142253-50-7|(S)-tert-Butyl 2-(cyanomethyl)pyrrolidine-1-carboxylate| Ambeed

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Quality Control of [ 142253-50-7 ] Purity: 97% SDS Specification

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Product Details of [ 142253-50-7 ]

CAS No. :	142253-50-7
Formula :	C₁₁H₁₈N₂O₂
M.W :	210.27
SMILES Code :	O=C(N1[C@H](CC#N)CCC1)OC(C)(C)C
MDL No. :	MFCD03094801
InChI Key :	GSNDDHMLFYORQI-VIFPVBQESA-N
Pubchem ID :	10727174

Safety of [ 142253-50-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 142253-50-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	0
Fraction Csp3	0.82
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	61.15
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.	2.31
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	1.36
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.92
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.	1.05
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	1.16
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.56

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.74
Solubility	3.86 mg/ml ; 0.0183 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.	-2.08
Solubility	1.74 mg/ml ; 0.00827 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	-1.49
Solubility	6.77 mg/ml ; 0.0322 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.	-6.62 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	0.0
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)	2.75

Application In Synthesis of [ 142253-50-7 ]

* 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 [ 142253-50-7 ]

[ 142253-50-7 ] Synthesis Path-Downstream 1~32

1
[ 151-50-8 ]
[ 86661-32-7 ]
[ 142253-50-7 ]

Yield	Reaction Conditions	Operation in experiment
66%	In dimethyl sulfoxide; at 90.0℃; for 6.5h;	c) _VBOC-(2>S)-2-Cyano-1-pyrrolidine. A mixture of -N-13OC-(2?)-2-([(4-methylphenyl)snlfonyl]oxy}methyl)-1-pyrrohdine (460 mg, 1 29mmol) and KCN (256 mg, 3.88 mmol) wore boated at 90 "C in DMSO (10 niL) for 6.5 h.The mixture was cooled to room temperature and IUtOAc and water were added. Theorganics were washed with water twice and then with brine. The aqueous layerswere extracted with EtOAc and the combined organics dried over NasSO*), filtered andconcentrated followed by flash chromatography purification to give ./V-BOC-(2S)-2-cyano-1-pyrrolidine (179 mg, 66%) as an oil. 1H NMR exists as rotomers(CDCl3) delta 3.99 (m, 1 H), 3.43-3.37 (m, 2 H), 2.83-2 51 (m, 2 H), 2.17-1.83 (m, 4 H), 1.46and 1,44 (s, 9 H rotomeric BOC £- butyl).

References: [1]Patent: WO2006/116764,2006,A1 .Location in patent: Page/Page column 121; 133.
[2]Tetrahedron Letters,1994,vol. 35,p. 8805 - 8808.
[3]Journal of Medicinal Chemistry,2002,vol. 45,p. 2571 - 2578.

2
[ 142253-50-7 ]
[ 239483-09-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With ammonia; hydrogen;dihydrogen hexachloroplatinate; nickel; In methanol; water; under 2068.65 Torr; for 24h;	Step d 2S-(2-Aminoethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The product of step c (1.45 g, 6.9 mmol) was suspended in methanol saturated with ammonia (50 ml), Raney-Nickel (ca. 1.0 g) and hydrogen hexachloroplatinate (IV) hydrate (80 mg dissolved in I ml of water) were added. The mixture was stirred in a Parr bottle under H2 pressure (about 40 psi) for 24 h. The reaction mixture was filtered through Celite and the filtrate was evaporated. The crude material was purified by flash chromatography (DCM:methanol:amonia (880) 90:10:1) to afford the title compound (1.18g, 80%). 1H NMR 3.90 (1H, m), 3.30 (2H, m), 2.71 (2H, t), 1.87-1.45 (17H, m).
50%	With ammonia; hydrogen;Raney-Ni; In ethanol; water; under 2585.81 Torr;	d) -V-BOC-(2S)-2-(2-Aminoethyl)-1-pyrrolidinc. A solution of NBOC- EPO <DP n="136"/>(2S) -2-cyano-1 -pyrrolidine (179 mg, 0.85 mmol) in ethanol saturated with anhydrousammonia was treated with Raney-Ni (1 mL of 50% aq. Suspension) and 50 psi of Hsovernight, The mixture was filtered through Cclitc and the filtrate was concentratedan vacuo. The residue was purified by flash chromatography (10% CH3OH/CH2CI2with 1% NH-iOH gradient elution) through a short plug of silica gel to give -7V-BOC-(2S)-2-(2-aminoethyl)-1-pyrrohdmo (90 mg, 50%) as a clear oil. 1H NMRexists as rotomers (CDCl3) delta 3.88-3,77 (m, 1 H), 3.33-3.24 (m, 2 H), 2.66 (m, 2 H),1.89- 1.54 (m, 6 H), 1.40 (s, 9 H),
	With ammonia; hydrogen;nickel; In methanol; for 14h;	a: Borane dimethylsulfide, THF, 14 h, RT b: METHANESULFONYLCHLORIDE, triethylamine, dichloromethane, 4 h, RT c: Sodium cyanide, DIMETHYLFORMAMIDE, 5 h, RT d: Raney nickel, ammonia gas in methanol, H2 2. 5 kg pressure, 14 h e: 1/ 1-methyl cinnamaldehyde, dichloromethane, 16 H, RT, N2 2/Sodium borohydride, methanol, 30 minutes at 0C Scheme 2: Preparation OF2- [2- (2-METHYL-3-PHENYL-ALLYLAMINO)-ETHYL- (S)-PYRROLIDINE-L-CARBOXYLIC acid tert-butyl ester [00138] Compound 2- [2- (2-Methyl-3-phenyl-allylamino)-ethyl- (S)- PYRROLIDINE-1-CARBOXYLIC acid tert-butyl ester (prepared from (S)-Pyrrolidine- 1, 2-DICARBOXYLIC ACID-1-TERT-BUTYL ester according to the scheme 2) 0.47 g (1.3 MMOL) and 3,4, 5-trimethoxy benzoic acid 0.3 g (1.6 MMOL) in dry dichloromethane 10ml, triethyl amine 0.1 ml was added and stirred at room temperature for 20 min. Then 1-DIMETHYLAMINOPROPYL-3-ETHYL CARBODIIMIDE 0.3 g (2 MMOL) and 1-hydroxybenzotriazole 0.018 g (0.13 MMOL) was added at 0C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and was washed with 10% sodium bicarbonate solution, water and brine, dried, concentrated and subjected to column chromatography (silica gel, n-hexane: ethylacetate as eluent) to yield 0.57 g 2-{2-[(2-METHYL-3-PHENYL-ALLYL)-3, 4,5-trimethoxy- BENZOYL)-AMINO]-ETHYL}-(S)-PYRROLIDINE-1-CARBOXYLIC acid tert-butyl ester (Yield : 76%). The compound 0.22 g (0.4 MMOL) was dissolved in 5ML of dry ether and 5ML of dry ether saturated with HCI was added at 0C. The reaction mixture was stirred at room temperature for 10 hrs. The ether was concentrated and the residue was washed with dry ether three to four times to yield 0.12 g as a white solid. Yield : 30%. [00139] LC-MSD, m/z for C26H34N204 [M+H] +: 439.3 [00140] 1H NMR (300 MHz, MeOD) : 8 1. 6-1.8 (m, 4 H), 2.0-2. 25 (m, 6H), 3.3-3. 5 (m, 3H), 3.2 (m, 3H), 3.5-4. 0 (m, 12H), 4.1 (s, 1H), 6.5 (s, 1H), 6.8-7. 0 (m, 2H), 7.2-7. 5 (m, 5H).

References: [1]Patent: EP1056733,2004,B1 .Location in patent: Page 34-35.
[2]Patent: WO2006/116764,2006,A1 .Location in patent: Page/Page column 121; 133-134.
[3]Tetrahedron Letters,1994,vol. 35,p. 8805 - 8808.
[4]Patent: WO2004/58705,2004,A2 .Location in patent: Page 40-42.
[5]Organic and Biomolecular Chemistry,2010,vol. 8,p. 3742 - 3750.

3
[ 143-33-9 ]
[ 132482-09-8 ]
[ 142253-50-7 ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 342 - 345.
[2]Bulletin de la Societe Chimique de France,1997,vol. 134,p. 713 - 718.

4
[ 142253-50-7 ]
[ 198493-30-0 ]

References: [1]Bulletin de la Societe Chimique de France,1997,vol. 134,p. 713 - 718.

5
[ 626-58-4 ]
[ 142253-50-7 ]
2-[2-(4-methyl-piperidin-1-yl)-ethyl]-pyrrolidine-1-carboxylic acid <i>tert</i>-butyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 342 - 345.

6
[ 142253-50-7 ]
2-[(2S)-pyrrolidin-2-yl]acetic acid hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 2571 - 2578.

7
[ 1004993-43-4 ]
[ 151-50-8 ]
[ 142253-50-7 ]

References: [1]Tetrahedron Asymmetry,2007,vol. 18,p. 2758 - 2767.

8
[ 15761-39-4 ]
Boc-MePhe-N(-CH₂-Merrifield resin)-Phe-OMeBoc-Leu-OH [ No CAS ]
[ 142253-50-7 ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 2571 - 2578.

9
[ 69610-40-8 ]
[ 142253-50-7 ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 2571 - 2578.
[2]Journal of Medicinal Chemistry,2000,vol. 43,p. 342 - 345.
[3]Bulletin de la Societe Chimique de France,1997,vol. 134,p. 713 - 718.
[4]Tetrahedron Letters,1994,vol. 35,p. 8805 - 8808.
[5]Patent: WO2014/71368,2014,A1 .
[6]Patent: WO2011/111875,2011,A1 .
[7]Patent: WO2016/196393,2016,A2 .
[8]Patent: WO2006/116764,2006,A1 .
[9]Journal of Organic Chemistry,2019,vol. 84,p. 1053 - 1063.

10
[ 84890-94-8 ]
[ 142253-50-7 ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 2571 - 2578.

11
[ 24424-99-5 ]
pentacarbonyl<1-<<(1R,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl>oxy>-(E)-3-phenyl-2-propenylidene>chromium [ No CAS ]
[ 142253-50-7 ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 342 - 345.

12
[ 142253-50-7 ]
4-Methyl-1-((S)-2-pyrrolidin-2-yl-ethyl)-piperidine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 342 - 345.

13
[ 142253-50-7 ]
(S)-4-methyl-1-(2-(1-(naphthalene-1-sulfonyl)-pyrrolidin-2-yl)-ethyl)-piperidine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 342 - 345.

14
[ 23356-96-9 ]
[ 142253-50-7 ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 342 - 345.
[2]Bulletin de la Societe Chimique de France,1997,vol. 134,p. 713 - 718.
[3]Journal of Organic Chemistry,2019,vol. 84,p. 1053 - 1063.

15
[ 24424-99-5 ]
[ 142253-50-7 ]

References: [1]Bulletin de la Societe Chimique de France,1997,vol. 134,p. 713 - 718.

16
[ 142253-50-7 ]
(S)-2-((4R,5R)-1,3-Dimethyl-4,5-diphenyl-imidazolidin-2-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Bulletin de la Societe Chimique de France,1997,vol. 134,p. 713 - 718.

17
[ 142253-50-7 ]
(S)-2-((4S,5S)-1,3-Dimethyl-4,5-diphenyl-imidazolidin-2-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Bulletin de la Societe Chimique de France,1997,vol. 134,p. 713 - 718.

18
[ 773837-37-9 ]
[ 132482-09-8 ]
[ 142253-50-7 ]

Yield	Reaction Conditions	Operation in experiment
	In DMF (N,N-dimethyl-formamide); at 20.0℃; for 5h;	a: Borane dimethylsulfide, THF, 14 h, RT b: METHANESULFONYLCHLORIDE, triethylamine, dichloromethane, 4 h, RT c: Sodium cyanide, DIMETHYLFORMAMIDE, 5 h, RT d: Raney nickel, ammonia gas in methanol, H2 2. 5 kg pressure, 14 h e: 1/ 1-methyl cinnamaldehyde, dichloromethane, 16 H, RT, N2 2/Sodium borohydride, methanol, 30 minutes at 0C Scheme 2: Preparation OF2- [2- (2-METHYL-3-PHENYL-ALLYLAMINO)-ETHYL- (S)-PYRROLIDINE-L-CARBOXYLIC acid tert-butyl ester [00138] Compound 2- [2- (2-Methyl-3-phenyl-allylamino)-ethyl- (S)- PYRROLIDINE-1-CARBOXYLIC acid tert-butyl ester (prepared from (S)-Pyrrolidine- 1, 2-DICARBOXYLIC ACID-1-TERT-BUTYL ester according to the scheme 2) 0.47 g (1.3 MMOL) and 3,4, 5-trimethoxy benzoic acid 0.3 g (1.6 MMOL) in dry dichloromethane 10ml, triethyl amine 0.1 ml was added and stirred at room temperature for 20 min. Then 1-DIMETHYLAMINOPROPYL-3-ETHYL CARBODIIMIDE 0.3 g (2 MMOL) and 1-hydroxybenzotriazole 0.018 g (0.13 MMOL) was added at 0C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and was washed with 10% sodium bicarbonate solution, water and brine, dried, concentrated and subjected to column chromatography (silica gel, n-hexane: ethylacetate as eluent) to yield 0.57 g 2-{2-[(2-METHYL-3-PHENYL-ALLYL)-3, 4,5-trimethoxy- BENZOYL)-AMINO]-ETHYL}-(S)-PYRROLIDINE-1-CARBOXYLIC acid tert-butyl ester (Yield : 76%). The compound 0.22 g (0.4 MMOL) was dissolved in 5ML of dry ether and 5ML of dry ether saturated with HCI was added at 0C. The reaction mixture was stirred at room temperature for 10 hrs. The ether was concentrated and the residue was washed with dry ether three to four times to yield 0.12 g as a white solid. Yield : 30%. [00139] LC-MSD, m/z for C26H34N204 [M+H] +: 439.3 [00140] 1H NMR (300 MHz, MeOD) : 8 1. 6-1.8 (m, 4 H), 2.0-2. 25 (m, 6H), 3.3-3. 5 (m, 3H), 3.2 (m, 3H), 3.5-4. 0 (m, 12H), 4.1 (s, 1H), 6.5 (s, 1H), 6.8-7. 0 (m, 2H), 7.2-7. 5 (m, 5H).

References: [1]Patent: WO2004/58705,2004,A2 .Location in patent: Page 40-42.
[2]Organic and Biomolecular Chemistry,2010,vol. 8,p. 3742 - 3750.

19
potassium cyanide [ No CAS ]
[ 86661-32-7 ]
[ 142253-50-7 ]

Yield	Reaction Conditions	Operation in experiment
57.5%	In dimethyl sulfoxide; at 110.0℃; for 3h;	Step c 2S-Cyanomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester. The product of step b (4.3 g, 12.1 mmol) and potassium cyanide (1.6 g, 24.2 mmol) were heated together in dimethyl sulfoxide at 110C for 3h. The reaction mixture was cooled to ambient temperature and poured into water (200 ml). The product was extracted with ethyl acetate (3x50 ml), the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate 70:30) to afford the the title compound as a colourless oil (1.46 g, 57.5%). 1H NMR 4.00 (1H, br s), 3.41 (2H,m), 2.74 (2H, m), 2.16 (1H, m), 1.92 (3H, m), 1.47 (9H, s).

References: [1]Patent: EP1056733,2004,B1 .Location in patent: Page 34.

Yield	Reaction Conditions	Operation in experiment
8.2 g (91.1%)		(S)-N-Boc-2-cyanomethylpyrrolidine (I-4): The mesylate salt of N-Boc-2-hydroxymethylpyrrolidine (12.0 g, 43.0 mmol) and NaCN (6.32 g) were mixed in 50 mL of DMSO and stirred at 55 C. for 20 hours. After cooling to room temperature, 200 mL of EtOAc was added and the mixture was washed successively with 10% aq. potassium carbonate (K2CO3, 1) and brine (2), dried with MgSO4 and filtered. The resulting solution was concentrated under reduced pressure. The residue was purified on a silica gel using hexane/EtOAc (1:1) to provide 8.2 g (91.1%) of the title product. 1H NMR (CDCl3, ppm): 1.43 (s, 9H); 1.75-2.05 (m, 3H); 2.13 (brd, 1H); 2.45-2.90 (m, 2H); 3.40 (m, 2H); 3.95 (brd, 1H). MS: 211 (M++1).
	In dimethyl sulfoxide; at 100.0℃; for 18h;	General procedure: Synthesis of Intermediate I-10 [0121] [0122] To a solution of I-1 (200 mg, 0.54 mmol) in DMSO (2.5 mL) was added KCN (71 mg, 1.1 mmol). The mixture was heated at 100 C. for 18 h then cooled to ambient temperature and partitioned between EtOAc and water. The organics were collected, dried over MgSO4, filtered and concentrated in vacuo to afford I-10 (quant, 120 mg). m/z 223.1 [M+H]

21
[ 773837-37-9 ]
[ 86661-32-7 ]
[ 142253-50-7 ]

Yield	Reaction Conditions	Operation in experiment
66%	In dimethyl sulfoxide; at 100.0℃; for 4h;	Intermediate 5(S)-tert-Butyl 2-(cyanomethyl)pyrrolidine- 1 -carboxy late[0231][Chemical Formula 36]To a solution of intermediate 6 (90.4 g, 255 mmol) in dimethylsulfoxide (255 mL) was added sodium cyanide (16.2 g, 331 mmol), and heated to 100C. After stirring for 4 hours, to the mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (hexane/ethyl acetate = 70/30 to 30/70) to give the title compound (35.2 g, 168 mmol, 66%).MS (ESI+) 211 (M++l, 100%)
		Intermediate 139: ferf-Butyl (S)-2-cyanomethylpyrrolidine-l-carboxylate[00485] Sodium cyanide (8.2g) was added to a solution of ferf-butyl (S)-2-(4- methylbenzenesulfonyloxymethyl)pyrrolidine-l-carboxylate (Intermediate 140, 29.6g) in DMSO (300mL) and the resultant mixture was stirred and heated at 90C for 5.5 hours. After cooling, the mixture was treated with saturated aqueous iron (II) sulphate solution and the mixture was stirred for a further 5 hours then extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SC>4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether (5%) to give ferf-butyl (S)-2-cyanomethylpyrrolidine-l-carboxylate (13.0g) as a light yellow oil which was used without further characterisation.
13.0 g		Intermediate 139: tert-Butyl (S)-2-cyanometh lpyrrolidine- 1 -carboxylate [00410] Sodium cyanide (8.2g) was added to a solution of tert-butyl (S)-2-(4- methylbenzenesulfonyloxymethyl)pyrrolidine-l -carboxylate (Intermediate 140, 29.6g) in DMSO (300mL) and the resultant mixture was stirred and heated at 90C for 5.5 hours. After cooling, the mixture was treated with saturated aqueous iron (II) sulphate solution and the mixture was stirred for a further 5 hours then extracted with ethyl acetate. The organic layer was washed with brine, dried ( a2S04) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether (5%) to give tert-butyl (S)-2-cyanomethylpyrrolidine- 1 -carboxylate (13.0g) as a light yellow oil which was used without further characterisation.

1.77 g

In dimethyl sulfoxide; at 90.0℃;Inert atmosphere;

Step 2: (S)-tert-butyl 2-(cyanomethyl)pyrrolidine-l-carboxylate [00277] To a solution of (S)-tert-butyl 2-(tosyloxymethyl)pyrrolidine-l-carboxylate (4.2 g) in DMSO (36 mL) was added sodium cyanide (0.97 g, 19.9 mmol). The reaction mixture was stirred at 90C under argon overnight. After cooled to room temperature, the reaction mixture was treated with saturated FeS04 solution (50 mL) at room temperature for another 5 hours and then extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with saturated NaCl solution (30 mL) and dried over Na2S04. Silica-gel chromatography with 25% EtOAc/Hexane gave the desired product (1.77 g, 84.7% overall yield for steps 1 & 2) as a colorless oil.

References: [1]Journal of Organic Chemistry,2019,vol. 84,p. 1053 - 1063.
[2]Patent: WO2011/111875,2011,A1 .Location in patent: Page/Page column 63-64.
[3]Patent: WO2012/154676,2012,A1 .Location in patent: Page/Page column 180.
[4]Patent: WO2014/71368,2014,A1 .Location in patent: Paragraph 00410.
[5]Patent: WO2016/196393,2016,A2 .Location in patent: Paragraph 00277.

22
[ 142253-50-7 ]
[ 1413085-67-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; at 40.0℃;	Intermediate 138: ((S)-Pyrrolidin-2-yl)a hydrochlorideHCI [00484] A solution of ferf-butyl (S)-2-cyanomethylpyrrolidine-l-carboxylate(Intermediate 139, 13.0g) in methanol (130mL) and concentrated hydrochloric acid (13mL) was stirred and heated at 40C overnight. After cooling, the mixture was concentrated under vacuum and the residue was diluted with toluene and reconcentrated. Ethanol (20mL) was added and the resultant solid was collected by filtration and washed with hexane to give ((S)- pyrrolidin-2-yl)acetonitrile hydrochloride (8.0g) as a white solid.LCMS (Method D) r/t 0.50 (M+H) 111.
8.0 g	With hydrogenchloride; water; In methanol; at 40.0℃;	Intermediate 138: ((S)-Pyrrolidin-2-yl)acetonitrile h drochloride HCI [00409] A solution of tert-butyl (S)-2-cyanomethylpyrrolidine- 1 -carboxylate (Intermediate 139, 13. Og) in methanol (130mL) and concentrated hydrochloric acid (13mL) was stirred and heated at 40C overnight. After cooling, the mixture was concentrated under vacuum and the residue was diluted with toluene and reconcentrated. Ethanol (20mL) was added and the resultant solid was collected by filtration and washed with hexane to give ((S)- pyrrolidin-2-yl)acetonitrile hydrochloride (8.0g) as a white solid. LCMS (Method D) r/t 0.50 (M+H) 1 11.
	With hydrogenchloride; water; In methanol; at 40.0℃;	Step 3 : tert-butyl 3-oxopropylcarbamate [00278] To a solution of (S)-tert-butyl 2-(cyanomethyl)pyrrolidine-l-carboxylate (1.77 g, 4.45 mmol) in methanol (18 mL) was added 12N HC1 (1.8 mL). The reaction mixture was stirred at 40C overnight. The solvent was removed under reduced pressure, the resulting residue was co-evaporated with toluene twice and high vacuum to give (S)-2-(pyrrolidin-2- yl)acetonitrile hydrochloride (1.35 g) as a white solid, which was used in the next step without further purification.

References: [1]Patent: WO2012/154676,2012,A1 .Location in patent: Page/Page column 179; 180.
[2]Patent: WO2014/71368,2014,A1 .Location in patent: Paragraph 00409.
[3]Patent: WO2016/196393,2016,A2 .Location in patent: Paragraph 00278.

23
tert-butyl (S)-2-hydroxyoxymethylpyrrolidine-1-carboxylate [ No CAS ]
[ 142253-50-7 ]

References: [1]Patent: WO2012/154676,2012,A1 .

24
[ 15761-39-4 ]
[ 142253-50-7 ]