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CAS No. : | 7531-52-4 | MDL No. : | MFCD00005253 |
Formula : | C5H10N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 114.15 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 33.66 |
TPSA : | 55.12 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.61 cm/s |
Log Po/w (iLOGP) : | 0.73 |
Log Po/w (XLOGP3) : | -0.87 |
Log Po/w (WLOGP) : | -1.16 |
Log Po/w (MLOGP) : | -0.78 |
Log Po/w (SILICOS-IT) : | -0.02 |
Consensus Log Po/w : | -0.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.07 |
Solubility : | 133.0 mg/ml ; 1.17 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.19 |
Solubility : | 178.0 mg/ml ; 1.56 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.34 |
Solubility : | 51.8 mg/ml ; 0.454 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.47 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In dichloromethane at 5℃; for 2 h; Inert atmosphere | Example 1 To 2L reaction flask, 400mL dichloromethane and 38.4mL chloroacetyl chloride was added, under nitrogen protection, the substance inside the above mentioned reaction flask was cooled to 5°C; 50g L- prolinamide was dissolved in 600mL of dichloromethane to obtain a solution C, to solution C was added 67.5 mL of triethylamine to obtain solution D. At 5°C, the above solution D was slowly added dropwise into the reaction flask, allowing the substances in the reaction flask to react at 5°C for 2h. (2) The first step's (1) substance in the reaction flask was concentrated under reduced pressure to remove dichloromethane, to the residue was then added 750mL water, 1500mL tetrahydrofuran and 500g of potassium carbonate, dissolved under stirring, after the substance in the reaction flask separates into layers, the aqueous layer was discarded. The remaining organic layer is concentrated under reduced pressure to give 80.2g of a slightly yellow solid substance. Thgrough identification, the slightly yellow solid material is the desired product (S)-1-(chloroacetyl)-pyrrolidine-2-carboxamide, the yield was 96percent , purity (HPLC) was 97.1percent |
92% | at 0℃; Reflux; Large scale | L- prolinamide 9 (15kg, 131mol, 1.0eq.) In anhydrous tetrahydrofuran (100L), cooled to 0 , and thereto is added chloroacetyl chloride (18kg, 159mol, 1.2eq.). Upon complete addition stirring slowly raised to room temperature, then heated under reflux until reaction was completed. Distillation under reduced pressure to remove most of the low-boiling solvent, allowed to stand for cooling, the precipitated solid was lot was filtered, washed with tetrahydrofuran and dried in vacuo to give an off-white solid powder (23kg of, yield 92percent |
90.7% | Stage #1: at 0℃; for 0.5 h; Stage #2: With potassium carbonate In tetrahydrofuran at 0 - 20℃; for 4 h; |
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 90.7percent. |
89.5% | at 60℃; | 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 89.5percent, purity 98.2percent. |
85% | With potassium carbonate In acetonitrile at 10 - 20℃; for 1 h; | 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- 85percent; HPLC purity >97percent). Impurity H is less than 0.2percent w/w relative to the amount of compound of formula IV as determined by HPLC. |
26 g | With potassium carbonate In chloroform at 25 - 30℃; | 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] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: With potassium carbonate In acetonitrile at 0 - 15℃; Stage #2: at 0 - 15℃; |
A process for the preparation of (S) -l_ (2-chloroacetylchloride) -2-cyanopyrrolidine, comprising the steps of: dissolving L-prolinamide (2 (0.17511101) Potassium carbonate (488,0.348111 0 1)To 4001 ^ acetonitrile, 0-15 ° (: stirring slowly dropping 16mL (0.2lmo 1)Chloroacetyl chloride (drop time 2-3 hours), after the completion of dropping, stirring room temperature overnight, TLC plate anti-Should be completely, the suction filter, the filtrate 0_15 ° C stirring drop 13.4111 to 0.094111 011 44, after the completion of the drop, 25 ° (: under stirringAfter overnight, the TLC plates were allowed to react completely, spin-dried, and then 20 mL of ethyl acetate was added to the kettle to carry excess TFAA,The residue was dissolved in 150 mL of ethyl acetate, the pH was adjusted to 8 with sodium carbonate solution, and the organic phase was washed with saturated brine,Dried over anhydrous sodium sulfate, filtered and dried to give an oil which was allowed to stand overnight and solidify (if not solidified,Seed crystal) as a light brown solid (Compound 2) in a yield of 92percent. |
92% | Stage #1: With potassium carbonate In acetonitrile at 0 - 20℃; Stage #2: at 0 - 25℃; |
L-prolinamide (20 g, 0.175 mol),Potassium carbonate (48 g, 0.34 mol) was added to 400 mL of acetonitrile,(0.21 mol) of chloroacetyl chloride (dropwise for 2-3 hours) was slowly added dropwise with stirring at 0 to 15 ° C,After completion of the dropwise addition,The reaction was stirred at room temperature overnight,After TLC plate reaction was complete,Filtration,The filtrate was stirred at 0-15 ° C and 13.4 mL (0.094 m) of TFAA was added dropwise,After completion of the dropwise addition,Stir overnight at 25 ° C,After TLC plate reaction was complete,Drying,Then, 20 mL of ethyl acetate was added to the autoclave to carry out excess TFAA,So repeated 3 times,The residue was dissolved in 150 mL of ethyl acetate,The pH was adjusted to 8 with sodium carbonate solution, and the organic phase was washed with saturated brine,Dried over anhydrous sodium sulfate,filter,Drying,To give an oil,Standing overnight,Curing (such as curing,Can be added before standing a little seed)12.2 g of a light brown solid (compound 2)Yield 92percent. |
83.4% | Stage #1: With trifluoroacetyl chloride In N,N-dimethyl-formamide at 50℃; for 1.5 h; Stage #2: With trifluoroacetyl chloride In N,N-dimethyl-formamide at 60℃; for 1.5 h; |
The reaction bottle into the 92.0 g trichlor and 6.4 g DMF, under stirring added in batches 8.0 g (S)- N - chloracetyl -2 - carbamino pyrrolidine, 60 °C reaction 1.5 h. After the reaction is distilled under reduced pressure steam out of the oxysilane.After treatment in the light of the embodiment 1, in the crystallization from toluene, shall be 6.0 g, yield 83.4percent. |
66% | Stage #1: at 15 - 35℃; for 2 h; Stage #2: With 1,3,5-trichloro-2,4,6-triazine In Isopropyl acetate; N,N-dimethyl-formamide at 25 - 35℃; for 0.75 h; |
EXAMPLE 3; This example illustrates the synthesis of a compound of formula (IV) in accordance with the invention.Synthesis of 1-chloroacetyl-2-cyanopyrrolidine. A 250 mL reactor with thermometer, condenser and magnetic stirring was charged with i-PrOAc (41 mL), dry DMF (5 mL) and chloroacetyl chloride (19.5 g, 173 mmol) under an inert atmosphere. The resulting solution was cooled to 15° C. and a solution of L-prolinamide (17.1 g, 150 mmol) in dry DMF (48 mL) was slowly added (IT35° C.). The reaction mixture was stirred 2 additional hours at 35° C. to obtain complete conversion. The internal temperature was adjusted to 25° C. and cyanuric chloride (13.8 g, 75 mmol) was added in portions (IT35° C.). The mixture was stirred for 45 minutes, poured into 200 mL of water and extracted with EtOAc (3.x.200 mL). The organic phase was washed with 5percent aqueous NaHCO3 (2.x.200 mL), dried over Na2SO4, filtered, and the solvents were evaporated under vacuum. The resulting oil was crystallized in 65 mL of isopropanol to obtain 17.16 g of 1-chloroacetyl-2-cyanopyrrolidine (66percent yield). |
5.2 g | Stage #1: at 25 - 30℃; Stage #2: With 2,6-dimethylpyridine In dichloromethane for 0.25 h; Stage #3: With trichlorophosphate In dichloromethane at 5 - 20℃; |
Exampie-8: Preparation of 1-chloroacetyl (S)-2-cyanopyrroiidine To a mechanically stirred solution of L-prolinamide (5g), and dichloromethane (40 ml), solution of chloroacetyl chloride (3.76 ml) in dichloromethane (10 ml) was added drop-wise over a period of 20-25 minute at temperature 25 to 30°C, exotherm observed till 40°C. Reaction mass was then stirred for additional 3 h at 25 to 30°C. 2, 6 lutidine (14.1 ml) was added to reaction mass and stirred for 15 minutes. Solution of POCI3 (6.12 ml) in dichloromethane (10 ml) was added slowly to reaction mass at 5 to 10°C. The reaction mass was stirred for 2-3 h at room temperature. Upon completion of reaction, the reaction mass was cooled to 0-5°C. DM water was slowly added to reaction mass, exotherm observed upto 40°C. Organic layer was washed with NaHCO3 solution (2X50 ml), followed by washing with aqueous 6percent HCI (3 X 30 ml) and DM water (2X30 ml). Organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give 1-chloroacetyl (S)-2-cyanopyrrolidine. [Yield: 5.2 gm; Purity: 97.31percent] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | In tetrahydrofuran; water | 2 EXAMPLE 2 To a solution of (S)-pyrrolidine-2-carboxamide (18.8 g:0.16 mole) in one liter of dried tetrahydrofuran was slowly added lithium aluminum hydride (33.9 g:0.89 mole) with stirring under cooling on ice, followed by refluxing the mixture for 48 hours. After cooling, the reaction mixture was treated with water and tetrahydrofuran by usual manner to give oil. This was distilled under reduced pressure to give 6.07 g of (S)-2-aminomethylpyrrolidine as colorless liquid. Yield: 37%, b.p. 80°-85° C. (20 mmHg). [α]D20 +10.02° (H2 O). (S)-2-aminomethylpyrrolidine was lead to (S)-1,1-cyclobutanedicarboxylate(2-aminomethylpyrrolidine)platinum(II) (Compound 2) by the same manner as described in Example 1. m.p. 240°-255° C. (decomposition). |
36.8% | With lithium aluminium tetrahydride In tetrahydrofuran for 33h; Heating; | |
20% | Stage #1: L-prolinamide With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux; Stage #2: With water In tetrahydrofuran |
With tetrahydrofuran; lithium aluminium tetrahydride | ||
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux; | General procedure for preparation of (S)-2-aminomethylpyrrolidine and (R)-2-amino- methylpyrrolidine: General procedure: (S)-2-aminomethylpyrrolidine and (R)-2-aminomethylpyrrolidine were prepared through modification of the method reported by Diakos and co-workers.5 (S)-Prolinamine or (R)-prolinamine (4.5660g, 40mmol) was dissolved in anhydrous THF (120mL) and cooled to 0°C. LiAlH4(9.1080g, 240mmol) was added slowly at 0°C and the resultant reaction solution was kept stirring at 0°C for 1.0h, then was warmed to room temperature slowly. After refluxing for 48.0h, the reaction mixture was cooled to room temperature, 100mL THF was added to dilute the reaction mixture at 0°C. Then H2O (20mL) in THF (100mL) was added to quench the reaction mixture at -10°C. The resultant solid was separated from the mixture by suction filtration, washed with hot THF (2×100mL). The filtrate was combined and evaporated under reduced pressure to afford (S)-2-aminomethylpyrrolidine or (R)-2-aminomethylpyrrolidine as orange oil. (S)-2-aminomethylpyrrolidine and (R)-2-aminomethylpyrrolidine were used in next step without further purification. | |
With lithium aluminium tetrahydride | ||
With lithium aluminium tetrahydride In tetrahydrofuran Inert atmosphere; Schlenk technique; | ||
Multi-step reaction with 2 steps 1: phosphorus pentoxide / 1 h / 320 °C 2: hydrogen / ethanol / 1 h / 88 °C / 45004.5 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 0.5h;Inert atmosphere; | General procedure: To the Boc N-protected amino acid, or peptide compound, in dichloromethane (0.1 M) is added TFA (25-55% v/v) slowly at 0 oC and the reaction left at room temperature for 30 min. After completion,solvents and excess TFA are removed in vacuo and the residue is triturated with diethylether until ahomogenous precipitate forms. The supernatant diethylether layer is removed and the solid redissolvedin dichloromethane followed by the addition of the amido-carboxylic acid. At 0 oC, DIPEA(2.0 equiv), HATU (1.2 equiv) and HOAt (1.0 equiv) are then added sequentially, followed by acatalytic amount of DMAP (0.1 equiv). The reaction is left stirring at room temperature. Aftercompletion, typically within 3-8 hours, the reaction mixture is evaporated in vacuo. The residueobtained is dissolved in ethyl acetate. The organic layer is washed with sat. sodium bicarbonatesolution and then with brine solution. The organic layer is finally dried over sodium sulphate andevaporated in vacuo. The residue is purified by silica gel flash column chromatography typicallyusing ethyl acetate/hexane mixtures | |
With trifluoroacetic acid; In dichloromethane; at 20℃; for 2h; | General procedure: TFA (8 mL) was added to the solution of (S)-tert-butyl 2-(piperidine-1-carbonyl)pyrrolidine-1-carboxylate 3 (0.82 g, 2.9 mmol), in DCM (2 mL) and stirred for 2 h at room temperature. The excess reagent and solvent were removed under reduced pressure and left under vacuum overnight. Then the residue was dissolved in DCM (15 ml). and cooled to 0 C. TEA (1.9 g, 18.85 mmol) was added followed by dropwise addition of 5-bromopentanoyl chloride (0.74 g, 3.73 mmol,), dissolved in DCM (8 ml). The stirring was continued for 12 h. Solvent was evaporated under reduced pressure and the N-acylated product 13 was purified by column chromatography using silica gel and a mixture of DCM/MeOH = 9/0.7 (v/v) as an eluting system to yield 0.74 g (74%) of product 13 as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; triethylamine In dichloromethane for 2h; cooling; | |
85.8% | Stage #1: 2-Bromoacetyl bromide; L-prolinamide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With potassium carbonate In tetrahydrofuran at 0 - 20℃; for 4h; | 2 Synthesis of (S)-1-(2-bromoacetyl)pyrrolidine-2-carboxamide The compound S-prolinamide (11.2 g, 100mmol) add to a solution of bromoacetyl bromide (20.0 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 2 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, after drying, obtained 20.1 g of compound (S)-1-(2-bromoacetyl)pyrrolidine-2-carboxamide (colorless oil), yield is 85.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine In tetrahydrofuran; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With hydrogen In ethanol; ethyl acetate at 20℃; for 14h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 4h; | |
85% | Stage #1: (2S,4S,5S)-1-(tert-butoxycarbonyl)-4-(methoxycarbonyl)-5-methyl-2-pyrrolidinecarboxylic acid With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide In 1,4-dioxane; dichloromethane at 20℃; for 0.166667h; Stage #2: L-prolinamide In 1,4-dioxane; dichloromethane for 16h; | 6.ii (ii) Preparation of (2S,4S,5S)-5-(2-carbamoyl-pyrrolidine-1-carbonyl)-2-methyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (9) A solution of DCC (454 mg, 2.2 mmol) in CH2Cl2 (3 mL) was added to a stirred solution of compound 8 (517 mg, 1.8 mmol), 4-DMAP (439 mg, 3.6 mmol) and HOBt (316 mg, 2.3 mmol) in 1,4-dioxane (3 mL). After 10 min at room temperature, (S)-pyrrolidine-2-carboxamide (251 mg, 2.2 mmol) in CH2Cl2 (2 mL) was added with stirring. The reaction mixture was stirred for 16 h and was then filtered. The filtrate was washed with saturated aqueous NaHCO3 (5 mL), 1 N aqueous citric acid (5 mL), water (5 mL), dried over MgSO4, and concentrated. The residue was purified by a silica gel column using CH2Cl2/MeOH (95:5) as eluent to yield compound 9 (586 mg, 1.5 mmol, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: <i>L</i>-proline With thionyl chloride In methanol for 2h; Heating; Stage #2: With ammonia In methanol at 20℃; for 96h; Further stages.; | |
Multi-step reaction with 3 steps 1: sodium hydroxide / H2O / Ambient temperature 2: 1.) triethylamine, isobutyl chloroformate, 2.) ammonia / 1.) chloroform, 0 deg C, 2 h, 2.) chloroform, RT, overnight 3: 88.4 percent / hydrogen / 10percent palladium on carbon / methanol / 9 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: thionyl chloride / -5 - 70 °C 2: ammonium hydroxide / butan-1-ol / 5 - 30 °C |
Multi-step reaction with 2 steps 1: thionyl chloride / 0 - 20 °C / Large scale 2: ammonia / methanol / Heating; Large scale | ||
With ammonia at 230℃; for 0.5h; | B Example B Preparation of the amide intermediate General procedure: In 1L reactor was added 500g of carboxylic acid raw material (chemically pure),And charged with NH3 moles contained in the carboxylic acid feedstock1.3 times the carboxyl group of ammonia (water content of 0.5wt%, industrial products),Closed reactor,Turn on stirring (600r / min).After the reaction was allowed to proceed at a reaction temperature of TA for TC hours,The contents of the reactor sampling,Do nuclear magnetic resonance spectroscopy and elemental analysis,To characterize the amide intermediate.The specific reaction conditions and characterization results are shown in Table B-1, Table B-2, Table B-3 and Table B-4 below. These signatures knotThe fruit shows that the amide intermediate obtained has an extremely high purity (99% or more).In this embodiment, the ammonia gas may be directly replaced with spent ammonia gas (from Yanbashi Chemical Works, containing about50% by weight of ammonia and the balance of toluene, oxygen, nitrogen, water vapor, carbon monoxide and carbon dioxide) or ammonium bicarbonate powder (chemically pure) having a mole number of ammonium ions of 1.4 times the carboxyl group contained in the carboxylic acid starting material. | |
Multi-step reaction with 2 steps 1: thionyl chloride / 3.5 h / -5 °C / Reflux 2: ammonia / methanol / 96 h / -25 °C / Sealed tube | ||
Multi-step reaction with 4 steps 1: sodium carbonate / water / 6 h / 8 - 30 °C / pH 7.6 2: thionyl chloride / dichloromethane / 6 h / 3 - 30 °C 3: ammonium hydroxide / dichloromethane / 3 h / 30 °C 4: hydrogenchloride / water / 2 h / 103 °C | ||
Stage #1: <i>L</i>-proline With chloroformic acid ethyl ester; triethylamine In dichloromethane at -10℃; for 1.5h; Stage #2: With ammonium hydroxide In dichloromethane at 25℃; for 0.5h; | 1.S2-3.S2 Step S3: Add the L-proline and dichloromethane prepared in step S2 into the reaction kettle, stir until the L-proline is completely dissolved, add ethyl chloroformate and triethylamine into the reaction kettle, At a temperature of -10, after the reaction for 1.5h, add ammonia water, at a temperature of 25, after the reaction for 30min, add phosphorus pentoxide, and carry out the reaction at a temperature of 60 30min, intermediate 1 is prepared; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.1% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 5 - 20℃; | 5-1 Example 5-1; tert-Butyl (LS)-2-[(2S)-2-CARBAMOYL-1-PYRROLIDINYL]- 1-hydroxymethyl-2-oxoethylcarbamate To a solution of (2S)-2-[(TERT-BUTOXYCARBONYL) AMINO]-3-HYDROXYPROPANOI c acid (5g), (2S) -2-pyrrolidinecarboxamide (2.78g), and 1-hydroxybenzotriazole hydrate (HOBT-H20, 4.47g) in N, N-dimethylformamide (DMF, 50ML) were added 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETHYLCARBODIIMIDE hydrochloride (WSCD-HC1, 5.14g) and DIISOPROPYLETHYLAMINE (DIEA, 5. lml) AT 50C THE REACTION mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the resulting residue was purified with silica gel column chromatography (SI02 200ML, CHCl3 : methanol=10 : 1). After removal of the solvent in vacuo, the residual oil was triturated with diethylether and solidified, washed with. diethylether to give the target compound as a white powder (5g, 68.1%). HNMR (CDCL3) : 1.43 (s, 9H), 1.90-2. 22 (m, 4H), 3.56-3. 96 (m, 4H), 4.25-4. 70 (m, 3H), 5.75 (m, 1H), 6.31 (s, 1H), 6.94 (s, 1H) MS : 302.16 (ES+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.03% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; at 0 - 25℃; for 6h; | DIEA (1.35 g, 10.46 mmol), HOBT (1.40 g, 10.37 mmol) sequentially added to piperazine acid (3.30 g, 10 mmol) and L-prolinamide (1.14 g, 10 mmol) in DCM (40 ml) at 0 C. A solution of DCC (2.40 g, 11.65 mmol) in DCM (30 ml) is added slowly at 0 C. over a period of 1 hr. Stirred another 1 hr. at 0 C. and then at 25 C. for 4 hrs. Filtered, DCM distilled off, diluted with ethyl acetate, washed sequentially with saturated aqueous solution of NaHCO3 and brine. Organic layer dried (Na2SO4), evaporated in vacuo purified by column chromatography (ethyl acetate). (Yield 2.6 g, 61.03%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate In acetonitrile at 20 - 50℃; for 20h; | 25 Preparation 25 1-[5-(5-BROMO-PYRIDIN-2-YL)-[1,3,4]OXADIAZOL-2-YLMETHYL]-PYRROLIDINE-(2S)-2- carboxylic acid amide The chloro compound of preparation 17 (500MG, 1. 82MMOL) and (S)-prolinamide (312mg, 2.73mmol) were dissolved in acetonitrile (10mL) and the mixture treated with potassium carbonate (503MG, 3. 64mmol). The reaction mixture was stirred at room temperature for 18 hours and then at 50°C for 2 hours. The reaction mixture was concentrated-in vacuo and the residue partitioned between ethyl acetate and water. The precipitate formed was filtered off and the organic layer of the filtrate washed with water, 1M SODIUM hydroxide solution and brine. The organic layer was then concentrated in vacuo to'yield the title product. 540mg, . 84% yield. 1HNMR(DMSO-D6, 400MHZ) No.: 1.70(M, 3H), 2.00 (m, 1H), 2.60 (m, 1H), 3 10 (M, 1H), 3.20(m, 1H), 4.00 (d. 1H), 4.20(d, 1H), 7.00-7.20(d, 2H), 8.10(d, 1H), 8.30(d, 1H), 8.90 (s, 1H). |
With potassium carbonate In acetonitrile at 20 - 50℃; for 20h; | 12 Preparation 12; 1-(r5-(5-Bromopyridin-2-yl)-1.3,4-oxadiazol-2-vnmethyl)-L-prolinamide; Potassium carbonate (503mg, 3.64mmol) was added to a mixture of the product of preparation 7 (500mg, 1.82mmol) and L-prolinamide (312mg, 2.73mmo.) in acetonitrile (1 OmL) and the mixture was stirred for 18 hours at room temperature and at 5O0C for 2 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and washed with water (2x50mL). The resulting precipitate was filtered off and the filtrate was washed with water, 2M sodium hydroxide solution and brine. The organic solution was then dried over sodium sulfate and concentrated in vacuo to afford the title compound. 1HNMR(400MHz, DMSO-Cf6) δ: 1.70(m, 3H)1 2.00(m, 1H), 2.60(m, 1H), 3.10(m, 1 H), 3.20(m, 1H), 4.00(d, 1H), 4.20(d, 1H), 7.00-7.20(d, 2H), 8.10(d, 1H), 8.30(d, 1H), 8.90(s, 1H); LRMS APCI m/z 354 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With HATU In N,N-dimethyl-formamide at 20℃; for 16h; | 5A A mixture of [5-{ [ (tert-butoxycarbonyl) amino]methyl}-6- isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid(0.50 g, 1.2 mmol), L-prolinamide (0.32 g, 2.8 mmol) , O- (7- azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (1.1 g, 2.8 mmol) and N, N-dimethylformamide (20 mL) was stirred at room temperature for 16 hrs. The reaction mixture was partitioned between ethyl acetate and water.The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.49 g, yield 81%) as a white powder.MS 523 (M+1) . |
8% | With HATU In N,N-dimethyl-formamide at 20℃; | 5.1.9. Methyl 3-([5-[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}amino)benzoate (12a) General procedure: A mixture of compound 10 (500 mg, 1.17 mmol), methyl 3-aminobenzoate (11a) (532 mg, 3.52 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (1.34 g, 3.52 mmol) in N,N-dimethylformamide (DMF) (5 mL) was stirred at room temperature for 16 h. To the reaction mixture was added water, and the mixture was extracted with AcOEt. The extract was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt = 30:70) to afford 12a (170 mg, 26%) as a pale yellow powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; | Aryl chloride 9 (200 mg, 0.44 mmol), DMSO (10 ml) and L-prolinamide (440 mg, 4.4 mmol) were combined and heated to 85 C. under argon. After 14 hours the mixture is cooled to room temperature and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer washed with EtOAc (3*). The combined organic layers were thoroughly washed with water (3*), brine, dried over MgSO4, filtered and concentrated to give 10 as a yellow film which was purified by flash chromatography (2.5% MeOH in CH2Cl2). 185 mg (97%). MS (ES): 435.8 (M++1). | |
In dimethyl sulfoxide; | Aryl chloride 9 (200 mg, 0.44 mmol), DMSO (10 ml) and L-prolinamide (440 mg, 4.4 mmol) were combined and heated to 85 C. under argon. After 14 hours the mixture is cooled to room temperature and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer washed with EtOAc (3*). The combined organic layers were thoroughly washed with water (3*), brine, dried over MgSO4, filtered and concentrated to give 10 as a yellow film which was purified by flash chromatography (2.5% MeOH in CH2Cl2). 185 mg (97%). MS (ES): 435.8 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | A process for the preparation of (S) -l_ (2-chloroacetylchloride) -2-cyanopyrrolidine, comprising the steps of: dissolving L-prolinamide (2 (0.17511101) Potassium carbonate (488,0.348111 0 1)To 4001 ^ acetonitrile, 0-15 (: stirring slowly dropping 16mL (0.2lmo 1)Chloroacetyl chloride (drop time 2-3 hours), after the completion of dropping, stirring room temperature overnight, TLC plate anti-Should be completely, the suction filter, the filtrate 0_15 C stirring drop 13.4111 to 0.094111 011 44, after the completion of the drop, 25 (: under stirringAfter overnight, the TLC plates were allowed to react completely, spin-dried, and then 20 mL of ethyl acetate was added to the kettle to carry excess TFAA,The residue was dissolved in 150 mL of ethyl acetate, the pH was adjusted to 8 with sodium carbonate solution, and the organic phase was washed with saturated brine,Dried over anhydrous sodium sulfate, filtered and dried to give an oil which was allowed to stand overnight and solidify (if not solidified,Seed crystal) as a light brown solid (Compound 2) in a yield of 92%. | |
92% | L-prolinamide (20 g, 0.175 mol),Potassium carbonate (48 g, 0.34 mol) was added to 400 mL of acetonitrile,(0.21 mol) of chloroacetyl chloride (dropwise for 2-3 hours) was slowly added dropwise with stirring at 0 to 15 C,After completion of the dropwise addition,The reaction was stirred at room temperature overnight,After TLC plate reaction was complete,Filtration,The filtrate was stirred at 0-15 C and 13.4 mL (0.094 m) of TFAA was added dropwise,After completion of the dropwise addition,Stir overnight at 25 C,After TLC plate reaction was complete,Drying,Then, 20 mL of ethyl acetate was added to the autoclave to carry out excess TFAA,So repeated 3 times,The residue was dissolved in 150 mL of ethyl acetate,The pH was adjusted to 8 with sodium carbonate solution, and the organic phase was washed with saturated brine,Dried over anhydrous sodium sulfate,filter,Drying,To give an oil,Standing overnight,Curing (such as curing,Can be added before standing a little seed)12.2 g of a light brown solid (compound 2)Yield 92%. | |
83.4% | The reaction bottle into the 92.0 g trichlor and 6.4 g DMF, under stirring added in batches 8.0 g (S)- N - chloracetyl -2 - carbamino pyrrolidine, 60 C reaction 1.5 h. After the reaction is distilled under reduced pressure steam out of the oxysilane.After treatment in the light of the embodiment 1, in the crystallization from toluene, shall be 6.0 g, yield 83.4%. |
66% | EXAMPLE 3; This example illustrates the synthesis of a compound of formula (IV) in accordance with the invention.Synthesis of 1-chloroacetyl-2-cyanopyrrolidine. A 250 mL reactor with thermometer, condenser and magnetic stirring was charged with i-PrOAc (41 mL), dry DMF (5 mL) and chloroacetyl chloride (19.5 g, 173 mmol) under an inert atmosphere. The resulting solution was cooled to 15 C. and a solution of L-prolinamide (17.1 g, 150 mmol) in dry DMF (48 mL) was slowly added (IT35 C.). The reaction mixture was stirred 2 additional hours at 35 C. to obtain complete conversion. The internal temperature was adjusted to 25 C. and cyanuric chloride (13.8 g, 75 mmol) was added in portions (IT35 C.). The mixture was stirred for 45 minutes, poured into 200 mL of water and extracted with EtOAc (3×200 mL). The organic phase was washed with 5% aqueous NaHCO3 (2×200 mL), dried over Na2SO4, filtered, and the solvents were evaporated under vacuum. The resulting oil was crystallized in 65 mL of isopropanol to obtain 17.16 g of 1-chloroacetyl-2-cyanopyrrolidine (66% yield). | |
With potassium carbonate; trifluoroacetic anhydride; In tetrahydrofuran; ethyl acetate; | A. 1-Chloroacetyl-2-(S)-cyanopyrrolidine 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-(S)-cyanopyrrolidine as a yellow solid. Alternatively, the reaction may be carried out by using, as base, a mixture, e.g. 2-ethyl-hexanoic acid/sodium hydride. | |
5.2 g | Exampie-8: Preparation of 1-chloroacetyl (S)-2-cyanopyrroiidine To a mechanically stirred solution of L-prolinamide (5g), and dichloromethane (40 ml), solution of chloroacetyl chloride (3.76 ml) in dichloromethane (10 ml) was added drop-wise over a period of 20-25 minute at temperature 25 to 30C, exotherm observed till 40C. Reaction mass was then stirred for additional 3 h at 25 to 30C. 2, 6 lutidine (14.1 ml) was added to reaction mass and stirred for 15 minutes. Solution of POCI3 (6.12 ml) in dichloromethane (10 ml) was added slowly to reaction mass at 5 to 10C. The reaction mass was stirred for 2-3 h at room temperature. Upon completion of reaction, the reaction mass was cooled to 0-5C. DM water was slowly added to reaction mass, exotherm observed upto 40C. Organic layer was washed with NaHCO3 solution (2X50 ml), followed by washing with aqueous 6% HCI (3 X 30 ml) and DM water (2X30 ml). Organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give 1-chloroacetyl (S)-2-cyanopyrrolidine. [Yield: 5.2 gm; Purity: 97.31%] | |
Initially, the mixture of L-prolinamide (1.14 g, 0.01 M) and DMF (15 mL) was taken in a round-bottom flask and the temperature is adjusted to 0 C. Then, triethylamine and chloroacetyl chloride (2.25 g, 0.02 M) were added in drop wise, and the reaction mixture was kept as such about 1 h at 0 C. After that, the cyanuric chloride (3.68 g, 0.02 M) was added and then the reaction mixture was stirred for about 50 min at room temperature. Then, reaction mixture was poured into ice water, and the obtained crude product was filtered, dried and purified by column chromatography using ethyl acetate/hexane (3:7) as an eluent. The obtained compound was found to retain with levorotatory behaviour based on the specific rotation measurement value. Yield 84%, m.p.: 54-56 C (52-53 C [33]), [alpha]D20 = -1022 (c 0.01 g, 0.0057 M, CH3CN). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: C20H26FN3O5 With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 1h; Stage #2: L-prolinamide With 4-methyl-morpholine In N,N-dimethyl-formamide at 20℃; | 93.B To a stirring solution of the title compound Preparative Example 91 (125 mg) in DMF(5 ml) was HOBt (46 mg), followed by EDCI (65 mg) and DMAP (5 mg). After 1 h commercially available L-proline amide (68 mg) and N-methyl morpholine (100 μl) were added and stirring was continued at rt overnight. The solvent was removed in vacuo, the residue diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic phase was separated, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica (CftbCb/acetone, 4:1) to afford the title compound (137 mg; 88 %; MH+ = 504). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: fumaryl dichloride; L-prolinamide With dmap; triethylamine In dichloromethane at 0 - 20℃; for 16h; Stage #2: With trifluoroacetic anhydride In dichloromethane at 0 - 20℃; for 24 - 48h; | 2.A Commercially available L-prolinamide (25 g) was dissolved in CH2Cl2 (1200 ml) and triethylamine (30 ml) and 4-dimethylaminopyridine (1.9 g) added. The mixture was cooled to 0 0C and treated with fumaryl chloride (11.7 ml). The dark mixture was stirred at it for 16 h and cooled to 0 °C. TFAA (77 ml) was added dropwise under stirring and the solution allowed to warm to rt over 6 hours. The reaction mixture was stirred at rt for 1 to 2 days. Ice (500 g) was added followed by cautious addition of sat. NaHCO3 (600 ml). After the evolution of gas had ceased, the organic phase was separated and washed with sat. NaHCO3 (350 ml), H2O (350 ml), and brine (200 ml). The organic phase was dried over MgSO4 and concentrated to afford the title compound (28.6 g; 98%). EPO 1HNMR δ (CDCl3) 2.12-2.30 (m, 8H)S 3.58-3.69 (m, 2H), 3.73-3.89 (m, 2 H)5 4.72-4.83 (m, 2H), 7.26 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.08% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 35℃; for 24h; | 1.2 Step -2 Preparation of (S, S) [2- (2-carbamoyl-pyrroIidin-l-yI) -1- (5-hydroxy-lH-indol-3-ylmethyl) -2-oxo-ethyl]-carbamic acid tert-butyl ester To a stirred solution of 2-tert-Butoxycarbonylamino-3- (5 -hydroxy- lH-indol-3-yl) - propionic acid (0.5 g, 1.56 mmole) in 3 mL of tetrahydro furan (THF) : N, N-dimethyl formamide (DMF) (1: 1) , Pyrrolidine -2-carboxylic acid amid (0.258 g, 1.717 mmol) , 1- hydroxy benzotriazole (HOBT) (0.316 g, 2.341 mmole) and N, N-diisopropyl ethyl amine (DIPEA) (0.807 g, 6.243 mmole) was added. Maintaining the temperature at 0° C N-ethyl-N'- (3- dimethylaminopropyl) carbodiimide (EDCI) (0.509g, 2.653 mmol) was also added the reaction mass .and kept it in stirring mood for 24 h in room temperature. Diluted the reaction mass with ethyl acetate (200 mL) and gave water (100 mL) and brine (100 mL) wash .The organic layer was dried over sodium sulfate and concentrated in vacuum. Yield: (0.50 Ig, 77.08%) . EPO MS m/z 416.9 (M + H+) .1H NMR (DMSOd6, 300 MHz) δl.3 (m, HH) , 2.0 (m, 6H) , 2.7 (m, IH) , 2.8 (m, IH) , 2.9 (s,IH) , 3.0 (m, IH) , 3.2 (m, IH) , 3.6 (m, 2H) , 4.3 (m, 2H) , 6.6 (d, 2H) , 6.9 (m, 3H) , 7.1 (d, 2H), 7.2 (m, IH) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.2% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 35℃; for 8 - 12h; | 37.3 Step -3 Preparation of (S) [2- (2-CarbamoyI-pyrroIidin-l-yI) -1- (5-nitro-lH-indol-3-ylmethyl) -2- oxo-ethyl]-carbamic acid tert-butyl ester To the stirred solution of 2-tert-butoxycarbonylamino-3- (5-nitro-lH-indol-3-yl) -prop ionic acid (0.200 g, 0.5730 mmol), L- (-) prolinamide (0.094 g, 0.6303 mmol) , N-ethyl-N'- (3- dimethylaminopropyl) carbodiimide (EDCI) (0.186 g, 0.9743 mmol) , 1 -hydroxy benzotriazole (HOBT) (0.116 g, 0.8595 mmol) , tetrahydro furan (THF) (0.5 mL) and dimethylformamide (0.5 mL) which was cooled to O0 C, then diisopropyl ethyl amine (0.369 g, 2.8653 mmol) was added .The reaction mixture was stirred for 8-12 h. at 25-35° C under nitrogen atmosphere and was diluted with ethyl acetate (200 mL) . The organic layer was washed with water (150 mL x 3) , sodium bicarbonate solution (100 mL) , dried over anhydrous sodium sulphate and was finally concentrated at high vacuum toget crude product. The crude product was recrystalized with ethyl acetate and hexane toget yellow product Yield (0.220 g, 86.2%) . MS m/z 446(M + H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 3h; | 1 1-((2R)-3-cyclopentyI-2-[formyI(hydroxy)amino]methyI}propanoyl)-M" [(phenyloxy)carbonyl]-L-prolinamide(2f?)-3-cyclopentyl-2-({formy)[(phenylmethyl)oxy]amino}methyl)propanoic acid (WO 2003101442, 38.2 g, 0.125 mol), L-prolinamide (14.3 g, 0.125 mo),) N-methyl morpholine (34.4 ml_, 0.313 mol,) and HOBt (18.65 g, 0.138 mol) were dissolved in DMF (400 ml_) with stirring. EDC (26.46 g, 0.138 mol) was added portionwise and the solution was stirred at room temperature for 3 hours. The majority of the DMF was removed in vacuo and the residue was diluted with ethyl acetate (1 L.) This solution was washed with cold 0.5M HCI solution (200 ml_), twice with water (200 ml_), saturated aqueous NaHCO3 solution, brine, and then dried over MgSO4. After filtering and evaporating, the crude material was dissolved in hot ethyl acetate (-150 ml.) with stirring. While keeping the solution hot, hexanes (-150 mL) was added until the solution was cloudy. Cooling slowly to room temperature while stirring gave a thick slurry. The solid was filtered off and washed with 1 :1 ethyl acetate: hexanes, followed by a wash with hexanes. After drying, the product 1- [(2/?)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-L- prolinamide was obtained as a white solid (34.4 g, 69% yield). LC/MS m/z 402 (MH+) |
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 25℃; for 18h; | To a solution of 1-(t-Boc-amino)-1-cyclohexane-carboxylic acid (0.60 g, 2.46 mmol) in DCM (10 mL) were added DCC (0.51 g, 2.46 mmol), HOBt (0.38 g, 2.46 mmol) and L-ProNH2 (0.28 g, 2.46 mmol). The reaction mixture was stirred at 25 C. for 18 h. The solid was filtered and the clear elude washed with saturated NaHCO3 (50 mL), brine (50 mL), dried (Na2SO4) and concentrated. Flash chromatography on silica gel (DCM/MeOH 9/1) gave [1-(N-t-Boc-amino)-1-cyclohexane-carboxylic acid]-L-ProNH2 (0.50 g, 60%) as a white foam: TLC (EtOAc) Rf 0.3; mp 220 C.; 1H NMR (CDCl3) delta 1.2-1.1.5 (m, 2H), 1.44 (s, 9H), 1.6-2.2 (m, 12H), 3.4-3.6 (m, 1H), 3.7-3.9 (m, 1H), 4.65 (dd, 1H, J=5.1, 8.1 Hz), 5.15 (bs, 1H), 5.22 (bs, 1H), 7.44 (bs, 1H); 13C NMR (CDCl3) delta 21.1, 21.3, 24.9, 25.7, 28.3, 28.5, 31.2, 31.7, 47.9, 58.8, 62.2, 80.6, 154.8, 172.7, 175.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 18h; | 7.4 To a solution of N-FMOC-L-t-butyl-cysteine (0.50 g, 1.25 mmol) in DCM (20 mL) were added DCC (0.26 g, 1.25 mmol), HOBt (0.196 g, 1.25 mmol) and L-ProNH2 (0.143 g, 1.25 mmol). The resulting mixture was stirred at 25° C. for 18 h. The white residue was filtered off and the clear solution washed with saturated NaHCO3 (2*50 mL), brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel using DCM/MeOH (9/1) as eluant to afford N-FMOC-L-t-butyl-cysteine-L-ProNH2 (0.55 g, 89%) as a white foam: 1H-NMR (CDCl3) δ 1.32 (s, 9H), 1.9-2.1 (m, 3H), 2.3-2.4 (m, 1H), 2.8-3.0 (m, 2H), 3.7-3.8 (m, 2H), 4.15-4.25 (m, 2H), 4.6-4.8 (m, 2H), 5.7 (bs, 1H), 5.90 (d, 1H, J=8.4 Hz), 6.9 (bs, 1H), 7.31 (t, 2H, J=6.6 Hz), 7.40 (t, 2H, J=7.5 Hz), 7.59 (d, 2H, J=7.5 Hz), 7.76 (d, 2H, J=7.8 Hz); 13C NMR (CDCl3) δ 24.5, 28.3, 30.8, 31.3, 43.3, 47.0, 47.8, 51.7, 60.1, 67.2, 120.0, 125.0, 125.1, 127.0, 127.7, 141.2, 143.7, 155.6, 170.7, 173.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate In ethanol at 60℃; for 24h; | 1.b A mixture of Trifernal (0.65 g, 4.4 mmol), S-prolinamide (0.50 g, 4.4 mmol) and K2Cθ3 in ethanol (4.48 g) was heated to 6O0C for 24 h. Then the solvent was removed under vacuum at 400C. The residue was taken up in ether and the solvent evaporated to yield 1.03 g (97%) of an oil as a mixture of diastereoisomers. HR-ESI-MS (pos.): 245.1658 [M+H]+; Ci5H21N2O+, calc: 245.1653. |
97% | With potassium carbonate In ethanol at 60℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.8% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; | 1.1 Preparation of [2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethyl] -carbamic acid tert-butyl ester 1f; 1) Preparation of [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester N-tert-butyloxycarbonyl glycine (5 g, 28.56 mmol) and L-pyrrolidine -2-carboxamide (3.25 g, 28.50 mmol) were dissolved in 75 mL N,N-dimethylformamide at 0 , then 1-hydroxybenzotriazole (11.8 g, 87.3 mmol) and N-ethyl-N'-(dimethylaminopropyl)-carbodiimide (11.3 g, 59 mmol) and triethylamine (12.1 mL, 87.3 mmol) were adding under stirring. Upon completion of the addition, the reaction mixture was naturally raised to room temperature, stirred overnight. The resulting mixture was concentrated under reduced pressure below 50 , extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization with ethyl acetate to give the title compound [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1f (7.42 g, yield 95.8%) as a white powder. MS m/z (ESI) : 272.1[M+1]. |
95.8% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; | 1.1 1) Preparation of [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic Acid tert-butyl Ester; N-tert-butyloxycarbonyl glycine (5 g, 28.56 mmol) and L-pyrrolidine-2-carboxamide (3.25 g, 28.50 mmol) were dissolved in 75 mL N,N-dimethylformamide at 0°, then 1-hydroxybenzotriazole (11.8 g, 87.3 mmol) and N-ethyl-N'-(dimethylaminopropyl)-carbodiimide (11.3 g, 59 mmol) and triethylamine (12.1 mL, 87.3 mmol) were adding under stirring. Upon completion of the addition, the reaction mixture was naturally raised to room temperature, stirred overnight. The resulting mixture was concentrated under reduced pressure below 50°, extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization with ethyl acetate to give the title compound [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1f (7.42 g, yield 95.8%) as a white powder.MS m/z (ESI): 272.1 [M+1]. |
95.8% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; | 1 N-tert-butyloxycarbonyl glycine 1a (5 g, 28.56 mmol) and L-prolinamide (3.25 g, 28.50 mmol) were dissolved in 75 mL of N,N-dimethylformamide, the resulting solution was cooled down to 0°C (centigrade), and 1-hydroxybenzotriazole (11.8 g, 87.3 mmol), N-ethyl-N'-(dimethylaminopropyl)-carbodiimide (11.3 g, 59 mmol) and triethylamine (12.1 mL, 87.3 mmol) were then added with stirring. Upon completion of the addition, the reaction mixture was allowed to increase to room temperature, and stirred overnight. After thin lay chromatography showed the starting material disappeared, N,N-dimethylformamide was evaporated below 50°C, and the reaction solution was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization with ethyl acetate to obtain the title compound [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (7.42 g, yield 95.8%) as a white powder. MS m/z (ESI): 272.1(M+1) |
95.8% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; | 1.1 Step 1 Preparation of [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b N-tert-butyloxycarbonyl glycine 1a (5 g, 28.56 mmol) and L-prolinamide (3.25 g, 28.50 mmol) were dissolved in 75 mL of N,N-dimethylformamide and the mixture was cooled to 0 °C. Then 1-hydroxybenzotriazole (11.8 g, 87.3 mmol), N-ethyl-N'-(dimethylaminopropyl)-carbodiimide (11.3 g, 59 mmol) and triethylamine (12.1 mL, 87.3 mmol) were added with stirring. The reaction mixture was warmed up to room temperature and stirred overnight. The reaction was monitored by thin layer chromatography (TLC) until the disappearance of the starting materials. N,N-dimethylformamide was evaporated below 50 °C. The resulting mixture was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the title compound [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (7.42 g, yield 95.8%) as a white powder. MS m/z (ESI): 272.1 [M+1] |
71% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane; N,N-dimethyl-formamide at 20℃; for 3h; | |
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
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81% | With sodium hydroxide In 1,4-dioxane; water at 20℃; for 2h; | 35 Synthesis of N-(2,2,2-trifluoroethoxycarbonyl)-L-prolinamide (hereinafter referred to as the compound (XV-2)) To 65 ml of water containing 5.0 g of prolinamide was added dropwise 7 ml of dioxane containing 8.54 g of 2,2,2-trifluoroethoxycarbonyl chloride at room temperature. When the pH of the reaction solution became 8, dropwise addition of a 8 weight % aqueous sodium hydroxide solution also started at the same time, and the pH of the reaction solution was maintained at 8 +/- 0.5. After the completion of dropwise addition, the solution was stirred for 2 hours, and then ethyl acetate was added to the solution to carry out liquid separation. The organic layer was dried over sodium sulfate and filtered, and then the filtrate was put under reduced pressure to remove the solvent. The obtained solid was the title compound. Quantity of white solid: 8.48 g (Yield: 81%) 1H NMR(DMSO-d6) δ1.82(3H,m),2.16(1H,m),3.38(1H,m),3.46(1H,m),4.13(1H,m),4.6-4. 7(2H,m),6.99(1H,s),7.41(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | Example 6 (S)-pyrrolidine-1 ,2-dicarboxylic acid 2-amide 1-[(2-tert-butyl-4'-methyl- [4,5']bithiazolyl-2'-yl)-amide]; A mixture of imidazole-1-carboxylic acid (2-tert-butyl-4'-methyl-[4,5']bithiazolyl-2'-yl)-amide (40 mg), L-proline amide (20 mg) and triethylamine (0.02 ml) in DMF (1 ml) is allowed to stand at room temperature for 18 hours. Following evaporation of the reaction mixture purification by crystallisation from aqueous methanol gives the title compound as a white solid. Hplc/MS (Method B) RT 2.40 minutes, M+H 394.1 and M-H 392.3. |
Yield | Reaction Conditions | Operation in experiment |
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79% | Stage #1: trans-(2S,4S)-4-(2-(tert-butoxy)-2-oxoethyl)-1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,4-dioxane; dichloromethane at 20℃; for 0.166667h; Stage #2: L-prolinamide In 1,4-dioxane; dichloromethane for 16h; | 1 Example 1 Preparation of (2S)-1-({(2S,4S)-4-[2-(1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-5-oxopyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile (compound 1) (2S,4S)-1-(tert-butoxycarbonyl)-4-(2-tert-butoxy-2-oxoethyl)-5-oxopyrrolidine-2-carboxylic acid was prepared according to the method described in Tetrahedron Lett. 1988, 39, 2199-2202. To a solution containing this compound (343 mg, 1.0 mmol) and N-hydroxybenzotrizole (HOBt, 168 mg, 1.1 mmol) in 1,4-dioxane (5 mL) was added a solution of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC, 211 mg, 1.1 mmol) in CH2Cl2 (5 mL). The mixture was stirred for 10 min at room temperature. (S)-Pyrrolidine-2-carboxamide (125 mg, 1.1 mmol) in CH2Cl2 (4 mL) was added with stirring. After 16 h, the reaction mixture was washed with saturated aqueous NaHCO3 solution (10 mL), 1 N aqueous citric acid solution (10 mL), and brine (10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The resulting residue was purified over silica gel using CH2Cl2/MeOH (95:5) as an eluant to yield compound A (347 mg, 0.79 mmol, 79%). |
Stage #1: trans-(2S,4S)-4-(2-(tert-butoxy)-2-oxoethyl)-1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,4-dioxane; dichloromethane at 20℃; Stage #2: L-prolinamide In 1,4-dioxane; dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h; | To a solution of ter?-butoxycarbonylamino(4-hydroxyphenyl)acetic acid (3.Og, 11.2mmol) in DCM (75mL) was added (S)-prolinamide (1.54g, 13.5mmol), EDCI (2.15g, 11.2mmol), HOBt (2.06g, 13.47mmol) and DIPEA (4.69mL, 26.9mmol) and the reaction was stirred at r.t. for 24h. The reaction mixture was diluted with DCM and washed with IM citric acid, sat. NaHCO3 solution, water then brine and dried (MgSO4). Removal of the solvent in vacuo and purification by column chromatography (SiO2, DCM:MeOH, 95:5, 90:10) afforded the title compound: RT = 2.50 min; mlz (ES+) = 364.3 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
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83% | Stage #1: di-t-butoxycarbonyl-L-cystine With benzotriazol-1-ol; dicyclohexyl-carbodiimide In ethyl acetate; N,N-dimethyl-formamide at 25℃; for 2h; Stage #2: L-prolinamide In ethyl acetate; N,N-dimethyl-formamide at 25℃; for 18h; | 7.12.2 To a solution of N,N'-[bis(tert-butoxycarbonyl)]-cystine (1.0 g, 2.27 mmol) in EtOAc (15 mL) and DMF (5 mL) were added DCC (1.03 g, 5.0 mmol, 1.1 equiv) and HOBt (0.78 g, 5.0 mmol, 1.1 equiv). The resulting mixture was stirred at 25° C. for 2 h. L-ProNH2 (0.53 g, 4.65 mmol, 1.03 equiv) was added and the mixture stirred at 25° C. for an additional 18 h. The white residue was filtered off and the clear solution concentrated under reduced pressure. The residue was dissolved in CHCl3 (60 mL), and the solution was washed with, saturated NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude oil was purified by silica gel column chromatography (DCM/MeOH 9/1) to afford the title compound (1.2 g, 83%) as a white solid: Rf 0.4 (CH2Cl2/MeOH 9/1); mp 128-131° C.; 1H NMR (CDCl3) δ 1.44 (s, 18H), 1.90-2.40 (m, 8H), 3.01 (dd, 2H, J=6.0 and 13.2 Hz), 3.16 (dd, 2H, J=6.3 and 13.5 Hz), 3.70-3.82 (m, 4H), 4.50-4.65 (m, 2H), 4.70-4.82 (m, 2H), 5.75 (br d, 2H, J=8.7 Hz), 6.37 (br s, 2H), 6.78 (br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: N-(tert-butoxycarbonyl)-L-histidine With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 25℃; for 2h; Stage #2: L-prolinamide In N,N-dimethyl-formamide at 25℃; for 18h; | 7.13.1 To a solution of Nα-(tert-butoxycarbonyl)-L-histidine (0.5 g, 1.96 mmol) in DMF (10 mL) were added DCC (0.44 g, 2.15 mmol, 1.1 equiv) and HOBt (0.34 g, 2.15 mmol, 1.1 equiv). The resulting mixture was stirred at 25° C. for 2 h. L-ProNH2 (0.23 g, 2.01 mmol, 1.03 equiv) was added and the mixture stirred at 25° C. for an additional 18 h. The white residue was filtered off and the clear solution concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (CHCl3/MeOH/NH3 40/10/1) to afford the title compound (0.70 g, 73%) as a white solid: mp 97-101° C.; 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.86-2.08 (m, 2H), 2.09-2.26 (m, 2H), 3.00-3.16 (m, 2H), 3.20-3.38 (m, 1H), 3.60-3.70 (m, 1H), 4.51 (t, 1H, J=6.6 Hz), 4.57-4.70 (m, 1H), 5.59 (br s, 1H), 6.20 (br s, 1H), 6.84 (s, 1H), 7.42 (s, 1H). |
Stage #1: N-(tert-butoxycarbonyl)-L-histidine With HONB; diisopropyl-carbodiimide In N,N-dimethyl-formamide for 0.25h; Stage #2: L-prolinamide In N,N-dimethyl-formamide at 20℃; | Synthesis of Thyrotropin-ReleasingHormone (TRH) General procedure: Boc-L-His-OH (1.2 mmol) (1) was dissolved in about10-12 mL of dry DMF followed by addition of 1.8 mmol(1.5 equiv.) of HONB and DIC each and the reactionmixture was stirred for 15 minutes (Scheme 1).This was followed by addition of 1.8 mmol (1.5 equiv.) of L-Prolinamide and reaction mixture was stirred for36 h at room temperature to afford Boc-L-His-L-Pro-NH2(2), which was purified using column chromatography.Further, the Boc group was deprotected using 10 mL of 7N-methanolic HCl and the resulting substrate wasneutralized using 3 equiv. of DIPEA and then coupled withL-Pyro-Glu-OH in the presence of HONB (1.5 equiv.) andDIC (1.5 equiv.) under constant stirring for 36 hours atroom temperature to obtain L-pGlu-L-His-L-Pro-NH2 (4).The final product 4 was purified using column chromatographyand all the synthesized compounds were analyzedand characterized at each stage using 1H-NMR and massspectrometry. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: (2S)-2-[(t-butoxycarbonyl)amino]-3-{4-[(5-nitropyridin-2-yl)oxy]phenyl}propanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: L-prolinamide In N,N-dimethyl-formamide at 20℃; for 15h; | 9.III Step III; Preparation of (2S)-1-{(2S)- 2-[(*-butoxycarbonyl) amino]-3-[4-(5-nitro pyridin-2- yloxy) phenyl] propanoyl} pyrrolidine-2-carboxamide; To a solution of (2S)-2-[(t-butoxycarbonyl)amino]-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanoic acid (0.54g, 1.3mmol) in dimethylformamide (20ml), was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.3Og, l.mmol), diisopropylethyl amine (0.296ml, l.mmol) and HOBt (0.36g, 2.6mmol) and the reaction mixture was stirred for 30 minutes at room temperature. To the above reaction mixture was added pyrrolidine-2-carboxamide (0.183g, 1.6mmol) and it was stirred for 15 hours at room temperature. Subsequently the reaction mixture was poured on to 5% aqueous HCl and was extracted with ethylacetate; the organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated to give the crude product, which was subjected to column chromatography to afford the title compound (0.6 Ig, 92%); m/zM+1 500.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: L-prolinamide With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; optical yield given as %de; diastereoselective reaction; | General Procedure for the reaction between compound 1 and L-prolinamide (L-prolinol) derivatives: Under N2 atmosphere, Cs2CO3 (326 mg, 1.00 mmol) and L-prolinamide (0.6 mmol) in dry DMF (5 mL) were placed in a 10 mL Schlenk flask at rt. The suspension was stirred for 30 min. (Z)-methyl-2-bromo-4,4,4 -trifluorobut-2-enoate 1 (117 mg, 0.5 mmol) was added at this temperature. The solution was stirred until the reaction was completed (usually 3~5 h). The reaction was then quenched by adding saturated aqueous NH4Cl solution (10 mL). The mixture was extracted with EtOAc (3x10 mL). The combined organic layer was washed with brine and dried over Na2SO4. After the removal of solvents under vacuum, the crude product was further purified by silica gel column chromatography (PE:EA = 2:1 v/v) to afford pure products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With ammonia In methanol | 2 (2) Preparation of L-prolineamide synthetic solution Add 375ml (2.5v/w) of methanol to the obtained L-proline methyl oil, stir to dissolve, transfer to a 1L four-necked flask, cool to 0.0-5.0, control the temperature at 0.0-5.0 and pass liquid ammonia (Total about 14eq), after ventilation, keep at 0.05.0 and react for 10-15 hours. After 10 hours of reaction, start sampling and control. TLC control until the spots of L-prolinol disappear. (Developer: methanol: two Methyl chloride=1:5, ninhydrin color development), and L-proline amide synthesis solution is obtained. Example L-proline amide synthesis solution purification preparation L-proline amide. Take the above L-proline amide synthesis solution, first control the vacuum degree to -0.06-0.09MPa to remove the ammonia gas, slowly increase the temperature to 15.020.0, degas it until there are basically no bubbles in the kettle, stop degassing. The material liquid is filtered, the filter cake is rinsed with 0.5v/w methanol, the filtrates are combined, the filter cake is discarded, the filtrate is adjusted to pH=9.510.0 with solid sodium hydroxide at 20-30, and then hydroxide is added dropwise Sodium methanol solution (2mol/L), adjust pH=10.5, heat to 30.035.0°C and stir for 1 hour, retest the pH unchanged. Filter the material liquid, rinse the filter cake with 15ml (0.1v/w) methanol, combine the filtrate, and desolvate the filtrate under reduced pressure at 50.055.0, vacuum degree -0.06-0.09MPa, and then dry to almost no solvent After removal, crude L-prolineamide is obtained. Add 903g (7v/w) toluene to the crude L-prolineamide, raise the temperature to 80.0-85.0, keep it for 10 minutes, and perform hot filtration. The filtrate is cooled to 0-5 within 5-6 hours, and then kept for 2h. The wet product of L-proline amide is obtained by filtration, and the wet product is placed in a vacuum drying oven. First, it is dried at 25-30 and -0.1MPa for 12 hours, and then heated to 50.0-55.0 for further drying for 12 hours to obtain L-proline amide 136g The total yield is 91%, purity: 99.38% (HPLC), 99.72% (GC), external standard content (potentiometric titration): 99.65%. |
85% | With ammonia In methanol at 0 - 20℃; for 15h; Large scale; | 4 Preparation of L-prolinamide The L-proline methyl ester hydrochloride obtained in Example 1 was dissolved in 400 L of methanol,Stirring cooling to 0 ~ 10 ° C, Start into the ammonia reaction,Temperature control 15 ~ 20 ° C,For 15 hours.At the end of the reaction,The methanol was evaporated to dryness under reduced pressure.Add 700L dichloromethane stirring dissolved,Cool to 0 ~ 10 ° C.A concentrated solution of potassium hydroxide was added dropwise(75kg dissolved in 45kg of water) drained, drops complete,The reaction was stirred for 1 hour with heat preservation.The inorganic salt was removed by filtration.The filtrate was stratified,The aqueous layer was extracted twice more with dichloromethane,Each 250L.The organic layers were combined,Dichloromethane was evaporated under reduced pressure.50 L of ethyl acetate was added,Continue to dry under reduced pressure.Ethyl acetate 440L was added to the solution,Activated carbon decolorization,Hot filtration,Cool to 0-5 ° C and stir for 2 hours.filter,Drying oven around 45 ° C, To obtain the target product L-prolinamide 84. 3kg,Yield 85.0%.Product purity (HPLC): 99.8%; titration content: 99.5%; D-prolinamide: 0.3% (GC). |
55% | With ammonia In methanol at -25℃; for 96h; Sealed tube; | 1 4.1.14. (2S)-pyrrolidine-2-carboxamide (15) A cooled to -25 °C solution of compound 14 in methanol (40 ml) was saturated by gaseous ammonia. A precipitation of ammonia hydrogenchloride was observed. After saturation, the reaction mixturewas resealed for 4 days. The reaction mixture was filtered, and thewhite precipitate was washed by methanol (20 ml). Methanol was removedunder vacuo and the obtained residue was recrystallized frommethanol: ethyl acetate. White solid, 2.9 g, 55% yield. 1H NMR(400 MHz, CDCl3) δ 1.58-1.79 (m, 2H) 1.80-1.93 (m, 1H) 2.03-2.14(m, 1H) 2.18 (s, 1H) 2.82-3.01 (m, 2H) 3.67 (dd, J=9.20, 5.57 Hz,1H) 6.25 (br. s., 1H) 7.38 (br. s., 1H) |
With ammonia; butan-1-ol at 20℃; for 10h; | 4 Example- 4: Preparation of L-proIinamide:To L-proline methyl ester hydrochloride (100 grams) in 1200 ml of n-butanol was added and stirred for 10 minutes. 650 ml of aqueous ammonia was added to the reaction mixture and stirred for 10 hours at room temperature. The aqueous and organic layers were separated. The organic layer was dried over sodium sulfate. The solvent was distilled off completely from organic layer. To the obtained compound, cyclohexane (300 ml) was added and stirred for 30 minutes. The reaction mixture was filtered and the solid obtained was dried to get the title compound.Yield: 55 grams. | |
18 kg | With ammonia In methanol Heating; Large scale; | 7 Preparation of L- prolinamide L- proline methyl ester hydrochloride 8 (First step 6 product) was dissolved in dry methanol (200L), and thereto via NH3 gasTo saturation. Then heat the reaction to the raw material pressurizing complete conversion. Most of the solvent was removed by distillation under reduced pressure, the resulting solidFiltered, washed with diethyl ether. The resulting solid was added in an appropriate amount of benzo-50 ° C when dissolved, add 2 volumes of n-hexane, to slowSlow cooling to room temperature, and then allowed to stand in the freezer to precipitate crystals, was filtered, the resulting solid was dried in vacuo to give L- prolinamide 9 (18kg, wide two steps 93%) as white powdery crystals. |
15.8 g | With ammonia at 0℃; for 26h; | 2 In a 1000 mL three-neck flask, 20 g of L-proline was added.Add 280 mL of alcohol to stir.Cool down to -5°C22 g of dimethyl carbonate and 23 g of triphosgene were added.The temperature was warmed to 30°C and the reaction was complete for 9 hours.Rotate the reaction solution to dryness,After cooling down to 0°C, add 400mL of ammonia alcohol solution.Transferred to the high pressure reactor,Ammonia control pressure is 0.3MPaThe reaction was stopped for 26 hours.The reaction solution was concentrated until solid precipitated and cooled to 0°C.The filtrate is added with potassium hydroxide,N,N'-dicyclohexylcarbimide so that pH = 8-13,Cool down to 0 °C suction filter,The filtrate is dried under reduced pressure,Solvents dissolve,Then 80 °C filtration,The filtrate was stirred at a high speed (800-1200r/min) and crystallized.With crystal precipitation,Reduce the stirring speed (50-500r/min),Make crystals grow slowly,Cool down to 0 °C filter,The cake was vacuum-dried at 30-50°C for 3-6 hours.The dry weight of the product is 15.8g.The total yield is 79.7%.Detect D-isomer 0.14%The purity was 99.82% by high performance liquid chromatography (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 6h; | Example-5: Preparation of BOC protected L-prolinamide:To a solution of L-prolinamide (50 grams) of in 300 ml of dichloromethane triethyl amine (121.5 ml) was added and cooled the mixture to 0-5C. Di-tert-butyl dicarbonate (154.5 ml dissolved in 200 ml of dichloromethane) was added slowly to the reaction mixture. The reaction mixture was stirred for 6 hrs at room temperature. The solvent was distilled off completely from the reaction mixture. Dichloromethane was added to the residue, stirred for 30 min and distilled off to get the title compound.Yield: 85 grams. | |
With potassium carbonate; In dichloromethane; at 10 - 15℃;Inert atmosphere; | Dichloromethane (500 ml), L-Prolinamide (100 g), potassium carbonate (60.50 g) were mixed and stirred under nitrogen atmosphere in round bottom flask The reaction mass was cooled to 10-15C and then Di-tert-butyl dicarbonate (210.30 g) was added. Reaction mixture was stirred till completion of the reaction. After completion water (500m1) was added and product was extracted in dichloromethane. Dichloro methane was removed and then dimethyl formamide (140 ml) and dichloromethane (700 ml) were added under nitrogen atmosphere. Cyanuric chloride (72.70 g) was charged in 2-3 equal lots to the reaction mass at 20-25C under nitrogen atmosphere. The reaction mass was maintained at 35-40C for 4-5 hrs. After completion of the reaction solid was filtered and washed with MDC. Methane sulfonic acid (252.60 g) was added to the filtrate and heated the reaction mass to 40-45C for 3-4 hrs. After completion of the reaction the reaction mass was cooled at 0-5C and Triethyl amine (88.65 g) and Chloroacetyl chloride (118.70 g) were added. The reaction mass was maintained at 20-30C for 1-2 hrs under nitrogen atmosphere. After completion of the reaction water was charged and product was extracted in dichloromethane. Organic layer was washed first with dilute HC1 solution and then with ammonia solution. Organic solvent was removed and product was crystallized using isopropyl alcohol. Yield: 75.0gm | |
With triethylamine; In dichloromethane; at -15℃; for 12h; | To a clean and dry four-necked flask, L-prolinamide 22.3g (0.195ml), dichloromethane 90mL, triethylamine 30.0g (0.297mol), cooled to -15 C Stirring the reaction; dropping a solution of Boc anhydride dichloromethane solution, the Boc anhydride 0.234mol, dropwise addition time 2h, incubated for 10h, TLC was monitored until the end of the reaction to obtain a solution containing the formula shown in Formula II Compound first reaction solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 20℃; for 17h; | 5.1.1. (2S)-α-(2-carbamoylpyrrolidinyl)-acetic acid ethyl ester (2S)-5 Ethyl bromoacetate (1.1 mL, 9.95 mmol) was added drop-wise to a stirred, cooled (0 °C, ice-salt bath) mixture of l-prolineamide (1.40 g, 12.26 mmol), N,N-diisopropyl-N-ethylamine (1.58 mL, 12.26 mmol) and acetonitrile (100 mL) over 10 min. The mixture was warmed to room temperature, stirred (17 h) and the solvent was evaporated in vacuo. The residue was purified by FC (gradient: petroleum ether:ethyl acetate 1:1 to ethyl acetate:methanol 9.5:0.5) to give 1.28 g (69%) of (2S)-5. White powder; mp 97-98 °C; [α]D = -66.5 (c 1, CHCl3); IR (KBr): 752, 1207, 1416, 1632, 1732, 2978, 3194, 3387; TLC (ethyl acetate): Rf = 0.37; 1H NMR (500 MHz, CDCl3): δ 1.28 (t, 3J = 7.0, 3H, OCH2CH3), 1.85 (m, 2H, H-4, H'-4), 2.00 (m, 1H, H-3), 2.25 (4t, 2J = 13.0, 3J1 = 8.0, 3J2 = 10.5, 1H, H'-3), 2.62 (dt, 2J = 3J1 = 9.0, 3J2 = 6.5, 1H, H-5), 3.25 (m, 2J = 9.0, 3J1 = 6.5, 3J2 = 2.5, 1H, H'-5), 3.35 (dd, 3J1 = 10.0, 3J2 = 4.0, 1H, H-2), 3.39 (d, 2J = 17.0, 1H, H-α), 3.54 (d, 2J = 17.0, 1H, H'-α), 4.18 (q, 3J = 7.0, 2H, OCH2CH3), 5.48 (bs, 1H, CONH), 7.52 (bs, 1H, CONH'); 13C NMR (125 MHz, CDCl3): δ 14.4 (OCH2CH3), 25.1 (C-4), 31.2 (C-3), 54.4 (C-5), 55.7 (C-2), 61.0 (OCH2CH3), 67.1 (C-α), 171.4 (CONH2), 178.2 (COOCH3); HRMS (ESI) calculated for C9H16N2O3Na: 223.1059 (M + Na)+ found 223.1032. |
68% | With potassium carbonate In acetonitrile at 80℃; | 46.1 Intermediate STEP 1 : To (2S)-pyrrolidine-2-carboxamide (1.0g, 8.76mmol, 1.0eq) was added MeCN (100mL) followed by the addition of ethyl bromoacetate (7.31 g, 43.80mmol, 5.0eq) and K2CO3 (3.63g, 26.28mmol, 3.0eq). The reaction was stirred at 80°C overnight. Solvent was then removed in vacuo and the residue purified by column chromatography using an eluent of 0-5% MeOH in DCM reached via a gradient to give ethyl 2-[(2S)-2-carbamoylpyrrolidin-1-yl]acetate (1.2g, 68%).UPLC-MS (ES+, Method C): 0.37 min, m/z 201.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18.5h; Inert atmosphere; | 1 5.2 General procedure for the amidation reaction General procedure: To a solution of the appropriate acid derivative (1 mmol) in dryDMF (5 mL) O-benzotriazol-1-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate (HBTU, 2 mmol) was added followed by 1-hydroxybenzotriazole (HOBt, 1 mmol), diisopropylethylamine (DIPEA, 1.5 mmol) and the appropriate amine (1.2 mmol). The mixture was stirred under N2 atmosphere at room temperature for 30 min and DIPEA (1.5 mmol) was added again. The reaction mixture was stirred at room temperature for 18 h, poured into water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product, unless otherwise indicated, was recrystallized from EtOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With copper(l) iodide; potassium carbonate In toluene at 110℃; for 24h; Inert atmosphere; Sealed tube; | |
75% | With caesium carbonate; copper(l) chloride; N,N`-dimethylethylenediamine In toluene at 50℃; for 18h; Schlenk technique; Sealed tube; Inert atmosphere; regioselective reaction; | 4.1.1 General procedure for the chiral α-amino anilides (3a-3n) General procedure: A 25-mL Schlenk-type tube equipped with a magnetic stir bar was charged with a chiral amino acid amide or its hydrochloride (1.2 mmol), Cs2CO3 (2.0 mmol; 3.0 mmol was used when an amino acid amide hydrochloride was used), and CuCl (0.1mmol) before sealing. A syringe was used under a nitrogen atmosphere to add aryl halide (1.0 mmol), DMEDA (1.0mmol) and toluene (4.0 mL). If aryl halides were solid at room temperature, they were added with CuCl and Cs2CO3 at the same time. The tube was placed into an oil bath pot preheated to 50°C and stirred at a steady temperature for 18 h. The reaction mixture was then cooled to room temperature, quenched with water, and extracted with ethyl acetate (20 mL) for three times. The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a solution of dichloromethane and ethyl alcohol (80/1 to 10/1) to afford the chiral α-amino anilides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 50℃; | To a mixture of <strong>[6299-85-0]methyl 2,6-dichloropyrimidine-4-carboxylate</strong> (2.074 g, 10.02 mmol) in acetonitrile (50 mL) was added (S)-pyrrolidine-2-carboxamide (1.150 g, 10.07 mmol) and iPr2NEt (1.92 mL, 11.02 mmol). The mixture was heated at 50C overnight and then filtered while still warm. The filter cake was washed with acetonitrile (1 x 10 mL) then dried under vacuum at 40C to give a first batch of (S)-methyl 6-(2-carbamoylpyrrolidin-1-yl)-2-chloropyrimidine-4-carboxylate as a tan solid (0.671 g, 2.36 mmol, 24% yield). The filtrate and washes were evaporated in vacuo and triturated with warm acetonitrile (10 mL). The solid was filtered, washed with acetonitrile (2 x 5 mL), and dried under vacuum at 40C to give a second batch of (S)-methyl 6-(2-carbamoylpyrrolidin-1-yl)-2-chloropyrimidine-4-carboxylate as a solid (0.849 g, 2.98 mmol, 30% yield). LC/MS: m/z= 285.1 [M+H]+. |
1.52 g | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 50℃; | EXAMPLE 27 Preparation of (S)-6-(2-carbamoylpyrrolidin- 1 -yl)-2-(4-(4-chloro-2- fluorophenoxy)phenyl)pyrimidine-4-carboxamide (Cpd. No. 78) Scheme 55 (S)-methyl 6-(2-carbamoylpyrrolidin-l-yl)-2-chloropyrimidine-4-carboxylate: To a mixture of <strong>[6299-85-0]methyl 2,6-dichloropyrimidine-4-carboxylate</strong> (2.074 g, 10.02 mmol) in acetonitrile (50 mL) was added (S)-pyrrolidine-2-carboxamide (1.150 g, 10.07 mmol) and iPr2NEt (1.92 mL, 1 1.02 mmol). The mixture was heated at 50C overnight and then filtered while still warm. The filter cake was washed with acetonitrile (1 x 10 mL) then dried under vacuum at 40C to give a first batch of (S)-methyl 6-(2-carbamoylpyrrolidin-l-yl)-2-chloropyrimidine-4-carboxylate as a tan solid (0.671 g, 2.36 mmol, 24% yield). The filtrate and washes were evaporated in vacuo and triturated with warm acetonitrile (10 mL). The solid was filtered, washed with acetonitrile (2 x 5 mL), and dried under vacuum at 40C to give a second batch of (S)-methyl 6-(2-carbamoylpyrrolidin-l-yl)-2-chloropyrimidine-4- carboxylate as a solid (0.849 g, 2.98 mmol, 30% yield). LC/MS: m/z= 285.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 15h; | |
79.6% | With triethylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 14-18 Example 14 Synthesis of compound Alpelisib represented by formula I At room temperature, compound 6 (39.5 g, 0.1 mol) was added to DMF (400 mL), and Et3N (30.4 g, 0.3 mol) was slowly added under stirring, and compound 7 (14.8 g, 0.13 mol) was added under stirring at room temperature, protected by N2 The reaction was stirred overnight.The reaction solution was quenched by adding saturated NaHCO3 solution (300 mL), extracted with ethyl acetate (100 mL * 3 times), the organic phase was washed with saturated NaHCO3 solution, dried and concentrated and purified by column chromatography (column chromatography using a volume ratio of 8: 1 Dichloromethane and methanol mixed solvent elution) to obtain the compound of formula I Alpelisib,The yield was 35.1 g, the yield was 79.6%, and the HPLC purity was 99.8%. |
With triethylamine In N,N-dimethyl-formamide for 14h; Reflux; Inert atmosphere; | 1.II I. Synthesis of (5)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-[5-(2-tert-butylpyridin-4- yl)-4-methyl-thiazol-2-yl]amide} General procedure: Et3N (1.54 niL, 11.1 mmol, 3 eq) is added to a solution of imidazole-1-carboxylic acid [5-(2-tert-butylpyridin-4-yl)-4-methyl-thiazol-2-yl]-amide (Step 1.1) (1.26 g, 3.7 mmol) and L-prolinamide (0.548 g, 4.8 mmol, 1.3 eq) in DMF (25 mL), under an argon atmosphere. The reaction mixture is stirred for 14 h at rt, quenched by addition of a saturated solution of NaHCO3 and extracted with EtOAc. The organic phase is washed with a saturated solution of NaHCO3 , dried (Na2S04), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH, 1 :0→ 94:6), followed by trituration in Et2O to afford 1.22 g of the title compound as an off-white solid: ESI-MS: 388.1 [M+H] ; tR= 2.35 min (System 1); TLC: Rf = 0.36 (DCM/MeOH, 9: 1). 1H NMR (400 MHz, DMSO-d6) 5(ppm): 1.32 (s, 9 H) 1.75-1.95 (m, 3 H) 1.97 - 2.13 (m, 1 H) 2.39 (s, 3 H) 3.38-3.50 (m, 1 H) 3.52-3.65 (m., 1 H) 4.10-4.40 (m, 1 H) 6.94 (br. s., 1 H) 7.22 (d, 1 H) 7.30 - 7.48 (m, 2 H) 8.49 (d, 1 H) 10.87 (br. s., 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 15℃; for 3h; | 3 Step 3: (S)-fert-Butyl 2-(2-carbamoylpyrrolidine-1-yl)-2-oxoethylcarbamate Step 3: (S)-fert-Butyl 2-(2-carbamoylpyrrolidine-1-yl)-2-oxoethylcarbamate. A solution of the N-hydroxysuccinimidate obtained from step 2 (8.22g, 46.9mmol) in dichloromethane (100 mL) was cooled in a cooling bath to 15°C. After 15 min, a solution of (S)- pyrrolidine-2-carboxamide (5.1 g, 44.7 mmol, bought from commercial supplier Fluorochem) and 2.1 eq of Hunig's base in 50 m L of dichloromethane were added. After 3h, the resulting solution was washed with 1 N hydrochloric acid, with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtrated and evaporated to dryness. The crude mixture was purified using flash chromatography with 5% methanol in DCM. Yield: 8.61 g, 71 % 1 H NMR (400 MHz, DMSO -cfe): δ 1 .38 (s, 9H), 1 .72-2.22 (m , 4H), 3.38-3.45 (m,1 H), 3.49-3.55 (m,1 H), 3,74 (d, J = 5.7 Hz, 2H), 4.18 (dd, J =8.8, 2.8 Hz, 1 H), 5.43 (br s, 1 H), 5.54 (br_s, 1 H) , 6.83 (br s, 1 H) MS (ESI) m/z 294.2 [M + Na]+. |
71% | Stage #1: tert-butyl N-{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}carbamate In dichloromethane at 15℃; for 0.25h; Stage #2: L-prolinamide In dichloromethane | 3 Step 3: (S)-tert-Butyl 2-(2-carbamoylpyrrolidine-1-yl)-2-oxoethylcarbamate A solution of the N-hydroxysuccinimidate obtained from step 2 (8.22 g, 46.9 mmol) in dichloromethane (100 mL) was cooled in a cooling bath to 15° C. After 15 min, a solution of (S)-pyrrolidine-2-carboxamide (5.1 g, 44.7 mmol, bought from commercial supplier Fluorochem) and 2.1 eq of Hünig's base in 50 mL of dichloromethane were added. After 3 h, the resulting solution was washed with 1N hydrochloric acid, with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtrated and evaporated to dryness. The crude mixture was purified using flash chromatography with 5% methanol in DCM. Yield: 8.61 g, 71% 1H NMR (400 MHz, DMSO-d6): δ 1.38 (s, 9H), 1.72-2.22 (m, 4H), 3.38-3.45 (m, 1H), 3.49-3.55 (m, 1H), 3.74 (d, J=5.7 Hz, 2H), 4.18 (dd, J=8.8, 2.8 Hz, 1H), 5.43 (br s, 1H), 5.54 (br_s, 1H), 6.83 (br s, 1H) MS (ESI) m/z 294.2 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 3h; | 42.3 (S)-1-(3,3‘-difluoro-4’-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide 3,3'-difluoro-4'-((1-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (0.04 g, 0.10 mmol) and (S)-pyrrolidine-2-carboxamide (0.02 g, 0.19 mmol) were dissolved in DMF 1 mL. DIPEA (0.08 mL, 0.47 mmol), EDCI (0.04 g, 0.19 mmol) and HOBt (0.03 g, 0.19 mmol) were added thereto slowly, following with stirring at 60 °C for 3 hours. After the completion of the reaction, excess amount of water was added to the reaction mixture. The resulting precipitate was filtered to yield the title compound as brown solid (0.04 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.21 (m, 5 H), 7.00 (t, 1 H, J = 8.4 Hz), 6.89 (brs, 1 H), 5.41 (brs, 1 H), 4.81 - 4.80 (m, 1 H), 3.91 (brs, 2 H), 3.53 - 3.41 (m, 2 H), 3.13 - 2.43 (m, 4 H), 2.21 - 1.86 (m, 3 H), 1.71 - 1.23 (m, 10 H); MS (ESI) m/z 518 (M+ + H). |
75% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 3h; | 42.3 Compound 730 3,3'-difluoro-4'-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid (0.04 g, 0.10 mmol) and (S)-pyrrolidine-2-carboxamide (0.02 g, 0.19 mmol) were dissolved in DMF 1 mL. DIPEA (0.08 mL, 0.47 mmol), EDCI (0.04 g, 0.19 mmol) and HOBt (0.03 g, 0.19 mmol) were added thereto slowly, following with stirring at 60° C. for 3 hours. After the completion of the reaction, excess amount of water was added to the reaction mixture. The resulting precipitate was filtered to yield the title compound as brown solid (0.04 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.24-7.21 (m, 5H), 7.00 (t, 1H, J=8.4 Hz), 6.89 (brs, 1H), 5.41 (brs, 1H), 4.81-4.80 (m, 1H), 3.91 (brs, 2H), 3.53-3.41 (m, 2H), 3.13-2.43 (m, 4H), 2.21-1.86 (m, 3H), 1.71-1.23 (m, 10H); MS (ESI) mz 518 (M++H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h; | 55.9 (S)- 1-(2'-cyano-3-fluoro-4’-((1-(2-fluoro-2- methylpropyl)piperidin-4-yl)methoxy)biphenylcarbonyl)pyrrolidine-2-carboxamide 2'-cyano-3-fluoro-4'-((1-(2-fluoro-2-methylpropyl)piperidin-4- yl)methoxy)biphenyl-4-carboxylic acid (0.04 g, 0.10 mmol), L-prolinamide (0.01 g, 0.12 mmol), HOBt (0.02 g, 0.21 mmol), EDC (0.04 g, 0.21 mmol) and DIPEA (0.03 mL, 0.21 mmol) were dissolved in CH2Cl2 (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours, added with saturated NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0 % to 15 %), and concentrated to yield the title compound as white solid (0.05 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.52 - 7.56 (m, 1 H), 7.41 (dd, 2 H, J = 8.0, 1.7 Hz), 7.30 - 7.33 (m, 2 H), 7.19 - 7.22 (m, 1 H), 6.91 (s, 1 H), 5.45 (s, 1 H), 4.83 (dd, 1 H, J = 7.6, 3.9 Hz), 3.87 (d, 2 H, J = 6.0 Hz), 3.44 - 3.56 (m, 2 H), 2.99 - 3.02 (m, 2 H), 2.48 - 2.52 (m, 2 H), 2.43 (s, 1 H), 2.06 - 2.21 (m, 4 H), 1.91 - 1.94 (m, 2 H), 1.79 - 1.81 (m, 2H), 1.635 (s, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H); MS (ESI) m/z 525.3 (M+ + H). |
92% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h; | 55.9 Compound 1028 2′-cyano-3-fluoro-4′-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)biphenyl-4-carboxylic acid (0.04 g, 0.10 mmol), L-prolinamide (0.01 g, 0.12 mmol), HOBt (0.02 g, 0.21 mmol), EDC (0.04 g, 0.21 mmol) and DIPEA (0.03 mL, 0.21 mmol) were dissolved in CH2Cl2 (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours, added with saturated NR4Cl aqueous solution, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanoldichloromethane=0% to 15%), and concentrated to yield the title compound as white solid (0.05 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.52-7.56 (m, 1H), 7.41 (dd, 2H, J=8.0, 1.7 Hz), 7.30-7.33 (m, 2H), 7.19-7.22 (m, 1H), 6.91 (s, 1H), 5.45 (s, 1H), 4.83 (dd, 1H, J=7.6, 3.9 Hz), 3.87 (d, 2H, J=6.0 Hz), 3.44-3.56 (m, 2H), 2.99-3.02 (m, 2H), 2.48-2.52 (m, 2H), 2.43 (s, 1H), 2.06-2.21 (m, 4H), 1.91-1.94 (m, 2H), 1.79-1.81 (m, 2H), 1.635 (s, 2H), 1.41 (s, 3H), 1.35 (s, 3H); MS (ESI) mz 525.3 (M++H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h; | 111.5 Compound 1051 4-(5-((1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methyloxy)pyrimidin-2-yl)benzoic acid (0.04 g, 0.10 mmol), L-prolinamide (0.01 g, 0.13 mmol), HOBt (0.02 g, 0.21 mmol), EDC (0.04 g, 0.21 mmol) and DIPEA (0.03 mL, 0.21 mmol) were dissolved in CH2Cl2 (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours. The reaction mixture was added with saturated NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanoldichloromethane=0% to 15%), and concentrated to yield the title compound as white solid (0.05 g, 93%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 2H), 8.41 (d, 2H, J=8.4 Hz), 7.64 (d, 2H, J=8.3 Hz), 7.08 (s, 1H), 5.71 (s, 1H), 4.82 (dd, 1H, J=7.3, 5.1 Hz), 3.95 (d, 2H, J=6.0 Hz), 3.50-3.66 (m, 2H), 2.99-3.02 (m, 2H), 2.40-2.49 (m, 3H), 2.05-2.17 (m, 4H), 1.65-1.91 (m, 4H), 1.41-1.49 (m, 4H), 1.20-1.26 (m, 2H), 0.91 (t, 6H, J=7.5 Hz); MS (ESI) mz 512.3 (M++H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h; | 113.3 Compound 1054 4-(5-((1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)pyrimidin-2-yl)-2-fluorobenzoic acid (0.04 g, 0.10 mmol), L-prolinamide (0.01 g, 0.12 mmol), HOBt (0.02 g, 0.20 mmol), EDC (0.04 g, 0.20 mmol) and DIPEA (0.03 mL, 0.20 mmol) were dissolved in CH2Cl2 (1 mL) at room temperature. The solution was stirred at the same temperature for 18 hours. The reaction mixture was added with saturated NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanoldichloromethane=0% to 15%), and concentrated to yield the title compound as white solid (0.05 g, 90%). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 2H), 823 (d, 1H, J=8.0 Hz), 8.14 (d, 1H, J=11.1 Hz), 7.52 (t, 1H, J=7.5 Hz), 6.96 (s, 1H), 5.71 (s, 1H), 4.81-4.84 (m, 1H), 3.96 (d, 2H, J=6.0 Hz), 3.38-3.56 (m, 2H), 3.03-3.00 (m, 2H), 2.44-2.50 (m, 3H), 1.26-2.18 (m, 14H), 0.90 (t, 6H, J=7.5 Hz); MS (ESI) mz 530.3 (M++H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 24h; | 114.5 Compound 937 4′-((1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)methoxy)-2,3′-difluorobiphenyl-4-carboxylic acid (40 mg, 0.09 mmol), EDC (34 mg, 0.18 mmol) and HOBt (24 mg, 0.18 mmol) was added thereto, DIPEA (32 μL, 0.18 mmol) was dissolved in CH2Cl2 (1 mL). At room temperature, (S)-pyrrolidine-2-carboxamide (20 mg, 0.18 mmol) was added thereto, following with stirring for a day. The reaction mixture was added with water, and extracted with EtOAc. The obtained organic layer was washed with saturated aqueous brine solution, and then. The organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (CH2Cl2MeOH=95%5%) to yield the title compound as white solid (35 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.47 (t, 1H, J=7.8 Hz), 7.40-7.27 (m, 4H), 7.03 (t, 1H, J=8.6 Hz), 6.89 (brs, 0.5H), 5.47 (brs, 0.5H), 4.82-4.79 (m, 1H), 3.92 (d, 2H, J=6.2 Hz), 3.66-3.57 (m, 2H), 3.00 (d, 2H, J=10.4 Hz), 2.49-2.43 (m, 2H), 2.18-2.06 (m, 4H), 1.92-1.66 (m, 10H), 1.47-1.41 (m, 2H), 0.92 (s, 3H), 0.88 (s, 3H); MS (ESI) mz 546 (M++H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: N(α)-t-butoxycarbonyl-2,5-di-iodo-L-histidine With N-hydroxy-5-norbornene-endo-2,3-dicarboximide; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: L-prolinamide In N,N-dimethyl-formamide at 4℃; for 36h; | N-a-Boc-L-His(2,5-diodo)-L-ProNH2 (6d) General procedure: To a solution of N-a-Boc-5-halo/2,5-dihalo-L-histidine (3-4,1 mmol) in anhydrous DMF (10 mL) was added HONB (1.1 mmol) and DIC (1.1 mmol) in one portion. Reaction mixture was stirredfor additional 5 min at 0 C and then L-ProNH2 (5, 1 mmol) wasadded. The reaction was stirred for additional 36 h at 4 C.Solvent was evaporated under reduced pressure and the crude productwas purified by column chromatography using MeOH/CH2Cl2(15:85) as eluant to afford 6a-g |
74% | Stage #1: N(α)-t-butoxycarbonyl-2,5-di-iodo-L-histidine With endo-N-hydroxy-5-norbornene-2,3-dicarboxyimide; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: L-prolinamide In N,N-dimethyl-formamide at 4℃; for 36h; | 4.1 4.1 General method for the synthesis of N-α-Boc-L-His(5-halo/2,5-dihalo-1-alkyl)-L-ProNH2 (5a-o) General procedure: To a solution of N-α-Boc-1-alkyl-5-halo-l-histidine or N-α-Boc-2,5-dihalo-1-alkyl-l-histidine (4, 1 mmol) in anhydrous DMF (10 mL) cooled to 0 °C was added DIC (1.1 mmol) and HONB (1.1 mmol) in one portion. Reaction mixture was stirred for additional 5 min at 0 °C, and then L-ProNH2 (1.1 mmol) was added. The reaction mixture was stirred for additional 36 h at 4 °C. Solvent was evaporated under reduced pressure and the crude product was purified by column chromatography using MeOH:CH2Cl2 (15:85) as eluent to afford 5 in good yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: N-α-Boc-5-bromo-1-methyl-L-histidine With N-hydroxy-5-norbornene-endo-2,3-dicarboximide; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: L-prolinamide In N,N-dimethyl-formamide at 4℃; for 36h; | N-a-Boc-L-His(5-bromo-1-methyl)-L-ProNH2 (6e) General procedure: To a solution of N-a-Boc-5-halo/2,5-dihalo-L-histidine (3-4,1 mmol) in anhydrous DMF (10 mL) was added HONB (1.1 mmol) and DIC (1.1 mmol) in one portion. Reaction mixture was stirredfor additional 5 min at 0 C and then L-ProNH2 (5, 1 mmol) wasadded. The reaction was stirred for additional 36 h at 4 C.Solvent was evaporated under reduced pressure and the crude productwas purified by column chromatography using MeOH/CH2Cl2(15:85) as eluant to afford 6a-g |
76% | Stage #1: N-α-Boc-5-bromo-1-methyl-L-histidine With endo-N-hydroxy-5-norbornene-2,3-dicarboxyimide; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: L-prolinamide In N,N-dimethyl-formamide at 4℃; for 36h; | 4.1 4.1 General method for the synthesis of N-α-Boc-L-His(5-halo/2,5-dihalo-1-alkyl)-L-ProNH2 (5a-o) General procedure: To a solution of N-α-Boc-1-alkyl-5-halo-l-histidine or N-α-Boc-2,5-dihalo-1-alkyl-l-histidine (4, 1 mmol) in anhydrous DMF (10 mL) cooled to 0 °C was added DIC (1.1 mmol) and HONB (1.1 mmol) in one portion. Reaction mixture was stirred for additional 5 min at 0 °C, and then L-ProNH2 (1.1 mmol) was added. The reaction mixture was stirred for additional 36 h at 4 °C. Solvent was evaporated under reduced pressure and the crude product was purified by column chromatography using MeOH:CH2Cl2 (15:85) as eluent to afford 5 in good yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In tetrahydrofuran; for 1h;Reflux; Resolution of racemate; | 100 g of <strong>[178306-51-9]2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong> was dissolved in 1000 ml of THF, and 41.9 g of L-proline amide was added. The reaction was refluxed with stirring for 1 hour, cooled to room temperature and stirred for 30 minutes. The resulting crystals were filtered and washed with 100 ml of THF. The resulting solid was vacuum-dried to obtain 64 g (yield: 45%, optical purity: 93% ee) of (S) -<strong>[178306-51-9]2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong> L-prolinamide salt. S) -<strong>[178306-51-9]2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong> L-prolineamide salt was suspended in 600 ml of THF and stirred at reflux for 1 hour. The reaction was cooled to ambient temperature and stirred for 30 min. The resulting crystals were filtered. 55 g of the obtained compound was suspended in 550 ml of a mixed solvent of THF: H2O = 30: 1, and the mixture was refluxed with stirring for 1 hour. The reaction was cooled to ambient temperature and stirred for 30 minutes. The resulting crystals were filtered and dried in vacuo to give 44g of (S) -<strong>[178306-51-9]2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong> L-prolinamide salt (yield: 73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.9% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h; | 314 Example 314: Compound 11812,(S)-i -(2-(N-(4-(5-(difluoromethyl)- 1,3 ,4-oxadiazol-2-yl)benzyl)-N-phenylsulfamoyl)et hyl)pyffolidine-2-carboxamide Asolutionof N(4-(5-(difluoromethyl)- 1,3 ,4-oxadiazol-2-yl)benzyl)-N-phenylethenesulfonamide(0.100 g, 0.255 mmol), L-prolinamide (0.058 g, 0.5 11 mmol) and N,N-diisopropylethylamine (0.176 mL, 1.022 mmol) in dichloromethane (5 mL) was stilTed at the room temperature for 18 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (Waters, Cl 8; acetonitrile / aqueous 0.1%-formic acid solution = 10 % to 90 %) to give (S)-i -(2-(N-(4-(5-(difluoromethyl)- 1,3 ,4-oxadiazol-2-yl)benzyl)-N-phenylsulfamoyl)et hyl)pyffolidine-2-carboxamide as white solid (0.120 g, 92.9 %).‘H NMR (400 MHz, DMSO-d6) ö7.95 (d, 2 H, J= 8.0 Hz), 7.48 (d, 2 H, J= 8.1Hz), 7.39 - 7.21 (m, 6 H), 7.08 (br, 2 H), 4.99 (s, 2 H), 3.99 (q, 1 H, J= 5.3 Hz), 3.45(m, 2 H), 3.32 - 3.15 (m, 2 H), 2.95 - 2.82 (m, 2 H), 2.31 (m, 1 H), 2.07 (m, 1 H), 1.74- 1.69 (m, 2 H); LRMS (ES) mlz 506.3 (M÷+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With N-ethyl-N,N-diisopropylamine; sodium iodide; In acetonitrile; at 90℃; for 18h;Sealed tube; | General procedure: A mixture of the corresponding bromide (1.0 mmol), Nal (0.2 mmol), DIPEA (2.0 mmol) and the corresponding amine (1.2 mmol) in ACN (4.0 mL) was heated in a sealed tube at 90C for 18 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with MeOH/DCM gradient, to provide the desired amine intermediates. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.1% | Stage #1: L-prolinamide With 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-d<SUB>6</SUB>-formamide at 0 - 10℃; for 2h; Stage #2: With hydrogenchloride In ethanol; ethyl acetate at 0 - 10℃; for 2h; | 1 Synthesis of Vildagliptin Intermediate-1 1L reaction flask was added 100g L-prolinamideAnd 300ml N,N-dimethylformamide,Temperature control with stirring to 010°C,Slowly add 80.8g cyanuric chloride in batchesThe reaction was incubated at 0-10 °C for 2 h.The reaction solution was poured into 600 ml of purified water, adjusted to pH 9-10 with saturated aqueous sodium carbonate, and extracted with ethyl acetate 3 times, 600 ml each time.The organic phases were combined, washed with 500 ml of saturated aqueous sodium bicarbonate solution, added with 50 g of anhydrous sodium sulfate, and stirred at 20-30[deg.] C. for 1 h.filter,100 ml of ethyl acetate wash cake,The filtrate was concentrated to dryness under reduced pressure to give an oil,Add 300ml of ethyl acetate,Adjust the pH to 2~3 with 30% ethanol solution of hydrogen chloride.Cool down to 0 ~ 10 °C, stirring crystallization 2h.Filter and wash the filter cake with 100 ml of ethyl acetate.Filter cake 40 ~ 50 °C vacuum drying 4h,116.0 g of Intermediate-1 was obtained in a yield of 89.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h; | [000232] To a solution of <strong>[4313-73-9]Z-Phe-Leu-OH</strong> (206 mg, 0.5 mmol) and Pro- H2 (86 mg, 0.75 mmol) in 5 mL DCM, HBTU (569 mg, 1.5 mmol), HOBt (67 mg. 0.5 mmol) and DIEA (323 mg, 2.5 mmol) were added. The mixture was stirred at rt. for 18 hrs. The solution was washed with 1 N NaHS04, saturated NaHC03 and brine. After drying over anhydrous Na2S04, the solution was concentrated and purified with silica gel column (Hexane/EtOAc=10/l to 7/1) to obtain ZL0141 (278 mg, quant.) as a white foam. 1H MR (300 MHz, CDC13) delta 7.65 (s, 1H), 7.33 (m, 4H), 7.15 (m, 6H), 6.87 (s, 1H), 5.57 - 5.32 (m, 2H), 5.11 - 4.96 (m, 2H), 4.86 (d, J = 4.8 Hz, 1H), 4.71 (s, 1H), 4.52 (s, 1H), 3.86 - 3.54 (m, 2H), 3.12 - 2.89 (m, 2H), 2.22 (m, 2H), 2.01 (s, 2H), 1.55 (m, 3H), 0.93 (dd, J = 17.1, 6.2 Hz, 6H). 13C NMR (75 MHz, CDC13) delta 173.74, 172.10, 170.94, 155.98, 136.48, 136.32, 129.37, 128.48, 128.09, 127.83, 126.79, 66.84, 59.53, 55.48, 49.01, 47.42, 41.63, 39.20, 38.61, 28.27, 25.03, 24.59, 23.28, 21.86. ESI-MS (M + H)+ m/z 509.3. HR ESI-MS (M + H)+ m/z = 509.2761 (calcd for C28H37N405: 509.2764) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate; potassium iodide; In tetrahydrofuran; at 25 - 30℃; for 15h; | 5g intermediate-2, 4.0g L-prolinamide, 12.0g potassium carbonate, 0.25g potassium iodide were added to the 250ml reaction flask.And 50 ml of THF, the temperature was controlled to 25 to 30 C under stirring, and the mixture was stirred for 15 hours, and the reaction was completely detected by TLC. Filtered, rinsed with 50ml THFFilter cake. The combined filtrate and washings were concentrated to dryness under reduced pressure to give an oily material.Add 60 ml of ethyl acetate to 70-80 C and stir for 0.5 h, cool to room temperature, suction filtration, rinse with 20 ml of ethyl acetate.The filter cake was dried under vacuum at 45 C to give 5.0 g of pale yellow solid compound 1 with a yield of 69.0% and a purity of 99.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 50℃; for 1h; | To a solution of 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (0.5 g, 2.7 mmol) in 2-Propanol (6 mL) was added (S)-pyrrolidin-2-ylmethanol (0.39 mL, 4.0 mmol), DIPEA (1.39 mL, 8.0 mmol) and heated at 90 C for 1 hr. The reaction was cooled to room temperature and solid obtained was collected by filtration to afford (S)-(l-(2-chloropyrrolo[2,l-f][l,2,4]triazin-4- yl)pyrrolidin-2-yl)methanol (96a) (0.49 g, 73 % yield) as a white solid; NMR (300 MHz, DMSO-i/e): delta 7.70 (dd, J= 2.6, 1.4 Hz, 1H), 6.97 (dd, J= 4.7, 1.6 Hz, 1H), 6.80 - 6.57 (m, 1H), 5.15 (t, J = 5.7 Hz, 1H, D2O exchangeable), 4.87 (t, J= 5.7 Hz, 1H), 4.44 (d, J= 17.8 Hz, 1H), 4.05 - 3.82 (m, 1H), 3.72 - 3.39 (m, 2H), 2.22 - 1.84 (m, 4H). MS (ES+): 253.3, 255.3 (M+2); MS (ES-): 287.2, 289.2 (M+Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 50℃; for 1h; | 166.1 Step- 1 : Preparation of (S)-(l-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-2- yl)methanol (96a) General procedure: To a solution of 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (0.5 g, 2.7 mmol) in 2-Propanol (6 mL) was added (S)-pyrrolidin-2-ylmethanol (0.39 mL, 4.0 mmol), DIPEA (1.39 mL, 8.0 mmol) and heated at 90 °C for 1 hr. The reaction was cooled to room temperature and solid obtained was collected by filtration to afford (S)-(l-(2-chloropyrrolo[2,l-f][l,2,4]triazin-4- yl)pyrrolidin-2-yl)methanol (96a) (0.49 g, 73 % yield) as a white solid; NMR (300 MHz, DMSO-i/e): δ 7.70 (dd, J= 2.6, 1.4 Hz, 1H), 6.97 (dd, J= 4.7, 1.6 Hz, 1H), 6.80 - 6.57 (m, 1H), 5.15 (t, J = 5.7 Hz, 1H, D2O exchangeable), 4.87 (t, J= 5.7 Hz, 1H), 4.44 (d, J= 17.8 Hz, 1H), 4.05 - 3.82 (m, 1H), 3.72 - 3.39 (m, 2H), 2.22 - 1.84 (m, 4H). MS (ES+): 253.3, 255.3 (M+2); MS (ES-): 287.2, 289.2 (M+Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In isopropyl alcohol at 50℃; for 5h; | 176.1 Step- 1 : Preparation of (S)-(l-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-2- yl)methanol (96a) General procedure: To a solution of 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (0.5 g, 2.7 mmol) in 2-Propanol (6 mL) was added (S)-pyrrolidin-2-ylmethanol (0.39 mL, 4.0 mmol), DIPEA (1.39 mL, 8.0 mmol) and heated at 90 °C for 1 hr. The reaction was cooled to room temperature and solid obtained was collected by filtration to afford (S)-(l-(2-chloropyrrolo[2,l-f][l,2,4]triazin-4- yl)pyrrolidin-2-yl)methanol (96a) (0.49 g, 73 % yield) as a white solid; NMR (300 MHz, DMSO-i/e): δ 7.70 (dd, J= 2.6, 1.4 Hz, 1H), 6.97 (dd, J= 4.7, 1.6 Hz, 1H), 6.80 - 6.57 (m, 1H), 5.15 (t, J = 5.7 Hz, 1H, D2O exchangeable), 4.87 (t, J= 5.7 Hz, 1H), 4.44 (d, J= 17.8 Hz, 1H), 4.05 - 3.82 (m, 1H), 3.72 - 3.39 (m, 2H), 2.22 - 1.84 (m, 4H). MS (ES+): 253.3, 255.3 (M+2); MS (ES-): 287.2, 289.2 (M+Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.3% | With hydrogenchloride; In water; at 103℃; for 2h; | 44.41 g of 1-acetyl-2-pyrrolidinecarboxamide was added to 160 mL of 2N HCl.Raise the temperature to 103 C reflux reaction,During the reaction, the temperature of the system is kept at the micro-reflow state.Co-reacted for 2 hours,After completion of the reaction, the mixture was concentrated to a small volume until crystallization, pH was adjusted to 8, filtered, and dried to give the desired product, L-prolinamide, 31.05 g, yield 95.3%. Detection of D-type isomerismThe purity of the solution was 0.11%, and the purity was determined by high performance liquid chromatography HPLC to be 99.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.7% | Stage #1: 2-((4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)amino)-1H-benzo[d]imidazole-6-carboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.666667h; Inert atmosphere; Stage #2: L-prolinamide In N,N-dimethyl-formamide at 80℃; for 8h; Inert atmosphere; | 4 Example 4: (S)-1-(2-((4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)amino)-1H-benzo[ d)imidazole-6-carbonyl)pyrrolidine-2-carboxamide (Bz-4) Synthesis method: Dissolve Bz-3 (200mg) obtained in Example 3 in dry DMF (3ml), add DIPEA (0.14ml), HBTU (180mg), stir at room temperature under N2 for 40min, add L-prolinamide ( 53mg), heated and stirred at 80°C for 8h under the protection of N2, and the reaction was monitored by TLC. Ice water (5ml) was added to the reaction bottle, and after stirring for 5min, DCM (10ml) was added, after stirring for 5min, the DCM layer was separated, the aqueous layer was extracted with DCM (50ml×3), the DCM layers were combined, and washed with water (15ml×3) , Washed with saturated NaCl solution (15ml×1). The DCM layer was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Silica gel column chromatography (DCM: MeOH 97:3→10: 154 mg of off-white powder solid was obtained, yield 64.6%, purity 99.7%. |
79% | Stage #1: 2-((4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)amino)-1H-benzo[d]imidazole-6-carboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.666667h; Inert atmosphere; Stage #2: L-prolinamide In N,N-dimethyl-formamide at 80℃; for 8h; Inert atmosphere; | 4.1.3. General procedure for the preparation of compounds 19a-k General procedure: A mixture of 18 (200 mg, 0.4 mmol) in dry DMF (3.0 mL) wasadded DIPEA (138 mL, 0.8 mmol) and HBTU (182 mg, 0.5 mmol). Theresulting mixture was stirred at room temperature for 40 min undernitrogen atmosphere, and then, the corresponding secondaryamine or amide (0.4 mmol) was added. The mixture was stirredunder nitrogen atmosphere at 80 °C for 8.0 h. Pouring into icewater,the mixture was extract with DCM (50 mL 3). The combinedthe organic phases was washed with water (50 mL 3) andsaturated NaCl solution (50 mL 1), dried over Na2SO4. The solutionwas concentrated in vacuo and the crude product was purifiedby column chromatography on silica gel (DCM: MeOH 10:1) toafford the target compounds 19a-k in 40-90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: Fmoc-His(Trt)-OH; L-prolinamide With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dichloromethane at 5 - 15℃; for 13.5h; Stage #2: With piperidine In dichloromethane at 5 - 15℃; | 1 Example 1. Preparation of the intermediate of Formula 3 (His (Trt)-Pro-NH 2) N-fluorenylmethoxycarbonyl-N'-trityl-L-histidine(Fmoc-His(Trt)-OH) 10g and L-prolineamide (H-Pro-NH2) 2.03g methylene chloride(MC) It was suspended in 50 ml and cooled to 5-15 degreeC.PyBOP (benzotriazol-1-yl- oxytripyrrolidino- phosphonium hexafluorophosphate) in this mixed solution10.08 g was added, and 2.45 g of N-methylmorpholine was added dropwise over 30 minutes,After stirring at the same temperature for 1 hour, the mixture was stirred at room temperature for 12 hours.After completion of the reaction, the temperature of the mixed solution was cooled to 5 to 15°C, and 10.99 g of piperidine diluted in 8.8 ml of methylene chloride was added dropwise for 30 minutes.Stir for 1 to 2 hours at the same temperature, and 5% citric acid aqueous solutionWashed in the order of 30ml, saturated salt water 20ml, 3% sodium carbonate aqueous solution 30ml, and saturated salt water 20ml. The washed organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure so that the volume became 40-60 ml at 20-25°C. The concentrated solution was added dropwise to 400 ml of tertiary butyl methyl ether cooled to 5-10° C. for 15 minutes to generate crystals. Filter the resulting crystals,After dissolving in methylene chloride so that the final volume is 40-60 ml, the crystallization process is performed once more,The final filtrate was dried under vacuum at 20 to 25° C. to obtain 9.22 g (yield: 80%, content: 69%) of L-histidyl-trityl-L-prolineamide. |
Multi-step reaction with 2 steps 1.1: dicyclohexyl-carbodiimide; 1-hydroxy-pyrrolidine-2,5-dione / tetrahydrofuran / 0.17 h / 20 °C 1.2: 24.5 h / 20 - 25 °C 2.1: piperidine / dichloromethane / 7 h / 5 - 10 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; | 4.1.2. Compounds 7e27. General procedure General procedure: To a solution of methylsulfone 6 (0.1 g, 0.26 mmol) in dry DMF(5 mL), a proper amine (0.4 mmol) was added. The reaction mixtureswere heated at 80 C for a period between 0.5 and 12 h, andthen poured over ice water (50 mL), the formed solid was filteredand washed with 50% ethanol and recrystallized from absoluteethanol give the desired products. Physical properties and spectralanalysis of isolated products are listed below: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 4.1.1. Compounds 7-21. 4.1.1.1. General procedure. General procedure: The methylsulfone 6 (0.1 g, 0.26mmol) was stirred in dry DMF (5 mL) to complete dissolution, and then a proper alkylamine(0.4 mmol), used as obtained for the commercial source, was added. The reaction mixtureswere flushed with dry nitrogen and heated to 80 °C. The progress of the reaction was monitoredby TLC. After consuming all starting materials in a period ranging from 0.5 to 12 h, thereaction mixture was allowed to cool to room temperature and quenched with ice water (50mL). The formed solids were filtered, washed with 50% ethanol and purified by crystallizationfrom absolute ethanol to yield the desired products. The yields, physical properties and spectralanalyses of isolated products are listed below: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: 2-((4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)amino)pyrimidine-5-carboxylic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.666667h; Inert atmosphere; Stage #2: L-prolinamide In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 4.1.1.5. Synthesis of compounds 6aa-ao, 6ba-bd, 6ca-cc and 6da-db. General procedure: A mixture of 5 (0.4 mmol) in dry DMF (3 mL) was added DIPEA(0.8 mmol) and HBTU (0.48 mmol). The resulting mixture wasstirred at room temperature for 40 min under nitrogen atmosphere,and then, the corresponding secondary amine or amide(0.42 mmol) was added. The mixture was stirred under nitrogenatmosphere at 80 C for 8.0 h. Poured into ice-water, the mixturewas extract with DCM (50 mL 3). The combined the organicphases was washed with water (50 mL 3) and saturated NaClsolution (50 mL 1), and dried over Na2SO4. The solution wasconcentrated in vacuo and the crude product was purified by columnchromatography on silica gel (DCM: MeOH 10:1) to affordthe corresponding target compound in 40e90% yield. |
49% | Stage #1: 2-((4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)amino)pyrimidine-5-carboxylic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.666667h; Inert atmosphere; Stage #2: L-prolinamide In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 4.1.1.5. Synthesis of compounds 6aa-ao, 6ba-bd, 6ca-cc and 6da-db. General procedure: A mixture of 5 (0.4 mmol) in dry DMF (3 mL) was added DIPEA(0.8 mmol) and HBTU (0.48 mmol). The resulting mixture wasstirred at room temperature for 40 min under nitrogen atmosphere,and then, the corresponding secondary amine or amide(0.42 mmol) was added. The mixture was stirred under nitrogenatmosphere at 80 C for 8.0 h. Poured into ice-water, the mixturewas extract with DCM (50 mL 3). The combined the organicphases was washed with water (50 mL 3) and saturated NaClsolution (50 mL 1), and dried over Na2SO4. The solution wasconcentrated in vacuo and the crude product was purified by columnchromatography on silica gel (DCM: MeOH 10:1) to affordthe corresponding target compound in 40e90% yield. |
Tags: 7531-52-4 synthesis path| 7531-52-4 SDS| 7531-52-4 COA| 7531-52-4 purity| 7531-52-4 application| 7531-52-4 NMR| 7531-52-4 COA| 7531-52-4 structure
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P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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