[ CAS No. 109384-24-9 ] {[proInfo.proName]}

Name: 109384-24-9|(2S,4R)-tert-Butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate|97%
Brand: Ambeed
SKU: A261208
Price: 48.0 USD
Availability: InStock
Rating: 94 (30 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

2D 3D

Structure of 109384-24-9 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 109384-24-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 109384-24-9 ]

SDS Specification

Alternatived Products of [ 109384-24-9 ]

Product Details of [ 109384-24-9 ]

CAS No. :	109384-24-9	MDL No. :	MFCD16883081
Formula :	C₁₀H₁₈N₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ISGKNURQVBUGBO-RQJHMYQMSA-N
M.W :	230.26	Pubchem ID :	14796648
Synonyms :

Calculated chemistry of [ 109384-24-9 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	60.66
TPSA :	92.86 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.99 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.5
Log Po/w (XLOGP3) :	-0.4
Log Po/w (WLOGP) :	-0.54
Log Po/w (MLOGP) :	-0.48
Log Po/w (SILICOS-IT) :	-0.88
Consensus Log Po/w :	-0.16

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.75
Solubility :	40.8 mg/ml ; 0.177 mol/l
Class :	Very soluble
Log S (Ali) :	-1.09
Solubility :	18.9 mg/ml ; 0.082 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	0.21
Solubility :	376.0 mg/ml ; 1.63 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.16

Safety of [ 109384-24-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H317	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 109384-24-9 ]

* 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.

Upstream synthesis route of [ 109384-24-9 ]
Downstream synthetic route of [ 109384-24-9 ]

[ 109384-24-9 ] Synthesis Path-Upstream 1~6

1
[ 13726-69-7 ]
[ 109384-24-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -15℃; for 0.166667 h; Inert atmosphere Stage #2: With ammonia In tetrahydrofuran; water at -15 - 5℃; for 2 h;	Step 2 Preparation of (2S,4R)-tert-butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid 13b (86.4 g, 0.374 mol) was dissolved in 1.2 L of tetrahydrofuran followed by addition of triethylamine (41 g, 0.411 mol) under argon atmosphere. The reaction mixture was cooled to -15 °C, ethyl chlorformate (43.84 g, 0.411 mol) was added. After the mixture was stirred for 10 minutes, aqueous ammonia (236.8 mL) was added. The reaction mixture was slowly warmed up to 5 °C during 2 hours followed by addition of ammonium chloride (32 g). The reaction mixture was stirred for 30 minutes and separated. The separated organic phase was dried over anhydrous sodium sulfate, and the aqueous phase was extracted with ethyl acetate (100 mL.x.2). The combined organic extracts were concentrated under reduced pressure to obtain the title compound (2S,4R)-tert-butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate 13c (74 g, yield 86percent) as a white solid.
59%	Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -10℃; for 1 h; Stage #2: With ammonia In tetrahydrofuran; water at -5 - 20℃; for 2 h;	TERT-BUTYL 4R)-2-(AMINOCARBONYL)-4-HYDROXYPYRROLIDINE-1-CARBOXYLATE] with the general formula (VII), where Z means a group of formula (E) 36,32 g (157 mmol) of (2S, [4R)-L-(TERT-BUTOXYZARBONYL)-4-HYDROXY-PYRROLIDINE-2-] carboxylic acid [(ALDRICH)] was dissolved in 450 [ML] of tetrahydro-furane and to the solution 24 [ML] (172 mmol) of triethylamine was added. To the resulting mixture, at-10 C 16,3 ml (172 mmol) of ethyl chloroformate was added dropwise and at the same temperature it was stirred for 1 hour. Keeping the temperature below -5C, 110 ml of 25percent aqueous ammonia solution was added dropwise and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into 270 ml of saturated ammonium chloride solution. After separation the aqueous layer was extracted with 2x 50 mL of [TETRAHYDROFURANE.] The combined organic solution was dried over sodium sulphate and evaporated. On addition of diethyl ether 21,19 g (59 percent) of the above product crystallized.

Reference： [1] Chemical and Pharmaceutical Bulletin, 2006, vol. 54, # 12, p. 1709 - 1714
[2] Patent: EP2246347, 2010, A1, . Location in patent: Page/Page column 39
[3] Patent: WO2003/106456, 2003, A2, . Location in patent: Page 28
[4] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 23, p. 6053 - 6061

2
[ 24424-99-5 ]
[ 109384-24-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: With triethylamine In tetrahydrofuran at 0 - 5℃; for 0.333333 - 0.5 h; Stage #2: at 0 - 30℃; for 5.16667 - 6.25 h;	Preparation oftert-Butyl (2S, 4R)-2-(aminocarbonyl)-4-hydroxypyrrolidine-l -carboxylateTo a 5L 4-necked RB flask, fitted with a mechanical stirrer and condenser, tetrahydrofuran (1875ml) and (2S₅4R)-4-hydroxypyrrolidine-2-carboxamide (187.5g, 1.44 M) were added at a temperature of about 25-35 ⁰C while stirring. The reaction mixture was cooled to 0-5 ⁰C and maintained for 30 min while stirring. Triethylamine (291.5g, 2.88M) was added to reaction mixture at 0-5 ⁰C over a period of 10-15 min. The reaction mixture was stirred for 10-15 min. BOC-anhydride(377.3g, 1.73M) was charged very slowly for 10-15 min at 0-5 ⁰C. The reaction mass was stirred at 25-30 ⁰C for 5-6 hrs. The completion of the reaction was monitored on TLC. Subsequently, the reaction mass was filtered through a celite bed, and the celite cake was washed with hot ethyl acetate (852.0ml) thrice. The ethyl acetate was distilled off under vacuum at 45-50 ⁰C. To the crude product obtained after distillation was added toluene (852.0ml), and the mixture was stirred for an additional 30 min at reaction temperature. The slurry mass was filtered and the cake was washed with hexane (1.705L) to get a white solid. The product was dried under vacuum at 45-50 ⁰C until the moisture content reached < 1 percent. The dried product appeared as an off white to pale yellow solid (weight 301.Sg, yield 88-94percent, purity 97-98 percent by HPLC).

Reference： [1] Patent: WO2008/1195, 2008, A2, . Location in patent: Page/Page column 41

3
[ 1336-21-6 ]
[ 541-41-3 ]
[ 13726-69-7 ]
[ 109384-24-9 ]

Reference： [1] Patent: US5104867, 1992, A,

4
[ 13726-69-7 ]
[ 80029-43-2 ]
[ 109384-24-9 ]

Reference： [1] Patent: EP1333025, 2003, A1,

5
[ 74844-91-0 ]
[ 109384-24-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 11, p. 3068 - 3076

6
[ 109384-24-9 ]
[ 483366-12-7 ]

Yield	Reaction Conditions	Operation in experiment
74%	With trifluoroacetic anhydride In pyridine at -20 - 20℃; for 24 h;	7,82 g (34 mmol) [OF TERT-BUTYL (2S, 4R)-2-(AMINOCARBONYL)-4-HYDROXYPYRROLIDINE-1-] carboxylate was dissolved in 80 ml of pyridine and 12 ml (84 mmol) of trifluoroacetic anhydride was added to the solution dropwise, at-20 [CD.] The mixture was stirred at room temperature for a day. The excess of anhydride was hydrolised by addition of some drops of water. To this mixture 200 ml of ethyl acetate was added and it was washed with 10percent aqueous hydrogen chloride (to pH 3-5), 50 ml 2 N solution of sodium hydroxide and 50 ml brine. The organic solution was dried over sodium sulphate and evaporated to result in an oil. Yield: 5,35 g (74percent).
73%	at -20 - 20℃; Inert atmosphere	Step 3 Preparation of (2S,4R)-tert-butyl 2-cyano-4-hydroxypyrrolidine-1-carboxylate (2S,4R)-tert-Butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate 13c (74 g, 0.3217 mol) was dissolved in 740 mL of pyridine with stirring under argon atmosphere. The mixture was cooled to -20 °C followed by dropwise addition of trifluoroacetic anhydride (169 g, 0.804 mol). Upon completion of the addition, the reaction mixture was warmed up to room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was quenched with water and diluted with 0.8 L of ethyl acetate. The separated organic phase was washed with 500 mL of saturated brine and neutralized with 400 mL of concentrated hydrochloric acid to slight acidity. The resulting mixture was washed with 300 mL of aqueous sodium hydroxide (2 M) and 500 mL saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (2S,4R)-tert-butyl 2-cyano-4-hydroxypyrrolidine-1-carboxylate 13d (49.7 g, yield 73percent) as a brown oil.

Reference： [1] Patent: WO2003/106456, 2003, A2, . Location in patent: Page 28
[2] Patent: EP2246347, 2010, A1, . Location in patent: Page/Page column 39

[ 109384-24-9 ] Synthesis Path-Downstream 1~41

1
[ 13726-69-7 ]
[ 109384-24-9 ]

Yield	Reaction Conditions	Operation in experiment
86%		Step 2 Preparation of (2S,4R)-tert-butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid 13b (86.4 g, 0.374 mol) was dissolved in 1.2 L of tetrahydrofuran followed by addition of triethylamine (41 g, 0.411 mol) under argon atmosphere. The reaction mixture was cooled to -15 C, ethyl chlorformate (43.84 g, 0.411 mol) was added. After the mixture was stirred for 10 minutes, aqueous ammonia (236.8 mL) was added. The reaction mixture was slowly warmed up to 5 C during 2 hours followed by addition of ammonium chloride (32 g). The reaction mixture was stirred for 30 minutes and separated. The separated organic phase was dried over anhydrous sodium sulfate, and the aqueous phase was extracted with ethyl acetate (100 mL×2). The combined organic extracts were concentrated under reduced pressure to obtain the title compound (2S,4R)-tert-butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate 13c (74 g, yield 86%) as a white solid.
59%		TERT-BUTYL 4R)-2-(AMINOCARBONYL)-4-HYDROXYPYRROLIDINE-1-CARBOXYLATE] with the general formula (VII), where Z means a group of formula (E) 36,32 g (157 mmol) of (2S, [4R)-L-(TERT-BUTOXYZARBONYL)-4-HYDROXY-PYRROLIDINE-2-] carboxylic acid [(ALDRICH)] was dissolved in 450 [ML] of tetrahydro-furane and to the solution 24 [ML] (172 mmol) of triethylamine was added. To the resulting mixture, at-10 C 16,3 ml (172 mmol) of ethyl chloroformate was added dropwise and at the same temperature it was stirred for 1 hour. Keeping the temperature below -5C, 110 ml of 25% aqueous ammonia solution was added dropwise and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into 270 ml of saturated ammonium chloride solution. After separation the aqueous layer was extracted with 2x 50 mL of [TETRAHYDROFURANE.] The combined organic solution was dried over sodium sulphate and evaporated. On addition of diethyl ether 21,19 g (59 %) of the above product crystallized.
		A solution of (2S,4R)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2- carboxylic acid (6.00 g, 25.95 mmol) in DCM (50 mL) and DMF (5.0 mL) was added HATU (11.84 g, 31.14 mmol) and DIEA (10.06 g, 77.84 mmol) at 20 C. The reaction mixture was stirred at 20 C for 30 minutes. Then NH4C1 (2.78 g, 51.89 mmol) was added and stirred at 20 C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove solvents. The crude tert-butyl (2S,4R)-2-carbamoyl-4-hydroxypyrrolidine-l-carboxylate (5.974 g, 99%) as a yellow oil, which was used directly in the next step.

Reference： [1]Chemical and Pharmaceutical Bulletin,2006,vol. 54,p. 1709 - 1714
[2]Patent: EP2246347,2010,A1 .Location in patent: Page/Page column 39
[3]Patent: WO2003/106456,2003,A2 .Location in patent: Page 28
[4]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 6053 - 6061
[5]Patent: WO2019/84026,2019,A1 .Location in patent: Paragraph 0854

2
[ 109384-24-9 ]
(2S,4R)-4-hydroxypyrrolidin-2-carboxamide hydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 6053 - 6061

3
[ 74844-91-0 ]
[ 109384-24-9 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3068 - 3076

4
[ 124-63-0 ]
[ 109384-24-9 ]
[ 127423-45-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium chloride; triethylamine; In tetrahydrofuran; methanol; ethyl acetate;	1-(3) (2S,4R)-1-(t-Butoxycarbonyl)-2-carbamoyl-4-methanesulfonyloxypyrrolidine 1.85 ml of methanesulfonyl chloride was added, whilst ice-cooling, to a solution of 5.0 g of (2S,4R)-1-(t-butoxycarbonyl)-2-carbamoyl-4-hydroxypyrrolidine [prepared as described in step (2) above] in 250 ml of dry tetrahydrofuran, followed by 3.31 ml of triethylamine. The mixture was then stirred at 0 to 5 C. for 1 hour, after which it was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 5.5 g of the title compound as colorless crystals. Nuclear Magnetic Resonance Spectrum (CDCl3, 60 MHz) delta ppm: 1.43 (9H, singlet); 2.10-2.68 (2H, multiplet); 3.12 (3H, singlet); 3.10-3.40 (1H, broad singlet); 3.73 (2H, doublet, J=4.0 Hz); 4.32 (1H, triplet, J=7.0 Hz); 5.26 (1H, triplet, J=4.0 Hz); 6.68 (1H, broad singlet); 7.30 (1H, broad singlet).

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3068 - 3076
[2]Patent: US5104867,1992,A
[3]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2742 - 2746

5
[ 18162-48-6 ]
[ 109384-24-9 ]
[ 928776-64-1 ]

Yield	Reaction Conditions	Operation in experiment
8.9 g	With 1H-imidazole; dmap; In tetrahydrofuran; at 25℃; for 12h;	A mixture of TBSCI (5.87 g, 38.92 mmol), tert-butyl (2S,4R)-2-carbamoyl-4- hydroxypyrrolidine-l-carboxylate (5.974 g, 25.94 mmol), DMAP (316.96 mg, 2.59 mmol) and imidazole (5.300 g, 77.83 mmol) in THF (80 mL) was stirred at 25 C for 12 hours. Water (80 mL) was added and it was extracted with DCM (100 mL x 3), washed by brine (50 mL x 3). The organics were dried over Na2SC>4, concentrated, and purified by flash column chromatography (0-50% EtOAc in petroleum ether, Rf = 0.6) to give tert-butyl (2S,4R)-4-((tert- butyldimethylsilyl)oxy)-2-carbamoylpyrrolidine-l-carboxylate (8.900 g, 99.6%) as a colorless oil used in next step directly. XH NMR (400 MHz, CD3OD) delta 4.83-4.76 (m, 1H), 4.05-4.0 (m, 1H), 3.95-3.92 (m, 1H), 3.81-3.80 (m, 1 H), 2.70-2.67 (m, 1 H), 2.52-2.48 (m, 1 H), 1.96-1.91 (m, 9 H) ,1.39 (s, 1H), 0.60 (s, 6 H).

Reference： [1]Chemical and Pharmaceutical Bulletin,2006,vol. 54,p. 1709 - 1714
[2]Patent: WO2019/84026,2019,A1 .Location in patent: Paragraph 0854; 0855

6
[ 24424-99-5 ]
[ 109384-24-9 ]

Yield	Reaction Conditions	Operation in experiment
88 - 94%		Preparation oftert-Butyl (2S, 4R)-2-(aminocarbonyl)-4-hydroxypyrrolidine-l -carboxylateTo a 5L 4-necked RB flask, fitted with a mechanical stirrer and condenser, tetrahydrofuran (1875ml) and (2S54R)-4-hydroxypyrrolidine-2-carboxamide (187.5g, 1.44 M) were added at a temperature of about 25-35 0C while stirring. The reaction mixture was cooled to 0-5 0C and maintained for 30 min while stirring. Triethylamine (291.5g, 2.88M) was added to reaction mixture at 0-5 0C over a period of 10-15 min. The reaction mixture was stirred for 10-15 min. BOC-anhydride(377.3g, 1.73M) was charged very slowly for 10-15 min at 0-5 0C. The reaction mass was stirred at 25-30 0C for 5-6 hrs. The completion of the reaction was monitored on TLC. Subsequently, the reaction mass was filtered through a celite bed, and the celite cake was washed with hot ethyl acetate (852.0ml) thrice. The ethyl acetate was distilled off under vacuum at 45-50 0C. To the crude product obtained after distillation was added toluene (852.0ml), and the mixture was stirred for an additional 30 min at reaction temperature. The slurry mass was filtered and the cake was washed with hexane (1.705L) to get a white solid. The product was dried under vacuum at 45-50 0C until the moisture content reached < 1 %. The dried product appeared as an off white to pale yellow solid (weight 301.Sg, yield 88-94%, purity 97-98 % by HPLC).

Reference： [1]Patent: WO2008/1195,2008,A2 .Location in patent: Page/Page column 41

7
[ 109384-24-9 ]
(2R,4S)-4-tert-Butoxycarbonylamino-4-carbamoyl-2-hydroxy-butyric acid [ No CAS ]