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Product Details of [ 885618-31-5 ]

CAS No. :885618-31-5 MDL No. :MFCD11520864
Formula : C11H10ClN3O2S Boiling Point : -
Linear Structure Formula :- InChI Key :PFAKZIZFIXKDFP-UHFFFAOYSA-N
M.W : 283.73 Pubchem ID :45789985
Synonyms :

Safety of [ 885618-31-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P310 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 885618-31-5 ]

* 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 [ 885618-31-5 ]
  • Downstream synthetic route of [ 885618-31-5 ]

[ 885618-31-5 ] Synthesis Path-Upstream   1~14

  • 1
  • [ 68-12-2 ]
  • [ 885618-31-5 ]
YieldReaction ConditionsOperation in experiment
77%
Stage #1: With n-butyllithium In hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 3 h;
Reference Example 3: 2-Chloro-4-morpholin-4-yI-thienof3,2- dlpyrimidine-6-carbaldehyde (66) (66)To a suspension of 2-chloro-4-moφholin-4-yl-thieno[3,2-d]pyrimidine (65) (1.75g, 6.85mmol) in dry THF (4OmL) at -78°C was added a 2.5M solution of nBuLi in hexane (3.3mL, 1.2eq.). After stirring for 1 h, dry DMF (796μL, 1.5eq.) was added. The reaction mixture was stirred for 1 h at -780C and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield the title compound (1.50 g, 77percent)1H NMR (400 MHz, J6-DMSO) 3.76 (4H, t, J=4.9), 3.95 (4H, t, J=4.9), 8.28 (IH, s), 10.20 (IH, s), EPO <DP n="33"/>
77%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 3 h;
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (VII) (1.75 g, 6.85 mmol) in dry THF (40 mL) at -78° C. was added a 2.5M solution of nBuLi in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at -78° C. and then warmed slowly to room temperature. After a further 2 h at room-temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield the title compound (1.50 g, 77percent) 1H NMR (400 MHz, d6-DMSO) 3.76 (4H, t, J=4.9), 3.95 (4H, t, J=4.9), 8.28 (1H, s), 10.20 (1H, s).
77%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 3 h;
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (65) (1.75 g, 6.85 mmol) in dry THF (40 mL) at -78° C. was added a 2.5M solution of nBuLi in hexane (3.3 mL, 1.2 eq.).
After stirring for 1 hour, dry N,N-dimethylformamide (796 μL, 1.5 eq.) was added.
The reaction mixture was stirred for 1 hour at -78° C. and then warmed slowly to room temperature.
After a further 2 hours at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate.
This was collected by filtration and air-dried to yield the title compound (1.50 g, 77percent).
1H NMR (400 MHz, d6-DMSO) 3.76 (4H, t, J=4.9 Hz), 3.95 (4H, t, J=4.9 Hz), 8.28 (1H, s), 10.20 (1H, s).
77%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 3 h;
Stage #3: With water In tetrahydrofuran; hexanes at 0℃;
Reference Example 6: 2-Chloro-4-morphoIin-4-yl-thieno[3,2-d1pyrimidine-6-carbaIdehyde; To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1.75 g, 6.85 mmol) in dry tetrahydrofuran (40 mL) at -78 0C was added ^BuLi (3.3 mL, 1.2 equivalents, 2.5 M solution in hexanes). After stirring for 1 hour, dry N, N- dimethylformamide (796 μL, 1.5 equivalents) was added. The reaction mixture was stirred for 1 hour at -78 0C and then warmed slowly to room temperature. After a further 2 hours at room temperature the reaction mixture was poured onto ice-water yielding a yellow precipitate. This was collected by filtration and air-dried to yield the title compound (1.50 g, 77percent).<5H (400 MHz, d-6 DMSO) 10.20 (IH, s), 8.28 (IH, s), 3.95 (4H, t, J 4.9), 3.76 (4H, t, J 4.9).
77%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 3 h;
Example 3; 2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6- carbaldehyde 10[00270] To a suspension of 2-chloro-4-moφholin-4-yl-thieno[3,2-d]pyrimidine 4(1.75g, 6.85 mmol) in dry THF (4OmL) at -78 0C was added a 2.5M solution of n- butyllithium (nBuLi) in hexane (3.3 mL, 1.2eq.). After stirring for 1 h, dry DMF (796 μL, 1.5eq.) was added. The reaction mixture was stirred for 1 h at -78 0C and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.50 g, 77percent). 1H NMR (400 MHz, Cf6-DMSO) 3.76 (4H, t, ./=4.9), 3.95 (4H, t, J=4.9), 8.28 (IH, s), 10.20 (IH, s).

Reference: [1] Patent: WO2006/46031, 2006, A1, . Location in patent: Page/Page column 30
[2] Patent: US2008/76768, 2008, A1, . Location in patent: Page/Page column 7
[3] Patent: US2008/76758, 2008, A1, . Location in patent: Page/Page column 73
[4] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 63
[5] Patent: WO2007/127183, 2007, A1, . Location in patent: Page/Page column 136
  • 2
  • [ 68-12-2 ]
  • [ 16234-15-4 ]
  • [ 885618-31-5 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - -60℃; Inert atmosphere
Stage #2: at -78 - 0℃; for 1.5 h;
Step n:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (Compound 105)
To a suspension of compound 104 (20 g, 78.4 mmol, 1.0 eq) in THF (anhydrous, 320 mL) at -78° C. was added n-BuLi (in hexanes, 2.4 M, 40.8 mL, 102 mmol, 1.3 eq) slowly under nitrogen.
The resulting slurry was allowed to warm up to -60° C. to turn into a clear brown solution.
The reaction mixture was then cooled to -78° C. again and DMF (anhydrous, 9.1 mL, 118 mmol, 1.5 eq) was added slowly.
The resulting solution was stirred at -78° C. for 0.5 h, warmed up to 0° C. over 1 h and was poured slowly to a mixture of aq HCl (0.25 M, 660 mL) and ice water (320 mL).
The resulting slurry was stirred at 0-10° C. for 0.5 h, filtered, washed with cold water and dried in vacuo to afford compound 105 as a yellow solid (22 g, 98percent). M.p.: 260-265° C. LCMS (m/z): 284.0 [M+1]+ 1H NMR (400 MHz, DMSO-d6): δ 3.77 (t, J=5.2 Hz, 4H), 3.96 (t, J=5.2 Hz, 4H), 8.30 (s, 1H), 10.21 (s, 1H).
90%
Stage #1: With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexanes at -78 - -30℃; for 1 h;
Stage #2: at -78 - 20℃; for 0.5 h;
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-cT]pyrimidine (1.0 g, 3.91 mmol) in anhydrous THF (50 mL) was added A^V^V^-tetramethylethylenediamine (0.68 mL, 4.53 mmol) and the resulting mixture was cooled to -78 °C. n-Butyl lithium (2.5 M in hexanes, 1.9 mL, 4.75 mmol) was added dropwise and the resulting suspension allowed to warm to -30 0C over 1 h. The reaction mixture was cooled to -78 °C and treated with DMF (0.7 mL, 9.04 mmol), then stirred at RT for 30 min. The reaction mixture was cooled to 0 °C before an aqueous solution of HCl (0.5 M) was added and the mixture stirred for another 30 min. The precipitate that formed was collected by filtration, washed twice with water then dried in vacuo at 70 °C for 3 h. The title compound was obtained as a pale yellow solid (1.0 g, 90 percent).NMR δH (300 MHz, DMSO-de) 3.77 (m, 4 H), 3.95 (m, 4 H), 8.29 (s, 1 H) and 10.21 (s, 1 H).
77%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 3 h;
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4(1.75g, 6.85mmol) in dry THF (4OmL) at -78°C was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3mL, 1.2eq.). After stirring for 1 h, dry DMF (796 μL, 1.5eq.) was added. The reaction mixture was stirred for 1 h at -78 0C and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.50 g, 77percent). 1H NMR (400 MHz, J6-DMSO) 3.76 (4H, t, .7=4.9), 3.95 (4H, t, .7=4.9), 8.28 (IH, s), 10.20 (IH, s).
77%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 3 h;
Stage #3: With water In tetrahydrofuran; hexane at 20℃;
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4(1.75g, 6.85mmol) in dry THF (40 mL) at -78 °C was added a 2.5 M solution of n- butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at -78 0C and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air- dried to yield 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.50 g, 77percent). 1H NMR (400 MHz, J6-DMSO) 3.76 (4H, t, J=4.9), 3.95 (4H, t, J=4.9), 8.28 (IH, s), 10.20 (IH, s).
77%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 3 h;
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (1.75 g, 6.85 mmol) in dry THF (40 mL) at -78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.).
After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added.
The reaction mixture was stirred for 1 h at -78° C. and then warmed slowly to room temperature.
After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate.
This was collected by filtration and air-dried to yield 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.50 g, 77percent).
1H NMR (400 MHz, d6-DMSO) 3.76 (4H, t, J=4.9), 3.95 (4H, t, J=4.9), 8.28 (1H, s), 10.20 (1H, s).
77%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 3 h;
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.50 g, 77percent).
60%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 2 h;
Step 1b: 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (Intermediate 1b) To a suspension of Intermediate 1a (1.02 g, 4.0 mmol) in 30 ml THF at -78° C. was added LiHMDS (1.0 N, 6.0 ml, 6.0 mmol) slowly. The reaction mixture was stirred at -78° C. for 1 h, DMF (0.5 ml) was added and reaction mixture was allowed to warm up to room temperature over 2 hours. The reaction was quenched with NH4Cl aqueous solution and the THF was removed under vacuum. A 50-ml portion of EtOAc was added in and the mixture was washed with aqueous NaHCO3 and brine. The organic layer was separated and was dried over Na2SO4. After removal of solvent, the crude product was subject to chromatography on silica gel (eluents: EtOAc/hexane). A total of 0.6 g of the title compound was obtained (60percent). MS m/z: 284.2 (ES+, M+1).
35%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 11 h;
Step lg: 2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (Compound 0112)To a suspension of compound 0111 (1.75 g, 6.85 mmol) in dry tetrahydrofuran (40 mL) at -78 °C was added a 2.0 M solution of LDA in THF/hexane(20.55 mL, 41.1 mmol). After stirring for 1 h, dry N,N-dimethylformamide (3.2 mL, 41.1 mmol) was added. The reaction mixture was stirred for 1 h at -78 °C and then warmed slowly to room temperature. After a further stir for 10 h at room temperature, the reaction mixture was poured ontoNH4C1 saturated solution, extracted with ethyl acetate (100 mL x 3), dried over Na2S04 and filtered. The filtrate was concentrated to leave a residue which was washed with ethyl acetate (10 mL x 2) to give the title compound 0112 (0.66 g, 35percent) as a yellow solid: LCMS: 284 [M+l]+; 1H NMR (400 MHz, DMSO-<3/4): .pound.3.76 (t, J= 4.8 Hz, 4H), 4.10 (t, J = 4.8 Hz, 4H), 8.29(s, 1H), 10.21 (s, 1H).
35%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 11 h;
Step 1g: 2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (Compound 0112)[0177]To a suspension of compound 0111 (1.75 g, 6.85 mmol) in dry tetrahydrofuran (40 mL) at −78° C. was added a 2.0 M solution of LDA in THF/hexane (20.55 mL, 41.1 mmol). After stirring for 1 h, dry N,N-dimethylformamide (3.2 mL, 41.1 mmol) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further stir for 10 h at room temperature, the reaction mixture was poured onto NH4Cl saturated solution, extracted with ethyl acetate (100 mL×3), dried over Na2SO4 and filtered. The filtrate was concentrated to leave a residue which was washed with ethyl acetate (10 mL×2) to give the title compound 0112 (0.66 g, 35percent) as a yellow solid: LCMS: 284 [M+1]+; 1H NMR (400 MHz, DMSO-d6): δ3.76 (t, J=4.8 Hz, 4H), 4.10 (t, J=4.8 Hz, 4H), 8.29 (s, 1H), 10.21 (s, 1H).
35%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 11 h;
In dry tetrahydrofuran (40mL), the suspension of the compound 0111 (1.75g, 6.85mmol), at -78 , was added 2.0M solution of THF / hexane (20.55mL, 41.1mmol) medium LDA. After stirring for 1 hour, dry N, N- dimethylformamide (3.2mL, 41.1mmol) was added. The reaction mixture was stirred for 1 h at -78 , then was slowly warmed to room temperature. After stirring for a further 10 hours at room temperature, the reaction mixture was poured into NH4Cl saturated solution and extracted with ethyl acetate (100mL x 3), dried over Na2SO4, and filtered. Remainder residue and concentration of the filtrate, which was washed with ethyl acetate (10mL x 2), to give the title compound 0112 (0.66g, 35percent) as a yellow solid:
24.5 kg With n-butyllithium In tetrahydrofuran; hexane at -80 - -78℃; Inert atmosphere; Large scale Compound 104 (21.1 kg, 82.51 mol, 1.0 equiv) was added to anhydrous tetrahydrofuran (201 kg)Cooling to -80 ~ -70 degrees Celsius. Under a nitrogen atmosphere, 2.5 M n-butyllithium n-hexane solution (35.7 kg, 127.5 mol, 1.54 eq)In the -80 ~ -70 degrees Celsius slowly into the mixture. Drip after the temperature rise to -65 ~ -60 degrees Celsius stirring 1 to 2 hours. The temperature of the reactants was reduced to -80 to -70 ° C and N, N-dimethylformamide (9.5 kg, 130 molL, 1.57 eq.) Was slowly added dropwise to the reaction. The reaction is stirred at -80 to -70 ° C for 1 to 2 hours. extendReaction time 1 to 2 hours. The sample was quenched with 0.5 M dilute hydrochloric acid solution. No progress in response. The reactants were raised to -30 to -20In degrees Celsius, the reactants were added to 0.5 M dilute hydrochloric acid solution (570 kg) and stirred at 0 to 10 degrees Celsius for 1 hour. Centrifugal,The filter cake is rinsed with water (50 kg). The wet product was dried under vacuum at 50 to 60 ° C to give a yellow solid product 2-chloro-4-Morpholine thiophene [3,2-d] pyrimidine-6-aldehyde (24.5 kg, yield: 87.9percent).

Reference: [1] Patent: US9249156, 2016, B2, . Location in patent: Page/Page column 37
[2] Patent: WO2009/53715, 2009, A1, . Location in patent: Page/Page column 64
[3] Organic Process Research and Development, 2013, vol. 17, # 1, p. 97 - 107
[4] Patent: WO2008/70740, 2008, A1, . Location in patent: Page/Page column 134
[5] Patent: WO2008/73785, 2008, A2, . Location in patent: Page/Page column 160
[6] Journal of Medicinal Chemistry, 2008, vol. 51, # 18, p. 5522 - 5532
[7] Patent: US9335320, 2016, B2, . Location in patent: Page/Page column 71
[8] Patent: JP5658565, 2015, B2, . Location in patent: Paragraph 0336-0337
[9] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 703 - 706
[10] Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 8, p. 1037 - 1045
[11] Patent: US2011/230476, 2011, A1, . Location in patent: Page/Page column 247
[12] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 129
[13] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0177
[14] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0175
[15] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 8, p. 2408 - 2411
[16] Journal of Medicinal Chemistry, 2010, vol. 53, # 3, p. 1086 - 1097
[17] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7686 - 7695
[18] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 4023 - 4035
[19] Patent: CN104292242, 2017, B, . Location in patent: Paragraph 0126; 0127; 0128
  • 3
  • [ 16234-15-4 ]
  • [ 885618-31-5 ]
YieldReaction ConditionsOperation in experiment
98% With hydrogenchloride; n-butyllithium In tetrahydrofuran; water at -78 - 0℃; for 1.5 h; Inert atmosphere To a suspension of compound 104 (20 g, 78.4 mmol, 1.0 eq) in THF (anhydrous,320 mL) at -78°C was added n-BuLi (in hexanes, 2.4 M, 40.8 mL, 102 mmol, 1.3 eq) slowly under nitrogen. The resulting slurry was allowed to warm up to -60°C to turn into aclear brown solution. The reaction mixture was then cooled to -7 8°C again and DMF (anhydrous, 9.1 mL, 118 mmol, 1.5 eq) was added slowly. The resulting solution was stirred at -78°C for 0.5 h, warmed up to 0°C over 1 h and was poured slowly to a mixture of aq HC1 (0.25 M, 660 mL) and ice water (320 mL). The resulting slurry was stirred at 0- 10°C for 0.5 h, filtered, washed with cold water and dried in vacuo to afford compound105 as ayellowsolid(22g, 98percent). M.p.:260-265°C. LCMS (m/z): 284.0 [M+1j ‘HNMR(400 MHz, DMSO-d6): ö 3.77 (t, J= 5.2 Hz, 4H), 3.96 (t, J= 5.2 Hz, 4H), 8.30 (s, 1H),
Reference: [1] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 25; 31
[2] Patent: US2010/233164, 2010, A1,
  • 4
  • [ 16234-14-3 ]
  • [ 885618-31-5 ]
Reference: [1] Patent: US2011/230476, 2011, A1,
[2] Patent: WO2011/130628, 2011, A1,
[3] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 703 - 706
[4] Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 8, p. 1037 - 1045
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7686 - 7695
[6] Organic Process Research and Development, 2013, vol. 17, # 1, p. 97 - 107
[7] Patent: US9249156, 2016, B2,
[8] Patent: US9335320, 2016, B2,
[9] Patent: JP2015/187145, 2015, A,
[10] Patent: JP5658565, 2015, B2,
[11] Patent: CN104292242, 2017, B,
[12] Patent: WO2018/85342, 2018, A1,
[13] Patent: US2013/102595, 2013, A1,
  • 5
  • [ 16233-51-5 ]
  • [ 885618-31-5 ]
Reference: [1] Patent: WO2011/130628, 2011, A1,
[2] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 703 - 706
[3] Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 8, p. 1037 - 1045
[4] Organic Process Research and Development, 2013, vol. 17, # 1, p. 97 - 107
[5] Patent: US9249156, 2016, B2,
[6] Patent: US9335320, 2016, B2,
[7] Patent: JP2015/187145, 2015, A,
[8] Patent: JP5658565, 2015, B2,
[9] Patent: CN104292242, 2017, B,
[10] Patent: WO2018/85342, 2018, A1,
[11] Patent: US2013/102595, 2013, A1,
  • 6
  • [ 22288-78-4 ]
  • [ 885618-31-5 ]
Reference: [1] Patent: WO2011/130628, 2011, A1,
[2] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 703 - 706
[3] Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 8, p. 1037 - 1045
[4] Organic Process Research and Development, 2013, vol. 17, # 1, p. 97 - 107
[5] Patent: US9249156, 2016, B2,
[6] Patent: US9335320, 2016, B2,
[7] Patent: JP2015/187145, 2015, A,
[8] Patent: JP5658565, 2015, B2,
[9] Patent: WO2018/85342, 2018, A1,
[10] Patent: WO2018/85342, 2018, A1,
[11] Patent: US2013/102595, 2013, A1,
  • 7
  • [ 113400-36-5 ]
  • [ 885618-31-5 ]
Reference: [1] Patent: US2011/269244, 2011, A1, . Location in patent: Page/Page column
  • 8
  • [ 98-79-3 ]
  • [ 885618-31-5 ]
Reference: [1] Patent: US2011/269244, 2011, A1,
  • 9
  • [ 885618-31-5 ]
  • [ 955979-15-4 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: at 20℃; Inert atmosphere
Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at 20℃; Inert atmosphere
To a solution of compound 105 (20.0 g, 70.4 mmol, 1.0 eq) in methanol (125 mL) was added methylamine solution in methanol (27percent v/v, 75 mL, 563.2 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight and the solvent was removed in vacuo to give a crude solid product, which was dissolved in methanol (550 mL) and THF (220 mL) under nitrogen. Sodium borohydride (8g, 211.2mmol) was added in portions and reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo and water (300 mL) was added. The aqueous mixture was extracted with methylene chloride and the combined extracts were dried over Na2504 and concentrated. The residue was dissolved in 6M HC1 (230 mL) and stirred for 30 mm. The aqueous solution was washed with methylene chloride forseveral times, and adjusted to pH 9-10 with NaOH (4N). The precipitated solid was collected by filtration and dried (60°C, 6h) to give a light yellow solid (18 g, 85percent). M.p.:240-245°C. LCMS (m/z): 299 [M+1j ‘H NMR (400 MHz, DMSO-d6): ö 2.32 (s, 3H),3.74 (t, J 5.2 Hz, 4H), 3.88 (t, J 5.2 Hz, 4H), 3.96 (s, 2H), 7.24 (s, 1H).
Reference: [1] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 25; 31
[2] Patent: US2011/230476, 2011, A1,
[3] Patent: WO2011/130628, 2011, A1,
[4] Patent: US9249156, 2016, B2,
[5] Patent: JP2015/187145, 2015, A,
[6] Patent: US2013/102595, 2013, A1,
  • 10
  • [ 885618-31-5 ]
  • [ 74-89-5 ]
  • [ 955979-15-4 ]
YieldReaction ConditionsOperation in experiment
90.9%
Stage #1: at 20 - 30℃; Large scale
Stage #2: at 20 - 30℃; Large scale
A solution of 30percent methanol (60.5 kg, 584.35 mol, 8.0 equiv) was added to compound 105 (20.6 thousandG, 72.7 mol, 1 eq.) In methanol (115 kg). The reaction mixture is stirred at 20 to 30 degrees Celsius for 10 to 12 hours. The mixture was concentrated under reduced pressure. Methanol (405 kg) and tetrahydrofuran (185 kg)Was added to the concentrated mixture, and then anhydrous magnesium sulfate (20.6 kg) was added to ensure that the reaction system was dry throughout the reaction.Sodium borohydride (10 kg, 264.34 mol, 3.64 equiv) was added portionwise to the mixture,The mixture was stirred at 20 to 30 degrees Celsius for 6 to 7 hours. Water (110 kg) was added to the mixture at the end of the reaction and stirred at 20 to 30 ° C for 30 minutes. The mixture was concentrated under reduced pressure in vacuo. After concentration, 6M hydrochloric acid solution (222 kg) and dichloromethane (181 kg) were added. The reaction mixture is stirred at 20 to 30 degrees Celsius for 30 to 40 minutes, allowed to stand and the organic phase is separated. The water phase is 4MSodium hydroxide solution (316.0 kg) to adjust the pH to 9 ~ 10. The mixture was stirred at 20 to 30 degrees Celsius for 1 to 2 hours. The precipitated solid was centrifuged and dried at 40-50 ° C for 60 hours to give N- (2-chloro-4-morpholinothiazine [3,2-d] pyrimidine-6methyl) -methyl Amine (29.5 kg, yield: 90.9percent).
53%
Stage #1: for 24 h; Inert atmosphere
Stage #2: With sodium tetrahydroborate In tetrahydrofuran; toluene at 20℃; for 24 h;
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 (2.0 g) was dissolved in 50 mL toluene and 50 mL THF followed by the addition of 20 mL of 40percent methylamine in H2O.
The reaction mixture was stirred at room temp under N2 for 24 hours.
The solvents were removed in vacuo and the residue was dissolved in 50 mL methanol and 50 mL THF and the NaBH4 added portion-wise.
This reaction mixture was stirred at room temp under N2 for 24 hours and complete reaction was confirmed by LCMS.
The solvents were removed in vacuo and the crude product purified by flash chromatography (EtOAc/EtOH) to give 1.12 g 35 (53percent yield). MS (Q1) 300 (M+).
53%
Stage #1: at 20℃; for 24 h; Inert atmosphere
Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at 20℃; for 24 h; Inert atmosphere
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 (2.0 g) was dissolved in 50 mL toluene and 50 mL THF followed by the addition of 20 mL of 40percent methylamine in H2O. The reaction mixture was stirred at room temp under N2for 24 hours. The solvents were removed in vacuo and the residue was dissolved in 50 mL methanol and 50 mL THF and the NaBH4added portion-wise. This reaction mixture was stirred at room temp under N2for 24 hours and complete reaction was confirmed by LCMS. The solvents were removed in vacuo and the crude product purified by flash chromatography (EtOAc/EtOH) to give 1.12 g 35 (53percent yield).
Reference: [1] Patent: CN104292242, 2017, B, . Location in patent: Paragraph 0129; 0130; 0131
[2] Patent: US9335320, 2016, B2, . Location in patent: Page/Page column 72; 73
[3] Patent: JP5658565, 2015, B2, . Location in patent: Paragraph 0346-0347
  • 11
  • [ 885618-31-5 ]
  • [ 955979-15-4 ]
YieldReaction ConditionsOperation in experiment
53% With sodium tetrahydroborate; methylamine In tetrahydrofuran; methanol; water; toluene Example 6
(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine 35
2-Chloro-4-morpholinothieno[3,2-c]pyrimidine-6-carbaldehyde 10 (2.0 g) was dissolved in 50 mL toluene and 50 mL THF followed by the addition of 20 mL of 40percent methylamine in H2O.
The reaction mixture was stirred at room temp under N2 for 24 hours.
The solvents were removed in vacuo and the residue was dissolved in 50 mL methanol and 50 mL THF and the NaBH4 added portion-wise.
This reaction mixture was stirred at room temp under N2 for 24 hours and complete reaction was confirmed by LCMS.
The solvents were removed in vacuo and the crude product purified by flash chromatography (EtOAc/EtOH) to give 1.12 g 35 (53percent yield). MS (Q1) 300 (M+).
Reference: [1] Patent: US2010/233164, 2010, A1,
  • 12
  • [ 885618-31-5 ]
  • [ 957054-30-7 ]
Reference: [1] Patent: WO2011/130628, 2011, A1,
[2] Patent: US9335320, 2016, B2,
[3] Patent: JP2015/187145, 2015, A,
[4] Patent: US2013/102595, 2013, A1,
  • 13
  • [ 55276-43-2 ]
  • [ 885618-31-5 ]
  • [ 957054-30-7 ]
Reference: [1] Patent: JP5658565, 2015, B2,
  • 14
  • [ 885618-31-5 ]
  • [ 1339928-25-4 ]
Reference: [1] Patent: US9249156, 2016, B2,
[2] Patent: US9249156, 2016, B2,
[3] Patent: US9249156, 2016, B2,
[4] Patent: WO2018/85342, 2018, A1,
[5] Patent: WO2018/85342, 2018, A1,
[6] Patent: WO2018/85342, 2018, A1,
[7] Patent: WO2018/85342, 2018, A1,
[8] Patent: WO2018/85342, 2018, A1,
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