CN1935811A - 3-aryl-5,6-substituted thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, and its synthesizing method and use - Google Patents

3-aryl-5,6-substituted thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, and its synthesizing method and use Download PDF

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CN1935811A
CN1935811A CN200610117097.XA CN200610117097A CN1935811A CN 1935811 A CN1935811 A CN 1935811A CN 200610117097 A CN200610117097 A CN 200610117097A CN 1935811 A CN1935811 A CN 1935811A
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carbonyl
aryl
mercaptoacetonitrile
thienopyrimidine
substituted thienopyrimidine
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CN100430403C (en
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王科
李晋峰
袁钧瑛
袁承业
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The invention relates to 3-aryl-5, 6-displaced thieno pyrimidine-4-carbonyl-2- sulfhydryl acetonitrile synthetic method and use. The synthetic method includes the following steps: 2-(aryl thioureido)-thiophene-3-ethyl formate and inorganic base are reacting for 0.5-2h in polar solvent at room temperature, then reacting with halogenating acetonitrile for 0.5-1h at room temperature. It is suited for industrialization production which has the features of fast, moderate reaction condition, simple post processing, and high yield.

Description

3-aryl-5,6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile,, preparation method and use
Technical field
The present invention relates to a kind of organic compound, specifically a kind of 3-aryl-5,6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile,, simple synthesis and purposes.
Background technology
3-aryl-5,6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, might be that a class potential suppresses the downright bad active lead compound structure of programmed cell, can develop into useful medicine, and its structural formula is as follows:
Figure A20061011709700041
But the chemical structure of target compound and synthetic method find no reported in literature through SciFinder system and other literature searches.
Document is relevant for its analogue 5, the report of 6-substituted thienopyrimidine-4-4-ketone, its synthetic synthetic ([1] Vishnu J.R.et al.J. Heterocyclic Chem.1981,18,1277 of two steps that generally are divided into; [2] Devani, M.B.et al.J.Pharm.Sci.1976,65,660-664; [3] Duval, E.et al.Bioorg ﹠amp; Med.Chem.lett.2005,15,1885-1890.), 2-(phenylthiourea base)-thiophene-3-ethyl formate (1) closes ring and generates 2-sulfydryl-3-phenyl-4-carbonyl-5,6-substituted thienopyrimidine-4 (2) is in ethanolic soln and haloalkane reaction, because product (A) is dissolved in the ethanol system, its aftertreatment is more loaded down with trivial details, and reaction formula is as follows:
Figure A20061011709700042
，
So people expect to have a kind of 3-aryl-5, the simple synthesis of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile.
Summary of the invention
The purpose of this invention is to provide a kind of 3-aryl-5,6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile.
Purpose of the present invention also provides a kind of above-mentioned 3-aryl-5,6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, simple synthesis.
Another object of the present invention provides a kind of above-mentioned 3-aryl-5, the purposes of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile.
3-aryl-5 of the present invention, 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, compound has following structural formula:
Figure A20061011709700051
Wherein, R 1, R 2=H or C 1～6Alkyl; Perhaps R 1, R 2=-(CH 2) n-, n=1～6;
Y=H, Me, F, Cl, OR 3Or 3,4-O 2(CH 2); R 3=C 1～4Alkyl.
Method of the present invention be in polar solvent and room temperature under, adopt 2-(aryl thiourea base)-thiophene-3-ethyl formate (1) and mineral alkali reaction 0.5-2 hour, at room temperature reacted 0.5-1 hour with the halogen acetonitrile again, promptly generate target compound 3-aryl-5,6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, (3), reaction formula is as follows:
Figure A20061011709700052
Wherein, R 1, R 2=H or C 1～6Alkyl, as CH 3, C 2H 5Or C 3H 7Or R 1, R 2=-(CH 2) n-, n=3～6 are recommended as-(CH 2) 3-,-(CH 2) 4-or-(CH 2) 5-;
X=Cl or Br; Y=H, Me, F, Cl, OR 3(R 3=C 1～4Alkyl) or 3,4-O 2(CH 2) etc.;
Described polar solvent is alcohol, H 2O or pure and mild H 2The mixed solvent of O; Recommendation is the aqueous solution that contains 40～95% alcohol.
Described mineral alkali is the mineral alkali of monovalence or divalent metal; As: LiOH, NaOH, KOH, Na 2CO 3Or K 2CO 3Deng;
Described alcohol is the C of low carbon chain 1-4Alkyl alcohol, as CH 3OH, C 2H 5OH or C 4H 9OH etc.
The mol ratio of described 2-(aryl thiourea base)-thiophene-3-ethyl formate, mineral alkali and halogen acetonitrile is 1: 3～5: 1～2; Recommend mol ratio to be followed successively by 1: 3～4: 1～1.5.
Adopt method of the present invention to synthesize 18 compound 3-aryl-5, the typical consequence of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, (3) is as shown in table 1.
Table 1 3-aryl-5,6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile,
Sequence number Compound R 1 R 2 Y Productive rate (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q 3r CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 Et CH 3 n-Pr -(CH 2) 3- -(CH 2) 3- -(CH 2) 3- -(CH 2) 3- -(CH 2) 4- -(CH 2) 4- -(CH 2) 4- -(CH 2) 4- -(CH 2) 4- -(CH 2) 4- -(CH 2) 4- -(CH 2) 5- -(CH 2) 5- 4-OCH 3 3，4-O 2(CH 2) 4-OC 2H 5 4-OCH 3 4-OCH 3 H 4-OCH 3 4-OC 2H 5 3，4-O 2(CH 2) H CH 3 F Cl 4-OCH 3 4-OC 2H 5 3，4-O 2(CH 2) H 4-OCH 3 92 85 91 87 87 90 88 91 85 92 89 83 91 92 88 82 84 88
The synthetic method of reacting by 2-amino-thiophene-3-ethyl formate and aromatic yl different sulfur cyanic acid ester by document [1] report of 2-(aryl thiourea base)-thiophene-3-ethyl formate (1) is synthesized.
Figure A20061011709700071
Method of the present invention at 2-(aryl thiourea base)-thiophene-3-ethyl formate (1) at mineral alkali/alcohol-H 2Key with the halogen acetonitrile reaction in the O system is to have adopted alcohol-water as mixed solvent, has the following advantages:
Figure A20061011709700082
1) reaction intermediate 4 easily forms: usually compound 1 adds an amount of mineral alkali at alcohol-water in as mixed solvent, stirs in 0.5-1 hour under the room temperature and can be converted into 4 fully;
2) intermediate 4 need not to separate, and at room temperature with the halogen acetonitrile reaction, is converted into product 3 in one hour fully;
3) intermediate 4, raw material halogen acetonitrile, mineral alkali and by product all are dissolved in solvent, and target product 3 is insoluble to solvent (alcohol-water), separates out in reaction system, and aftertreatment only needs simple filtering can obtain purer product;
4) by the ratio of alcohol in the adjusting solvent, can obtain best reaction result with water.
Characteristics such as this method has mild condition, reaction is quick, aftertreatment is simple, productive rate height are applicable to organic preparation in batches to be expected to be developed as industrialized producing technology.
The amplification of reaction scale does not influence its productive rate, purity.The present invention is with disposable 100 gram mass-producing compound 3-p-methoxyphenyls-5,6-tetramethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3n), productive rate＞90% of having synthesized of this method.
What deserves to be mentioned is, also can synthesize 5 of document [1] report easily with this method, 6-substituted thienopyrimidine-4-4-ketone compounds, the for example reaction in reaction formula 1, the present invention need not to generate earlier to close and encircles intermediate 2, by 2-(3-aryl thiourea base)-4,5-substituted thiophene-3-ethyl formate (1) and haloalkane single step reaction get final product product A, and all be better than literature method in the simplicity of operation and reaction times etc.
Compound of the present invention can be used to prepare the medicine of the procedural necrosis of anti-cell, can be used for the treatment of the medicine of apoplexy, cancer.The 3n compound of following structural formula of the present invention for example
Figure A20061011709700091
3-p-methoxyphenyl-5,6-tetramethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3n), the result measures, and the activity (necroptosis) of its procedural necrosis of anti-cell reaches EC50=0.24 μ M.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Thermometer is not proofreaied and correct among the embodiment, 1H NMR tests on Mercury300 type nuclear magnetic resonance analyser; The EI-MS spectrum is measured by the HP-5989 mass spectrograph; Infrared spectra is by Bio-Rad FTS-185 type determination of infrared spectroscopy.Working method according to document [1] prepares 2-(3-aryl thiourea base)-4,5-substituted thiophene-3-ethyl formate (1)
Figure A20061011709700092
General experimental implementation:
In the 50ml circle neck flask of the doubtful pipe of returned cold is housed, 1mmol 2-amino-thiophene-3-ethyl formate and 1.2mmol substituted-phenyl lsothiocyanates are dissolved in 20 milliliters of alcohol, reacted 12-96 hour down at 40-80 ℃, there are a large amount of solids to separate out, TLC tracks to raw material 2-amino-thiophene-3-ethyl formate and reacts completely, and cool to room temperature and standing over night are filtered, filter cake washs for several times and drying treatment with small amount of ethanol, and the gained solid is a product 1.
2-(3-p-methoxyphenyl thioureido)-4,5-thioxene-153-154 ℃ of .MS-ESI:365.1 (M of 3-ethyl formate (1a) fusing point +), IR (KBr) γ Max: 3196,2984,1662,1565 (s), 1234 (s), 1195,1038.MS m/Z (rel.intensity): 363 (M +-1,1.97), 329 (9.01), 258 (7.79), 215 (15.78), 180 (67.95), 153 (73.81), 105 (94.87), 77 (base). ultimate analysis C 17H 20N 2O 3S 2: calculated value C, 56.02; H, 5.53; N, 7.69. measured value: C, 56.19; H, 5.56; N, 7.59.
2-(3 ', 4 '-methylenedioxyphenyl base thioureido)-4,198-199 ℃ of 5-thioxene-3-ethyl formate (1b) fusing point. 1H NMR (CDCl 3) (δ): 1.28 (t, J=7.2Hz, 3H, OCH 2C H 3), 2.19 (s, 3H, C H 3), 2.25 (s, 3H, C H 3), 4.17 (q, J=7.2Hz, 2H, OC H 2CH 3), 6.04 (s, 2H, (C H 2) O 2), 6.79-6.90 (m, 3H, Ar H), 7.66 (NH), 12.11 (NH) .IR (KBr, cm -1): 3219,2980,1664 (C=O), 1566,1498,1211,1037,784.ESI-MS:377 (M-1). ultimate analysis C 17H 18N 2O 4S 2: calculated value C, 53.95; H, 4.79; N, 7.40. measured value: C, 53.93; H, 4.84; N, 7.35.
150-152 ℃ of 2-(3-p-methoxyphenyl thioureido)-4-methyl-5-ethylthiophene-3-ethyl formate (1d) fusing point. 1H NMR (DMSO) is (δ): 1.13 (t, J=7.8Hz, 3H, CH 2C H 3), 1.25 (t, J=6.9Hz, 3H, OCH 2C H 3), 2.19 (s, 3H, C H 3), 2.81 (q, J=7.5Hz, 2H, C H 2CH 3), 3.78 (s, 3H, OC H 3), 4.18 (q, J=6.3Hz, 2H, OC H 2CH 3), 6.97 (d, J=9.0Hz, 2H, Ar H), 7.34 (d, J=11.4Hz, 2H, Ar H), 9.43 (NH), 11.78 (NH) .IR (KBr, cm -1): 3161,2962,1660 (C=O), 1558,1510,1236,1199.ESI-MS:379 (M+1). ultimate analysis C 18H 22N 2O 3S 2: calculated value C, 57.12; H, 5.86; N, 7.40. measured value: C, 57.68; H, 5.87; N, 7.51.
2-(phenylthiourea base)-4,186-187 ℃ in 5-trimethylene thiophene-3-ethyl formate (1f) fusing point. 1H NMR (CDCl 3) (δ): 1.25 (t, J=6.9Hz, 3H, OCH 2C H 3), 2.31 (m, 2H, C H 2), 2.80-2.86 (m, 4H, C H 2), 4.09-4.17 (m, 2H, OC H 2CH 3), 7.27-7.39 (m, 3H, Ar H), 7.45-7.51 (m, 2H, Ar H), 7.93 (NH), 11.80 (NH) .IR (KBr, cm -1): 3198,2855,1660 (C=O), 1567,1504,1232,1195,1053,784.ESI-MS:345 (M-1). ultimate analysis C 17H 18N 2O 2S 2: calculated value C, 58.93; H, 5.24; N, 8.09. measured value: C, 58.82; H, 5.21; N, 7.97
2-(3-p-methoxyphenyl thioureido)-4,185-186 ℃ in 5-trimethylene thiophene-3-ethyl formate (1g) fusing point. 1H NMR (CDCl 3) (δ): 1.25 (t, J=6.6Hz, 3H, OCH 2CH 3), 2.29-3.36 (m, 2H, C H 2), 2.80-2.91 (m, 4H, C H 2), 3.86 (s, 3H, OC H 3), 4.11 (q, J=6.6Hz, 2H, OC H 2CH 3), 6.98 (d, J=8.4Hz, 2H, Ar H), 7.23 (d, J=8.7Hz, 2H, Ar H), 7.67 (NH), 11.70 (NH) .IR (KBr, cm -1): ESI-MS:375.0 (M-1). ultimate analysis C 18H 20N 2O 3S 2: calculated value C, 57.42; H, 5.35; N, 7.44. measured value: C, 57.46; H, 5.47; N, 7.41.
2-(3 ', 4 '-methylenedioxyphenyl base thioureido)-4,188-189 ℃ in 5-trimethylene thiophene-3-ethyl formate (1i) fusing point. 1H NMR (CDCl 3) (δ): 1.27 (t, J=7.2Hz, 3H, OCH 2C H 3), 2.30-2.38 (m, 2H, C H 2), 2.79-2.88 (m, 4H, C H 2), 4.15 (q, J=6.9Hz, 2H, OC H 2CH 3), 6.04 (s, 2H, (C H 2) O 2), 6.80 (s, 1H, Ar H), 6.82-6.89 (m, 2H, Ar H), 7.76 (NH), 11.79 (NH) .IR (KBr, cm -1): 3188,2950,1672 (C=O), 1561 (s), 1486,1438,1214,1054,931,781.ESI-MS:389.0 (M-1). ultimate analysis C 18H 18N 2O 4S 2: calculated value C, 55.37; H, 4.65; N, 7.17. measured value: C, 54.96; H, 4.87; N, 7.09.
2-(phenylthiourea base)-4,5-tetramethylene thiophene-3-ethyl formate (1j) fusing point 1H NMR (CDCl 3) (δ): 1.23 (t, J=6.9Hz, 3H, OCH 2C H 3), 1.73-1.78 (m, 4H, C H 2), 2.60-2.64 (m, 2H, C H 2), 2.69-2.73 (m, 2H, C H 2), 4.11 (q, J=7.2Hz, 2H, OC H 2CH 3), 7.30-7.37 (m, 3H, Ar H), 7.43-7.48 (m, 2H, Ar H), 8.14 (N H), 12.14 (N H) .IR (KBr, cm -1): 3189,2939,1656,1566 (s), 1233,1196,1035.ESI-MS:359.0 (M-1). ultimate analysis C 18H 20N 2O 2S 2: calculated value C, 59.97; H, 5.59; N, 7.77. measured value: C, 59.82; H, 5.60; N, 7.78.
2-(4-rubigan thioureido)-4,5-tetramethylene thiophene-3-ethyl formate (1m) fusing point 1H NMR (CDCl 3) (δ):
2-(3-p-methoxyphenyl thioureido)-4,154 ℃ in 5-tetramethylene thiophene-3-ethyl formate (1n) fusing point. 1H NMR (CDCl 3) (δ): 1.23 (t, J=6.6Hz, 3H, OCH 2C H 3), 1.72-1.81 (m, 4H, C H 2), 2.59-2.63 (m, 2H, C H 2), 2.63-2.75 (m, 2H, C H 2), 3.84 (s, 3H, OC H 3), 4.10 (q, J=7.5Hz, 2H, OC H 2CH 3), 6.97 (d, J=8.7Hz, 2H, Ar H), 7.23 (d, J=7.8Hz, 2H, Ar H), 8.10 (NH), 11.96 (NH) .ESI-MS:391 (M+1). ultimate analysis C 19H 22N 2O 3S 2: calculated value C, 58.44; H, 5.68; N, 7.17. measured value: C, 58.51; H, 6.18; N, 6.80.
2-(3-is to the ethoxyl phenenyl thioureido)-4,134-135 ℃ in 5-tetramethylene thiophene-3-ethyl formate (1o) fusing point. 1H NMR (CDCl 3) (δ): 1.23 (t, J=7.5Hz, 3H, OCH 2C H 3), 1.40 (t, J=7.2Hz, 3H, OCH 2C H 3), 1.55-1.66 (m, 4H, CH 2), 1.65-1.76 (m, 2H, C H 2), 2.60-2.64 (m, 2H, C H 2), 2.68-2.72 (m, 2H, C H 2), 3.99-4.14 (m, 4H, OC H 2CH 3+ OC H 2CH 3), 6.96 (d, J=8.7Hz, 2H, Ar H), 7.22 (d, J=8.4Hz, 2H, Ar H), 7.88 (C (S) N H), 11.97 (C (S) N H) .ESI-MS:404.9 (M). ultimate analysis C 20H 24N 2O 3S 2: calculated value C, 59.38; H, 5.98; N, 6.92. measured value: C, 59.48; H, 6.02; N, 6.99.
2-(3 ', 4 '-methylenedioxyphenyl base thioureido)-4,190-191 ℃ in 5-tetramethylene thiophene-3-ethyl formate (1p) fusing point. 1H NMR (CDCl 3) (δ): 1.28 (t, J=6.9Hz, 3H, OCH 2C H 3), 1.71-1.82 (m, 4H, C H 2), 2.60-2.66 (m, 2H, C H 2), 2.68-2.77 (m, 2H, C H 2), 4.16 (q, t=6.9Hz, 2H, OC H 2CH 3), 6.04 (s, 2H, (C H 2) O 2), 6.79-6.90 (m, 3H, Ar H), 7.69 (NH), 12.10 (NH) .IR (KBr, cm -1): 3207,2928,1663 (C=O), 1562,1497,1206,1036,785.ESI-MS:403.0 (M-1). ultimate analysis C 19H 20N 2O 4S 2: calculated value C, 56.42; H, 4.98; N, 6.93. measured value: C, 56.48; H, 5.12; N, 6.88.
2-(phenylthiourea base)-4,5-pentamethylene thiophene-3-ethyl formate (1q) 1H NMR (CDCl 3) (δ): 1.21 (t, J=6.9Hz, 3H, OCH 2C H 3), 1.56-1.65 (m, 4H, C H 2), 1.81-1.83 (m, 4H, C H 2), 2.70-2.74 (m, 2H, C H 2), 2.95-2.99 (m, 2H, C H 2), 4.10 (q, J=7.2Hz, 2H, OC H 2CH 3), 7.31-7.38 (m, 3H, Ph H), 7.44-7.49 (m, 2H, Ph H), 7.86 (N H), 11.94 (N H). ultimate analysis C 19H 22N 2O 2S 2: calculated value C, 60.93; H, 5.92; N, 7.48. measured value C, 61.03; H, 5.93; N, 7.51.
Embodiment 1 3-aryl-5, the preparation of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, (3)
General experimental implementation:
In the round neck flask of 50ml, at room temperature add 1mmol 2-(3-aryl thiourea base)-4 respectively, 5-two substituted thiophenes-3-ethyl formate (1), the 3.3mmol mineral alkali is in the aqueous solution of 25m140～95% alcohol, induction stirring 0.5-2 hour to clarification, add the 1.1mmol bromoacetonitrile, continue to stir after 0.5-1 hour, have a large amount of white solids to separate out, after reacting completely, filter,, get product 3 after the vacuum-drying with less water and washing with alcohol filter cake several.Product 3 usefulness ethanol-chloroform (or ethanol) recrystallizations.
3-p-methoxyphenyl-5,6-thioxene and pyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3a) white solid, productive rate 324mg (92%), fusing point 218-220 ℃. 1H NMR (CDCl 3) (δ): 2.40 (s, 3H, C H 3), 2.42 (s, 3H, C H 3), 3.88 (s, 5H, C H 2CN+OC H 3), 7.05 (d, J=8.7Hz, 2H, OCH 3-Ph H), 7.22 (d, J=8.7Hz, 2H, OCH 3-Ph H) .IR (KBr, cm -1): 2977,2928,2247 (C ≡ N), 1668 (s, C=O), 1525,1508 (s), 1255,777.MS m/Z (rel.intensity): 357 (M +, 42.66), 285 (53.07), 146 (base). ultimate analysis C 17H 15N 3O 2S 2: calculated value C, 57.12; H, 4.23; N, 11.76. measured value: C, 56.85; H, 4.17; N, 11.73.
3-(3 ', 4 ')-(methylene radical dioxy base) phenyl-5,6-thioxene and pyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3b) white solid, productive rate 315mg (85%), fusing point 236-237 ℃. 1H NMR (CDCl 3) (δ): 2.40 (s, 3H, C H 3), 2.42 (s, 3H, C H 3), 3.88 (s, 2H, C H 2CN), 6.07 (s, 1H, C H 2(O) 2), 6.12 (s, 1H, C H 2(O) 2), 6.75-6.80 (m, 2H, Ar H), 6.94 (d, J=8.1Hz, 1H, Ar H) .IR (KBr, cm -1): 2982,2920,2250 (C ≡ N), 1695 (s, C=O), 1523 (s), 1487,1252,779.MS m/Z (rel.intensity): 371 (M +, 84.68), 331 (9.08), 299 (66.16), 160 (base).
3-is to ethoxyl phenenyl-5,6-thioxene and pyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3c) white solid, productive rate 337mg (91%), fusing point 219-221 ℃. 1H NMR (CDCl 3) (δ): 1.46 (t, J=7.2Hz, 3H, OCH 2C H 3), 2.40 (s, 3H, C H 3), 2.42 (s, 3H, C H 3), 3.89 (s, 2H, C H 2CN), 4.09 (q, J=7.2Hz, 2H, OC H 2CH 3), 7.02 (d, J=8.7Hz, 2H, Ar H), 7.20 (d, J=8.7Hz, 2H, Ar H) .IR (KBr, cm -1): 2984,2931,2252 (C ≡ N), 1697 (s, C=O), 1506 (s), 1252,1229,1177,774.MS m/Z (rel.intensity): 371 (M +, 41.87), 299 (61.23), 160 (base), 132 (35.90). ultimate analysis C 18H 17N 3O 2S 2: calculated value C, 58.20; H, 4.61; N, 11.31. measured value: C, 57.92; H, 4.67; N, 11.19.
3-p-methoxyphenyl-5-methyl-6-ethylthiophene and pyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3d) white solid, productive rate 323mg (87%), fusing point 193-194 ℃. 1H NMR (CDCl 3) (δ): 1.29 (t, J=7.5Hz, 3H, CH 2C H 3), 2.44 (s, 3H, C H 3), 2.80 (q, J=7.5Hz, 2H, C H 2CH 3), 3.87 (s, 5H, C H 2CN+OCH 3), 7.05 (d, J=8.7Hz, 2H, OCH 3-Ph H), 7.21 (d, J=8.7Hz, 2H, OCH 3-Ph H) .IR (KBr, cm -1): 2974,2927,2249 (C ≡ N), 1671 (s, C=O), 1525,1506 (s), 1252,1025,809.MS m/Z (rel.intensity): 371 (M +, base), 356 (22.42), 299 (75.21), 146 (93.58). ultimate analysis C 18H 17N 3O 2S 2: calculated value C, 58.20; H, 4.61; N, 11.31. measured value: C, 58.03; H, 4.67; N, 11.15.
3-p-methoxyphenyl-5-methyl-6-propyl group Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3e) white solid, productive rate 334mg (87%), fusing point 179-180 ℃. 1H NMR (CDCl 3) (δ): 0.99 (t, J=7.5Hz, 3H, CH 2CH 2C H 3), 1.58-1.70 (m, 2H, CH 2C H 2CH 3), 2.43 (s, 3H, C H 3), 2.76 (t, J=7.8Hz, 2H, C H 2CH 2CH 3), 3.87 (s, 3H, OC H 3), 3.90 (s, 2H, C H 2CN), 7.03 (d, J=6.6Hz, 2H, OCH 3-Ph H), 7.22 (d, J=6.6Hz, 2H, OCH 3-Ph H) .IR (KBr, cm -1): 2957,2932,2247,1693 (s), 1521,1509 (s), 1257,1025,805.MS m/Z (rel.intensity): 385 (M +, 86.67), 356 (base), 313 (34.65), 241 (13.76), 146 (58.54). ultimate analysis C 19H 19N 3O 2S 2: calculated value C, 59.20; H, 4.97; N, 10.90. measured value: C, 59.33; H, 4.91; N, 10.97.
3-phenyl-5,6-trimethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3f) white solid, productive rate 305mg (90%), fusing point 231-233 ℃. 1H NMR (CDCl 3) (δ): 2.40-2.52 (m, 2H, C H 2), 2.94-3.05 (m, 4H, C H 2), 3.89 (s, 3H, C H 2CN), 7.27-7.32 (m, 2H, Ar H), 7.55-7.59 (m, 3H, Ar H) .IR (KBr, cm -1): 2978,2927,2852,2248 (C ≡ N), 1672 (s, C=O), 1512 (s), 1222,742.MS m/Z (rel.intensity): 339 (M +, base), 319 (64.42), 299 (38.78), 267 (48.20), 165 (74.61). ultimate analysis C 17H 13N 3OS 2: calculated value C, 60.15; H, 3.86; N, 12.38. measured value: C, 59.74; H, 4.02; N, 12.25.
3-p-methoxyphenyl-5,6-trimethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3g) white solid, productive rate 324mg (88%), fusing point 225-226 ℃. 1H NMR (CDCl 3) (δ): 2.43-2.48 (m, 2H, C H 2), 2.94-3.04 (m, 4H, C H 2), 3.88 (s, 5H, OC H 3+ C H 2CN), 7.04 (d, J=5.1Hz, 2H, Ar H), 7.22 (d, J=5.1Hz, 2H, Ar H) .IR (KBr, cm -1): 2931,2857,2248 (C ≡ N), 1693 (s, C=O), 1606,1508 (s), 1252,820.MS m/Z (rel.intensity): 369 (M +, 3.66), 297 (2.56), 272 (10.28), 257 (8.07), 120 (31.69), 43 (base). ultimate analysis C 17H 16N 2O 2S 2: calculated value C, 58.52; H, 4.09; N, 11.37. measured value: C, 58.41; H, 4.13; N, 11.34.
3-is to ethoxyl phenenyl-5,6-trimethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3h) white solid, productive rate 348mg (91%), fusing point 242-244 ℃. 1H NMR (CDCl 3) (δ): 1.46 (t, J=7.5Hz, OCH 2C H 3), 2.42-2.50 (m, 2H, CH 2C H 2CH 2), 2.92-3.03 (m, 4H, CH 2CH 2C H 2), 3.89 (s, 2H, SC H 2CN), 4.08 (q, J=7.5Hz, OC H 2CH 3), 7.01 (d, J=6.0Hz, 2H, OEt-Ph H), 7.17 (d, J=6.0Hz, 2H, OEt-Ph H) .IR (KBr, cm -1): 2980,2931,2252 (C ≡ N), 1682 (s, C=O), 1606,1509 (s), 1256,811.MS m/Z (rel.intensity): 383 (M+, 53.24), 311 (44.47), 160 (base). ultimate analysis C 19H 17N 3O 2S 2: calculated value C, 59.21; H, 4.47; N, 10.96. measured value: C, 59.19; H, 4.47; N, 10.84.
3-(3 ', 4 ')-(methylene radical dioxy base) phenyl-5,6-trimethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3i) white solid, productive rate 324mg (85%), fusing point 231-233 ℃. 1H NMR (CDCl 3) (δ): 2.43-2.50 (m, 2H, CH 2C H 2CH 2), 2.94-3.05 (m, 4H, CH 2CH 2C H 2), 3.89 (s, 2H, C H 2CN), 6.07 (s, 1H, C H 2(O) 2), 6.11 (s, 1H, C H 2(O) 2), 6.74-6.79 (m, 2H, Ar H), 6.93 (d, J=8.7Hz, 1H, Ar H) .IR (KBr, cm -1): 2969,2922,2252 (C ≡ N), 1690 (s, C=O), 1515 (s), 1486 (s), 1250,1039,933.MS m/Z (rel.intensity): 382 (M +, 9.34), 342 (1.51), 311 (6.45), 212 (28.01), 155 (35.85), 91 (base). ultimate analysis C 18H 13N 3O 3S 2: calculated value C, 56.38; H, 3.42; N, 10.96. measured value C, 55.92; H, 3.37; N, 10.86.
3-phenyl-5,6-tetramethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3j) white solid, productive rate 324mg (92%), 268 ℃ of fusing points. 1HNMR (CDCl 3) (δ): 1.80-1.88 (m, 4H, C H 2), 2.76-2.79 (m, 2H, C H 2), 2.94-3.00 (m, 2H, C H 2), 3.89 (s, 2H, C H 2CN), 7.26-7.32 (m, 2H, Ar H), 7.55-7.59 (m, 3H, Ar H) .IR (KBr, cm -1): 2973,2931,2246 (C ≡ N), 1666 (s), 1515 (s), 1221,771.MS m/Z (rel.intensity): 353 (M +, base), 313 (38.32), 281 (60.95), 237 (34.81), 179 (32.76). ultimate analysis C 18H 15N 3OS 2: calculated value C, 61.17; H, 4.28; N, 11.89. measured value: C, 61.15; H, 4.23; N, 11.73.
3-p-methylphenyl-5,6-tetramethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3k) white solid, productive rate 326mg (89%), mp.234-235 ℃. 1H NMR (CDCl 3) (δ): 1.82-1.90 (m, 4H, C H 2), 2.46 (s, 3H, PhC H 3), 2.77-2.81 (m, 2H, C H 2), 2.93-2.97 (m, 2H, C H 2), 3.89 (s, 2H, C H 2CN), 7.18 (d, J=8.1Hz, 2H, Ar H), 7.36 (d, J=8.1Hz, 2H, Ar H) .IR (KBr, cm -1): 2939,2848,2249 (C ≡ N), 1689 (s, C=O), 1552 (s), 1444,1321,1262,1106,1010,960,872.MS m/Z (rel.intensity): 367 (M +) (24.68), 340 (100, Base), 206 (26.32), 179 (81.73) 151 (22.79), 91 (18.57). ultimate analysis C 19H 17N 3OS 2: calculated value C, 62.09; H, 4.41; N, 11.37. measured value: C, 61.92; H, 4.63; N, 11.31.
3-is to fluorophenyl-5,6-tetramethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (31) white solid, productive rate 308mg (83%), mp.255-257 ℃. 1H NMR (CDCl 3) (δ): 1.86-1.91 (m, 4H, C H 2), 2.75-2.82 (m, 2H, C H 2), 2.93-2.98 (m, 2H, C H 2), 3.91 (s, 2H, C H 2CN), 7.25-7.31 (m, 4H, Ar H) .IR (KBr, cm -1): 2939,2252 (C ≡ N), 1683 (s, C=O), 1537 (s), 1228,1200.MS m/Z (rel.intensity): 371 (M +) (100, base), 299 (58.18), 237 (36.88), 179 (35.53). ultimate analysis C 18H 14FN 3OS 2: calculated value C, 58.20; H, 3.80; N, 11.31. measured value: C, 58.58; H, 3.60; N, 11.23.
3-rubigan-5,6-tetramethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3m) white solid, productive rate 348 mg (91%), fusing point 216-218 ℃. 1H NMR (CDCl 3) (δ): 1.86-1.89 (m, 4H, C H 2), 2.78-2.82 (m, 2H, C H 2), 2.93-2.98 (m, 2H, C H 2), 3.93 (s, 2H, C H 2CN) 7.25 (d, J=8.7Hz, 2H, Ar H), 7.57 (d, J=8.7Hz, 2H, Ar H) .IR (KBr, cm -1): 2935,2252 (C ≡ N), 1693 (C=O), 1519,1232,794.MS m/Z (rel.intensity): 387 (M +), 347,315,284,179,91. ultimate analysis C 18H 14N 3OS 2Cl:C, 55.74; H, 3.64; N, 10.83. measured value: C, 55.68; H, 3.63; N, 10.82.
3-p-methoxyphenyl-5,6-tetramethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3n) white solid, productive rate 352mg (92%), fusing point 212-214 ℃. 1H NMR (CDCl 3) (δ): 1.82-1.90 (m, 4H, C H 2), 2.77-2.97 (m, 4H, C H 2), 3.89 (s, 5H, OC H 3+ C H 2CN), 7.1 8 (d, J=8.7Hz, 2H, OCH 3-Ph H), 7.36 (d, J=8.7Hz, 2H, OCH 3-Ph H) .IR (KBr, cm -1): 2939,2848,2249 (C ≡ N), 1630 (s, C=O), 1444,1321,1262,872.MS m/Z (rel.intensity): 383 (M +) (31.21), 311 (27.60), 146 (base). ultimate analysis C 19H 17N 3O 2S 2: calculated value C, 59.21; H, 4.47; N, 10.96. measured value: C, 59.13; H, 4.48; N, 10.80.
When dehydrated alcohol was adopted in reaction as solvent, reaction yield was 36%; And when adopting water to be solvent, productive rate is 25%.
3-is to ethoxyl phenenyl-5,6-tetramethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3o) white solid, productive rate 349mg (88%), fusing point 202-204 ℃. 1H NMR (CDCl 3) (δ): 1.46 (t, J=6.9Hz, 3H, OCH 2C H 3), 1.82-1.90 (m, 4H, C H 2), 2.73-2.79 (m, 2H, C H 2), 2.91-2.98 (m, 2H, C H 2), 3.88 (s, 2H, C H 2CN), 4.07-4.14 (m, 2H, OC H 2CH 3), 7.03 (d, J=9.0Hz, 2H, Ar H), 7.20 (d, J=9.0Hz, 2H, Ar H) .IR (KBr, cm -1): 2941,2248 (C ≡ N), 1686 (s, C=O), 1521,1507 (s), 1237,1176,799,773,732.MS m/Z (rel.intensity): 397 (M +) (64.89). ultimate analysis C 20H 19N 3O 2S 2: calculated value C, 60.43; H, 4.82; N, 10.57. measured value: C, 60.21; H, 5.11; N, 10.48.
3-(3 ', 4 ')-(methylene radical dioxy base) phenyl-5,6-tetramethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3p) white solid, productive rate 326mg (82%), fusing point 246-247 ℃. 1H NMR (CDCl 3) (δ): 1.80-1.89 (m, 4H, C H 2), 2.73-2.78 (m, 2H, C H 2), 2.92-2.96 (m, 2H, C H 2), 3.88 (s, 2H, C H 2CN), 6.07 (s, 1H, C H 2(O) 2), 6.11 (s, 1H, C H 2(O) 2), 6.73-6.79 (m, 2H, Ar H), 6.93 (d, J=8.1Hz, 1H, Ar H) .IR (KBr, cm -1): 2930,2245 (C ≡ N), 1689 (s, C=O), 1520 (s), 1485 (s), 1238,1035,791.ESI-MS m/Z (rel.intensity): 398. ultimate analysis C 19H 15N 3O 3S 2: calculated value C, 57.42; H, 3.80; N, 10.57. measured value: C, 57.29; H, 3.93; N, 10.57.
3-phenyl-5,6-pentamethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3q) white solid, productive rate 308mg (84%), fusing point 234-235 ℃. 1H NMR (CDCl 3) (δ): 1.62-1.68 (m, 2H, C H 2), 1.68-1.73 (m, 2H, C H 2), 1.88-1.89 (m, 2H, C H 2), 2.84-2.88 (m, 2H, C H 2), 3.25-3.29 (m, 2H, C H 2), 3.89 (s, 2H, C H 2CN), 7.27-7.32 (m, 2H, Ph- H), 7.55-7.57 (m, 3H, Ph- H) .IR (KBr, cm -1): 3050,2928,2845,2254 (C ≡ N), 1687 (s, C=O), 1516 (s), 1232,698.MS m/Z (rel.intensity): 367 (M +, base), 352 (4.91), 295 (40.45), 251 (93.55), 192 (33.43), 77 (37.77). ultimate analysis C 19H 17N 3OS 2: calculated value C, 62.10; H, 4.66; N, 11.43. measured value: C, 61.73; H, 4.82; N, 11.29.
3-p-methoxyphenyl-5,6-pentamethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3r) white solid, productive rate 349mg (88%), fusing point 221-222 ℃. 1H NMR (CDCl 3) (δ): 1.62-1.68 (m, 2H, C H 2), 1.68-1.73 (m, 2H, C H 2), 1.88-1.89 (m, 2H, C H 2), 2.85 (d, J=10.8Hz, 2H, C H 2), 3.27 (d, J=10.8Hz, 2H, C H 2), 3.87 (s, 5H, C H 2CN+OC H 3), 7.03 (d, J=9.0Hz, 2H, Ar H), 7.21 (d, J=9.0Hz, 2H, Ar H) .IR (KBr, cm -1): 2927,2250 (C ≡ N), 1687 (s, C=O), 1508 (s), 1253,805.MS m/Z (rel.intensity): 397 (M +) (91.38), 382 (2.02), 357 (13.99), 325 (40.82), 146 (base). ultimate analysis C 20H 19N 3O 2S 2: calculated value C, 60.43; H, 4.82; N, 10.57. measured value: C, 60.06; H, 4.86; N, 10.37.
Embodiment 2 3-p-methoxyphenyls-5, a large amount of preparations of 6-tetramethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile, (3n)
Figure A20061011709700161
In single neck circle neck flask of 1000ml, add 111 gram (0.3mol) 2-(3-p-methoxyphenyl thioureido)-4 respectively, 5-tetramethylene thiophene-3-ethyl formate (1n), 56 gram (1mol) potassium hydroxide are in the 750ml aqueous ethanolic solution, continue to stir 0.5-1 hour to clarification, add the 0.33mol bromoacetonitrile, stir after 0.5-1 hour, there are a large amount of white solids to separate out, (1n) reacts completely to raw material, filter,, get product (3n) 97 grams (productive rate 91%) after the vacuum-drying with less water and ethanol difference washing leaching cake several.

Claims (9)

1. 3-aryl-5,6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, compound, it has following structural formula:
Figure A2006101170970002C1
Wherein, R 1, R 2=H or C 1～6Alkyl; Perhaps R 1, R 2=-(CH 2) n-, n=1～6; Y=H, Me, F, Cl, OR 3Or 3,4-O 2(CH 2); R 3=C 1～4Alkyl.
2, a kind of 3-aryl-5 as claimed in claim 1, the compound of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, is characterized in that this compound is a 3-p-methoxyphenyl-5,6-tetramethylene Thienopyrimidine-4-carbonyl-2-mercaptoacetonitrile.
3, a kind of 3-aryl-5, the synthetic method of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile,, it is characterized in that under polar solvent and room temperature, 2-(aryl thiourea base)-thiophene-3-ethyl formate and mineral alkali reaction 0.5-2 hour, react 0.1-1 hour generation 3-aryl-5,6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, again with under the halo acetonitrile room temperature;
Wherein, described mineral alkali is the mineral alkali of monovalence or divalent metal;
Described polar solvent is alcohol, H 2O or pure and mild H 2The mixed solvent of O;
Described alcohol is the C of low carbon chain 1-4Alkyl alcohol;
The mol ratio of described 2-(aryl thiourea base)-thiophene-3-ethyl formate, mineral alkali and halo acetonitrile is 1: 3～5: 1～2;
Described 2-(aryl thiourea base)-thiophene-3-ethyl formate and 3-aryl-5, the structural formula of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, is as follows respectively:
Figure A2006101170970002C2
Wherein, R 1, R 2=H or C 1～6Alkyl; Perhaps R 1, R 2=-(CH 2) n-, n=1～6; Y=H, Me, F, Cl, OR 3Or 3,4-O 2(CH 2); R 3=C 1-4Alkyl.
4, a kind of 3-aryl-5 as claimed in claim 3, the synthetic method of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, is characterized in that described mineral alkali is LiOH, NaOH, KOH, Na 2CO 3Or K 2CO 3
5, a kind of 3-aryl-5 as claimed in claim 3, the synthetic method of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, is characterized in that described C 1-4Alkyl alcohol be CH 3OH, C 2H 5OH or C 4H 9OH.
6, a kind of 3-aryl-5 as claimed in claim 3, the synthetic method of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, is characterized in that described R 1Or R 2=H, CH 3, C 2H 5Or C 3H 7
7, as claimed in claim 3-kind of 3-aryl-5, the synthetic method of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, is characterized in that described R 1And R 2=-(CH 2) 3-,-(CH 2) 4-or-(CH 2) 5-.
8, a kind of 3-aryl-5 as claimed in claim 3, the synthetic method of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, is characterized in that described pure and mild H 2The mixed solvent of O is the aqueous solution that contains 40～95% alcohol.
9, a kind of 3-aryl-5 as claimed in claim 1, the purposes of 6-substituted thienopyrimidine-4-4-carbonyl-2-mercaptoacetonitrile, compound is characterized in that being used to prepare the medicine of the procedural necrosis of anti-cell.
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CN112079828A (en) * 2020-09-09 2020-12-15 广州辉睿生物科技有限公司 2-amino-cyclopenteno [ b ] thiophene-3-carboxylate derivative and preparation method and application thereof

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JP2012513481A (en) * 2008-12-23 2012-06-14 プレジデント アンド フェロウズ オブ ハーバード カレッジ Small molecule inhibitors of necrotosis
CN112079828A (en) * 2020-09-09 2020-12-15 广州辉睿生物科技有限公司 2-amino-cyclopenteno [ b ] thiophene-3-carboxylate derivative and preparation method and application thereof

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