[ CAS No. 1146629-77-7 ] {[proInfo.proName]}

Name: 1146629-77-7|(4-(1H-Pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate|97%
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SKU: A186222
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Quality Control of [ 1146629-77-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1146629-77-7 ]

Product Details of [ 1146629-77-7 ]

CAS No. :	1146629-77-7	MDL No. :	MFCD28975987
Formula :	C₁₅H₁₇N₅O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CPGIWDOJHYCMRW-UHFFFAOYSA-N
M.W :	299.33	Pubchem ID :	57868869
Synonyms :

Calculated chemistry of [ 1146629-77-7 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	14
Fraction Csp3 :	0.33
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	81.43
TPSA :	85.69 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.78 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.17
Log Po/w (XLOGP3) :	1.89
Log Po/w (WLOGP) :	2.22
Log Po/w (MLOGP) :	0.88
Log Po/w (SILICOS-IT) :	1.97
Consensus Log Po/w :	1.83

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.03
Solubility :	0.281 mg/ml ; 0.000939 mol/l
Class :	Soluble
Log S (Ali) :	-3.31
Solubility :	0.146 mg/ml ; 0.000488 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.36
Solubility :	0.013 mg/ml ; 0.0000435 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.66

Safety of [ 1146629-77-7 ]

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 [ 1146629-77-7 ]

* 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 [ 1146629-77-7 ]
Downstream synthetic route of [ 1146629-77-7 ]

[ 1146629-77-7 ] Synthesis Path-Upstream 1~2

1
[ 269410-08-4 ]
[ 1146629-75-5 ]
[ 1146629-77-7 ]

Yield	Reaction Conditions	Operation in experiment
82.27%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water for 14 h; Heating	(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate (10 g; Formula V), water (50 mL), and potassium carbonate (15.5 g) were added into a reaction vessel at ambient temperature. 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (8.7 g; Formula VIII), 1,4-dioxane (100 mL), and tetrakis(triphenylphosphine)palladium(0) (0.08 g) were added to the reaction mixture. The reaction mixture was heated to a temperature of 80°C to 85°C, and then stirred at the same temperature for 14 hours. The progress of the reaction was monitored by thin layer chromatography. On completion, ethyl acetate (100 mL) was added to the reaction mixture. The contents were stirred for 1 hour,then filtered through a Hyflo, and then washed with ethyl acetate (40 mL). The organic layer was separated, and then concentrated under reduced pressure to obtain [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl]methyl pivalate. Yield: 82.27percent

Reference： [1] Patent: WO2016/88094, 2016, A1, . Location in patent: Page/Page column 10

2
[ 1146629-76-6 ]
[ 1146629-77-7 ]

Reference： [1] Organic Letters, 2009, vol. 11, # 9, p. 1999 - 2002
[2] Patent: US2009/233903, 2009, A1, . Location in patent: Page/Page column 68
[3] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 52-53

[ 1146629-77-7 ] Synthesis Path-Downstream 1~33

1
[ 1146629-76-6 ]
[ 1146629-77-7 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of crude 18 in THF (1 L, 12.3mol) was treated with a 4 N aqueous HCl solution (500 mL) at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for 5 h. When the reaction was deemed complete, the reaction mixture was cooled to 0-5 C. before the pH was adjusted to 9-10 with a 1 M aqueous sodium hydroxide (NaOH) solution (2 L). The mixture was then concentrated under reduced pressure to remove most of the THF and the resulting suspension was stirred at room temperature for 2 h. The solids were collected by filtration, washed with water (3×500 mL), and dried in vacuum oven to afford [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 157.5 g, 204.43 g theoretical, 77% yield for three steps) as off-white solids, which was found to be sufficiently pure (>98 area % by HPLC) to do the subsequent reaction without further purification. For 19: 1H NMR (DMSO-d6, 400 MHz) delta 13.42 (br s, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 7.68 (d, 1H, J=3.8 Hz), 7.11 (d, 1H, J=3.8 Hz), 6.21 (s, 2H), 1.06 (s, 9H) ppm; 13C NMR (DMSO-d6, 100 MHz) delta 177.74, 152.31, 152.09, 151.91, 139.52, 130.39, 120.51, 113.93, 101.91, 67.26, 38.98, 27.26 ppm; C15H17N5O2 (MW, 299.33), LCMS (EI) m/e 300 (M++H).
		To a solution of crude {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (4) in THF (1 L, 12.3 mol), a 4 N aqueous HCl solution (500 mL) was added at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for 5 h. When the reaction was deemed complete as confirmed by TLC and LCMS, the reaction mixture was cooled to 0-5 C. before pH was adjusted to 9-10 with a 1 M aqueous sodium hydroxide (NaOH) solution (2 L). The mixture was concentrated under reduced pressure to remove most of THF and the resulting suspension was stirred at room temperature for 2 h. The solids were collected by filtration, washed with water (3×500 mL), and dried in vacuum to afford crude [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (5, 157.5 g, 204.43 g theoretical, 77% yield for three steps) as white to off-white solids, which was found to be sufficiently pure (>98area % by HPLC) to do the subsequent reaction without further purification. For 5: 1H NMR (DMSO-d6, 400 MHz) delta ppm 13.42 (br s, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 7.68 (d, 1H, J=3.8 Hz), 7.11 (d, 1H, J=3.8 Hz), 6.21 (s, 2H), 1.06 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) delta ppm 177.74, 152.31, 152.09, 151.91, 139.52, 130.39, 120.51, 113.93, 101.91, 67.26, 38.98, 27.26; C15H17N5O2 (MW, 299.33), LCMS (EI) m/e 300 (M++H).
0.42 g	With hydrogenchloride; In tetrahydrofuran; water; at 5 - 20℃; for 6h;	To a solution of the crude product containing (4-(1-(1-ethoxyethyl)-1 H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (1.2 g, 1.86 mmol) in THF (6.9 mL) at 5 C.-10 C. , 4M HCl aqueous solution (1.4 mL, 5.6 mmol) was added dropwise. The mixture was warmed to room temperature to conduct reaction for 6 hours. When the reaction was deemed to complete, the reaction mixture was cooled to 5 C.-10 C. The reaction mixture was quenched with 1M NaOH aqueous solution (6 mL); further adding enough amount of the basic solution to adjust the pH of the mixture solution to 9-10. The mixture was concentrated under reduced pressure to remove most of the THF and the resulting suspension was stirred at room temperature for 30 min. The solids were collected by filtration, washed with water (5 mL*2), and dried under vacuum to give (4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (0.42 g) as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): delta 13.40 (br s, 1H), 8.76 (s, 1H), 8.66 (s, 1H), 8.33 (s, 1H), 7.69 (d, 1H, J=4 Hz), 7.11 (d, 1H, J=3.6 Hz), 6.23 (s, 2H), 1.08 (s, 9H) ppm. 13C NMR (DMSO-d6,100 MHz): delta 176.99, 151.56, 151.38, 151.19, 138.76, 129.61, 119.77, 113.22, 101.17, 66.51, 38.23, 26.52 ppm. LCMS calculated for C15H17N5O2 (M+H)+: 300.1416. Found: 300. LCMS calculated for C15H16N5O2Na (M+Na)+: 322.1235. Found: 322.

With hydrogenchloride; In tetrahydrofuran; at 20℃;

Compound 2a was dissolved in 500mL tetrahydrofuran, and 4N hydrochloric acid solution (800mL) was added dropwise, reacted at room temperature overnight, and HPLC showed that the starting material was consumed, and purity of target compound was 73.1%. 10% sodium hydroxide solution was slowly added drop wise in ice-water bath until pH = 7-8, and a large amount of solid was generated. After filtration, the filter cake was rinsed with water, oven dried to obtain solid 3a (193g), purity 92%, and the yield of the two-steps was 56%.

Reference： [1]Organic Letters,2009,vol. 11,p. 1999 - 2002
[2]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 68
[3]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 52-53
[4]Patent: US2019/202834,2019,A1 .Location in patent: Paragraph 0069; 0070
[5]Russian Journal of Organic Chemistry,2019,vol. 55,p. 1569 - 1574
Zh. Org. Khim.,2019,vol. 55,p. 1569 - 1574,6
[6]Patent: EP3572415,2019,A1 .Location in patent: Paragraph 0100; 0101

2
[ 1146629-77-7 ]
[ 118235-51-1 ]
[ 1146629-79-9 ]
(1S)-(4-(1-(1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate [ No CAS ]

Reference： [1]Organic Letters,2009,vol. 11,p. 1999 - 2002

3
[ 1146629-77-7 ]
[ 1187595-85-2 ]
[ 1187595-90-9 ]

Yield	Reaction Conditions	Operation in experiment
	1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 15 - 25℃;	To a suspension of [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 10.0 g, 33.4 mmol) and <strong>[1187595-85-2]2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile</strong> (11, 6.22 g, 33.4 mmol, 1.0 equiv) in N,N-dimethylformamide (DMF, 20 mL) was added DBU (254 mg, 1.67 mmol, 0.05 equiv) drop wise to keep the reaction temperature between 15-25 C. After adding DBU, the reaction mixture became homogeneous within 90 min. The reaction mixture was stirred for 3 h at room temperature. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (120 mL) and acetonitrile (80 mL). The resulting mixture was stirred at room temperature for an additional 30 min. The solids were collected by filtration, washed with a mixture of acetonitrile and water (2/3 by volume, 2×20 mL), and dried in vacuum oven at 40-45 C. for 24 h to afford crude (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 14.5 g, 16.2 g theoretical, 89.5% yield) as white solids, which was found to be sufficiently pure (>98.0% by HPLC) for the subsequent reaction without further purification. For 20: 1HNMR (CDCl3, 300 MHz), delta 8.87 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 7.51 (d, 1H, J=3.6 Hz), 6.76 (d, 1H, J=3.6 Hz), 6.26 (s, 2H), 4.64 (d, 2H, J=9.6 Hz), 4.25 (d, 2H, J=9.6 Hz), 3.41 (s, 2H), 3.09 (q, 2H, J=7.6 Hz), 1.42 (t, 3H, J=7.6 Hz), 1.17 (s, 9H) ppm; C22H27N7O4S (MW, 485.56), LCMS (EI) m/e 486 (M++H).
2.248 g	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 5 - 10℃; for 3h;	A suspension of (4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (1.5 g, 5.01 mmol) and <strong>[1187595-85-2]2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile</strong> (EAYA) (0.95 g, 5.10 mmol) in DMF (4.5 mL) was cooled to 5 C.-10 C., then 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) (0.045 g, 0.06 mmol) was added dropwise into the solution to keep the temperature between 5 C.-10 C. After adding DBU, the mixture was stirred at 5 C.-10 C. to conduct reaction for 3 hours. When the reaction was deemed to complete, the reaction mixture was quenched with acetonitrile (12 mL) and water (18 mL). The resulting suspension was stirred at room temperature for 1 hour. The solids were collected by filtration, washed with a mixture of acetonitrile and water (2/3 by volume, 3 mL*2), and dried under vacuum to give 4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (2.248 g) as an off-white solid.

Reference： [1]Patent: US2009/233903,2009,A1 .Location in patent: Page/Page column 68-69
[2]Patent: US2019/202834,2019,A1 .Location in patent: Paragraph 0071; 0072
[3]Russian Journal of Organic Chemistry,2019,vol. 55,p. 1569 - 1574
Zh. Org. Khim.,2019,vol. 55,p. 1569 - 1574,6

4
[ 1146629-77-7 ]
[ 941685-68-3 ]
(4-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.7%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	4-(1-(2-Cyano-1-cyclopentylvinyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (9).; To a 500 mL round bottom flask equipped with a stir bar and the nitrogen inlet was charged 3-cyclopentylpropiolonitrile (8, 8.50 g, 0.0713 mol, 1.52 equiv), N,N-dimethylformamide (DMF, 84 mL, 1.08 mol) and <strong>[1146629-77-7][4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate</strong> (5, 14.0 g, 0.0468 mol) and solid potassium carbonate (K2CO3, 0.329 g, 0.00238 mol, 0.05 equiv) at room temperature. The resulting reaction mixture was then stirred at room temperature for 60 min. When TLC and HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with 20% aqueous brine (75 mL) and the resulting solution was extracted with ethyl acetate (EtOAc, 3×75 mL). The combined organic extracts were washed with 20% aqueous brine (75 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0 to 20% ethyl acetate/hexane gradient elution) to afford 4-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (9, 16.4 g, 19.6 g theoretical, 83.7% yield) as white solids. For 9: 1H NMR (DMSO-d6, 300 MHz) delta 9.09 (s, 1H), 8.84 (s, 1H), 8.63 (s, 1H), 7.78 (d, 1H, J=3.8 Hz), 7.17 (d, 1H, J=3.8 Hz), 6.24 (s, 2H), 5.82 (s, 1H), 3.55 (m, 1H), 1.92 (m, 2H), 1.59 (br m, 6H), 1.06 (s, 9H); C23H26N6O2 (MW, 418.49), LCMS (EI) m/e 419 (M++H).

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 54

5
[ 1146629-77-7 ]
[ 591769-05-0 ]
[ 1236033-05-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 5h;Product distribution / selectivity;	Method B.; To a stirred suspension of [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 158 mg, 0.50 mmol) and <strong>[591769-05-0]3-cyclopentylacrylonitrile</strong> (8, 122 mg, 1.0 mmol, 2.0 equiv) in dimethyl sulfoxide (DMSO, 1.0 mL, 14 mmol) at room temperature was added powder potassium carbonate (K2CO3, 10.4 mg, 0.075 mmol, 0.15 equiv). The reaction mixture was then stirred at room temperature for 5 h. The reaction mixture became a clear solution in 2 h. When LCMS showed the reaction was deemed complete, the reaction was quenched with water (H2O, 5 mL) and extracted with ethyl acetate (EtOAc, 3.x.15 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (10 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2, 0-50percent EtOAc/hexanes gradient elution) to afford racemic (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 172.6 mg, 210 mg theoretical, 82percent yield) as a white solid. For 20: 1H NMR (CDCl3, 400 MHz) delta ppm 8.87 (s, 1H), 8.30 (s, 1H), 8.29 (s, 1H), 7.47 (d, 1H, J=3.9 Hz), 6.75 (d, 1H, J=3.9 Hz), 6.24 (s, 2H), 4.25 (m, 1H), 3.12 (dd, 1H, J=17.0, 8.7 Hz), 2.95 (dd, 1H, J=17.0, 3.9 Hz), 2.58 (m, 1H), 1.95 (m, 1H), 1.72-1.52 (m, 5H), 1.25 (m, 2H), 1.14 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 88

6
[ 1146629-77-7 ]
[ 118235-51-1 ]
[ 1146629-79-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With (2R)-2-(bis[3,5-bis(trifluoromethyl)phenyl][(triethylsilyl)oxy]methyl)pyrrolidine; 4-nitro-benzoic acid; In chloroform; at 20℃; for 23.16h;	(1R)-(4-(1-(1-Cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-37).; A solution of (2E)-3-cyclopentylacrylaldehyde (28, 345 mg, 2.50 mmol, 5.0 equiv), (2R)-2-bis[3,5-bis(trifluoromethyl)phenyl][(triethylsilyl)oxy]methylpyrrolidine ((R)-35, 16 mg, 0.025 mmol, 0.05 equiv) and 4-nitrobenzoic acid (4.3 mg, 0.025 mmol, 0.05 equiv) in anhydrous chloroform (CHCl3, 2.0 mL, 25 mmol) was stirred at room temperature for 10 min before <strong>[1146629-77-7][4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate</strong> (5, 0.150 g, 0.50 mmol) was added. The resulting reaction mixture was stirred at room temperature for 23 h. After LCMS showed that the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was directly purified by Combiflash with 0-80% EtOAc/hexane gradient elution to afford (1R)-(4-(1-(1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-pivalate ((R)-37, 169 mg, 211.8 mg theoretical, 80% yield) as a pale yellow foam. For (R)-37: C23H29N5O3 (MW, 423.51), LCMS (EI) m/e 424 (M++H).

Reference： [1]Patent: US2010/190981,2010,A1 .Location in patent: Page/Page column 69

7
[ 1146629-77-7 ]
3-(2,2,5,5-d4-cyclopentyl)acrylonitrile [ No CAS ]
(±)-(4-(1-(2-cyano-1-(2,2,5,5-d₄-cyclopentyl)ethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;	Step 6. (+/-)-(4-(1 -(2-Cyano- 1 -(2,2,5,5 -d4-cyclopentyl)ethyl)- 1 H-pyrazol-4- yl)-7H-pyrrolol2,3-dlpyrimidin-7-yl)methyl pivalate ((+/-)38). To a solution of 37 (400 mg, 1.34 mmol, preparation described in Lin, Q. et al. Org. Lett., 2009, 1], 1999-2002) in acetonitrile (10 mL) was added 36 (418 mg, 3.34 mmol) followed by DBU (421 tL, 2.81 mmol). The reaction stirred at room temperature for 15 hours then was concentrated under reduced vacuum. The resulting crude mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with iN HC1, dried (Na2SO4), filtered and concentrated underreduced pressure. Purification via normal phase column chromatography (Si02, 0-60% ethyl acetate/hexanes) followed by reverse phase column chromatography (C 18, 5-70% acetonitrile/water containing 0.1% formic acid) afforded (+/-)38 (68 mg, 12%) as a white foam. 1H NMR (DMSO-d6, 400 MHz) oe 8.84 (s, 1H), 8.79 (s, 1H),8.40 (s, 1H), 7.74 (d, J= 3.8 Hz, 1H), 7.12 (d, J- 3.8 Hz, lH), 6.24 (s, 2H), 4.54 (td, J= 9.7, 4.3 Hz, 1H), 3.30-3.15 (m, 2H), 2.39 (d, J 9.8 Hz, 1H), 1.68- 1.36 (m, 4H), 1.08 (s, 9H); MS (ESI) 425.3 [(M + H)j.
12%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;	37 in acetonitrile (400mg, 1.34mmol, Lin, Q. et al. Org. Lett., 2009, 11, to a solution (10mL) of the is preparation) described in 1999-2002, 36 (418mg, 3.34mmol), followed by the addition of DBU (421muL, 2.81mmol). The reaction was stirred for 15 hours at room temperature, and then concentrated under reduced pressure. The resulting crude mixture was diluted with water, and extracted with ethyl acetate (3x50mL). The organic layers were combined, washed with 1N HCl, dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Normal phase column chromatography (SiO2, 0 to 60% ethyl acetate/hexanes) after purification on, by reverse phase column chromatography (5-70% acetonitrile/water containing C18,0.1% formic acid), white foam to obtain a thing of (+/-)38 (68mg, 12%).
12%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;	Add to a solution of 37 (400 mg, 1.34 mmol, prepared in Lin, Q. et al., Org. Lett., 2009, 11, 1999-2002) in acetonitrile (10 mL)36 (418 mg, 3.34 mmol),Then DBU (421 muL, 2.81 mmol) was added.The reaction was stirred at room temperature for 15 hours.It was then concentrated under reduced pressure. The crude mixture was diluted with water and extracted with EtOAc EtOAc. The organic layers were combined, washed with EtOAc EtOAc m.Purification by normal phase column chromatography (SiO2, 0-60% ethyl acetate / hexanes) and purified by reverse column chromatography (C18, 5-70% acetonitrile/water containing 0.1% formic acid) +/-) 38 (68 mg, 12%).

68 mg

With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;

37 in acetonitrile(418 mg, 3.34 mmol) was added to a solution (10 mL) of a solution (400 mg, 1.34 mmol, preparation described in Lin, Q. et al. Org. Lett., 2009, 11, 1999-2002)DBU (421 muL, 2.81 mmol) was then added.The reaction was stirred at room temperature for 15 h,Then,And concentrated under reduced pressure.The resulting crude mixture was diluted with water,And extracted with ethyl acetate (3 × 50 mL).The organic layers were combined, washed with 1 N HCl, dried (Na 2 SO 4), filtered and concentrated under reduced pressure. After purification by normal phase column chromatography (SiO 2, 0 to 60% ethyl acetate / hexane), reverse phase column chromatography (C 18, 0 to 5% 70% acetonitrile / water containing 0.1% formic acid) was performed to obtain a white foam Of (+/-) 38 (68 mg, 12%).

Reference： [1]Patent: WO2013/188783,2013,A1 .Location in patent: Page/Page column 27; 29
[2]Patent: JP2015/117185,2015,A .Location in patent: Paragraph 0106; 0112
[3]Patent: CN104725380,2019,B .Location in patent: Paragraph 0142; 0145; 0151
[4]Patent: JP2018/172421,2018,A .Location in patent: Paragraph 0107; 0112

8
[ 269410-08-4 ]
[ 1146629-75-5 ]
[ 1146629-77-7 ]

Yield	Reaction Conditions	Operation in experiment
82.27%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 14h;Heating;	(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate (10 g; Formula V), water (50 mL), and potassium carbonate (15.5 g) were added into a reaction vessel at ambient temperature. 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (8.7 g; Formula VIII), 1,4-dioxane (100 mL), and tetrakis(triphenylphosphine)palladium(0) (0.08 g) were added to the reaction mixture. The reaction mixture was heated to a temperature of 80C to 85C, and then stirred at the same temperature for 14 hours. The progress of the reaction was monitored by thin layer chromatography. On completion, ethyl acetate (100 mL) was added to the reaction mixture. The contents were stirred for 1 hour,then filtered through a Hyflo, and then washed with ethyl acetate (40 mL). The organic layer was separated, and then concentrated under reduced pressure to obtain [4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl]methyl pivalate. Yield: 82.27%

Reference： [1]Patent: WO2016/88094,2016,A1 .Location in patent: Page/Page column 10

9
[ 1146629-77-7 ]
3-(3,3,4,4-d4-cyclopentyl)acrylonitrile [ No CAS ]
(±)-(4-(1-(2-cyano-1-(3,3,4,4-d₄-cyclopentyl)ethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;	37 in acetonitrile (514mg, 1.72mmol, Lin, Q. et al. Org. Lett., 2009, 11, to a solution (15mL) of the is preparation) described in 1999-2002, 44 (537mg, 4.29mmol), followed by the addition of DBU (540muL, 3.61mmol). The reaction was stirred at room temperature for 15 hours, then concentrated under reduced pressure. The resulting mixture of crude was diluted with water and extracted with ethyl acetate (3 x 50mL). The combined organic layers were washed with 1N HCl, dried (Na2SO4), filtered, and concentrated in vacuo. Normal phase column chromatography (SiO 2, 0~60% ethyl acetate / hexanes) Purification on to give a white foam (+/-)-45 (368mg, 50%).
50%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;	To a solution of 37 (514 mg, 1.72 mmol, prepared as described in Lin, Q. et al., Org. Lett., 2009, 11, 1999-2002) in acetonitrile (15 mL) was added 44 (537 mg, 4.29 mmol).Then DBU (540 muL, 3.61 mmol) was added.The reaction was stirred at room temperature for 15 hours.It was then concentrated under reduced pressure in vacuo.The crude mixture was diluted with water and extracted with EtOAc EtOAc.Organic layer merger,Wash with 1N hydrochloric acid,Dry (Na2SO4), filtered and concentrated.Purification by normal phase column chromatography (SiO2, 0-60% ethyl acetate / hexane)(+/-) 45 (368 mg, 50%) to white foam.
368 mg	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;	To a solution (15 mL) of 37 (514 mg, 1.72 mmol, preparation described in Lin, Q. et al. Org. Lett., 2009, 11, 1999-2002) in acetonitrile was added 44 (537 mg, 4.29 mmol) , Then DBU (540 muL, 3.61 mmol) was added. The reaction was stirred at room temperature for 15 h and then concentrated under reduced pressure. The resulting crude mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with 1 N HCl, dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by normal phase column chromatography (SiO 2, 0 to 60% ethyl acetate / hexane) gave (+/-) 45 as a white foam (368 mg, 50%)

Reference： [1]Patent: JP2015/117185,2015,A .Location in patent: Paragraph 0116; 0122
[2]Patent: CN104725380,2019,B .Location in patent: Paragraph 0155; 0157; 0163
[3]Patent: JP2018/172421,2018,A .Location in patent: Paragraph 0117; 0122

10
[ 1146629-77-7 ]
3-(2,2,3,3,4,4,5,5-d8-cyclopentyl)acrylonitrile [ No CAS ]
(±)-(4-(1-(2-cyano-1-(2,2,3,3,4,4,5,5-d₈-cyclopentyl)ethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;	37 in acetonitrile (619mg, 2.07mmol, Lin, Q. et al. Org. Lett., 2009, 11, to a solution (15mL) of the is preparation) described in 1999-2002, 51 (673mg, 5.17mmol), followed by the addition of DBU (650muL, 4.35mmol). The reaction was stirred for 15 hours at room temperature, and concentrated under reduced pressure. The resulting mixture of crude was diluted with water, and extracted with ethyl acetate (3x50mL). The combined organic layers were washed with 1N HCl, dried (Na2SO4), filtered and concentrated under reduced pressure. Normal phase column chromatography (SiO2, 0~60% ethyl acetate / hexanes) Purification on to give a white foam (+/-)-52 (447mg, 50%).

Reference： [1]Patent: JP2015/117185,2015,A .Location in patent: Paragraph 0126; 0132

11
[ 1146629-77-7 ]
(4-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate hydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/109524,2017,A1

12
[ 1146629-77-7 ]
(4-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl 2,2-dimethylpropanoate [ No CAS ]

Reference： [1]Patent: WO2017/109524,2017,A1
[2]Patent: EP3572415,2019,A1

13
[ 1146629-77-7 ]
[ 1187595-90-9 ]

Reference： [1]Patent: WO2017/109524,2017,A1

14
[ 1153949-11-1 ]
[ 1146629-77-7 ]
tert-butyl 3-(cyanomethyl)-3-[4-(7-[(2,2-dimethylpropanoyl)oxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 20℃; for 4h;	The production of tert-butyl-3-(cyanomethyl)-3-[4-(7-[(2,2- dimethylpropanoyl)oxy] methyl}-7H-pyrrolo[2,3 -d]pirimidin-4-yl)- lH-pyrazol-1-yl] azetidine-1-carboxylate of formula (I) 6.49 ml (6.6 g; 43.43 mmol; 0.5 equ.) of l l,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) is added drop by drop at room temperature to a suspension of 26.00 g (86.87 mmol) of 4-(lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pirimidin-7-yl]methyl 2,2-dimethylpropanoate of formula (X) and 16.87 g (86.87 mmol) of ieri-butyl 3-(cyanomethylidene)azetidine-l-carboxylate of formula (IV) made with 520 ml of acetonitrile. The reaction mixture is stirred for 2 hours at room temperature, then for a further 2 hours at 0-5 C. The precipitated solid material is filtered, then washed on the filter with 2x25 ml of 5 C acetonitrile, then dried at room temperature and atmospheric pressure until constant weight is achieved. In this way 38.8 g (90.0%) of a white solid product is obtained, the purity of which measured with LC MS at 254 nm is 99.8%.Mp. 181.0-183.5 C. IR (KBr): 1739, 1693, 1585, 1380,1124. HNMR (DMSO-ifc, 500 MHz): 8.94 (s, 1H), 8.82 (s, 1H), 8.48 (s, 1H), 7.76 (d, J=3.7 Hz, 1H), 7.22 (d, J=3.8 Hz, 1H), 6.26 (s, 2H), 4.53 (d, J=8.9 Hz, 2H), 4.24 (d, J=9.4 Hz, 2H), 3.68 (s, 2H), 1.42 (s, 9H), 1.10 (s, 9H). CNMR (DMSO-ifc, 125 MHz): 177.16, 155.52, 151.70, 151.69, 150.34, 140.01, 130.14, 130.06, 121.66, 116.94, 113.61, 101.41, 79.60, 66.68, 58.62, 57.05, 26.98, 26.70. Element analysis calculating for the formula theta5Eta3iotaNu704 (M: 493.57); C 60.84%; H 6.33%; N 19.86%.Measured: C 60.39%; H 6.25%; N 19.88%
81%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 4.5h;Cooling with ice;	Compound 3a (189g) and tert-butyl 3-(cyanomethylene)azetidin-1-carboxylic acid (184g, SM-4) were added to acetonitrile (1L), cooled in ice water bath, and added to DBU. The mixture was maintained under the temperature to react for 0.5 h, and then reacted under room temperature for 4 h. A large amount of solid was precipitated. MTBE 500mL was added, stirred for 10min after filtration, and the filter cake was washed with MTBE. Dried in oven at 45C overnight, and solid 4a (254g) was produced; yield 81%, purity 95%.
16.3 g	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20℃;	(1) Weighing <strong>[1146629-77-7][4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate</strong> (10.0 g, 33.4 mmol) and 3 -(Cyanomethylene)azetidin-1-carboxylic acid tert-butyl ester (6.8 g, 35.07 mmol, 1.05 eq.) was placed in a 100 ml reaction flask. Add 30ml of DMF, stir the solids to be completely dissolved, add DBU (0.25g, 1.67mmol, 0.05eq.) dropwise at room temperature, slowly dissolve the solid and then quickly precipitate the solid product, continue to stir the reaction for 1-2 hours. After confirming the completion of the reaction by TLC, 150 ml of water was added, and the mixture was stirred for 30 min, filtered, and the filter cake was washed with water (20 ml × 4), and the obtained solid was dried under vacuum at 60 C for 10 h to afford 16.3 g of white solid.

Reference： [1]Patent: WO2017/109524,2017,A1 .Location in patent: Page/Page column 8; 9
[2]Patent: EP3572415,2019,A1 .Location in patent: Paragraph 0102; 0103
[3]Patent: CN108976233,2018,A .Location in patent: Paragraph 0062-0063

15
[ 1146629-77-7 ]
3-(perdeuterocyclopentyl)acrylonitrile [ No CAS ]
(+/-)-(4-(1-(2-cyano-1-(1,2,2,3,3,4,4,5,5-nonadeuterocyclopentyl)ethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;	To 37 (619 mg, 2.07 mmol, in Lin, Q. et al. Org. Lett.,51 (673 mg, 5.17 mmol) was added to a solution of acetonitrile (15 mL) prepared as described in 2009, 11, 1999-2002.Then DBU (650 muL, 4.35 mmol) was added.The reaction was stirred at room temperature for 15 hours.It was then concentrated under reduced pressure.The crude mixture was diluted with water and extracted with EtOAc EtOAc.Organic layer merger,Wash with 1N hydrochloric acid,Dry (Na2SO4), filtered and concentrated.Normal phase column chromatography (SiO2, 0-60% ethyl acetate / hexane)Purification gave (+/-) 52 (447 mg, 50%) as a white foam.
447 mg	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;	To a solution (15 mL) of 37 (619 mg, 2.07 mmol, preparation described in Lin, Q. et al. Org. Lett., 2009, 11, 1999-2002) in acetonitrile 51 (673 mg, 5.17 mmol) , Then DBU (650 muL, 4.35 mmol) was added. The reaction was stirred at room temperature for 15 h and concentrated under reduced pressure. The resulting crude mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with 1 N HCl, dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Purification by normal phase column chromatography (SiO 2, 0 to 60% ethyl acetate / hexane) gave (+/-) 52 as a white foam (447 mg, 50%).

Reference： [1]Patent: CN104725380,2019,B .Location in patent: Paragraph 0167; 0170; 0176
[2]Patent: JP2018/172421,2018,A .Location in patent: Paragraph 0127; 0132

16
[ 1146629-77-7 ]
tert-butyl 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)-azetidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: CN108976233,2018,A

17
[ 1146629-77-7 ]
[ 1187594-16-6 ]

Reference： [1]Patent: CN108976233,2018,A

18
[ 55052-28-3 ]
[ 1146629-77-7 ]

Reference： [1]Patent: US2019/202834,2019,A1
[2]Patent: US2019/202834,2019,A1

19
[ 18997-19-8 ]
[ 1146629-77-7 ]

Reference： [1]Patent: US2019/202834,2019,A1
[2]Patent: US2019/202834,2019,A1
[3]Patent: EP3572415,2019,A1
[4]Russian Journal of Organic Chemistry,2019,vol. 55,p. 1569 - 1574
Zh. Org. Khim.,2019,vol. 55,p. 1569 - 1574,6

20
[ 1146629-75-5 ]
[ 1146629-77-7 ]

Reference： [1]Patent: US2019/202834,2019,A1
[2]Patent: EP3572415,2019,A1
[3]Russian Journal of Organic Chemistry,2019,vol. 55,p. 1569 - 1574
Zh. Org. Khim.,2019,vol. 55,p. 1569 - 1574,6

21
(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate [ No CAS ]
[ 1146629-77-7 ]

Yield	Reaction Conditions	Operation in experiment
5.28 g	With acetyl chloride; In methanol; at 5 - 20℃; for 6h;	To a solution of the crude product containing 13 (4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (10.83 g, 7.16 g theoretical, 18.67 mmol) in 23 methanol (MeOH) (72 mL) at 5 C.-10 C., 24 acetyl chloride (4.4 g, 56.05 mmol) was added dropwise. The mixture was warmed to room temperature to conduct reaction for 6 hours. When the reaction was deemed to complete, the reaction mixture was cooled to 5 C.-10 C. The reaction mixture was quenched with 1M 25 NaOH aqueous solution (60 mL); further adding enough basic solution to adjust the pH of the mixture solution to 9-10. The mixture was concentrated under reduced pressure to remove most of the MeOH and the resulting suspension was stirred at room temperature for 90 min. The solids were collected by filtration, washed with water (20 mL×2), and dried under vacuum to give 26 (4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (5.28 g) as an off-white solid.

Reference： [1]Patent: US2019/202834,2019,A1 .Location in patent: Paragraph 0067; 0068

22
[ 1146629-77-7 ]
C₂₇H₄₀N₈O₃SSi [ No CAS ]

Reference： [1]Patent: EP3572415,2019,A1

23
[ 1146629-77-7 ]
C₂₁H₃₀N₈OSSi [ No CAS ]

Reference： [1]Patent: EP3572415,2019,A1

24
[ 1146629-77-7 ]
C₁₅H₁₆N₈OS [ No CAS ]

Reference： [1]Patent: EP3572415,2019,A1

25
[ 1146629-77-7 ]
C₂₂H₂₈N₈O₃S [ No CAS ]

Reference： [1]Patent: EP3572415,2019,A1

26
[ 1146629-77-7 ]
C₁₆H₁₈N₈OS [ No CAS ]

Reference： [1]Patent: EP3572415,2019,A1

27
[ 3680-69-1 ]
[ 1146629-77-7 ]

Reference： [1]Patent: EP3572415,2019,A1
[2]Russian Journal of Organic Chemistry,2019,vol. 55,p. 1569 - 1574
Zh. Org. Khim.,2019,vol. 55,p. 1569 - 1574,6

28
[ 1146629-77-7 ]
[ 1187594-09-7 ]