Home Cart 0 Sign in  
X

[ CAS No. 16233-51-5 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
3d Animation Molecule Structure of 16233-51-5
Chemical Structure| 16233-51-5
Chemical Structure| 16233-51-5
Structure of 16233-51-5 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 16233-51-5 ]

Related Doc. of [ 16233-51-5 ]

Alternatived Products of [ 16233-51-5 ]

Product Details of [ 16233-51-5 ]

CAS No. :16233-51-5 MDL No. :MFCD09909655
Formula : C6H4N2O2S Boiling Point : -
Linear Structure Formula :- InChI Key :QAFVXBQPQCSSLI-UHFFFAOYSA-N
M.W : 168.17 Pubchem ID :7059273
Synonyms :

Calculated chemistry of [ 16233-51-5 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 43.07
TPSA : 93.96 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.0 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.88
Log Po/w (XLOGP3) : 0.46
Log Po/w (WLOGP) : 0.28
Log Po/w (MLOGP) : -0.05
Log Po/w (SILICOS-IT) : 2.98
Consensus Log Po/w : 0.91

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.78
Solubility : 2.8 mg/ml ; 0.0167 mol/l
Class : Very soluble
Log S (Ali) : -2.0
Solubility : 1.68 mg/ml ; 0.00996 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.4
Solubility : 0.662 mg/ml ; 0.00394 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.31

Safety of [ 16233-51-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 16233-51-5 ]

* 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 [ 16233-51-5 ]
  • Downstream synthetic route of [ 16233-51-5 ]

[ 16233-51-5 ] Synthesis Path-Upstream   1~26

  • 1
  • [ 22288-78-4 ]
  • [ 16233-51-5 ]
YieldReaction ConditionsOperation in experiment
94% With potassium cyanate; acetic acid In water at 20℃; for 21 h; To a mixture of 3-aminothiophene-2-carboxylate (101) (100.0 g,636.9 mmol, 1.0 eq), acetic acid (705 mL) and water (600 mL) was added a solution of potassium cyanate (154.8 g, 1.91 mol, 3.0 eq) in water (326 mL) slowly over a period of 1 h. The resulting mixture was stirred at room temperature for 20 h, filtered and rinsed with water (500 mL). The cake was charged to a suitably sized reactor and 2 M aqueous sodiumhydroxide solution (1.65 L) was added, the slurry was stirred for 2 h and LCMS confirmed the formation of the desired product. The mixture was cooled to 10°C and 3 M aqueous hydrochloric acid (1.29 L) was added until the pH = 5.0 6.0. The slurry was filtered, rinsed with water (700 mL), and dried in vacuum oven at 50°C for 24 h to afford compound 102 (100 g, 94percent) as an off-white solid. LCMS (m/z): 169.1 [M+1j ‘HNMR(400MHz,DMSO-d6): ö6.92(d,J5.2Hz, 1H), 8.04(d,J5.2Hz, 1H), 11.14(s, 1H),11.51 (s, 1H).
81%
Stage #1: With sodium isocyanate In water; acetic acid at 20℃; for 5 h;
Stage #2: With sodium hydroxide In water at 0℃;
To a solution in which sodium cyanate (5.0 g, 77.0 mmol) was dissolved in water (15.0 mL), methyl 3-aminothiophen-2-carboxylate (6.05 g, 38.4 mmol) dissolved in a mixture solution (90 mL) of 50percent glacial acetic acid and water was slowly added dropwise. After stirring for 5 hours at room temperature, thus prepared white precipitate was filtered. The white solid was dissolved in 2.0 N sodium hydroxide solution (90.0 mL). The mixture solution was cooled to 0 °C and acidified using acetic acid. Filtration of thus prepared white solid followed by drying yielded the target compound thieno[3,2-d]pyrimidin-2,4(1H,3H)-dione (5.2 g, 81percent yield). [0138] 1H NMR (400 MHz, DMSO-d 6) δ 11.33 (bs, 2H), 8.10 (d, J = 5.2 Hz, 1H), 8.10 (d, J = 5.2 Hz, 1H), MS m/z: 168.94 [M+1].
81%
Stage #1: With sodium isocyanate; acetic acid In water at 20℃; for 5 h;
Stage #2: With sodium hydroxide In water at 0℃;
Step 1:
thieno[3,2-d]pyridin-2,4(1H,3H)-dione
To a solution in which sodium cyanate (5.0 g, 77.0 mmol) was dissolved in water (15.0 mL), methyl 3-aminothiophen-2-carboxylate (6.05 g, 38.4 mmol) dissolved in a mixture solution (90 mL) of 50percent glacial acetic acid and water was slowly added dropwise.
After stirring for 5 hours at room temperature, thus prepared white precipitate was filtered.
The white solid was dissolved in 2.0 N sodium hydroxide solution (90.0 mL).
The mixture solution was cooled to 0° C. and acidified using acetic acid.
Filtration of thus prepared white solid followed by drying yielded the target compound thieno[3,2-d]pyrimidin-2,4(1H,3H)-dione (5.2 g, 81percent yield).
1H NMR (400 MHz, DMSO-d6) δ 11.33 (bs, 2H), 8.10 (d, J=5.2 Hz, 1H), 8.10 (d, J=5.2 Hz, 1H), MS m/z: 168.94 [M+1].
Reference: [1] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 25; 30
[2] Patent: WO2011/49332, 2011, A2, . Location in patent: Page/Page column 16
[3] Patent: US2012/277424, 2012, A1, . Location in patent: Page/Page column 7
[4] Journal of Chemical Research, Miniprint, 1993, # 2, p. 548 - 575
[5] Patent: CN103980287, 2016, B, . Location in patent: Paragraph 0117; 0118; 0119
[6] Patent: KR2016/38615, 2016, A,
  • 2
  • [ 590-28-3 ]
  • [ 22288-78-4 ]
  • [ 16233-51-5 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: With acetic acid In water at 20℃; for 21 h;
Stage #2: With sodium hydroxide In water for 2 h;
Step k:
Thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (Compound 102)
Urea Method:
A mixture of methyl 3-aminothiophene-2-carboxylate (101) (90.0 g, 573 mmol, 1.0 eq) and urea (277.6 g, 4.6 mol, 8.0 eq) was heated at 190° C. for 3-4 h and cooled to room temperature.
To the reaction mixture was added aq. NaOH (10percent, 800 mL).
After stirring at ambient temperature for 1 h, the solid was removed by filtration.
The filtrate was acidified with HCl to pH 3-4, the precipitated solid was collected by filtration, washed with water and dried in vacuo to give the desired product compound 102 as an off-white solid (87 g, 89percent).
m.p.: 280-285° C. LCMS (m/z): 169.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6): δ 6.92 (d, J=5.2 Hz, 1H), 8.05 (d, J=5.2 Hz, 1H), 11.0-11.5 (br, 2H).
89.3% With acetic acid In water at 20 - 30℃; Large scale A mixture of methyl 3-amino-2-thiophenecarboxylate (Compound 101) (18.0 kg, 114.5 mol, 1.0 equiv), acetic acid(113.6 kg, 2224.8 moles, 19.4 equivalents) and water (110 kg)Was slowly added to an aqueous solution (59 kg) of potassium cyanate (27.31 kg, 336.5 mol, 2.94 equiv.). The mixture was stirred at room temperature for 10 to 12 hours. Wet water (27 kg) rinse. Sodium hydroxide (23.3 kg) was slowly added to the water (146 kg) at 20 to 40 ° C and stirred until the solid was completely dissolved. The solid obtained by centrifugation was added to the solution of sodium hydroxide. The mixture was stirred at 20 to 30 degrees Celsius for 4 to 6 hours. The mixture was cooled to 10 to 15 degrees Celsius. The pH of the mixture was adjusted to 6 to 2 with 2M hydrochloric acid solution (285 kg)8. The mixture was stirred at 10 to 15 degrees Celsius for 1 hour. Centrifuge, filter cake with water (33 kg) rinse. Vacuum in the 55 ~ 60Celsius drying. A mixture of thiophene [3,2-d] pyrimidine-2,4- (1H, 3H) -dione (17.2 kg, yield:89.3percent).
71% With acetic acid In water at 20℃; for 16 h; In a dry flask methyl-3-amino-2-thiophene carboxylate 3 (5.00 g, 31.80 mmol) was dissolved in acetic acid (100 mL) to obtain a yellow solution to which potassium cyanate (10.31 g, 127.30 mmol) dissolved in water (80 mL) was added dropwise over 3 h. The resultant suspension was stirred overnight (16 h) at which point the suspension was filtered. The white solid residue was dissolved in 2N NaOH (80 mL) by warming to 70 °C. The clear solution was then acidified by AcOH (pH 4–5), the resulting white precipitate was filtered, washed with water then acetone and dried to obtain 4 as a white solid (3.80 g, 22.60 mmol, 71 percent). Spectroscopy data agrees with literature.
71% With acetic acid In water for 19 h; In a dry flask methyl-3-amino-2-thiophene carboxylate 3 (5.00 g, 31.80 mmol) was dissolved in acetic acid (100 mL) to obtain a yellow solution to which potassium cyanate (10.31 g, 127.30 mmol) dissolved in water (80 mL) was added dropwise over 3 h. The resultant suspension was stirred overnight (16 hr) at which point the suspension was filtered. The white solid residue was dissolved in 2N NaOH (80 mL) by warming to 70° C. The clear solution was then acidified by AcOH (pH 4-5), the resulting white precipitate was filtered, washed with water then acetone and dried to obtain 4 as a white solid (3.80 g, 22.60 mmol, 71percent).

Reference: [1] Patent: US9249156, 2016, B2, . Location in patent: Page/Page column 36
[2] Patent: CN104292242, 2017, B, . Location in patent: Page/Page column 0103; 0117; 0118; 0119
[3] Nucleosides and Nucleotides, 1994, vol. 13, # 4, p. 925 - 937
[4] Organic Process Research and Development, 2013, vol. 17, # 1, p. 97 - 107
[5] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 7, p. 2113 - 2122
[6] Patent: US2016/257696, 2016, A1, . Location in patent: Paragraph 0062
  • 3
  • [ 22288-78-4 ]
  • [ 57-13-6 ]
  • [ 16233-51-5 ]
YieldReaction ConditionsOperation in experiment
94% at 180℃; for 5 h; A solid mixture of methyl-S-aminothiophene^-carboxylate (76g, 480mmol) and urea (189g, 3140mmol) was heated, with stirring, to 18O0C for 5h. The mixture was cooled to 900C and water (1000ml) added. After stirring at room temperature for 16h, a cream coloured solid was filtered and washed twice with further water. The solid was dried in vacuo at 40 0C to give the title compound in 94percent yield, >95percent purity. LC-MS m/z=169.0 [M+H]+; RT=1.29min; LC-MS method 2. 1H NMR: δH (400MHz, D6-DMSO) 6.90 (1 H, d, J 5.5Hz),
93.45% at 200℃; for 2 h; Neat (no solvent) Methyl 3-aminothiophene-2-carboxylate (1, 1 g, 6.36 mmol) and urea (2.19 g, 36.62 mmol) were mixed together and heated at 200 °C for 2 h. The solid obtained was dissolved in 5percent aq. NaOH and filtered. The filtrate was acidified to pH 5.5 by dropwise addition of 2M HC1, resulting in a precipitate. The resultant precipitate was filtered and dried to afford cream white solid of thieno[3,2- d]pyrimidine-2,4( l H,3H)-dione (2, 1.07 g, 93.45percent). 'HNMR (DMSO-6): 1 1.55 (bs, 1 H), 1 1.20 (bs, 1 H), 8.05 (d, 1 H), 6.95 (d, 1 H).
92% at 200℃; for 2 h; Methyl-S-amino^-thiophenecarboxylate (2Og, 127mmol) and urea (44g, 732mmol) were heated for 2h at 200°C. The solids obtained were dissolved in 5percent aq. NaOH (50OmL) and the yellow solution filtered. The basic solution was acidified to pH 5.5 by dropwise addition of 2M HCI and the precipitate collected by filtration to afford the product as a cream/white solid (19.7g, 92percent). 1H NMR (DMSO-d6, 300 MHz): l 1.28 φr. s, 2H), 8.03 (d, J=5.1 Hz, I H), 6.90 (d, J=5.1 Hz, I H); LRMS (ESI): w/z calcd for [M-H]" 166.99 found 167.1.
89%
Stage #1: at 190℃;
Stage #2: With sodium hydroxide In water at 120℃; for 1 h;
Step k:
Thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (Compound 102)
Urea Method:
A mixture of methyl 3-aminothiophene-2-carboxylate (101) (90.0 g, 573 mmol, 1.0 eq) and urea (277.6 g, 4.6 mol, 8.0 eq) was heated at 190° C. for 3-4 h and cooled to room temperature.
To the reaction mixture was added aq. NaOH (10percent, 800 mL).
After stirring at ambient temperature for 1 h, the solid was removed by filtration.
The filtrate was acidified with HCl to pH 3-4, the precipitated solid was collected by filtration, washed with water and dried in vacuo to give the desired product compound 102 as an off-white solid (87 g, 89percent).
m.p.: 280-285° C. LCMS (m/z): 169.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6): δ 6.92 (d, J=5.2 Hz, 1H), 8.05 (d, J=5.2 Hz, 1H), 11.0-11.5 (br, 2H).
89% With sodium hydroxide In water at 20 - 190℃; for 1 h; A mixture of methyl 3-aminothiophene-2-carboxylate (101) (90.0 g, 573 mmol, 1.0 eq) and urea (277.6 g, 4.6 mol, 8.0 eq) was heated at 190°C for 3-4 h and cooled to room temperature. To the reaction mixture was added aq. NaOH (10percent, 800 mL).After stirring at ambient temperature for 1 h, the solid was removed by filtration. The filtrate was acidified with HC1 to pH 3-4, the precipitated solid was collected by filtration, washed with water and dried in vacuo to give the desired product compound 102 as an off- white solid (87 g, 89percent). m.p. :280-285°C. LCMS (m/z): 169.0 [M+1f. ‘H NMR (400 MHz, DMSO- d6): ö 6.92 (d, J= 5.2 Hz, 1H), 8.05 (d, J 5.2 Hz, 1H), 11.0-11.5 (br, 2H).
81.7% at 180℃; for 4 h; Compound 4-1 (4 g) and urea (10 g) were loaded into 100 ml eggplant-shaped flask and mixed uniformly. Themixture was heated to 180° C for 4 hours and 100 ml of water was added. A large amount of solids was precipitated.The solids were filtered by suction, washed with water and dried, thereby obtaining the product 4-2 (3.5 g) in 81.7percentyield. MS: 169.0[M+H]+.
81.7% at 180℃; for 4 h; Synthesis of 4-2 [0134] Compound 4-1 (4 g) and urea (10 g) were loaded into 100 ml eggplant-shaped flask and mixed uniformly. The mixture was heated to 180° C. for 4 hours and 100 ml of water was added. A large amount of solids was precipitated. The solids were filtered by suction, washed with water and dried, thereby obtaining the product 4-2 (3.5 g) in 81.7percent yield. MS: 169.0[M+H]+.
79% at 200℃; for 1.5 h; 3-Amino-2-thiophenecarboxylic acid methyl ester (1 g, 6.36 mmol) and urea (3 g, 50 mmol) were placed in a round-bottomed flask, and the mixture was heated at 200 °C for 1.5 h. After the reaction was complete, the residue was dissolved in 40 mL of 20percent NaOH, and a solution of 10percent HCl was added to adjust the pH to 5–6. The precipitate was filtered and washed with water to produce a white solid. Yield: 79percent, mp: 311–314 °C. 1H NMR (CDCl3, 300 MHz) δ: 6.89 (t, 1H, J = 3.00 Hz, S–CC–H), 8.02 (t, 1H, J = 3.00 Hz, S–C–H), 11.19 (s, 1H, –CONH), 11.54 (s, 1H, –CONHCO–). MS-EI m/z 169 (M + 1).
79% at 200℃; for 1.5 h; 3-Amino-2-thiophenecarboxylic acid methyl ester (1 g, 6.36 mmol) and urea (3 g, 50 mmol) were placed in a round bottomed flask, and the mixture was heated at 200 °C for 1.5 h. After the reaction was complete, the residue was dissolved in 20percent NaOH (40 mL) and a solution of 10percent HCl was added to adjust the pH to 5–6. The resulting solid was filtered, washed with water and dried. Yield: 79percent, mp: 311–314 °C. 1H-NMR (CDCl3) δ: 6.89 (t, 1H, J = 3.00 Hz, S-C=C-H), 8.02 (t, 1H, J = 3.00 Hz, S-C-H),11.19 (s, 1H, -CONH), 11.54 (s, 1H, -CONHCO-). MS-EI m/z 169 (M + 1).
67%
Stage #1: at 190℃; for 2 h;
Stage #2: Heating
Stage #3: With hydrogenchloride In water
Step Id: Thieno[3,2-d]pyrimidine-2,4(7H,JH)-dione (Compound 0109)A mixture of methyl 3-amino-2-thiophenecarboxylate (0108) (13.48 g, 85.85 mmol) and urea (29.75 g, 0.43 mol) was heated at 190 °C for 2 h. The hot reaction mixture was poured into sodium hydroxide solution and insoluble material was removed by filtration.The mixture was then acidified by 2 N HCl solution. The resulting solid was collected by filtration, dried to give title compound 0109 (9.62 g, 67percent) as a white solid: LCMS: 169[M+l]+; 1H NMR (400 MHz, DMSO-<3/4): δ 6.92 (d, J= 4.0 Hz, 1H), 8.04 (d, J= 4.0 Hz ,1H), 11.19 (d, J= 14.0 Hz , 1H), 11.60 (s, 1H).
67% at 190℃; for 2 h; Step 1d: Thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (Compound 0109)[0174]A mixture of methyl 3-amino-2-thiophenecarboxylate (0108) (13.48 g, 85.85 mmol) and urea (29.75 g, 0.43 mol) was heated at 190° C. for 2 h. The hot reaction mixture was poured into sodium hydroxide solution and insoluble material was removed by filtration. The mixture was then acidified by 2 N HCl solution. The resulting solid was collected by filtration, dried to give title compound 0109 (9.62 g, 67percent) as a white solid: LCMS: 169 [M+1]+; 1H NMR (400 MHz, DMSO-d6): δ 6.92 (d, J=4.0 Hz, 1H), 8.04 (d, J=4.0 Hz, 1H), 11.19 (d, J=14.0 Hz, 1H), 11.60 (s, 1H).
67% at 190℃; for 2 h; Methyl 3-amino-2-thiophene-carboxylate (0108) (13.48g, 85.85mmol) andA mixture of urea (29.75g, 0.43mol) was heated for 2 hours at 190 . The hot reaction mixture was poured into hydroxide sodium solution, insoluble material was removed by filtration. Then, the mixture was acidified by 2NHCl solution. The resulting solid was collected by filtration and dried to give the title compound 0109 (9.62g, 67percent) as a white solid:
67% at 220℃; for 2 h; A mixture of methyl 3-aminothiophene-2-carboxylate (11, 13.48 g, 1 equiv.) and urea (26.75 g, 5.2 equiv.) was heated at 220° C for 2 h. The hot reaction mixture was poured into sodium hydroxide solution and insoluble material was removed by filtration. The mixture was then neutralized with 2N HCl to get grey solid of compound 12 (9.62 g, 67percent). *H NMR (400 MHz, DMS0-< ppm): δ 11.60 (s, 1H), 11.19 (d, / = 14.0 Hz, 1H), 8.04 (d, / = 4.0 Hz, 1H), 6.92 (d, / = 4.0 Hz, 1H); ESI-MS: m/z 169.12 [M+H]+.
67% at 190℃; for 2 h; A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g, 85.85 mmol) and urea (29.75 g, 0.43 mo ) was heated at 190 °C for 2 h. Then the hot reaction mixture was poured into sodium hydroxide solution and insoluble material was removed by filtration. The mixture was then acidified by 2 N of HCl solution, collected by filtration and air dried, to give title compound (9.62 g, 67percent) as a white precipitate.
67% at 190℃; for 2 h; A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g, 85.85 mmol) and urea (29.75 g, 0.43 mol) was heated at 190 °C for 2 h. Then the hot reaction mixture was poured into sodium hydroxide solution and insoluble material was removed by filtration. The mixture was then acidified by 2 N of HCl solution, collected by filtration and air dried, to give title compound (9.62 g, 67percent) as a white precipitate.
66% at 190℃; for 2 h; Reference Example 1 : 2,4-Dichloro-thieno[3,2-dlpyrimidine (64) (63) (64) EPO <DP n="31"/>A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g, 85.85mmol) and urea (29.75g, 5eq.) was heated at 190°C for 2 h. The hot reaction mixture was then poured onto sodium hydroxide solution and any insoluble material removed by filtration. The mixture was then acidified (HCl, 2N) to yield lH-thieno [3,2- d]pyrimidine-2,4-dione (63) as a white precipitate, which was collected by filtration and air dried (9.49g, 66percent).1H NMR (400 MHz, 6-DMS0) 6.90 (IH, d, J=5.2Hz), 8.10 (IH, d, J=5.2Hz), 11.60-11.10 (2H, br s).
66% at 190℃; for 2 h; A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g, 85.85 mmol) and urea (29.75 g, 5 eq.) was heated at 190° C. for 2 h. The hot reaction mixture was then poured onto sodium hydroxide solution and any insoluble material removed by filtration. The mixture was then acidified (HCl, 2N) to yield H-thieno[3,2-d]pyrimidine-2,4-dione (IX) as a white precipitate, which was collected by filtration and air dried (9.49 g, 66percent). 1H NMR (400 MHz, d6-DMSO) 6.90 (1H, d, J=5.2 Hz), 8.10 (1H, d, J=5.2 Hz), 11.60-11.10 (2H, br s).
66%
Stage #1: at 190℃; for 2 h;
A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g, 85.85 mmol) and urea (29.75 g, 5 eq.) was heated at 190° C. for 2 hours.
The hot reaction mixture was then poured onto sodium hydroxide solution and any insoluble material removed by filtration.
The mixture was then acidified (HCl, 2N) to yield 1H-thieno[3,2-d]pyrimidine-2,4-dione) as a white precipitate, which was collected by filtration and air dried (9.49 g, 66percent).
1H NMR (400 MHz, d6-DMSO) 6.90 (1H, d, J=5.2 Hz), 8.10 (1H, d, J=5.2 Hz), 11.60-11.10 (2H, br, s).
66% at 190℃; for 2 h; A mixture of methyl 3-amino-2-thiophenecarboxylate 1 (13.48 g, 85.85 mmol) and urea (29.75 g, 5 eq.) was heated at 190 °C for 2 hours. The hot reaction mixture was poured onto sodium hydroxide solution and any insoluble material was removed by filtration. The mixture was then acidified (HCl, 2N) to yield lH-thieno [3,2-d]pyrimidine-2,4-dione 2 as a white precipitate, which was collected by filtration and air dried (9.49g, 66percent). 1H NMR 400 MHz, J6-DMSO) 6.90 (IH, d, J=5.2Hz), 8.10 (IH5 d, J=5.2Hz), 11.60-11.10 (2H, br s). [00242] A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49g, 56.49mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75percent). 1H NMR (400 MHz, CDCl3) 7.56 (IH, d, J=5.5Hz), 8.13 (IH, d, J=5.5Hz).
66%
Stage #1: at 190℃; for 2 h;
Stage #2: With sodium hydroxide In water
Stage #3: With hydrogenchloride In water
A mixture of methyl 3-amino-2-thiophenecarboxylate 1 (13.48 g, 85.85 mmol) and urea (29.75 g, 5 eq.) was heated at 190 °C for 2 hours. The hot reaction mixture was poured onto sodium hydroxide solution and any insoluble material was removed by filtration. The mixture was then acidified (HCl, 2N) to yield lH-thieno [3,2-d]pyrimidine-2,4-dione 2 as a white precipitate, which was collected by filtration and air dried (9.49g, 66percent). 1H NMR 400 MHz, J6-DMSO) 6.90 (IH, d, J=5.2Hz), 8.10 (IH, d, J=5.2Hz), 11.60-11.10 (2H, br s).
66%
Stage #1: at 190℃; for 2 h;
Stage #2: With sodium hydroxide In water
Stage #3: With hydrogenchloride In waterAcidic aqueous solution
A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g, 85.85 mmol) and urea (29.75 g, 5 equivalents) was heated at 190 °C for 2 hours. The hot reaction mixture was then poured onto sodium hydroxide solution (2N, 300 mL) and any insoluble material removed by filtration. The mixture was then acidified to pη 6 by the addition concentrated HCl with cooling. The resultant white precipitate was collected by filtration and air dried (9.49g, 66percent). M (400 MHz, d-6 DMSO) 11.60-11.10 (2H, br, s), 8.10 (IH, d, J 5.2), 6.90 (IH, d, J 5.2).
66% at 190℃; for 2 h; A mixture of methyl 3-amino-2-thiophenecarboxylate 1 (13.48 g, 85.85 mmol) and urea (29.75 g, 5 eq.) was heated at 190° C. for 2 hours.
The hot reaction mixture was poured onto sodium hydroxide solution and any insoluble material was removed by filtration.
The mixture was then acidified (HCl, 2N) to yield 1H-thieno[3,2-d]pyrimidine-2,4-dione 2 as a white precipitate, which was collected by filtration and air dried (9.49 g, 66percent).
1H NMR 400 MHz, d6-DMSO) 6.90 (1H, d, J=5.2 Hz), 8.10 (1H, d, J=5.2 Hz), 11.60-11.10 (2H, br s).
66% at 190℃; for 2 h; A mixture of methyl 3-amino-2-thiophenecarboxylate 1 (13.48 g, 85.85 mmol) and urea (29.75 g, 5 eq.) was heated at 190° C. for 2 hours. The hot reaction mixture was poured onto sodium hydroxide solution and any insoluble material was removed by filtration. The mixture was then acidified (HCl, 2N) to yield 1H-thieno[3,2-d]pyrimidine-2,4-dione 2 as a white precipitate, which was collected by filtration and air dried (9.49 g, 66percent).
66% at 190℃; for 2 h; Reference Example 3; 1H-Thieno f 3 ,2-di p yrimidine-2,4-dioiie; A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g, 85.85 mmol) and urea (29.75 g, 5 equivalents) was heated at 190 0C for 2 hours. The hot reaction mixture was then poured onto sodium hydroxide solution (2N, 300 niL) and any insoluble material removed by filtration. The mixture was then acidified to pR 6 by the addition concentrated HCl with cooling. The resultant white precipitate was collected by filtration and air dried (9.49g, 66percent). M (400 MHz, d-6 DMSO) 11.60-11.10 (2H, br, s), 8.10 (IH, d, J 5.2), 6.90 (IH, d, J 5.2).
66% at 190℃; for 2 h; Example 1 2,4-DicMoro-tMeno[3,2-d]pyrimidine 3[00265] A mixture of methyl 3-amino-2-thiophenecarboxylate 1 (13.48 g, 85.85 mmol) and urea (29.75 g, 5 eq.) was heated at 190 0C for 2 hours. The hot reaction mixture was poured onto sodium hydroxide solution and any insoluble material was removed by filtration. The mixture was then acidified (HCl, 2N) to yield lH-thieno [3,2-d]pyrimidine- 2,4-dione 2 as a white precipitate, which was collected by filtration and air dried (9.49g, 66percent). 1HNMR 400 MHz, ^6-DMSO) 6.90 (IH, d, J=5.2Hz), 8.10 (IH, d, J=5.2Hz), 11.60- 11.10 (2H, br s).
66% at 190℃; for 2 h; A mixture of methyl 3-amino-2-tbiophenecarboxylate (20) (13.48 g, 85.85 mmol) and urea (21) (29.75 g, 5 equivalents) was heated at 1900C for 2 hours. The hot reaction mixture was then poured onto sodium hydroxide solution and any insoluble material removed by filtration. The mixture was then acidified (HCl, 2N) to yield IH- <n="38"/>thieno [3,2-d]pyrimidine-2,4-dione (22) as a white precipitate which was collected by filtration and air dried (9.49g, 66percent).A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione (22) (9.49 g, 56.49 mmol) and phosphorous oxy chloride (150 rnL) was heated at reflux for 6 hours. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine, (Ilia), as a white solid (8.68 g, 75percent).
61.5% at 190℃; for 12 h; Preparation of thieno[3,2-^pyrimidine-2,4(TH.,3H)-dioneMethyl 3-aminothiophene-2-carboxylate (4.9 g, 31.3 mmol) and urea (19 g, 187 mmol) were dissolved in NN-dimethylformamide (10 mL), the reaction temperature was raised to 190 °C, followed by stirring for 12 hours. After the reaction was complete, the reaction mixture was added to IN NaOH aqueous solution, cooled to room temperature and filtered under a reduced pressure to remove the insoluble precipitate. The filtrate was acidified (pH 2) with 2N HC1 aqueous solution, and the resulting solid was filtered under a reduced pressure with washing using distilled water. The resulting solid was dried under a reduced pressure to obtain the title compound (yield: 3.2 g, 61.5 percent).1H-NMR (300MHz, CDC13) 5 11.59 (s, 1H), 11.14 (s, 1H), 8.00 (d, 1H), 6.90 (d, 1H).
28% at 180℃; for 5 h; [00349] A mixture of methyl 3-aminothiophene-2-carboxylate (3.5 g, 22.3 mmol) and urea (8.75 mL, 144.7 mmol) was heated at 180 °C for 5 h. The mixture was cooled to -90 °C and water (40 mL) was added. The mixture was stirred at r.t. overnight and the resulting precipitate isolated via filtration to afford the title compound (3.66 mg, 98percent) as an off-white powder. [00350] Method A: LC-MS m/z = 214.0 [M + H]+; RT = 0.79 min.
23.8 g
Stage #1: at 190℃; for 2 h;
Stage #2: With sodium hydroxide In water
A mixture of 3-amino-2-thiophene carboxylic acid methyl ester (20.8g, 132.3mmol) and urea (45.9g, 661.7mmol) was heated at 190°C. After 2h, 7.5percent NaOH solution (100mL) was poured into the reaction mixture and a white solid precipitated. The solid filtered and the filtrate washed with 2M HCl. A large amount of white solid was precipitated, filtered and the filter cake was dried to give the white solid product 2 (23.8g). Yield 98percent.

Reference: [1] Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 8, p. 1037 - 1045
[2] European Journal of Medicinal Chemistry, 2012, vol. 57, p. 162 - 175
[3] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 64 - 73
[4] Patent: WO2009/37463, 2009, A1, . Location in patent: Page/Page column 14; 15
[5] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 20, p. 5945 - 5949
[6] Patent: WO2011/79231, 2011, A1, . Location in patent: Page/Page column 82
[7] Patent: WO2009/62258, 2009, A1, . Location in patent: Page/Page column 90
[8] Patent: US9249156, 2016, B2, . Location in patent: Page/Page column 36
[9] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 25; 30
[10] Patent: EP2786998, 2014, A1, . Location in patent: Paragraph 0055
[11] Patent: US2014/323466, 2014, A1, . Location in patent: Paragraph 0133-0134
[12] European Journal of Medicinal Chemistry, 2012, vol. 56, p. 139 - 144
[13] Molecules, 2015, vol. 20, # 4, p. 6827 - 6843
[14] Organic Process Research and Development, 2013, vol. 17, # 1, p. 97 - 107
[15] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 128
[16] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0174
[17] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0172
[18] Patent: WO2017/90058, 2017, A1, . Location in patent: Page/Page column 16-17
[19] Patent: WO2017/96100, 2017, A1, . Location in patent: Paragraph 00142; 00145; 00146
[20] Patent: WO2017/96095, 2017, A1, . Location in patent: Paragraph 00111; 00114
[21] Patent: WO2006/46031, 2006, A1, . Location in patent: Page/Page column 28-29
[22] Patent: US2008/76768, 2008, A1, . Location in patent: Page/Page column 7
[23] Patent: US2008/76758, 2008, A1, . Location in patent: Page/Page column 73
[24] Patent: WO2008/70740, 2008, A1, . Location in patent: Page/Page column 133
[25] Patent: WO2008/73785, 2008, A2, . Location in patent: Page/Page column 159
[26] Patent: WO2009/53715, 2009, A1, . Location in patent: Page/Page column 63
[27] Patent: US9335320, 2016, B2, . Location in patent: Page/Page column 70
[28] Patent: JP5658565, 2015, B2, . Location in patent: Paragraph 0331-0332
[29] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 62
[30] Patent: WO2007/127183, 2007, A1, . Location in patent: Page/Page column 135
[31] Patent: WO2007/132171, 2007, A1, . Location in patent: Page/Page column 36-37
[32] Patent: WO2011/162515, 2011, A2, . Location in patent: Page/Page column 33-34
[33] Patent: WO2017/59191, 2017, A1, . Location in patent: Paragraph 00347-00350
[34] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 703 - 706
[35] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 358 - 365
  • 4
  • [ 22288-78-4 ]
  • [ 917-61-3 ]
  • [ 16233-51-5 ]
YieldReaction ConditionsOperation in experiment
86.7%
Stage #1: With acetic acid In water at 20℃; for 5 h;
Stage #3: With acetic acid In water at 0℃;
Thieno [3,2-d\\ pyrimidine-2,4-dione (7a).; A solution of sodium cyanate (5.0 g, 77.0 mmol) in water (15.0 rnL) was added dropwise to a mixture of 6a (6.05 g, 38.4 mmol) in a solution 50percent of glacial acetic acid in water (90.0 mL) and the resulting mixture was stirred for 5 hours at room temperature. The resulting precipitate was collected by filtration and then dissolved in NaOH 2N (90.0 mL). The solution was cooled to 0 0C, acidified with acetic acid and the solid filtered and dried in an oven at 60 0C to give 7a (86.7percent yield) as white solid (mp >300°C); 1H NMR (DMSO-J6) δ 9.17 (bs, IH), 7.91 (d, IH, J= 5.2 Hz), 7.72 (d, IH, J= 5.2 Hz), 6.70 (bs, IH); ESI-MS m/z191 (M+Na)+; Anal. (C6H4N2O2S): C,H,N .
86.7%
Stage #1: With acetic acid In water at 20℃; for 5 h;
Stage #3: With acetic acid In water at 0℃;
Thieno [3,2-d\\ pyrimidine-2,4-dione (7a).; A solution of sodium cyanate (5.0 g, 77.0 mmol) in water (15.0 rnL) was added dropwise to a mixture of 6a (6.05 g, 38.4 mmol) in a solution 50percent of glacial acetic acid in water (90.0 mL) and the resulting mixture was stirred for 5 hours at room temperature. The resulting precipitate was collected by filtration and then dissolved in NaOH 2N (90.0 mL). The solution was cooled to 0 0C, acidified with acetic acid and the solid filtered and dried in an oven at 60 0C to give 7a (86.7percent yield) as white solid (mp >300°C); 1H NMR (DMSO-J6) δ 9.17 (bs, IH), 7.91 (d, IH, J= 5.2 Hz), 7.72 (d, IH, J= 5.2 Hz), 6.70 (bs, IH); ESI-MS m/z191 (M+Na)+; Anal. (C6H4N2O2S): C,H,N .
81%
Stage #1: With acetic acid In water at 20℃; for 5 h;
Stage #2: With sodium hydroxide In water
Stage #3: With acetic acid In water at 0℃;
To a solution in which sodium cyanate (5.0 g, 77.0 mmol) was dissolved in water (15.0 mL), methyl 3-aminothiophen-2-carboxylate (6.05 g, 38.4 mmol) dissolved in a mixture solution (90 mL) of 50percent glacial acetic acid and water was slowly added dropwise. After stirring for 5 hours at room temperature, thus prepared white precipitate was filtered. The white solid was dissolved in 2.0 N sodium hydroxide solution (90.0 mL). The mixture solution was cooled to 0 °C and acidified using acetic acid. Filtration of thus prepared white solid followed by drying yielded the target compound (5.2 g, 81percent yield).1H NMR (400 MHz, DMSO-d6 ) δ 11.33 (bs, 2H), 8.10 (d, J = 5.2 Hz, 1H), 8.10 (d, J = 5.2 Hz, 1H), MS m/z: 168.94 [M+1].
81% at 20℃; for 5 h; Step 1:
thieno[3,2-d]pyridin-2,4(1H,3H)-dione
To a solution in which sodium cyanate (5.0 g, 77.0 mmol) was dissolved in water (15.0 mL), methyl 3-aminothiophen-2-carboxylate (6.05 g, 38.4 mmol) dissolved in a mixture solution (90 mL) of 50percent glacial acetic acid and water was slowly added dropwise.
After stirring for 5 hours at room temperature, thus prepared white precipitate was filtered.
The white solid was dissolved in 2.0 N sodium hydroxide solution (90.0 mL).
The mixture solution was cooled to 0° C. and acidified using acetic acid.
Filtration of thus prepared white solid followed by drying yielded the target compound (5.2 g, 81percent yield).
1H NMR (400 MHz, DMSO-d6) δ 11.33 (bs, 2H), 8.10 (d, J=5.2 Hz, 1H), 8.10 (d, J=5.2 Hz, 1H), MS m/z: 168.94 [M+1].

Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 20, p. 6614 - 6618
[2] Patent: WO2008/31888, 2008, A2, . Location in patent: Page/Page column 13
[3] Patent: WO2008/31888, 2008, A2, . Location in patent: Page/Page column 13
[4] Patent: WO2011/62372, 2011, A2, . Location in patent: Page/Page column 17; 18
[5] Patent: US2013/12703, 2013, A1, . Location in patent: Paragraph 0129-0131
  • 5
  • [ 31895-77-9 ]
  • [ 16233-51-5 ]
YieldReaction ConditionsOperation in experiment
75% With chloroacetic acid In 1,4-dioxane; water at 110℃; for 12 h; The compound of formula 1 obtained in Preparation Example 2 90g (0.29 mol) of 2-thioxo-2,3-dihydrosothieno[3,2-d]pyrimidin-4(1H)-one was added to 675 mL of dioxane and 675 mL of water, 90 g of chloroacetic acid And the mixture was refluxed at 110 °C for 12 hours. The reaction was cooled to room temperature and stirred for 1 hour. The resulting solid was separated by filtration under reduced pressure, washed with methanol: water (1: 1) and acetone (90 mL) and dried to obtain 61 g of the title compound (75percent yield).
Reference: [1] Patent: KR2016/38615, 2016, A, . Location in patent: Paragraph 0055; 0056
  • 6
  • [ 51322-68-0 ]
  • [ 16233-51-5 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: With sodium hydroxide In methanol; water for 1 h; Heating / reflux
Stage #2: With sulfuric acid In methanol; water
To a solution of methyl3- (aminocarbonyl) aminolthiophene-2-carboxylate (Method58,4.78 g) inMeOH (50 ml) was added the solution of sodium hydroxide(1. 2 g, 30 mmol) in water (15 ml). The reaction mixture was heated to reflux for1 hr. Water was added to dissolve the solid. 50percent sulfuric acid was added to adjust thepH < l. The resulting off white solid was filtered to give desired product (2.41 g, 66percent for 2steps). lH NMR (400 MHz) : 8 6.91(d, J = 5.2 Hz,1 H), 8. 05 (d, J = 5.2 Hz,1 H), 11. 2 (br s,1 H), 11.5 (br s,1 H).
Reference: [1] Patent: WO2005/49033, 2005, A1, . Location in patent: Page/Page column 108
  • 7
  • [ 147123-47-5 ]
  • [ 16233-51-5 ]
YieldReaction ConditionsOperation in experiment
65% With hydrogenchloride; urea In pyridine; water Part A:
The preparation of 2,4-thieno[3,2-d]pyrimidinedione.
To a solution of 4.6 g of 3-aminothiophene-2-carboxamide in 125 mL of pyridine were added 3.89 g of urea and 10 drops of 6N hydrochloric acid.
The reaction was refluxed overnight and most of the pyridine was removed by evaporation.
The residue was suspended in water and adjusted to pH=6 with dilute hydrochloric acid.
The solid precipitate was collected by filtration, washed with water and dried to yield the product as an off white powder (3.47 g, 65percent); 1 H NMR (DMSO-d6, 300 MHz) δ11.58 (s, 1H), 11.20 (s, 1H), 8.05 (d, 1H), 7.95 (d, 1H).
Reference: [1] Patent: US5187168, 1993, A,
  • 8
  • [ 1132690-58-4 ]
  • [ 16233-51-5 ]
Reference: [1] Patent: US2009/75970, 2009, A1, . Location in patent: Page/Page column 13
  • 9
  • [ 22288-78-4 ]
  • [ 16234-14-3 ]
  • [ 16233-51-5 ]
Reference: [1] Patent: US2010/233164, 2010, A1,
  • 10
  • [ 137844-98-5 ]
  • [ 16233-51-5 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1993, # 2, p. 548 - 575
  • 11
  • [ 1189-71-5 ]
  • [ 22288-78-4 ]
  • [ 16233-51-5 ]
Reference: [1] MedChemComm, 2014, vol. 5, # 12, p. 1821 - 1828
  • 12
  • [ 57-13-6 ]
  • [ 147123-50-0 ]
  • [ 16233-51-5 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1993, # 2, p. 548 - 575
  • 13
  • [ 16233-51-5 ]
  • [ 16234-40-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 7, p. 2113 - 2122
  • 14
  • [ 16233-51-5 ]
  • [ 16234-15-4 ]
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] European Journal of Medicinal Chemistry, 2012, vol. 57, p. 162 - 175
[5] Organic Process Research and Development, 2013, vol. 17, # 1, p. 97 - 107
[6] Patent: US2013/102595, 2013, A1,
[7] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 358 - 365
[8] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 64 - 73
[9] Patent: US9249156, 2016, B2,
[10] Patent: JP2015/187145, 2015, A,
[11] Patent: WO2017/90058, 2017, A1,
[12] Patent: JP5658565, 2015, B2,
[13] Patent: CN103980287, 2016, B,
[14] Patent: CN104292242, 2017, B,
[15] Patent: WO2018/85342, 2018, A1,
[16] Patent: WO2007/122410, 2007, A1,
[17] Patent: WO2007/127183, 2007, A1,
  • 15
  • [ 16233-51-5 ]
  • [ 16234-14-3 ]
YieldReaction ConditionsOperation in experiment
100% for 2 h; Heating / reflux To a suspension of the uracil (5g, 29mmol) in POCI3 (4OmL) was added diisopropylethylamine (13mL, 74mmol) and the reaction heated at reflux for 2h. The excess POCb and diisopropylethylamine were then removed by distillation under reduced pressure and the brown solid obtained dissolved in chloroform and partitioned against water. The aqueous phase was made basic by the addition of 5M NaOH, and extracted twice further with chloroform. The combined organic fractions were washed with water and brine, dried (Na2SO4) filtered and concentrated to afford the product as a pale brown solid (6.05g, quantitative yield). 1H NMR (CDCl3, 300 MHz): 8.16 (d, J=5.4Hz, IH), 7.56 (d, J=5.7Hz, IH); LRMS (ESI): m/z calcd for [M+H]+ 204.94, 206.94 found 205.1, 207.0.
92% at 105℃; for 16 h; A mixtureof thieno [3,2-d] pyrimidine-2,4 (1H, 3H)-dione (Method 62,380 mg, 2.3 mmol), phosphorus oxychloride(10 ml) and diethylaniline(1 ml) was heated at105 C for 16 hrs. Solvent was then removed and ice was added to the mixture. The solid was filtered and gave pink colour solid product (432.4 mg, 92percent). 1H NMR (400 MHz):8 7.98 (d, J = 5.6 Hz, 1 H), 8. 94 (d,J = 5. 6 Hz, 1 H).
87.3% for 2 h; Reflux Thieno[3,2-d]pyrimidine-2,4(lH,3H)-dione (2, 5 g, 29 mmol) was taken up in POCl3 (41 mL) to form a mixture. N,N-diisopropylethylamine (DIEA) (13 mL, 74 mmol) was added to the mixture and the mixture was heated to reflux for 2 h, after which product (3) was detected in the mixture by LCMS. The POCl3 and DIEA were then removed from the mixture under vacuum. Water was added to the resultant residue, and the obtained aqueous layer was extracted with dichloromethane (DCM). The aqueous layer was made basic by the addition of 5N NaOH and extracted with DCM. The combined DCM extracts were then dried over and concentrated to obtain a brown solid of 2,4- dichlorothieno[3,2-d]pyrimidine (3, 6.07g, 87.30percent).'HNMR (CDCIj): 8.15 (d, 1H), 7.66 (d, 1H).
84% With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 0 - 85℃; for 48 h; Thieno [3,2-d] pyrimidine-2,4 (1 H, 3H) -dione(IX-1) (5.0 g, 29.7 mmol)And 3 mL of N, N-dimethylaniline were dissolved in acetonitrileWas dissolved in 25 mL,It was cooled to 0 ° C.,16 mL of phosphorus oxychloride was slowly added dropwise.The resulting purple slurry was heated to 80-85 ° C.,And the mixture was stirred for 24 hours.Further, phosphorus oxychloride (10 mL) was added and the mixture was heated for 24 hours.The obtained purple transparent solution was poured into ice water,The phosphorus oxychloride was completely decomposed.The slurry was filtered, the solid was dried at 45 ° C.,It was then dissolved in 100 mL of ethyl acetate,Washed with saturated sodium bicarbonate water, and 5 g of activated carbon was added and stirred.It was then filtered through celite and concentrated to afford the dichloro compound(IIa-1) 5.11 g (yield: 84percent).
83% With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 20 - 85℃; for 24 h; Cooling Step l:
2,4-Dichlorothieno[3,2-d]pyrimidine (Compound 103)
Phosphorous oxychloride (152 mL, 1.67 mol, 7.0 eq) was added slowly to cold solution of compound 102 (40 g, 238 mmol, 1.0 eq) and N,N-dimethylaniline (22.5 mL, 179 mmol, 0.75 eq) in acetonitrile (250 mL) while maintaining the temperature below 20° C.
The mixture was then heated to 85° C. and stirred for 24 h.
The reaction mixture was cooled to 15° C., and then poured slowly onto a mixture of ice and cold water (360 mL).
The resulting slurry was filtered, rinsed with cold water (200 mL).
The cake was dried in vacuum oven at 40° C. for 24 h to afford compound 103 (40.5 g, 83percent) as an off-white solid. M.p.: 245-250° C. LCMS (m/z): 205.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6): δ 7.75 (d, J=5.2 Hz, 1H), 8.71 (d, J=5.2 Hz, 1H).
83% With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline; acetonitrile at 15 - 85℃; for 24 h; Phosphorous oxychloride (152 mL, 1.67 mol, 7.0 eq) was added slowly to cold solution of compound 102 (40 g, 238 mmol, 1.0 eq) and N,N-dimethylaniline (22.5 mL,179 mmol, 0.75 eq) in acetonitrile (250 mL) while maintaining the temperature below20°C. The mixture was then heated to 85°C and stirred for 24 h. The reaction mixture was cooled to 15°C, and then poured slowly onto a mixture of ice and cold water (360 mL). The resulting slurry was filtered, rinsed with cold water (200 mL). The cake was dried in vacuum oven at 40°C for 24 h to afford compound 103 (40.5 g, 83percent) as an off- whitesolid. M.p. :245-250°C. LCMS (m/z): 205.0 [M+1f. ‘H NMR (400 MHz, DMSO-d6): ö7.75 (d, J 5.2 Hz, 1H), 8.71 (d, J 5.2 Hz, 1H).
82% at 105 - 110℃; for 16 h; Inert atmosphere In a dry flask, thieno[3,2-d]pyrimidin-2,4(1H,3H)-dione 4 (4.00 g, 23.78 mmol) was refluxed in freshly distilled POCl3 (50 mL) under nitrogen overnight (16 h) at which point the POCl3 was evaporated and the residue extracted with CH2Cl2 (50 mL). The organic layer was washed with saturated NaHCO3 solution (50 mL), brine (50 mL), dried over MgSO4 and concentrated. The residue was crystallized from EtOAc to obtain 1 as a pale green-yellow solid (4.00 g, 19.50 mmol, 82 percent). Mp: 135–137 °C. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H, J=5.0Hz), 8.12 (d, 1H, J=5.5Hz). 13C NMR (100 MHz, CDCl3): δ 124.6, 129.4, 139.3, 155.8, 156.3, 163.5. FAB-MS m/z for C6H2Cl2N2S calculated [M+H]+ 204.9388, found 204.9400 (2x35Cl), 206.9366 (35Cl 37Cl).
82% for 16 h; Inert atmosphere; Reflux In a dry flask, thieno[3,2-d]pyrimidin-2,4(1H,3H)-dione 4 (4.00 g, 23.78 mmol) was refluxed in freshly distilled POCl3 (50 mL) under nitrogen overnight (16 h) at which point the POCl3 was evaporated and the residue extracted with CH2Cl2 (50 mL). The organic layer was washed with saturated NaHCO3 solution (50 mL), brine (50 mL), dried over MgSO4 and concentrated. The residue was crystallized from EtOAc to obtain 1 as a pale green-yellow solid (4.00 g, 19.50 mmol, 82percent). Mp: 135-137° C. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H, J=5.0 Hz), 8.12 (d, 1H, J=5.5 Hz). 13C NMR (100 MHz, CDCl3): δ 124.6, 129.4, 139.3, 155.8, 156.32, 163.5. FAB-MS m/z for C6H2Cl2N2S calculated [M+H]+ 204.9388. found 204.9400 (2× 35Cl), 206.9366 (35Cl37Cl).
81.7% at 0℃; for 8 h; Reflux 50 g (0.30 mol) of intermediate Ila were placed in 87 mL (0.60 mol) of triethylamine,Ice bath down to 0 ° C,Keep 0 ° C slowly dropping300 mL (3.29 mol) of phosphorus oxychloride,2h plus completed, heated to reflux reaction 6h.After the reaction, the reaction solution was concentrated to 150 mL, and the residue was poured into 1000 g of ice water with stirring. A large amount of white solid was precipitated and filtered. The filter cake was washed with water at a temperature of 45 ° C for 24 h, 50.3 g of white flocculent crystals, Yield 81.7percent; purity 99.7percent
79.6% With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 50 - 85℃; Large scale A mixture of compound 102 (16.7 kg, 99.41 mol, 1.0 equiv) and N, N-dimethylaniline (9.4 kg, 77.57Mole, 0.78 equiv.) Was added to anhydrous acetonitrile (138 kg). The mixture is cooled to 0 to 10 degrees Celsius, the phosphorus oxychloride(111.2 kg, 725.4 moles, 7.3 equiv) was added slowly to the mixture at 50 ° C. The mixture was heated to 80 to 85 degrees Celsius and stirred for 16 to 20 hours at this temperature Celsius, and the mixture was stirred at 80 to 85 degrees Celsius for 3 to 4 hours. The mixture was cooled to 20 to 30 degrees Celsius and then ice water (441 kg) was slowly added below 40 degrees Celsius. The mixture was cooled to 0 to 10 degrees Celsius and stirred at this temperature for 1 hour. Centrifuge, filter cake with ice water rinse (36 kg). The wet product was dried under vacuum at 55-60 ° C to give 2,4-dichlorothiophene [3,2-d] pyrimidine (18.2 kg, yield: 79.6percent) as a white product.
75% for 6 h; Heating / reflux A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione (9.49g, 56.49mmol) and phosphorous oxychloride (15OmL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2- d]pyrimidine (64) as a white solid (8.68 g, 75percent) 1H NMR (400 MHz, CDCl3) 7.56 (IH, d, J=5.5Hz), 8.13 (IH, d, J=5.5Hz).
75% for 6 h; Heating / reflux A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine (VIII) as a white solid (8.68 g, 75percent) 1H NMR (400 MHz, CDCl3) 7.56 (1H, d, J=5.5 Hz), 8.13 (1H, d, J=5.5 Hz).
75% for 6 h; Heating / reflux A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 hours.
The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate.
The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine as a white solid (8.68 g, 75percent).
1H NMR (400 MHz, CDCl3) 7.56 (1H, d, J=5.5 Hz).
8.13 (1H, d, J=5.5 Hz).
75% for 6 h; Heating / reflux A mixture of methyl 3-amino-2-thiophenecarboxylate 1 (13.48 g, 85.85 mmol) and urea (29.75 g, 5 eq.) was heated at 190 °C for 2 hours. The hot reaction mixture was poured onto sodium hydroxide solution and any insoluble material was removed by filtration. The mixture was then acidified (HCl, 2N) to yield lH-thieno [3,2-d]pyrimidine-2,4-dione 2 as a white precipitate, which was collected by filtration and air dried (9.49g, 66percent). 1H NMR 400 MHz, J6-DMSO) 6.90 (IH, d, J=5.2Hz), 8.10 (IH5 d, J=5.2Hz), 11.60-11.10 (2H, br s). [00242] A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49g, 56.49mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75percent). 1H NMR (400 MHz, CDCl3) 7.56 (IH, d, J=5.5Hz), 8.13 (IH, d, J=5.5Hz).
75%
Stage #1: for 6 h; Heating / reflux
A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49g, 56.49mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75percent). 1H NMR (400 MHz, CDCl3) 7.56 (IH, d, J=5.5Hz), 8.13 (IH, d, J=5.5Hz).
75% With trichlorophosphate In acetonitrile for 24 h; Heating / reflux To a suspension of lH-thieno[3,2-d]pyrimidine-2,4-dione (10.0 g, 59.52 mmol) in acetonitrile (50 mL) was added phosphorous oxychloride (300 mmol, 5 equivalents, 28 mL) and the mixture heated at reflux for 24 hours in a flask fitted with a mechanical stirrer. The reaction mixture was then cooled and poured cautiously onto ice-water (250 mL) maintaining the temperature below 20 0C. The mixture was filtered to yield 2,4-dichloro-thieno[3,2- d]pyrimidine as an off-white solid (9.15 g, 75percent). SH. (400 MHz, CDCl3) 8.13 (IH, d, J 5.5), 7.56 (IH, d, J 5.5).
75% for 6 h; Reflux A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 h.
The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate.
The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75percent). H NMR (400 MHz, CDCl3) 7.56 (1H, d, J=5.5 Hz), 8.13 (1H, d, J=5.5 Hz).
75% for 6 h; Reflux A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75percent).
75% With trichlorophosphate In acetonitrile for 24 h; Heating / reflux Reference Example 4: 2,4-Dichloro-tfaienor3,2-d1pyrimidme; To a suspension of lH-thieno[3,2-d]pyrimidine-2,4-dione (10.0 g, 59.52 mmol) in acetonitrile (50 mL) was added phosphorous oxychloride (300 mmol, 5 equivalents, 28 mL) and the mixture heated at reflux for 24 hours in a flask fitted with a mechanical stirrer. The reaction mixture was then cooled and poured cautiously onto ice-water (250 mL) maintaining the temperature below 20 °C. The mixture was filtered to yield 254-dichloro-thieno[3,2-d]pyrimidine as an off-white solid (9.15 g, 75percent). <5H (400 MHz, CDCl3) 8.13 (IH, d, J 5.5), 7.56 (IH, d, J 5.5).
75% for 6 h; Heating / reflux A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49g, 56.49mmol) and phosphorous oxychloride (15OmL) was heated at reflux for 6 h. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75percent). 1H NMR (400 MHz, CDCl3) 7.56 (IH, d, J=5.5Hz), 8.13 (IH, d, J=5.5Hz).
75% for 6 h; Heating / reflux A mixture of methyl 3-amino-2-tbiophenecarboxylate (20) (13.48 g, 85.85 mmol) and urea (21) (29.75 g, 5 equivalents) was heated at 1900C for 2 hours. The hot reaction mixture was then poured onto sodium hydroxide solution and any insoluble material removed by filtration. The mixture was then acidified (HCl, 2N) to yield IH- <n="38"/>thieno [3,2-d]pyrimidine-2,4-dione (22) as a white precipitate which was collected by filtration and air dried (9.49g, 66percent).A mixture of lH-thieno[3,2-d]pyrimidine-2,4-dione (22) (9.49 g, 56.49 mmol) and phosphorous oxy chloride (150 rnL) was heated at reflux for 6 hours. The reaction mixture was then cooled and poured onto ice/water with vigorous stirring yielding a precipitate. The mixture was then filtered to yield 2,4-dichloro-thieno[3,2-d]pyrimidine, (Ilia), as a white solid (8.68 g, 75percent).
74% for 10 h; Reflux Step le: 2,4-Dichlorothieno[3,2-d]pyrimidine (Compound 0110)A mixture of compound 0109 (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 10 h. The solvent was then removed and the residue was poured onto ice/water with vigorous stirring to give title compound 0110 (8.62 g, 74percent) as a white solid: LCMS: 205 [M+l]+; 1H NMR (400 MHz, CDC13): δ 7.48 (d, J= 5.6 Hz, 1H), 8.05 (d, J= 5.6 Hz , 1H).
74% for 5 h; Reflux Compound 1 (1 g, 5.9 mmol) was dissolved in phosphorus oxychloride (15 mL) and stirred under reflux for 5 h. Two-thirds of the solvent was removed under a vacuum. The mixture was poured into ice-water (50 mL). The precipitate that separated was collected by filtration, washed with water, and dried to give compound 2 as a white solid. Yield: 74percent, mp: 140–143 °C. 1H NMR (CDCl3, 300 MHz) δ: 7.55 (d, 1H, J = 6.00 Hz, S–CC–H), 8.13 (d, 1H, J = 6.00 Hz, S–C–H). MS-EI m/z 205 (M + 1).
74% for 10 h; Reflux Step 1e: 2,4-Dichlorothieno[3,2-d]pyrimidine (Compound 0110)[0175]A mixture of compound 0109 (9.49 g, 56.49 mmol) and phosphorous oxychloride (150 mL) was heated at reflux for 10 h. The solvent was then removed and the residue was poured onto ice/water with vigorous stirring to give title compound 0110 (8.62 g, 74percent) as a white solid: LCMS: 205 [M+1]+; 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J=5.6 Hz, 1H), 8.05 (d, J=5.6 Hz, 1H).
74% at 110℃; for 5 h; Compound 1 (1 g, 5.9 mmol) was dissolved in phosphorus oxychloride (15 mL) and stirred under reflux for 5 h. Two-thirds of the solvent was removed under vacuum. The mixture was poured into ice-water (50 mL). The precipitate that separated was collected by filtration, washed with water, and dried to give compound 2 as a white solid. Yield: 74percent, mp: 140–143 °C. 1H-NMR (CDCl3) δ: 7.55 (d,1H, J = 6.00 Hz, S-C=C-H), 8.13 (d, 1H, J = 6.00 Hz, S-C-H). MS-EI m/z 205 (M + 1).
74% for 10 h; Reflux Compound 0109 (9.49g, 56.49mmol) was heated 10 h under reflux a mixture of and phosphorus oxychloride (150 mL). The solvent was then removed, stirring vigorously injected residue onto ice / water with to afford the title compound 0110 a (8.62g, 74percent) as a white solid:
73.3% at 200℃; for 3 h; Preparation of 2,4-dichlorothienor3,2-< )pyrimidineThe compound (3.2 g, 19.4 mmol) obtained in Step 1 was dissolved in phosphorous oxy chloride (12 mL) and refluxed with stirring for 3 hours at 200 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and added dropwise to 4 °C distilled water with stirring vigorously. The resulting solid was filtered under a reduced pressure with washing using distilled water, and the resulting solid was dried under a reduced pressure to obtain the title compound (yield: 2.9 g, 73.3 percent).1H-NMR (300MHz, DMSO-d6) δ 8.74 (d, 1H), 7.78 (d, 1H).
70% for 10 h; Reflux A mixture of compound 12 (8.68 g, 56.49 m mol) and POCl3 (150 mL) was heated at reflux for 10 h. After completion of the reaction, reaction mixture was concentrated to half of the initial volume. Then, it was poured onto child ice with vigorous stirring to get compound 13 (7.42 g, 70percent) as white solid. NMR (400 MHz, CDC13, ppm): δ 8.05 (d, / = 5.6 Hz, 1H), 7.48 (d, / = 5.6 Hz, 1H); ESI-MS: m/z 205.05 [M+H]+.
67% for 16 h; Reflux General procedure: A total of 0.8 mL N,N-dimethylaniline was added to 3.0 g of thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione 6a in 20 mL POCl3. The mixture was then heated under reflux for 16 h. Excess POCl3 was removed in vacuo, and the resulting residue was treated with ice water to yield a precipitate. The solid was collected by filtration, washed with water and dried over a funnel to afford solid 7a (1.3 g, yield 35.5percent). 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 6.4 Hz, 1H), 7.43 (d, J = 6.4 Hz, 1H).
41% at 106℃; for 3 h; Inert atmosphere Under a nitrogen streamThieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione (8.41 g, 50.0 mmol)Chloride (170 ml) was added thereto, and the mixture was stirred at 106 ° C for 3 hours. After completion of the reaction, ethyl acetate was added to the organic layerAnd the water was removed using MgSO4. After removal of the organic layer solvent, the residue was purified by column chromatography2,4-dichlorothieno [3,2-d] pyrimidine (4.2 g, 20.5 mmol, yield 41percent) was obtained.
36% at 135℃; for 5 h; (1) 1 g of raw material B2With POCl3And PCl5The reaction was refluxed at 135 ° C for 5 h to give the intermediate C20.43 g, yield 36percent; the specific reaction equation is as follows:
28% at 116℃; for 5 h; A mixture of thieno[3,2-d]pyrimidine-2,4(lH,3H)-dione (1.02 g, 6.07 mmol) and phosphonyl chloride (15 mL, 161 mmol) was heated at 116 0C for 5 h. Upon completion of the reaction, the reaction mixture was poured into ice and extract with ethyl acetate 3 times. The combined organic layers were, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography, eluting with Hexanes/Elhyl Acetate (9: 1) afforded the product as a white solid (343 mg, 28percent): [002391 1H NMR (DMSO, 300 MHz) δ 7.73 (d, J = 5.4 Hz, IH), 8.69 (d, J = 5.7 Hz, IH).
16.9 g for 6 h; Reflux Compound 2 (23.8g, 140.7mmol) was dissolved in POC13 (200mL), the mixture was heated under reflux for 6h. After removal of most POC13 under pressure, the remaining reaction solution was slowly poured into ice/water while vigorously stirred yielding a gray precipitate. This was collected by filtration and air-dried to yield a gray solid 3 (16.9g). Yield 58.3percent.

Reference: [1] Patent: WO2009/62258, 2009, A1, . Location in patent: Page/Page column 91
[2] Patent: WO2005/49033, 2005, A1, . Location in patent: Page/Page column 108
[3] Organic Process Research and Development, 2013, vol. 17, # 1, p. 97 - 107
[4] Patent: WO2011/79231, 2011, A1, . Location in patent: Page/Page column 82
[5] Patent: JP6120311, 2017, B2, . Location in patent: Paragraph 0130-0131
[6] Patent: US9249156, 2016, B2, . Location in patent: Page/Page column 36; 37
[7] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 25; 30
[8] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 7, p. 2113 - 2122
[9] Patent: US2016/257696, 2016, A1, . Location in patent: Paragraph 0063-0064
[10] Patent: CN103980287, 2016, B, . Location in patent: Paragraph 0117; 0120; 0121
[11] Patent: CN104292242, 2017, B, . Location in patent: Paragraph 0120; 0121; 0121
[12] Patent: WO2006/46031, 2006, A1, . Location in patent: Page/Page column 28-29
[13] Patent: US2008/76768, 2008, A1, . Location in patent: Page/Page column 7
[14] Patent: US2008/76758, 2008, A1, . Location in patent: Page/Page column 73
[15] Patent: WO2008/70740, 2008, A1, . Location in patent: Page/Page column 133
[16] Patent: WO2008/73785, 2008, A2, . Location in patent: Page/Page column 159
[17] Patent: WO2009/53715, 2009, A1, . Location in patent: Page/Page column 63
[18] Patent: US2010/233164, 2010, A1,
[19] Patent: US9335320, 2016, B2, . Location in patent: Page/Page column 70
[20] Patent: JP5658565, 2015, B2, . Location in patent: Paragraph 0331-0333
[21] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 62
[22] Patent: WO2007/127183, 2007, A1, . Location in patent: Page/Page column 135
[23] Patent: WO2007/132171, 2007, A1, . Location in patent: Page/Page column 36-37
[24] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 129
[25] European Journal of Medicinal Chemistry, 2012, vol. 56, p. 139 - 144
[26] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0175
[27] Molecules, 2015, vol. 20, # 4, p. 6827 - 6843
[28] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0173
[29] Patent: WO2011/162515, 2011, A2, . Location in patent: Page/Page column 34
[30] Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 8, p. 1037 - 1045
[31] European Journal of Medicinal Chemistry, 2012, vol. 57, p. 162 - 175
[32] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 64 - 73
[33] Patent: WO2017/90058, 2017, A1, . Location in patent: Page/Page column 17
[34] European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 71 - 76
[35] Patent: KR2015/36982, 2015, A, . Location in patent: Paragraph 0135-0139
[36] Patent: CN106083742, 2016, A, . Location in patent: Paragraph 0161; 0162; 0163
[37] Patent: WO2008/58285, 2008, A2, . Location in patent: Page/Page column 48
[38] Patent: US5187168, 1993, A,
[39] Patent: US2009/75970, 2009, A1, . Location in patent: Page/Page column 13
[40] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 703 - 706
[41] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 358 - 365
[42] MedChemComm, 2014, vol. 5, # 12, p. 1821 - 1828
[43] Patent: WO2017/96100, 2017, A1, . Location in patent: Paragraph 00142; 00147; 00148
[44] RSC Advances, 2017, vol. 7, # 82, p. 52227 - 52237
[45] Patent: WO2017/96095, 2017, A1, . Location in patent: Paragraph 00111; 00115
  • 16
  • [ 16233-51-5 ]
  • [ 16234-14-3 ]
YieldReaction ConditionsOperation in experiment
61% With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline at 125℃; for 22 h; A solution of thienoyleneurea (6.0 g) and N,N-dimethylaniline (2.9 mL) in phosphorus oxychloride (35 mL) was heated at 125° C. (oil bath) for 22 h under argon.
The solution cooled to 50° C. and was poured into cold water (0° C., 8.0 mL) while vigorously stirring.
The precipitate was filtered, washed with water, and dissolved in EtOAc.
The organic solution was filtered, washed with water, and the organic phase was dried over MgSO4, filtered and concentrated to afford a yellow precipitate (4.5 g, 61percent yield).
Reference: [1] Patent: US2004/14755, 2004, A1, . Location in patent: Page/Page column 9
  • 17
  • [ 16233-51-5 ]
  • [ 16234-14-3 ]
YieldReaction ConditionsOperation in experiment
100% at 100℃; Preparation of 2,4-Dichloro-thieno[3,2-d]pyrimidineStep 1A 85 mg portion of thieno[3,2-d]pyrimidine-2,4-diol (0.5 mmol) is suspended in 1.25 mL POCl3. The mixture is heated at 100° C. overnight. POCl3 is removed under reduced pressure. The mixture is dissolved in dichloromethane and quenched with ice. The product is collected by extraction with dichloromethane (2.x.). The combined organic layers are dried over MgSO4 and concentrated to give the title compound in quantitative yield that was used in the next step without further purification.
93% for 14 h; Heating / reflux 2,4-dichlorothieno[3,2-d]pyrimidine (III): 7.97 g (47.0 mmol) of thieno[3,2-d]pyrimidine-2,4-diol (II) is placed in 50 mL (54.5 mmol) of phosphorus oxychloride, then refluxed for 14 hours, with stirring.
The mixture is then concentrated by evaporation, the residue is combined with ice water.
The precipitate formed is suction filtered and dried. 9.00 g of product III (93percent) is obtained as a powder.
80% With 1-methyl-pyrrolidin-2-one; trichlorophosphate In tolueneReflux; Inert atmosphere (see Scheme 1). To a suspension of theno[3,2-d]pyrimidine-2,4-diol (2) (8.0 g, 47.61 mmol) in toluene were added NMP (1.0 mL, catalytic) and POCl3 (35 mL) at room temperature. Following refluxing of the mixture tasted for 16 h. Upon completion of the reaction, excess of POCl3 was distilled off. The residue was poured into ice cold water and filtered off to give the compound 3 as off white solid, yield 80percent, mp 136–140 °C. 1H NMR spectrum, δ, ppm: 7.72 d (J = 5.5 Hz, 1H, ArH), 8.70 t (J = 4.4 Hz, 1H, ArH). ESI–MS: m/z: 204.9 [M + H]+.
80% With 1-methyl-pyrrolidin-2-one; trichlorophosphate In toluene for 16 h; Reflux To a suspention of thieno[3,2-d]pyrimidine-2,4-diol (2) (8.0 g, 47.61 mmol) in toluene was added N-methyl-2-pyrrolidone(NMP) (1.0 mL, catalytic), followed by the addition and POCl3 (35 mL) at room temperature and heated to reflux for 16 h. After completion of reaction, excess POCl3 was removed by distillation, crude residue was poured into ice cold water and filtered the formed precipitate compound 3 as off white solid. Yield: 7.7g, 80 percent; m.p. 136-140 °C; 1H NMR (300 MHz, DMSO-d6): 8.70 (t, J = 4.4 Hz, 1H, ArH), 7.72 (d, J = 5.5 Hz,1H, ArH), ESI-MS: m/z, 204.9 (M+H)+.
79% With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 80 - 85℃; for 72 h; 2,4-Dichlorothieno[3,2-i ]pyrimidine (15).; To a solution of 14 (500 mg, 2.97 mmol) and N,N-dimethylaniline (0.29 mL, 2.23 mmol) in MeCN (2.5 mL) cooled to 0 °C was slowly added POCI3 (1.4 mL, 14.9 mmol). The purple slurry was heated to 80-85 °C and stirred for 48 h. A second portion of POCI3 (1.0 mL) was added after 24 h. The resulting clear purple solution was poured into ice and water and stirred for 5 min. The slurry was filtered, and the solid was dried at 45 °C. The solid was dissolved in EtOAc, washed with sat. aq. NaHCC"3, and stirred with activated charcoal. The solution was filtered through Celite.(R). and concentrated to provide 15 (482 mg, 79percent) as a yellow solid: Mp 138.8-139.3 °C (H20); IR (ATR, neat) 3066, 3088, 1545, 1508, 1307, 1204, 798 cm"1; 1H NMR (DMSO-d6, 300 MHz) δ 8.70 (d, 1 H, J= 5.4 Hz), 7.74 (d, 1 H, J= 5.4 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 163.6, 154.8, 154.7, 142.4, 129.3, 124.1; HRMS (EI) m/z calcd for C6H2N2SCl2 203.9316, found 203.9312.
74.4% for 14 h; Heating / reflux To a suspension of thieno[3,2-d]-pyrimidine-2,4-diol 1b (38.2 g, 227 mmol) in POCI3 (300 mL) was added dimethylaniline (8 mL). The mixture was refluxed for 14 h to give a homogenous solution. Excess of POCI3 was evaporated under vacuum. Chloroform EPO <DP n="61"/>(500 mL) was added to the oily residue and concentrated again. This process was repeated once. More chloroform (50 mL) was added and the suspension was slowly poured into ice-water (1.5 L) with vigorously stirring. After warming up to room temperature, the phases were separated. The precipitate in the aqueous phase was collected and dried to give a crude solid. The solid was dissolved in chloroform (500 mL) and insoluble impurities were removed by filtration. The filtrate was concentrated to give the title compound 1c as a yellow solid (34.7 g, 74.4percent). Rf: 0.32 (9:1 hexanes/ethyl acetate); Mp: 130-132 0C; APCI MS: m/z 206; H-NMR (300 MHz, DMSO-cfe): δ 8.12 (d, J = 5.46 Hz, 1 H), 7.55 (d, J = 5.46 Hz, 1H).
60% at 180℃; for 4 h; A mixture of Example 1 (20 g, 119 mmol) in phenylphosphonic dichloride (120 ml, 850 mmol) was stirred and heated to 180 0C for 4 h. The resulting dark solution was cooled to 80 0C and transferred slowly by pipette onto stirred ice / water (800ml). After an hour of vigorous stirring, the yellow-orange precipitate was filtered off, washed and dried at 40 0C /. vac. The solid was dissolved in DCM (ca. 20 volumes). The solution was passed through a pad of silica and washed through with ethyl acetate : iso-hexane (1 :1 ). The filtrate was reduced /. vac. to yield 2,4-dichloro-thieno[3,2-d]pyrimidine (14.56 g, 60percent yield) as a yellow crystalline product. LC-MS: m/z = 205 [M+H+]; RT = 4.36 (LC-MS method 2) 1H-NMR: δH (400 MHz, d6-DMSO) 7.74 (1 H, d, J 5.52 Hz), 8.70 (1 H, d, J 5.52 Hz)
51.2% With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline for 3 h; 2,4-Dihydroxythieno[3,2-d]pyrimidine (M1) (3.38 g, 0.020 mol) was added to the reaction flask.Phosphorus oxychloride (11.6 ml, 0.127 mol) was added.N,N-dimethylaniline (7.44 ml, 0.058 mol) was added dropwise with stirring at room temperature for 3 hours under reflux.Stop heating,Pour into 100ml of ice water.Precipitating a brownish black solid,Filtering,dry,Column chromatography (petroleum ether - ethyl acetate = 3: 1) to give a pale yellow solid 2.10g,The yield was 51.2percent.

Reference: [1] Patent: US2009/192176, 2009, A1, . Location in patent: Page/Page column 46-47
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 375 - 379
[3] Patent: US2007/259846, 2007, A1, . Location in patent: Page/Page column 46-47
[4] Patent: WO2006/111549, 2006, A1, . Location in patent: Page/Page column 94-95
[5] Russian Journal of General Chemistry, 2017, vol. 87, # 6, p. 1275 - 1280[6] Zh. Obshch. Khim., 2017, vol. 87, # 6, p. 1275 - 1280,6
[7] Asian Journal of Chemistry, 2017, vol. 29, # 7, p. 1515 - 1521
[8] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 2, p. 154 - 159
[9] Patent: WO2012/78859, 2012, A2, . Location in patent: Page/Page column 58-59
[10] Patent: WO2007/23382, 2007, A2, . Location in patent: Page/Page column 59-60
[11] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 9, p. 2920 - 2923
[12] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 9, p. 2916 - 2919
[13] Patent: WO2009/37468, 2009, A1, . Location in patent: Page/Page column 15; 14
[14] Patent: CN107652273, 2018, A, . Location in patent: Paragraph 0150; 0151; 0155; 0156
[15] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 640 - 643
  • 18
  • [ 22288-78-4 ]
  • [ 16234-14-3 ]
  • [ 16233-51-5 ]
Reference: [1] Patent: US2010/233164, 2010, A1,
  • 19
  • [ 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,
  • 20
  • [ 16233-51-5 ]
  • [ 955979-15-4 ]
Reference: [1] Patent: WO2011/130628, 2011, A1,
[2] Patent: US9249156, 2016, B2,
[3] Patent: US9335320, 2016, B2,
[4] Patent: JP2015/187145, 2015, A,
[5] Patent: JP5658565, 2015, B2,
[6] Patent: CN104292242, 2017, B,
[7] Patent: WO2018/85342, 2018, A1,
[8] Patent: US2013/102595, 2013, A1,
  • 21
  • [ 16233-51-5 ]
  • [ 957054-30-7 ]
Reference: [1] Patent: WO2011/130628, 2011, A1,
[2] Patent: US9335320, 2016, B2,
[3] Patent: JP2015/187145, 2015, A,
[4] Patent: JP5658565, 2015, B2,
[5] Patent: US2013/102595, 2013, A1,
  • 22
  • [ 16233-51-5 ]
  • [ 1119280-68-0 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 2, p. 154 - 159
[2] Patent: WO2012/78859, 2012, A2,
  • 23
  • [ 16233-51-5 ]
  • [ 1119280-68-0 ]
Reference: [1] Patent: WO2011/79231, 2011, A1,
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 7, p. 2113 - 2122
  • 24
  • [ 16233-51-5 ]
  • [ 1152475-42-7 ]
Reference: [1] Patent: WO2011/49332, 2011, A2,
[2] Patent: US2012/277424, 2012, A1,
[3] Patent: WO2011/79231, 2011, A1,
  • 25
  • [ 16233-51-5 ]
  • [ 1353553-07-7 ]
Reference: [1] Patent: WO2011/162515, 2011, A2,
  • 26
  • [ 16233-51-5 ]
  • [ 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,
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 16233-51-5 ]

Amides

Chemical Structure| 1628-29-1

[ 1628-29-1 ]

1-(10H-Phenothiazin-10-yl)ethanone

Similarity: 0.64

Chemical Structure| 22288-79-5

[ 22288-79-5 ]

Methyl 3-acetamidothiophene-2-carboxylate

Similarity: 0.63

Chemical Structure| 31169-25-2

[ 31169-25-2 ]

7-Bromothieno[3,2-d]pyrimidin-4(3H)-one

Similarity: 0.60

Chemical Structure| 908494-87-1

[ 908494-87-1 ]

5-Bromo-N-isopropylthiophene-2-carboxamide

Similarity: 0.59

Chemical Structure| 331987-72-5

[ 331987-72-5 ]

N,N'-(1,3-Phenylenebis(methylene))bis(thiophene-2-carboxamide)

Similarity: 0.59

Related Parent Nucleus of
[ 16233-51-5 ]

Other Aromatic Heterocycles

Chemical Structure| 1628-29-1

[ 1628-29-1 ]

1-(10H-Phenothiazin-10-yl)ethanone

Similarity: 0.64

Chemical Structure| 31169-25-2

[ 31169-25-2 ]

7-Bromothieno[3,2-d]pyrimidin-4(3H)-one

Similarity: 0.60

Chemical Structure| 69627-02-7

[ 69627-02-7 ]

Thieno[3,2-b]pyridin-7(4H)-one

Similarity: 0.59

Chemical Structure| 4751-61-5

[ 4751-61-5 ]

7,8-Dihydro-4H-thieno[3,2-b]azepin-5(6H)-one

Similarity: 0.58

Chemical Structure| 188614-01-9

[ 188614-01-9 ]

Methyl 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate

Similarity: 0.55