[ CAS No. 474707-30-7 ] {[proInfo.proName]}

Name: 474707-30-7|(R)-3-Methoxypyrrolidine hydrochloride|95%
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Quality Control of [ 474707-30-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 474707-30-7 ]

Product Details of [ 474707-30-7 ]

CAS No. :	474707-30-7	MDL No. :	MFCD11849816
Formula :	C₅H₁₂ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SQMYKVUSWPIFEQ-NUBCRITNSA-N
M.W :	137.61	Pubchem ID :	45789898
Synonyms :

Calculated chemistry of [ 474707-30-7 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	38.8
TPSA :	21.26 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) :	-6.68 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.65
Log Po/w (WLOGP) :	0.42
Log Po/w (MLOGP) :	0.21
Log Po/w (SILICOS-IT) :	0.85
Consensus Log Po/w :	0.43

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.04
Solubility :	12.6 mg/ml ; 0.0919 mol/l
Class :	Very soluble
Log S (Ali) :	-0.67
Solubility :	29.3 mg/ml ; 0.213 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.86
Solubility :	19.0 mg/ml ; 0.138 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.55

Safety of [ 474707-30-7 ]

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 [ 474707-30-7 ]

* 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.

Upstream synthesis route of [ 474707-30-7 ]
Downstream synthetic route of [ 474707-30-7 ]

[ 474707-30-7 ] Synthesis Path-Upstream 1~1

1
[ 549532-08-3 ]
[ 474707-30-7 ]

Yield	Reaction Conditions	Operation in experiment
1000 mg	With hydrogenchloride In 1,4-dioxane at 20℃; for 16 h;	A mixture of tert-butyl (3R)-3-methoxypyrrolidine-l-carboxylate (1100 mg, 5.47 mmol) in 4M HCl/dioxane (15 mL, 60 mmol) was stirred at 20 °C for 16 hours to give a mixture. The reaction mixture was concentrated to give the crude (1000 mg, 7.27 mmol) as an oil. *H NMR CDC13, 400MHz δ_H = 10.10 - 9.39 (m, 2H), 4.13 - 4.04 (m, 1H), 3.51 - 3.35 (m, 4H), 3.31 (s, 3H), 2.24 - 2.12 (m, 1H), 2.08 - 1.95 (m, 1H).

Reference： [1] Patent: WO2005/49616, 2005, A1, . Location in patent: Page/Page column 79
[2] Patent: WO2005/97799, 2005, A1, . Location in patent: Page/Page column 125-126
[3] Patent: WO2004/37809, 2004, A1, . Location in patent: Page 50
[4] Patent: WO2018/148745, 2018, A1, . Location in patent: Page/Page column 168

[ 474707-30-7 ] Synthesis Path-Downstream 1~26

1
[ 549532-08-3 ]
[ 474707-30-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In dichloromethane; at 0 - 20℃; for 48h;	Hydrogen chloride gas was bubbled through an ice-cooled solution of the compound from preparation 1 (6. 02g, 30. Ommol) in dichloromethane (30mL), and the reaction then allowed to warm to room temperature and stirred for 48 hours. The solution was concentrated under reduced pressure and the residue triturated with ether. The resulting crystals were filtered off and dried in vacuo to afford the title compound. 'H NMR(CD30D, 400MHz) b : 2.06 (m,1H), 2.20 (m,1H), 3.26-3. 42 (m, 7H), 4.17 (m,1H).
	With hydrogenchloride; In dichloromethane; at 0 - 20℃; for 48h;	Preparation 45; (3R)-3-Methoxypyrrolidine hydrochloride; Hydrogen chloride gas was bubbled through an ice-cooled solution of the compound from preparation 43 (6.02g, 30.0mmol) in dichloromethane (30mL), and the reaction then allowed to warm to room temperature and stirred for 48 hours. The solution was concentrated under reduced pressure and the residue triturated with ether. The resulting crystals were filtered off and dried in vacuo to afford the title compound. ¹H NMR (CD30D, 400MHz) 8: 2.06 (m, 1 H), 2.20 (m, 1 H), 3.26-3.42 (m, 7H), 4.17 (m, 1 H).
	With hydrogenchloride; In 1,4-dioxane; at 0 - 20℃; for 4h;	A solution of HCI in dioxan (4M, 13ML) was added drop wise to an ice-cooled solution of the product of preparation 46 (2.12g, 10. 5MMOL) in dioxan (2ML). The reaction was allowed to warm to room temperature and stirred for a further 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue azeotroped with ether. The solid was triturated with ether, and the solid filtered off and DRIED IN VACUO to give the product as a brown oil, 1.34g.

1000 mg

With hydrogenchloride; In 1,4-dioxane; at 20℃; for 16h;

A mixture of tert-butyl (3R)-3-methoxypyrrolidine-l-carboxylate (1100 mg, 5.47 mmol) in 4M HCl/dioxane (15 mL, 60 mmol) was stirred at 20 C for 16 hours to give a mixture. The reaction mixture was concentrated to give the crude (1000 mg, 7.27 mmol) as an oil. *H NMR CDC13, 400MHz deltaH = 10.10 - 9.39 (m, 2H), 4.13 - 4.04 (m, 1H), 3.51 - 3.35 (m, 4H), 3.31 (s, 3H), 2.24 - 2.12 (m, 1H), 2.08 - 1.95 (m, 1H).

Reference： [1]Patent: WO2005/49616,2005,A1 .Location in patent: Page/Page column 79
[2]Patent: WO2005/97799,2005,A1 .Location in patent: Page/Page column 125-126
[3]Patent: WO2004/37809,2004,A1 .Location in patent: Page 50
[4]Patent: WO2018/148745,2018,A1 .Location in patent: Page/Page column 168

2
[ 474707-30-7 ]
[ 474707-29-4 ]

Yield	Reaction Conditions	Operation in experiment
		Production Example 84 6-Bromo-4-[(3R)-3-methoxytetrahydro-1H-1-pyrrolyl]quinoline 500 mg 6-bromo-4-chloroquinoline and 300 mg (3R) -3-methoxy pyrrolidine monohydrochloride were reacted by the same method as in Production Example 82, to give 284 mg of the title compound as a yellow oil.1H-NMR (CDCl3) delta: 2.00-2.15(m, 1H), 2.20-2. 30 (m, 1H), 3.39(s, 3H), 3.60-3.71(m, 2H), 3. 83-3. 92 (m, 2H), 4.10-4.16(m, 1H), 6.47 (d, J=7.4Hz, 1H), 7.64(d, J=8.4Hz, 1H), 7.83(d, J=8.4Hz, 1H), 8.33(s, 1H), 8.48(d, J=7.4Hz, 1H)

Reference： [1]Patent: EP1382603,2004,A1 .Location in patent: Page 72

4
[ 800400-48-0 ]
[ 474707-30-7 ]
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [1-(S)-(4-fluorobenzyl)-2-(3-(R)-methoxypyrrolidin-1-yl)-2-oxoethyl]amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h;	To a solution of 2-(S)-[(5-chloro-1H-pyrrolo [2,3-c] pyridine-2- carbonyl) amino] -3-phenylpropionic acid (EXAMPLE 42,104mg, 0. 29MMOL) and (R) -3-methoxypyrrolidine hydrochloride (Preparation 70,40mg, 0. 29MMOL) in DMF (5ML) was added HOBt (44mg, 0. 29mmol), DIPEA (0. 15mL, 0. 88mmol) and EDCI (66mg, 0. 344MMOL). After stirring at rt for 12h the mixture was added to diluted brine (lOOmL, water/brine: 1/1). Extraction with ethyl acetate (4 x 25mL), washing of the combined extracts with brine (50ML) and drying (MGS04) gave, after concentration, a residue which was recrystallised from acetonitrile to give the title compound as a colourless solid. m/z (ES+) = 445.31 [M+ H] + ; RT = 3.36min.

Reference： [1]Patent: WO2004/104001,2004,A2 .Location in patent: Page 113

5
[ 474707-30-7 ]
[ 287714-35-6 ]
[ 1314019-94-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 140℃; for 0.5h;Microwave irradiation;	1.3.1 Intermediate 10 ADiisopropylethylamine (1.5 mL, 8.7 mmol) was added to a mixture of methyl 2- chloropyrimidine-5-carboxylate (0.5 g, 2.9 mmol) and <strong>[474707-30-7](3R)-3-methoxypyrrolidine hydrochloride</strong> (0.48 g, 3.48 mmol) in acetonitrile (6 mL) and the mixture was micro waved at 140 C for 30 min. The reaction was diluted with ethyl acetate (20 mL), water (10 mL) and sodium carbonate (sat., aq., 10 mL). The phases were separated and the aqueous phase was re- extracted with ethyl acetate (2 x 20 mL) and the combined organic phases were washed with water (10 mL), brine (2 x 10 mL), dried (MgS04), filtered and concentrated. The residue was purified by silica chromatography, 0-100% ethyl acetate in petrol to give product as a light yellow solid methyl 2-[(3R)-3-methoxypyrrolidin-l-yl]pyrimidine-5-carboxylate (0.66 g, 95 % yield). NMR (400 MHz, CD3OD) delta 8.80 (s, 2H), 4.10 - 4.16 (m, 1H), 3.86 (s, 3H), 3.71 - 3.81 (m, 2H), 3.55 - 3.70 (m, 2H), 3.36 (s, 3H), 2.04 - 2.24 (m, 2H)MS (ES+) 238
95%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 140℃; for 0.5h;Microwave irradiation;	Intermediate 10A; Diisopropylethylamine (1.5 mL, 8.7 mmol) was added to a mixture of methyl 2-chloropyrimidine-5-carboxylate (0.5 g, 2.9 mmol) and <strong>[474707-30-7](3R)-3-methoxypyrrolidine hydrochloride</strong> (0.48 g, 3.48 mmol) in acetonitrile (6 mL) and the mixture was microwaved at 140 C. for 30 min. The reaction was diluted with ethyl acetate (20 mL), water (10 mL) and sodium carbonate (sat., aq., 10 mL). The phases were separated and the aqueous phase was re-extracted with ethyl acetate (2×20 mL) and the combined organic phases were washed with water (10 mL), brine (2×10 mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica chromatography, 0-100% ethyl acetate in petrol to give product as a light yellow solid methyl 2-[(3R)-3-methoxypyrrolidin-1-yl]pyrimidine-5-carboxylate (0.66 g, 95% yield).1H NMR (400 MHz, CD3OD) delta 8.80 (s, 2H), 4.10-4.16 (m, 1H), 3.86 (s, 3H), 3.71-3.81 (m, 2H), 3.55-3.70 (m, 2H), 3.36 (s, 3H), 2.04-2.24 (m, 2H)MS (ES+) 238

Reference： [1]Patent: WO2011/83314,2011,A1 .Location in patent: Page/Page column 21-22
[2]Patent: US2011/172204,2011,A1 .Location in patent: Page/Page column 8

6
[ 474707-30-7 ]
[ 1314040-66-8 ]
[ 1314040-64-6 ]

Yield	Reaction Conditions	Operation in experiment
49%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 140℃; for 4h;Microwave irradiation;	Step b)Example 16 A 5 ml microwave vial was charged with 6-chloro-2-((3-cyclopentyl-2,3,4,5-tetrahydro- l H-3- benzazepin-7-yl)methyl)-lH-pyrrolo[3,4-c]pyridin-3(2H)-one ¾(Int 18) (125 mg, 0.32 mmol),<strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> (130 mg; 0.95 mmol), and DIPEA (0.28 ml, 1.58 mmol) in MeCN (7 ml). The reaction was irradiated in the microwave at 140 C for 3 h. Further (/?)-3-methoxypyrrolidine hydrochloride (43 mg, 0.32 mmol) and DIPEA (0.06 ml, 0.32 mmol) were added and the reaction heated to 140 C under microwave conditions for a further hour. The reaction was diluted with EtOAc and washed with sodium carbonate (x 3). The combined organics were dried over MgSC^, evaporated to dryness and purified by column chromatography eluting with 30-100 % EtOAc/petrol to yield (R)-2-((3-Cyclopentyl-2,3,4,5- tetrahydro-lH-3-benzazepin-7-yl)methyl)-6-(3-methoxypyrrolidin-l-yl)-lH-pyrrolo[3,4- c]pyridin-3(2H)-one as a white solid (71 mg, 49 %). NMR (400 MHz, DMSO-d6) delta 8.41 (s, 1H), 7.03 - 7.10 (mi 1H), 6.92 - 7.00 (m, 2H), 6.54 (s, 1H), 4.56 (s, 2H), 4.26 (s, 2H), 4.06 - 4.12 (m, 1H), 3.49 - 3.59 (m, 3H), 3.38 - 3.46 (m, 1 H), 3.25 (s, 3H), 2.75 - 2.87 (m, 5H), 2.53 - 2.62 (m, 4H), 2.03 - 2.12 (m, 2H), 1.70 - 1.81 (m, 2H), 1.53 - 1.64 (m, 2H), 1.41 - 1.53 (m, 2H), 1.31 - 1.41 (m, 2H). MS (ES+) 461

Reference： [1]Patent: WO2011/83316,2011,A1 .Location in patent: Page/Page column 44-45

7
[ 474707-30-7 ]
[ 20263-26-7 ]
[ 1443992-94-6 ]

Yield	Reaction Conditions	Operation in experiment
420 mg	With trifluoromethylsulfonic anhydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at -78 - 20℃; for 3h;	Triflic anhydride (1M in DCM, 1.67 mL, 1.67 mmol) was added to a solution of (R)-l- (trityloxy)propan-2-ol (505 mg, 1.59 mmol) and diisopropylethylamine (0.55 mL, 3.16 mmol) in DCM (10 mL) at -78 C . The reaction was allowed to warm to -20 C over 1 h. Diisopropylethylamine (0.32 mL, 1.84 mmol) and <strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> (255 mg, 1.85 mmol) were added to the reaction and the mixture was allowed to warm to room temperature over 3h. The reaction mixture was washed with 2 x10 mL saturated aqueous NaHC03, washed with 10 mL brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to yield (R)-3-methoxy-l-((S)-l-(trityloxy)propan-2-yl)pyrrolidine (420 mg). 'H NMR (DMSO-de): delta 7.40-7.20 (m, 15H), 3.76 (m, 1H), 3.26 (m, 1H), 3.11 (s, 3H), 3.09 (m, 1H), 2.82 (m, 1H), 2.64 (m, 1H), 2.48 (m, 1H), 2.38 (m, 2H), 1.84 (m, 1H), 1.55 (m, 1H), 1.05 (d, 3H).

Reference： [1]Patent: WO2013/90829,2013,A1 .Location in patent: Paragraph 00361

8
[ 474707-30-7 ]
1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid [ No CAS ]
(1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3R)-3-methoxypyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.074 g	With triethylamine; HATU; In N,N-dimethyl-formamide; at 10 - 35℃; for 3h;	Example 304 (1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidin-4-yl)((3R)-3-methoxypyrrolidin-1-yl)methanone A mixture of 1-(4-(4-fluorophenyl)pyrimidin-5-yl)piperidine-4-carboxylic acid (0.10 g), <strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> (50 mg), HATU (0.16 g), triethylamine (0.19 mL) and DMF (1.1 mL) was stirred at room temperature for 3 hr. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.074 g). 1H NMR (300 MHz, CDCl3) delta 1.66-2.22 (6H, m), 2.31-2.51 (1H, m), 2.58-2.76 (2H, m), 3.21-3.38 (5H, m), 3.39-3.77 (4H, m), 3.90-4.07 (1H, m), 7.16 (2H, t, J = 8.7 Hz), 8.15 (2H, dd, J = 8.7, 5.7 Hz), 8.41 (1H, s), 8.90 (1H, s).

Reference： [1]Patent: EP2933247,2015,A1 .Location in patent: Paragraph 0439

9
[ 474707-30-7 ]
1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid [ No CAS ]
(1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3R)-3-methoxypyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.076 g	With triethylamine; HATU; In N,N-dimethyl-formamide; at 10 - 35℃; for 3h;	Example 300 (1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)((3R)-3-methoxypyrrolidin-1-yl)methanone A mixture of 1-(4-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid (0.10 g), <strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> (49 mg), HATU (0.16 g), triethylamine (0.18 mL) and DMF (1.1 mL) was stirred at room temperature for 3 hr. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was crystallized from ethyl acetate/hexane to give the title compound (0.076 g). 1H NMR (300 MHz, CDCl3) 5 1.73-2.20 (6H, m), 2.36-2.55 (1H, m), 2.68-2.83 (2H, m), 3.13 (2H, dd, J = 11.4, 3.0 Hz), 3.34 (3H, d, J = 5.3 Hz), 3.41-3.76 (4H, m), 3.92-4.07 (1H, m), 7.60 (1H, d, J = 5.3 Hz), 7.66 (1H, s), 8.39 (1H, d, J = 5.3 Hz), 8.45 (1H, s), 8.60 (1H, s).

Reference： [1]Patent: EP2933247,2015,A1 .Location in patent: Paragraph 0435

10
[ 474707-30-7 ]
1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidine-4-carboxylic acid [ No CAS ]
((3R)-3-methoxypyrrolidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.039 g	With triethylamine; HATU; In N,N-dimethyl-formamide; at 10 - 35℃; for 3h;	Example 302 ((3R)-3-methoxypyrrolidin-1-yl)(1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)methanone A mixture of 1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-ylypiperidine-4-carboxylic acid (100 mg), <strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> (53 mg), HATU (0.17 g), triethylamine (0.20 mL) and DMF (1.2 mL) was stirred at room temperature for 3 hr. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.039 g). 1H NMR (300 MHz, CDCl3) delta 1.72-2.21 (9H, m), 2.33-2.55 (1H, m), 2.72 (2H, td, J = 12.0, 2.5 Hz), 3.14 (2H, d, J = 12.1 Hz), 3.34 (3H, d, J = 5.3 Hz), 3.43-3.76 (4H, m), 3.90-4.11 (1H, m), 7.53 (1H, s), 7.61 (1H, d, J = 4.9 Hz), 8.29-8.43 (3H, m).

Reference： [1]Patent: EP2933247,2015,A1 .Location in patent: Paragraph 0437

11
[ 474707-30-7 ]
(6-bromo-imidazo[1,2-a]pyridine)-3-sulfonyl chloride [ No CAS ]
(R)-6-bromo-3-((3-methoxypyrrolidin-1-yl)sulfonyl)imidazo[1,2-a]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With triethylamine; In dichloromethane; at 20℃; for 2h;	TEA (0.71 mL, 5.0755 mmol) was added to a room temperature stirred solution of (S)-3-methoxypyrrolidine hydrochloride (0.349 g, 2.5377 mmol) in DCM (5 mL), followed by the addition of a solution of Intermediate 3 (0.5 g, 1.6918 mmol) in DCM (5 mL). The reaction mixture was stirred at rt for 2h and, after completion, was concentrated under reduced pressure. The product obtained was purified by silica gel chromatography using a gradient of 50-70% ethyl acetate in hexane as eluent. The fractions were combined and concentrated to afford the title compound (0.2 g, 33%) as a semisolid; MH+360.14;

Reference： [1]Patent: WO2017/66876,2017,A1 .Location in patent: Page/Page column 109; 110

12
[ 474707-30-7 ]
[ 540-51-2 ]
2-[(3R)-3-methoxypyrrolidin-1-yl]ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In acetonitrile; at 20℃; for 18h;	Step 1. Synthesis of 2-[(3R)-3-methoxypyrrolidin-1-yl]ethanol A solution of <strong>[474707-30-7](3R)-3-methoxypyrrolidine hydrochloride</strong> (282 mg, 2.05 mmol), 2-bromoethanol (0.145 mL, 2.05 mmol), and potassium carbonate (566 mg, 4.10 mmol) in CH3CN (8.0 mL) was stirred at room temperature for 18 h. The solution was filtered off and washed with CH2Cl2. The filtrate was concentrated and dried under high vacuum to give 2-[(3R)-3-methoxypyrrolidin-1-yl]ethanol (308 mg, quantitative yield) as a colorless oil which was directly used to next step without further purification. 1H NMR (CDCl3, 400 MHz) delta 3.95-3.90 (m, 1H), 3.63 (dd, 2H), 3.27 (s, 3H), 2.80-2.72 (m, 2H), 2.67-2.63 (m, 3H), 2.56-2.50 (m, 1H), 2.11-2.02 (m, 1H), 1.85-1.79 (m, 1H).

Reference： [1]Patent: US2017/253569,2017,A1 .Location in patent: Paragraph 1076-1077

13
[ 474707-30-7 ]
[ 15448-47-2 ]
(R)-1-((R)-3-methoxypyrrolidin-1-yl)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With triethylamine; at 65℃; for 18h;Sealed tube;	In a sealed tube, <strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> (1.00 g, 7.27 mmol), TEA (2.03 mL, 14.5 mmol) and R-(+)-Propylene oxide (1.27 mL, 18.2 mmol) were heated to 65C for 18 hours. The reaction was cooled and concentrated in vacuo. The resulting residue was purified by silica gel (0-12% MeOH in DCM) to provide (R)-l-((R)-3 -methoxypyrrolidin- 1- yl)propan-2-ol (775 mg, 4.87 mmol, 67.0 % yield).
67%	With triethylamine; at 65℃; for 18h;Sealed tube;	In a sealed tube, <strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> (1.00 g, 7.27 mmol), TEA (2.03 mL, 14.5 mmol) and R-(+)-Propylene oxide (1.27 mL, 18.2 mmol) were heated to 65° C. for 18 hours. The reaction was cooled and concentrated in vacuo. The resulting residue was purified by silica gel (0-12% MeOH in DCM) to provide (R)-1-((R)-3-methoxypyrrolidin-1-yl)propan-2-ol (775 mg, 4.87 mmol, 67.0% yield).

Reference： [1]Patent: WO2017/201161,2017,A1 .Location in patent: Paragraph 0184
[2]Patent: US2019/144444,2019,A1 .Location in patent: Paragraph 0304-0305

14
[ 474707-30-7 ]
[ 645-00-1 ]
(R)-3-methoxy-1-(3-nitrophenyl)pyrrolidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 16h;	To a solution of 1-iodo-3-nitrobenzene (0.2 g, 0.80 mmol) and (R)-3-methoxy-pyrrolidine hydrochloride (0.11 g, 0.80 mmol) in 1,4-dioxane (4 ml) was added Cs2CO3 (0.65 g, 2.0 mmol) at rt. The reaction mixture was degassed for 10 mm before adding Pd2(dba)3 (0.037 g, 0.04 mmol) andXantphos (0.023 g, 0.04 mmol) and then heating at 110C for 16 h. The resulting mixture was poured into water (40 ml) and extracted with EtOAc (2 x 15 ml). The combined organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure to yielding (R)-3-methoxy-1-(3- nitrophenyl)pyrrolidine (0.2 g, quantitative). This material was used directly for the next step without further purification. LCMS: Method C, 2.24 mi MS: ES+ 223.16.

Reference： [1]Patent: WO2017/93718,2017,A1 .Location in patent: Page/Page column 65; 66

15
[ 474707-30-7 ]
tert-butyl (R)-3-(5-(2-chloropyridin-4-yl)-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)pyrrolidine-1-carboxylate [ No CAS ]
tert-butyl (R)-3-(5-(2-((R)-3-methoxypyrrolidin-1-yl)pyridin-4-yl)-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; In toluene; at 110℃; for 48h;	To a solution of tert-butyl (R)-3-(5-(2-chloropyridin-4-yl)- 1,1 -dioxido- 1 ,2,5-thiadiazolidin-2-yl)pyrrolidine-1-carboxylate (0. lOg, 0.24 mmol) in toluene (3 ml) was added(R)-3-methoxy-pyrrolidine hydrochloride (0.07g, 0.50 mmol) at rt. NaOtBu (0.04 g, 0.49 mmol) andRuPhose (0.Olg, 0.02 mmol) was added in to reaction mixture and degassed for 15 mm. Pd2(dba)3(0.02 g, 0.02 mmol) was added in to reaction mixture and heated at 110C for 48 hrs. The resultingreaction mixture was poured into water (50 ml) and extracted with EtOAc (3 x 15 ml). The combined organic layer was washed with brine solution (50 ml). The organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (5% MeOH in DCM) yielding tert-butyl (R)-3-(5-(2-((R)-3-methoxypyrrolidin- 1 -yl) pyridin-4-yl)- 1,1 -dioxido- 1 ,2,5-thiadiazolidin-2-yl)pyrrolidine- 1 -carboxylate (0.20 g, quantitative). LCMS: Method C, 1.87 mi MS: ES+ 468.61.

Reference： [1]Patent: WO2017/93718,2017,A1 .Location in patent: Page/Page column 66

16
[ 474707-30-7 ]
[ 1369485-80-2 ]
C₁₀H₁₃N₅O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25.42%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 0 - 180℃; for 2h;Microwave irradiation;	To a mixture of 48.1 (0.5g, 2.5mmol, 1.Oeq) in Nmethylpyrrolidine (2mL) and (R)-3 -methoxypyrrolidine hydrgochloride (0.41 g, 3. Ommol, 1. 2eq) was added di-isopropyl ethyl amine (0.8mL, 6.25mmol, 2.5eq) at 0C. Reaction mixture was stirred at 180C 2h in microwave. Upon completion, reaction mixture was transferred into cold water, extracted with ethyl acetate. Organic layers were combined, dried over Na2SO4 and concentrated in vacuo to obtain crude product. This was purified by column chromatography and compound was eluted in 30% ethyl acetate in hexane as eluant to obtain pure 48.2 (0. 140g, 25.42%). MS(ES) : m/z 220.25 [M+H]t

Reference： [1]Patent: WO2018/75937,2018,A1 .Location in patent: Paragraph 00458; 00459

17
[ 474707-30-7 ]
[ 1369485-80-2 ]
C₁₀H₁₃N₅O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25.42%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 0 - 180℃; for 2h;Microwave irradiation;	To compound of 117.1 (0.5g, 2.5mmol, 1.Oeq) in N- methyl pyrrolidine (lmL) compound <strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> 1.1 (0.41g, 3 .Ommol, 1 .2eq) was added followed by addition of di-isopropylethylamine (1 .OmL, 6.2mmol, 2.5eq) dropwise at 0C. Reaction mixture was stirred at 180C 2h in microwave. Upon completion, reaction mixture was transferred into cold water extracted with ethyl acetate. Organic layer combined, dried over Na2SO4 and concentrated in vacuo to obtain crude product. This was purified by column chromatography using 30% ethyl acetate in hexane as eluant to obtain pure 117.2 (0.140g, 25.42%). MS(ES) : m/z 220.25 [M+H]t

Reference： [1]Patent: WO2018/75937,2018,A1 .Location in patent: Paragraph 00653; 00654

18
[ 474707-30-7 ]
{2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3(2H)-yl}acetic acid [ No CAS ]
C₂₁H₁₉F₃N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 25℃; for 2h;	To the mixture of 2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]-l,3-benzoxazol-3- yljacetic acid (200 mg, 0.57 mmol), <strong>[474707-30-7](3R)-3-methoxypyrrolidine hydrochloride</strong> (116.87 mg, 0.85 mmol) and HATU (645.83 mg, 1.7 mmol) in DMF (3 mL) was added the DIPEA (0.3 mL, 1.7 mmol). And the mixture was stirred at 25 C for 2 hours to give the solution. The mixture was diluted with H20 (10 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SC>4, filtered. The filtrate was concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE : EtOAc = 1 : 1) to give the impure product. The impure product was further purified by triturating from z-Pr20 (2 mL) to give the product (81.18 mg, 0.18 mmol, 33% yield) as a solid. 1H NMR DMSO-i+D20 400MHz deltaH = 7.69 (d, 2H), 7.43 - 7.35 (m, 5H), 4.77 - 4.59 (m, 2H), 4.10 - 3.94 (m, 1H), 3.69 - 3.41 (m, 3H), 3.34 - 3.18 (m, 4H), 2.13 - 1.83 (m, 2H). LCMS Rt = 1.26 min in 2.0 min chromatography, MS ESI calcd. for C2iH20F3N2O5 [M+H]+ 437.1, found 436.8.

Reference： [1]Patent: WO2018/148745,2018,A1 .Location in patent: Page/Page column 168

19
[ 474707-30-7 ]
9-chloro-6-(3-chloropropoxy)-7-methoxy-1H,2H,3H-cyclopenta[b]quinoline [ No CAS ]
(3R)-1-[3-({9-chloro-7-methoxy-1H,2H,3H-cyclopenta[b]quinolin-6-yl}oxy)propyl]-3-methoxypyrrolidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%		A mixture of (3R)-3-methoxypynolidine hydrochloride (101.24 mg; 0.74 mmol; 2.00 eq.), Hunigs base (95.08 mg; 0.74 mmol; 2.00 eq.) in N,N-dimethylformamide (2.40 mL) was allowed tostir at rt for 20 mm. To the mixture was added 9-chloro-6-(3-chloropropoxy)-7-methoxy-1H,2H,3H- cyclopenta[b]quinoline (Intermediate 6) (120.00 mg; 0.37 mmol; 1.00 eq.), cesium carbonate (479.41 mg; 1.47 mmol; 4.00 eq.) and KI (30.53 mg; 0.18 mmol; 0.50 eq.) The resulting mixture was heated at 90 C for 1 hr and the allowed to left at rt for 14 h. The solid was filtered through a small pad of celite. The filtrate was treated with slow addition of water and extracted twice with EtOAc(twice) and 25% ?PrOH/ CHC13. The combined organic layers were dried over Mg504, filtered andconcentrated. The remaining residue was purified by chromatography on silica gel using 1%NH4OH/9%MeOH/90%CH2C12 to provide the product as brown solid as off-white solid (90 mg,63%). LCMS (ES) [M+1] mlz 390.8

Reference： [1]Patent: WO2019/36384,2019,A1 .Location in patent: Page/Page column 155

20
[ 474707-30-7 ]
ethyl 2-((1-(pyridin-3-yl)propyl)amino)thieno[3,2-d]pyrimidine-4-carboxylate [ No CAS ]
((R)-3-methoxypyrrolidin-1-yl)(2-((1-(pyridin-3-yl)propyl)amino)thieno[3,2-d]pyrimidin-4-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	General procedure: To a solution of 2-[[(l,S)-l-(3- pyridyl)ethyl]amino]thieno[3,2-<i]pyrimidine-4-carboxylic acid dihydrochloride (37 mg, 0.1 mmol) in DMF (2 mL) were added (3R)-3-fluoropyrrolidine hydrochloride (19 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol), and DIEA (87 uL, 0.5 mmol). The mixture thus obtained was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 5% NaHCC , water, and brine, then dried over MgS04. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (12 g HP silica, Teledyne Isco) eluting with 10% to 50% solvent A (DCM/MeOH/NH4OH, 100/10/1) in DCM to provide ((R)-3-fluoropyrrolidin-l-yl)(2-(((5)-l-(pyridin-3- yl)ethyl)amino)thieno[3,2-<i]pyrimidin-4-yl)methanone (31 mg, 84% yield) as a light yellow solid. MR (400 MHz, CDCb) delta 1.64 (3H, d, J= 7.2 Hz), 1.99 (1H, m), 2.27 (1H, m), 3.60-3.86 (2H, m), 3.97-4.15 (2H, m), 4.43 (1H, m), 5.20 (1H, m), 5.43 (1H, d, J= 6.4 Hz), 7.18 (1H, d, J= 5.2 Hz), 7.25 (1H, m), 7.71 (1H, dt, J= 6.4, 1.6 Hz), 7.96 (1H, t, J= 6.0 Hz), 8.49 (1H, dd, J= 4.8, 1.6 Hz), 8.69 (1H, d, J= 1.6 Hz) ppm. LCMS m/z = 372.2 [M+H+].

Reference： [1]Patent: WO2019/46784,2019,A1 .Location in patent: Paragraph 0785; 0786; 0823; 0824

21
[ 474707-30-7 ]
N-(1-benzyl-1H-pyrazol-4-yl)-5-chloroisoxazole-3-carboxamide [ No CAS ]
(R)-N-(1-benzyl-1H-pyrazol-4-yl)-5-(3-methoxypyrrolidin-1-yl)isoxazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1h;	Example 73. Preparation of (R)-N-(1-benzyl-1H-pyrazol-4-yl)-5-(3-methoxypyrrolidin-1-yl)isoxazole-3-carboxamide (188) To a solution of N-(1-benzyl-1H-pyrazol-4-yl)-5-chloroisoxazole-3-carboxamide (0.1 g, 0.331 mmol) and <strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> (113 mg, 0.828 mmol) in N,N-dimethylformamide (3.0 mL) was added potassium carbonate (68 mg, 0.497 mmol). The reaction mixture was heated to 90 C. and stirred for 1 h. The crude sample was dissolved in minimum amount of N,N-dimethylformamide and purified by prep-HPLC (Boston C18 21*250 mm 10 mum column. The mobile phase was acetonitrile/10 mM ammonium acetate aqueous solution) to give (R)-N-(1-benzyl-1H-pyrazol-4-yl)-5-(3-methoxypyrrolidin-1-yl)isoxazole-3-carboxamide (21.1 mg, 0.057 mmol, 17%) as a light yellow solid. 1H NMR (500 MHz, Dimethylsulfoxide-d6) delta 10.64 (s, 1H), 8.11 (s, 1H), 7.63 (s, 1H), 7.35-7.22 (m, 5H), 5.41 (s, 1H), 5.31 (s, 2H), 4.09-4.08 (m, 1H), 3.52-3.36 (m, 4H), 3.26 (s, 3H), 2.08-2.03 (m, 2H); LCMS (ESI) m/z: 368.0 [M+H]+.

Reference： [1]Patent: US2019/330198,2019,A1 .Location in patent: Paragraph 1085

22
[ 474707-30-7 ]
N-(1-benzyl-1H-pyrazol-4-yl)-5-chloroisoxazole-3-carboxamide [ No CAS ]
(S)-N-(1-benzyl-1H-pyrazol-4-yl)-5-(3-methoxypyrrolidin-1-yl)isoxazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1h;	Example 71. Preparation of (S)-N-(1-benzyl-1H-pyrazol-4-yl)-5-(3-methoxypyrrolidin-1-yl)isoxazole-3-carboxamide (189) To a solution of N-(1-benzyl-1H-pyrazol-4-yl)-5-chloroisoxazole-3-carboxamide (0.1 g, 0.331 mmol), <strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> (0.136 g, 0.993 mmol) in N,N-dimethylformamide (3.0 mL) was added potassium carbonate (0.068 g, 0.497 mmol). The reaction mixture was heated at 90 C. for 1 h, cooled to room temperature and concentrated in vacuo. The crude sample was dissolved in minimum amount of N,N-dimethylformamide and purified by prep-HPLC (Boston C18 21*250 mm 10 mum column. The mobile phase was acetonitrile/10 mM ammonium acetate aqueous solution) to give (R)-N-(1-benzyl-1H-pyrazol-4-yl)-5-(3-methoxypyrrolidin-1-yl)isoxazole-3-carboxamide (19.0 mg, 0.052 mmol, 15%) as a light yellow solid. 1H NMR (500 MHz, Dimethylsulfoxide-d6) delta 10.64 (s, 1H), 8.11 (s, 1H), 7.63 (s, 1H), 7.35-7.22 (m, 5H), 5.41 (s, 1H), 5.31 (s, 2H), 4.09-4.08 (m, 1H), 3.52-3.36 (m, 4H), 3.26 (s, 3H), 2.09-2.03 (m, 2H); LCMS (ESI) m/z: 368.2 [M+H]+.

Reference： [1]Patent: US2019/330198,2019,A1 .Location in patent: Paragraph 1078

23
[ 474707-30-7 ]
2-(5-amino-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-phenylpropanoic acid [ No CAS ]
2-(5-amino-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-1-((R)-3-methoxypyrrolidin-1-yl)-2-phenylpropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 20℃; for 15h;	To a stirred solution of 2- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4, 3-e] [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yl) -2-phenylpropanoic acid (50 mg, 0.13 mmol) , HATU (54 mg, 0.14 mmol) and DIEA (50 mg, 0.39 mmol) in THF (15 ml) was added (R) -3-methoxypyrrolidine hydrochloride (18 mg, 0.13 mmol) . The reaction mixture was stirred at rt for 15h. After completion, the reaction mixture was diluted with EA (30 ml) and then washed with H2O (15 ml X 2) . The organic layer was dried over Na2SO4, filtered and then concentrated under reduced pressure to afford a residue. The residue was purified by prep-TLC with PE: EA (1: 5) to afford the product (26.5 mg, 44%) .1H NMR (400 MHz, DMSO-d6) delta 8.30-8.22 (m, 1H) , 8.05 (s, 2H) , 7.95 (s, 1H) , 7.37-7.11 (m, 6H) , 6.80-6.70 (m, 1H) , 3.83-3.44 (m, 3H) , 3.32-3.30 (m, 2H) , 3.15-2.86 (m, 3H) , 2.40-2.28 (m, 4H) , 1.71-1.66 (m, 1H) ppm. MS: M/e 473 (M+1)+.

Reference： [1]Patent: WO2020/20097,2020,A1 .Location in patent: Paragraph 0935-0936

24
[ 474707-30-7 ]
2-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)cyclopentyl 4-nitrobenzenesulfonate [ No CAS ]
5-((2-((R)-3-methoxypyrrolidin-1-yl)cyclopentyl)oxy)isobenzofuran-1(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		Step 1. Single Enantiomer of 5-((2-((R)-3-methoxypyrrolidin-1-yl)cyclopentyl)oxy)isobenzofuran-1(3H)-one (170-2) <strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> (170-1, 31 mg, 0.23 mmol) and Cs2CO3 (99 mg, 0.31 mmol) were suspended in MeCN (1.4 mL) and the resulting mixture stirred at rt. for 20 minutes. The reaction mixture was added to a flask containing 154-4 (Example 154, 80 mg, 0.19 mmol) and DIPEA (50 muL, 0.29 mmol) and then purged with nitrogen while sonicating for 20 minutes. The resulting mixture was stirred at 120 C. for 3 h under muW radiation. Additional Cs2CO3 (99 mg, 0.31 mmol) and <strong>[474707-30-7](R)-3-methoxypyrrolidine hydrochloride</strong> (31 mg, 0.23 mmol) were added and stirring was continued at 120 C. for 3 h under muW radiation. The reaction mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, passed through a phase separator, and concentrated onto Celite. The crude material was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane then 0-20% MeOH in DCM to afford 170-2 (12.3 mg, 0.0390 mmol, 20% yield) as a brown oil. MS [M+H]+=318.2.

Reference： [1]Patent: US2020/17461,2020,A1 .Location in patent: Paragraph 1894-1895

25
(S)-5-((1-(5-fluoropyridin-3-yl)ethyl)amino)-2-methylthiazolo[4,5-d]pyrimidine-7-carboxylic acid [ No CAS ]
[ 474707-30-7 ]
(5-(((S)-1-(5-fluoropyridin-3-yl)ethyl)amino)-2-methylthiazolo[4,5-d]pyrimidin-7-yl)((R)-3-methoxypyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		To a solution of (S)-5-((1-(5-fluoropyridin-3-yl)ethyl)amino)-2-methylthiazolo[4,5-d]pyrimidine-7-carboxylic acid (17 mg, 0.05 mmol) in DMF (2 mL) were added (3R)-3-methoxypyrrolidine hydrochloride (10.3 mg, 0.075 mmol) (commercially obtained from Ark Pharm, Arlington Heights, IL), HATU (28 mg, 0.075 mmol), and N,N-diisopropylethylamine (35 uL, 0.2 mmol). The mixture thus obtained was stirred at room temperature for 2 h and the reaction mixture was diluted with ethyl acetate and washed with 5% NaHCO3, water, and brine, then dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified flash chromatography on silica gel (4 g HP silica, Teledyne Isco) eluting with 10% to 50% solvent A (DCM/MeOH/NH4OH, 100/10/1) in DCM to provide (5-(((S)-1-(5-fluoropyridin-3-yl)ethyl)amino)-2-methylthiazolo[4,5-d]pyrimidin-7-yl)((R)-3-methoxypyrrolidin-1-yl)methanone as a white solid (16 mg, 77% yield). 1H NMR (400 MHz, CDCl3) delta 1.65 (3H, d, J = 6.8 Hz), 1.89 (1H, m), 2.08 (1H, m), 2.84 (3H, s), 3.36 (3H, s), 3.64-3.99 (5H, m), 5.27 (1H, m), 5.53 (1H, m), 7.44 (1H, m), 8.35 (1H, m), 8.51 (1H, m) ppm. ESI MS: m/z [M+H+] for C19H21FN6O2S, calcd 417.1, found 417.2.

Reference： [1]Patent: EP3616753,2020,A1

26
[ 474707-30-7 ]
(S)-5-((1-(5-fluoropyridin-3-yl)ethyl)amino)-2-methylthiazolo[4,5-d]pyrimidine-7-carboxylic acid [ No CAS ]
(5-(((S)-1-(5-fluoropyridin-3-yl)ethyl)amino)-2-methylthiazolo[4,5-d]pyrimidin-7-yl)((R)-3-methoxypyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;	Synthesis of (5-(((S)-1-(5-fluoropyridin-3-yl)ethyl)amino)-2-methylthiazolo[4,5-d]pyrimidin-7-yl)((R)-3-methoxypyrrolidin-1-yl)methanone (40): To a solution of (S)-5-((1-(5-fluoropyridin-3-yl)ethyl)amino)-2-methylthiazolo[4,5-d]pyrimidine-7-carboxylic acid (17 mg, 0.05 mmol) in DMF (2 mL) were added <strong>[474707-30-7](3R)-3-methoxypyrrolidine hydrochloride</strong> (10.3 mg, 0.075 mmol) (commercially obtained from Ark Pharm, Arlington Heights, IL), HATU (28 mg, 0.075 mmol), and N,N-diisopropylethylamine (35 uL, 0.2 mmol). The mixture thus obtained was stirred at room temperature for 2 h and the reaction mixture was diluted with ethyl acetate and washed with 5% NaHCO3, water, and brine, then dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified flash chromatography on silica gel (4 g HP silica, Teledyne Isco) eluting with 10% to 50% solvent A (DCM/MeOH/NH4OH, 100/10/1) in DCM to provide (5-(((S)-1-(5-fluoropyridin-3-yl)ethyl)amino)-2-methylthiazolo[4,5-d]pyrimidin-7-yl)((R)-3-methoxypyrrolidin-1-yl)methanone as a white solid (16 mg, 77% yield). 1H NMR (400 MHz, CDCl3) delta 1.65 (3H, d, J = 6.8 Hz), 1.89 (1H, m), 2.08 (1H, m), 2.84 (3H, s), 3.36 (3H, s), 3.64-3.99 (5H, m), 5.27 (1H, m), 5.53 (1H, m), 7.44 (1H, m), 8.35 (1H, m), 8.51 (1H, m) ppm. ESI MS: m/z [M+H+] for C19H21FN6O2S, calcd 417.1, found 417.2

Reference： [1]Patent: EP3616753,2020,A1 .Location in patent: Paragraph 0751-0752

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P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 474707-30-7 ] {[proInfo.proName]}

Quality Control of [ 474707-30-7 ]

Related Doc. of [ 474707-30-7 ]

Product Details of [ 474707-30-7 ]

Calculated chemistry of [ 474707-30-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 474707-30-7 ]

Application In Synthesis of [ 474707-30-7 ]

[ 474707-30-7 ] Synthesis Path-Upstream 1~1

[ 474707-30-7 ] Synthesis Path-Downstream 1~26

Related Functional Groups of [ 474707-30-7 ]

Ethers

Related Parent Nucleus of [ 474707-30-7 ]

Aliphatic Heterocycles

Pyrrolidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 474707-30-7 ]

Related Parent Nucleus of
[ 474707-30-7 ]