[ CAS No. 481704-21-6 ] {[proInfo.proName]}

Name: 481704-21-6|(2R,4S)-Methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride|97%
Brand: Ambeed
SKU: A107793
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Quality Control of [ 481704-21-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 481704-21-6 ]

SDS Specification

Alternatived Products of [ 481704-21-6 ]

Product Details of [ 481704-21-6 ]

CAS No. :	481704-21-6	MDL No. :	MFCD00135747
Formula :	C₆H₁₂ClNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KLGSHNXEUZOKHH-UYXJWNHNSA-N
M.W :	181.62	Pubchem ID :	44118802
Synonyms :	tans-4-Hydroxy-D-proline methyl ester hydrochloride	Chemical Name :	(2R,4S)-Methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride

Calculated chemistry of [ 481704-21-6 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.83
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	44.97
TPSA :	58.56 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) :	-7.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.24
Log Po/w (WLOGP) :	-0.7
Log Po/w (MLOGP) :	-0.5
Log Po/w (SILICOS-IT) :	-0.25
Consensus Log Po/w :	-0.24

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.99
Solubility :	18.8 mg/ml ; 0.103 mol/l
Class :	Very soluble
Log S (Ali) :	-1.03
Solubility :	16.9 mg/ml ; 0.0933 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.06
Solubility :	159.0 mg/ml ; 0.873 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.51

Safety of [ 481704-21-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 481704-21-6 ]

* 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 [ 481704-21-6 ]
Downstream synthetic route of [ 481704-21-6 ]

[ 481704-21-6 ] Synthesis Path-Upstream 1~3

1
[ 3398-22-9 ]
[ 481704-21-6 ]

Yield	Reaction Conditions	Operation in experiment
87.6%	With acetyl chloride In methanol; diethyl ether at 20℃;	[TRANS-4-HYDROXY-L-PROLINE] (1; 10 g, 76.3 mmol) was dissolved in 200 ml of methanol, acetyl chloride (7.6 ml, 106.8 mmol) was added therein and the mixture was refluxed with stirring up for overnight. The mixture was cooled to RT (room temperature) and 500 ml of ether was added to form white crystal followed by filtration and drying under vacuum to yield the compound 2 (12.7 g, 87.6 percent):

Reference： [1] Patent: WO2003/104249, 2003, A1, . Location in patent: Page 14

2
[ 647857-51-0 ]
[ 481704-21-6 ]

Reference： [1] Patent: WO2004/7444, 2004, A2, . Location in patent: Page 141

3
[ 67-56-1 ]
[ 142347-81-7 ]
[ 481704-21-6 ]

Reference： [1] Patent: WO2013/49164, 2013, A1, . Location in patent: Paragraph 838-839
[2] Patent: WO2013/49174, 2013, A1, . Location in patent: Paragraph 0833-0834

[ 481704-21-6 ] Synthesis Path-Downstream 1~17

1
[ 481704-21-6 ]
(2R,4S)-methyl 1-benzyl-4-hydroxypyrrolidine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.5%	With potassium carbonate; benzyl chloride;tetra(tert-butyl)ammonium iodide; In ethyl acetate; acetonitrile;	Synthesis of 1-Benzyl-4-hydroxy-pyrrolidine-2- carboxylic acid methyl ester (3) The above-prepared compound 2 (12.7 g, 66.6 mmol), [K2CO3] (26.4 g, 199.8 mmol), BnCl (6.5 ml, 56.6 mmol) and tBu4NI (cat. ) were dissolved with dried [CH2CN] (100 ml) and refluxed with stirring up for overnight. The mixture was cooled to RT, diluted with 200 ml of DW, extracted three times with 50 ml of AcOEt and washed with DW. The final concentrate in oil phase was obtained by drying organic phase with [MGSO4.] The concentrate was separated through a column chromatography (MC: MeOH = 20 : 1/15: 1) and colorless oily compound 3 (10.57 g, 67. [5percent)] was yielded

Reference： [1]Patent: WO2003/104249,2003,A1 .Location in patent: Page 14, 15

2
[ 3398-22-9 ]
[ 481704-21-6 ]

Yield	Reaction Conditions	Operation in experiment
87.6%	With acetyl chloride; In methanol; diethyl ether; at 20℃;	[TRANS-4-HYDROXY-L-PROLINE] (1; 10 g, 76.3 mmol) was dissolved in 200 ml of methanol, acetyl chloride (7.6 ml, 106.8 mmol) was added therein and the mixture was refluxed with stirring up for overnight. The mixture was cooled to RT (room temperature) and 500 ml of ether was added to form white crystal followed by filtration and drying under vacuum to yield the compound 2 (12.7 g, 87.6 percent):

Reference： [1]Patent: WO2003/104249,2003,A1 .Location in patent: Page 14

3
[ 647857-51-0 ]
[ 481704-21-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; at 23℃; for 3h;	[4S-HYDROXYOXY-1-TRITYLPYRROLIDINE-2R-CARBOXYLIC] acid methyl ester (510 mg, 1.32 mmol, [1] eq. ) was treated with anhydrous 4.0 M [HC1] in dioxane (20 mL, excess). The resulting mixture was stirred vigorously at [23 JC] for 3 h, then concentrated to give 4S- hydroxyoxy-1-pyrrolidine-2R-carboxylic acid methyl ester hydrochloride salt.

Reference： [1]Patent: WO2004/7444,2004,A2 .Location in patent: Page 141

4
[ 481704-21-6 ]
[ 24424-99-5 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 0 - 20℃; for 1h;	Add di-tert-butyl dicarbonate (11.2 g, 51.35 mmol) to a solution of 4-(S)- hydroxypyrrolidine-2- (R)-carboxylic acid methyl ester hydrochloride (7.17 g, 39.5 mmol) in 1,4-dioxane (80 mL). Cool in an ice bath and add N,N-diisopropylethylamine (11.7 mL, 67.2 mmol). Remove ice bath and stir 1 h at room temperature. Concentrate and dissolve in ethyl acetate, wash with 5percent aqueous citric acid solution (2 x100 mL), water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a white solid (9.83 g, 100percent). MS (ES): m/z = 246.1 [M+H].

Reference： [1]Patent: WO2005/108358,2005,A2 .Location in patent: Page/Page column 38-39

5
[ 481704-21-6 ]
[ 98-59-9 ]
[ 1075183-51-5 ]

Reference： [1]Organic Letters,2008,vol. 10,p. 5023 - 5026

6
[ 481704-21-6 ]
[ 1155877-67-0 ]
[ 1155876-75-7 ]

Yield	Reaction Conditions	Operation in experiment
8%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 96h;	A-005 (2R,4S)-4-Hydroxy-1-(6-methoxy-3'-nitro-biphenyl-3-ylmethyl)-pyrrolidine-2-carboxylic acid methyl ester Into a 20 mL vial with stir bar added Int-2 (0.30 g, 0.93 mmol), <strong>[481704-21-6](2R,4S)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride</strong> (0.62 mmol), Cs2CO3 (0.20 g, 0.62 mmol), and DMF (2 mL). The reaction was stirred for 4 days at room temperature and then 10 mL water was added. The product was extracted with ethyl acetate (3*10 mL) and the organics were combined and concentrated. The residue was purified by flash column chromatography using 0-5percent methanol/dichloromethane to obtain 36 mg (8percent) of A-005. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 2.03-2.15 (m, 1H) 2.27 (dt, J=13.8, 7.1 Hz, 1H) 2.51 (dd, J=10.2, 3.6 Hz, 1H) 3.37 (dd, J=10.1, 5.6 Hz, 1H) 3.57-3.73 (m, 5H) 3.83 (s, 3H) 3.90 (d, J=12.9 Hz, 1H) 4.48 (br. s., 1H) 6.96 (d, J=8.3 Hz, 1H) 7.29 (d, J=2.0 Hz, 1H) 7.33 (dd, J=8.3, 2.0 Hz, 1H) 7.56 (t, J=8.0 Hz, 1H) 7.86 (d, J=7.7 Hz, 1H) 8.17 (dd, J=8.2, 1.3 Hz, 1H) 8.37-8.44 (m, 1H). LC/MS=93.7percent, 387.1, (APCI+)

Reference： [1]Patent: US2009/136473,2009,A1 .Location in patent: Page/Page column 22

7
[ 481704-21-6 ]
[ 110855-51-1 ]
[ 1408313-90-5 ]

Yield	Reaction Conditions	Operation in experiment
50%		b) (2R,4S)-4-Hydroxy-l-[4-(2,2,2-trifluoro-ethoxy)-phenylcarbamoyl]-pyrrolidine-2- carboxylic acid methyl esterTo a solution of <strong>[481704-21-6](2R,4S)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester, hydrochloride</strong> (3 g, 16.57 mmol) in THF (15 mL) was added solid Na2C03 (2.10 g, 19.88 mmol) and stirred for 15 min. To this mixture, freshly prepared l-Isocyanato-4- (2,2,2- trifluoro-ethoxy)-benzene (4.3 g, 19.88 mmol) in THF (10 mL) was added and stirred for 2 h at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in DCM and washed with water and brine, dried over Na2S04 and concentrated to dryness. The residue was purified by column chromatography over silica (5percent MeOH in DCM) to yield 2.7g (50percent) of the title compound as a white solid. LC-MS: 363.2 [M+l]+.
		b) (2R,4S)-4-Hydroxy-1-[4-(2,2,2-trifluoro-ethoxy)-phenylcarbamoyl]-pyrrolidine-2-carboxylic acid methyl ester To a solution of <strong>[481704-21-6](2R,4S)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester, hydrochloride</strong> (3 g, 16.57 mmol) in THF (15 mL) was added solid Na2CO3 (2.10 g, 19.88 mmol) and stirred for 15 min. To this mixture, freshly prepared 1-Isocyanato-4-(2,2,2-trifluoro-ethoxy)-benzene (4.3 g, 19.88 mmol) in THF (10 mL) was added and stirred for 2 h at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in DCM and washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography over silica (5percent MeOH in DCM) to yield 2.7 g (50percent) of the title compound as a white solid. LC-MS: 363.2 [M+1]+.

Reference： [1]Patent: WO2012/152663,2012,A1 .Location in patent: Page/Page column 54
[2]Patent: US2012/289549,2012,A1 .Location in patent: Page/Page column 21

8
[ 67-56-1 ]
[ 142347-81-7 ]
[ 481704-21-6 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 0 - 25℃; for 4h;	Example 65A[838] (2R,45)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride[839] To a suspension of iraws-4-hydroxy-D-proline hydrochloride (150 g, 0.89 mol, 1 equivalent) in methanol (1.25 L), thionyl chloride (130 mL, 1.79 mol, 2 equivalents) was added drop-wise at 0-5 °C. Then the reaction mixture was stirred for 4 hours at 20- 25 °C. The reaction mixture was concentrated under reduced pressure. This crude material was stirred in a mixture of ethanol-methyl tert-butyl ether (1:4, 750 mL) for 30 minutes and the solid was collected by filtration. The wet cake was dried in a vacuum tray dryer for 8 hours at about 50 °C to afford the title compound. lR NMR (300 MHz, DMSO-i?) ? ppm 2.03 -2.23 (m, 2H), 3.06 (d, 1H, J=12.0Hz), 3.37 (dd, 2H, J=4.5Hz, J=12.0Hz), 3.75 (s, 3H), 4.41- 4.48 (m, 2H), 5.64 (bs, 1H), 9.43 (bs, 1H), 10.48 (bs, 1H).
	With thionyl chloride; at 0 - 25℃; for 4h;	Example 17A[0833] (2R,45)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride[0834] To a suspension of iraws-4-hydroxy-D-proline hydrochloride (150 g, 0.89 mol, 1 equivalent) in methanol (1.25 L), thionyl chloride (130 mL, 1.79 mol, 2 equivalents) was added drop-wise at 0-5 °C. Then the reaction mixture was stirred for 4 hours at 20-25 °C. The reaction mixture was concentrated under reduced pressure. This crude material was stirred in a mixture of ethanol-methyl tert-butyl ether (1 :4, 750 mL) for 30 minutes and the solid was collected by filtration. The wet cake was dried in a vacuum tray dryer for 8 hours at about 50 °C to afford the title compound. XH NMR (300 MHz, DMSO-i¾) delta ppm 2.03 -2.23 (m, 2H), 3.06 (d, 1H, J=12.0Hz), 3.37 (dd, 2H, J=4.5Hz, J=12.0Hz), 3.75 (s, 3H), 4.41- 4.48 (m, 2H), 5.64 (bs, 1H), 9.43 (bs, 1H), 10.48 (bs, 1H).

Reference： [1]Patent: WO2013/49164,2013,A1 .Location in patent: Paragraph 838-839
[2]Patent: WO2013/49174,2013,A1 .Location in patent: Paragraph 0833-0834

9
[ 481704-21-6 ]
[ 79-04-9 ]
[ 1429199-81-4 ]

Yield	Reaction Conditions	Operation in experiment
	In benzene; at 20℃; for 3h;Reflux;	Example 65B[840] (2R,45)-methyl 1 -(2-chloroacetyl)-4-hydroxypyrrolidine-2-carboxylate[841] To a suspension of Example 65 A (100 g, 0.55 mol, 1 equivalent) in benzene (2.5 L), chloroacetylchloride (62.4 g, 0.50 mol, 1 equivalent) was added dropwise at 20-25 °C. The reaction mixture was refluxed for 3 hours. Then charcoal (2 g) was added, and the mixture was hot filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to get a solid. To this crude material, methyl tert-butyl ether (500 mL) was added and stirred for 30 minutes. The solid was collected by filtration, and the wet cake was dried in a vacuum tray dryer for 5 hours at about 50 °C to afford the title compound. XH NMR (300 MHz, DMSO-i?) ? ppm 2.06 -2.15 (m, 1H), 2.31-2.39 (m, 1H), 3.64 (d, 1H, J=l l. lHz), 3.76 (s, 3H), 3.76-3.86 (m, 2 H), 4.09 (s, 2H), 4.6-4.65 (m, 2H).
	In benzene; for 3h;Reflux;	Example 17B[0835] (2R,45)-methyl 1 -(2-chloroacetyl)-4-hydroxypyrrolidine-2-carboxylate[0836] To a suspension of Example 17A (100 g, 0.55 mol, 1 equivalent) in benzene (2.5 L), chloroacetyl chloride (62.4 g, 0.50 mol, 1 equivalent) was added dropwise at 20-25 °C. The reaction mixture was refluxed for 3 hours. Then charcoal (2 g) was added, and the mixture was hot filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to get a solid. To this crude material, methyl tert-butyl ether (500 mL) was added and stirred for 30 minutes. The solid was collected by filtration, and the wet cake was dried in a vacuum tray dryer for 5 hours at about 50 °C to afford the title compound. XH NMR (300 MHz, DMSO-i/6) delta ppm 2.06 -2.15 (m, 1H), 2.31-2.39 (m, 1H), 3.64 (d, 1H, J=l l . lHz), 3.76 (s, 3H), 3.76-3.86 (m, 2 H), 4.09 (s, 2H), 4.6-4.65 (m, 2H).

Reference： [1]Patent: WO2013/49164,2013,A1 .Location in patent: Paragraph 840-841
[2]Patent: WO2013/49174,2013,A1 .Location in patent: Paragraph 0835-0836

10
[ 481704-21-6 ]
[ 1429197-85-2 ]