* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 8 % Pd/C; hydrogen In methanol at 55 - 65℃; Autoclave
In a 1 L autoclave,(S) -indoline-2-carboxylic acid (0.3 mol, 49.0 g) and methanol (600 mL)Then, 4.9 g of 8percent wet palladium carbon wetted with methanol was added,Mechanical agitation. Through the nitrogen replacement air 3 times,And then hydrogen gas replacement nitrogen 3 times,Replace the kettle when the pressure is 0.5Mpa. after finishing,Continue to hydrogen to 5.0Mpa, set the heating temperature at 60 ,Maintaining the temperature of the reaction system at 55 to 65 ° C,TLC (developing solvent: chloroform: methanol: triethylamine = 6: 4: 1, ninhydrin)Tracking to the raw point of the reaction is complete. The hydrogen was vented and the hydrogen was replaced with nitrogen three times.Discharge, filter, take the filtrate under reduced pressure,A crude solid was obtained as a white solid. Finally, recrystallization from ethanol,A white solid was obtained in 37.3 g yield, 73.5percent yield,Purity 98.6percent (HPLC),
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 80 - 100℃; for 3.5 - 4 h;
Example 1 (S)-2,3-dihydro-1 H-indole-2-carboxylic acid: Conversion of (S)-2-bromophenylalanine with 2 molpercent CuCl in NMP at 100°C A flask was charged successively with 366 mg (1.5 mmol) (S)-2-bromophenylalanine, 217 mg (1.6 mmol) K2CO3, 3.2 mg (0.03 mmol) CuCl and 3.2 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 100°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 4 hours, full conversion of (S)-2-bromophenylalanine was found. The yield (measured in solution) of (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was 95.9 percent, ee > 98.6percent.; Example 2 (S)-2,3-dihydro-1H-indole-2-carboxylic acid: Conversion of (S)-2-bromophenylalanine with 1 molpercent CuCl in NMP at 80°C A flask was charged successively with 9.76 g (40.0 mmol) (S)-2-bromophenylalanine, 5.80 g (42.0 mmol) K2CO3, 40 mg (0.4 mmol) CuCl and 40 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 80°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 3.5 h full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25°C and then 40 mL H2O and 50 mL aqueous EtOAc were added. The pH of this mixture was adjusted to 3.3 with 3.5 g 37percent aqueous HCl. The phases were separated. The H2O phase was extracted with 2 x 50 mL aqueous EtOAc. The combined organic layers were washed with 25 mL sat aqueous NaCl. Then the organic phase was concentrated. The residu was dissolved in 16 mL 5N aqueous HCl, followed by pH adjustment to 2.1 with 9.4 g 32percent aqueous NaOH. The precipitated (S)-2,3-dihydro-1H-indole-2-carboxylic acid was isolated by filtration and washed with 2 x 10 mL H2O. 3.24 g (19.8 mmol) (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was found after drying. Yield 49.5percent, ee >99percent.
95.6%
With potassium carbonate In water at 95℃; for 22 h;
A flask was charged successively with 366 mg (1.5 mmol) (S)-2-bromophenylalanine, 217 mg (1.6 mmmol) K2CO3 and 3 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 5h hour the conversion was approximately 37percent. After 22h full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25°C and analyzed by HPLC. The yield in solution of (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was 95.6 percent, ee > 99percent.
81.1%
With potassium carbonate In water at 95℃; for 2 - 4 h;
Example 3 (S)-2,3-dihydro-1 H-indole-2-carboxylic acid: Conversion of (S)-2-bromophenylalanine with 2 molpercent CuCl in water at 95°C A flask was charged successively with 366 mg (1.5 mmol) (S)-2-bromophenylalanine, 217 mg (1.6 mmol) K2CO3, 3 mg (0.03 mmol) CuCl and 3.4 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 2 hour full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25°C and analyzed by HPLC. The yield in solution of (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was 81.1 percent, ee > 99percent.; Example 4 (S)-2,3-dihydro-1 H-indole-2-carboxylic acid: Conversion of (S)-2-bromophenylalanine with 0.01 molpercent CuCl in water at 95°C A flask was charged successively with 4.89 g (20.0 mmol) (S)-2-bromophenylalanine, 2.93 g (21.2 mmol) K2CO3, 0.2 mg CuCl (2.9 mmol) and 39.7 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 4h hour full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25°C. Then the reaction mixture was acidified with 4.47 g 5M aqueous HCI until pH = 4.4. The precipitated (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was isolated by filtration and washed with 2 x 10 mL H2O. Found after drying 2.24 g (13.7 mmol) (S)-2,3-dihydro-1 H-indole-2-carboxylic acid. Yield 69percent, ee >99percent.
69%
Stage #1: With potassium carbonate; copper(l) chloride In water at 95℃; for 4 h;
Example 4; (S)-2,3-dihydro-1 H-indole-2-carboxylic acid: Conversion of (S)-2- bromophenylalanine with 0.01 molpercent CuCI in water at 95°C EPO <DP n="30"/>; A flask was charged successively with 4.89 g (20.0 mmol) (S)-2- bromophenylalanine, 2.93 g (21.2 mmol) K2CO3, 0.2 mg CuCI (2.9 mmol) and 39.7 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 4h hour full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25°C. Then the reaction mixture was acidified with 4.47 g 5M aqueous HCI until pH = 4.4. The precipitated (S)-2,3-dihydro-1H-indole-2-carboxylic acid was isolated by filtration and washed with 2 x 10 ml_ H2O. Found after drying 2.24 g (13.7 mmol) (S)-2,3-dihydro-1H- indole-2-carboxylic acid. Yield 69percent, ee >99percent.
49.5%
Stage #1: With potassium carbonate; copper(l) chloride In 1-methyl-pyrrolidin-2-one at 80℃; for 3.5 h; Stage #2: With hydrogenchloride; water In ethyl acetate
Example 2; (S)-2,3-dihydro-1H-indole-2-carboxylic acid: Conversion of (S)-2- bromophenylalanine with 1 molpercent CuCI in NMP at 800C; A flask was charged successively with 9.76 g (40.0 mmol) (S)-2- bromophenylalanine, 5.80 g (42.0 mmol) K2CO3, 40 mg (0.4 mmol) CuCI and 40 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 800C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 3.5 h full conversion of (S)- 2-bromophenylalanine was found. The reaction mixture was cooled to 25°C and then 40 ml_ H2O and 50 mL aqueous EtOAc were added. The pH of this mixture was adjusted to 3.3 with 3.5 g 37percent aqueous HCI. The phases were separated. The H2O phase was extracted with 2 x 50 mL aqueous EtOAc. The combined organic layers were washed with 25 mL sat aqueous NaCI. Then the organic phase was concentrated. The residu was dissolved in 16 mL 5N HCI, followed by pH adjustment to 2.1 with 9.4 g 32percent aqueous NaOH. The precipitated (S)-2,3-dihydro-1H-indole-2- carboxylic acid was isolated by filtration and washed with 2 x 10 mL H2O. 3.24 g (19.8 mmol) (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was found after drying. Yield 49.5percent, ee >99percent.
95.9 %Chromat.
With potassium carbonate; copper(l) chloride In 1-methyl-pyrrolidin-2-one at 100℃; for 4 h;
Examplei; (S)-2,3-dihydro-1H-indole-2-carboxylic acid: Conversion of (S)-2-bromophenylalanine with 2 molpercent CuCI in NMP at 1000C; A flask was charged successively with 366 mg (1.5 mmol) (S)-2- bromophenylalanine, 217 mg (1.6 mmol) K2CO3, 3.2 mg (0.03 mmol) CuCI and 3.2 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon.The reaction mixture was stirred and heated until 1000C and kept at this temperature.Samples were taken regularly and analyzed by HPLC. After 4 hours, full conversion of(S)-2-bromophenylalanine was found. The yield (measured in solution) of (S)-2,3- dihydro-1 H-indole-2-carboxylic acid was 95.9 percent, ee > 98.6percent.
81.1 %Chromat.
With potassium carbonate; copper(l) chloride In water at 95℃; for 2 h;
Example 3; (S)-2,3-dihydro-1 H-indole-2-carboxylic acid: Conversion of (S)-2- bromophenylalanine with 2 molpercent CuCI in water at 95°C; A flask was charged successively with 366 mg (1.5 mmol) (S)-2- bromophenylalanine, 217 mg (1.6 mmol) K2CO3, 3 mg (0.03 mmol) CuCI and 3.4 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 2 hour full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25°C and analyzed by HPLC. The yield in solution of (S)-2,3-dihydro-1H-indole-2-carboxylic acid was 81.1 percent, ee > 99percent.
95.6 %Chromat.
With potassium carbonate In water at 95℃; for 22 h;
Example 5; (S)-2,3-dihydro-1H-indole-2-carboxylic acid: Conversion of (S)-2- bromophenylalanine without CuCI in water at 95°C; A flask was charged successively with 366 mg (1.5 mmol) (S)-2- bromophenylalanine, 217 mg (1.6 mmmol) K2CO3 and 3 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 5h hour the conversion was approximately 37percent. After 22h full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25°C and analyzed by HPLC. The yield in solution of (S)-2,3-dihydro-1 H- indole-2-carboxylic acid was 95.6 percent, ee > 99percent.
With carbon disulfide; carbon dioxide; hydrogen iodide; hydrogen; potassium iodide In ethanol at 90℃; for 5 h; Autoclave; Large scale
In a 1000 ml autoclave, 78 g of indole-2-carboxylic acid and 200 ml of ethanol were added. After adding 8 g of phosphorus iodide and a concentrated hydroiodic acid catalyst, the mixture was filled with carbon dioxide to a pressure of 5 kg. After re-evacuating three times, Pressure to 10 kg, and then re-exhaust gas three times, after the exhaust gas flushing carbon disulfide pressure to 20 kg, and then hydrogen pressure 35 kg, temperature 90 ° C hydrogenation, until the hydrogen pressure is not reduced, the reaction time of about 5 hours, the reaction was completed Cooling exhaust, discharging, suction filtration catalyst recovery, and then recovered ethanol after distillation colorless liquid 56 grams, a yield of 87.5percent, a purity of 93.5percent.
Reference：
[1] Patent: CN106631977, 2017, A, . Location in patent: Paragraph 0014; 0015; 0016; 0017
5
[ 103616-89-3 ]
[ 79815-20-6 ]
Yield
Reaction Conditions
Operation in experiment
76.6%
With potassium carbonate In water at 95℃; for 40 h;
A flask was charged successively with 3.00 g (15.0 mmol) (S)-2-amino-3-(2-chloro-phenyl)-propionic acid, 2.17 g (15.7 mmol) K2CO3, 15 mg CuCl (2.9 mmol) and 15 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature for 22 h. Samples were taken regularly and analyzed by HPLC. The conversion after 22 h was approximately 40percent. Then 15 mL water was added and the mixture stirred and heated for an additional 18 h. HPLC indicated full conversion of (S)-2-chlorophenylalanine. The reaction mixture was cooled to ca 25°C. The pH of the solution was then decreased from 7.6 to ca 3.5. The precipitated (S)-2,3-dihydro-1H-indole-2-carboxylic acid was isolated by filtration and washed with 2 x 10 mL 0.01 aqueous M HCl. Found after drying 1.88 g (11.5 mmol) (S)-2,3-dihydro-1 H-indole-2-carboxylic acid. Yield 76.6 percent, ee > 99percent.
76.6%
Stage #1: With potassium carbonate; copper(l) chloride In water at 95℃; for 40 h; Stage #2: at 25℃; Acidic conditions
Step (iii):; (S)-2,3-dihvdro-1 H-indole-2-carboxylic acid: Conversion of (S)-2-amino-3-(2- chloro-phenyD-propionic acid with 1 molpercent CuCI in water at 95°C; A flask was charged successively with 3.00 g (15.0 mmol) (S)-2- amino-3-(2-chloro-phenyl)-propionic acid, 2.17 g (15.7 mmol) K2CO3, 15 mg CuCI (2.9 mmol) and 15 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature for 22 h. Samples were taken regularly and analyzed by HPLC. The conversion after 22 h was approximately 40percent. Then 15 mL water was added and the mixture stirred and heated for an additional 18 h. HPLC indicated full conversion of (S)- 2-chlorophenylalanine. The reaction mixture was cooled to ca 25°C. The pH of the solution was then decreased from 7.6 to ca 3.5. The precipitated (S)-2,3-dihydro-1 H- indole-2-carboxylic acid was isolated by filtration and washed with 2 x 10 mL 0,01 M EPO <DP n="33"/>HCI. Found after drying 1.88 g (11.5 mmol) (S)-2,3-dihydro-1 H-indole-2-carboxylic acid. Yield 76.6 percent, ee > 99percent.
Example 3 [70] Preparation of (S) -indoline-2-Carboxylic Acid Through Hydrolysis; [71] Into a 250 ml reactor equipped with a pH meter, 8.1 g of (S)-indoline-2-carboxylic acid methyl ester prepared in Example 2 and 50 ml of 1N aqueous sodium hydroxide solution were placed and strongly stirred at room temperature. Whether (S) -indoline-2-carboxylic acid methyl ester was converted to (S)-indoline-2-carboxylic acid was confirmed. Then, while the temperature of the reactor was maintained at 20 C or less, 1N aqueous hydrochloric acid solution was slowly added to the reactor to control pH 5. The resultant reaction product was extracted three times with 50 ml of ethyl acetate by use of the separating funnel, and the organic layer was placed into a round bottom flask. The solvent in the organic layer was removed through distillation <Desc/Clms Page number 11>under reduced pressure, to give 7.0 g of (S) -indoline-2-carboxylic acid. The thus prepared (S) -indoline-2-carboxylic acid was analyzed for optical purity by means of liquid chromatography. [72] As for the liquid chromatographic conditions, a chiralpak AD column (Daicel) composed of amylose derivatives was used and hexane, isopropanol and triflu- oroacetic acid having a ratio of 95: 5: 0.1 as an eluent were applied at 1 ml/min. The reaction product was detected at UV 220 nm. As the reactants of the above reaction, (S) -indoline-2-carboxylic acid methyl ester was detected at 119 min, while (R) -indoline-2-carboxylic acid methyl ester was detected at 12.4 min. Further, as the hydrolyzed products, (S) -indoline-2-carboxylic acid was at 23.8 min, while (R) -indoline-2-carboxylic acid at 32.0 min. [73] Analytic results were represented by yield [percent] and optical purity [percent e. e. ], in which the yield of (S) -ester was calculated according to Equation 3, and the optical purity thereof accorded to Equation 2: 9
The product obtained in step 4-2 (0.25 mol, 54.8 g) was added to a 500 mL three-necked flask,And the newly prepared 30percent sulfuric acid aqueous solution 300mL,Heated to reflux.Solid gradually dissolved,TLC (developing solvent: chloroform: methanol: triethylamine = 6: 4: 1)Tracking to the raw point of the reaction is complete, stop heating,Naturally cool to room temperature.Then adjust the pH to 4 to 5 with 10percent aqueous sodium hydroxide solution,A large amount of white solid precipitated. Filter,The filter cake was washed three times with 50 mL of water, dried in vacuo,A white solid was obtained 35.4 g,The yield was 86.8percentPurity 97.1percent (HPLC),
Reference：
[1] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 109, p. 136 - 142
10
[ 3433-80-5 ]
[ 79815-20-6 ]
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 1, p. 163 - 168
[2] Journal of the American Chemical Society, 2003, vol. 125, # 1, p. 163 - 168
11
[ 496790-47-7 ]
[ 79815-20-6 ]
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 1, p. 163 - 168
12
[ 496790-43-3 ]
[ 79815-20-6 ]
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 1, p. 163 - 168
Reference：
[1] Journal of Medicinal Chemistry, 1983, vol. 26, # 3, p. 394 - 403
15
[ 79854-38-9 ]
[ 79815-20-6 ]
Yield
Reaction Conditions
Operation in experiment
52.8%
With hydrogenchloride In water for 2 h;
Step A1: (2S)-indoline-2-carboxylic Acid The white precipitate collected in Step A is recrystallised from isopropanol and then dissolved in 13 litres of water, and 12 litres of a 1N hydrochloric acid solution are added. After stirring for 2 h, the precipitate is filtered off and then washed and dried to yield (2S)-indoline-2-carboxylic acid (<<1st portion>>) in the form of crystals (1.80 kg) with a chemical purity of 98percent and an enantiomeric purity greater than 99.5percent.; Step C: Recycling of indoline-2-carboxylic Acid The racemic indoline-2-carboxylic acid obtained in Step B (2.34 kg) is resolved according to the procedure in Step A. The (R)-α-methylbenzylamine salt of (2S)-indoline-2-carboxylic acid so formed is isolated and then treated with hydrochloric acid according to the procedure in Step A1 to yield (2S)-indoline-2-carboxylic acid (<<2nd portion>>) in the form of crystals (0.84 kg) having a chemical purity of 98percent and an enantiomeric purity greater than 99.5percent. The 1st portion, obtained in Step A1, and the 2nd portion, obtained in Step C, are then combined. (2S)-indoline-2-carboxylic acid is thereby obtained in a total yield of 52.8percent, a chemical purity of 98percent and an enantiomeric purity greater than 99.5percent.
With thionyl chloride at 0 - 65℃; for 16h; Inert atmosphere;
Step 1 - Methyl (2S)-2,3-dihydro-1H-indole-2-carboxylate
To a stirred solution of (2S)-2,3-dihydro-1H-indole-2-carboxylic acid (500.00 g, 3064.2 mmol, CAS 79815-20-6)) in MeOH (7.50 L) was added SOCl2 (333.43 mL, 2802.6 mmol) dropwise at 0 C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 65 C under nitrogen atmosphere. On completion, the reaction mixture was allowed to cool down to rt. Then the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (3000 mL) then neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 (3 x 1500 mL). The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (500 g, 92% yield) as a brown oil.1H NMR (400 MHz, Chloroform- d) δ 7.15-7.04 (m, 2H), 6.81-6.72 (m, 2H), 4.42 (dd, J = 10.2, 5.5 Hz, 1H), 3.78 (s, 3H), 3.44-3.34 (m, 2H); LC/MS (ESI, m/z): [(M + H)]+ = 178.1.
95%
With thionyl chloride at 0 - 65℃; for 16h; Inert atmosphere;
Step 1 - Methyl (2S)-2,3-dihydro-1H-indole-2-carboxylate
To a stirred solution of (2S)-2,3-dihydro-1H-indole-2-carboxylic acid (500.00 g, 3064.2 mmol, CAS 79815-20-6)) in MeOH (7.50 L) was added SOCl2 (333.43 mL, 2802.6 mmol) dropwise at 0 C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 65 C under nitrogen atmosphere. On completion, the reaction mixture was allowed to cool down to rt. Then the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (3000 mL) then neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 (3 x 1500 mL). The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (500 g, 92% yield) as a brown oil.1H NMR (400 MHz, Chloroform- d) δ 7.15-7.04 (m, 2H), 6.81-6.72 (m, 2H), 4.42 (dd, J = 10.2, 5.5 Hz, 1H), 3.78 (s, 3H), 3.44-3.34 (m, 2H); LC/MS (ESI, m/z): [(M + H)]+ = 178.1.
89.01%
With sulfuric acid at 80℃; for 16h;
1.1.1 Synthesis of (S)-2,3-Dihydro-lH-indole-2-carboxylic acid methyl ester [Scheme 1, Step- 1] :
To a suspension of 1 (30.0 g, 184 mmol) in MeOH (300 mL) was added sulfuric acid (22.3 L) drop wise at room temperature. After addition, resultant mixture was allowed to stir at 80 °C for 16 h. After completion, solvent was removed under vacuum and residue was neutralized with 15 % aqueous NaOH solution. Then reaction mixture was extracted with EtOAc (2 x 150 mL). Combined organic part was further washed with IN aqueous NaOH, brine (100 mL), dried (MgSOr), filtered and evaporated under reduced pressure to afford compound 2 (29 g, 89%) as light brown gummy liquid. NMR complies.
82%
With thionyl chloride at 0 - 70℃; for 16h; Cooling with ice;
75%
With thionyl chloride
With thionyl chloride
With sulfuric acid at 80℃; for 6h;
20.3 g
With sulfuric acid at 80℃; for 6h;
With thionyl chloride Inert atmosphere;
> 99.9 % ee
With thionyl chloride
With thionyl chloride
With thionyl chloride at -10℃; for 3h; Reflux; Inert atmosphere;
1-(tert-Butoxycarbonyl)-2-carbomethoxyindoline
Intermediate (S)-1-(tert-butoxycabonyl)-2-carbomethoxy indoline was prepared according to literature [4]. To the mixture of indoline-2-carboxylic acid (445 g, 2.79 mmol) in methanol (10 mL) was added thionyl chloride (0.24 mL, 3.4 mmol) at -10 °C. The solution was allowed to stir at -10 °C for one hour, and then was heated at reflux for 2 hours. The thionyl chloride was removed by successive additions of methanol (3*15 mL) followed by concentration in vacuo, and the resulting yellow oil was carried on without purification. To the mixture were added 6 mL of CH2Cl2 and the solution was cooled to 0 °C. Then Et3N (0.97 mL, 7.0 mmol) and di-tert-butyldicarbonate (916 mg, 4.19 mmol) were added. The solution was stirred at r.t. for 24 h. The reaction was quenched with water (10mL), and the aqueous solution was extracted with ether (3*25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Following chromatography purification with 5% EtOAc/hexane as the eluent, methyl ester (448 mg, 63%) was obtained as a white solid
(S)-2,3-Dihydro- lH-indole-2-carboxylic acid (20 g, 0.123 mol) was suspended in absolute ethanol (200 mL) and the suspension was cooled to 0°C. SOCl2 (18 mL, 0.25 mol) was then added dropwise to the reaction mixture and it was allowed to warm to RT and was stirred for 16 hrs. The solvent was then evaporated and the residue was swapped twice with ethanol (100 mL) to get a brown solid. This solid was dissolved triethylamine (34.2 mL, 0.245 mol) and acetic anhydride (170 mL) and the mixture was stirred at RT for 2 hrs. Then it was diluted with EtOAc (500 mL) and washed with NaHC03 (2 x 200 mL, aqueous, saturated solution) and citric acid (2 x 200 mL, aqueous, saturated solution). The combined organic layers were dried over sodium sulphate and concentrated to give a brown solid. This solid was dissolved in acetic anhydride (200 mL) and a solution of nitric acid (11.1 mL) in acetic anhydride (161 mL) was added dropwise at 0°C. The reaction mixture was left at 0°C for 15 min then warm to RT and stirred for 3 hrs. Cold water (250 mL) was added to the reaction mixture and the product was extracted with EtOAC (3 x 450 mL). The combined organic layers were dried over sodium sulphate and concentrated. The two isomers obtained were separated by normal phase column chromatography using 10 % to 30% ethyl acetate in hexanes as the eluent to give first, (5^)-l -acetyl-5-nitro-2,3-dihydro-l H-indole-2-carboxylic acid ethyl ester as a yellow solid (18.49 g, 54%) and second, (5)-l -acetyl-7-nitro-2,3-dihydro- lH-indole-2- carboxylic acid ethyl ester as an orange oil (8.21 g, 24%).
(2S)-2,3-dihydro-1H-indole-2-carboxylic acid (500 mg, 306 mmol) was suspended in EtOH (5 mL) at 0°C and thionyl chloride (0.45 mL, 6.13 mmol, 2 eq.) was added. The resulting clear mixture was allowed to come to RT and stirred for 16 hrs. The reaction mixture was then concentrated to dryness and swapped with EtOH (2 x 10 mL). The solid obtained was dried well under reduced pressure to give ethyl (2S -2,3-dihydro-lH-indole-2-carboxylate hydrochloride as a light brown solid (0.58 g, quantitative). 1H NMR (400 MHz, DMSO-rf6) δ 1.18 (3H, s), 3.10-3.18 (IH, m), 3.30-3.40 (IH, m), 4.05-4.17 (2H, m), 4.55 (I H, bs), 6.80 (2H, bs), 7.02-7.08 (2H, m), 7.7 (2H, bs). Compound was used further as described.
100%
With thionyl chloride In ethanol at 0 - 20℃; for 16h;
(S)-ethyl indoline-2-carboxylate hydrochloride (I-8)
(S)-indoline-2-carboxylic acid (500 mg, 306 mmol) was suspended in EtOH (5 mL) at 0° C. and thionyl chloride (0.450 mL, 6.127 mmol, 2 eq.) was added. The resulting clear mixture was allowed to come to RT and stirred for 16 hours. The reaction mixture was then concentrated to dryness and swapped with EtOH (2*10 mL). The solid obtained was dried well under reduced pressure to give a light brown solid (0.58 g, quantitative). 1H NMR (400 MHz, DMSO-d6) δ 1.18 (3H, s), 3.10-3.18 (1H, m), 3.30-3.40 (1H, m), 4.05-4.17 (2H, m), 4.55 (1H, bs), 6.80 (2H, bs), 7.02-7.08 (2H, m), 7.7 (2H, bs).
100%
With thionyl chloride at 0 - 20℃; for 16h;
ethyl (2S)-1-(2-[(tert-butoxy)carbonyl]amino}acetyl)-2,3-dihydro-1H-indole-2-carboxylate (I-1)
General procedure: 2S)-2,3-dihydro-1H-indole-2-carboxylic acid (500 mg, 306 mmol) was suspended in EtOH (5 mL) at 0°C and thionyl chloride (0.45 mL, 6.13 mmol, 2 eq) was added. The resulting clear mixture was allowed to come to RT and stirred for 16 hours. The reaction mixture was then concentrated to dryness and swapped with EtOH (2x10 mL). The solid obtained was dried well under reduced pressure to give ethyl (2S)-2,3-dihydro-1H-indole-2-carboxylate hydrochloride as a light brown solid (0.58 g, quantitative). H1 NMR (400 MHz, DMSO-d6) δ 1.18(3H, s), 3.10-3.18(1H, m), 3.30-3.40(1H, m), 4.05-4.17(2H, m), 4.55(1H, bs), 6.80(2H, bs), 7.02-7.08(2H, m), 7.7(2H, bs). Compound was used further as described.
Stage 1E: (2S,3aS,7aS)-2-Carboxyoctahydroindole Place 25 kg of (S)-2-carboxyindoline, obtained previously, in 110 liters of methanol in a vessel. Keep stirred. Charge the rhodium (5% dry) catalyst into a mixer. Start up the stirring in a hydrogenator, charge the methanolic suspension of (S)-2-carboxyindoline by passing it through the mixer and rinse the assembly with water. Heat to 60 C. and pressurize with hydrogen (30 bars). Filter off the catalyst on a single-plate filter. Collect the hydroalcoholic liquors in a reactor and evaporate the methanol off under vacuum. After concentrating, charge approximately 300 kg of dioxane. Heat to boiling and add water until a solution is obtained. Allow to cool. Filter off and dry. 22.3 kg of crystals are obtained. Yield: 86.1%.
73.5%
With 8 % Pd/C; hydrogen; In methanol; at 55 - 65℃; under 37503.8 Torr;Autoclave;
In a 1 L autoclave,(S) -indoline-2-carboxylic acid (0.3 mol, 49.0 g) and methanol (600 mL)Then, 4.9 g of 8% wet palladium carbon wetted with methanol was added,Mechanical agitation. Through the nitrogen replacement air 3 times,And then hydrogen gas replacement nitrogen 3 times,Replace the kettle when the pressure is 0.5Mpa. after finishing,Continue to hydrogen to 5.0Mpa, set the heating temperature at 60 ,Maintaining the temperature of the reaction system at 55 to 65 C,TLC (developing solvent: chloroform: methanol: triethylamine = 6: 4: 1, ninhydrin)Tracking to the raw point of the reaction is complete. The hydrogen was vented and the hydrogen was replaced with nitrogen three times.Discharge, filter, take the filtrate under reduced pressure,A crude solid was obtained as a white solid. Finally, recrystallization from ethanol,A white solid was obtained in 37.3 g yield, 73.5% yield,Purity 98.6% (HPLC),
S-Indoline-2-carboxylic acid (50 gm) (0.31 mole), sodium hydroxide (12.27 gm) (0.31 mole), 5% rhodium on alumina (7.5 gm), were mixed with water (1 lit) in an autoclave and hydrogenated at a pressure of 12 bar at 50C. The catalyst was filtered off and the bed washed with water (200 ml). The reaction mass was cooled to 15-20C and acidified to pH 3.0 to 3.2 using conc. HCI and washed with (4 x 250 ml) ethyl acetate. The pH of the aqueous phase was adjusted to 6.5 with 10% sodium hydroxide solution. Water was then removed by distillation under vacuum and the traces were further removed by addition of toluene and continuing the distillation. The product was isolated by addition of acetonitrile (500 ml) and filtration. The crude product was recrystallized from methanol to give the title compound (40 gm).
With hydrogen;palladium 10% on activated carbon; In methanol; at 60℃; under 37503.8 Torr; for 40h;Product distribution / selectivity;
(S)-indoline-2-carboxylic acid (25 g) and 200 ml of methanol were hydrogenated in the presence of 2.5 g of 10 % Pd/C (dry basis) for 40 h at 60 C and at a pressure of 5 MPa. The catalyst was filtered off and the filtrate was concentrated by distilling off methanol. 50 ml of water were added to the residue and the mixture was heated to 70 C to obtain a clear solution. Then, at 70 C 140 ml of 1,2-dimethoxyethane were added dropwise to the clear solution. The mixture turned cloudy and was cooled spontaneously to room temperature. The precipitated solid was collected and dried to obtain 11 g of the title compound (optical rotation: -47.7). This solid was purified again to obtain 6 g of the title compound (optical rotation: -45.5). The same yield and optical rotation can be obtained by using 50 ml of water and 200 ml of THF at 65 C instead of water and 1,2-dimethoxyethane.
With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether Inert atmosphere;
Chiral Auxiliaries and Phosphoramidites
To a solution of (2S)-dihydro-1 H-indole-2-carboxylic acid 1 (1 .63 g, 10.0 mmol) in ether (50 mL) was added a solution of LiAIH4 in THE (2M, 7.5 mL, 15.0 mmol) under argon, and the mixture was stirred overnight. After completion of the reaction, the mixture was quenched with Na2SO41 0H20. The solidwas filtered off and washed with ethyl acetate, and the filtrate was dried over anhydrous Na2SO4. Themixture was filtered, and the solvent evaporated to give a residue, which was subjected to flash silica gelcolumn purification on an 1500 (hexane/ethyl acetate, 10-70%) to give 1 .44 g (96%) of compound 2 as agray solid. 1H NMR (500 MHz, CDCI3 ppm): O7.10 (1H, d, J7.5 Hz), 7.04 (1H, t, J7.5 Hz), 6.75 (1H, t, J7.5 Hz), 6.69 (1 H, d, J 7.5 Hz), 4.10-4.06 (2H, m), 3.75 (1 H, dd, J 11.0, 4.0 Hz), 3.60 (1 H, dd, J 11 .0, 6.0Hz), 3.12(1 H, dd, J 16.0, 9.0 Hz), 2.87(1 H, dd, J 16.0, 8.0 Hz); ESI MS for C9HllNOcalculated 149.2, observed [M÷H] 150.1.
87%
Stage #1: (S)-indoline-2-carboxylic acid With dimethylsulfide borane complex; boron trifluoride diethyl etherate In tetrahydrofuran Reflux;
Stage #2: With hydrogenchloride; methanol; water In tetrahydrofuran Reflux;
Stage #3: With sodium hydroxide In water
A.1.1
Synthesis of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)indolin-2-yl)methoxy)acetic acid (S4); Stage 1: (S)-Indolin-2-ylmethanol; BH3-DMS solution (18.4 mmol, 2 eq) was added dropwise to a solution of (S)-indoline-2-carboxylic acid (9.2 mmol, 1.0 eq) in THF (18 ml) and the mixture was refluxed for 12 h. Methanol (7.5 ml) and concentrated HCl (2.5 ml) were added to the reaction mixture with cooling, then refluxing was continued for a further 2 hours. The solvent was removed under vacuum and the residue made alkaline with 40% NaOH solution and extracted with DCM. The organic phase was washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated to small volume under vacuum. The crude product was processed by column chromatography. Yield: 87%
87%
Stage #1: (S)-indoline-2-carboxylic acid With dimethylsulfide borane complex In tetrahydrofuran for 12h; Reflux;
Stage #2: With hydrogenchloride In tetrahydrofuran; methanol for 2h; Reflux;
Stage #3: With sodium hydroxide In tetrahydrofuran; methanol; water
1
To a solution of (S)-indoline-2-carboxylic acid (9.2 mmol, 1.0 equiv.) in THF (18 ml) was added dropwise BH3-DMS solution (18.4 mmol, 2 equiv.) and the reaction mixture was heated to reflux for 12 h. The mixture was quenched with methanol (7.5 ml) and cone. HCI (2.5 ml) with cooling and was then refluxed for additional 2 h. The solvent was evaporated and the residue was basified with 40% NaOH solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified by silica gel column chromatography. Yield: 87%
85%
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 5h; Inert atmosphere;
1.7. (S)-Indolin-2-ylmethanol (S-19).
General procedure: To a stirred suspension of LiAlH4 (698 mg, 18.4 mmol) in THF (15 mL) under N2 at 0 °C, was added (S)-indoline-2-carboxylic acid (1 g, 6.1 mmol) solution in THF (20 mL). The reaction mixture was stirred at 0 oC for 5 h. The reaction mixture was quenched with saturated ammonium chloride and then extracted with dichloromethane. The combined organic layers were washed withe brine then dried over Na2SO4 and concentrated on rotary evaporator. The residue was purified by column chromatography (EtOAc/hexane = 6:4, 600 mL) to give desired alcohol as light brown solid (780 mg, 85%) (Mp: 65-66 °C). 1H-NMR (400 MHz, CDCl3): δ 7.05 (d, J = 7.5 Hz, =CH, 1H), 6.99 (t, J = 7.5 Hz, =CH, 1H), 6.70 (t, J = 7.5 Hz, =CH, 1H), 6.59 (d, J = 7.5 Hz, =CH, 1H), 3.97-3.90 (m, CH, 1H), 3.70 (br, OH, 1H), 3.62 (dd, J = 10.9, 3.8 Hz, A part of AB systems, CH2, 1H), 3.49 (dd, J = 10.9, 7.1 Hz, B part of AB systems, CH2, 1H), 3.04 (dd, J = 15.8, 9.2 Hz, A part of AB systems, CH2, 1H), 2.72 (dd, J = 15.8, 7.6 Hz, B part of AB systems, CH2, 1H); 13C-NMR (100 MHz, CDCl3): δ 150.5, 128.8, 127.5, 124.9, 119.2, 110.10, 65.4, 60.5, 32.1. IR (CH2Cl2, cm-1): 3328, 3047, 2918, 2845, 1608, 1485, 1398, 1337, 1317, 1246, 1155, 1039, 748. HPLC (OJ column; hexane/2-propanol = 80/20; flow rate 1.0 mL/ min; T=25 °C; 254 nm): tR-(+) = 9.4 min. Enantiomeric rate: (+) = 100.0 and (-) = 0.0. Anal. Calcd for C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.44; H, 7.40; N, 9.35.
84%
With borane-THF at 0℃; for 24h;
80%
With lithium aluminium tetrahydride In tetrahydrofuran
72%
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 60℃; for 16h;
2 (2S)-2,3-Dihydro-1H-indole-2-ylmethanol (19B)
To a solution of (2S)-2,3-dihydro-1H-indole-2-carboxylic acid (17B, 19.5 g, 119.5 mmol) in THF (150 mL) was added dropwise 10 M borane dimethylsulfide in THF (35.9 mL, 358.5 mmol) at 0 °C, and the reaction mixture was stirred at 60 °C for 16 h. To the mixture were added MeOH (50 mL) and 6 M HCl (50 mL) at 0 °C, and the mixture was stirred at 50 °C for 1 h. After the mixture was concentrated under reduced pressure, the residue was basified with 8 M NaOH, and the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-50% EtOAc in n-hexane) to give 19B (12.8 g, 72%) as white solid; 1H NMR (300 MHz, DMSO-d6): δ 2.62 (1H, dd, J = 15.9, 6.8 Hz), 2.96 (1H, dd, J = 15.9, 9.3 Hz), 3.19-3.52 (2H, m), 3.65-3.89 (1H, m), 4.71 (1H, t, J = 5.4 Hz), 5.50 (1H, s), 6.36-6.57 (2H, m), 6.87 (1H, t, J = 7.6 Hz), 6.96 (1H, d, J = 7.2 Hz); MS (ESI): m/z 150.1 (M+H)+.
52%
With lithium aluminium tetrahydride In tetrahydrofuran for 2h; Heating;
38%
With diborane In tetrahydrofuran at 0 - 20℃; for 48h;
Intermediate 37 (S)-inclolln-2-ylmethanol
Borane (38ml, 1GM in THF,38mmol) was added drop wise to a suspension of (6)- indoline-2-carboxylic acid (2.SOg, 15.2mmol) at 0 °C and the resultant solution stirred at RT for 48 hours. To this was added DCM and water and the organic phase washedwith water (2 x 2Oml). The organic phase was separated, dried and concentrated to give an orange oil (856 mg, 38%); 1H NMR (400 MHz, CHLOROFORM-cl) ö ppm 7.08 (d, J=7.33 Hz, 1 H), 7.02 (d, J1.37 Hz, 1 H), 6.72 (td, J7.44, 1.14 Hz, I H), 6.64 (d, J=7.79 Hz, I H), 4.02 (m, 1 H), 3.70 (dd, J=10.76, 3.89 Hz, 1 H), 3.56 (dd, J10.76,6.64 Hz1 I H), 3.08 (d, J9.16 Hz, I H), 2.83 (d, J7.78 Hz, 1 H); LC-MS (ESI): (MHt)150.
27%
With lithium aluminium tetrahydride In diethyl ether
With sodium hydroxide; dimethylsulfide borane complex Yield given. Multistep reaction;
With sodium tetrahydroborate; iodine In tetrahydrofuran for 18h; Heating;
With lithium aluminium tetrahydride In tetrahydrofuran for 1h; Heating;
Multi-step reaction with 2 steps
1: SOCl2
2: AlLiH4
R.9.1 (RS)-2-hydroxymethylindoline
In the same manner as in Reference Example 9-1, a compound of Reference Example 9-2 was synthesised from (S)-indoline-2-carboxylic acid. Reference Example 9-2: (S)-2-hydroxymethylindoline
724 mg
With borane-THF In tetrahydrofuran at 20℃;
37 Compound 305
Borane THF complex (1M; 15 ml) was added to a cooled (0° C.) solution of (S)-indoline carboxylic acid (979 mg, 5.95 mmol) in dry THF (12 ml). The clear solution was stirred overnight at room temperature, quenched with water (gas evolution occurs). The mixture was extracted with diethyl ether (3×10 ml). The organic layer was washed with saturated NaHCO3 (2×5 ml) and brine (10 ml). The solvent was removed under reduced pressure. The residue could be used for the next step without further purification (724 mg). [0334] 1H-NMR (500 MHz, CDCl3) δ: 1.24-1.45 (m, 1H, 1 of Ar-CH2), 2.62-2.76 (m, 1H, 1 of Ar-CH2), 3.01-3.06 (m, 1H, CHCH2OH), 3.56-3.75 (m, 3H, CH2OH), 3.99 (bs, 1H, NH), 6.53-6.71 (m, 2H, ArH), 6.93-7.04 (m, 2H, ArH). [0335] LCMS: m/z 150.10 ([M+H]+, 100%); Rt 3.2 min, purity >95% DAD (180-450).
With methyl dichlorophosphite; triethylamine; 1-methyl-3-methylimidazol-3-ium dimethyl phosphate In toluene at 145℃; for 1h; Microwave irradiation; stereoselective reaction;
93%
With methyl dichlorophosphite; triethylamine; 1-methyl-3-methylimidazol-3-ium dimethyl phosphate In toluene at 145℃; for 1h; Microwave irradiation;
83%
With triethylamine In toluene for 5h; Heating;
76%
With dicyclohexyl-carbodiimide In tetrahydrofuran for 1h; Ambient temperature;
76%
With dicyclohexyl-carbodiimide In tetrahydrofuran for 1h; Ambient temperature;
With sodium hydrogencarbonate In water; toluene Ambient temperature;
93%
With sodium hydroxide at 5 - 20℃; for 5h;
35%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 5 - 20℃; for 3.33333h;
1.1
Cbz-Cl (20 niL, 0.13 mol) in MeCN (50 mL) was added dropwise to (S)- indoline-2-carboxylic acid(20 g, 0.12 mol) and DIEA (43 mL, 0.25 mol) in MeCN (350 mL) at 5-10 0C over 20 min. The mixture was allowed to warm up r.t. After 3 h, volatiles were removed under vacuum. The oily residue was dissolved in EtOAc and washed with 1% aq. HCl, water, brine, and dried (MgSO4). Solvent was removed under vacuum to afford the product as a thick oil that crystallized in refrigerator into a brown solid. Yield 35 g (100%).
With hydrogenchloride In sodium hydroxide
16.a a)
a) Preparation of N-benzyloxycarbonyl-2(S)-indolinecarboxylic acid A solution of 20 g (122.56 mmol) of 2(S)-indolinecarboxylic acid in 2N NaOH (62 ml) is cooled in an ice/water bath and the solution is stirred using a powerful magnetic stirrer. 20.0 ml (140.09 mmol) of benzyl chloroformate and 68 ml of 2N NaOH are added thereto alternately in about 10 portions over 60 minutes. The temperature of the reaction mixture is maintained between 0° and 5° C. by controlling the rate of addition of the reactants. 50 ml of NaOH are then added and the mixture is maintained at room temperature for 30 minutes. The alkaline solution is washed with ether (4*150 ml) and is then acidified by addition of 5N HCl (80 ml, pH<2). A crystalline mass precipitates after leaving overnight at room temperature. It is filtered off and washed with distilled water (500 ml). After drying over P2O5, the desired product is obtained. m.p.=117-118° C. 1H-NMR (400 MHz, CDCl3, ppm): 8.30-6.90 (10H, m, ArH and COOH); 5.45-5.14 (2H, m, CH2-Ph); 5.08-4.92 (1H, m, αH); 3.65-3.46 (1H, m, CH2 indoline); 3.30-3.15 (1H, m, CH2 indoline). Mass spectrum (FAB): m/e (% intensity)=342 ((M-H+2Na)+, 0.2); 320 ((M+Na)+, 4.3); 298 (MH+, 5.7); 297 (M+, 9.3); 91 (C7H7+, 100).
With N-ethyl-N,N-diisopropylamine In acetonitrile at 5 - 20℃;
1
Cbz-Cl (20 mL, 0.13 mol) in MeCN (50 mL) was added dropwise to Intermediate 1 (20 g, 0.12 mol) and DIEA (43 mL, 0.25 mol) in MeCN (350 mL) at 5-10° C. over 20 min. The mixture was allowed to warm up r.t. After 3 h, volatiles were removed under vacuum. The oily residue was dissolved in EtOAc and washed with 1% aq. HCl, water, brine, and dried (MgSO4). Solvent was removed under vacuum to afford the product as thick oil that crystallized in refrigerator into a brownish solid.
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 4h;
74 %
With sodium hydroxide at 0℃;
(S)-N-Carbobenzoxyindoline-2-carboxylic acid (15):
(S)-Indoline-2-carboxylicacid (15.0 g, 92 mmol) dissolved in 2N NaOH (50 mL)and stirred at 0 °C, benzyl chloroformate (15 mL, 106 mmol)and 2N NaOH (50 mL) were added dropwise over 10 min at0 °C. After the mixture was stirred for 30 min at 0 °C, thereaction solution was washed with diethyl ether (100 mL)and then acidified with 10% HCl. The solution was extractedwith EtOAc (50 mL, 3 times) and then the organic solutionwas washed with brine. The organic solution was dried overanhydrous MgSO4. The solvent was removed in vacuo to givethe product (S)-N-carbobenzoxyindoline-2-carboxylic acid (15:20.2 g, yield 74%). 15: Amorphous; 1H-NMR (δ): 3.20 and 3.52(each 1H, m), 4.96 (1H, m), 5.22 (2H, s), 6.98 (2H, m, Ar-H),7.11 (2H, m, Ar-H), 7.31 (5H, m, Ar-H).
74 %
With sodium hydroxide at 0℃;
(S)-N-Carbobenzoxyindoline-2-carboxylic acid (15):
(S)-Indoline-2-carboxylicacid (15.0 g, 92 mmol) dissolved in 2N NaOH (50 mL)and stirred at 0 °C, benzyl chloroformate (15 mL, 106 mmol)and 2N NaOH (50 mL) were added dropwise over 10 min at0 °C. After the mixture was stirred for 30 min at 0 °C, thereaction solution was washed with diethyl ether (100 mL)and then acidified with 10% HCl. The solution was extractedwith EtOAc (50 mL, 3 times) and then the organic solutionwas washed with brine. The organic solution was dried overanhydrous MgSO4. The solvent was removed in vacuo to givethe product (S)-N-carbobenzoxyindoline-2-carboxylic acid (15:20.2 g, yield 74%). 15: Amorphous; 1H-NMR (δ): 3.20 and 3.52(each 1H, m), 4.96 (1H, m), 5.22 (2H, s), 6.98 (2H, m, Ar-H),7.11 (2H, m, Ar-H), 7.31 (5H, m, Ar-H).
With sodium hydroxide In 1,4-dioxane at 20℃; for 12h;
96%
With sodium carbonate In <i>tert</i>-butyl alcohol at 20℃; for 12h;
90%
With sodium hydroxide In 1,4-dioxane at 0 - 20℃;
(6 mL) and NaOH solution (0.5 M, 12 mL) was added slowly di- ri-butyl dicarbonate (1.47 g, 6.74 mmol) in dioxane (6 mL) at 0°C. The reaction mixture was warmed to RT and stirred overnight. The reaction mixture was then washed with hexanes (10 mL). The separated water layer was acidified using saturated solution of citric acid and extracted with ethyl acetate (3 x 15 mL). The organic layer was washed with brine, separated, dried over sodium sulfate and concentrated to give (25)-l -[(iert-butoxy)carbonyl]-2,3-dihydro-lH-indole-2-carboxylic acid, as light orange colored solid (1.45 g, 90%), used further as described. 1H NMR (400 MHz, DMSO-< 6) δ 1.41 (9H, s), 2.99-3.04 (IH, d, J=20 Hz), 3.48-3.55 (IH, dd, J=12, 16 Hz), 4.74-4.78 (IH, dd, J=4, 12 Hz), 6.91 -6.95 (IH, t, J=8 Hz), 7.14-7.18 (2H, m), 7.72-7.74 (IH, d, J=8 Hz), 12.85 (I H, bs), MS (LC/MS) m/z observed 285.89, expected 286.1 1 [M+Na].
87%
With sodium hydroxide In 1,4-dioxane at 20℃; for 16h;
In sodium hydroxide; <i>tert</i>-butyl alcohol
3.1 Step 1:
Step 1: Preparation of (S)-N-tert-butoxycarbonylindoline-2-carboxylic acid To a solution of (S)-indoline-2-carboxylic acid (1.0 g) in 1N aqueous sodium hydroxide (12 ml) is added a solution of di-tert-butyl dicarbonate (1.47 g) in tert-butanol (9 ml) and the solution is stirred at room temperature for about 2 days. The aqueous solution is adjusted to pH 2 with 1N hydrochloric acid, extracted with ethyl acetate and the ethyl acetate solution dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product which is used, without further treatment, for the next step.
With triethylamine In N,N-dimethyl-formamide at 20℃;
20
(S)-2,3-Dihydro-indole-l,2-dicarboxylic acid 1-tert-butyl ester(S)-2,3-Dihydro-lH-indole-2-carboxylic acid (207.4 mg, 1.27 mmol) was dissolved in DMF (10 mL). Triethylamine (375 μL, 2.69 mmol) was added followed by di-tert-buty dicarbonate (300.7 mg, 1.38 mmol). The reaction was stirred at ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.
With sodium hydroxide In 1,4-dioxane; water at 0℃; for 14h; Inert atmosphere;
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; Inert atmosphere;
1
To a stirred solution of (s)-(-)-Indoline-2-carboxylic acid 1 (3.43 g, 21.0 mmol) in anhydrous methanol (42 mL) was added thionyl chloride (3.1 mL, 42.0 mmol) dropwise at 0 0C. The ice bath was removed after 30 minutes and the mixture continued to be stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and the residue was further dried on high vacuum to give methyl ester 2, which was dissolved in anhydrous THF ((70 mL) in a 500 mL round bottom flask. The solution was cooled to 0 0C and tri ethyl amine (9.7 mL, 69.3 mmol) was added, fol]owed quickly by addition of freshly prepared acetyl chloride 4 in anhydrous THF (70 mL) via canula at 0 0C. The mixture was stirred at 0~5 0C for another 1.5 hours then at room temperature for 30 minutes. The reaction was quenched by addition of cold 5% HCl and then diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed subsequently with brine, saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate and filtered. The solvents were evaporated under reduced pressure and the residue was purified via silica gel chromatography (Hexanes/Ethyl acetate, 2:1, 1.5:1) to give (2S)-1-[5-methoxy-2-nitro-4- (phenylmethoxy)-benzoyl]-2-indolinecarboxylic acid methyl ester 5 as a yel]ow solid (9.1 g, y = 94%). 1H NMR (400 MHz, CDCl3): the compound appears as three distinct rotomers. δ 8.27 (d, J = 8.4 MHz, 0.3H), 7.90 (s, 0.1H), 7.82 (s, 0.6H), 7.79 (s, 0.3H), 7.50-7.28 (m, 5.4H), 7.20-7.09 (m, 1.3H), 7.05 (s, 0.6H), 6.97-6.81 (m, 1.6H), 6.76 (s, 0.1H), 5.85 (d, J = 8.0 MHz, 0.1H), 5.70 (d, J = 8.0 MHz, 0.6H), 5.45-5.41 (m, 0.6H), 5.33-5.21 (m, 2.1H), 4.55 (dd, J1 = 10.8 MHz, J2 = 2.8 MHz, 0.3H), 3.98 (s, 1.8H), 3.94 (s, 0.9H), 3.83-3.81 (m, 2.4H), 3.62 (dd, J1 = 16.4 MHz, J2 = 11.4 MHz, IH), 3.56 (s, 0.9H), 3.27-3.13 (m, IH); 13C NMR (400 MHz, CDCl3): 171.5, 164.7, 155.2, 154.4,148.6, 148.3, 140.3, 137.4, 135.11, 135.05, 130.5, 129.2, 128.7, 128.4, 127.9, 127.6, 127.5,126.7, 125.5, 124.8, 124.3, 123.9, 117.6, 112.4, 110.1, 109.2, 108.8, 71.3, 71.2, 61.5, 60.2, 60.1, 56.7, 56.5, 52.5, 52.4, 33.6, 31.4; HRMS(ESI, m/z): calc. 463.1505 (M + H)+, found 463.1516.
99%
With thionyl chloride at -10 - 20℃;
99%
With thionyl chloride at 20℃; for 53h;
With thionyl chloride In methanol for 72h; Heating;
With thionyl chloride at 0 - 20℃; for 3.5h;
5.21 kg
With thionyl chloride at 0 - 25℃; for 16h; Large scale;
1.5 Step 5:
To a mixture of compound 6 (1.00 kg, 6.13 mol) in MeOH (10 L) was added SOCl2 (1.46 kg, 12.26 mol, 889.37 mL) drop wise at 0 °C. After the addition, the result mixture was stirred at 25 °C for 16 h. TLC (petroleum ether: ethyl acetate = 1: 1, Rf = 0.47) showed the reaction was completed. 5 batches of such reaction mixture were combined and concentrated under reduced pressure to dryness. Compound 6a (5.21 kg, 89.50% yield, HC1) was obtained as grey solid.
Multi-step reaction with 3 steps
1.1: 98 percent / aq. NaOH / dioxane / 12 h / 20 °C
2.1: aq. Cs2CO3 / methanol / 0.17 h / 20 °C
2.2: 90 percent / dimethylformamide / 12 h / 20 °C
3.1: TFA / CH2Cl2 / 1 h / 20 °C
Multi-step reaction with 2 steps
1: thionyl chloride / CH2Cl2 / 0.5 h / ice cooling
2: CH2Cl2 / 1 h / Heating
With sulfuric acid In methanol
37 Preparation of Methyl Indoline-2(S)-carboxylate
Preparation of Methyl Indoline-2(S)-carboxylate Indoline-2(S)-carboxylic acid (10 g, 64 mmol) was refluxed in a mixture of methanol (50 ml) and sulphuric acid (8 ml) for 5 h. The solvent was removed to give the product in the form of an oil.
With potassium carbonate In acetone at 50℃; for 24h; Inert atmosphere;
With potassium carbonate In DMF (N,N-dimethyl-formamide); acetone at 20℃;
27 Reference example 27; (2S)-1-methylindoline-2-carboxylic methyl ester
Reference example 27 (2S)-1-methylindoline-2-carboxylic methyl ester (S)-(-)-indoline-2-carboxylic acid (2.0g) was dissolved to a mixture of acetone (20ml) and N, N-dimethylformamide (20ml), and potassium carbonate (6.78g) and methyliodide (3.05ml) were added at room temperature.. The reactive mixture was stirred at room temperature over night, and then filtered.. The filtrate was concentrated by vacuum concentration and the obtained residue was diluted with ethyl acetate.. The solution is poured into water and the water layer has been extracted by ethyl acetate.. The organic layer was sequentially washed with water and saturated brine, and then dried by anhydrous sodium sulfate.. The residue by removal of the solvent was purified by silica gel column chromatography (hexane: ethyl acetate=4:1) to give a title compound (1.7g) having the following physical properties. TLC:Rf 0.70 (hexane: ethyl acetate=7:3); NMR(CDCl3):δ 7.11 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.70 (t, J = 7.5 Hz, 1H), 6.51 (d, J = 7.5 Hz, 1H), 4.05 (t, J = 9.6 Hz, 1H), 3.80 (s, 3H), 3.34 (dd, J = 15.6, 9.6 Hz, 1H), 3.13 (dd, J = 15.6, 9.6 Hz, 1H), 2.84 (s, 3H).
Stage #1: (S)-indoline-2-carboxylic acid methyl ester With sodium hydroxide; water at 20℃;
Stage #2: With hydrogenchloride; water at 20℃;
3
Example 3 [70] Preparation of (S) -indoline-2-Carboxylic Acid Through Hydrolysis; [71] Into a 250 ml reactor equipped with a pH meter, 8.1 g of (S)-indoline-2-carboxylic acid methyl ester prepared in Example 2 and 50 ml of 1N aqueous sodium hydroxide solution were placed and strongly stirred at room temperature. Whether (S) -indoline-2-carboxylic acid methyl ester was converted to (S)-indoline-2-carboxylic acid was confirmed. Then, while the temperature of the reactor was maintained at 20 C or less, 1N aqueous hydrochloric acid solution was slowly added to the reactor to control pH 5. The resultant reaction product was extracted three times with 50 ml of ethyl acetate by use of the separating funnel, and the organic layer was placed into a round bottom flask. The solvent in the organic layer was removed through distillation under reduced pressure, to give 7.0 g of (S) -indoline-2-carboxylic acid. The thus prepared (S) -indoline-2-carboxylic acid was analyzed for optical purity by means of liquid chromatography. [72] As for the liquid chromatographic conditions, a chiralpak AD column (Daicel) composed of amylose derivatives was used and hexane, isopropanol and triflu- oroacetic acid having a ratio of 95: 5: 0.1 as an eluent were applied at 1 ml/min. The reaction product was detected at UV 220 nm. As the reactants of the above reaction, (S) -indoline-2-carboxylic acid methyl ester was detected at 119 min, while (R) -indoline-2-carboxylic acid methyl ester was detected at 12.4 min. Further, as the hydrolyzed products, (S) -indoline-2-carboxylic acid was at 23.8 min, while (R) -indoline-2-carboxylic acid at 32.0 min. [73] Analytic results were represented by yield [%] and optical purity [% e. e. ], in which the yield of (S) -ester was calculated according to Equation 3, and the optical purity thereof accorded to Equation 2: 9
Stage #1: (S)-indoline-2-carboxylic acid; (R)-(-)-2,3-Dihydro-1H-Indole-2-Carboxylic Acid With sodium hydroxide In water at 170℃; for 3h; Racemisation;
Stage #2: With hydrogenchloride In water at 20 - 25℃;
B
Step B: Racemisation Introduce into an autoclave the precipitate obtained in Step A2 (2.6 kg), and then 12 litres of water and 3.1 litres of an 8.65N sodium hydroxide solution, then heat at 170° C. for 3 h under a pressure of 7 bars. The reaction mixture is subsequently brought to ambient temperature and then transferred to a reactor, and concentrated hydrochloric acid is subsequently added until a pH of 3.4 is reached while maintaining the temperature between 20 and 25° C. The mixture is then stirred for 1 h and the precipitate is subsequently filtered off, washed and dried to yield racemic indoline-2-carboxylic acid in a yield of 90% (2.34 kg).
With potassium carbonate;copper(l) chloride; In water; at 95℃; for 40h;Product distribution / selectivity;
A flask was charged successively with 3.00 g (15.0 mmol) (S)-2-amino-3-(2-chloro-phenyl)-propionic acid, 2.17 g (15.7 mmol) K2CO3, 15 mg CuCl (2.9 mmol) and 15 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95C and kept at this temperature for 22 h. Samples were taken regularly and analyzed by HPLC. The conversion after 22 h was approximately 40%. Then 15 mL water was added and the mixture stirred and heated for an additional 18 h. HPLC indicated full conversion of (S)-2-chlorophenylalanine. The reaction mixture was cooled to ca 25C. The pH of the solution was then decreased from 7.6 to ca 3.5. The precipitated (S)-2,3-dihydro-1H-indole-2-carboxylic acid was isolated by filtration and washed with 2 x 10 mL 0.01 aqueous M HCl. Found after drying 1.88 g (11.5 mmol) (S)-2,3-dihydro-1 H-indole-2-carboxylic acid. Yield 76.6 %, ee > 99%.
76.6%
Step (iii):; (S)-2,3-dihvdro-1 H-indole-2-carboxylic acid: Conversion of (S)-2-amino-3-(2- chloro-phenyD-propionic acid with 1 mol% CuCI in water at 95C; A flask was charged successively with 3.00 g (15.0 mmol) (S)-2- amino-3-(2-chloro-phenyl)-propionic acid, 2.17 g (15.7 mmol) K2CO3, 15 mg CuCI (2.9 mmol) and 15 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95C and kept at this temperature for 22 h. Samples were taken regularly and analyzed by HPLC. The conversion after 22 h was approximately 40%. Then 15 mL water was added and the mixture stirred and heated for an additional 18 h. HPLC indicated full conversion of (S)- 2-chlorophenylalanine. The reaction mixture was cooled to ca 25C. The pH of the solution was then decreased from 7.6 to ca 3.5. The precipitated (S)-2,3-dihydro-1 H- indole-2-carboxylic acid was isolated by filtration and washed with 2 x 10 mL 0,01 M EPO <DP n="33"/>HCI. Found after drying 1.88 g (11.5 mmol) (S)-2,3-dihydro-1 H-indole-2-carboxylic acid. Yield 76.6 %, ee > 99%.
With potassium carbonate;copper(l) chloride; In 1-methyl-pyrrolidin-2-one; at 80 - 100℃; for 3.5 - 4h;Product distribution / selectivity;
Example 1 (S)-2,3-dihydro-1 H-indole-2-carboxylic acid: Conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> with 2 molpercent CuCl in NMP at 100°C A flask was charged successively with 366 mg (1.5 mmol) <strong>[42538-40-9](S)-2-bromophenylalanine</strong>, 217 mg (1.6 mmol) K2CO3, 3.2 mg (0.03 mmol) CuCl and 3.2 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 100°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 4 hours, full conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> was found. The yield (measured in solution) of (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was 95.9 percent, ee > 98.6percent.; Example 2 (S)-2,3-dihydro-1H-indole-2-carboxylic acid: Conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> with 1 molpercent CuCl in NMP at 80°C A flask was charged successively with 9.76 g (40.0 mmol) <strong>[42538-40-9](S)-2-bromophenylalanine</strong>, 5.80 g (42.0 mmol) K2CO3, 40 mg (0.4 mmol) CuCl and 40 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 80°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 3.5 h full conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> was found. The reaction mixture was cooled to 25°C and then 40 mL H2O and 50 mL aqueous EtOAc were added. The pH of this mixture was adjusted to 3.3 with 3.5 g 37percent aqueous HCl. The phases were separated. The H2O phase was extracted with 2 x 50 mL aqueous EtOAc. The combined organic layers were washed with 25 mL sat aqueous NaCl. Then the organic phase was concentrated. The residu was dissolved in 16 mL 5N aqueous HCl, followed by pH adjustment to 2.1 with 9.4 g 32percent aqueous NaOH. The precipitated (S)-2,3-dihydro-1H-indole-2-carboxylic acid was isolated by filtration and washed with 2 x 10 mL H2O. 3.24 g (19.8 mmol) (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was found after drying. Yield 49.5percent, ee >99percent.
95.6%
With potassium carbonate; In water; at 95℃; for 22h;Product distribution / selectivity;
A flask was charged successively with 366 mg (1.5 mmol) <strong>[42538-40-9](S)-2-bromophenylalanine</strong>, 217 mg (1.6 mmmol) K2CO3 and 3 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 5h hour the conversion was approximately 37percent. After 22h full conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> was found. The reaction mixture was cooled to 25°C and analyzed by HPLC. The yield in solution of (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was 95.6 percent, ee > 99percent.
81.1%
With potassium carbonate;copper(l) chloride; In water; at 95℃; for 2 - 4h;Product distribution / selectivity;
Example 3 (S)-2,3-dihydro-1 H-indole-2-carboxylic acid: Conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> with 2 molpercent CuCl in water at 95°C A flask was charged successively with 366 mg (1.5 mmol) <strong>[42538-40-9](S)-2-bromophenylalanine</strong>, 217 mg (1.6 mmol) K2CO3, 3 mg (0.03 mmol) CuCl and 3.4 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 2 hour full conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> was found. The reaction mixture was cooled to 25°C and analyzed by HPLC. The yield in solution of (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was 81.1 percent, ee > 99percent.; Example 4 (S)-2,3-dihydro-1 H-indole-2-carboxylic acid: Conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> with 0.01 molpercent CuCl in water at 95°C A flask was charged successively with 4.89 g (20.0 mmol) <strong>[42538-40-9](S)-2-bromophenylalanine</strong>, 2.93 g (21.2 mmol) K2CO3, 0.2 mg CuCl (2.9 mmol) and 39.7 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 4h hour full conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> was found. The reaction mixture was cooled to 25°C. Then the reaction mixture was acidified with 4.47 g 5M aqueous HCI until pH = 4.4. The precipitated (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was isolated by filtration and washed with 2 x 10 mL H2O. Found after drying 2.24 g (13.7 mmol) (S)-2,3-dihydro-1 H-indole-2-carboxylic acid. Yield 69percent, ee >99percent.
69%
Example 4; (S)-2,3-dihydro-1 H-indole-2-carboxylic acid: Conversion of (S)-2- bromophenylalanine with 0.01 molpercent CuCI in water at 95°C EPO <DP n="30"/>; A flask was charged successively with 4.89 g (20.0 mmol) (S)-2- bromophenylalanine, 2.93 g (21.2 mmol) K2CO3, 0.2 mg CuCI (2.9 mmol) and 39.7 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 4h hour full conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> was found. The reaction mixture was cooled to 25°C. Then the reaction mixture was acidified with 4.47 g 5M aqueous HCI until pH = 4.4. The precipitated (S)-2,3-dihydro-1H-indole-2-carboxylic acid was isolated by filtration and washed with 2 x 10 ml_ H2O. Found after drying 2.24 g (13.7 mmol) (S)-2,3-dihydro-1H- indole-2-carboxylic acid. Yield 69percent, ee >99percent.
49.5%
Example 2; (S)-2,3-dihydro-1H-indole-2-carboxylic acid: Conversion of (S)-2- bromophenylalanine with 1 molpercent CuCI in NMP at 800C; A flask was charged successively with 9.76 g (40.0 mmol) (S)-2- bromophenylalanine, 5.80 g (42.0 mmol) K2CO3, 40 mg (0.4 mmol) CuCI and 40 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 800C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 3.5 h full conversion of (S)- 2-bromophenylalanine was found. The reaction mixture was cooled to 25°C and then 40 ml_ H2O and 50 mL aqueous EtOAc were added. The pH of this mixture was adjusted to 3.3 with 3.5 g 37percent aqueous HCI. The phases were separated. The H2O phase was extracted with 2 x 50 mL aqueous EtOAc. The combined organic layers were washed with 25 mL sat aqueous NaCI. Then the organic phase was concentrated. The residu was dissolved in 16 mL 5N HCI, followed by pH adjustment to 2.1 with 9.4 g 32percent aqueous NaOH. The precipitated (S)-2,3-dihydro-1H-indole-2- carboxylic acid was isolated by filtration and washed with 2 x 10 mL H2O. 3.24 g (19.8 mmol) (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was found after drying. Yield 49.5percent, ee >99percent.
95.9%Chromat.
With potassium carbonate; copper(l) chloride; In 1-methyl-pyrrolidin-2-one; at 100℃; for 4h;Product distribution / selectivity;
Examplei; (S)-2,3-dihydro-1H-indole-2-carboxylic acid: Conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> with 2 molpercent CuCI in NMP at 1000C; A flask was charged successively with 366 mg (1.5 mmol) (S)-2- bromophenylalanine, 217 mg (1.6 mmol) K2CO3, 3.2 mg (0.03 mmol) CuCI and 3.2 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon.The reaction mixture was stirred and heated until 1000C and kept at this temperature.Samples were taken regularly and analyzed by HPLC. After 4 hours, full conversion of<strong>[42538-40-9](S)-2-bromophenylalanine</strong> was found. The yield (measured in solution) of (S)-2,3- dihydro-1 H-indole-2-carboxylic acid was 95.9 percent, ee > 98.6percent.
81.1%Chromat.
With potassium carbonate; copper(l) chloride; In water; at 95℃; for 2h;Product distribution / selectivity;
Example 3; (S)-2,3-dihydro-1 H-indole-2-carboxylic acid: Conversion of (S)-2- bromophenylalanine with 2 molpercent CuCI in water at 95°C; A flask was charged successively with 366 mg (1.5 mmol) (S)-2- bromophenylalanine, 217 mg (1.6 mmol) K2CO3, 3 mg (0.03 mmol) CuCI and 3.4 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 2 hour full conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> was found. The reaction mixture was cooled to 25°C and analyzed by HPLC. The yield in solution of (S)-2,3-dihydro-1H-indole-2-carboxylic acid was 81.1 percent, ee > 99percent.
95.6%Chromat.
With potassium carbonate; In water; at 95℃; for 22h;Product distribution / selectivity;
Example 5; (S)-2,3-dihydro-1H-indole-2-carboxylic acid: Conversion of (S)-2- bromophenylalanine without CuCI in water at 95°C; A flask was charged successively with 366 mg (1.5 mmol) (S)-2- bromophenylalanine, 217 mg (1.6 mmmol) K2CO3 and 3 g H2O. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 95°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 5h hour the conversion was approximately 37percent. After 22h full conversion of <strong>[42538-40-9](S)-2-bromophenylalanine</strong> was found. The reaction mixture was cooled to 25°C and analyzed by HPLC. The yield in solution of (S)-2,3-dihydro-1 H- indole-2-carboxylic acid was 95.6 percent, ee > 99percent.
EXAMPLE 20 STR55 A) Preparation of Cbz-D-hPro-Ohi-OH
EXAMPLE 20 STR55 A) Preparation of Cbz-D-hPro-Ohi-OH HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%).
78%
With hydrogenchloride In ethanol
15 EXAMPLE 20 STR61 A) Preparation of Cbz-D-hPro-Ohi-OH.
EXAMPLE 20 STR61 A) Preparation of Cbz-D-hPro-Ohi-OH. HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%).
78%
With hydrogenchloride In ethanol
20.A A)
A) Preparation of Cbz-D-hPro-Ohi-OH HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%).
78%
With hydrogenchloride In ethanol
EXAMPLE 20 STR50 A) Preparation of Cbz-D-hPro-Ohi-OH
EXAMPLE 20 STR50 A) Preparation of Cbz-D-hPro-Ohi-OH HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%).
78%
With hydrogenchloride In ethanol
EXAMPLE 20 STR61 A) Preparation of Cbz-D-hPro-Ohi-OH
EXAMPLE 20 STR61 A) Preparation of Cbz-D-hPro-Ohi-OH HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (500 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. to give (S)-indoline-2-carboxylic acid ethyl ester.HCl (25.7 g, 78%).
7.A Synthesis of D-hPro-cis-Ohi-ArgH.2 HCl (N-[(1-D-homoprolyl-cis-octahydro-1H-indol-2(S)-yl)carbonyl]-L-argininal dihydrochloride)
A) Preparation of (S)-cis-octahydroindole-2-carboxylic acid ethyl ester.HCl. HCl gas was bubbled through a stirring suspension of (S)-indoline-2-carboxylic acid (20 g, 110 mmol) in ethanol (400 mL). When the acid was completely dissolved, the solution was brought to reflux. After 16 hours, the solution was cooled and the solvent removed in vacuo. The residue was triturated with diethyl ether and the resulting off-white solid was collected by filtration, washed with hexanes and dried overnight in a vacuum oven at 30° C. (25.5 g, 100%). This solid, (S)-indoline-2-carboxylic acid ethyl ester hydrochloride, was dissolved in ethanol (455 mL). To this was added 5% Pd/C (25.5 g) and the resulting suspension was hydrogenated on a Parr shaker for 8 hours (4.1 bar, 60 psi). The solution was filtered to remove catalyst and the filtrate was concentrated in vacuo. The residue was triturated with diethyl ether and the resulting solid was isolated by filtration to give 18.8 g (73%) of a white powder. 1 H NMR FD-MS m/e 197 (M+) Analysis for C11 H19 NO2.HCl: Calc: C, 56.53; H, 8.63; N, 5.99; Found: C, 56.24; H, 8.44; N, 6.00.
1
The suspension of the above salt (5.15 g) in water (25 mL) was cooled to 0-5 °C andtreated with 15% NaOH solution to pH 2.9. The resulting suspension was filtered and rinsed with water. The solid was dried under vacuum to give 1.9 g of (»S)-mdolme-2-carboxylic acid, [α]o20 = -113.2 (c 1, IN HCl). A sample was converted to N-acetyl-indoline-2-carboxylic acid and analysis by chiral HPLC and showed 99.8% £ enantiomer.
Stage #1: 3,6-dichlorpyridazine; (S)-indoline-2-carboxylic acid With sodium t-butanolate In tetrahydrofuran at 20℃; for 0.5h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran
38
Reference Example 38 Preparation of (S)-1-(6-chloropyridazin-3-yl)indoline-2-carboxylic acid: 14.1 g of Sodium tert-butoxide was suspended in 100 ml of tetrahydrofuran, and thereto was added a suspension of 10 g of (S)-indoline-2-carboxylic acid in 50 ml of tetrahydrofuran at room temperature under nitrogen atmosphere, followed by adding dropwise a solution of 9.6 g of 3,6-dichloropyridazine in 40 ml of THF. The mixture was stirred for 30 minutes at room temperature, and thereto was added 500 ml of water under ice-cooling. Then, the mixture was allowed to be acidic (pH 3-4) by adding 1 mol/l hydrochloric acid. The precipitated crystal was filtrated, washed with water and dried to give 13.7 g of the desired compound. Melting point: 211-212°C
With N-ethyl-N,N-diisopropylamine In water; N,N-dimethyl-formamide at 0 - 20℃;
39
(S)-2,3-Dihydro-indole-l,2-dicarboxylic acid 1-benzyl ester(S)-2,3-Dihydro-lH-indole-2-carboxylic acid (254.4 mg, 1.6 mmol) was dissolved in DMF (15 mL) and distilled water (6 mL). The solution was cooled to 00C, and DIPEA (400 μL, 2.3 mmol) was added followed by benzyl chloroformate (0.330 mL, 2.3 mmol). The reaction was stirred at 00C and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.
With methyl dichlorophosphite; triethylamine; 1-methyl-3-methylimidazol-3-ium dimethyl phosphate In toluene at 145℃; for 1h; Microwave irradiation; stereoselective reaction;
With methyl dichlorophosphite; triethylamine; 1-methyl-3-methylimidazol-3-ium dimethyl phosphate In toluene at 145℃; for 1h; Microwave irradiation; stereoselective reaction;
Stage #1: C9H9NO2*C17H17Cl2N With sodium hydroxide In water; ethyl acetate
Stage #2: With hydrogenchloride In water
4 Preparation of (S)-Indoline-2-Carboxylic Acid
EXAMPLE 4 Preparation of (S)-Indoline-2-Carboxylic Acid 80 g of (S)-Indoline-2-carboxylic acid salt is suspended in 300 ml of ethyl acetate at 30° C. 150 ml of DM water is added to the suspension and stirred for 20 min. 15% NaOH solution is slowly added and adjusted pH to above 10. The clear solution is stirred and the layers are separated. The pH of aq layer is adjusted at about 4 to 5 with dil. HCl. The precipitate is cooled, filterer and washed with water. Dry the material at 60-65° C. to get 24.1 g of pure material. Melting range 171° C.-173° C. (decomposition) Specific optical rotation (at 26° C.) -117.38° (C = 1, IN HCl)
Stage #1: (S)-indoline-2-carboxylic acid With triethylamine In tetrahydrofuran at 20℃; for 0.166667h;
Stage #2: L-N-Boc-Ala With dicyclohexyl-carbodiimide at 20℃; for 6h;
1 EXAMPLE 1; Methyl(2S)-1-{(2S)-2-[(tert-butyloxycarbonyl)-amino]-propionyl}-2,3-dihydro-1H-indole-2-carboxylate
EXAMPLE 1 Methyl(2S)-1-{(2S)-2-[(tert-butyloxycarbonyl)-amino]-propionyl}-2,3-dihydro-1H-indole-2-carboxylate. There are introduced into a reactor, with stirring, 2.13 kg of methyl(2S)-2,3-dihydroindole-2-carboxylate, 1 kg of triethylamine, 30 litres of tetrahydrofuran and then, after 10 minutes' stirring at room temperature, 1.9 kg of N-[tert-butyloxycarbonyl]-(S)-alanine and 2 kg of dicyclohexylcarbodiimide. The heterogeneous mixture is then stirred at room temperature for 6 hours, and is subsequently cooled to 0° C. and filtered. The filtrate is then washed and recrystallised from a mixture of hexane/ethyl acetate 10/1 to yield the expected product in a yield of 81% and with a chemical purity of 98%. Melting Point: 130-131° C. Elemental Microanalysis: C% H%N% calculated 62.05 6.94 8.04 found 61.80 6.94 8.00
(2S)-1-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: (S)-indoline-2-carboxylic acid With potassium carbonate In water
Stage #2: 2,2-dimethylchromane-6-sulfonyl chloride In water; acetonitrile at 20℃; for 5h;
Stage #3: With hydrogenchloride In water; ethyl acetate; acetonitrile
IL
1 g (6.13 mmol) of 2,3-dihydro-(2S)-1H-indole-2-carboxylic acid, and 0.97 g (7.05 mmol) of potassium carbonate are solubilised in 2 ml of water. 1.6 g (6.13 mmol) of 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-sulfonyl chloride solubilised in 12 ml of acetonitrile and 2 ml of water are added. Agitation is allowed to take place for 5 hours at ambient temperature. Water is added to the reaction medium, washing is performed with ethyl acetate, the acidity of the aqueous phase is raised to pH 3 by a solution of hydrochloric acid 1 N, and then extraction is performed using ethyl acetate. The organic phases are collected, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/methanol (9/1; v/v) mixture. The expected product is obtained in the form of a beige foam with a yield of 73%. NMR 1H (DMSO, 300 MHz) δ: 7.59 (s, 1H); 7.44 (m, 1H); 7.31 (m, 1H); 7.20-7.05 (m, 2H); 6.96 (t, 1H); 6.75 (d, 1H); 7.74 (s wide, 1H); 3.1-2.85 (m, 2H); 2.85-2.60 (m, 2H); 1.73 (t, 2H); 1.25 (m, 6H).
4
In a first step, we prepared (S)-1-((5-(dimethy- lamino)naphthalene- 1 -yl)sulfonyl)indoline-2-carboxylicacid. Dansyl chloride (1.65 g, 6.13 mmol) was added to a stirred solution of (s)-(-)-indoline-2-carboxylic acid (1 g, 6.13 mmol) with K2C03 in DCM. The mixture was allowed to stir overnight and was quenched with the addition of 1 M sulthric acid. The solution was then extracted with 1 M sulthnc acid and the organic layers were dried over sodium sulfate. After filtration, the solvent was evaporated and the residue was purified over a column using 0-10% MeOH in DCM yielding 1.28 g of a yellow solid (53%).Characterization of prepared (5)- 1 -((5-(dimethy- lamino)naphthalene- 1 -yl)sulfonyl)indoline-2-carboxylicacid: ‘HNMR, DMSO-d5, 400 MHz ö: 13.23 (1H, s-br), 8.44 (1H, d), 8.19 (1H, d), 8.16 (1H, d), 7.56 (2H, m), 7.21 (1H, d), 7.13 (3H, m), 6.92 (1H, t), 5.06 (1H, dd), 3.36 (1H, dd), 3.07 (1H, dd), 2.77 (6H, s).
N-Tosyl-(S)-indoline-2-carboxylic acid (1f).
A solution of (S)-indoline-2-carboxylic acid (0.49 g, 3.0 mmol) in pyridine (12 ml) was cooled to 0°C, TsCl (0.69 g, 3.6 mmol) was added. The reaction mixture was stirred for 1 h at room temperature. The obtained solution was poured into H2O (120 ml), washed with CHCl3 (2×20 ml), then acidified with 4 N HCl to pH 2-3, and extracted with EtOAc (3×40 ml). The organic layer was washed with saturated aqueous NaCl solution (3×40 ml), dried over MgSO4, treated with activated carbon, and evaporated. The precipitate was recrystallized from H2O-MeOH mixture (7.0 : 5.5 ml). Yield 0.68 g (71%). Colorless powder. Mp 159-162° (H2O-MeOH). [α]D20 +120° ( 1.0, MeOH). 1H NMR spectrum, δ, ppm (J, Hz): 2.38 (3H, s, CH3); 3.11 (1H, dd, J = 16.5, J = 10.7) and 3.24 (1H, dd, J = 16.5, J = 4.2, 3-CH2); 4.77 (1H, dd, J = 10.7, J = 4.2, 2-); 7.03-7.08 (2H, m, indoline); 7.22-7.26 (3H, m, indoline, H Ts); 7.62-7.64 (3H,845m, indoline, H Ts); 3.0-9.0 (1H, br. s, COOH). Found, %: C 60.57; H 4.89; N 4.72; S 10.03. C16H15NO4S. Calculated, %: C 60.55; H 4.76; N 4.41; S 10.10.
60%
With triethylamine In dichloromethane
44%
With potassium carbonate In dichloromethane
3
In a first step, we prepared the intermediate (S)-i - tosylindoline-2-carboxylic acid. p-Toluene sulfonyl chloride (1.17 g, 6.13 mmol) was added to a stirred solution of(s)-(-)indoline-2-carboxylic acid (1 g, 6.13 mmol) with K2C03 in DCM. The mixture was allowed to stir overnight and was quenched with the addition of 1M sulfuric acid. The solution was then extracted with 1 M sulfuric acid and the organic layers were dried over sodium sulfate. Afier filtration, the solvent was evaporated and the residue was purified over a column using 0-10% MeOH in DCM yielding 852 mg of a sticky oil (44%).Characterization of (S)-i -tosylindoline-2-carboxy- lic acid: ‘HNMR, DMSO-d5, 400 MHz ö: 7.64 (2H, d), 7.43 (1H, d), 7.31 (2H, d), 7.18 (1H, t), 7.07 (1H, d), 6.97 (1H, t), 4.70 (1H, dd), 3.03 (1H, dd), 2.87 (1H, dd), 2.30 (3H, s).
With triethylamine In tetrahydrofuran; water at 90 - 125℃; for 12.25h; Microwave irradiation;
1
General procedure: General procedure B A solution of amino nucleophile (3 equiv.), triethylamine (10 equiv.), and Intermediate 1 (1 equiv.) was stirred in dioxane and water (2:1 ratio) at 90 °C until complete consumption of starting material was observed by LC/MS. The solution was diluted withiN hydrochloric acid and dichloromethane. The layers were then separated and thelayer was extracted with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification yielded theproduct The title compound was prepared following general procedure B, except (S)-indoline-2-carboxylic acid was the amine reactant (1 equiv.), and the contents were heated at 90°C for 12 has a solution in THF/water (1:1), followed by heating at 125 °C for 15 mm in the microwave. The contents extracted with ethyl acetate during workup. The crude material was purified via by reverse phase HPLC using 5 to 95% acetonitrile in water spiked with 0.1% trifluoroacetic acid to afford the desired compound, Compound 1-90 (3.9 mg, 15% yield) as an off-white solid.1H-NMR (500 MHz, DMSO-d6) ö (ppm): 9.10 - 9.21 (d, 1H), 8.61 - 8.75 (m, 1H), 8.47 - 8.57 (d, 1H), 7.49 - 7.58 (s, 1H), 7.33 - 7.41 (m, 1H), 7.22 - 7.33 (m, 4H), 7.10 - 7.20 (m, 2H), 6.98- 7.10 (m, 1H), 5.95 (s, 2H), 5.39 - 5.53 (m, 1H), 3.64 - 3.74 (dd, 1H), 3.20 - 3.32 (dd, 2H).
With sulfuric acid; nitric acid at -20 - 20℃; for 3h;
Ethyl (25)-6-mtro-2,3-dihydro-lH-indole-2-carboxylate (2 g, 8.474 mmol) and 10% Pd on activated carbon (0.4 g, 20% wt./wt.) in ethanol (60 mL) was stirred under hydrogen (balloon) for 3 hrs. The reaction mixture was filtered through a bed of CELITE and washed with ethanol (4 X 30 mL). Collected filtrate was concentrated and dried well under vacuum to yield I-ll as pale yellow oil (1.4 g, 80%). 1H NMR (400 MHz, CDC13) δ 1.14-1.18 (3H, t, J=8 Hz), 2.94-3.01 (3H, m), 3.30 (1H, s), 4.57-4.61 (1H, t, J=8 Hz), 7.45-7.48 (1H, q, J=4 Hz), 8.03 (1H, s), 8.06- 8.09 (IH, m), 8.41-8.42 (IH, d, J=4 Hz), 8.96-8.97 (IH, d, J=4 Hz), MS (LC/MS) m/z observed 207.09, expected 207.1 1 [M+H].
With amidase from Cupriavidus necator JMP134; water In aq. phosphate buffer at 30℃; Enzymatic reaction; stereoselective reaction;
2.4. Enzyme assay
General procedure: During the purification and characterization of amidase from Cupriavidus sp. KNK-J915, an enzyme assay was performed with (R,S)-BNPD as a substrate. The standard reaction mixture (0.2 mL) contained 100 mM potassium phosphate buffer (pH 7.0), 45.8 mM BNPD, and an appropriate amount of the enzyme. After the reaction was performed at 30°C for 0.5-1 h, the amount of BNPA was determined using HPLC. One unit of the enzyme was defined as the amount catalyzing the formation of 1 mol of BNPA per minute under the aforementioned condition. Protein content was determined by the Bradford method [11] with BSA as a standard using a kit from Bio-Rad Laboratories Ltd. (Tokyo, Japan).
With potassium carbonate; copper(I) bromide In water at 100 - 105℃; Inert atmosphere;
1.5-a Step 5-a: (S) -indoline-2-carboxylic acid (Formula IA)
At room temperature,Protected by nitrogen in a 500 mL three-necked flask,Then add the product obtained in step 4-1(0.3 mol, 84.2 g),Potassium carbonate (0.6 mol, 83.0 g),Cuprous bromide (1.4 mmol, 0.2 g) and water 250 mL,Mechanical agitation,The reaction solution was dissolved.Heating up to 105 ,Maintaining the reaction system temperature of 100 ~ 105 ,Reflux reaction.TLC (developing agent is n-hexane: ethyl acetate = 2: 1) to the raw material point to complete the reaction.The reaction solution was poured directly into 2 L of ice water,There are a lot of light yellow solid precipitation, pumping filter,The filter cake was washed three times with 50 mL of water, dried in vacuo,To obtain 42.2 g of a pale yellow solid, the yield was 86.2%Purity 99.5% (HPLC),
2.5-b Step 5-b: (S) -indoline-2-carboxylic acid (Formula IA)
The product obtained in step 4-2 (0.25 mol, 54.8 g) was added to a 500 mL three-necked flask,And the newly prepared 30% sulfuric acid aqueous solution 300mL,Heated to reflux.Solid gradually dissolved,TLC (developing solvent: chloroform: methanol: triethylamine = 6: 4: 1)Tracking to the raw point of the reaction is complete, stop heating,Naturally cool to room temperature.Then adjust the pH to 4 to 5 with 10% aqueous sodium hydroxide solution,A large amount of white solid precipitated. Filter,The filter cake was washed three times with 50 mL of water, dried in vacuo,A white solid was obtained 35.4 g,The yield was 86.8%Purity 97.1% (HPLC),
With carbon disulfide; carbon dioxide; hydrogen iodide; hydrogen; potassium iodide In ethanol at 90℃; for 5h; Autoclave; Large scale;
3 Example 3
In a 1000 ml autoclave, 78 g of indole-2-carboxylic acid and 200 ml of ethanol were added. After adding 8 g of phosphorus iodide and a concentrated hydroiodic acid catalyst, the mixture was filled with carbon dioxide to a pressure of 5 kg. After re-evacuating three times, Pressure to 10 kg, and then re-exhaust gas three times, after the exhaust gas flushing carbon disulfide pressure to 20 kg, and then hydrogen pressure 35 kg, temperature 90 ° C hydrogenation, until the hydrogen pressure is not reduced, the reaction time of about 5 hours, the reaction was completed Cooling exhaust, discharging, suction filtration catalyst recovery, and then recovered ethanol after distillation colorless liquid 56 grams, a yield of 87.5%, a purity of 93.5%.
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 50℃; for 1h;
481.1 Step 1
Step 1 To a 40-mL vial was added (4-(trifluoromethyl)phenyl)methanamine (0.32 g, 1.84 mmol), (S)-(-)-indoline-2-carboxylic acid (0.30 g, 1.84 mmol), ethyl acetate (6.1 mL), pyridine (3.1 mL), and 1-propanephosphonic acid cyclic anhydride (1.84 mL, 1.84 mmol). The vial was capped and heated to 50° C. for 1 h. The reaction was concentrated and purified by silica gel chromatography using 0-50% EtOAc/heptane to give (rac)-N-(4-(trifluoromethyl)benzyl)indoline-2-carboxamide (0.336 g). LCMS-ESI (POS.) m/z: 321.2 (M+H)+.
Stage #1: (S)-indoline-2-carboxylic acid; isopropyl alcohol In tetrahydrofuran at 20℃; for 0.333333h;
Stage #2: With sulfuryl dichloride In tetrahydrofuran for 3h; Reflux;
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