190141-99-2|tert-Butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate| Ambeed

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Quality Control of [ 190141-99-2 ] Purity: 95% SDS Specification

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Product Details of [ 190141-99-2 ]

CAS No. :	190141-99-2
Formula :	C₉H₁₈N₂O₃
M.W :	202.25
SMILES Code :	O=C(N1CC(N)C(O)C1)OC(C)(C)C
MDL No. :	MFCD14705159
InChI Key :	MOZOQDNRVPHFOO-UHFFFAOYSA-N
Pubchem ID :	11229445

Safety of [ 190141-99-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 190141-99-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	0
Fraction Csp3	0.89
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	55.66
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	75.79 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.93
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	-0.61
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-0.46
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.	-0.27
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	-0.83
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	-0.05

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.51
Solubility	62.3 mg/ml ; 0.308 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.	-0.51
Solubility	62.5 mg/ml ; 0.309 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	0.16
Solubility	295.0 mg/ml ; 1.46 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	No
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.	-7.97 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)	3.13

Application In Synthesis of [ 190141-99-2 ]

* 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 [ 190141-99-2 ]

[ 190141-99-2 ] Synthesis Path-Downstream 1~28

1
[ 24424-99-5 ]
[ 190141-99-2 ]
[ 203434-46-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	In dichloromethane; for 4.0h;	Preparation Example 1-114-23-tert-Butoxycarbonylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester To 2.93 g (15.80 mmol) of the compound obtained from Preparation Example 1-114-1 was added 25 mL of ammonia water and stirred at 60 C. for 15 hours. The reaction solution was distilled in vacuo, diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate (MgSO4) and distilled in vacuo. To the residue was added 30 mL of dichloromethane and 14.21 g (65.10 mmol) of di tert-butyl dicarbonate and stirred for 4 hours. The reaction solution was distilled in vacuo and purified by column chromatography using a mixed solution of dichloromethane and methanol in the ratio of 95:5 to obtain the title compound 2.95 g (2-step 62%).1H NMR (400 MHz, CDCl3); delta 4.67 (1H, br), 4.21 (1H, br), 3.91 (1H, br), 3.76 (2H, br), 3.27 (1H, br), 3.17 (1H, br), 1.44 (18H, s)

References: [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 221 - 226.
[2]Patent: US2011/166121,2011,A1 .Location in patent: Page/Page column 67-68.

2
[ 203434-45-1 ]
[ 190141-99-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 221 - 226.

3
[ 2018-66-8 ]
[ 190141-99-2 ]
[ 190142-00-8 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 725 - 736.

4
[ 33099-08-0 ]
[ 190141-99-2 ]
3-[2-(benzyloxycarbonyl-methyl-amino)-4-methyl-pentanoylamino]-4-hydroxy-pyrrolidine-1-carboxylic acid <i>tert</i>-butyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 725 - 736.

5
[ 73286-70-1 ]
[ 190141-99-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 221 - 226.
[2]Patent: US2011/166121,2011,A1 .
[3]Patent: EP3543227,2019,A1 .

6
[ 114214-49-2 ]
[ 190141-99-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With ammonia; In water;Reflux;	The mixture of tert-butyl 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (20 g, 0.11 mol) and aqueous ammonia (200 mL) was heated overnight at reflux. The reaction was concentrated in vacuo to afford the product tert-butyl 3-amino-4- hydroxypyrrolidine-1-carboxylate (21 g, 96%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): delta 3.98-3.97 (m, IH), 3.75-3.61 (m, 2H), 3.36-3.22 (m, 2H), 3.08-3.17 (m, IH), 1.45 (s, 9H).
		Reference O; Synthesis of 3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester; 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tart-butyl ester (12.1 g, 65.3 mmol) was dissolved in a 8:1 methanol/water mixture (108 mL). Ammonium chloride (15 g) andsodium azide (21.4 g, 329 mmol) was added and the reaction mixturewas heated at 60 Covernight. After dilution with ether (500 mL), the reaction mixturewas washed with saturatedaqueous NaHCOs (200 mL) and brine (200 mL), dried with MgSC>4 and evaporated undervacuum. The crude product was dissolved in methanol (200 mL). 10% Palladium on activatedcarbon (1.5 g) was added and the reaction mixturewas stirred at ambient temperature under ahydrogen atmosphere until TLC analysis showed the disappearance of the starting material. Thereaction mixture was filtered through a pad of Celite and evaporated to dryness under vacuum.The product was purified by flash chromatography on silica gel using 5% methanol in ethylacetate to 20% methanol, 3% triethylamine in ethyl acetate to give 4.3 g of 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-bntyl ester as yellowish solid.
		Reference M Synthesis OF 3-AMINO-4-HYDROXOPYRROLIDINE-1-CARBOXYLIC acid TERT-BUTYL ester 6-Oxa-3-aza-bicyclo [3.1. 0] hexane-3-carboxylic acid tert-butyl ester (12.1 g, 65.3 mmol) was dissolved in a 8: 1 methanol/water mixture (108 mL). Ammonium chloride (15 g) and sodium azide (21.4 g, 329 mmol) was added and the reaction mixturewas heated at 60 C overnight. After dilution with ether (500 mL), the reaction mixture was washed with saturated aqueous NAHCO3 (200 mL) and brine (200 ML), dried with MgS04 and evaporated under vacuum. The crude product was dissolved in methanol (200 mL). 10% Palladium on activated carbon (1.5 g) was added and the reaction mixturewas stirred at ambient temperature under a hydrogen atmosphere until TLC analysis showed the disappearance of the starting material. The reaction mixture was filtered through a pad OF CELITETM and evaporated to dryness under vacuum. The product was purified by flash chromatography on silica gel using 5% methanol in ethyl acetate to 20% methanol, 3% triethylamine in ethyl acetate to give 4.3 g of 3-amino-4- hydroxy-pyrrolidine-1-carboxylic acid TERT-BUTYL ester as yellowish solid.

		Reference N Synthesis [OF 3-AMINO-4-HYDROXOPYRROLIDINE-1-CARBOXYLIC] acid [TERT-BUTYL] ester 6-Oxa-3-aza-bicyclo [3.1. 0] hexane-3-carboxylic acid [TERT-BUTYL] ester (12.1 g, 65.3 mmol) was dissolved in a 8: 1 methanol/water mixture (108 mL). Ammonium chloride (15 g) and sodium azide (21.4 g, 329 mmol) was added and the reaction mixturewas heated at [60 C] overnight. After dilution with ether (500 mL), the reaction mixturewas washed with saturated aqueous [NAHCO3] (200 mL) and brine (200 mL), dried with MgS04 and evaporated under vacuum. The crude product was dissolved in methanol (200 mL). 10% Palladium on activated carbon (1.5 g) was added and the reaction mixturewas stirred at ambient temperature under a hydrogen atmosphere until TLC analysis showed the disappearance of the starting material. The reaction mixture was filtered through a pad of Celite and evaporated to dryness under vacuum. The product was purified by flash chromatography on silica gel using 5% methanol in ethyl acetate to 20% methanol, 3% triethylamine in ethyl acetate to give 4.3 g [OF 3-AMINO-4-HYDROXY-PYRROLIDINE-1-CARBOXYLIC] acid [TERT-BUTYL] ester as yellowish solid.
	With ammonia; In water; at 60℃; for 15.0h;	Preparation Example 1-114-23-tert-Butoxycarbonylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester To 2.93 g (15.80 mmol) of the compound obtained from Preparation Example 1-114-1 was added 25 mL of ammonia water and stirred at 60 C. for 15 hours. The reaction solution was distilled in vacuo, diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate (MgSO4) and distilled in vacuo. To the residue was added 30 mL of dichloromethane and 14.21 g (65.10 mmol) of di tert-butyl dicarbonate and stirred for 4 hours. The reaction solution was distilled in vacuo and purified by column chromatography using a mixed solution of dichloromethane and methanol in the ratio of 95:5 to obtain the title compound 2.95 g (2-step 62%).1H NMR (400 MHz, CDCl3); delta 4.67 (1H, br), 4.21 (1H, br), 3.91 (1H, br), 3.76 (2H, br), 3.27 (1H, br), 3.17 (1H, br), 1.44 (18H, s)
8 g	With ammonium hydroxide; at 90℃; for 4.0h;	A solution of Example 34A (9.0 g , 48.59 mmol) in 90 ml ammonia water was heated to 90C and stirred for 4hours. The reaction solution became reddish brown. The reaction solution was rotatory evaporated until dry, into whichwere added dichloromethane 200 ml and methanol 20 ml, the mixture was dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated to give the product Example 34B (8 g) as a reddish brown oil, which was useddirectly in the next step.

References: [1]Patent: WO2010/114971,2010,A1 .Location in patent: Page/Page column 153.
[2]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 221 - 226.
[3]Patent: WO2004/108661,2004,A1 .Location in patent: Page/Page column 48-49.
[4]Patent: WO2005/28454,2005,A1 .Location in patent: Page/Page column 50-51.
[5]Patent: WO2004/838,2003,A1 .Location in patent: Page 71.
[6]Patent: US2011/166121,2011,A1 .Location in patent: Page/Page column 67-68.
[7]Patent: EP3543227,2019,A1 .Location in patent: Paragraph 0412-0413.

7
[ 190141-99-2 ]
[ 203434-47-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 221 - 226.

8
[ 190141-99-2 ]
3-tert-Butoxycarbonylamino-4-[(E)-methoxyimino]-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 221 - 226.

9
[ 190141-99-2 ]
3-tert-Butoxycarbonylamino-4-[(Z)-methoxyimino]-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 221 - 226.

10
[trans-(+/-)]-3-hydroxy-4-[(phenylmethyl)amino]-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester [ No CAS ]
[ 190141-99-2 ]

Yield	Reaction Conditions	Operation in experiment
	palladium; In ethanol; ethyl acetate;	Preparation 22 [trans-(+-)]-3-Amino-4-hydroxy-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester A solution of [trans-(+-)]-3-hydroxy-4-[(phenylmethyl)amino]-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester (1.1 g, 3.76 mmol) in ethanol (150 ml) was hydrogenated over 10% palladium-on-carbon (0.05 g) for 3.5 h. The catalyst was removed by filtration, washed with ethanol (50 ml) and the combined ethanolic solution was evaporated to leave an oil which was taken up in ethyl acetate (75 ml). The solution was filtered and the filtrate evaporated to leave a solid which was crystallized from ethyl acetate/cyclohexane to give the title compound (0.643 g), nmr(delta,CDCl3) 1.45(s, 9H), 1.6-2.2(bm, 3H), 3.1(m,1H), 3.3(m,2H), 3.68(m,2H), 3.98(m,1H).

References: [1]Patent: US5889178,1999,A .

11
[ 1136103-30-4 ]
[ 190141-99-2 ]
C₃₀H₃₈BrF₄N₃O₆S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 675 - 679.

12
[ 875272-89-2 ]
[ 190141-99-2 ]
C₃₀H₃₉F₄N₃O₆S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 675 - 679.

13
[ 1877-72-1 ]
[ 190141-99-2 ]
[ 1247884-24-7 ]

Yield	Reaction Conditions	Operation in experiment
62%		A solution of 3-cyanobenzoic acid (1.58 g, 0.01 mol), HOBT (3.03 g, 0.02 mol), EDCI (3.8 g, 0.02 mol), DIEA (2.5 g, 0.02 mol) in DCM (200 mL) was stirred at RT for 15 min. tert-Butyl 3-amino-4-hydroxypyrrolidine-l-carboxylate (2.3 g, 0.01 mol) was added, and the mixture was stirred at RT overnight. The reaction was diluted with DCM, washed with H2O, and dried over Na2SO4. Purification by silica gel chromatography (PE : EtOAc gradient = 8:1 to 2:1) afforded the product tert-butyl 3-(3- cyanobenzamido)-4-hydroxypyrrolidine-l-carboxylate (2 g, 62%) as a white solid. The product was carried directly to the next step.

References: [1]Patent: WO2010/114971,2010,A1 .Location in patent: Page/Page column 153-154.

14
[ 24424-99-5 ]
[ 190141-99-2 ]

References: [1]Patent: US2011/166121,2011,A1 .

15
5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one [ No CAS ]
[ 190141-99-2 ]
3-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A. (5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}-1,3-thiazol-4(5H)-one 3-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and <strong>[190141-99-2]3-Amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester</strong> following General Procedure C. LC/MS (m/z) [M+1]+622.5 (calculated for C28H27ClF3N5O4S, 621.14).

References: [1]Patent: US2011/200587,2011,A1 .

16
[ 75-36-5 ]
[ 190141-99-2 ]
[ 945217-66-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5361 - 5366.

17
[ 155447-71-5 ]
[ 190141-99-2 ]
[ 1456616-49-1 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5361 - 5366.

18
[ 190141-99-2 ]
(3S,4S)-3-amino-4-hydroxypyrrolidine dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol; at 20℃; for 24.0h;	[00707] (3S,4S)-tert-Butyl 3-amino-4-hydroxypyrrolidine-l-carboxylate (0.3 g, 1.439 mmol) in 1.25 M HCl 1.25 M in EtOH (11.51 mL, 14.39 mmol) was stirred for 24 h at RT. The white suspension was evaporated to dryness under reduced pressure and the residue was suspended in MeOH (10 mL) and evaporated again to afford the title compound.

References: [1]Patent: WO2013/171640,2013,A1 .Location in patent: Paragraph 00706-00707.

19
[ 1610703-67-7 ]
[ 190141-99-2 ]
[ 1610710-12-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; at 20 - 90℃; for 15.0h;	To a solution of iert-butyl (3R,4R and 3S,4S)-3-amino-4-hydroxypyrrolidine-l-carboxylate (commercially available from Advanced Chemb locks Inc.) in t-BuOH (5 mL) at RT was added DIEA (0.37 mL, 2 mmol) and Intermediate IA (130 mg, 0.5 mmol). The mixture was heated to 90 C and stirred at this temperature for 15 h. The reaction was then cooled and the solvents were removed under reduced pressure. The residue thus obtained was purified with reverse- phase preparative HPLC (Column: Xbridge Prep C18 10 um OBD, 19 x 250 mm; Mobile phase: A: water (10 mM NH4HCO3), B: MeCN; Flow rate: 30 mL/min; UV detection: 214/254 nm) to afford ((3R,4R)- and (3S,4S))-tert-butyl 3- [9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6- yl] amino }-4-hydroxypyrrolidine-l-carboxylate (1-15). 1H NMR (400 MHz, CDC13) delta 9.02 (s, 2H), 8.43 (s, 1H), 6.18 - 5.94 (m, 1H), 4.57 - 4.29 (m, 4H), 4.10 - 3.82 (m, 2H), 3.51 - 3.29 (m, 2H), 2.87 (s, 3H), 2.00 - 1.90 (m, 2H)1.52 - 1.40 (m, 12H). MS (ESI) calc'd for [M+H]+, 441; found, 441

References: [1]Patent: WO2014/75393,2014,A1 .Location in patent: Page/Page column 64.

20
[ 190141-99-2 ]
[ 945217-66-3 ]

References: [1]Patent: WO2014/101373,2014,A1 .

21
[ 190141-99-2 ]
[ 1235591-17-9 ]

References: [1]Patent: WO2014/101373,2014,A1 .

22
[ 75-36-5 ]
[ 190141-99-2 ]
[ 1235591-22-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at -20℃; for 1.5h;	To a stirred solution of tert-butyl 3-arnino-4-hydroxypyrrolidine-l-carboxylate (5.6 g, 27.7 mrnol) in DCM (277 ml) was added TEA (3.86 ml, 27.7 mmol) and acetyl chloride (1.969 ml, 27.7 mrnol) drop wise at -20C. The reaction mixture was stirred at -20C for 1 .5hr. The reaction was quenched by addition of 2OrnL of MeOH. The reaction mixture was stirred vigorously for I 0mm. Sat. NaHCO3 (aq, 400mL) was added and extracted with 10%MeOH/DCM (x3) and organic layer was dried over MgSO4, filtered and concentrated to give tert-butyl 3-acetamido-4-hydroxypyrrolidine-l-carboxylate. The crude product was used for the next step without further purification.
	With triethylamine; In dichloromethane; at -20℃; for 1.5h;	To a stirred solution of tert-butyl 3-amino-4-hydroxypyrrolidine-l-carboxylate (5.6 g, 27.7 mmol) in DCM (277 ml) was added TEA (3.86 ml, 27.7 mmol) and acetyl chloride (1.969 ml, 27.7 mmol) drop wise at -20C. The reaction mixture was stirred at -20C for 1.5hr. The reaction was quenched by addition of 20mL of MeOH. The reaction mixture was stirred vigorously for lOmin. Sat. NaHC( (aq, 400mL) was added and extracted with 10% MeOH/DCM (x3) and organic layer was dried over MgSC>4, filtered and concentrated to give tert-butyl 3-acetamido-4-hydroxypyrrolidine-l-carboxylate. The crude product was used for the next step without further purification.

References: [1]Patent: WO2014/105666,2014,A1 .Location in patent: Paragraph 0243.
[2]Patent: WO2014/101373,2014,A1 .Location in patent: Page/Page column 116.

23
[ 190141-99-2 ]
C₁₈H₂₆N₂O₇S [ No CAS ]