228244-04-0|(S)-tert-Butyl 2-cyanopyrrolidine-1-carboxylate| Ambeed

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Quality Control of [ 228244-04-0 ] Purity: 96% SDS Specification

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Product Details of [ 228244-04-0 ]

CAS No. :	228244-04-0
Formula :	C₁₀H₁₆N₂O₂
M.W :	196.25
SMILES Code :	N#C[C@H]1N(C(OC(C)(C)C)=O)CCC1
MDL No. :	MFCD01861224
InChI Key :	MDMSZBHMBCNYNO-QMMMGPOBSA-N
Pubchem ID :	6951263

Safety of [ 228244-04-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302+H312+H332-H315-H319
Precautionary Statements:	P261-P264-P280-P337+P313-P302+P352+P312-P304+P340+P312

Computational Chemistry of [ 228244-04-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	0
Fraction Csp3	0.8
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	56.34
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	53.33 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.36
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.42
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.53
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.76
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.77
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.37

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.75
Solubility	3.46 mg/ml ; 0.0176 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.14
Solubility	1.41 mg/ml ; 0.00717 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.08
Solubility	16.1 mg/ml ; 0.0822 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.49 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.63

Application In Synthesis of [ 228244-04-0 ]

* 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.

Downstream synthetic route of [ 228244-04-0 ]

[ 228244-04-0 ] Synthesis Path-Downstream 1~35

1
[ 67-56-1 ]
[ 228244-04-0 ]
(2S)-N-(tert-butoxycarbonyl)pyrrolidine-2-carboximidic acid methyl ester [ No CAS ]

References: [1]Tetrahedron Asymmetry,1999,vol. 10,p. 573 - 585.
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6340 - 6345.

2
[ 76-05-1 ]
[ 228244-04-0 ]
(S)-pyrrolidine-2-carbonitrile trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 0℃; for 2.33333h;Inert atmosphere;	Boc-2(S)-cyanopyrrolidine was synthesized according to a literature procedure [39]. TFA (20mL, 260mmol) was added dropwise to a solution of Boc-2(S)-cyanopyrrolidine (0.99g, 5.0mmol) in DCM (60mL) under argon at 0C. After 2h 20min the solvent was evaporated yielding the TFA salt of 2(S)-cyanopyrrolidine, which was used directly in the reaction below.

References: [1]Angewandte Chemie - International Edition,2017,vol. 56,p. 10750 - 10754.
Angew. Chem.,2017,vol. 129,p. 10890 - 10894,5.
[2]Canadian Journal of Chemistry,2007,vol. 85,p. 85 - 95.
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 6672 - 6684.
[4]Journal of Medicinal Chemistry,2003,vol. 46,p. 4543 - 4551.
[5]Journal of Medicinal Chemistry,2005,vol. 48,p. 4772 - 4782.
[6]Journal of Medicinal Chemistry,2011,vol. 54,p. 3524 - 3548.
[7]European Journal of Medicinal Chemistry,2014,vol. 79,p. 436 - 445.

3
[ 35150-07-3 ]
[ 228244-04-0 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 1,3,5-trichloro-2,4,6-triazine; In N,N-dimethyl-formamide; at 20℃; for 1h;	General procedure: A mixture of compound 2 (5 g, 23.3 mmol) and cyanuric chiloride (2.58 g, 14.0 mmol) in DMF (10 mL) was stirred at room temperature for 1 h (monitored by TLC). After the reaction completed, the solution was extracted with EtOAc, washed, dried, concentrated, and purified by flash chromatography on silica gel, eluted with a mixture of PE/EA (1/1, v/v), to afford 3 (3.48 g, 76%) as a white solid. 1H NMR (300 MHz, CDCl3) delta 4.76 (s, 1H), 3.51 (s, 2H), 2.34-2.31 (m, 1H), 2.17-2.10 (m, 2H), 1.90-1.87 (m, 1H), 1.49 (s, 9H). MS (ESI) m/z 197 [M+H]+.
76%	With 1,3,5-trichloro-2,4,6-triazine; In N,N-dimethyl-formamide; at 20℃; for 1h;	A mixture of compound 9 (5 g, 23.3 mmol) and cyanuric chiloride (2.58 g, 14.0 mmol) in DMF (10 mL) was stirred at roomtemperature for 1 h (monitored by TLC). After the reaction completed, thesolution was extracted with EtOAc, washed, dried, concentrated, and purified byflash chromatography on silica gel, eluted with a mixture of PE/EA (1/1, v/v)to afford 10 (3.48 g, 76%) as a white solid. 1H NMR (CDCl3,300 MHz): delta4.76(s, 1H), 3.51 (s, 2H), 2.34-2.31 (m, 1H), 2.17-2.10 (m, 2H), 1.90-1.87 (m, 1H),1.49 (s, 9H). MS (ESI) m/z 197[M+H]+.
	With 1,3,5-trichloro-2,4,6-triazine; N,N-dimethyl-formamide; In dichloromethane; at 20 - 40℃;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

55 g

With triethylamine; trifluoroacetic anhydride; In dichloromethane; at -15℃; for 3h;

step 1:The first reaction solution containing the compound represented by Formula II was cooled to -15.0 C., 30.0 g of triethylamine,A dichloromethane solution containing 0.357 mol of trifluoroacetic anhydride (TFAA) was added dropwise,Dropping time 2h, after the addition was completed, incubated for 1h,Insulation temperature was -15.0 , TLC monitoring showed that the reaction was completed;Step 2: To the solution in Step 1 was added purified water 100mL, washed and stratified;The pH was adjusted to 1 with 1 M hydrochloric acid, the temperature was controlled below 0 C,Stirring for 30-45min, standing stratification;Step 3: The mass concentration of 5% -10% dilute salt water 100mL wash phase;The organic layer was dried over sodium sulfate, filtered and the methylene chloride removed under reduced pressure.55.0 g (0.280 mol) of an oil was obtained as a compound of the formula III.

References: [1]Journal of Agricultural and Food Chemistry,2012,vol. 60,p. 8544 - 8551.
[2]Canadian Journal of Chemistry,2007,vol. 85,p. 85 - 95.
[3]Synthetic Communications,2009,vol. 39,p. 395 - 406.
[4]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7418 - 7429.
[5]European Journal of Medicinal Chemistry,2014,vol. 75,p. 111 - 122.
[6]Tetrahedron,2009,vol. 65,p. 9536 - 9541.
[7]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5257 - 5261.
[8]Journal of Medicinal Chemistry,2009,vol. 52,p. 6672 - 6684.
[9]Tetrahedron,2010,vol. 66,p. 6718 - 6724.
[10]Journal of Medicinal Chemistry,2011,vol. 54,p. 3524 - 3548.
[11]Letters in Organic Chemistry,2013,vol. 10,p. 159 - 163.
[12]Patent: WO2014/20462,2014,A1 .Location in patent: Page/Page column 9.
[13]Patent: CN107033054,2017,A .Location in patent: Paragraph 0070; 0071; 0075; 0076-0082; 0111; 0115-0118.
[14]Russian Journal of Bioorganic Chemistry,2019,vol. 45,p. 374 - 380.
Bioorg. Khim.,2019,vol. 45,p. 374 - 380,7.

4
[ 228244-04-0 ]
[ 681239-91-8 ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 4953 - 4975.

5
[ 15761-39-4 ]
Fmoc-Glu(tBu)-OHFmoc-Lue-OH [ No CAS ]
[ 228244-04-0 ]

References: [1]Canadian Journal of Chemistry,2007,vol. 85,p. 85 - 95.

6
[ 228244-04-0 ]
(2'S)-5-<2'-N-(tert-butoxycarbonyl)pyrrolidinyl>-3,6-bis(trifluoromethyl)-1,2,4-triazine [ No CAS ]

References: [1]Tetrahedron Asymmetry,1999,vol. 10,p. 573 - 585.

7
[ 228244-04-0 ]
[ 867326-86-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium azide; ammonium chloride; In DMF (N,N-dimethyl-formamide); at 93℃;	Example 7 (S)-2-(1H-Tetrazol-5-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (A). To a solution of (S)-2-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.55 mmol) in N,N-dimethyl-formamide (20 mL) is added sodium azide (174 mg, 2.68 mmol) and ammonium chloride (150 mg, 2.81 mmol). The solution is stirred at 93 C. over night. The solution is poured into 5% citric acid solution with ice, and the mixture is extracted with EtOAc. The organic extract is washed with brine, dried and concentrated under vacuum. The crude oil is used directly in the next step without further purification. M+H+=240.
	With diethylaluminum azide; In toluene; at 20 - 40℃; for 20 - 30h;Product distribution / selectivity;	Example 2: 2-(1 H-Tetrazol-5-yl)pyrrolidine-1- carboxylic acid tert-butyl ester390 mg of granular sodium azide (6mmol) are added at 0 0C to a solution of 2.4 ml of diethyl aluminium chloride (6 mmol, 2.5 molar in toluene) and the mixture is stirred at room temperature for 4 to 7 hours. 981 mg of 2-cyano-pyrrolidine-1 -carboxylic acid t-butyl ester (5 mmol) are added to the diethyl aluminum azide solution at r.t. The mixture is stirred 20 to 30 h at 400C. After complete conversion the mixture is added dropwise to a cold solution (0 0C) of 25 ml of KHSO4 (10%) containing 1.24 g of NaNO2(18 mmol), and extracted four times with 25 ml portion of ethyl acetate. The solvent is removed to give 1.4 g of the crude product which is dissolved again in 20 ml of ethyl acetate. This phase is washed several times with K2CO3 (10%) to extract the product to the aqueous phase as the potassium salt. The basic aqueous phase is carefully treated at 0 0C with KHSO4 solution to pH 5 to avoid the degradation of the Boc-group and the product is then extracted several times with portions of ethyl acetate. The solvent is removed to give the product as a white solid. EPO <DP n="28"/>EI-MS: 238;140 m/z; [g£ = -75.68 (in MeOH1 c= 0.63); TLC: (Eluent: toluene / etylacetate / acetic acid 20:20:1): Rf= 0.22; \|R: s1669 cm"1; s1423 cm"1;m 1372 cm"1; 1160 cm"1; Raman: ml 553cm"1; s1450 cm 1;1H-NMR (500MHz; DMSO): 120C: 1.29 ppm (s, 9H); 1.91 ppm (m, 3H); 2.34 ppm (m, 1 H); 3.49 ppm (m, 2H); 5.1 ppm ( m, 1H);
	With diethylaluminum azide; In toluene; xylene; at 0 - 45℃; for 8 - 14h;Product distribution / selectivity;	Example 2: 2-(1 H-Tetrazol-5-yl)pyrrolidine-1- carboxylic acid tert-butyl ester390 mg of granular sodium azide (6mmol) are added at 0 0C to a solution of 2.4 ml of diethyl aluminium chloride (6 mmol, 2.5 molar in toluene) and the mixture is stirred at room temperature for 4 to 7 hours. 981 mg of 2-cyano-pyrrolidine-1 -carboxylic acid t-butyl ester (5 mmol) are added to the diethyl aluminum azide solution at r.t. The mixture is stirred 20 to 30 h at 400C. After complete conversion the mixture is added dropwise to a cold solution (0 0C) of 25 ml of KHSO4 (10%) containing 1.24 g of NaNO2(18 mmol), and extracted four times with 25 ml portion of ethyl acetate. The solvent is removed to give 1.4 g of the crude product which is dissolved again in 20 ml of ethyl acetate. This phase is washed several times with K2CO3 (10%) to extract the product to the aqueous phase as the potassium salt. The basic aqueous phase is carefully treated at 0 0C with KHSO4 solution to pH 5 to avoid the degradation of the Boc-group and the product is then extracted several times with portions of ethyl acetate. The solvent is removed to give the product as a white solid. EPO <DP n="28"/>EI-MS: 238;140 m/z; [g£ = -75.68 (in MeOH1 c= 0.63); TLC: (Eluent: toluene / etylacetate / acetic acid 20:20:1): Rf= 0.22; \|R: s1669 cm"1; s1423 cm"1;m 1372 cm"1; 1160 cm"1; Raman: ml 553cm"1; s1450 cm 1;1H-NMR (500MHz; DMSO): 120C: 1.29 ppm (s, 9H); 1.91 ppm (m, 3H); 2.34 ppm (m, 1 H); 3.49 ppm (m, 2H); 5.1 ppm ( m, 1H);

References: [1]Angewandte Chemie - International Edition,2007,vol. 46,p. 8440 - 8444.
[2]Patent: US2005/234042,2005,A1 .Location in patent: Page/Page column 27.
[3]Patent: WO2007/9716,2007,A1 .Location in patent: Page/Page column 26-27.
[4]Patent: WO2007/9716,2007,A1 .Location in patent: Page/Page column 29-30.

8
[ 79-37-8 ]
[ 35150-07-3 ]
[ 228244-04-0 ]

Yield	Reaction Conditions	Operation in experiment
66%	With pyridine; In ethyl acetate; N,N-dimethyl-formamide; acetonitrile;	Preparation 116 tert-butyl (2S)-2-cyano-1-pyrrolidinecarboxylate A solution of oxalyl chloride (11.0 ml, 0.126 mol) and DMF (11.4 ml, 0.138 mol) in MeCN (170 ml) was treated dropwise with a solution of N-Boc-L-proline amide (12.3 g, 0.57mol) and pyridine (20.4 ml, 0.253 mol) in MeCN (30 ml) at 0 C. and stirred at this temperature for 15 minutes. The reaction mixture was diluted with EtOAc and washed with H2O (*3). The organic extract was dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was purified on a silica column eluding with a solvent gradient of pentane:EtOAc (80:20) gradually changing to (60:40) to afford the title compound (7.40 g, 66%). 1H nmr: (d6DMSO) 1.40 (9H, s), 1.88 (2H, brs), 2.05-2.30 (2H, m), 3.21 (1H, m), 3.35 (1H, brs), 4.60 (1H, d). MS: 214 (MNH4+)

References: [1]Patent: US2002/151535,2002,A1 .

9
[ 104-15-4 ]
[ 228244-04-0 ]
[ 204387-54-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	In water; acetonitrile; for 24h;	General procedure: A solution of compound 3 (10.0 g, 50.96 mmol) in CH3CN (50 mL) was added 4-methylbenzenesulfonic acid hydrate (14.54 g, 76.43 mmol) and stirred at room temperature for 24 h. After the reaction completed, the solution was removed in vacuo. The residual white solid was dissolved in EtOAc (100 mL) and put into fridge overnight, the product 4 (10.3 g, 75%) was precipitated as a white needle crystal. 1H NMR (300 MHz, CD3OD) delta 7.77 (d, J = 7.8 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 4.76-4.75 (m, 1H), 3.51-3.50 (m, 2H), 2.38 (s, 3H), 2.34-2.31 (m, 1H), 2.17-2.09 (m, 2H), 1.90-1.87 (m, 1H). MS (ESI) m/z 97 [M+H]+
75%	In acetonitrile; at 20℃; for 24h;	A solution of compound 10 (10.0 g, 50.96mmol) in CH3CN (50 mL) was added 4-methylbenzenesulfonic acidhydrate (14.54 g, 76.43mmol) and stirred at room temperature for 24 h. After the reaction completed,the solution was removed in vacuo.The residual white solid was dissolved in EtOAc (100 mL) and put into fridgeovernight, the product 11 (10.3 g, 75%) was precipitated as a white needlecrystal. 1H NMR (CD3OD, 300 MHz): delta 7.77 (d, J = 7.8 Hz, 2H), 7.20 (d, J= 8.1 Hz, 2H), 4.76-4.75 (m, 1H), 3.51-3.50 (m, 2H), 2.38 (s, 3H), 2.34-2.31(m, 1H), 2.17-2.09 (m, 2H), 1.90-1.87 (m, 1H). MS (ESI) m/z 97[M+H]+.

References: [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7418 - 7429.
[2]European Journal of Medicinal Chemistry,2014,vol. 75,p. 111 - 122.
[3]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5257 - 5261.

10
[ 228244-04-0 ]
[ 867326-86-1 ]

References: [1]Synthetic Communications,2009,vol. 39,p. 395 - 406.

11
[ 228244-04-0 ]
[ 681239-91-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; sodium hydrogencarbonate; In methanol; at 20 - 60℃; for 1.5h;	Hydroxylamine HCI (429 mg, 6.1 1 mmol) was added to a rt solution of (S)-1-Boc-pyrrolidine-2- carbonitrile (800 mg, 4.08 mmol), and NaHC03 (514 mg, 6.1 1 mmol) in MeOH (10 ml_). The resulting suspension was stirred at 60C for 1 .5h, then filtered (washed with MeOH) and concentrated in vacuo to yield the title compound D-1 as a white solid that was used further without purification. LC-MS B: tR = 0.36 min; [M+H]+ = 230.1 1.

References: [1]ChemMedChem,2020.
[2]Tetrahedron,2009,vol. 65,p. 9536 - 9541.
[3]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6340 - 6345.
[4]Patent: WO2014/57435,2014,A1 .Location in patent: Page/Page column 117.

13
[ 228244-04-0 ]
[ 119020-01-8 ]

References: [1]Tetrahedron,2010,vol. 66,p. 6718 - 6724.

14
[ 15761-39-4 ]
[ 228244-04-0 ]

Yield	Reaction Conditions	Operation in experiment
50%		To a flame dried flask was added 2 grams (9.3 mmols) of N-Boc proline followed by 93 ml, of dichloromethane and 4.24 grams (41.85 mmols) of triethylamine. The reaction mixture was then cooled to -25 C. and 2.5 grams (18.6 mmols) of iso-butylchloroformate was added dropwise. After stirring for 45 minutes at this low temperature, 0.83 grams (49 mmol) of ammonia was added to the reaction mixture as a 7N solution in methanol. The flask was allowed to warm to ambient temperature and stir for an additional 16 hours. After this time, the reaction mixture was evaporated to dryness and reconstituted in 200 mL of EtOAc. The organic layer was washed four 15 mL portions of 1N HCl, dried with MgSO4 and evaporated to dryness. The crude material was then immediately dehydrated to the nitrile according to general procedure E using 1.9 grams (18.88 mmols) of triethylamine and 2.34 grams (11.16 mmols) of trifluoroacetic anhydride in 93 mL of THF. After standard work-up and purification techniques (column chromatography, 25% EtOAc in hexanes), 0.91 grams (4.65 mmols, 50%) of the title product was recovered as a yellow oil. 1H NMR (300 MHz, CDCl3) delta 4.53 (d, J=5.5 Hz, 0.5H), 4.48-4.38 (m, 0.5H), 3.57-3.41 (m, 1H), 3.41-3.22 (m, 1H), 2.31-1.92 (m, 4H), 1.47 (d, J=9.4 Hz, 9H). 13C NMR (75 MHz, CDCl3) delta 153.25, 119.38, 81.64, 47.39, 45.93, 31.86, 31.01, 28.52, 24.88, 24.04.

References: [1]Patent: US2012/214858,2012,A1 .Location in patent: Page/Page column 27-28.
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 3524 - 3548.
[3]Journal of Agricultural and Food Chemistry,2012,vol. 60,p. 8544 - 8551.
[4]European Journal of Organic Chemistry,2013,p. 5886 - 5892.
[5]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7418 - 7429.
[6]European Journal of Medicinal Chemistry,2014,vol. 75,p. 111 - 122.
[7]Russian Journal of Bioorganic Chemistry,2019,vol. 45,p. 374 - 380.
Bioorg. Khim.,2019,vol. 45,p. 374 - 380,7.

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[ 24424-99-5 ]
[ 228244-04-0 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3524 - 3548.
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 3524 - 3548.
[3]Journal of Agricultural and Food Chemistry,2012,vol. 60,p. 8544 - 8551.
[4]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7418 - 7429.
[5]European Journal of Medicinal Chemistry,2014,vol. 75,p. 111 - 122.
[6]Russian Journal of Bioorganic Chemistry,2019,vol. 45,p. 374 - 380.
Bioorg. Khim.,2019,vol. 45,p. 374 - 380,7.

16
[ 37784-17-1 ]
[ 228244-04-0 ]