* 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.
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]
Reference：
[1] Patent: CN106045891, 2016, A, . Location in patent: Paragraph 0046; 0047-0049
[2] Patent: CN105523985, 2016, A, . Location in patent: Paragraph 0054; 0055
[3] Patent: CN107501154, 2017, A, . Location in patent: Paragraph 0068-0108
[4] Patent: US2008/167479, 2008, A1, . Location in patent: Page/Page column 5
[5] Patent: US6432969, 2002, B1,
[6] Patent: WO2013/179300, 2013, A2, . Location in patent: Page/Page column 30
2
[ 23500-10-9 ]
[ 207557-35-5 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine; ammonium bicarbonate In acetonitrile at 20℃; for 4.5 h; Stage #2: at 40℃; for 4 h;
Acetonitrile (50 mL), CDMT (homemade 11,12,3.85g,3.85 mol), NH4HCO3 (9.12 g, 0.12 mol) and compound 3 (3.85 g, 0.02 mol) were added to a 150 mL three-neck flaskwhich was equipped with a thermometer, a condenser pipe anda constant pressure funnel. N-Methyl morpholine (2.4 mL,0.022 mol) was added after the mixture stirred for 10 min.The reaction mixture was stirred at room temperature for 4.5 hand monitored by TLC (95 percent CH2Cl2 -CH3OH). After completion of the reaction, the mixture was filtered and the filter cake was washed with methylene chloride (3 × 40 mL). The filtrates were collected, combined and concentrated undervacuum to give some oily mass. To this oily mass was added DMF (20 mL) and TCT (2 g, 0.011 mol) and the reactionmixture was then stirred at 40 °C for 4 h. The reaction was monitored by TLC (95 percent CH2Cl2 -CH3OH). After completingthe reaction, water (100 mL) and ethyl acetate (100 mL) were added and the organic layer was collected. The aqueous layerwas re-extracted with ethyl acetate (3 × 30 mL). The combinedorganic layers were washed with saturated sodium bicarbonate solution (3 × 30 mL) and dried over anhydrous sodium sulfate,then concentrated under vacuum to give a honey-like residue.To this residue 15 mL isopropyl ether was added under stirring,the resulting crystalline solid was filtered and dried at 45 °Cunder vacuum to afford compound 4 (2.4 g, 70 percent). m.p. 62-63 °C, IR (KBr, ν max , cm -1 ): 2952, 2887, 2241, 1655; 1 H NMR(400 MHz, CDCl 3 ): δ 2.15-2.4 (m, 4H, CH 2 ), 3.55-3.65 (m,1H, CH 2 ), 3.7-3.8 (m, 1H, CH 2 ), 4.075-4.125 (s, 2H, CH 2 Cl),4.725-4.875 (m, 1H, CHCN); 13 C NMR (75 MHz, DMSO-d 6 ) δ 22.5, 24.5, 25, 30, 32.3, 41.7, 46.5, 46.8, 47.1, 117.9, 164.5,165; MS (m/z): 173.1 [M + 1] 5 .
Reference：
[1] Asian Journal of Chemistry, 2014, vol. 26, # 18, p. 6275 - 6278
[2] Patent: WO2011/101861, 2011, A1,
[3] Letters in Organic Chemistry, 2013, vol. 10, # 3, p. 159 - 163
[4] Asian Journal of Chemistry, 2014, vol. 26, # 12, p. 3489 - 3492
[5] Letters in Organic Chemistry, 2014, vol. 11, # 10, p. 780 - 784
[6] European Journal of Organic Chemistry, 2016, vol. 2016, # 30, p. 5160 - 5168
[7] Patent: CN104817482, 2017, B,
3
[ 204387-53-1 ]
[ 79-04-9 ]
[ 207557-35-5 ]
Yield
Reaction Conditions
Operation in experiment
90.2%
With potassium carbonate In tetrahydrofuran at 0 - 10℃; for 1 h; Inert atmosphere
In the presence of nitrogen, 9.61 g (100 mmol) of (S)-2-cyanopyrrolidine was dissolved in tetrahydrofuran to dissolve potassium carbonate.27.64 g (200 mmol) was added to the reaction system, and then the system was cooled down to 0 ~ 10 °C and chloroacetyl chloride 12.42 g was added dropwise(110 mmol) stirring reaction for 1 hour, TLC detection reaction is completed, saturated sodium bicarbonate washing, dichloromethane extraction, decompression concentratedAfter fractionation and column chromatography, 15.57 g of vildagliptin intermediate (S)-1-(2-chloroacetyl)-2-cyanopyrrolidine was obtained.90.2percent, purity 99.37percent.
75 g
at 20 - 30℃; 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 10-15°C 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 20-25°C under nitrogen atmosphere. The reaction mass was maintained at 35-40°C 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 40-45°C for 3-4 hrs. After completion of the reaction the reaction mass was cooled at 0-5°C and Triethyl amine (88.65 g) and Chloroacetyl chloride (118.70 g) were added. The reaction mass was maintained at 20-30°C 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
Reference：
[1] Patent: CN107954914, 2018, A, . Location in patent: Paragraph 0064; 0065; 0066
[2] Patent: WO2014/20462, 2014, A1, . Location in patent: Page/Page column 9
4
[ 204387-54-2 ]
[ 79-04-9 ]
[ 207557-35-5 ]
Yield
Reaction Conditions
Operation in experiment
88.6%
With triethylamine In dichloromethane at -5℃;
(S) -2-cyanopyrrolidine p-toluenesulfonate (40 g, 0.15 mol) and dichloromethane (200 mL) were added to a reaction flask and cooled to -10 ° C. triethylamine 0.15 mol) and stirred to clarify the solution. Chloroacetyl chloride (0.225 mol) was added dropwise to the resulting clear solution and the temperature was controlled at -5 ° C. After completion of the dropwise addition, the reaction was continued until the reaction was complete. After adding 100 mL of water to quench the reaction, S) -2-cyanopyrrolidine p-toluenesulfonate was reacted with triethylamine to form pyrrolidine-2-carbonitrile. The pyrrolidine-2-carbonitrile was detected by thin layer chromatography. The organic phase was washed twice with saturated NaHC03 solution, and the volume of the saturated NaHC03 solution was 100 mL each. After washing, the solution was allowed to stand still and the solution was allowed to stand in the same manner. The organic phase was washed with anhydrous magnesium sulfate and concentrated to give 23 g of a white solid in 88.6percent yield.The resulting white solid was subjected to nuclear magnetic resonance detection as (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile,HPLC method for determination of purity of 99.5percent, chiral HPLC determination of optical purity> 99.9percent, nuclear magnetic resonance detection map as shown in Figure 1
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 30℃; for 5 h;
1L reaction flask was added 100g of intermediate-1And 500ml methylene chloride,Cool down to 010°CJoin 214.5g DIEA,173.5g EDCIAnd 20.4g HoBt,After addition, stir for 1 h at 0-10 °C.82.0 g chloroacetic acid was added in batches,After the addition,Warming to 20 ~ 30 °C heat reaction 5h.The reaction solution was poured into 500 ml of purified water.Stir for 10 min and let stand for phase separation.The aqueous phase was discarded and the organic phase was washed with 300 ml of 5percent aqueous sodium bicarbonate solution. The organic phase was added with 50 g of anhydrous sodium sulfate and stirred for 1 h at 20-30°C.After filtration, the filter cake was washed with 50 ml of dichloromethane, and the filtrate was concentrated to dryness under reduced pressure. 300 ml of isopropanol was added and the mixture was stirred at 0 1010° C. for 2 h.After filtration, the filter cake was washed with 100 ml of isopropanol, and the filter cake was dried under vacuum at 45° C. for 4 h to obtain 115.9 g of Intermediate-2. The yield was 89.0percent.
Reference：
[1] Patent: CN106966947, 2017, A, . Location in patent: Paragraph 0027; 0035; 0039; 0042; 0048; 0052
6
[ 214398-99-9 ]
[ 207557-35-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
With 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 35 - 48℃; for 4 h;
In a 100 mL single-neck round bottom flask, compound 8(4.0 g, 0.021 mol) was dissolved in anhydrous DMF (20 mL)TCT (2.24 g, 0.012 mol) was added at room temperature inone portion and the reaction mixture was then stirred at 35-48 °C for 4 h. The reaction was monitored by TLC (5percentMeOH-CH2Cl2). After completion, the mixture was pouredinto 100 mL water and extracted with ethyl acetate (4 x 40mL). The collected organic phase was washed with 5percentaqueous of sodium bicarbonate (2 x 50 mL). The organicphase were dried over anhydrous Na2SO4 and concentratedunder vacuum. The oily residue was stirred in diisopropylether (20 mL) for 0.5 h in ice-bath and the mixture was thencooled to 0 °C for 2 h. The precipitated crystalline whitesolid was filtered, washed with cold diisopropyl ether anddried at 40°C under vacuum to afford compound 9 (3.45 g,yield 90percent). mp 62–63 °C (lit [10] 52–53 °C)
90%
With 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 40℃; for 4 h;
Compound 4 (4 g, 0.021mol) and TCT (2 g, 0.011mol)were added to the solution of DMF (40mL). Then the mixturewas reacted at 40°C for 4 h and extracted with ethylacetate (110mL). The combined organic layers were concentratedunder vacuum and the resultant precipitate was filteredand dried to give compound 5. (Yield 90percent); mp 62-63 °C(65-66°C [12]); IR (KBr, cm-1): 2952, 2887, 2241, 1655; 1HNMR (400MHZ, CDCl3) : 2.15-2.4 (m, 4H, CH2), 3.55-3.65 (m, 1H, CH2), 3.7-3.8(m, 1H, CH2), 4.075-4.125(s, 2H,CH2Cl), 4.725-4.875 (m, 1H, CHCN); 13C NMR (75 MHz,CDCl3): 22.67 (C4), 25.12 (C3), 29.87 (C5), 32.39 (C5),41.53 (C2), 46.43 (C2’), 46.72 (C2’), 46.82 (C2’), 47.04(C2’), 117.85 (CN), 165.22 (C=O)); MS m/z 173.1 [M+1].
83.8%
With trifluoroacetic anhydride In tetrahydrofuran at 0 - 10℃; for 1 h;
Add 100g of intermediate-1 and 1000ml of tetrahydrofuran to the 2000ml reaction flask, stir to reduce the temperature to 0~10 °C,A mixed solution of 137.7 g of trifluoroacetic anhydride and 100 ml of tetrahydrofuran was added dropwise over 1 h, and the mixture was stirred for 1 h, and the reaction was complete by TLC.The reaction solution was concentrated to dryness under reduced pressure. EtOAc was evaporated. Reaction solution600ml of ethyl acetate, cooled to 15 ~ 25 ° C, slowly added 400ml of saturated sodium bicarbonate aqueous solution, stirred for 10 min, pH1 ~2. The pH was adjusted to 7-8 with sodium bicarbonate solids (about 45 g of sodium bicarbonate), stirred for 0.5 h, the pH was measured again, and the solution was allowed to stand for separation.The organic phase was retained and the aqueous phase was extracted with EtOAc EtOAc EtOAc. The combined organic phases were added to 400 ml of a saturated aqueous solution of sodium chloride.Stir for 1 h and let stand for phase separation. The organic phase was added with 50 g of anhydrous sodium sulfate and 2 g of activated carbon, and stirred for 0.5 h. Filtered, 50ml ethyl acetateWash the filter cake. The filtrate was concentrated to near dryness, 80 ml of ethyl acetate was added, heated to 40-45 ° C, stirred until the solid dissolved, and cooled to2535°C, add 240ml of isopropyl ether, stir at 2035°C for 1h, cool down to 05°C and stir for 1h. Filter, 100mlThe filter cake was washed with isopropyl ether, and the filter cake was dried under vacuum at 35 to 45 ° C for 3 hours to obtain Intermediate-2 75.8 g, yield 83.8percent, purity 99.5percent.
82%
With trichlorophosphate In dichloromethane at 5 - 15℃; for 1 h;
Add 25g L-prolinamide to a 1000ml dry reaction flask.250 ml of dichloromethane, 25 g of triethylamine,Forming a mixture, cooling the mixture to -20 ° C ~ -25 ° C,A mixture of 26 g of chloroacetyl chloride and 50 ml of dichloromethane was added dropwise to the reaction flask.After the completion of the dropwise addition, the reaction was stirred at -20 ° C for 3 hours.A reaction liquid I containing 1-chloroacetylpyrrolidine-2-carboxamide was obtained.The above reaction solution was heated to 5 ° C,The temperature of the reaction solution 1 is controlled to be 5 ° C to 15 ° C, and 45 g of phosphorus oxychloride is added dropwise.After the dropwise addition is completed, the reaction is kept at 5 ° C to 15 ° C for 1 hour.The reaction liquid 2 was obtained.Slowly added to the reaction solution II100ml water, the internal temperature does not exceed 20 ° C,Stir for 30 minutes and let stand for stratification.The aqueous layer was extracted twice with dichloromethane.Each time the amount of dichloromethane is 100ml,The dichloromethane layers were combined.The dichloromethane layer was concentrated to dryness under reduced pressure.An oil was obtained, 200 ml of isopropanol was added and stirred for 5 minutes.The temperature was lowered to -5 ° C for 3 hours.Filter and wash with a small amount of isopropyl alcohol.Dry under reduced pressure,Obtaining (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile solid about 31 g,The yield was 82percent, and the HPLC content was 99.2percent.
80.2%
With trichlorophosphate In N,N-dimethyl-formamide at -5 - 5℃; for 2 h;
(S)-1-(2-Chloroacetyl chloride)pyrrolidine-2-carboxamide suspension is warmed to -5-5°C without separation,147.2 g (2.0164 mol) of DMF (N,N-dimethylformamide) was successively added dropwise to the reaction flask.And 150.8g (0.9837moL) phosphorus oxychloride, after the completion of dropping, -5-5 °C insulation reaction 2h,The sample was dissolved and diluted with methanol, and the TLC reaction was complete.The reaction was quenched by the dropwise addition of 700.0 g of water, and the layers were separated. The aqueous layer was extracted twice with 350 g of dichloromethane, and the organic layers were combined.352g water wash 1 time, vacuum solvent removal,185.3 g of brown oil was obtained; 200.0 g of anhydrous ethanol was added to the brown oil.Stir and dissolve, cool down to -5-5°C,Precipitate a lot of solids, stir for 1h; continue to cool to -25 °C, stir 1h; filter,40.0g-25°C pure ethanol elution filter cake,Drying under reduced pressure (50°C, -0.09--0.1MPa),121.0 g of white powder was obtained (yield 80.2percent,HPLC purity 99.80percent,DSC 64.82-66.82°C.
79.3%
With trifluoroacetic anhydride In dimethyl sulfoxide at 10℃; for 3 h; Industrial scale
The 7.3kg (34.8 mol) of trifluoroacetic anhydride in 3 batches (equal to the amount per batch) was added to the above step 1) was obtained in the reaction, the reaction 3h at 10 , adding 24Kg quenched with water After completion of the reaction, 40Kg extracted with dichloromethane, the aqueous layer was extracted with dichloromethane 20Kg × 2 times, methylene chloride layers were combined, washed with saturated sodium carbonate solution until neutral, 20Kg × organic phase was washed with saturated brine twice, the organic phase was no after drying over anhydrous magnesium sulfate and concentrated, n-butanol as white crystals recrystallization 2.4Kg, total yield 79.3percent, HPLC purity> 99.0percent.
78%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In 1,4-dioxane for 5.5 h; Reflux
Compound (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide (17.2 g, 90.7mmol) is dissolved in 200mL of 1,4-dioxane, at room temperature propanephosphonic anhydride solution in 1,4-dioxane (50 w / wpercent, 300mL, 179mmol) is added slowly, the mixture is heated at 98 ° C for 30 minutes, and then warmed to reflux, carry on reaction for 5 hours. After cooling at room temperature, the filtrate is concentrated under reduced pressure to 1/3 volume, add 200mL of ethyl acetate, after that add 500mL of de-ionized water, continue stirring for 30 minutes, liquid separation, ethyl acetate layer is added to 300mL de-ionized water, stirred for 30 minutes. After standing stratified liquid separation to collect the ethyl acetate layer, saturated sodium chloride solution (100mL), after drying (anhydrous sodium sulfate) for 1 hour, the filtrate is concentrated, fully dried and then obtained 12.1g of compound (S) –1-(2-chloroacetyl)pyrrolidine-2-carbonitrile colorless oil), yield is 78.0percent.
68%
With trichlorophosphate In ethyl acetate at 80 - 85℃;
In a clean round bottom flask, 100gm compound lv, 3000m1 ethyl acetate and phosphorous oxychioride were charged and temperature of reaction mass was raised to about 80-85°C. The reaction mass was cooled to about 5-10°C and water was added. Aqueous layer was extractedwith ethyl acetate and pH was adjusted to about 7-8 by NaOH solution. Ethyl acetate layer was concentrated under vacuum to get residue and IPA and methyl tert butyl ether was added to residue. The precipitated solid was stirred for about 2 hours at about 0-5°C, filtered, washed with cold methyl tert butyl ether and dried under vacuum and product isolated as a solid 5 8-62gm (Yield 65-68percent; HPLC purity> 99percent).
61.8%
at 20℃; for 14 h;
Step 9) (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile To a solution of (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide 1j (prepared in Step 8) was added trifluoroacetic anhydride (30.2 g, 142.8 mmol, Aladdin) at rt. The mixture was stirred at rt for 14 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate (20 mL). The solution was washed with saturated aqueous sodium bicarbonate (200 mL) and then saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo give the title compound 1k as brown oil (9.35 g, 61.8percent) without further purification. The compound was characterized by the following spectroscopic data: MS m/z (ESI): 173.1 (M+1); and 1H NMR (400 MHz, DMSO-d6) δ: 4.79-4.78 (m, 1H), 4.35-4.45 (s, 2H), 3.61-3.3.66 (m, 1H), 3.39-3.50 (m, 1H), 2.49-2.51 (m, 2H), 2.03-2.16 (m, 2H).
50%
With trifluoroacetic anhydride In dichloromethane for 2 h;
A solution of (2S)-1-(chloroacetyl)pyrrolidine-2-carboxamide 16(0.26 mmol) in dichloromethane (4 ml), trifluoroacetic anhydride(6.4 mmol, 0.9 ml) was added dropwise. After 2 h the reaction mixturewas poured into water (20 ml) and the product was extracted with dichloromethane(3×10 ml). Combined extracts were washed with saturatedsodium bicarbonate solution (5 ml), brine (5 ml) and dried overmagnesium sulfate. Solvent was evaporated under reduced pressure andresidue was purified by column chromatography using dichloromethane:methanol (100:1 to 10:1) as eluent to afford 17. Lightorange solid, 200 mg, 50percent yield. 1H NMR (400 MHz, CDCl3) δ2.07–2.44 (m, 4H), 3.51 (br. s., 1H), 3.74 (br. s., 1H), 4.00–4.25 (m,2H), 4.71–4.78 (m, 0.85H), 4.85 (dd, J=7.59, 2.08 Hz, 0.15H).
2.5 g
With trifluoroacetic anhydride In tetrahydrofuran at 0 - 30℃;
Example-3: Preparation of 1-chloroacetyl (S)-2-cyanopyrrolidine To a stirred solution of 1-chloroacetyl (S)-2-carboxamidepyrrolidine (5 g) and tetrahydrofuran (50 ml), trifluoro acetic anhydride (7.3 ml) was charged at 0 to 5° C. Reaction mass was stirred at 25°C to 30°C until reaction completion. Upon completion of the reaction, ammonium bicarbonate (15.8 gm) was added lot-wise at temperature 5°C to 10°C, the resulting reaction mixture was stirred for 1 hour at 25 to 30°C. Reaction mass was then concentrated under vacuum to obtain oily residue, followed by addition of water (20 ml), washing with n-heptane (10 ml x 2). Aqueous layer was separated and extracted with toluene (60 ml X 3). Toluene layer was concentrated under reduced pressure to get 1-chloroacetyl (S)-2-cyanopyrrolidine as a product. [Yield: 2.3 to 2.5 g]
115 g
With trichlorophosphate In dichloromethane at 0℃; Reflux
To a solution of L-Prolinamide (100 gms) dissolved in DCM (1000 mL) was added triethyl amine (88.6 gms) and DMAP (1.07 gms) at 25-30°C under N2 atmosphere and stirred for 15 min at 25-30°C. This solution was added to a solution of chloroacetyl chloride (98.9 gms) in DCM (500 mL) under N2 atmosphere at -5 to 0°C over 2-3 hr. Raised the reaction mass temperature to 0-5°C and stirred for lhr. After reaction completion, charged phosphorus oxy chloride (201.5 gms) to the reaction mass at 0-5 °C, heated the reaction mass temperature to reflux and stirred for 6hr at same temperature. After reaction completion, allowed to cool to 10-20°C and added DM water (500 mL). Aqueous layer was separated and the organic layer was washed with DM water. To the organic layer DM water (300 mL) was added at 25-30°C and adjusted the reaction mass pH to 6.5-7.5 with -500 mL of sodium bicarbonate solution (-40 g of NaHC03 dissolved in 500 mL of DM Water). Separated the aqueous layer and concentrated the organic layer under vacuum at temperature of 30-40°C to get residual mass. Charged isopropanol (100 mL) and distilled out solvent completely under vacuum at <50°C. The resulting residue was allowed to cool to 30-40°C and charged isopropanol (500 mL). Heated the reaction mass temperature to 40- 45°C, stirred for 30 min at 40-45°C, allowed to cool to 0-5°C, stirred for 2 hr, filtered and washed wet cake with chilled isopropanol (100 mL), dried at 40-45°C for 6 hr to provide 115 gms of (2S)-l-(CMoroace1yl)-2-pyrrolidinecarbonitrile. HPLC Purity: 99.86percent.
63.16 g
With trichlorophosphate In N,N-dimethyl-formamide at 0 - 5℃; for 2 h;
N,N-dimethylformamide (DMF) (16.8 ml, 217 mmol) was added to a three-necked flask equipped with a thermometer, a nitrogen protection device and a constant pressure dropping funnel, cooled to 5 ° C in an ice bath, Phosphorus oxychloride (7.8 ml, 84 mmol). After completion of the dropwise addition, compound 5 (4.0 g, 21-10) was added and the temperature was controlled between 0 and 5 ° C. The reaction was continued for 2 hours. The reaction was completed, the reaction solution was poured into ice and adjusted to pH 8 to 9 with saturated sodium bicarbonate. Ethyl acetate (120ml) was added and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (60 ml X2). The organic layers were combined and washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, The solvent was evaporated and recrystallized from ethyl acetate: n-hexane = 1: 5 to give 63.16 g of a white powder compound having a purity of 98.94percent
Reference：
[1] Letters in Organic Chemistry, 2013, vol. 10, # 3, p. 159 - 163
[2] Letters in Organic Chemistry, 2014, vol. 11, # 10, p. 780 - 784
[3] European Journal of Organic Chemistry, 2016, vol. 2016, # 30, p. 5160 - 5168
[4] Asian Journal of Chemistry, 2014, vol. 26, # 12, p. 3489 - 3492
[5] Patent: CN108689905, 2018, A, . Location in patent: Paragraph 0091-0092; 0094
[6] Patent: CN104262227, 2018, B, . Location in patent: Paragraph 0015-0030
[7] Patent: CN104945299, 2017, B, . Location in patent: Paragraph 0038; 0039; 0041; 0044-0045; 0047; 0050-0051; 0053
[8] Patent: CN106699627, 2017, A, . Location in patent: Paragraph 0041; 0042; 0044
[9] Patent: CN105884669, 2016, A, . Location in patent: Paragraph 0074-0076; 0080; 0083
[10] Patent: WO2014/102815, 2014, A1, . Location in patent: Page/Page column 16
[11] Patent: EP2865666, 2015, A1, . Location in patent: Paragraph 0157; 0166
[12] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 15, p. 4402 - 4409
[13] Journal of Medicinal Chemistry, 2003, vol. 46, # 13, p. 2774 - 2789
[14] Journal of Medicinal Chemistry, 2002, vol. 45, # 12, p. 2362 - 2365
[15] Patent: WO2004/92127, 2004, A1, . Location in patent: Page 10
[16] Patent: US2010/256080, 2010, A1, . Location in patent: Page/Page column 6
[17] Patent: US2006/217428, 2006, A1, . Location in patent: Page/Page column 8; 9
[18] Patent: US2006/217428, 2006, A1, . Location in patent: Page/Page column 9
[19] Patent: US2006/217428, 2006, A1, . Location in patent: Page/Page column 9
[20] Patent: WO2011/12322, 2011, A2, . Location in patent: Page/Page column 42-43
[21] Patent: WO2011/101861, 2011, A1, . Location in patent: Page/Page column 21-22
[22] Patent: WO2013/179300, 2013, A2, . Location in patent: Page/Page column 27; 28
[23] Organic Process Research and Development, 2015, vol. 19, # 4, p. 551 - 554
[24] Patent: WO2015/145467, 2015, A1, . Location in patent: Page/Page column 21-22
[25] Patent: CN104817482, 2017, B, . Location in patent: Paragraph 0005; 0062; 0067; 0068
7
[ 204387-53-1 ]
[ 79-11-8 ]
[ 207557-35-5 ]
Yield
Reaction Conditions
Operation in experiment
51%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 30℃; for 5 h;
Add 100g (S)-2-cyanopyrrolidine to 1L reaction flaskAnd 500ml methylene chloride,Cool down to 010°CJoin 214.5g DIEA,173.5g EDCIAnd 20.4g HoBt,After addition, stir for 1 h at 0-10 °C.82.0 g chloroacetic acid was added in batches,After the addition, the temperature was raised to 20-30°C and the reaction was incubated for 5 hours.The reaction solution was poured into 500 ml of purified water, stirred for 10 minutes, and allowed to stand for phase separation.The aqueous phase was discarded and the organic phase was washed with 300 ml of 5percent aqueous sodium bicarbonate solution. The organic phase was added with 50 g of anhydrous sodium sulfate and stirred for 1 h at 20-30°C.After filtration, the filter cake was washed with 50 ml of dichloromethane, and the filtrate was concentrated to dryness under reduced pressure. 300 ml of isopropanol was added and the mixture was stirred at 0 1010° C. for 2 h.Filtration, washing the filter cake with 100 ml of isopropanol, vacuum drying the filter cake at 45[deg.] C. for 4 h to obtain 91.6 g of Intermediate-2, yield 51.0percent
Reference：
[1] Patent: CN106966947, 2017, A, . Location in patent: Paragraph 0045
8
[ 7531-52-4 ]
[ 207557-35-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 13, p. 2774 - 2789
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 12, p. 2362 - 2365
[3] Patent: WO2011/101861, 2011, A1,
[4] Letters in Organic Chemistry, 2013, vol. 10, # 3, p. 159 - 163
[5] Patent: WO2014/20462, 2014, A1,
[6] Patent: WO2014/102815, 2014, A1,
[7] Patent: EP2865666, 2015, A1,
[8] Organic Process Research and Development, 2015, vol. 19, # 4, p. 551 - 554
[9] Patent: WO2015/145467, 2015, A1,
[10] Patent: CN105884669, 2016, A,
[11] Patent: CN104945299, 2017, B,
[12] Patent: CN106966947, 2017, A,
[13] Patent: CN106966947, 2017, A,
[14] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 15, p. 4402 - 4409
[15] Patent: CN108689905, 2018, A,
9
[ 147-85-3 ]
[ 207557-35-5 ]
Reference：
[1] Patent: WO2006/90244, 2006, A1, . Location in patent: Page/Page column 28
[2] Patent: WO2007/99385, 2007, A1, . Location in patent: Page/Page column 26
[3] Patent: WO2011/101861, 2011, A1,
[4] Letters in Organic Chemistry, 2013, vol. 10, # 3, p. 159 - 163
[5] Asian Journal of Chemistry, 2014, vol. 26, # 12, p. 3489 - 3492
[6] Letters in Organic Chemistry, 2014, vol. 11, # 10, p. 780 - 784
[7] Chemical Biology and Drug Design, 2015, vol. 85, # 4, p. 439 - 446
[8] European Journal of Organic Chemistry, 2016, vol. 2016, # 30, p. 5160 - 5168
[9] Patent: CN104817482, 2017, B,
[10] Asian Journal of Chemistry, 2014, vol. 26, # 18, p. 6275 - 6278
[11] Patent: CN107954914, 2018, A,
[12] Patent: CN107954914, 2018, A,
[13] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 15, p. 4402 - 4409
[14] Patent: WO2006/11035, 2006, A1, . Location in patent: Page/Page column 30
(2S)-1-[1H-1,2,4-triazol-1-ylmethyl(tricyclo[3.3.1.03,7]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of l-(lH-l,2,4-triazol-l-ylmethyl) tricyclo [3.3.1.O3'7] nonan- 3-amine (0.06g, 0.38 mmol) and K2CO3 (0.13 g, 0.96 mmol) in DMSO (1 mL) at an ice bath temperature was added compound (2iS)-l-(chloroacetyl)pyrrolidine-2-carbonitrile (0.07 g, 0.32 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain the triazole derivative of (2S)-l-[lH-l,2,4-triazol-l-ylmethyl (tricyclo [3.3.1.03'7]non-3-ylamino) acetyl] pyrrolidine-2-carbonitrile (0.07 g) in 60% yield as an off-white solid, M.R: 230-235 C. m/z (M+l) 355. IR cm"1 3429, 2929, 2224, 1658, 1511,1426, 1330, 1276, 1141,1018, 747. 1H NMR (CDCl3) 300 MHz delta 8.0 (s, IH), 7.9 (s, IH), 4.78 (bd, J= 6.3 Hz, IH), 4.09 (s, 2H), 3.65-3.35 (m, 4H), 2.40-2.05 (m, 8H), 1.80- 1.62 (m, 4H), 1.58-1.32 (m, 4H).
(2S)-1-{N-[2-(1H-tetrazol-1-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 3h;
To a stirred solution of the hydrochloride salt obtained in step II (0.162g, 0.62 mmol) in DMSO (2.5 mL) at room temperature under nitrogen atmosphere was added (25)-l-(chloroacetyl)pyrrolidine-2-carbonitrile (0.11 g, 0.62 mmol) and K2CO3 (0.34 g, 2.48 mmol). After stirring the reaction mixture for 3 h, it was diluted with EtOAc, and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2,S)-l-{N-[2-(lH-tetrazol-l-ylmethyl) hexahydro-2,5-methanorhoentalen-3a(lH)-yl] glycyl} pyrrolidine -2-carbonitrile as an off-white solid (0.09 g) in 40% yield, m/z (M+ 1) 355; 1eta NMR (CDCl3) 300 MHz delta 8.49 (s, IH), 4.77 (d, J = 6.7 Hz, IH), 4.56 (s, 2H), 3.64-3.38 (m, 2H), 3.40 (s, 2H), 2.40-2.05 (m, 6H), 1.80-1.65 (m, 5H), 1.60-1.40 (m, 5H).
1-[(4-methylpiperazin-1-yl)methyl]tricyclo[3.3.1.03,7]nonan-3-amine trihydrochloride[ No CAS ]
[ 207557-35-5 ]
(2S)-1-{N-[2-[(4-methylpiperazin-1-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 3h;
To a stirred solution of the hydrochloride (0.33 g, 0.92 mmol) obtained in step II, in DMSO (3.7 mL) at room temperature under nitrogen atmosphere (2iS)-l-(chloroace- tyl)pyrrolidine-2-carbonitrile (0.16 g, 0.92 mmol) and K2CO3 (0.76 g, 5.53 mmol) were added. After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)- 1- {N- [2-[(4-methylpiperazin-l-yl) methyl] hexahydro-2,5-methanopentalen-3a (lH)-y glycyl} pyrrolidine-2-carbonitrile as an off-white solid (0.12 g) in 47% yield, m/z (M+l) 386; 1H NMR (CDC13+CD3OD) 300 MHz delta 4.78 (d, J= 5.7 Hz, IH), 3.85-3.50 (m, 4H), 3.30-3.10 (m, 5H), 2.85-2.70 (m, 8H), 2.52-2.45 (m, 2H), 2.38-2.20 (m, 4H), 2.10-1.90 (m, 4H), 1.70-1.40 (m, 5H), 1.40-1.27 (m, IH).
1-(thiomorpholin-4-ylmethyl)tricyclo[3.3.1.03,7]nonan-3-amine dihydrochloride[ No CAS ]
[ 207557-35-5 ]
(2S)-1-{N-[2-(thiomorpholin-4-ylmethyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 3h;
To a stirred solution of the hydrochloride salt (0.17 g, 0.51 mmol) obtained in step II above in DMSO (2.0 mL) at room temperature under nitrogen atmosphere was added (26)-l-(chloroacetyl)pyrrolidine-2-carbonitrile (0.09 g, 0.52 mmol) and K2CO3 (0.35 g, 2.55 mmol. After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (25)-l-{7V-[2-(thiomorpholin-4-ylmethyl)hexahydro-2,5-methanorhoentalen-3a(lJf/)-yl] glycyl} pyrrolidine-2-carbonitrile as an off-white solid (0.07 g) in 35% yield, m/z (M+l) 389; 1H NMR (CDCl3) 300 MHz delta 4.83-4.75 (m, IH), 3.90-3.45 (m, 4H), 2.85-2.70 (m, 4H), 2.70-2.60 (m, 4H), 2.48-2.35 (m, 2H), 2.35-2.15 (m, 4H), 2.0-1.75 (m, 4H), 1.68-1.40 (m, 5H), 1.38-1.25 (m, IH).
1-[(1,1-dioxidoisothiazolidin-2-yl)methyl]tricyclo[3.3.1.03,7]nonan-3-amine[ No CAS ]
[ 207557-35-5 ]
(2S)-1-{N-[2-[(1,1-dioxidoisothiazolidin-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of the amine obtained in step IV (0.26 g, 0.96 mmol) and K2CO3 (0.42 g, 2.9 mmol) in DMSO (4.0 mL) at ice bath temperature was added under nitrogen atomsphere (S)-l-(2-chloro-acetyl) pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol). After stirring the reaction mixture for 3 h at r.t, it was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and the solvent was evaporated under reduced <n="89"/>pressure. The crude product was purified by column chromatography to obtain (IS)- 1- (N- [2-[(l,l-dioxidoisothiazolidin-2-yl) methyl]hexahydro-2,5-inethanopentalen-3a(lH)-yl] glycyl} pyrrolidine-2-carbonitrile as an off-white solid (0.17 g) in 43% yield, m/z (M+l) 407; 1H NMR (CDCl3) 300 MHz delta 4.87-4.76 (m, IH), 3.70-3.40 (m, 2H), 3.44 (s, 2H), 3.32 (t, J= 6.7 Hz, 2H), 3.10 (t, J= 7.5 Hz, 2H), 2.93 (s, 2H), 2.41-2.10 (m, 8H), 1.90-1.46 (m, 7H), 1.43-1.35 (m, IH).
(2S)-1-{N-[2-[(2,4-dioxo-1,3-thiazolidin-3-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 3h;
To a stirred solution of the hydrochloride salt obtained in step II (0.165g, 0.54 mmol) in DMSO (2.2 mL) at room temperature under nitrogen atmosphere (S)-I -(2- chloro-acetyl)pyrrolidine-2-carbonitrile (0.1 g, 0.54 mmol) and K2CO3 (0.23 g, 1.62 mmol) was added sequentially. After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain(2lS)-l-{N-[2-[(2,4-dioxo-l,3-thiazolidin-3-yl)methyl]hexahydro-2,5-methano pentalen-3a(lH)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.11 g) in 50% yield, m/z (M+l) 358; 1eta nuMR (CDCl3) 300 MHz delta 4.77 (d, J = 7.4 Hz, IH), 3.96 (s, 2H), 3.75-3.38 (m, 2H), 3.56 (s, 2H), 3.41 (s, 2H), 2.40-2.10 (m, 6H), 1.90-1.57 (m, 10H), 1.57-1.33 (m, 4H).
(2S)-1-{N-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of the compound obtained from step II (0.4 g, 0.98 mmol) and K2CO3 (0.54 g, 3.92 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atomsphere was added (S)-I -(2-chloro-acetyl) pyrrolidine-2-carbonitrile (0.17 g, 1.0 <n="92"/>mmol). After stirring the reaction mixture at r.t for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-l-{N-[2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2yl)methyl]hexahydro-2,5- methanopentalen-3a(lH)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.18 g) in 43% yield, m/z (M+l) 433; 1H NMR (CDCl3) 300 MHz delta 7.90-7.80 (m, 2H), 7.75-7.65 (m, 2H), 4.86-4.72 (m, IH), 3.72-3.38 (m, 2H), 3.60 (s, 2H), 3.40 (s, 2H), 2.40-2.05 (m, 7H), 1.90-1.78 (m, 2H), 1.70-1.40 (m, 3H).
(2S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of l-[4-(l,l-dioxidoisothiazolidin-2-yl) phenyl] tricyclo [3.3.1.O3'7] nonan-3-amine (0.4 g, 1.2 mmol) and K2CO3 (0.48 g, 3.6 mmol) in DMSO (4.8 mL) at ice bath temperature was added (25)-l-(chloroacetyl) pyrrolidine-2-carbonitrile (0.25 g, 1.44 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-I-(N- [2- [4~(l,l-dioxidoisothiazolidin-2-yl) phenyl] hexahydro-2,5~methano pentalen-3a(lH)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.28 g) in 50% yield. M.R, 214-216 C m/z (M+l) 469; IR cm"1 3436, 2932, 2240, 1658, 1517, 1414, 1308, 1137, 952, 740. 1H NMR (300 MHz, CD3OD)delta: 7.35 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 4.85 (t, J = 5.4 Hz5 IH), 4.15-3.95 (m, 2H), 3.81-3.70 (m, 3H), 3.60-3.50(m, IH), 3.42(t, J= 7.4 Hz, 2H), 2.65-2.45(m, 4H), 2.40-1.75 (m, 14 H).
(2S)-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred solution of l-[4-(3-amino1ricyclo[3.3.1.03'7]non-l-yl)phenyl] pyrrolidin-2-one obtained in step II (0.36 g, 1.2 mmol) in DMSO (4.8 niL) at an ice bath temperature under nitrogen atmosphere was added K2CO3 (0.48 g, 3.6 mmol) followed by addition of (25)-l-(chloroacetyl) pyrrolidine-2-carbonitrile (0.21 g, 1.2 mmol). After stirring the reaction mixture at r.t for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain the title compound (2S)- l-{iV-[2-[4-(2-oxopyrrolidin-l-yl) phenyl] hexahydro-2,5-methano pentalen-3a(li7)-yl] glycyl} pyrrolidine-2-carbonitrile as a white solid (0.26 g) in 50% yield. M.R: 254-256C; m/z (M+l) 433; 1H NMR (300 MHz, CDCl3)delta: 7.54 (d, J = 8.5 Hz, 2H), 7.23 (d, J= 8.5 Hz, 2H), 4.30-4.20 (m, IH), 4.06-4.18 (m, 2H), 3.87 (t, J= 7.0 Hz, IH), 3.80-3.50 (m, 4H), 2.64 (t, J= 7.8 Hz5 2H), 2.58-1.60 (m, 18 H).
2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-amine[ No CAS ]
[ 207557-35-5 ]
(2S)-1-{N-[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of the compound obtained from step II (0.41 g, 1.5 mmol) and K2CO3 (0.62 g, 4.5 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-l-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.26 g, 1.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (25)-l-{N-[2-[4-(lH-pyrrol-l-yl)phenyl]hexahydro-2,5-methano pentalen-3a (lH)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.2 g) in 32% yield as off-white solid, m/z (M+l) 415; 1H NMR (CDCl3) 300 MHz delta 7.38-7.26 (m, 4H), 7.10- 7.05 (m, 2H), 6.36-6.32 (m, 2H), 4.84-4.78 (m, IH), 3.75-3.40 (m, 2H), 3.50 (s, 2H), 2.50- 2.42 (m, IH), 2.38-2.28 (m, 2H), 2.25-2.0 (m, 6H), 2.0-1.70 (m, 7H).
1-[4-(3-aminotricyclo[3.3.1.03,7]non-1-yl)phenyl]imidazolidin-2-one[ No CAS ]
[ 207557-35-5 ]
(2S)-1-{N-[2-[4-(2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of the compound obtained from step II (0.4 g, 1.35 mmol) and K2CO3 (0.56 g, 4.05 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-l-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.23g, 1.35 mmol).The reaction mixture was gradually warmed to room temperature and stirred for 3 <n="103"/>h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-l-{N-[2-[4~(2-oxoimidazolidin-l-yl)phenyl]hexahydro-2,5~ methanopentalen-3a(lH)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.21 g) in 36% yield, m/z (M+l) 434; 1H NMR (CDCl3) 300 MHz delta 7.45 (d, J= 8.8 Hz, 2H), 7.23 (d, J= 8.8 Hz, 2H), 4.86-4.76 (m, IH), 4.67 (s (br), IH), 3.93 (t, J= 7.4 Hz, 2H), 3.75-3.40 (m, 4H), 3.48 (s, 2H), 3.46-2.38 (m, IH), 2.36-2.23 (m, 2H), 2.23-1.70 (m, 12H), 1.65-1.57 (m, IH).
(2S)-1-[(tricyclo[3.3.1.03,7]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of tricyclo [3.3.1.03'7] nonan-3-amine (0.28 g, 2.0 mmol) and K2CO3 (0.83 g, 6.0 mmol) in DMSO (8 mL) at ice bath temperature under N2 atmosphere was added (S)-l-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.34 g, 2.0 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)- 1 -[(tricyclo [3.3.1.0 ' ] non-3 -ylamino) acetyl]pyrrolidine-2-carbonitrile as a viscous liquid (0.23 g) in 42% yield, m/z (M+l) 274; IH NMR (CDCl3) 300 MHz delta 4.87-4.76 (m, IH), 3.71-3.40 (m, 2H), 3.41 (s, 2H), 2.35-2.05 (m, 7H), 1.92-1.74 (m, 6H), 1.68-1.48 (m, 4H).
(2S)-1-[(1-hydroxytricyclo[3.3.1.03,7]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of the compound obtained in step I (280 mg, 1.5 mmol) and K2CO3 (820 mg, 6 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-l-(2-chloro-acetyl) pyrrolidine-2-carbonitrile (205 mg, 1.2 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain <n="105"/>(25)-l-[(l-hydroxytricyclo [3.3.1.0 ' ]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile as a viscous liquid (150 mg) in 35% yield, m/z (M+l) 291; IH NMR (CDCl3) 300 MHz delta 4.78 (d, J= 7.0 Hz, IH), 3.75-3.38 (m, 2H), 3.43 (s, 2H), 2.45-37 (m IH), 2.35-1.95 (m, 8H), 1.90-1.60 (m, 6H), 1.53-1.40 (m, 2H).
1-methoxytricyclo[3.3.1.03,7]nonan-3-amine[ No CAS ]
[ 207557-35-5 ]
(2S)-1-[(1-methoxytricyclo[3.3.1.03,7]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 3h;
To a stirred solution of the amino compound obtained by step V (0.16g, 0.95 mmol) in DMSO (4.0 mL) was added (S)-I -(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 0.96 mmol) and K2CO3 (0.4 g, 2.9 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc and washed with water ad brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-I- [(1-methoxytricyclo [3.3.1.03'7]non-3-yl)amino]acetyl}pyrrolidine-2- carbonitrile (0.12 g) in 41% yield, m/z (M+l) 304; IH NMR (CDCl3) 300 MHz delta 4.82- 4.75 (m, IH)5 3.75-3.40- m5 4H), 3.27 (s, 3H)5 2.47-2.40 (m, IH), 2.35-1.68 (13H)5 1.57- 1.41 (m, 2H).
tert-butyl (3-aminotricyclo[3.3.1.03,7]non-1-yl)carbamate[ No CAS ]
[ 207557-35-5 ]
tert-butyl (2S)-1-[(1-aminotricyclo[3.3.1.03,7]non-3-yl)carbamate]acetyl}pyrrolidine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of the compound obtained in preparation 8 (0.3 g, 1.2 mmol) and K2CO3 (0.5 g, 3.6 mmol) in DMSO (5 mL) at ice bath temperature under N2 atmosphere was added (S)-l-(2-chloro-acetyl) pyrrolidine-2-carbonitrile (0.14 g, 0.83 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain te^-Butyl-(25)-l-[(l-aminotricyclo [3.3.1.03'7]non-3-yl) carbamate] acetyl}pyrrolidine-2-carbonitrile as a viscous liquid (0.18 g) in 40% yield, m/z (M+l) 389; 1H NMR (CDCl3) 300 MHz delta 4.79 (d, J = 7.5 Hz, IH), 4.70 (s (br), IH), 3.70- 3.40 (m, 2H), 3.46 (s, 2H), 2.40-2.32 (m, IH), 2.32-1.90 (m, 6H), 1.90-1.63 (m, 5H), 1.55- 1.43 (m, IH).
(2S)-1-[N-(2-fluorohexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of the hydrochloride salt obtained from step II (0.19 g, 0.98 mmol) and K2CO3 (0.53 g, 4.0 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atmosphere (S)-l-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol) was added. After stirring the reaction mixture at r.t. for 3 h, the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (25)-l-[N-(2-fluorohexahydro-2,5-methanopentalen-3a(lT)-yl) glycyl] pyrrolidine-2-carbonitrile as an off-white solid (0.11 g) in 38% yield, m/z (M+l) 292; IH NMR (CDCl3) 300 MHz delta 4.80-4.73 (m, IH), 3.77-3.32 (m, 2H), 3.52 (s, 2H), 2.50-2.42 (m, IH), 2.87-2.08 (m, 6H), 2.0-1.60 (m, 6H), 1.50-1.42 (m, IH).
1-(3-aminotricyclo[3.3.1.03,7]non-1-yl)pyrrolidin-2-one[ No CAS ]
[ 207557-35-5 ]
(2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of l-(3-aminotricyclo [3.3.1.0 '7]non-l-yl)pyrrolidin-2-one prepared as in preparation 9 (0.25 g, 1.1 mmol) and K2CO3 (0.46 g, 3.3 mmol) in DMSO (5 mL) at an ice bath temperature was added (S)-l-(2-chloro-acetyl)pyrrolidine-2- carbonitrile (0.2 g, 1.1 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-I-[N- [2- (2-oxopyrrolidin-l-yl) hexahydro-2,5-methanopentalen-3a (lH)-yl]glycyl} pyrrolidine-2-carbonitrile as a viscous liquid (0.16 g) in 40% yield, m/z (M+l) 357; 1H NMR (CDCl3) 300 MHz delta 4.78 (d, J= 7.4 Hz, IH), 3.70-3.38 (m, 2H), 3.46 (s, 2H), 3.41 (t, J= 7.0 Hz, 2H), 2.60 (dd, J= 4.0, 10.2 Hz, IH), 2.40-1.75 (m, 17H), 1.72-1.62 (m, IH), 1.58-1.50 (m, IH).
1-(1,1-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.03,7]nonan-3-amine[ No CAS ]
[ 207557-35-5 ]
(2S)-1-{N-[2-(1,1-dioxidoisothiazolidin-2-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of l-(l,l-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.0 ' Jnonan- 3-amine prepared as in preparation 10 (0.17 g, 0.66 mmol), and K2CO3 (0.28 g, 2.0 mmol) in DMSO (2.6 mL) at ice bath temperature was added (S)-I -(2-chloro-acetyl)pyrrolidine-2- carbonitrile (0.13 g, 0.66 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4,and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (25)-l-{N-[2-(l,l-dioxidoisothiazolidin-2-yl) hexahydro-2,5-methanopentalen-3a (lH)-yl] glycyl}pyrrolidine -2-carbonitrile as a viscous liquid (0.1 g) in 40% yield, m/z (M+l) 393; 1H NMR (CDCl3) 300 MHz delta 4.80-4.75 (m, IH), 3.70-3.37 (m, 4H), 3.36 (t, J = 6.6 Hz, 2H), 3.16 (t, J = 7.4 Hz, 2H), 2.43-2.37 (m, IH), 2.35-2.13 (m, 9H), 2.05-1.99 (m, IH), 1.95-1.75 (m, 5H), 1.70-1.63 (m, IH), 1.54- 1.47 (m, IH).
1-phenyltricyclo[3.3.1.03,7]nonan-3-amine[ No CAS ]
[ 207557-35-5 ]
(2S)-1-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of the compound obtained from step II (0.2 g, 0.94 mmol) and K2CO3 (0.39 g, 2.8 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atomsphere (S)-l-(2-chloro-acetyl) pyrrolidine-2-carbonitrile (0.16 g, 0.94 mmol) was added. After stirring the reaction mixture for 3 h at r.t, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (25)-l-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(lH)-yl)glycyl]pyrrolidine-2- carbonitrile as off-white solid (0.16 g) in 48% yield, m/z (M+l) 350; 1H NMR (CDCl3) 300 MHz delta 7.35-7.16 (m, 5H), 4.4.85-4.76 (m, IH), 3.76-3.40 (m, 2H), 3.50 (s, 2H), 2.48- 2.41 (m, IH), 2.36-2.27 (m, 2H), 2.23-2.0 (m, 6H), 1.94-1.68 (m, 4H), 1.66-1.60 (m, IH).
(2S)-1-{N-[2-(4-nitrophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of l-(4-nitrophenyl)tricyclo[3.3.1.03'7]nonan-3-amine as obtained in Step III preparation 4 (0.77 g, 3.0 mmol) and K2CO3 (1.25 g, 9.0 mmol) in DMSO (12 mL) at ice bath temperature under N2 atmosphere was added (S)-l-(2-chloro-acetyl)pyrrolidine- 2-carbonitrile (0.51 g, 3.0 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction, the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (25)-l-{N-[2-(4-nitrophenyl) hexahydro -2,5-methanopentalen- 3a(lH)-yl] glycyl} pyrrolidine-2-carbonitrile as an off-white solid (0.5 g) in 42% yield, m/z (M+l) 395; 1H nuMR (CDCl3) 300 MHz delta 8.14 (d, J= 8.9 Hz, 2H), 7.41 ((d, J= 8.9 Hz, 2H), 4.83-4.73 (m, IH), 3.78-3.40 (m, 2H), 3.48 (s, 2H), 2.51-2.45 (m, IH), 2.37-2.06 (m, 6H)5 2.02-1.60 (m, 9H).
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 3h;
TO a stirred solution of the compound obtained from step III (0.12 g, 0.36 mmol) in DMSO (1.5 mL) at room temperature under nitrogen atmosphere was added, (S)-l-(2- chloro-acetyl)pyrrolidine-2-carbonitrile (0.06 g, 0.0.36 mmol) and K2CO3 (0.2 g, 1.44 mmol). After stirring the reaction mixture for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain ((2S)-I- {N- [2-(l,2,4-oxadiazol-3-ylmethyl) hexahydro-2,5-methano pentalen-3a(lH)-yl] glycyl} pyrrolidin-2-yl)acetonitrile as an off-white solid (0.05 g) in 40% yield, m/z (M+l), 356; IH <n="120"/>NMR (CDCl3) 300 MHz delta 8.64 (s, IH), 4.84-4.75 (m, IH)5 3.75-3.40 (m, 2H), 3.49 (s, 2H), 2.81 (s, 2H), 2.40-2.10 (m, 6H), 1.92-1.70 (m, 6H), 1.68-1.48 (m, 4H).
1-[4-(3a-aminohexahydro-2,5-methanopentalen-2(1H)-yl)phenyl]-3-methylimidazolidin-2-one[ No CAS ]
[ 207557-35-5 ]
C26H33N5O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 3h;
To a stirred mixture of the compound obtained from step II (0.15 g, 0.48 mmol) and K2CO3 (0.21 g, 1.5 mmol) in DMSO (2 mL) at ice bath temperature was added compound (S)-l-(2-chloro-acetyl) pyrrolidine-2-carbonitrile (0.09 g, 0.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain ((2S)- 1 - {iV-[2-[4-(3-methyl-2-oxoimidazolidin-l -yl) phenyl] hexahydro-2,5-methano rhoentalen-3a(lH)-yl]glycyl}pyrrolidin-2-yl) acetonitrile as an off-white solid (0.09 g) in 42% yield, m/z (M+l) 449; IH NMR (CDCl3) 300 MHz delta 7.47 (d, J= 8.6 Hz, 2H)5 7.22 (t, J= 8.6 Hz, 2H), 4.85-4.76 (m, IH), 3.79 (t, J= 7.3 Hz, 2H), 3.75-3.40 (m, 4H), 3.48 (s, 2H), 2.89 (s, 3H), 2.46-2.39 (m, IH), 2.36-2.15 (m, 3H), 2.12-1.58 (m, 12H).
methyl (2S)-2-amino-3-{4-[4-(pyridin-2-ylamino)phenoxy]phenyl}propanoate dihydrochloride[ No CAS ]
[ 207557-35-5 ]
methyl (2S)2-[2-((2S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl]amino}-3-{4-[4-(pyridin-2-ylamino)phenoxy]phenyl}propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.7%
With potassium carbonate; In dichloromethane; at 0 - 20℃; for 50h;
Step II; Preparation of methyl (2S) 2-[2-((2S)-2-cyanopyrrolidin-l-yl)-2-oxoethyl] amino}- 3-{4-[4-(pyridin-2-yIamino) phenoxy] phenyl} propanoate; To a solution of methyl (2S)-2-amino-3-{4-[4-(pyridin-2-ylamino) phenoxy] phenyl}propanoate dihydrochloride (0.65g,1.7mmol) in methylene chloride was added potassium carbonate (0.737g, 5.3mmol) followed by (2,S)-l-(chloroacetyl)pyrrolidine- <n="51"/>2-carbonitrile at 0 0C and the reaction mixture was stirred for 2 hours after which it was allowed to attain room temperature gradually and was stirred further for 48 hours at room temperature. Subsequently the reaction mixture was filtered, the filtrate was concentrated and chromatographed over neutral alumina column using methylene chloride/methanol: 9.9/0.1 as the eluent to yield the product (0.025g, 2.7%), 1HNMR. [DMSOd6, 400 MHz] delta ppm: 1.96 (m, 2H), 2.09 (d, 2H)5 2.87 (m, 2H), 3.30 (d, 2H), 3.47 (m, IH), 3.53 (dd, 2H), 3.59 (s, 3H), 4.710, IH), 6.71(t, IH), 6.79(dd, IH), 6.84(dd, 2H), 6.95(dd, 2H), 7.14 (dd, 2H), 7.540, 2H), 7.68(dd, 2H), 8.1 l(d, IH), 9.01(bs, IH); m/zM+1 500.2.
(3R)-1-[(2S)-2-amino-3-{4-[(3-nitropyridin-2-yl)oxy]phenyl}propanoyl]pyrrolidin-3-ol dihydrochloride[ No CAS ]
[ 207557-35-5 ]
C25H28N6O6[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;potassium iodide; In dichloromethane; at 0 - 20℃; for 50h;
Example 31; Synthesis of (2S) l-([(lS)-2-((3R) 3-hydroxy-pyrrolidine)-l-(-4-(3-nitro pyridin-2- yloxy) benzyl)-2-oxoethyl] amino} acetyl)-pyrrolidine-2-carbonitrile; To a solution of (3R)-l-[(2S)-2-amino-3-{4-[(3-nitropyridin-2~ yl)oxy]phenyl}propanoyl]pyrrolidin-3-ol dihydrochloride (0.213g, 5mmol, prepared as in example 24) in methylene chloride was added potassium carbonate (0.236g, 1.7mmol), catalytic amount of potassium iodide and (25)-l-(chloroacetyl)pyrrolidine- 2-carbonitrile (0.049g, 2.8mmol) at 0 0C and the reaction mixture was stirred for 2 hours after which it was allowed to attain room temperature gradually and was stirred further for another 48 hours at room temperature. Subsequently the reaction mixture was filtered, the filtrate was concentrated and chromatographed over neutral alumina column using methylene chloride/methanol: 9.9/0.1 as the eluent to yield 0.06Og of the product. 1HNMR. (DMSOd6, 400 MHz) delta ppm: 1.25(dd, 2H), 1.70(d, 2H), 1.950, 2H), <n="52"/>2.10 (t, 2H)5 2.79 (m, 2H), 3.4 (m, 7H), 4.20 (dd, IH), 4.70(t, IH), 7.10(d, 2H), 7.28(m, 2H), 7.36(t, IH), 8.38 (d, IH), 8 .56(dd, IH). m/zM+1 509.2
(3RS)-8-methoxy-2,3,4,9-tetrahydro-1H-3-carbazolamine[ No CAS ]
[ 207557-35-5 ]
1-{2-[(3RS)-8-methoxy-2,3,4,9-tetrahydro-1H-3-carbazolyl-amino]acetyl}pyrrolidine-2(S)-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With potassium carbonate; In tetrahydrofuran; at -10 - 20℃; for 20h;
Step C : A solution of intermediate from step B (0. 151 g, 0. 875 mmol) in dry THF (5 ML) was added drop-wise to A cooled (-10 C) and stirred mixture of the amine from Step A (0. 378 g, 1. 748 MMOL . and K2CO2 (0. 361 g, 2. 615 mmol) in dry THF (5 ML) under nitrogen atmosphere. The temperature of the reaction mixture was slowly raised to RT and maintained at RT for 20 H. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified on A neutral alumina column using 3 % methanol in dichloromethane to give 0. 130 G (42 %) of the compound as A light brown solid ; 1H NMR (CD13, 300 MHz) 8 1. 7-1. 9 (M, 4H), 2. 08-2. 33 (M, 4H), 2. 46-2. 6 (M, 1H), 2. 78-2. 9 (M, 2H), 2. 96-3. 1 (M, 2H), 3. 4-3. 72 (M, 3H), 3. 94 (S, 3H), 4. 76-4. 8 (S, 1H), 6. 61 (D, J= 7. 5 HZ, 1H), 6. 69-7. 1 (M, 2H), 7. 96 (B, 1H) ; IR (KBR) 3322, 2923, 2850, 1656, 1573, 1426, 1257, 1192, 1099, 777, 753, 730 cm-1; MS (M/Z) : 353 (M+H).
With potassium carbonate; sodium iodide; In acetone; at 0 - 20℃; for 15.5h;
The t-butyl(2-amino-2-methyl-1-propyl)carbamate(7.9g) obtained above, sodium iodide (8.7 g), and potassium carbonate (8.0 g) were suspended in acetone (230 ml). A solution of (S)-1-(2'-chloroacetyl) pyrrolidine-2-carbonitrile (10 g) in acetone (80 ml) was added thereto with ice cooling, and stirred as such for 30 minutes. The reaction mixture was stirred for 15 hours at room temperature and then concentrated under reduced pressure. The residue was dissolved in chloroform, then insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluding solvent; dichloromethane: methanol 80: 1 ? 60: 1 ? 40: 1) to give t-butyl (S)-{2-[(2-cyanopyrrolidine-1-yl)-2-oxoethylamino]-2-methyl -1-propyl} carbamate (12 g, Y.: 91%). 1H NMR; (DMSO-d6) delta (ppm): 0.9 (6H, s), 1. 4 (9H, s), 1.9-2.2 (4H, m), 2.9 (2H, d), 3.2-3.5 (4H, m), 3.5-3.7 (1H, m), 4.7-4.8 (1H, m), 6.6-6.7 (1H, brt). ESI/MS (m/z): 325 (M+H)+, 323 (M-H)-.
91%
With potassium carbonate; sodium iodide; In acetone; at 20℃;Cooling with ice;
A solution of (S)-1-(2chloroacetyl) pyrrolidine-2-carbonitrile (10 g) in acetone (80 ml) was added dropwise to an ice-cooled stirred suspension of t-butyl (2-amino-2-methyl-1-propyl)carbamate (7.9 g), NaI (8.7 g), and K2CO3 (8.0 g) in acetone (230 ml). The reaction mixture was stirred at room temperature overnight. The resulting mixture was filtered to remove insoluble materials, and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (dichloromethane/methanol=80/160/140/1) to give (S)-t-butyl (2-((2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)amino)-2-methylpropyl)carbamate (12 g, Y.: 91%).1H NMR: d 0.9 (6H, s), 1.4 (9H, s), 1.9-2.2 (4H, m), 2.9 (2H, d), 3.2-3.5 (4H, m), 3.5-3.7 (1H, m), 4.7-4.8 (1H, m), 6.6-6.7 (1H, brt); MS (m/z): 325 (M+H)+, 323 (M-H)-.
With diisopropylamine; sodium iodide; In dichloromethane; at 35 - 40℃; for 5h;
To the above residue, dichloromethane (3.5 L), (S)-l-(2-chloroacetyl)pyrrolidine-2- carbonitrile (chloro pyrrolidine) (400 gm), sodium iodide (334 gm), and diisopropyl amine (226 gm) were added. The reaction mixture was heated to 35-40 C and maintained for 5 hours. The reaction mixture was cooled to 25-30 C and water (2.5 L) was added and stirred the solution for 30 minutes. The organic layer was separated and distill-off the solvent to get the title compound (850 gm). HPLC purity: >90 % Dimer impurity: 2.5%
With potassium carbonate; potassium iodide; In acetone; at 0 - 40℃; for 4h;
Example-2: Preparation of (t-butyl-(S)-{2-[2-cyanopyrrolidine-l-yI)-2-oxoethylamino}-2-propyI}carbamate To the solution of 50gm t-butyl2-amino-2methyl-propylcarbamate in 1000ml acetone added catalytic amount of potassiumiodide, 58.7gm potassiumcarbonate and cooled to 0- 5C. Added solution of 41.1 gm S-l-(chloroacetyl)pyrrolidine-2-carbonitrile in acetone and stirred at 38-40C for 4 hours. Insolubles were removed by filtration and the filtrate was concentrated under reduced pressure to givet-butyl-(S)-{2-[2-cyanopyrrolidine-l-yl)- 2-oxoethylamino } -2-propyl } carbamate. HPLC purity: 95% Example 3: Purification oft-butyl-(S)-{2-[2-cyanopyrrolidine-l-yl)-2- oxoethylamino}-2-propyl}carbamate The 84gm crude residue of example-2 Cooled to ambient temperature and Added mixture of 175ml ethylacetate and 45ml methanol and stirred for 2hours -5 to 0C. Filtered the mass and washed with chilled 30ml ethylacetate. Dried the material under vacuum pressure at 50C to give 58% t-butyl-(S)-{2-[2-cyanopyrrolidine-l-yl)-2-oxoethylamino}- 2-propyl } carbamate . HPLC purity:99%
(S)-1-{2-[3-(1,3-dihydroisoindol-2-yl)-1,1-dimethyl-3-oxopropylamino]acetyl}pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With potassium carbonate; sodium iodide; In acetone; at 0 - 20℃; for 8h;
(Example 61) (S)-1-{2-[3-(1,3-Dihydroisoindol-2-yl)-1,1-dimethyl-3-oxopr opylamino]acetyl}pyrrolidine-2-carbonitrile Potassium carbonate (370 mg) and sodium iodide (200 mg) were added to a solution of 3-amino-1-(1,3-dihydroisoindol-2-yl)-3-methylbutan-1-one (0.55 g) in acetone. (S)-1-(2'-Chloroacetyl)pyrrolidine-2-carbonitrile (467 mg) was added thereto with ice cooling, and the mixture was stirred for 8 hours at room temperature. Dichloromethane was added thereto, then insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluding solvent; dichloromethane: methanol 20: 1) to give the title compound (0.54 g, 61%). 1H NMR; (DMSO-d6) delta (ppm): 1.39, 1.40 (6H, 2s), 2.00-2.25 (4H, m), 2.85-2.95 (2H, m), 3.30-4.10 (4H, m), 4.71, 4. 90 (4H, 2s), 4.85-4.90 (1H, m), 7.30-7.40 (4H, m). ESI/MS (m/z): 355 (M+H)+.
Intermediate 18; (2S)-1- (2-Chloroacetyl)-2-pyrrolidinecarbonitrile; This intermediate was prepared from L- (-)-proline using a literature procedure (J. Med. Chem., 2003, 46, 2774-2789).
(2S)-1-([9-(hydroxymethyl)-3-oxaspiro[5.5]undec-9-yl]amino}acetyl)-2-pyrrolidinecarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In dichloromethane; at 20℃; for 144h;
90 ml of dichloromethane, 6 mmol of (2S)-1-(chloroacetyl)-2-pyrrolidinecarbonitrile and then 24 mmol of potassium carbonate are added to 12 mmol of the compound obtained in the above Step. After stirring for 6 days at 20 C., the precipitate formed is filtered off and rinsed with dichloromethane, and the filtrates are concentrated to dryness. The residue obtained is purified by chromatography on silica (eluant: dichloromethane/methanol 97/3) to yield the expected product in the form of a yellow oil which solidifies in the cold to yield a white powder.
Intermediate 3; (2S)-l-(2-Chloroacetyl)-2-pyrrolidinecarbonitrileThis intermediate was prepared from L-(-)-proline using a literature procedure (J. Med. Chem., 2003, 46, 2774-2789).
Intermediate 8 (2S)-l-(2-ChIoroacetyl)-2-pyrrolidinecarbonitrileThis intermediate was prepared from L-(-)-proline using a literature procedure (J. Med. Chem., 2003, 46, 2774-2789).
Intermediate 7; (2S)-l-(2-Chloroacetyl)-2-pyrrolidinecarbonitrile; This intermediate was prepared from L-(-)-proline using a literature procedure (/.Med. Chem., 2003, 46, 2774-2789).
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