution. After the addition is complete, stir at 0 - 5 °C for 25 - 30 min until the starch potassium iodide test paper no longer shows color. Let it stand for liquid separation, and wash the aqueous phase with 400 ml of dichloromethane. Separate it out, add 1.0 g of isopropyl xanthate potassium salt to the aqueous phase, stir at 0 - 5 °C for 30 min, and filter the insoluble substances. Add 1.0 g of isopropyl xanthate potassium salt to the aqueous phase, stir at 0 - 5 °C for 30 min, and filter to remove the insoluble substances. Add 2.0 g of activated carbon to the aqueous phase, stir at 0 - 5 °C for 15 - 20 min, filter, and wash the filter cake with 60 ml of purified water. Cool the aqueous phase to 0 - 5 °C, dropwise add 5% hydrochloric acid to adjust the pH to 4.0, add 0.4 g of tazobactam seed crystal, and stir at 0 - 5 °C for 30 min. Then adjust the pH to 1.0 - 1.5 with 5% hydrochloric acid, carry out crystal cultivation for 2 h, filter, wash the filter cake with 120 ml of purified water, take out the solid, control the temperature at 30 - 35 °C and dry until the water content ≤ 0.1%, collect the material to obtain 31.98 g of tazobactam product, yield: 62.1%, purity ≥ 99.5% (the liquid chromatogram is as Figure 1 shown). The isomer impurity ≤ 0.05%, the palladium residue ≤ 0.1 ppm, meeting the pharmaceutical standard.

[0038] Comparative Example 1: Synthesis of tazobactam and its isomers (liquid phase purification and separation process) by reacting sulbactam acid with 1H - 1,2,3 - triazole

[0039]

[0040] Under nitrogen protection, add 2.00 g of sulbactam acid, 0.89 g of 1H - 1,2,3 - triazole (1.5 eq.), 0.11 g of Pd(CH3CN)2Cl2 (5 mol%), 0.13 g of L - proline ligand (10 mol%), 3.35 g of cesium carbonate (1.2 eq.) and 20 ml of hexafluoroisopropanol (10 Vol.) into a reaction flask with magnetic stirring. After replacing the nitrogen system three times, use a syringe to dropwise add 2.6 ml of a decane solution of tert - butyl hydroperoxide (concentration 5 mol / L, 1.5 eq.) to the reaction system, which takes about 30 min. After the addition is complete, heat the reaction system to 55 - 65 °C and stir the reaction for 12 h. Detect the formation of tazobactam and tazobactam isomer impurities in the reaction by HPLC, and the molar ratio of their formation is 3:1.

[0041] Cool the reaction solution to 0 - 5 °C, add 20 ml of dichloromethane; control the temperature at 0 - 5 °C, and dropwise add 20 ml of 5% (w / w) sodium thiosulfate solution. After the addition is complete, stir at 0 - 5 °C for 10 - 15 min until the starch potassium iodide test paper no longer shows color. Separate the layers, wash the aqueous phase with 20 ml of dichloromethane. Separate out, add 20 ml of dichloromethane to the aqueous phase, adjust the pH to 1.0 - 1.5 with 5% hydrochloric acid, stir for 15 min, and then let it stand for phase separation. Store the organic phase at 0 - 5 °C, back-extract the aqueous phase with 20 ml of dichloromethane, let it stand for phase separation, combine the two organic phases, concentrate at 20 - 25 °C, and purify the residue by preparative liquid chromatography to collect 0.93 g of tazobactam, yield: 36.1%, purity ≥ 99.0%. Collect 0.24 g of tazobactam isomer impurity, yield: 9.2%, purity ≥ 98.5%.

[0042] Judging from the yields of Examples 1 - 2 and Comparative Example 1, the triazole in Comparative Example 1 was not protected, and both the reaction activity and site selectivity were worse than those of the triazole protected with trimethylsilyl, with the formation of isomer impurities and a low yield.

Claims

1. A method for synthesizing tazobactam, characterized in that, Using sulbactam as the starting material, it undergoes a one-step coupling reaction with 1R-1,2,3-triazole under the combined action of a palladium-based catalyst, a proline ligand, an oxidant, a base, and a corresponding solvent, and then aztreonam is obtained through post-treatment; the R is any one of a silyl protecting group, a lithium atom, a sodium atom, a potassium atom, or a cesium atom; the proline ligand is an L-proline derivative with a nitrogen protecting group PG.

2. The synthetic method of tazobactam according to claim 1, characterized in that, The silyl protecting group is any one of trimethylsilyl, triethylsilyl, tri-n-propylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triphenylsilyl.

3. A method for synthesizing tazobactam according to claim 1, characterized in that, The palladium catalyst is one or a combination of palladium catalysts such as bis(acetonitrile)dichloropalladium(II), bis(acetylacetonato)palladium(II), bis(benzonitrile)dichloropalladium(II), bis(dibenzylideneacetone)palladium(0), allyldichloropalladium(II) dimer, palladium(II) acetate, palladium(II) trifluoroacetate, palladium(II) dichloride, palladium(II) dibromide, tetrakis(acetonitrile)palladium(II) tetrafluoroborate, tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane adduct, bis(tricyclohexylphosphine)palladium(0), bis(triethylphosphine)dichloropalladium(II), bis(triphenylphosphine)palladium(II) acetate, bis(triphenylphosphine)dichloropalladium(II), bis(tri-tert-butylphosphine)palladium(0), bis[1,2]-bis(diphenylphosphino)ethane]palladium(0), bis[tris(o-tolyl)phosphine]dichloropalladium(II), dichlorobis(tricyclohexylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), and trans-benzyl(chloro)bis(triphenylphosphine)palladium(II).

4. The synthetic method of tazobactam as described in claim 1, characterized in that, The PG is one or more of phenyl, heteroaryl, heterocyclic group, C1-C6 alkyl, and C1-C6 alkoxy.

5. The synthesis method of tazobactam as claimed in claim 4, characterized in that, The phenyl and heteroaryl are substituted by one or more of fused C3-C6 cycloalkyl, C3-C6 heterocyclic group, acetyl, propionyl, trifluoroacetyl, pivaloyl, benzoyl, benzoyl, substituted benzoyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, and substituted benzyloxycarbonyl.

6. The synthetic method of tazobactam as described in claim 1, characterized in that, The oxidant is one or a combination of oxidants such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, cumene hydroperoxide, tert-butyl hydroperoxide, lauroyl peroxide, benzoyl peroxide, di-tert-butyl peroxide, tert-butyl perbenzoate, tert-butyl peracetate, 2,2,6,6-tetramethylpiperidine-N-oxyl radical, iodobenzene diacetate, [bis(trifluoroacetoxy)iodo]benzene, [bis(tert-butylcarbonyloxy)iodo]benzene, N-fluorodibenzenesulfonamide, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), ammonium persulfate, sodium persulfate, potassium persulfate, potassium monopersulfate, silver carbonate, and copper acetate.

7. The synthesis method of tazobactam according to claim 1, characterized in that, The base is an inorganic base or an organic base; The inorganic base is any one of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, cesium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, cesium acetate, sodium trifluoroacetate, potassium trifluoroacetate; The organic base is one or a combination of bases such as trimethylamine, triethylamine, tetramethylguanidine, dimethylamine, diethylamine, pyridine, piperidine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-bis(dimethylamino)naphthalene.

8. The synthetic method of tazobactam according to claim 1, characterized in that, The reaction temperature is 40 to 80 °C.

9. A method for synthesizing tazobactam according to any one of claims 1-8, characterized in that, The solvent is one or a combination of solvents such as dichloromethane, 1,2-dichloroethane, ethyl acetate, chlorobenzene, acetonitrile, 1,4-dioxane, tetrahydrofuran, methyl tert-butyl ether, toluene, isopropanol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, hexafluoroisopropanol, and tert-butanol.

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