[ CAS No. 114525-81-4 ] {[proInfo.proName]}

Name: 114525-81-4|(R)-4-(tert-Butoxycarbonyl)thiomorpholine-3-carboxylic acid|95%
Brand: Ambeed
SKU: A723901
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Quality Control of [ 114525-81-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 114525-81-4 ]

CAS No. :	114525-81-4	MDL No. :	MFCD04114906
Formula :	C₁₀H₁₇NO₄S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CTDIKDIZNAGMFK-ZETCQYMHSA-N
M.W :	247.31	Pubchem ID :	2755966
Synonyms :

Safety of [ 114525-81-4 ]

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

Application In Synthesis of [ 114525-81-4 ]

* 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 [ 114525-81-4 ]
Downstream synthetic route of [ 114525-81-4 ]

[ 114525-81-4 ] Synthesis Path-Upstream 1~2

1
[ 24424-99-5 ]
[ 65527-54-0 ]
[ 114525-81-4 ]

Yield	Reaction Conditions	Operation in experiment
64.6%	With sodium hydrogencarbonate In methanol at 20℃; for 24 h;	To a 1000 mL round bottom flask, 2R-thiomorpholine carboxylic acid, hydrochloride (10.0 g, 0.054 mol), di-tert-butyl dicarbonate (13.0 g, 0.060 mol), sodium bicarbonate (45.0 g, 0.536 mol) and methanol (500 mL) were added, and stirred at room temperature for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of methanol, dissolved with water, washed 3 times with ethyl ether, adjusted to pH = 2 with saturated potassium hydrogen sulfate, and extracted 3 times with dichloromethane. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate/acetic acid), to give 8.63 g of a white product, yield 64.6percent. [0077] ¹H-NMR (400 MHz, CDCl₃) δ ppm: 5.33 (1H, d, J = 90.4 Hz), 4.39 (1H, brm), 3.30 (2H, brm), 2.95 (1H, m), 2.71 (1H, m), 2.53 (1H, m), 1.53 (9H, s); EI-MS (m/z): 247.1[M]⁺.

Reference： [1] Patent: EP2805947, 2014, A1, . Location in patent: Paragraph 0076-0077
[2] Patent: US5679674, 1997, A,

2
[ 24424-99-5 ]
[ 114525-81-4 ]

Yield	Reaction Conditions	Operation in experiment
64.6%	With sodium hydrogencarbonate In methanol at 20℃; for 24 h;	To a 1000 mL round bottom flask, 2R-thiomorpholine carboxylic acid, hydrochloride (10.0 g, 0.054 mol), di-tert-butyl dicarbonate (13.0 g, 0.060 mol), sodium bicarbonate (45.0 g, 0.536 mol) and methanol (500 mL) were added, and stirred at room temperature for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of methanol, dissolved with water, washed 3 times with ethyl ether, adjusted to pH=2 with saturated potassium hydrogen sulfate, and extracted 3 times with dichloromethane. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate/acetic acid), to give 8.63 g of a white product, yield 64.6percent.¹H-NMR (400 MHz, CDCl₃) δ ppm: 5.33 (1H, d, J=90.4 Hz), 4.39 (1H, brm), 3.30 (2H, brm), 2.95 (1H, m), 2.71 (1H, m), 2.53 (1H, m), 1.53 (9H, s); EI-MS (m/z): 247.1[M]⁺.

Reference： [1] Patent: US2015/126500, 2015, A1, . Location in patent: Paragraph 0129; 0130

[ 114525-81-4 ] Synthesis Path-Downstream 1~28

1
[ 24424-99-5 ]
[ 65527-54-0 ]
[ 114525-81-4 ]

Yield	Reaction Conditions	Operation in experiment
64.6%	With sodium hydrogencarbonate; In methanol; at 20℃; for 24h;	To a 1000 mL round bottom flask, 2R-thiomorpholine carboxylic acid, hydrochloride (10.0 g, 0.054 mol), di-tert-butyl dicarbonate (13.0 g, 0.060 mol), sodium bicarbonate (45.0 g, 0.536 mol) and methanol (500 mL) were added, and stirred at room temperature for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of methanol, dissolved with water, washed 3 times with ethyl ether, adjusted to pH = 2 with saturated potassium hydrogen sulfate, and extracted 3 times with dichloromethane. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate/acetic acid), to give 8.63 g of a white product, yield 64.6%. [0077] 1H-NMR (400 MHz, CDCl3) delta ppm: 5.33 (1H, d, J = 90.4 Hz), 4.39 (1H, brm), 3.30 (2H, brm), 2.95 (1H, m), 2.71 (1H, m), 2.53 (1H, m), 1.53 (9H, s); EI-MS (m/z): 247.1[M]+.
	With triethylamine; citric acid; In 1,4-dioxane; ethyl acetate;	(R)-3-(1-Pyrrolidinylmethyl)thiomorpholine 32.6 g of di-t-butyl dicarbonate and 94.2 ml of triethylamine were added to a solution of 0.20 g of thiomorpholine-(R)-3-carboxylic acid in 800 ml of aqueous dioxane (1:1) and the mixture was stirred at room temperature for 3 hours. After the solvent was distilled off, 400 ml of ethyl acetate were added to the residue, which was washed with 70 ml of a saturated aqueous solution of citric acid and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was recrystallized from a mixture of ethyl acetate and hexane to give 27.2 g of (N-t-butoxycarbonyl)-thiomorpholine-(R)-3-carboxylic acid. m.p.: 136-137 C.

Reference： [1]Patent: EP2805947,2014,A1 .Location in patent: Paragraph 0076-0077
[2]Patent: US5679674,1997,A

2
[ 114525-81-4 ]
[ 219529-84-7 ]
[ 253153-07-0 ]

Yield	Reaction Conditions	Operation in experiment
		(Scheme F, F-3: where RF-1 and RF-2 are the same and equal to proton, RF-3 is CH3, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R,S)). [C00175] [00415] To a cooled (0 C.) solution of <strong>[114525-81-4]Boc-L-thiomorpholine-3-carboxylic acid</strong> ((a) Van Der Auwera, C.; Anteunis, M. J. O. Iit. J. Peptide Protein Res. 1987, 29, 574: (b) Kogami, Y.; Okawa, K. Bull. Chem. Soc. Jpn. 1987, 60, 2963: (c) Larsson U.; Carlson R. ACTA Chemica. Scand. 1994, 48, 517: (d) Carson J. F.; Wong F. F. J. Org. Chem. 1964, 29, 2203.) (Scheme F, F-1: where RF-1 and RF-2 are the same and equal to proton and stereochemistry is (R)) (6.7 g, 27 mmol) in CH2Cl2 (100 mL) was added HOBt (4.0 g, 29.7 mmol), DMAP (700 mg), EDC (5.7 g, 29.7 mmol) and triethylamine (13.5 mL, 97 mmol). The reaction mixture was stirred for 10 min, then the amino acid derivative F-2 (Scheme F, where R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl, RF-3 is CH3, and stereochemistry is (S)) (10.0 g, 24.7 mmol) was added. After 20 h, volatiles were removed in vacuo and the residue partitioned between 2.5% aqueous HCl (100 mL) and H2O (100 mL). The organic layer was separated and washed saturated aqueous NaHCO3 (100 mL), dried and concentrated in vacuo. Purification of the residue by chromatography on SiO2 (500 g) using CH2Cl2/ethyl acetate (10%) as eluent afforded the title compound (12.31 g) as a solid: 1H NMR (CDCl3) delta 1.44 (9H), 2.35 (1H), 2.70 (3H), 3.13 (2H), 3.33 (1H), 3.77 (3H), 4.22 (1H), 5.00 (1H), 6.48 (1H), 7.18 (2H), 7.31 (3H), 7.44 (1H), 7.56 (2H); 13C NMR (CDCl3) delta 171.6, 168.9, 162.5, 136.5, 135.9, 132.4, 131.0, 130.2, 128.2, 120.5, 81.7, 77.3, 53.3, 52.6, 37.0, 28.2, 26.5; IR (mull) 3296, 2924, 1744, 1685, 1668, 1605, 1536, 1515, 1432, 1412, 1321, 1294, 1260, 1244, 1213, 1195, 1161, 798 cm-1; MS (FAB) m/z (rel. intensity) 598 (M+H, 3), 596 (M+H, 5), Anal. Calcd for C27H31Cl2N3O6S: C, 54.36; H, 5.24; N, 7.04. Found: C, 54.23; H, 5.24; N, 6.86. Corrected for 0.60% H2O, found by Karl Fischer analysis.

Reference： [1]Patent: US6685617,2004,B1 .Location in patent: Page/Page column 105

3
[ 114525-81-4 ]
C₂₀H₂₂Cl₂N₂O₃ [ No CAS ]
[ 253155-08-7 ]

Yield	Reaction Conditions	Operation in experiment
		(Scheme F, F-3: where RF-1 and RF-2 are the same and equal to proton, RF-3 is t-butyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (R,S)). [C00180] [00425] To a cooled (0-5 C.) solution of <strong>[114525-81-4]Boc-L-thiomorpholine-3-carboxylic acid</strong> (Scheme F, F-1: where RF-1 and RF-2 are the same and equal to proton and stereochemistry is (R)) (1.34 g, 5.4 mmol) in methylene chloride (20 mL) was added HOBt (800 mg, 5.94 mmol), DMAP (140 mg, EDC (1.14 g, 5.94 mmol) and triethylamine (2.7 mL, 19.4 mmol). After 10 min, F-2 (Scheme F where RF-1 and RF-2 are the same and equal to proton, RF-3 is t-butyl, R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S)) (2.02 g, 4.94 mmol) was added, the reaction allowed to warm to ambient temperature and stirred for 24 h. Volatiles were removed in vacuo and the residue partitioned between methylene chloride and 2.5% aqueous HCl. The organic layer was separated and washed with sat. aqueous NaHCO3, dried and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride/ethyl acetate (5%) as eluant afforded the title compound (1.64 g): IR (mull) 1730, 1687, 1667, 1606, 1538, 1515, 1431, 1412, 1395, 1320, 1294, 1258, 1250, 1194, 1158 cm-1; 1H NMR (300 MHz, CDCl3) delta 1.44 (9H), 1.46 (9H), 2.35 (1H), 2.67 (3H), 3.22 (3H), 4.25 (1H), 4.73 (1H), 4.97 (1H), 6.52 (1H), 7.29 (5H), 7.53 (3H); MS (FAB) m/z (rel. intensity) 638 (M+H, 2), Anal. Calcd for C30H37Cl2N3O6S: C, 56.42; H, 5.84; N, 6.58. Found: C, 56.13; H, 5.98; N, 6.58.

Reference： [1]Patent: US6685617,2004,B1 .Location in patent: Page/Page column 108-109

4
[ 114525-81-4 ]
[ 99-73-0 ]
[ 1228968-53-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethyl acetate; at 20℃; for 2h;	Referring to Scheme 5-2, a mixture of compound 17 (667 mg, 2.4 mmol), (R)-N-Boc-thiomorpholine-3-carboxylic acid (594 mg, 2.4 mmol) and Et3N (486 mg, 4.8 mmol) in EtOAc (20 mL) was stirred at rt for 2h. Subsequently, the reaction mixture was concentrated and the residue was dried in vacuo to give crude compound 19, which was used for the next step without further purification. LC-MS (ESI): m/z 466.0 (M+Na)+.
	With triethylamine; In ethyl acetate; at 20℃; for 2h;	Step a. Referring to Scheme 5-2, a mixture of compound 17 (667 mg, 2.4 mmol), (i^-N-Boc-thiomorpholine-S-carboxylic acid (594 mg, 2.4 mmol) and Et3N (486 mg, 4.8 mmol) in EtOAc (20 mL) was stirred at rt for 2h. Subsequently, the reaction mixture was concentrated and the residue was dried in vacuo to give crude compound 19, which was used for the next step without further purification. LC-MS (ESI): m/z 466.0 (M+Na)+.

Reference： [1]Patent: WO2011/150243,2011,A1 .Location in patent: Page/Page column 118; 119
[2]Patent: WO2010/65668,2010,A1 .Location in patent: Page/Page column 118-119

5
[ 67-56-1 ]
[ 114525-81-4 ]
[ 78865-47-1 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4114 - 4122

6
[ 668980-23-2 ]
[ 114525-81-4 ]
C₂₈H₃₃Cl₂N₇O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.5%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;	To a 100 mL round bottom flask, Intermediate 15 (1.28 g, 3.28 mmol), Intermediate 9 (0.81 g, 3.28 mmol), EDCI (0.94 g, 4.92 mmol), HOBt (0.66 g, 4.92 mmol), DIEA (0.85 g, 6.56 mmol) and tetrahydrofuran (40 mL) were added, and stirred at room temperature overnight. Thereafter, the reaction product was subjected to vacuum distillation for removal of solvent, dissolved with water, and extracted 3 times with ethyl acetate. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: ethyl acetate/methanol/ammonia), to give 1.63 g of a white foamy solid product, yield 80.5%. [0091] 1H-NMR (400 MHz, CDCl3) delta ppm: 8.77 (1H, m), 8.02 (1H, m), 7.43 (1H, m), 7.31 (1H, m), 7.20 (1H, m), 7.05 (1H, m), 6.56 (1H, m), 4.85 (2H, d, J = 5.2 Hz), 4.02-3.44(10H, brm), 3.13 (1H, m), 2.83 (2H, m), 2.44 (2H, m), 2.02 (9H, s); EI-MS (m/z): 618.2 [M+H]+.

Reference： [1]Patent: EP2805947,2014,A1 .Location in patent: Paragraph 0090-0091
[2]Molecules,2012,vol. 17,p. 9961 - 9970

7
[ 114525-81-4 ]
[ 1436422-32-0 ]
[ 1436423-27-6 ]

Yield	Reaction Conditions	Operation in experiment
	With HATU; In N,N-dimethyl-formamide; at 20℃; for 12h;	To a solution of Intermediate 3 (0.2g, 0.419 mmol) in DMF (5 mL), were added (R)-4- (teri-butoxycarbonyl)thiomorpholine-3-carboxylic acid (0.104 g, 0.419 mmol) and 2-(3H- [1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-l , 1 ,3,3-tetramethylisouronium hexafluorophosphate(V) (0.191 g, 0.503 mmol) at an ambient temperature. After stirring for 12 h, the reaction was extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure to give Compound 454 and was treated with 4.0 M HQ in dioxane (5mL). After 5 h, the reaction was concentrated under reduced pressure, neutralized with 2.0 M NaOH and then extracted with ethyl acetate. The organic layer was dried over MgS04 and concentrated under reduced pressure to give the crude title compound, which was used for the next step without further purification (0.169 g, 66.9 ). LCMS m/z = 606.50.10 [M+H]+.

Reference： [1]Patent: WO2013/70657,2013,A1 .Location in patent: Page/Page column 173

8
[ 114525-81-4 ]
[ 28920-43-6 ]
(R)-4-[{(9H-fluoren-9-yl)methoxy}carbonyl]thiomorpholine-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.00 g		Trifluoroacetic acid (4 mL, 23.5 mmol) was added to a stirred solution of (R)-4-(tert- butoxycarbonyl)thiomorpholine-3-carboxylic acid (1.0 g, 4.05 mmol) in CH2CI2 (20 mL), and the reaction mixture was stirred at room temperature for 2 h. Volatile byproducts were removed at reduced pressure and the residue was concentrated from toluene (2 x 20 mL) and dried under high vacuum for 30 min. The crude residue was dissolved in 1,4-dioxane (10 mL) and water (10 mL) was added followed by NaHCC (1.02 g, 12.15 mmol) and a solution of FMOC-C1 (1.04 g, 4.05 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to remove volatile organic solvent and the residue was washed with MTBE (2 x 20 mL). The aqueous layer was acidified with IN aqueous HC1 to pH 2 and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous a2S04, filtered and concentrated. The residue was purified by reverse phase column chromatography (CI 8; eluent: 10-100% acetonitrile/water) to afford the title compound (1.00 g) as a white semi-solid.

Reference： [1]Patent: WO2013/148478,2013,A1 .Location in patent: Page/Page column 37; 38

9
[ 114525-81-4 ]
(R)-(9H-fluoren-9-yl)methyl-3-[2-{(tert-butoxycarbonylamino)methyl}-5-chlorobenzylcarbamoyl]thiomorpholine-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2013/148478,2013,A1
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1111 - 1115

10
[ 114525-81-4 ]
(R)-tert-butyl-4-chloro-2-{(thiomorpholine-3-carboxamido)-methyl}-benzyl-carbamate [ No CAS ]

Reference： [1]Patent: WO2013/148478,2013,A1
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1111 - 1115

11
[ 114525-81-4 ]
(R)-1-((R)-3-[2-{(tert-butoxycarbonylamino)methyl}-5-chlorobenzylcarbamoyl]thiomorpholino)-3,3-dimethyl-1-oxobutan-2-yl [ No CAS ]