| 92.4% |
With sodium carbonate In dichloromethane at -5 - 5℃; for 2h; |
1.1; 2.1 Step 1. Preparation of Compound I
10.0 g of L-prolinamide,23.2g sodium carbonate and 200mL dichloromethane were added to a 1000mL three-neck bottle.Mechanically agitated and cooled to -5 ° C,Add 11.9 g of chloroacetyl chloride,After the feeding is completed,The reaction was carried out at 5 ° C for 2 hours, filtered, and washed with 200 mL of acetone.Combine the organic phases and concentrate to near dryness.Add 60 mL of isopropyl ether, stir, filter, and dry to constant weight at 45 ° C.Obtaining 15.4 g of Compound I,The yield was 92.4%, and the HPLC purity was 99.34%. |
| 90.7% |
Stage #1: chloroacetyl chloride; L-prolinamide In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: With potassium carbonate In tetrahydrofuran at 0 - 20℃; for 4h; |
1 Synthesis of (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide
The compound S-prolinamide (11.2 g, 100mmol) add to a solution of chloroacetyl chloride (11.5 g, 100mmol) in tetrahydrofuran solution (200mL) which has been pre-cooled at 0 ° C, the solution is incubated at 0 ° C for 30 minutes, Potassium carbonate (27. 3g, 200mmol) is added to the mixed solution, the resulting mixed solution is incubated with stirring at 0 ° C for 1 hour, the reaction solution is then warmed at room temperature and stirring is continued for 3 hours.LC detection to the end of reaction, until the compound S-prolinamide disappeared completely after that, the reaction is filtered; the filter cake is washed with tetrahydrofuran (50mL), the combined filtrates. Rotate the solvent to get dryness, the residual oil is added to ethyl acetate to dissolve. The resulting ethyl acetate solution is washed with water (50mL × 2), dry over anhydrous sodium sulfate for 2 hours. After removing the desiccant, it is concentrated. After drying, obtained 17.2 g of compound (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (colorless oil), yield is 90.7%. |
| 89% |
With potassium carbonate In tetrahydrofuran |
|
| 89% |
With potassium carbonate In tetrahydrofuran at 20℃; for 18h; |
|
| 89.5% |
In tetrahydrofuran at 60℃; |
2 Example 2
11.4 g (0.1 mol) of L-prolinamide was dissolved in 100 ml of tetrahydrofuran at 60 degrees, and 15 ml (0.2 mol) of chloroacetyl chloride was added. The temperature of the system was maintained at 60 degrees. The end point of the reaction was detected by HPLC and the reaction was completed after one hour. Heat filtration, washing the solids with tetrahydrofuran, drying and weighing to give a pale yellow solid 20.3g, yield 89.5%, purity 98.2%. |
| 89.3% |
With methyloxirane In tetrahydrofuran at -20 - 0℃; for 2h; |
1-6 Example 6
Weigh 100g of L-proline amide into a 2000mL four-neck flask, add 1000mL of THF,Increase the temperature to 40 ° C under stirring to dissolve the L-proline amide, and cool to -20 ° C after dissolution.100g of propylene oxide (2.00eq) was added, and 178.1 chloroacetyl chloride (1.79eq) was added dropwise. After the dropwise addition was completed, the reaction was held for 1 hour.The temperature was raised to 0 ° C, the reaction was held for 1 h, and filtered with suction to obtain a white solid.The product was washed with THF and dried under vacuum at 40 ° C to obtain 149.1 g of the product, with a yield of 89.3% and an HPLC detection content of 99.63%. |
| 85% |
With potassium carbonate In acetonitrile at 10 - 20℃; for 1h; |
1 Example 1: Preparation of (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide,• compound of Formula IV.
In a clean round bottom flask, 100gm L-prolinamide, 1800m1 acetonitrile and 290.16gm K2C03were charged. The reaction mass was stirred, cooled to about 10-20°C and 108.8gm ofchioroacetyl chloride was added. Temperature of reaction mass was raised to about RT, stirred for about one hour, filtered, washed with acetonitrile and concentrated under vauum. 300m1 ethyl acetate was added to reaction mass, stirred at about 50-5 5 °C, cooled to about 0-5 °C and stirred for about 1-2 hour. The reaction mass was filtered, washed with ethyl acetate and driedunder vacuum and product isolated as a solid 13 0-140gm. (Yield: 77- 85%; HPLC purity >97%). Impurity H is less than 0.2% w/w relative to the amount of compound of formula IV as determined by HPLC. |
| 80.5% |
With potassium carbonate In acetonitrile at 0 - 10℃; for 2h; |
1; 1; 2 Synthesis of Compound 1 of Example 1
80 g of L-prolinamide was added to a 2000 mL reaction flask.145.3 g of potassium carbonate and 1600 ml of acetonitrile were stirred and lowered to 0 to 10 ° C, and a mixed solution of 102.9 g of chloroacetyl chloride and 200 ml of acetonitrile was added dropwise over 2 hours.010°C, stir and stir for 2h,The reaction was completely detected by TLC, filtered, and washed with 160 ml of acetonitrile.The filtrate was concentrated under reduced pressure until the remaining 200-300 ml of the reaction solution.Cool down to -5 to 10 ° C, incubate for 2 h, filter,Wash with 80 ml of cold acetonitrile. The filter cake was dried under vacuum at 40 to 50 ° C to obtain Intermediate -1 107.5 g, yield 80.5%, purity 97.8%. |
| 48% |
With potassium carbonate In chloroform at 30℃; for 15.5h; Inert atmosphere; |
|
|
With sodium 2-ethylhexanoic acid In tetrahydrofuran Yield given; |
|
|
In DMF (N,N-dimethyl-formamide); Isopropyl acetate at 15 - 35℃; for 2.75h; |
1.a Examples Example 1) Preparation of PYRROLIDINE, 1- [ (3-HYDROXY-1-ADAMANTYL) AMINO] ACETYL-2-CYANO-, (S): Step (a)
A 1500 ml reactor, equipped with a mechanical stirrer, is charged with 212 G isopropyl-acetate and 19.8 G dimethylformamide. The reactor is inertized. At about IT (internal temperature) 15 °C, 125 G CHLOROACETYLCHLORIDE is added within 15 min. , after complete addition the IT is adjusted to about 15 °C, and a solution of 110 G L-prolinamide in 304 G DIMETHYLFORMAMIDE is added within 1 h. The addition funnel is rinsed with 18 G isopropyl-acetate. The reaction mixture is warmed to about IT 35 °C for 1.5 h. |
|
With potassium carbonate In tetrahydrofuran at 20℃; for 2.75h; |
1.B
To a mechanically stirred solution of 20.0 g (180.0 mmol) of chloroacetylchloride and 97 g (0.70 mmol) of potassium carbonate in 150 mL of tetrahydrofuran is added a solution of L-prolinamide 20.0 g (180.0 mmol) in 500 mL of tetrahydrofuran in a dropwise fashion over 45 minutes. This reaction is then mechanically stirred for an additional two hours at room temperature. The reaction is then filtered to remove potassium salts and the filtrate is dried over Na2SO4. The Na2SO4 is then removed via filtration and to this colorless filtrate is added trifluoroacetic anhydride (25.0 mL, 0.180 mmol) in one portion. The reaction is then magnetically stirred for 1 hour at room temperature and the resulting clear yellow/orange solution is concentrated via rotovap. The excess trifluoroacetic anhydride is removed by adding ethyl acetate to the concentrated oil and reconcentrating via rotovap. This removing operation is performed three times.The resulting oil is partitioned between ethyl acetate and water. The product is then extracted into the ethyl acetate and the aqueous layer is then washed twice with ethyl acetate. The combined organic layers are then washed successively with water and brine dried over magnesium sulfate, filtered and concentrated to obtain 1-chloroacetyl-2-cyanopyrrolidine as a yellow solid. |
|
With triethylamine In dichloromethane at -50 - 0℃; for 2 - 2.5h; |
1; 2; 3; 4
Example 1 A 500 mL double jacketed glass reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a reflux condenser, a dropping funnel and a nitrogen inlet was charged with 77.8 mL (1007 mmol) of dimethylformamide and 35 mL of methylenechloride. The solution was cooled and treated with phosphorous oxychloride (75.4 g, 482 mmol) within maximal 60 min at 0° C. to 7° C. The dropping funnel was rinsed with 5 mL of methylenechloride. The clear solution was stirred at 0° C. to 5° C. for 60 to 120 min. This solution was then transferred into a 250 mL dropping funnel. The reactor was rinsed with 10 mL of methylenechloride. A 1000 mL double jacketed glass reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a reflux condenser, a dropping funnel and a nitrogen inlet was charged with 50.0 g (483 mmol) of L-Prolinamide and 230 mL of methylenechloride. The suspension was stirred and treated with 51.2 g (504 mmol) of triethylamine and cooled to -40° C. to -50° C. and a solution of 58.0 g (508 mmol) of chloroacetylchloride in 50 mL of methylenechloride was added within 60 to 90 min. The dropping funnel was rinsed with 5 mL of methylenechloride. The suspension was warmed up to -5° C. to 0° C. within 1 h. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was dehydrated while adding the solution of the Vilsmeier-Reagent from the first reaction within 1 to 15 min at -5° C. to 5° C. The dropping funnel was rinsed with 5 mL of methylenechloride and the resulting mixture was stirred for about 1 h at -5° C. to 5° C. The reaction mixture was then poured onto 175 mL of water within 10 to 30 min and at a temperature of 5° C. to 20° C. The reactor was rinsed with 5 mL of methylenechloride. The mixture was stirred at RT for at least 30 min. The phases were separated and the aqueous phase was twice extracted with a total of 170 mL of methylenechloride. The organic phases were unified and washed with 88 mL of water. The resulting organic phase was concentrated under vacuum (500 mbar to 50 mbar) at 20° C. to 50° C. The resulting oil was treated within 10 to 30 min with 325 mL of isopropanol and heated to 45° C. Subsequently, the solution was again cooled to 25° C. to 30° C. within 20 min and inoculated where after the product started to precipitate. The suspension was stirred for 1 h at this temperature and then cooled down to -15° C. to -20° C. within 4 h. The crystallization was completed by the addition of 85 ml of n-heptane and the mixture was kept stirring for another 2 h. The precipitate was filtered with suction, the filter cake was washed with cold (-10° C. to 20° C.) n-heptane (140 mL) and dried to constant weight (50° C., 50 mbar, 3 h) to afford 62.6 g of (S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 83%, assay: 100% (m/m) based on HPLC). The HPLC analysis was performed with an external standard of pure (S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile. Conditions for HPLC: Column Atlantis dC18 Waters, 3.9×150 mm, 3 μm, UV detection 205 nm, solutions for gradient: water (A), acetonitrile (B), pH 4.9 buffer KH2PO4 (C); flow 1.2 mL/min, 40° C. Gradient: Min A B C 0 90 5 5 isocratic 15 25 70 5 linear gradient 5 90 5 5 post time Retention times: (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide: approx. 3.26 min N-Formyl (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide: approx. 4.68 min (S)-1-(2-Chloroacetyl)-pyrrolidine-2-carbonitrile: approx. 5.56 min; Example 2 This example was run in an analogous manner as example 1 but starting from 20.0 g (175.2 mmol) of L-Prolinamide (1), 20.5 g (201 mmol) of triethylamine, 23.2 g (203 mmol) of chloroactylchloride and totally 112 mL of methylenechloride. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was dehydrated while adding a solution of the Vilsmeier-Reagent at RT that was prepared from 33.8 mL (438 mmol) of DMF, 20 mL of methylenechloride and 25.3 g (201 mmol) of thionylchloride. The resulting mixture was stirred for 90 min, then quenched with water and extracted in an analogous manner as example 1. Crystallization from Isopropanol/n-heptane and drying afforded 24.7 g of (S)-1-(2-Chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 82%, assay: 99.9% (m/m) based on HPLC).; Example 3 This example was run in an analogous manner as example 1 but starting from 20.0 g (175.2 mmol) of L-Prolinamide (1), 22.0 g (217 mmol) of triethylamine, 24.7 g (218 mmol) of Chloroactylchloride and totally 112 mL of methylenechloride. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was treated at 2° C. to 5° C. with a solution of 26.1 g (198 mmol) of chloromethylen-dimethyliminium chloride in 14 mL (438 mmol) of DMF. The resulting mixture was stirred at least for 35 min at 1.5° C. to 5° C. showing a complete turnover (HPLC). According to HPLC, the reaction profile corresponded with example 1.; Example 4 This example was run in an analogous manner as example 1 but starting from 20.0 g (175.2 mmol) of L-Prolinamide (1), 17.6 g (173.5 mmol) of triethylamine, 22.7 g (199.4 mmol) of Chloroactylchloride and totally 152 mL of methylenechloride. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was treated with 20 mL of DMF and 12.7 g (67.5 mmol) of cyanurchloride at 20° C. The resulting mixture was heated to 35° C., stirred for 2 h at this temperature and treated with 2.6 mL of water. The suspension was stirred for 1 h at RT and filtered with suction. The filter cake was washed with 20 mL of methylenechloride and the filtrate was treated with 100 mL of water. The layers were separated and the aqueous phase was twice washed with a total of 68 mL of methylenechloride. The organic layers were unified and concentrated under vacuum at a jacket temperature of 40° C. (400 mbar to 28 mbar). The remaining oil was treated with 130 mL of Isopropanol and inoculated at 30° C. The suspension was cooled to -22° C. within 4 h, stirred over night at this temperature and treated with 34 mL of n-heptane. The precipitate was filtered with suction, the filter cake was washed with 112 mL of a cold (-10° C. to 20° C.) mixture of n-heptane/2-propanol (8:2 (v/v)) and dried to constant weight (50° C., 50 mbar, 3 h) to afford 24.0 g of (S)-1-(2-Chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 80%, assay: 100% (m/m) based on HPLC). |
|
Stage #1: chloroacetyl chloride; L-prolinamide In tetrahydrofuran; water at 35℃; for 1.5h; Inert atmosphere; Cooling with ice;
Stage #2: With potassium carbonate In tetrahydrofuran; water Inert atmosphere; |
1A
Example IAPreparation of (S)-l-(2-chloroacetyl) pyrrolidin-2- carboxamideA 25 rtiL dry flask, equipped with a magnetical stirrer and inertized with Ar atmosphere, is charged with 0.46 g (4 mmol) L-prolinamide, 300 mL of water and 10 mL tetrahydrofuran. First on an ice bath and later at a temperature below 35°C .54 g (4.8 mmol) chloroacetyl chloride is added. The reaction mixture is stirred at room temperature for 1.5 hours. After completion of the reaction, 0.55 g of potassium carbonate (4 mmol) are added. The volatile components are partly evaporated and the residue is dissolved in 30 mL of dichloromethane . The organic phase is washed 3-times with 10 mL of water, and 10 mL of brine. The organic phase is dried over anhydrous Na2SO4, filtered and the solvent is evaporated in vacuo. |
|
Stage #1: chloroacetyl chloride With potassium carbonate In tetrahydrofuran at 0℃; for 0.166667h;
Stage #2: L-prolinamide In tetrahydrofuran at 0 - 20℃; for 5h; |
10
Example-10: Preparation of (S)-l-(2-chloroacetyI) pyrrolidine-2-carboxamide compound of formula-8:A mixture of potassium carbonate (121 grams) and tetrahydrofuran was cooled to 0-5° C. Added chloroacetyl chloride (29.72 grams) to the reaction mixture at 0° C and then stirred the reaction mixture at 0° C for 10 minutes. L-prolinamide (25 grams) in tetrahydrofuran (500 ml) was added to the reaction mixture slowly at 0-5° C. Stirred the reaction mixture at room temperature for 5 hours. Filtered the reaction mass and washed with tetrahydrofuran (25 ml). The filtrate was distilled under reduced pressure. Methyl tertiary butyl ether (200ml) was added to the residue and stirred for 1 hour at room temperature. The solid obtained was filtered, washed with methyl tertiary butyl ether and then dried to get the title compound.Yield: 25 grams. |
|
In tetrahydrofuran |
|
| 26 g |
With potassium carbonate In chloroform at 25 - 30℃; |
2 Example-2: Preparation of 1-chloroacetyl (S)-2-carboxamidepyrrolidine
Example-2: Preparation of 1-chloroacetyl (S)-2-carboxamidepyrrolidine To a mechanically stirred solution of L-prolinamide (20 g), potassium carbonate (48.4 g) and chloroform (370 ml), the solution of chloroacetyl chloride (15.3 ml) in chloroform (30 ml) was added slowly over a period of 1 hour at temperature 25 to 30°C (exotherm observed till 40°C). Reaction mass was stirred for additional 2 hours at 25°C to 30°C. Upon completion of reaction, the reaction mass was filtered and the obtained solid was washed with chloroform (200 ml<2). Filtrate was dried over anhydrous sodium sulfate and filtrate was concentrated under reduced pressure to get residue. Ethyl acetate (100 ml) was added to the residue at temperature 25°C to 30°C and the slurry was stirred for 30 minutes. Obtained solid was filtered and washed with ethyl acetate (20 ml) and dried under vacuum at 35°C to 40°C for 5 to 6 hours. [Yield: 24 to 26 g] |
|
With potassium carbonate In tetrahydrofuran at 20℃; for 3.5h; |
1.8 Step 8) (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide
Step 8) (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide To a mixture of chloroacetyl chloride (9.94 g, 88.0 mmol, Shanghai han hong chemical Co., Ltd) and potassium carbonate (48.5 g, 350.9 mmol, Chengdu kelon company) in tetrahydrofuran was added a solution of L-prolinamide 1i (9.00 g, 78.8 mmol, Shao yuan chemical (Shanghai) technology Co., Ltd) in tetrahydrofuran (300 mL) dropwise over a period of 1 hour. The mixture was further stirred for 2.5 hours at rt to give the title compound 1j. The reaction mixture was filtered. The filtrate was concentrated in vacuo. The residue was used without further purification. The compound was characterized by the following spectroscopic data: MS m/z (ESI): 191.0 (M+1). |
|
In Isopropyl acetate; N,N-dimethyl-formamide at 15 - 25℃; for 3h; |
|
|
In N,N-dimethyl-formamide at -5 - 25℃; Inert atmosphere; |
I Example ItPreparation of 2(S)-l-(chloro acetyl) pyrroHdine-2-carbonitriIe (formula- Ill)
Example ItPreparation of 2(S)-l-(chloro acetyl) pyrroHdine-2-carbonitriIe (formula- Ill) To the 550 cc methanol charged 0.87 mole of formula-IV and stirred for 10-30 min at room temperature below 10°C preferably at 0±5°C. Added 1.45 mole thionylchloride at 40-70°C. After completion of reaction methanol was distilled out toobtain formula-V. Added 500cc 1-butanol and 60 cc aq. ammonia at 5-30°C and stirred for 30-60 mins. Filtered solid ammonium chloride and charged excess 600cc 1-butanol and 590cc aqueous ammonia at 5-30°C. After stirring for 10-14 hrs at ambient temperature separated butanol layer and solvent was distilled out to obtain formula- VI. To the degassed mass charged 375cc N, N-dimethylformamide and 0.82 mole chloro acetyl chloride and stirred at -5 to 25°C to produce formula- VII. Charged 0.47 mole phosphorous oxy chloride in the temperature range of -5 to 20 °C and stirred for l-2hrs.Then charged saturated sodium bi carbonate solution and extracted in lOOOcc ethyl acetate. Collected ethyl acetate layer and washed with 500cc saturated sodium chloride solution and distilled out ethyl acetate and crystallized with 2-isopropanol to afford nitrile compound of formula III with an yield of 40%. HPLC PURITY: 96-99% |
|
Stage #1: L-prolinamide With dmap; triethylamine In dichloromethane at 25 - 30℃; for 0.25h; Inert atmosphere;
Stage #2: chloroacetyl chloride In dichloromethane at -5 - 5℃; Inert atmosphere; |
1 EXAMPLE 1: Preparation of (2S)-1-(Chloroacetyl)-2-pyrrolidinecarbonitrile.
To a solution of L-Prolinamide (100 gms) dissolved in DCM (1000 mL) was added triethyl amine (88.6 gms) and DMAP (1.07 gms) at 25-30°C under N2 atmosphere and stirred for 15 min at 25-30°C. This solution was added to a solution of chloroacetyl chloride (98.9 gms) in DCM (500 mL) under N2 atmosphere at -5 to 0°C over 2-3 hr. Raised the reaction mass temperature to 0-5°C and stirred for lhr. After reaction completion, charged phosphorus oxy chloride (201.5 gms) to the reaction mass at 0-5 °C, heated the reaction mass temperature to reflux and stirred for 6hr at same temperature. After reaction completion, allowed to cool to 10-20°C and added DM water (500 mL). Aqueous layer was separated and the organic layer was washed with DM water. To the organic layer DM water (300 mL) was added at 25-30°C and adjusted the reaction mass pH to 6.5-7.5 with -500 mL of sodium bicarbonate solution (-40 g of NaHC03 dissolved in 500 mL of DM Water). Separated the aqueous layer and concentrated the organic layer under vacuum at temperature of 30-40°C to get residual mass. Charged isopropanol (100 mL) and distilled out solvent completely under vacuum at <50°C. The resulting residue was allowed to cool to 30-40°C and charged isopropanol (500 mL). Heated the reaction mass temperature to 40- 45°C, stirred for 30 min at 40-45°C, allowed to cool to 0-5°C, stirred for 2 hr, filtered and washed wet cake with chilled isopropanol (100 mL), dried at 40-45°C for 6 hr to provide 115 gms of (2S)-l-(CMoroace1yl)-2-pyrrolidinecarbonitrile. HPLC Purity: 99.86%. |
|
With triethylamine In dimethyl sulfoxide; ethyl acetate at 10 - 15℃; for 5h; Industrial scale; |
5.1
clean, dry 100L enamel reactor was added 2.36kg (20.8 mol) of chloroacetyl chloride, 4.72Kg ethyl acetate, 3.52 kg (34.8 mol) of triethylamine was added dropwise with stirring at 10 ± 2 under a 2Kg (17.4mol) L- prolinamide with a solution composed of 8Kg DMSO dropwise at 15 , the reaction incubated 5h, after the completion of the reaction, cooling to 10 , without any treatment, the standby. |
|
Stage #1: chloroacetyl chloride With potassium carbonate In tetrahydrofuran at 20℃; for 0.5h;
Stage #2: L-prolinamide In tetrahydrofuran at 20℃; for 2h; |
4.1 Example 4 A method of preparation of vildagliptin amide impurities by the present invention, the following steps:
S1, to 250 ml three-mouth bottle by adding 50 ml tetrahydrofuran, 18.1 g potassium carbonate, 5.2 g chloro acetyl chloride, stirring at the room temperature 30 min; the 5 g L - prolinamides dissolved in 150 ml in tetrahydrofuran, slowly to the reaction bottle; the completion of the dropping, the reaction at room temperature 2 h, filtering, the filtrate is concentrated to 50 ml, to obtain concentrated liquor; |
|
With triethylamine In dichloromethane at -25 - -15℃; for 1h; |
1; 3 Preparation of (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile
2L three bottle,100.0 g (0.8772 moL) of L-prolinamide was added sequentially,640g dichloromethane and 102.4g (1.0139moL) triethylamine formed a suspension,Stir and cool down to -25°C,116.0 g (1.0265 moL) of chloroacetyl chloride was added dropwise to the suspension.Control dropping temperature ≤ -15°C; after completion of dropping, stir reaction at -25 - 15°C for 1h,The sample was dissolved with methanol, and the TLC reaction was complete.Obtain (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamideSuspension |
|
Stage #1: L-prolinamide With dmap; triethylamine In dichloromethane at -10℃; for 0.5h;
Stage #2: chloroacetyl chloride In dichloromethane at -10 - 0℃; for 6h; |
2 4.1.15. (2S)-1-(chloroacetyl)pyrrolidine-2-carboxamide (16)
A solution of (2S)-pyrrolidine-2-carboxamide 15 (2.6 mmol,300 mg), triethylamine (2.8 mmol, 0.39 ml) and catalytic amount ofdimethylaminopyridine (DMAP) in dichloromethane (3 ml) was addeddropwise over 30 min to -10 °C cooled solution of chloroacetylchloride (2.9 mmol, 0.23 ml) in dichloromethane (3 ml). Reactionmixture was stirring for 2 h at -10 °C and then 4 h at 0 °C. Reactionmixture was allowed to reach room temperature and poured into ethylacetate (25 ml). Formed white precipitate of triethyl amine hydrochloridewas filtered and washed with ethyl acetate (10 ml). The solventwas removed under reduced pressure and residue was used infollowing reaction without further purification. |
|
With triethylamine In dichloromethane at -25 - -20℃; for 3h; |
1-4 Preparation of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile
Add 25g L-prolinamide to a 1000ml dry reaction flask.250 ml of dichloromethane, 25 g of triethylamine,Forming a mixture, cooling the mixture to -20 ° C ~ -25 ° C,A mixture of 26 g of chloroacetyl chloride and 50 ml of dichloromethane was added dropwise to the reaction flask.After the completion of the dropwise addition, the reaction was stirred at -20 ° C for 3 hours.A reaction liquid I containing 1-chloroacetylpyrrolidine-2-carboxamide was obtained. |
| 7.9 g |
With potassium carbonate In dichloromethane at 0 - 20℃; for 1h; |
To a mixture of L-proline amide (5.0 g, 43.8 mmol) and K2CO3(12.1 g, 87.6 mmol) in CH2Cl2 (50 mL) was added chloroacetyl chloride(7.3 mL, 87.6 mmol) dropwise at 0 °C. The reaction mixture waswarmed to ambient temperature and stirred for 1 h. The mixture wasdiluted with CH2Cl2 (100 mL) and washed with brine (30 mL×2). Theorganic layer was dried over anhydrous MgSO4, filtered and evaporatedto give the crude product as a yellow solid (7.9 g). To the solution ofamide and pyridine (10.0 mL, 123.9 mmol) in CH2Cl2 (75 mL) wasadded trifluoroacetic acid anhydride (8.7 mL, 61.9 mmol) dropwise at0 °C under nitrogen atmosphere. The reaction mixture was warmed toambient temperature and stirred for 4 h and quenched with ice water(60 mL). The organic layer was washed with 15% HCl (50 mL). anddried over anhydrous MgSO4, filtered and evaporated. The crude productwas purified by silica gel column chromatography (petroleumether: EtOAc=2: 1) to afford the desired product as a yellow oil (5.4 g,72% in two steps). |
|
With potassium carbonate In tetrahydrofuran; water at 25℃; for 0.0616667h; |
1.a; 2.a; 3.a
Step a: Dissolve 0.175 mol of L-proline amide in 150 mL of tetrahydrofuran to obtain material A with a concentration of 1.17 mol / L;Dissolve 0.18 mol of potassium carbonate in 50 mL of deionized water to obtain material B with a concentration of 3.6 mol / L, and dissolve 0.180 mol of chloroacetyl chloride in 20 mL of tetrahydrofuran to obtain material C with a concentration of 9 mol / L;The materials A, B, and C were introduced into the microchannel reactor at a throughput of 2 mL / min, 0.81 mL / min, and 0.46 mL / min, and reacted at 25 ° C for 3.7 minutes. The reaction liquid, the upper organic phase was collected after liquid separation; |
|
With triethylamine In dichloromethane at -25 - -10℃; Inert atmosphere; |
1.1.1; 2-6
Under the protection of inert gas (nitrogen in this example), compound I (L-prolineamide, (S)-pyrrolidine-2-carboxamide, purity ≥96%), compound II (Chloroacetyl chloride) and Alkaline substances (used to neutralize the hydrogen chloride generated during the reaction, can be one or more of inorganic bases, basic inorganic salts and organic amines. In this embodiment, triethylamine is used) in an organic solvent (in this implementation) In the example, dichloromethane), the reaction is carried out at a temperature of -25°C to -10°C, and the reaction is basically complete as detected by thin-layer chromatography (the remaining amount of compound I is less than or equal to 5%, and this example controls it to less than or equal to 2%) After that, it is directly used in the next reaction;Wherein, the molar ratio of compound I to compound II is 1:0.8 to 1.5 (for example, 1:1.05), and the molar ratio of compound I to basic substance is 1:0.8 to 2.0 (for example, 1:1.2). The dosage can be adjusted appropriately according to the actual situation. For example, the dosage of the organic solvent is 0.5kg5.0kg (for example, 3.0kg) per mole of compound I; in this step of this embodiment, compound I, compound II and The amount of alkaline substance (triethylamine) is 1.31mol, 1.38mol, 1.58mol, and the amount of organic solvent (dichloromethane) is 3.98kg; |
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