CN114539123A - Method for synthesizing TMC-205 in one step - Google Patents

Abstract

The invention belongs to the technical field of chemical synthesis, and discloses a method for synthesizing TMC-205 in one step, which comprises the following steps: sequentially adding 6-bromoindole-3-formic acid, palladium acetate, tri (o-methylphenyl) phosphorus, 2, 6-di-tert-butyl-4-methylphenol, N-dimethylformamide, tri-N-propylamine and 1, 1-dimethylallyl alcohol into a sealed tube under the protection of nitrogen by magnetic stirring; sealing the sealed tube, placing the sealed tube in an oil bath for reaction, cooling the reaction mixture to room temperature, filtering a reaction crude product through a silica gel short column, and washing the reaction crude product with ethyl acetate; the filtrate was diluted with ethyl acetate and washed with water and brine; the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, and the mixture was purified by flash column chromatography as eluent petroleum ether, ethyl acetate to obtain the title compound. The method has the advantages of simple synthesis process, simple and convenient operation, easily obtained synthesis raw materials, lower preparation cost and improvement of the total yield of the reaction and the atom economy of the reaction.

Description

A method for one-step synthesis of TMC-205

technical field

The invention belongs to the technical field of chemical synthesis, in particular to a method for synthesizing TMC-205 in one step.

Background technique

In 2001, TMC-205 was isolated from the secondary metabolites of an unidentified fungal strain TC1630 by Japanese scientists Masaaki Sakurai et al. Antiproliferative activity and also activates the SV40 promoter. Kazunori Koide's group first completed the total synthesis of TMC-205 in 2014. The synthetic route is shown in Figure 3.

In this synthetic route, Kazunori Koide's research group used 6-bromoindole as the starting material, and trifluoroacetic anhydride was acylated with trifluoroacetic anhydride to introduce a trifluoroacetyl group at the 3-position of the indole ring to obtain compound 2; Sodium is hydrolyzed, and after neutralization with hydrochloric acid, the trifluoroacetyl group at position 3 is converted into a carboxyl group to obtain compound 3; then (trimethylsilane) diazomethane TMSCHN ₂ is reacted with the carboxyl group to generate a carboxylate to obtain compound 4; compound 4 is at zero Under the action of palladium complex and base, 6-bromoindole-3 carboxylate and isoprenyl boronate are introduced into isoprene group at the 6-position of indole ring through Suzuki-Miyaura coupling reaction to obtain compound 5; Finally, TMC-205 is obtained under the action of sodium hydroxide hydrolysis and potassium hydrogen sulfate neutralization. (Five-step reaction, overall yield 64%). This method requires independent preparation of the isoprene moiety and involves multiple steps to finally build the 3-carboxy group (see Figure 4).

The original idea of Kazunori Koide's group was to use 6-bromoindole as the starting material, and to introduce a trifluoroacetyl group at the 3-position of the indole ring through Friedel-Crafts acylation with trifluoroacetic anhydride; the second step was carried out with sodium hydroxide. After hydrolysis, the trifluoroacetyl group at position 3 was converted into a carboxyl group after neutralization with hydrochloric acid, and then the target product was obtained by Suzuki-Miyaura coupling with a carboxylic acid substrate and isopentenyl boronate ester, but it was unsuccessful (see Figure 5). .

After the failure of synthetic route 2, Kazunori Koide's group tried to synthesize the target product by Stille coupling of carboxylic acid substrate and isopentenyl organotin compound, but the yield was only 10%. Looking at the three routes, only the first route (the longest route) was successful, but this method required independent preparation of the isoprene moiety and involved multiple steps to finally build the 3-carboxy group.

The above three synthetic routes by using Friedel-Crafts acylation, esterification (using TMSCHN ₂ ) and Suzuki-Miyaura coupling as key steps, TMC-205 was obtained in 64% overall yield through 5-step reaction (see Figure 6) . In addition, the first route also has inherent limitations, such as demanding reaction conditions (strong acids and bases, etc.) and expensive and toxic reagents (Pd(PPh ₃ ) ₄ , Cs ₂ CO ₃ , etc.). Therefore, previous synthetic methods are complex and not universal for other similar substrates. In order to better test its biological activity, it is urgent to develop a simple and efficient synthetic route.

Through the above analysis, the existing problems and defects in the prior art are: the existing route requires harsh reaction conditions and the use of expensive and toxic reagents (Pd(PPh ₃ ) ₄ , Cs ₂ CO ₃ , etc.), etc., the steps are cumbersome, and the total Low yields, poor atom economy, and the drawbacks of Pinnick-oxidation reactions in industrial production.

The difficulty of solving the above problems and defects is as follows:

1. How to make the Heck reaction take place in the presence of an acidic group in high yield.

2. How to complete the coupling and elimination of the Heck reaction in one step in a green, economical and efficient manner.

The significance of solving the above problems and defects is:

In the presence of an acidic group, a reaction involving a base without a protective group is realized.

The use of toxic reagents and the defects of Pinnick-oxidation reaction in industrial production are avoided, and a green, cost-effective reaction in synthesis is realized.

SUMMARY OF THE INVENTION

Aiming at the problems existing in the prior art, the present invention provides a method for synthesizing TMC-205 in one step.

The present invention is achieved by a method for synthesizing TMC-205 in one step, wherein the method for synthesizing TMC-205 in one step is composed of Alcohol 2 undergoes a Heck reaction with the participation of palladium catalyst and removes the tertiary hydroxyl group to obtain TMC-205 in a yield of 75%.

Further, the synthetic route of described TMC-205 is:

Further, the method for the one-step synthesis of TMC-205 comprises the following steps:

Step 1, under magnetic stirring and nitrogen protection, put 6-bromoindole-3-carboxylic acid, palladium acetate, tris(o-methylphenyl)phosphorus, 2,6-di-tert-butyl-4-methyl in sequence into a sealed tube phenol, N,N-dimethylformamide, tri-n-propylamine and 1,1-dimethylallyl alcohol;

Step 2, sealing the tube and placing it in an oil bath for reaction, cooling the reaction mixture to room temperature, filtering the crude reaction product through a short column of silica gel, and washing with ethyl acetate;

Step 3, the filtrate is diluted with ethyl acetate and washed with water and brine;

In step 4, the combined organic layers are dried over anhydrous sodium sulfate and concentrated in vacuo, and the mixture is purified by flash column chromatography. The eluents are petroleum ether and ethyl acetate to obtain the target compound.

Further, the 6-bromoindole-3-carboxylic acid in the step 1 was 0.208 mmol, the palladium acetate was 0.0208 mmol, the tris(o-methylphenyl) phosphorus was 0.052 mmol, and the 2,6- Di-tert-butyl-4-methylphenol is 0.0208 mmol, the N,N-dimethylformamide is 1.1 mL, the tri-n-propylamine is 0.166 mmol, the 1,1-dimethylallyl alcohol is is 0.936 mmol.

Further, the solvent in the step 1 can be replaced with N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, toluene, benzene, 1,2-dichloroethane, chlorobenzene, Either acetonitrile or N-methylpyrrolidone.

The palladium acetate catalyst can be replaced with palladium chloride, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium-chloroform adduct, tris(dibenzylideneacetone)dipalladium, palladium carbon, tetrakis Any one of triphenylphosphine palladium chloride, trifluoroacetate palladium or palladium chloride.

The tris(o-methylphenyl)phosphorus can be replaced by triphenylphosphine, trimethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tricyclohexylphosphine fluoroborate, tri-n-butylphosphine, Any one of 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, bis(2-diphenylphosphonyl) ether or tris(2-furyl) phosphine or no addition Phosphorus ligand.

The acid binding agent tri-n-propylamine can be replaced by triethylamine, N,N-diisopropylethylamine, tri-n-octylamine, 1,8-diazabicycloundec-7-ene, tetrabutylamine ammonium chloride, tetrabutylammonium bromide, triethylenediamine, potassium acetate, sodium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium monohydrogen phosphate, diphosphate Any one of sodium hydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate or calcium phosphate or no alkali is added.

The polymerization inhibitor 2,6-di-tert-butyl-4-methylphenol can be replaced by 2,4-dimethyl-6-tert-butylphenol, p-tert-butylcatechol, N,N-diethyl Hydroxylamine, phenothiazine, tris(N-nitroso-N-phenylhydroxylamine) aluminum, 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy radical, 4-carbonyl-2, 2,6,6-Tetramethylpiperidinyloxy, tris(4-oxo-2,2,6,6-tetramethylpiperidinyloxy)phosphine or 1,1-diphenyl-2 -Any one of the picrohydrazino radicals.

Further, in the second step, the temperature of the oil bath is 115° C., and the reaction time of the oil bath is 6 hours.

Further, the ethyl acetate in the step 3 was 10 mL.

Further, the volume ratio of petroleum ether and ethyl acetate in the step 4 is 2:1.

Further, the target compound in the fourth step was 35.45 mg, and the yield was 75%.

Further, the experimental temperature of the method for synthesizing TMC-205 is between 95°C and 125°C.

Combined with all the above-mentioned technical solutions, the advantages and positive effects of the present invention are as follows: the method for one-step synthesis of TMC-205 provided by the present invention has the advantages of simple synthesis process, simple and convenient operation, readily available synthesis raw materials, low preparation cost and high yield. , the atom economy is good, the overall yield of the reaction and the atom economy of the reaction are improved, and the defects of the Pinnick-oxidation reaction in industrial production are avoided at the same time.

Description of drawings

In order to explain the technical solutions of the embodiments of the present invention more clearly, the following will briefly introduce the drawings that need to be used in the embodiments of the present invention. Obviously, the drawings described below are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can also be obtained from these drawings without creative effort.

1 is a flow chart of a method for one-step synthesis of TMC-205 provided in the embodiment of the present invention.

Fig. 2 is the synthetic route diagram of TMC-205 provided in the embodiment of the present invention.

3 is a schematic diagram of the TMC-205 synthesis route 1 of Kazunori Koide provided in the embodiment of the present invention.

4 is a schematic diagram of the TMC-205 synthesis route 2 of Kazunori Koide provided in the embodiment of the present invention.

5 is a schematic diagram of the TMC-205 synthesis route 3 of Kazunori Koide provided in the embodiment of the present invention.

6 is a schematic diagram of the TMC-205 synthesis route 4 of Kazunori Koide provided in the embodiment of the present invention.

Detailed ways

In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention, but not to limit the present invention.

In view of the problems existing in the prior art, the present invention provides a method for synthesizing TMC-205 in one step. The present invention will be described in detail below with reference to the accompanying drawings.

As shown in Figure 1, the method for one-step synthesis of TMC-205 provided in the embodiment of the present invention comprises the following steps:

S101, 6-bromoindole-3-carboxylic acid, palladium acetate, tris(o-methylphenyl)phosphorus, 2,6-di-tert-butyl-4-methyl are sequentially put into a sealed tube under magnetic stirring and nitrogen protection Phenol, N,N-dimethylformamide, tri-n-propylamine and 1,1-dimethylallyl alcohol;

S102, sealing the tube and placing it in an oil bath to react, cooling the reaction mixture to room temperature, filtering the crude reaction product through a short column of silica gel, and washing with ethyl acetate;

S103, the filtrate is diluted with ethyl acetate and washed with water and brine;

S104, the combined organic layers are dried over anhydrous sodium sulfate and concentrated in vacuo, and the mixture is purified by flash column chromatography. The eluent is petroleum ether and ethyl acetate to obtain the target compound.

The technical solutions of the present invention will be further described below with reference to specific embodiments.

According to the limitations of the three synthetic routes of Kazunori Koide's research group, the research group of the present invention developed a synthetic route with low preparation cost, high yield and good atom economy based on some problems in previous researches.

In this synthetic route, cheap 6-bromoindole-3-carbaldehyde 1 and 2-methyl-3-buten-2-ol 2 undergo Heck reaction under the participation of palladium catalyst, and the tertiary hydroxyl group is removed with a yield of 94%. Compound 3 was obtained. Compound 3 was oxidized to the carboxyl group by Pinnick-oxidation to obtain TMC-205 in 78% yield. The whole synthesis step went through 2 steps, and the total yield was 73.32%. This route avoids the use of toxic reagents (Pd(PPh ₃ ) ₄ , Cs ₂ CO ₃ , etc.), dangerous strong base reagents, highly flammable reagents, etc. The synthesis process is simple, the operation is simple and the synthesis raw materials are readily available, etc., but there are still There are certain limitations, such as the by-product hypochlorous acid during the Pinnick-oxidation reaction, which is not suitable for industrial large-scale production because hypochlorous acid is sensitive to metals during the production process. Therefore, the synthetic route needs to be further optimized.

As shown in Figure 2, the synthetic route of the present invention takes 6-bromoindole-3-carboxylic acid 5 and 2-methyl-3-buten-2-ol 2 to undergo a Heck reaction under the participation of a palladium catalyst and remove the tertiary hydroxyl group to TMC-205 was obtained in 75% yield. The target compound TMC-205 is obtained by only one step of reaction in the whole synthesis step. In the early stage, Kazunori Koide's research group also tried to synthesize the target product with a carboxylic acid substrate and an isopentenyl organotin compound through Stille coupling, but the yield was only 10%, and the route of the present invention also started from a carboxylic acid substrate. The Heck reaction was realized under the protective group and the tertiary hydroxyl group was removed to obtain the target compound in medium and high yield, and some problems encountered in the previous exploration of this route by the research group of the present invention were avoided, for example, the Pinnick-oxidation reaction was avoided in industrial production. defects in. In addition, it has the advantages of simple synthesis process, simple operation and easy availability of synthetic raw materials.

Technical problems to be solved by the present invention: 1. Avoid Pinnick-oxidation reaction. 2. Improve the overall yield of the reaction. 3. Improve the atom economy of the reaction.

The method for one-step synthesis of TMC-205 provided in the embodiment of the present invention specifically includes the following steps:

Under magnetic stirring and nitrogen protection, 50 mg (0.208 mmol) of 6-bromoindole-3-carboxylic acid (5), 4.67 mg (0.0208 mmol) of palladium acetate, and 15.8 mg of tris(o-methylphenyl) phosphorus were successively put into a sealed tube. mg (0.052 mmol), 4.6 mg (0.0208 mmol) of 2,6-di-tert-butyl-4-methylphenol, 1.1 mL of N,N-dimethylformamide, 31 μL of tri-n-propylamine (0.166 mmol), 1, 1-Dimethallyl alcohol 97.8 μL (0.936 mmol). Then the tube was sealed and placed in an oil bath at 115° C. to react for about 6 hours, the reaction mixture was cooled to room temperature, and the crude reaction product was filtered through a short column of silica gel and washed with 10 mL of ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, and the mixture was purified by flash column chromatography. The eluents were petroleum ether, ethyl acetate (volume ratio 2:1) to obtain the title compound 35.45 mg (yield 75%) .

Target Compound 4 Features:

Yellow solid. ¹ H NMR (400MHz, Acetone-d ₆ )δ10.98(s,1H),8.19-7.96(m,2H),7.61(s,1H),7.44(dd,J=8.4,1.4Hz, 1H), 7.00 (d, J=16.1Hz, 1H), 6.72 (d, J=16.1Hz, 1H), 5.16–5.01 (m, 2H), 2.00–1.93 (m, 3H). ¹³ C NMR (101MHz) ,Acetone)δ382.72,319.58,314.57,310.10,309.60,307.34,306.95,303.50,298.36,297.33,293.32,287.67,285.19,206.84,206.64,206.45,206.26,206.07,205.87,205.68,195.19.

The existing route has certain limitations, such as the use of harsh reaction conditions (strong acid and alkali, etc.) and expensive and toxic reagents (Pd(PPh ₃ ) ₄ , Cs ₂ CO ₃ , etc.) Low rate, poor atom economy, and the defects of Pinnick-oxidation reaction in industrial production.

The route of the invention has the advantages of simple synthesis process, simple operation, readily available synthesis raw materials, low preparation cost, high yield and good atom economy, and avoids the defects of Pinnick-oxidation reaction in industrial production.

The alternative of the present invention is as follows:

1. the solvent used in the steps of the present invention can be replaced by N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, toluene, benzene, 1,2-dichloroethane, chlorobenzene, Acetonitrile, N-methylpyrrolidone.

2. The palladium acetate catalyst used in step 1 of the present invention can be replaced with palladium chloride, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone) dipalladium-chloroform adduct, tris(dibenzylideneacetone) two Palladium, palladium carbon, tetrakistriphenylphosphine palladium chloride, palladium trifluoroacetate, palladium chloride.

3. Tris(o-methylphenyl) phosphorus used in the steps of the present invention can be replaced by triphenylphosphine, trimethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tricyclohexylphosphine fluoroborate, tricyclohexylphosphine n-Butylphosphorus, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, bis(2-diphenylphosphoranyl) ether, tris(2-furyl)phosphine or no addition Phosphorus ligand.

4. The acid binding agent tri-n-propylamine used in the steps of the present invention can be replaced by triethylamine, N,N-diisopropylethylamine, tri-n-octylamine, 1,8-diazabicycloundec-7 -ene, tetrabutylammonium chloride, tetrabutylammonium bromide, triethylenediamine, potassium acetate, sodium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, monophosphate Sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate, calcium phosphate or no alkali added.

5. The polymerization inhibitor 2,6-di-tert-butyl-4-methylphenol used in the steps of the present invention can be replaced by 2,4-dimethyl-6-tert-butylphenol, p-tert-butylcatechol, N , N-diethylhydroxylamine, phenothiazine, tris(N-nitroso-N-phenylhydroxylamine) aluminum, 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy radical, 4 -Carbonyl-2,2,6,6-tetramethylpiperidinyloxy radical, tris(4-oxo-2,2,6,6-tetramethylpiperidinyloxy radical)ylphosphine, 1,1- Diphenyl-2-picrohydrazino radical.

6. The experimental temperature used in the steps of the present invention is between 95°C and 125°C.

The above are only specific embodiments of the present invention, but the protection scope of the present invention is not limited to this, any person skilled in the art is within the technical scope disclosed by the present invention, and all within the spirit and principle of the present invention Any modifications, equivalent replacements and improvements made within the scope of the present invention should be included within the protection scope of the present invention.

Claims (10)

1. a method for synthesizing TMC-205 in one step, is characterized in that, the method for synthesizing TMC-205 in one step is with 6-bromoindole-3-carboxylic acid 5 and 2-methyl-3-butene-2-ol 2 The Heck reaction takes place in the presence of a palladium catalyst and the tertiary hydroxyl group is removed to obtain TMC-205 in a yield of 75%. 2. the method for one-step synthesis of TMC-205 as claimed in claim 1, is characterized in that, the synthetic route of described TMC-205 is:

3. the method for one-step synthesis of TMC-205 as claimed in claim 1, is characterized in that, the method for described one-step synthesis of TMC-205 comprises the following steps: Step 1, under magnetic stirring and nitrogen protection, put 6-bromoindole-3-carboxylic acid, palladium acetate, tris(o-methylphenyl)phosphorus, 2,6-di-tert-butyl-4-methyl in sequence into a sealed tube phenol, N,N-dimethylformamide, tri-n-propylamine and 1,1-dimethylallyl alcohol; Step 2, sealing the tube and placing it in an oil bath for reaction, cooling the reaction mixture to room temperature, filtering the crude reaction product through a short column of silica gel, and washing with ethyl acetate; Step 3, the filtrate is diluted with ethyl acetate and washed with water and brine; In step 4, the combined organic layers are dried over anhydrous sodium sulfate and concentrated in vacuo, and the mixture is purified by flash column chromatography. The eluents are petroleum ether and ethyl acetate to obtain the target compound. 4. the method for one-step synthesis TMC-205 as claimed in claim 3, is characterized in that, the 6-bromoindole-3-carboxylic acid in described step one is 0.208mmol, and described palladium acetate is 0.0208mmol, and described three (o-methylphenyl) phosphorus is 0.052 mmol, the 2,6-di-tert-butyl-4-methylphenol is 0.0208 mmol, the N,N-dimethylformamide is 1.1 mL, the tri- The n-propylamine was 0.166 mmol, and the 1,1-dimethylallyl alcohol was 0.936 mmol. 5. the method for one-step synthesis of TMC-205 as claimed in claim 3, is characterized in that, the solvent in described step 1 can be replaced with N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane , any one of toluene, benzene, 1,2-dichloroethane, chlorobenzene, acetonitrile or N-methylpyrrolidone; The palladium acetate catalyst can be replaced with palladium chloride, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium-chloroform adduct, tris(dibenzylideneacetone)dipalladium, palladium carbon, tetrakis Any one in triphenylphosphine palladium chloride, palladium trifluoroacetate or palladium chloride; The tris(o-methylphenyl)phosphorus can be replaced by triphenylphosphine, trimethylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tricyclohexylphosphine fluoroborate, tri-n-butylphosphine, Any one of 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, bis(2-diphenylphosphonyl) ether or tris(2-furyl) phosphine or no addition phosphorus ligand; The acid binding agent tri-n-propylamine can be replaced by triethylamine, N,N-diisopropylethylamine, tri-n-octylamine, 1,8-diazabicycloundec-7-ene, tetrabutylamine ammonium chloride, tetrabutylammonium bromide, triethylenediamine, potassium acetate, sodium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium monohydrogen phosphate, diphosphate Any one of sodium hydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate or calcium phosphate or no alkali is added; The polymerization inhibitor 2,6-di-tert-butyl-4-methylphenol can be replaced by 2,4-dimethyl-6-tert-butylphenol, p-tert-butylcatechol, N,N-diethyl Hydroxylamine, phenothiazine, tris(N-nitroso-N-phenylhydroxylamine) aluminum, 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy radical, 4-carbonyl-2, 2,6,6-Tetramethylpiperidinyloxy, tris(4-oxo-2,2,6,6-tetramethylpiperidinyloxy)phosphine or 1,1-diphenyl-2 -Any one of the picrohydrazino radicals. 6. The method for synthesizing TMC-205 in one step as claimed in claim 3, wherein the temperature of the oil bath in the second step is 115°C, and the reaction time of the oil bath is 6h. 7. the method for one-step synthesis of TMC-205 as claimed in claim 3, is characterized in that, the ethyl acetate in described step 3 is 10mL. 8. the method for one-step synthesis TMC-205 as claimed in claim 3, is characterized in that, the volume ratio of the sherwood oil in described step 4, ethyl acetate is 2:1. 9. The method for one-step synthesis of TMC-205 according to claim 3, wherein the target compound in the fourth step is 35.45 mg, and the yield is 75%. 10 . The method for synthesizing TMC-205 in one step according to claim 3 , wherein the experimental temperature of the method for synthesizing TMC-205 is between 95° C. and 125° C. 11 .

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