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[ CAS No. 76513-69-4 ] {[proInfo.proName]}

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Chemical Structure| 76513-69-4
Chemical Structure| 76513-69-4
Structure of 76513-69-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 76513-69-4 ]

CAS No. :76513-69-4 MDL No. :MFCD00009919
Formula : C6H15ClOSi Boiling Point : -
Linear Structure Formula :- InChI Key :BPXKZEMBEZGUAH-UHFFFAOYSA-N
M.W :166.72 Pubchem ID :2724271
Synonyms :

Calculated chemistry of [ 76513-69-4 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 4
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 44.71
TPSA : 9.23 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.22 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.63
Log Po/w (XLOGP3) : 2.96
Log Po/w (WLOGP) : 2.54
Log Po/w (MLOGP) : 1.89
Log Po/w (SILICOS-IT) : 0.69
Consensus Log Po/w : 2.14

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.47
Solubility : 0.559 mg/ml ; 0.00335 mol/l
Class : Soluble
Log S (Ali) : -2.82
Solubility : 0.254 mg/ml ; 0.00153 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.71
Solubility : 0.326 mg/ml ; 0.00195 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.96

Safety of [ 76513-69-4 ]

Signal Word:Danger Class:8,3
Precautionary Statements:P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405 UN#:2920
Hazard Statements:H225-H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 76513-69-4 ]

* 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 [ 76513-69-4 ]
  • Downstream synthetic route of [ 76513-69-4 ]

[ 76513-69-4 ] Synthesis Path-Upstream   1~8

  • 1
  • [ 75-77-4 ]
  • [ 1462-35-7 ]
  • [ 76513-69-4 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: for 4 h; Reflux
Stage #2: at 20℃;
The fourth step to take a small amount of intermediates made of reagents,After heating, the system slowly heated up to reflux, refluxed for 4 hours, cooled to 20 degrees, slowly dropping trimethylchlorosilane; the temperature of the solution was increased gradually; Fifth step to be the end of the reaction temperature of the end of desorption, decompression reactor temperature control of not more than 40 degrees, after the dissolution of the residual system residue residue for the viscous material, slowly adding alcohol to no bubbles, as waste Treatment, the solution obtained by desolvation, distillation of more than 99percent to 2 _ (trimethylsilyl) ethoxymethyl chloride.
80.4%
Stage #1: With n-butyllithium; butyl magnesium bromide In tetrahydrofuran; hexane at 15 - 30℃; for 0.333333 h;
Stage #2: at 30℃; for 0.333333 h;
1.5 L of tetrahydrofuran was taken and added to a 10 L reaction flask to start stirring.Cool to 15 °C. Then, 1.2 L of n-butylmagnesium chloride (2M, THF) and 1 L of n-butyllithium (2.5 M, n-hexane) were successively added, and the mixture was added to the reaction mixture to maintain an internal temperature of 25 ° C or lower.After the addition, the temperature is kept at 20-25 ° C for 10 min.Take 345 g of the chloromethylated intermediate, and slowly add dropwise to the reaction solution to maintain the temperature below 30 °C.After the completion of the dropwise addition, the reaction was kept at 20-30 ° C for 20 min.216 g of trimethylchlorosilane was added dropwise to the reaction liquid while maintaining the temperature at 30 ° C or lower.After the completion of the dropwise addition, the reaction was kept at 20-30 ° C for 20 min.The reaction solution was concentrated under reduced pressure to recover organic solvent and crude product.The crude water pump is rectified to obtain 268 g of product, the yield is 80.4percent, and the gas phase purity is 98percent.
Reference: [1] Patent: CN103408576, 2016, B, . Location in patent: Paragraph 0020; 0021; 0025
[2] Patent: CN108409776, 2018, A, . Location in patent: Page/Page column 5-7
  • 2
  • [ 50-00-0 ]
  • [ 2916-68-9 ]
  • [ 76513-69-4 ]
YieldReaction ConditionsOperation in experiment
33% at 0℃; for 0.5 h; Practical Example 1; 13.5 g (0.45 mol) of paraformaldehyde and 125.0 g (1.15 mol) of chlorotrimethylsilane were introduced into a 300-mL four-neck flask fitted with a thermometer and stirrer. 54.4 g (0.46 mol) of 2-trimethylsilylethanol was added dropwise over 30 minutes while stirring and cooling with an ice bath. After warming the reaction mixture to room temperature, the pressure was reduced to 100 mmHg using an aspirator, and the hydrogen chloride was removed. The low boiling fraction was distilled off, and additional vacuum distillation was carried out to provide 34.0 g of 2-(trimethylsilyl)ethoxymethyl chloride. The2-(trimethylsilyl)ethoxymethyl chloride product had a purity of 76percent, and the yield was 33percent.; Practical Example 2; 6.0 g (0.2 mol) of paraformaldehyde and 108.6 g (1 mol) of chlorotrimethylsilane were introduced into a 200-mL four-neck flask fitted with a thermometer and stirrer. 23.7 g (0.2 mol) of 2-trimethylsilylethanol was added dropwise over 30 minutes while stirring and cooling with an ice bath. After warming the reaction mixture to room temperature, the pressure was reduced to 100 mm Hg using an aspirator, and the hydrogen chloride was removed. After then adding 5 drops of diisopropylethylamine, the low boiling fraction was distilled off, and additional vacuum distillation was carried out to provide 22.9 g of 2-(trimethylsilyl)ethoxymethyl chloride. The purity of the obtained 2-(trimethylsiIyl)ethoxymethyl chloride was very high, i.e., 98percent, and the yield was 68percent.
Reference: [1] Journal of the American Chemical Society, 1982, vol. 104, p. 5719
[2] Tetrahedron Letters, 1980, vol. 21, # 35, p. 3343 - 3346
[3] Helvetica Chimica Acta, 1988, vol. 71, p. 957 - 963
[4] Patent: WO2006/40964, 2006, A1, . Location in patent: Page/Page column 6; 7
[5] Bulletin de la Societe Chimique de France, 1986, # 2, p. 245 - 252
[6] Patent: WO2006/40964, 2006, A1, . Location in patent: Page/Page column 7
  • 3
  • [ 5654-97-7 ]
  • [ 76513-69-4 ]
  • [ 879132-48-6 ]
YieldReaction ConditionsOperation in experiment
2.26 g
Stage #1: With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil at 0℃; for 1 h; Inert atmosphere
Stage #2: at 20℃; for 21 h; Inert atmosphere
To a solution of 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (2.00 g, 14.9 mmol) in DMF (30 mL) and THF (30 mL) under nitrogen at 0 °C was added sodium hydride, 60percent in mineral oil (0.600 g, 15.0 mmol). The reaction mixture was stirred at 0 °C for 1 h. Then (2- (chloromethoxy)ethyl)trimethylsilane (3.17 mL, 17.9 mmol) was added dropwise over 3 min and the reaction was allowed to warm up to rt without removing the cold bath over 21 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL), the aqueous was extracted with EtOAc (2 x 50 mL), the combined organic component was washed with water (2 x 50 mL), brine (50 mL), dried over MgS04, filtered, concentrated and purified with a Biotage Horizon (25percent EtOAc/hexanes) to afford the title compound (2.26 g ) as viscous orange oil. LC-MS retention time = 3.49 min; m/z = 265.20 [M+H]+. (Column: Phenomenex C18 50 x 2.0 mm 3 μιη. Solvent A = 90percent Water : 10percent MeOH : 0.1percent TFA. Solvent B = 10percent Water : 90percent MeOH : 0.1percent TFA. Flow Rate = 0.8 mL/min. Start percent B = 0. Final percent B = 100. Gradient Time = 4 minutes, then a l-minute hold at l00percent B. Oven temperature = 40 °C. Wavelength = 220 nm). 1H NMR (400 MHZ, DMSO-d6) δ 8.15 (d, J=5.0 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.05 (dd, J=7.2, 5.4 Hz, 1H), 5.07 (s, 2H), 3.69 (s, 2H), 3.59 (t, J=8.0 Hz, 2H), 0.85 (t, J=8.0 Hz, 2H), -0.06 (s, 9H).
Reference: [1] Patent: WO2016/172424, 2016, A1, . Location in patent: Page/Page column 90; 91
  • 4
  • [ 76513-69-4 ]
  • [ 879132-48-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9275 - 9295
[2] Patent: WO2016/55780, 2016, A1,
[3] Patent: WO2008/112159, 2008, A2,
[4] Patent: WO2008/153852, 2008, A1,
[5] Patent: WO2008/153849, 2008, A1,
[6] Patent: WO2009/120652, 2009, A2,
[7] Patent: WO2009/152010, 2009, A1,
  • 5
  • [ 269410-08-4 ]
  • [ 76513-69-4 ]
  • [ 894807-98-8 ]
YieldReaction ConditionsOperation in experiment
86% With potassium carbonate In 1-methyl-pyrrolidin-2-one at 20℃; for 16 h; Inert atmosphere Synthesis of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2~yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1 t-15a)lnt-15aTo a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- H- pyrazole (8.2 g, 41 mmol) in NMP (60 mL) was added K2C03 (12 g, 82 mmoi) and 2-(trimethylsilyi)ethoxymethy. chloride (7.8 mL, 43 mmol) in sequence. The reaction mixture was stirred at r.t. under N2 for 16 h. Then, the reaction mixture was diluted and filtered, and then the filtrate was diluted with EtOAc (300 mL). The resulting solution was washed with sat. NaHC03 (aq) (3 x 200 mL), H20 (4 x 200 mL), brine (1 x 200 mL), dried over Na2S04, filtered, concentrated and dried in vacuo to yield intermediate .nt-15a (11.4 g, 86 percent) as a clear yellowish oil.
86%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5 h; Inert atmosphere
Stage #2: at 0 - 20℃;
[96] SEM-pyrazolo-4-boronic acid pinacol ester was prepared according the procedure from WO2011/130146, page 84. A solution of pyrazolboronic acid pinacolester (20 g, 103 mmol) in DMF (180 mL) was cooled to 0° C and treated with sodium hydride (60 percent dispersion in oil) (6.2 g, 150 mmol) in nitrogen athmosphere. [97] The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then cooled to 0° C and (2-(chloromethoxy)ethyl)trimethylsilane (23.65 ml, 134 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. [98] The reaction mixture was poured into aqueous saturated ammonium chloride (200 mL) containing ice (approximately 200 mL) and stirred until the ice melted. The cold mixture was extracted with ethyl acetate twice. The combined organic extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford SEM-pyrazolo-4-boronic acid pinacol ester (27.6 g, 86 percent yield).
72% With sodium hydride In tetrahydrofuran at 20℃; Inert atmosphere Compound 280.1. 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazole.
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.82 g, 30.0 mmol) in tetrahydrofuran (80 mL). This was followed by the addition of NaH (70percent) (2.05 g, 85.4 mmol) in portions at 0 °C. To this was added SEMC1 (6.4 mL, 36.1 mmol) dropwise. The reaction mixture was stirred overnight at room temperature, then quenched with 50 mL of NH4CI (sat). The aqueous phase was extracted with 2 x 100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 7 g (72percent) of the title compound as colorless oil.
65.94% With caesium carbonate In tetrahydrofuran; acetonitrile at 20℃; for 2 h; 13.2 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl- ethoxymethyl)-1 H-p razole To a solution of 1H-pyrazole-4-boronic acid pinacol ester (0.5 g, 2.57 mmol), in tetrahydrofuran/acetonitrile (3:2, 20ml), 2-(chloromethoxylethyl)trimethyl- silane (0.51 g, 3.09 mmol) and cesium carbonate (1.67 g, 5.15 mmol) are added and stirred for 2 hours at room temperature. The reaction mixture is filtered through celite, and concentrated, the crude mass is taken in ethylacetate (30 ml), washed with water, brine solution, dried over anhydrous MgS04 and concentrated to get the product as brown oil (0.55 g, 65.94 percent); TLC: Pet ether/ethyl acetate(8/2) R - 0.5; 1H NMR: 400 MHz, DMSO-d6: δ [ppm] 8.08 (s, 1H), 7.64 (s, 1 H), 5.40 (s, 2H), 3.48-3.54 (m, 2H), 1.24 (s, 12H), 0.81-0.85 (m, 2H), -0.049(s, 9H);
61%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 60℃; for 0.333333 h;
Stage #2: for 16.0833 h;
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (348 mg, 1.8 mmol) was dissolved in DMF (5 mL) and sodium hydride (60percent dispersion, 86 mg, 2.15 mmol) added and the mixture heated to 60° C. for 5 min. Upon cooling and stirring for an additional 15 min, trimethylsilylethoxymethyl chloride (358 mg, 2.15 mmol, 381 μL) was added dropwise over 5 min and mixture stirred for 16 h. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 5percent lithium chloride (5.x.), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (40 g ISCO column eluting with hexanes and ethyl acetate; gradient 100percent hexanes to 50percent hexanes over 30 min at 30 mL/min) to provide the SEM-protected pyrazole (360 mg, 61percent) as a colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.80 (s, 1H), 5.42 (s, 2H), 3.56-3.53 (t, J=8.3 Hz, 2H), 1.31 (s, 12H), 0.91-0.87 (t, J=8.3 Hz, 2H), -0.03 (s, 9H).
56% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3 h; To a solution of methyl 4-(tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1H-pyrazole (1 .238 g, 6.316 mmol) in DMF (20 mL) was added potassium carbonate (2.62 g, 18.95 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (1 .68 mL, 9.48 mmol) at room temperature. The mixture was stirred for 3 hours and then partitioned between TBME (100 ml.) and water (50 ml_). The organic layer was separated, washed with water (2 x 30 mL) and brine (30 ml_), dried (Na2S04) and concentrated at reduced pressure. The residue was purified by Biotage Isolera™ chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluents, 0-50percent EtOAc in heptane]. The product containing fractions were combined, concentrated in vacuo to give the title compound (1 .20 g, 56percent yield) as colourless oil. 1H NMR (500 MHz, chloroform-d) δ [ppm] 7.88 (s, 1 H), 7.84 (s, 1 H), 5.46 (s, 2H), 3.61- 3.55 (m, 2H), 1 .35 (s, 12H), 0.96 - 0.90 (m, 2H), 0.00 (s, 9H). LCMS (Analytical Method A): Rt = 1 .34 mins; MS (ESIPos) m/z = 324.95 (M+H)\
46%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.0833333 h;
Stage #2: at 20℃; for 2 h;
32-(a) 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilylethoxymethyl)-1H-pyrazole; Under argon atmosphere, to 20 ml of tetrahydrofuran solution containing 1.09 g (5.62 mmol) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole was added 443 mg (11.1 mmol) of 60percent sodium hydride under ice-cooling, and the mixture was stirred for 5 minutes. Then, 3 ml (17.0 mmol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, and the solutions were washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 832 mg of the title compound as a colorless oil. (46percent) Mass Spectrum (CI, m/z): 325 (M++1). 1H-NMR Spectrum (CDCl3, δ ppm): -0.03 (s, 9H), 0.86-0.94 (m, 2H), 1.32 (s, 12H), 3.51-3.59 (m, 2H), 5.43 (s, 2H), 7.81 (d, J=0.5 Hz, 1H), 7.86 (d, J=0.5 Hz, 1H).
0.9 g
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 10 - 35℃; for 1 h; Cooling with ice
Stage #2: at 10 - 35℃; for 15 h;
A) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [1064] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (770 mg) in DMF (10 mL) was added sodium hydride (60percent, 114 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise (2-(chloromethoxy)ethyl)(trimethyl)silane (990 mg) at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 5percent aqueous lithium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.90 g). MS(ESI+): [M+H]+ 325.2. MS(ESI+), found: 325.2.

Reference: [1] Patent: WO2011/149874, 2011, A2, . Location in patent: Page/Page column 81-82
[2] Patent: WO2016/25918, 2016, A1, . Location in patent: Paragraph 96-98
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 10, p. 3075 - 3080
[4] Patent: WO2015/95767, 2015, A1, . Location in patent: Page/Page column 325
[5] Patent: WO2013/131609, 2013, A1, . Location in patent: Page/Page column 112
[6] Patent: US2008/153813, 2008, A1, . Location in patent: Page/Page column 7
[7] Patent: WO2018/114786, 2018, A1, . Location in patent: Page/Page column 141-142
[8] Patent: EP1982986, 2008, A1, . Location in patent: Page/Page column 233
[9] Patent: WO2008/57512, 2008, A2, . Location in patent: Page/Page column 97
[10] Patent: US2007/82900, 2007, A1, . Location in patent: Page/Page column 153
[11] Patent: US2007/105864, 2007, A1, . Location in patent: Page/Page column 205
[12] Patent: US2007/117804, 2007, A1, . Location in patent: Page/Page column 137-138
[13] Patent: WO2011/130146, 2011, A1, . Location in patent: Page/Page column 83-84
[14] Patent: WO2012/58174, 2012, A1, . Location in patent: Page/Page column 43; 44
[15] Patent: EP2857400, 2015, A1, . Location in patent: Paragraph 315.A
[16] Patent: WO2016/123391, 2016, A1, . Location in patent: Page/Page column 87; 88
  • 6
  • [ 76513-69-4 ]
  • [ 894807-98-8 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 60℃; for 0.333333 h;
Stage #2: at 60℃; for 16 h;
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (348 mg, 1.8 mmol) was dissolved in DMF (5 mL) and sodium hydride (60percent dispersion, 86 mg, 2.15 mmol) added. The mixture heated to 60° C. for 5 min. Upon cooling and stirring for an additional 15 min, trimethylsilylethoxymethyl chloride (358 mg, 2.15 mmol, 381 μL) was added dropwise over 5 min and mixture stirred for 16 h. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 5percent lithium chloride (5.x.), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (40 g ISCO column eluting with hexanes and ethyl acetate; gradient 100percent hexanes to 50percent hexanes over 30 min at 30 mL/min) to provide the SEM-protected pyrazole (360 mg, 61percent) as a colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.80 (s, 1H), 5.42 (s, 2H), 3.56-3.53 (t, J=8.3 Hz, 2H), 1.31 (s, 12H), 0.91-0.87 (t, J=8.3 Hz, 2H), -0.03 (s, 9H).
Reference: [1] Patent: US2006/142307, 2006, A1, . Location in patent: Page/Page column 7
  • 7
  • [ 76513-69-4 ]
  • [ 3680-69-1 ]
  • [ 941685-26-3 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 10℃; for 1 h; Cooling with ice; Inert atmosphere
Stage #2: at 10 - 20℃;
Under cooling with an ice-salt bath, sodium hydride (340 mg, 60percent) was added in two portions to a solution of 4-chloropyrrolopyrimidine (3a) (1.0 g, 6.5 mmol) in DMF (15 mL) while keeping the temperature of the reactants no higher than 10°C, and the reaction was stirred under nitrogen atmosphere protection for 1 h. SEMCI (1.4 g, 8.5 mmol) was slowly added via a syringe while keeping the temperature no higher than 10°C.
The reaction was warmed to room temperature, and stirred overnight.
The reaction was quenched with water, extracted with EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated, and purified by preparative flash chromatography (PE:EA=19:1), to afford 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3b) (1.834 g, oil product), yield: 97percent,. MS (ESI, m/z): 284 [M+H]+.
96.4%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at -30 - 20℃;
Stage #2: at 20℃;
Potassium t-butoxide (328.81 g, 2.93 mol)and tetrahydrofuran were added to the reaction flask at -30 ° C to -20 ° C,a solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (300 g, 1.95 mol) in tetrahydrofuran was added dropwise to the reaction flask. after completion of the dropwise addition, the mixture was stirred at room temperature for 4 to 6 hours to control the reaction flask the temperature is not higher than -15° C -5° C ,2- (trimethylsilyl) ethoxymethyl chloride (390.80g, 2.34mol)Is added to the reaction flask, and after completion of the dropwise addition, the temperature is raised to room temperature and the reaction is stirred at that temperature for 3 to 5 hours.After completion of the reaction, the reaction was quenched to neutral with dilute hydrochloric acid, concentrated in tetrahydrofuran in the reverse solution, stirred with ethyl acetate and the aqueous phase was separated. The aqueous phase was extracted with ethyl acetate once, and the reaction solution was cooled and filtered to obtain a wet product. The wet product was crystallized from n-hexane and dried to obtain 534.50 g of product, purity: 99.70percent, and the residue was purified. Yield: 96.40percent.
90.4%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h; Cooling with ice
Stage #2: for 1 h; Cooling with ice
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (20.0 g, 130.4 mmol, 1.0 eq.) in dry DMF was added NaH (6.6 g, 57percent content, 156.8 mmol, 1.2 eq.), under stirring in an ice bath.
After the reactants were stirred for 1 hr at room temperature, SEMCl (26.1 g, 156.5 mmol, 1.2 eq.) was added dropwise under the cooling of an ice bath.
After the addition was completed, the reactants were stirred for 1 hr in an ice bath, then the reaction was quenched by adding water, and the resulting mixture was extracted with ethyl acetate.
The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.
The resulting residue was separated by column chromatography on silica gel column to give 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (33.43 g, 90.4percent yield).
1HNMR (400MHz, CDCl3) δ 8.67 (s, 1H), 7.39 (d, J =3.6 Hz, 1H), 6.67 (d, J =3.6 Hz, 1H), 5.65 (s, 2H), 3.53 (dd, J =9.2 Hz, J =8.0 Hz, 2H), 0.91 (t, J =8.4 Hz, 2H), 0.00 (s, 9H).
m/z=284[M+1]+.
90%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h; Cooling with ice
Stage #2: for 1 h; Cooling with ice
With ice bath,To a solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (20.0 g, 130.4 mmol, 1.0 eq.In dry DMF, NaH (6.6 g, 57percent content, 156.8 mmol, 1.2 eq) was added. The reaction was stirred at room temperature for 1 hour,Further, SEMCl (26.1 g, 156.5 mmol, 1.2 eq.) Was added dropwise with cooling in an ice bath.After the addition was completed, the reaction mixture was stirred in an ice bath for 1 hour, quenched with water,Extraction with ethyl acetate and washing of the combined organic phases with brine,Dried over sodium sulfate, filtered and concentrated in vacuo.Column chromatography silica gel column isolated4-Chloro-7 - [2- (trimethylsilyl) ethoxy] methyl} -Pyrrolo [2,3-d] pyrimidine (33.4 g, 90percent yield).
88.9%
Stage #1: With sodium hydride In n-heptane; ISOPROPYLAMIDE at 0 - 20℃; Cooling with ice/brine bath
Stage #2: at 0 - 5℃;
To a flask equipped with a nitrogen inlet, an addition funnel, a thermowell, and the mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and N,N-dimethylacetimide (DMAC, 9.6 L) at room temperature.
The mixture was cooled to 0-5° C. in an ice/brine bath before solid sodium hydride (NaH, 60 wt percent, 174 g, 4.35 mol, 1.1 equiv) was added in portions at 0-5° C.
The reaction mixture went to a dark solution during 15 minutes.
Trimethylsilylethoxymethyl chloride (2, SEM-Cl, 763 mL, 4.31 mol, 1.1 equiv) was then added slowly via an addition funnel at a rate that the internal reaction temperature did not exceed 5° C.
The reaction mixture was then stirred at 0-5° C. for 30 minutes.
When the reaction was deemed complete determined by TLC and HPLC, the reaction mixture was quenched by water (1 L).
The mixture was then diluted with water (12 L) and MTBE (8 L).
The two layers were separated and the aqueous layer was extracted with MTBE (8 L).
The combined organic layers were washed with water (2*4 L) and brine (4 L) and dried over sodium sulfate (Na2SO4).
The solvents were removed under reduced pressure.
The residue was then dissolved in heptane (2 L), filtered and loaded onto a silica gel (SiO2, 3.5 Kg) column eluding with heptane (6 L), 95percent heptane/ethyl acetate (12 L), 90percent heptane/ethyl acetate (10 L), and finally 80percent heptane/ethyl acetate (10 L).
The fractions containing the pure desired product were combined and concentrated under reduced pressure to give 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3, 987 g, 1109.8 g theoretical, 88.9percent yield) as a pale yellow oil which partially solidified to an oily solid on standing at room temperature.
88.9%
Stage #1: With sodium hydride In N,N-dimethyl acetamide; mineral oil at -5℃; Inert atmosphere
Stage #2: at 5℃; Inert atmosphere
4-Chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a).; To a flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and dimethylacetimide (9.6 L). The mixture was cooled to -5° C. in an ice/brine bath and sodium hydride (NaH, 60 wt percent, 174 g, 4.35 mol, 1.1 equiv) was added in portions as a solid. The mixture went to a dark solution during 15 minutes and trimethylsilylethoxymethyl chloride (2, 763 mL, 4.31 mol, 1.1 equiv) was added slowly via an addition funnel at a rate that the temperature did not exceed 5° C. The reaction was stirred for 30 minutes, determined to be complete by TLC and HPLC, and water (1 L) was slowly added to quench the reaction. The mixture was then diluted with water (12 L) and MTBE (8 L). The layers were separated and the aqueous was re-extracted with MTBE (8 L). The combined organic layers were washed with water (2.x.4 L) and brine (4 L), dried over sodium sulfate (NaSO4), and solvents removed under reduced pressure.The residue was dissolved in heptane (2 L), filtered and loaded onto a silica gel (3.5 kg) column eluting with heptane (6 L), 95percent heptane/ethyl acetate (12 L), 90percent heptane/ethyl acetate (10 L), and finally 80percent heptane/ethyl acetate (10 L). The pure fractions were combined and concentrated under reduced pressure to give 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 987 g, 1109.8 g theoretical, 88.9percent yield) as a pale yellow oil that partially solidified to an oily solid on standing at room temperature. For 3a: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, -1.48; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H).
88.9%
Stage #1: With sodium hydride In N,N-dimethyl acetamide; mineral oil at 0 - 5℃; for 0.25 h;
Stage #2: at 0 - 5℃; for 0.5 h;
Step 1. 4-Chlow-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3) To a flask equipped with a nitrogen inlet, an addition funnel, a thermowell, and the mechanical stirrer was added 4-chloro-7H-pyirolo[2,3-c/]pyrirnidine (1, 600 g, 3.91 mol) and N,N-dimethylacetimide (DMAC, 9.6 L) at room temperature. The mixture was cooled to 0 - 5 °C in an ice/brine bath before solid sodium hydride (NaH, 60 wtpercent, 174 g, 4.35 mol, 1.1 equiv) was added in portions at 0 - 5 °C. The reaction mixture turned into a dark solution after 15 minutes. Trimethylsilylethoxymethyl chloride (2, SEM-C1, 763 mL, 4.31 mol, 1.1 equiv) was then added slowly via an addition funnel at a rate that the internal reaction temperature did not exceed 5 °C. The reaction mixture was then stirred at 0 - 5 °C for 30 minutes. When the reaction was deemed complete determined by TLC and HPLC, the reaction mixture was quenched by water (1 L). The mixture was then diluted with water (12 L) and methyl tert-b ty] ether (MTBE) (8 L). The two layers were separated and the aqueous layer was extracted with MTBE (8 L). The combined organic layers were washed with water (2 x 4 L) and brine (4 L) and solvent switched to 1-butanol. The solution of crude product (3) in 1 -butanol was used in the subsequent Suzuki coupling reaction without further purification. Alternatively, the organic solution of the crude product (3) in MTBE was dried over sodium sulfate (Na2SC>4). The solvents were removed under reduced pressure. The residue was then dissolved in heptane (2 L), filtered and loaded onto a silica gel (S1O2, 3.5 Kg) column eluting with heptane (6 L), 95percent heptane/ethyl acetate (12 L), 90percent heptane/ethyl acetate (10 L), and finally 80percent heptane/ethyl acetate (10 L). The fractions containing the pure desired product were combined and concentrated under reduced pressure to give 4-chloro-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-i/]pyrimidine (3, 987 g, 1 109.8 g theoretical, 88.9percent yield) as a pale yellow oil which partially solidified to an oily solid on standing at room temperature. For 3: NMR (DMSO-af6, 300 MHz) δ 8.67 (s, 1 H), 7.87 (d, 1 H, J = 3.8 Hz), 6.71 (d, 1 H, J= 3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J= 7.9 Hz), 0.80 (t, 2H, J= 8.1 Hz), 1.24 (s, 9H) ppm; 13C NMR (DMSO-cfe, 100 MHz) δ 151.3, 150.8, 150.7, 131.5, 1 16.9, 99.3, 72.9, 65.8, 17.1 , -1 .48 ppm; C,2H,8ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M+ + H).
87% With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1.5 h; General procedure: To a mixture of sodium hydride (60percent dispersion in mineral oil; 276 mg; 6.89 mmol) in DMF (10 mL) at 0 °C was added drop-wise a solution of 4-chloro-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine [prepared as detailed in Ref. 45] (1.145 g; 5.74 mmol) in anhydrous DMF (20 mL). When the addition was complete, 2-(trimethylsilyl)ethoxymethyl chloride (1.32 ml; 7.46 mmol) was added drop-wise and the reaction mixture was stirred at 0 °C for 1.5 h then allowed to warm to ambient temperature. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic phase was separated, dried over Na2SO4 and then filtered and the filtrate solvents evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (70 g) eluting with a solvent gradient of 05percent ethyl acetate in hexane to afford the title compound 42 (1.73 g, 91percent) as a colourless oil.
81%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 2 h;
Stage #2: at 20℃;
To a solution of NaH (3 g, 0.13 mol) in DMF (60 mL)Suspension is slowSlow to join 1(10 g, 0.066 mol) in DMF (40 mL).The reaction mixture was stirred at 0 & lt; 0 & gt; CStirring for 2 hours,A light brown cloudy mixture was obtained.And then slowly added to the mixture2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) (12.7 g, 0.08 mol)Stirred overnight at room temperature,The reaction was quenched with water and extracted with ethyl acetate,The filtrate was concentrated under reduced pressure. Purification by flash chromatography gave intermediate 2(15 g, 81percent),As a pale yellow oil;
79%
Stage #1: With sodium hydride In N,N-dimethyl acetamide; mineral oil at 0 - 5℃; for 0.416667 h; Inert atmosphere
Stage #2: at 4 - 7℃; for 1.75 h; Inert atmosphere
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1.5g, 9.77 mmol) was stirred in anhydrous N,N- dimethylacetamide (30ml), under nitrogen, with cooling to between 0°C and 5 °C as sodium hydride (60percent dispersion, 430mg, 10.75 mmol) was added in portions. After all effervescence had ceased (25 min.), (2-chloromethoxy-ethyl)-trimethylsilane (1.79g, 10.75 mmol) was added dropwise, maintaining the temperature between 4 °C and 7 °C. After stirring for a further lh 45 min. saturated aqueous NH4C1 and a little water were added and the product was extracted with 2 portions of t-butyl methyl ether. The extracts were washed with water, brine, dried over Na2S04 and the solvent evaporated. Purification on a Si-SPE ® cartridge (70g) eluting with EtOAc- cyclohexane (1 : 10 followed by 1 :6) afforded the title compound as a colourless oil (2.19g, 79percent) LCMS (Method 1, ESI): Rt 4.11 min., m/z 325 [M+42]+, 284 [M+H]+, 1H NMR (400 MHz, CDCI3): δ 8.67 (1H, s), 7.39 (1H, d, J = 3.5Hz), 6.67 (1H, d, J = 3.5Hz), 5.65 (2H, s), 3.50-3.56 (2H, m), 0.88-0.93 (2H, m), -0.06 (9H, s).
75%
Stage #1: With sodium hydride In N,N-dimethyl acetamide at -10℃; for 0.5 h;
Stage #2: at 20℃; for 2 h;
2L three-neck flask, 4-chloropyrrolopyrimidine (280 g, 1.83 mol) and N, N-dimethylacetamide (500 mL) were added, Cooling to -10 deg C, NaH (84 g) was added in triplicate, Plus, Stir for 0.5 hours. 2-(trimethylsilyl)ethoxymethyl chloride (385 mL, 1.98 mol) was added, Plus, After 2 hours of reaction at room temperature, The reaction solution was poured into 1 L of water, 500 mL of ethyl acetate was added, Stirring and extracting the ester layer, Washed with 300 mL of saturated sodium chloride once, Dried over anhydrous sodium sulfate, filter, Concentrated under reduced pressure to give 390 g of red product, Yield 75percent.
70% With sodium hydride In N,N-dimethyl acetamide at 5℃; for 4.25 h; Under ice-cooling conditions, 2.0g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 50mL N,N-dimethylacetamide. 0.58g of NaH was added dropwise to the solution and stirred for 15 minutes. 2.2g of 2-chloromethoxyethyl trimethylsilane was added and the reaction was continued maintaining the temperature at 5°C for 4h. The solution was then quenched with saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water. Each 100mL saline solution was washed three times. The organic phase was dried over anhydrous magnesium sulfate overnight. The mixture was filtered and the solvent was distilled off under reduced pressure to give a crude product. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to give 2.6g of intermediate 2 as a colorless liquid, yield: 70percent.
66%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25 h;
Stage #2: at 0 - 20℃; for 1 h;
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 32.56 mmol, 1 equiv) in DMF (50 mL) was added 60percent sodium hydride (1.5 g, 39.07 mmol, 1.2 equiv) at 000 and stirred for 15 mm followed by addition of (2-(chloromethoxy)ethyl)trimethylsilane(5.7 mL, 32.56 mmol, 1.0 equiv) at same temperature. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice water. The crude product was extracted in to ethyl acetate. The organic layer was dried over sodium sulphate and evaporated to obtain 4-chloro-7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo [2,3-d]pyrimidine as brown liquid (8.0 g, 66.0 percent). LCMS (ES) m/z =284.10 [M+H]. 1H NMR (400 MHz, DMSO-d6) O ppm -0.11 (s, 9H), 0.79-0.81 (m, 2H),3.50 (t, J= 8.0 Hz, 2H), 5.62 (s, 1H), 6.68-6.69 (m, 1H), 7.85 (d, J=4.0 Hz, 1H), 8.62 (s, 1H).
0.96%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.25 h; Reflux
Stage #2: for 0.5 h;
2.00 g of 4-hydroxypiperidine was added to a 100-mL round-bottomed flask, and then 20.0 mL of dichloromethane (CH2Cl2) and 20.0 mL of a saturated sodium hydrogen carbonate (NaHCO3) solution were added thereto. After 4.32 g of di-tert-butyl dicarbamate (Boc2O) was added thereto, the reaction mixture was vigorously stirred for about 15 hours and then concentrated under reduced pressure. The aqueous phase was extracted with 20.0 mL of ethyl acetate (EtOAc) to collect an organic phase. The collected organic phase was washed with 10.0 mL of deionized water and 15.0 mL of saturated brine. The organic phase was then filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure. As a result, 3.871 g of tert-butyl 4-hydroxypiperidine-1-carboxylate was obtained with a yield of about 97.2percent. (0319) 300 mg of 6-chloro-7-deazapurine was added to a 50-mL round-bottomed flask, and then 3.75 mL of N,N-dimethylformamide was added. After 86.0 mg of sodium hydride (60wtpercent) was added thereto at about 0°C, the reaction mixture was refluxed at room temperature for about 15 minutes. After 0.403 mL of 2-(trimethylsillyl)ethoxymethyl chloride) was added thereto, the reaction mixture was stirred for about 30 minutes and concentrated under reduced pressure. The reaction mixture was extracted with 4.50 mL of ethyl acetate (EtOAc) and 4.50 mL of deionized water to collect an organic phase. The collected organic phase was filtered with magnesium sulfate (MgSO4). The resulting filtrate was distilled under reduced pressure. As a result, 534 mg of 4-chloro-7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine was obtained with a yield of about 96.6percent. (0320) 408 mg of tert-butyl 4-hydroxypiperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 5.60 mL of dimethyl sulfoxide (DMSO) was added thereinto. After 61.4 mg of sodium hydride (60wtpercent) was added thereinto at about 0°C, the reaction mixture was refluxed at room temperature for about 1.5 hours. Then, a solution of 574 mg of 4-chloro-7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 4.60 mL of dimethyl sulfoxide (DMSO) was slowly dropwise added into the reaction mixture, and the reaction mixture was stirred at about 50°C for about 2 hours and then cooled down to room temperature. The reaction mixture was then extracted with 10.0 mL of ethyl acetate (EtOAc) and 10.0 mL of deionized water to collect an organic phase. The collected organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure, and then the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:5). As a result, 457 mg of tert-butyl 4-((7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was obtained with a yield of about 66.6percent. (0321) 452 mg of tert-butyl 4-((7-((2-(trimethylsillyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 5.00 mL of tetrahydrofuran was added thereinto. After 20.4 mL of a solution of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran was added thereinto, the reaction mixture was refluxed at room temperature for about 5 hours and then cooled down to room temperature. The reaction mixture was concentrated under reduced pressure and then extracted with 100 mL of ethyl acetate (EtOAc) and 100 mL of deionized water to collect an organic phase. The collected organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrated was distilled under reduced pressure, and then the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:6). As a result, 310 mg of tert-butyl 4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was obtained with a yield of about 95.7percent. (0322) 310 mg of tert-butyl 4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate was added to a 50-mL round-bottomed flask, and 6.00 mL of 1,4-dioxane was added thereinto. After 10.0 mL of 4N HCI solution was added thereinto, the reaction mixture was stirred at room temperature for about 2 hours. Then, 20.0 mL of ethyl acetate (EtOAc) was added into the reaction mixture and a 10percent ammonium hydroxide solution was added to basify the reaction mixture. An organic phase was filtered with sodium sulfate (Na2SO4). The resulting filtrate was distilled under reduced pressure. As a result, 230 mg of 4-(piperidine-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidine was obtained with a quantitative yield. (0323) 177 mg of 4-(piperidine-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidine was added to a 25-mL round-bottomed flask and then dissolved with 3.00 mL of dichloromethane (CH2Cl2). After 0.0480 mL of chloroacetyl chloride was added into the solution, the reaction mixture was treated with 0.211 mL of N,N-diisopropylethylamine and then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:6). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 56.0 mg of 1-(4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)-2-chloroethane-1-one was obtained with a yield of about 23.5percent. (0324) 55.6 mg of 1-(4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)-2-chloroethane-1-one was added to a 25-mL round-bottomed flask and then dissolved with 1.00 mL of N,N-dimethylformamide. After 24.3 mg of potassium cyanide was added into the solution, the reaction mixture was stirred overnight at about 30°C to 40°C. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (EtOAc:Hexane=1:1). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 35.4 mg of 3-(4-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)-3-oxopropanenitrile was obtained with a yield of about 49.4percent. (0325) 1H NMR (400 MHz, CDCl3) δ12.03 (s, 1H), 8.34 (s, 1H), 7.35 (t, J = 3.2 Hz, 1H), 6.47 (q, J = 2.0, 3.6 Hz, 1H), 5.58-5.43 (m , 1H), 4.08 (s, 2H), 3.90-3.86 (m, 1H), 3.63-3.59 (m, 1H), 3.47-3.32 (m, 2H), 2.09-2.00 (m, 2H), 1.82-1.77 (m, 1H), 1.69-1.61 (m, 1H). (0326) LRMS (ESI) calcd for (C14H15N5O2 + H+) 286.1, found 286.1.

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