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Structure of 2986-19-8 * Storage: {[proInfo.prStorage]}
* 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.
Reference:
[1] Journal of Organic Chemistry, 1959, vol. 24, p. 922,924
[2] Journal of the Chemical Society, 1946, p. 362,365
6
[ 2986-19-8 ]
[ 87-13-8 ]
[ 53554-29-3 ]
Reference:
[1] Journal of the American Chemical Society, 1943, vol. 65, p. 350,352
7
[ 2986-19-8 ]
[ 68-11-1 ]
[ 71-43-2 ]
[ 556-90-1 ]
Reference:
[1] Annali di Chimica (Rome, Italy), 1953, vol. 43, p. 832,838
8
[ 2986-19-8 ]
[ 68-11-1 ]
[ 71-43-2 ]
[ 74-93-1 ]
[ 556-90-1 ]
Reference:
[1] Annali di Chimica (Rome, Italy), 1953, vol. 43, p. 832,838
9
[ 85302-07-4 ]
[ 2986-19-8 ]
[ 21599-35-9 ]
Yield
Reaction Conditions
Operation in experiment
86%
With sodium acetate In N,N-dimethyl-formamide at 100℃; for 5 h;
Step 2: Synthesis of 2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one. To a solution of 2-((dimethylamino)methylene)cyclohexane-l,3-dione (0.5 g, 2.9 mmol) in DMF (2mL) was added sodium acetate (0.39 g, 4.7 mmol) and methyl carbamimidothioate (0.9 g, 3.5 mmol). The reaction mixture was heated at 100 0C for 5 hours. On completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL). The organic layer was separated and washed with water (2 X 30 mL). The solvent was then removed under reduced pressure and the residue dissolved in EtOAc (50 mL) and washed with water (2 x 30 mL). The organic layer was dried using sodium sulfate and concentrated under reduced pressure to give the desired product (0.5 g, 86percent) as a solid. 1H NMR (CDCl3, 400MHz): δ 8.94 (s, IH), 3.01 (t, J = 6 Hz, 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.58 (s, 3H), 2.14 (quintet, J = 6.2 Hz, 2H); LCSM [M+H]: 195.
With potassium hydroxide In water at 0 - 65℃; for 1.66667 h;
A round bottom flask containing ethyl formate (6 mL, 0.062 mol) and ethyl ether (30 mL) was placed in an ice water bath, Na (1.4 g, 0.062 mol) was added under stirring, and then methyl 2-methoxyacetate (6.5 g, 0.062 mol) was added dropwise. The mixture was stirred at room temperaturefor 4 h. The reaction was quenched by addition of ice water (25 mL), and the aqueous phase was separated. To the water layer, S-methyl isothiourea (5.6 g, 0.062 mol) and KOH (2.2 g, 0.062 mol) were added within 40 min, and then heated to 65 °C for 1 h. After cooling, the reaction mixture was neutralized with 37percent HCl. The crude product was collected by vacuum filtration, and then recrystallized with 95percent ethanol to afford 2 as a white needle crystal (4.3 g, 40.1percent yield). m.p. 193-195 °C.The intermediate 2 (1.7 g, 0.01 mol) was added slowly into POCl3 (4.6 g, 0.03 mol) in ice-water bath, and then the mixture was heated to 80 °C for 1 h until the reaction was completed. The reaction mixture was cooled to room temperature and neutralized with 25percent ammonia water. The precipitated solid was filtered and recrystallized with petroleum ether, decolorized by activated carbon. The intermediate 3 was obtained as a light yellow solid (1.8 g, 95.2percent yield). m.p. 74-75 °C. The intermediate 3 was dissolved in methanol (10 mL), 50percent hydrated hydrazine solution (1.6 g, 0.015 mol) was added dropwise in an ice-water bath. Then the mixture was heated to 50 °C and monitored by TLC until the reaction was finished. After cooling, the solvent was removed under reduced pressure, and the solid was recrystallized from ethyl acetate and petroleum ether to afford 5-methoxy-2-(methylthio) pyrimidin-4-yl hydrazine (4, 1.1 g, 96.2percentyield). m.p. 112-114 °C.
Reference:
[1] Letters in Drug Design and Discovery, 2016, vol. 13, # 4, p. 329 - 334
With potassium carbonate In ethanol for 48 h; Heating / reflux
2-Methyl-2-thiopseudourea (5 mmol) and ethyl ethoxymethylenecyanoacetate (5 mmol) were dissolved in 20 ml EtOH. To this was added K2CO3 (10 mmol). After the mixture was refluxed for 48 h, it was cooled to room temperature and filtered. The solvent was concentrated in vacuo and purified by column chromatography to give 4-hydroxy-2-(methylthio) pyrimidine-5-carbonitrile in a yield of 65percent.
Reference:
[1] Journal of medicinal chemistry, 2000, vol. 43, # 21, p. 3995 - 4004
14
[ 2986-19-8 ]
[ 24697-74-3 ]
Yield
Reaction Conditions
Operation in experiment
17 g
at 140℃; for 5 h;
Take the mother herb (11g) dissolved150 mL of DMF was addedS-methylisothiourea sulfuric acid (50 g) was added to the mixture140 , reaction 5h,TLC tracking. Recovery solvent, add sodium chloride aqueous solution for salting out, and then alkalized with sodium bicarbonate, immediately a large number of crystal precipitation, put the refrigerator, filter ash to get purple crystal. The crystals were recrystallized from methanol to give 17 g of white crystals having a melting point of 214-215 ° C.
Reference:
[1] Patent: CN106866464, 2017, A, . Location in patent: Paragraph 0066; 0067
15
[ 24424-99-5 ]
[ 2986-19-8 ]
[ 107819-90-9 ]
Reference:
[1] Patent: US6514964, 2003, B1,
16
[ 67751-23-9 ]
[ 2986-19-8 ]
[ 180869-36-7 ]
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 22, p. 3111 - 3116
17
[ 24424-99-5 ]
[ 2986-19-8 ]
[ 173998-77-1 ]
[ 322474-21-5 ]
Yield
Reaction Conditions
Operation in experiment
55%
With triethylamine; sodium hydroxide In dichloromethane at 0℃; for 4 h;
CH2Cl2 (5 ml) and triethylamine (TEA) (250 l, 1.79mmol) were added to a rapidly stirred solution of Smethylisothioureahemisulfate (500 mg, 3.59 mmol) inNaOH 1N (2.5 ml). The mixture was cooled to T=0°C on an ice bath, and a solution of di-tert-butyl dicarbonate (783.5mg, 3.59 mmol) in CH2Cl2 (2 ml) was added dropwise over 3h. Upon completion of the addition, the mixture was stirredan additional hour, diluted with 1 mL of CH2Cl2, and HCl 1Nwas added until pH 4. The organic layer was extracted withacidic water, and the aqueous layer was separated from theorganic phase and neutralized with NaOH 1N; CH2Cl2 (1 ml)was added and the aqueous phase was extracted twice. Theorganic layers were separated, dried over sodium sulfate,filtered and concentrated under reduced pressure. Diethylether was added and the solvent was evaporated under vacuumtwice. The compound purity was verified by HPLCanalysis as described above. The qualitative analysis of theproduct was finally confirmed by ESI-MS. The product wasthen used directly in the next step. (377 mg, 55 percent)1H NMR (200 MHz, DMSO-d6): 1.39 (s, 9H), 2.45 (s,3H).13C NMR (50 MHz, DMSO-d6): 13.8, 27.8, 79.2, 157.3,161.4.ESI-MS m/z =191 [M+H] +
S1, methylthiourea sulfate(75.2g, 0.4mol)Add to a mass fraction of 16% NaOH (250 mL, 1.18 mol) and stir for 30 min.Then diethyl ethoxymethylenemalonate (103.4 g, 0.48 mol)Soluble in 160mL of ethanol and slowly drip into the reaction solution,After the completion of the dropwise addition, the reaction was carried out at room temperature for 10 hours, when a large amount of white solid precipitated,Pumping,Washed,Drying in vacuo gave a white solid (84.7 g, 99.7%);
87.6%
With sodium ethanolate; In ethanol; at 20℃; for 3h;
To a solution of 2-ethoxymethylenemalonic acid diethyl ester (59.0 g, 273 mmol) in EtOH (300 mL) was added 2-methyl-isothiourea (41.5 g, 150 mmol) in an ice-H2O bath. An EtOHic solution of EtONa (2M, 300 mL) was added dropwise maintaining the reaction temperature under 5 C. The mixture was warmed to RT and stirred for 3h. After standing overnight, the solvent was removed under reduced pressure and the residue was dissolved in H2O (800 mL) at 0 C. The solution was acidified to pH 3 with cone. HCl and the precipitate collected by filtration and air-dried to yield 4-hydroxy-2- methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester as a white solid (50.8 g, 87.6% yield).
Stage #1: diethyl ethylidenemalonate; carbamimidothioic acid methyl ester With TEA In ethanol for 3h; Heating;
Stage #2: With N-Bromosuccinimide; potassium carbonate; dibenzoyl peroxide In 1,4-dioxane at 90℃; for 3h;
With potassium hydroxide; In water; at 20℃; for 6.08333h;Heating / reflux;
To a stirred solution of potassium hydroxide (1.97 g, 31.7 mmol) and 2-methyl-2- thiopseudourea sulfate (4.41 g, 31.7 mmol) in water (15 mL) was added dropwise of methyl tetrahydro-4-oxofuran-3-carboxylate (1.59 g, 15.9 mmol) over 5 min. The mixture was stirred at rt for 3 h and refluxed for 3 h. It was evaporated to dryness to give 4.1 g of crude product and used for next reaction without further purification.
(a). 5-Bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid; EPO <DP n="47"/>At 50C triethylamine (16.9 ml) was added dropwise to a solution of mucobromic acid (10.31 g) and 2-methyl-isothiourea (11.13 g) in water (200 ml). After stirring at 50C for3 h, the reaction mixture was allowed to warm up (room temperature) and stirring was continued for another 54 h. The reaction mixture was acidified with cone. HCl (33%). The title product was obtained by filtration. Yield: 4.1 g. MS-ESI: [M+H]+ = 249/251
Step A Tert-butyl (2Z)-2-aza-3-[(tert-butoxy)carbonylamino]-3-methylthioprop-2-enoate To a stirring solution of methylthiocarboxamidine in methylene chloride (0.2 M) was added di-tert-butyl dicarbonate (4 eq), followed by saturated sodium carbonate. After stirring for 18 hr the reaction was diluted with methylene chloride and separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (silica; 10percent CHCl3) afforded a colorless solid. EI-MS m/z 291(M+H)+
With sodium hydroxide; sulfuric acid; In methanol; water;
EXAMPLE 90 1-Amidino-3-piperidinecarboxylic acid hydrochloride 22 g of s-methylisothiourea 1/2 sulfuric acid was added with ice-cooling to a solution of 6.5 g of sodium hydroxide and 120 ml of water. To the mixture was added 20 g of <strong>[498-95-3]nipecotic acid</strong>, and the resulting mixture was stirred at room temperature for 40 hours. The reaction mixture was filtered to give crystals. The crystals were washed in turn with cold water, acetone and ether. Thereafter, the crystals were dissolved in 110 ml of 1 N hydrochloride, and the resulting solution was stirred at room temperature for 45 minutes. After removal of any insoluble materials by filtration, the filtrate was concentrated under reduced pressure to give white powder, and the powder was dissolved in methanol. Ether was added to the solution to give crystals which were then washed with ether to obtain 10 g of 1-amidino-3-piperidinecarboxylic acid hydrochloride as white powder having a melting point of 234 to 236 C. IR numaxKBr cm-1: 1710 (C=O). NMR(CD3 OD)delta: 1.40-3.80 (9H, m, piperidine protons).
With potassium carbonate; In ethanol;Heating / reflux;
<strong>[164650-68-4]3-chloro-5-methoxybenzaldehyde</strong> (6.52 g, 38.13 mmol), ethyl cyanoacetate (4.31 g, 38.13 mmol), methylthiocarboxamidine (10.61 g, 38.13 mmol), and potassium carbonate (5.26 g, 38.13 mmol) were refluxed in ethanol (100 mL) overnight. The stirbar was removed and water was added. The volatiles were removed and the aqueous layer was extracted with ethyl acetate, dried with sodium sulfate, and concentrated to give 12 g (100%) of the title compound as a brown oil. MS m/z calculated for (M + H)+ 308, found 308.
With potassium carbonate; In ethanol; for 48.0h;Heating / reflux;
2-Methyl-2-thiopseudourea (5 mmol) and ethyl ethoxymethylenecyanoacetate (5 mmol) were dissolved in 20 ml EtOH. To this was added K2CO3 (10 mmol). After the mixture was refluxed for 48 h, it was cooled to room temperature and filtered. The solvent was concentrated in vacuo and purified by column chromatography to give 4-hydroxy-2-(methylthio) pyrimidine-5-carbonitrile in a yield of 65%.
Example 1; Synthesis of {1 -[2-(2-chloro-benzylamino)-pyrido[4,3-d]pyrimidin-5-yl]-piperidin-4-yl}-(4- ethyl-piperazin-1-yl)-methanone 11 (Compound 72)a. Preparation of 4-Methyl-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester 3Equimolar quantities of ethyl 2-acetyl-3-ethoxy-2-propenoate 1 (20.0 g, 107 mmol), ((amino(imino)methyl)-sulfanyl)methane 2 (9.68 g, 107 mmol) and triethylamine (10.8 g, 107 mmol) in EtOH (100 ml.) were stirred at reflux for 48 hours. Then reaction mixture was concentrated and diluted with water. The biphasic mixture was transferred into a separatory funnel and extracted with DCM. Organic extract was washed with water, dried, filtered, and concentrated. The product was purified by crystallization from etha- nol/water to yield in a colorless solid (18.4 g, 86.7 mmol, 81 %).
With sodium acetate; In N,N-dimethyl-formamide; at 100℃; for 5.0h;
Step 2: Synthesis of 2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one. To a solution of 2-((dimethylamino)methylene)cyclohexane-l,3-dione (0.5 g, 2.9 mmol) in DMF (2mL) was added sodium acetate (0.39 g, 4.7 mmol) and methyl carbamimidothioate (0.9 g, 3.5 mmol). The reaction mixture was heated at 100 0C for 5 hours. On completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL). The organic layer was separated and washed with water (2 X 30 mL). The solvent was then removed under reduced pressure and the residue dissolved in EtOAc (50 mL) and washed with water (2 x 30 mL). The organic layer was dried using sodium sulfate and concentrated under reduced pressure to give the desired product (0.5 g, 86%) as a solid. 1H NMR (CDCl3, 400MHz): delta 8.94 (s, IH), 3.01 (t, J = 6 Hz, 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.58 (s, 3H), 2.14 (quintet, J = 6.2 Hz, 2H); LCSM [M+H]: 195.
A.3
To a solution of 0.73 g (5 mmol) of Compound 38 in water (30 mL) are added 1.41 g (5 mmol) of S-methylpseudothiourea and 0.20 g (5 mmol) of sodium hydroxide pellets. The reaction is stirred at 50° C. for 3 h. The reaction mixture is filtered and washed with water (5 mL). The solid is dried under reduced pressure at 40° C. The solid is melted at 220° C. to give 0.48 g of Amine I as a grey solid. Yield 57%; ES-MS: m/z 168 [M+H].
With potassium carbonate; In water; at 25.0℃;Reflux;
General procedure: Acetylacetone (50.0 g, 0.5 mol) and K2CO3 (138.0 g, 1.0 mol) were dissolved in H2O (250 mL). O-Methylisourea sulfate (61.5 g, 0.25 mol) was added and the reaction mixture was refluxed with stirring. After cooling, more K2CO3 (70 g) was added and the reaction mixture was left at 25 C for 48 h. The formed oil was separated, combined with the ether, extracted with the aqueous phase, and dried over MgSO4. The organic layer was concentrated in vacuo. Vacuum distillation gave 7a (48.3 g, 70%) as a yellow oil.
With sodium methylate In methanol for 12h; Reflux;
21 2-(Methylthio)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one
To a solution of sodium methoxide (62.8 mg, 1.16 mmol) in MeOH (5 mL) were added Ethyl 4-oxotetrahydro-2H-pyran-3-carboxylate (100 mg, 0.58 1 mmol) and methyl carbamimidothioate (78.5. mg, 0.872 mmol). The mixture was refluxed lbr 12 hrs. LCMS showed the reaction was completed. The solution was concentrated to give the crude product, which was purified byprep-TLC to give the titel compound (52 mg, yield: 45.2%). ‘H NMR (400 MHz, MeOH) ö 4.44 (2H, s), 3.92 (2H, t, J=5.6 Hz), 2.64 (2 H, t, J=5.6 Hz), 2.54 (3H, s).
With potassium hydroxide; In water; at 0 - 65℃; for 1.66667h;
A round bottom flask containing ethyl formate (6 mL, 0.062 mol) and ethyl ether (30 mL) was placed in an ice water bath, Na (1.4 g, 0.062 mol) was added under stirring, and then methyl 2-methoxyacetate (6.5 g, 0.062 mol) was added dropwise. The mixture was stirred at room temperaturefor 4 h. The reaction was quenched by addition of ice water (25 mL), and the aqueous phase was separated. To the water layer, S-methyl isothiourea (5.6 g, 0.062 mol) and KOH (2.2 g, 0.062 mol) were added within 40 min, and then heated to 65 C for 1 h. After cooling, the reaction mixture was neutralized with 37% HCl. The crude product was collected by vacuum filtration, and then recrystallized with 95% ethanol to afford 2 as a white needle crystal (4.3 g, 40.1% yield). m.p. 193-195 C.The intermediate 2 (1.7 g, 0.01 mol) was added slowly into POCl3 (4.6 g, 0.03 mol) in ice-water bath, and then the mixture was heated to 80 C for 1 h until the reaction was completed. The reaction mixture was cooled to room temperature and neutralized with 25% ammonia water. The precipitated solid was filtered and recrystallized with petroleum ether, decolorized by activated carbon. The intermediate 3 was obtained as a light yellow solid (1.8 g, 95.2% yield). m.p. 74-75 C. The intermediate 3 was dissolved in methanol (10 mL), 50% hydrated hydrazine solution (1.6 g, 0.015 mol) was added dropwise in an ice-water bath. Then the mixture was heated to 50 C and monitored by TLC until the reaction was finished. After cooling, the solvent was removed under reduced pressure, and the solid was recrystallized from ethyl acetate and petroleum ether to afford 5-methoxy-2-(methylthio) pyrimidin-4-yl hydrazine (4, 1.1 g, 96.2%yield). m.p. 112-114 C.
With sodium hydroxide; In ethanol; at 90℃; for 2.0h;Inert atmosphere; Microwave irradiation;
To a solution of ethyl 4, 4, 4-trifluoro-3-oxobutanoate (2g, 10.9mmol) and methyl carbamimidothioate (4g, 21.3mmol) in EtOH (10mL) was added 10N NaOH solution (2mL) dropwise under N2 atmosphere. The reaction mixture was microwaved at 90 for 2hrs. The reaction mixture was cooled to room temperature, then solvents were evaporated in vacuo. The residue was dissolved in H2O and acidified to PH2.0 with 1N HCl, then extracted by DCM 3 times. The organic layer was combined, washed with brine, dried over Na2SO4 and further purified by recrystalization with DCM/PE to give 1.8g of 2- (methylthio) -6- (trifluoromethyl) pyrimidin-4-ol as a white solid (43-01) (8.5mmol, 78) . 1H NMR (400 MHz, DMSO) : δ 6.59 (s, 1H) , 2.51 (s, 3H) .
1000 g of methyl formylacetate (compound of formula V in R is methyl) was diluted with 5 L of ethanol, and the solution of 510 g of methyl thiomethylisothiourea in 2.5 L of methanol was slowly dropped and reacted at 10C for 3 to 5 hours. The residue was washed with hot water and adjusted to pH 4 to 5 with acetic acid. After cooling, the solid was precipitated and filtered. The filter cake was washed with water and recrystallized from water to give 772 g of beige-like crystals in a yield of 96percent I.e. compounds of formula II.
A solution of 1000 g of n-propyl formylacetate (compound of formula V wherein R is n-propyl) was diluted with 5 L of isopropanol, and 510 g of isopropyl alcohol thiomethylisothiourea was slowly added dropwise, 35 °C for 5-8h. The residue was washed with water, and the residue was washed with water, and the residue was washed with water. Recrystallization from water gave 780.5 g of beige needle-like crystals in a yield of 97percent, i.e., the compound of formula II
1000 g of isopropyl formylacetate(Compound of formula V in which R is isopropyl) was diluted with 5 L of methanol, cooled slowly, and 510 g of thiomethylisothiourea was slowly added dropwise to a solution of 2.5 L of methanol at 25 °Cfor 3 to 5 hours. The residue was washed with water, and the residue was washed with water, and the residue was washed with water. The crystals were recrystallized to give 748 g of beige-like crystals in a yield of 93percent, and the residue was washed with water, I.e. compounds of formula II
1000 g of n-butyl formylacetate (compound of formula V wherein R is n-butyl) was cooled with 5 L of ethanol, and 510 g of thiomethylisothiourea was slowly added dropwise to a solution of 3.5 L of ethanol at 25 °C for 3 to 5 hours. The residue was washed with water, and the residue was washed with water, and the residue was washed with water. The crystals were recrystallized to give 748 g of beige-like crystals in a yield of 93percent, and the residue was washed with water, I.e. compounds of formula II.
1000 g of isobutyl formylacetate (compound of formula V wherein R is isobutyl) was diluted with 5 L of ethanol, cooled dropwise, and 510 g of thiomethylisothiourea was slowly added dropwise to a solution of 3.5 L of ethanol at 25C for 3 to 5 hours. The residue was washed with water, and the residue was washed with water, and the residue was washed with water. The crystals were recrystallized to give 748 g of beige-like crystals in a yield of 93percent, and the residue was washed with water, I.e. compounds of formula II.
A solution of 1000 g of t-butyl formylacetate (R is t-butyl compound of formula V) was diluted with 5 L of ethanol, and the solution of 510 g of thiomethylisothiourea in 3.5 L of ethanol was slowly dropped and reacted at 25C for 3 to 5 hours. The residue was washed with water, and the residue was washed with water, and the residue was washed with water. The crystals were recrystallized to give 748 g of beige-like crystals in a yield of 93percent, and the residue was washed with water, I.e. compounds of formula II.
A solution of 1000 g of ethyl formylacetate (compound of formula V in R is ethyl) was diluted with 5 L of methanol, and the solution of 510 g of thiomethylisothiourea in 3 L solution was slowly dropped and reacted at 5C for 3 hours. The residue was washed with water and the residue was washed with hot water. The acid was acidified to pH = 4. The solid was precipitated after cooling. The filter was washed with water and recrystallized from water to give 764 g of beige seed crystals in a yield of 94.9percent Compounds of formula II.
Take the mother herb (11g) dissolved150 mL of DMF was addedS-methylisothiourea sulfuric acid (50 g) was added to the mixture140 , reaction 5h,TLC tracking. Recovery solvent, add sodium chloride aqueous solution for salting out, and then alkalized with sodium bicarbonate, immediately a large number of crystal precipitation, put the refrigerator, filter ash to get purple crystal. The crystals were recrystallized from methanol to give 17 g of white crystals having a melting point of 214-215 C.
7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; sodium; In methanol; at 15℃; for 30h;
A suspension of MeOH (1000 mL) and Na (22.0 g, 957 mmol, 22.7 mL) was stirred for 30 min. To this mixture was added ethyl l-benzyl-3-oxo-piperidine-4-carboxylate (50 g, 191 mmoland 2-methylisothiourea (47.9 g, 344 mmol, 0.5 H2SO4) at 15 C. The reaction mixture was stirred at 15 C for 30 hours. The reaction mixture was acidified by HC1 (2 M) (300 mL) until pH=6 and concentrated under reduced pressure. The residue was suspended in 200 mL of water and stirred rapidly. The suspension was filtered and the white solid collected and washed with ethyl acetate. 7-benzyl-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-ol (68 g, 151 mmol, 79.1 % yield, 64.0 % purity) was obtained as a white solid.
tert-butyl 4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; sodium methylate; In methanol; at 25℃; for 16h;Inert atmosphere;
To a stirred solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-l,4-dicarboxylate (50.0 g, 184 mmol, 1.00 eq) in MeOH (1.00 L) at 25 °C under nitrogen was added NaOMe (49.8 g, 921 mmol, 5.00 eq), followed by 2-methylisothiourea (62.4 g, 331 mmol, 1.80 eq, H2SO4) as a solid. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was adjusted to pH 5 with HC1 (2 M), and the mixture was concentrated under reduced pressure to removed MeOH. The residue was suspended in 300 mL of ethyl acetate and 300 mL of water and stirred rapidly. The suspension was filtered and the white solid was collected. The filtrate was separated and the organic layer was washed with water (1 chi 300 mL) and brine (1 chi 200 mL). The combined organic layers were isolated, dried over Na2SC"4, filtered and concentrated to provide tert-butyl 4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7- carboxylate (51.0 g, 138 mmol, 75.4 percent yield, 81.0 percent purity) as a white solid which as used directly in the next step without further purification. ESI MS m/z 298.2 [M+H]+.
With triethylamine; sodium hydroxide; In dichloromethane; at 0℃; for 4h;
CH2Cl2 (5 ml) and triethylamine (TEA) (250 l, 1.79mmol) were added to a rapidly stirred solution of Smethylisothioureahemisulfate (500 mg, 3.59 mmol) inNaOH 1N (2.5 ml). The mixture was cooled to T=0C on an ice bath, and a solution of di-tert-butyl dicarbonate (783.5mg, 3.59 mmol) in CH2Cl2 (2 ml) was added dropwise over 3h. Upon completion of the addition, the mixture was stirredan additional hour, diluted with 1 mL of CH2Cl2, and HCl 1Nwas added until pH 4. The organic layer was extracted withacidic water, and the aqueous layer was separated from theorganic phase and neutralized with NaOH 1N; CH2Cl2 (1 ml)was added and the aqueous phase was extracted twice. Theorganic layers were separated, dried over sodium sulfate,filtered and concentrated under reduced pressure. Diethylether was added and the solvent was evaporated under vacuumtwice. The compound purity was verified by HPLCanalysis as described above. The qualitative analysis of theproduct was finally confirmed by ESI-MS. The product wasthen used directly in the next step. (377 mg, 55 %)1H NMR (200 MHz, DMSO-d6): 1.39 (s, 9H), 2.45 (s,3H).13C NMR (50 MHz, DMSO-d6): 13.8, 27.8, 79.2, 157.3,161.4.ESI-MS m/z =191 [M+H] +
2-(methylthio)-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With sodium acetate; In N,N-dimethyl-formamide; at 70℃; for 1h;
General procedure: A mixture of ethyl 2-cyano-3-phenylacrylate (1a) (Husseinet al. 1985) or ethyl 2-cyano-3-ethoxybutenoate (1b) (Yanget al. 2012) (10 mmol), S-methylisothiourea sulfate (11.0mmol), and anhydrous sodium acetate (2.0 g, 24.4 mmol) inDMF (1 ml) was heated at 70 C for 1 h. The reactionmixture was poured onto ice-cold H2O and the formedprecipitate was filtered and crystallized from EtOH (Husseinet al. 1985; Abdel-Aziz et al. 2011).2-(Methylthio)-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (2a) Yield 40%; mp 140-142 C; IR v/cm-1:3427 (NH), 2227 (C≡N), 1557 (C=N), 1495 (C=C-Ar); 1HNMR(DMSO-d6, 400MHz) δ/ppm: 8.31 (s, br, 1H, NH),2.25 (s, 3H, S-CH3), 2.11 (s, 3H, CH3) (Hussein et al. 1985).
With N-ethyl-N,N-diisopropylamine In acetonitrile at 25℃; for 48h; Alkaline conditions;
4.1.4. General synthesis steps for 8a 8z
To a mixture of 2-methyl-2-thiopseudourea sulfate (1.0 eq), DIPEA(3.0 eq) and acetonitrile (50 mL), isocyanate or chloroformate (3.0 eq)were added dropwise. The mixture was stirred for 48 h at 25 C. Afterthat, the solvent was removed. EtOAc (30 mL) and water (30 mL) wereused to extract product. The organic phase was washed with saturatedNaCl solution twice and dried over Na2SO4. After filtration and concentration,the received product was purified by silica gel chromatography.Target compounds were received after purification with silica gelchromatography.1,3-Bis(ethylaminocarbonyl)-2-methyl-2-thioisourea (8a). White oil(510 mg, 98.0% yield). 1H NMR (400 MHz, CDCl3) 12.59 (s, 1H), 5.40(d, J = 76.0 Hz, 2H), 3.27 (m, J = 13.8, 7.0 Hz, 4H), 2.31 (s, 3H), 1.16(dt, J = 15.4, 7.6 Hz, 6H). ESI-MS: m/z [M + H]+ calcd for C8H17N8O2S+233.11, found 232.79.
98%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 25℃; for 48h; Alkaline conditions;
4.1.4. General synthesis steps for 8a 8z
To a mixture of 2-methyl-2-thiopseudourea sulfate (1.0 eq), DIPEA(3.0 eq) and acetonitrile (50 mL), isocyanate or chloroformate (3.0 eq)were added dropwise. The mixture was stirred for 48 h at 25 C. Afterthat, the solvent was removed. EtOAc (30 mL) and water (30 mL) wereused to extract product. The organic phase was washed with saturatedNaCl solution twice and dried over Na2SO4. After filtration and concentration,the received product was purified by silica gel chromatography.Target compounds were received after purification with silica gelchromatography.1,3-Bis(ethylaminocarbonyl)-2-methyl-2-thioisourea (8a). White oil(510 mg, 98.0% yield). 1H NMR (400 MHz, CDCl3) 12.59 (s, 1H), 5.40(d, J = 76.0 Hz, 2H), 3.27 (m, J = 13.8, 7.0 Hz, 4H), 2.31 (s, 3H), 1.16(dt, J = 15.4, 7.6 Hz, 6H). ESI-MS: m/z [M + H]+ calcd for C8H17N8O2S+233.11, found 232.79.
With N-ethyl-N,N-diisopropylamine In acetonitrile at 25℃; for 48h; Alkaline conditions;
4.1.4. General synthesis steps for 8a 8z
General procedure: To a mixture of 2-methyl-2-thiopseudourea sulfate (1.0 eq), DIPEA(3.0 eq) and acetonitrile (50 mL), isocyanate or chloroformate (3.0 eq)were added dropwise. The mixture was stirred for 48 h at 25 C. Afterthat, the solvent was removed. EtOAc (30 mL) and water (30 mL) wereused to extract product. The organic phase was washed with saturatedNaCl solution twice and dried over Na2SO4. After filtration and concentration,the received product was purified by silica gel chromatography.Target compounds were received after purification with silica gelchromatography.1,3-Bis(ethylaminocarbonyl)-2-methyl-2-thioisourea (8a). White oil(510 mg, 98.0% yield).
81.8%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 25℃; for 48h; Alkaline conditions;
4.1.4. General synthesis steps for 8a 8z
General procedure: To a mixture of 2-methyl-2-thiopseudourea sulfate (1.0 eq), DIPEA(3.0 eq) and acetonitrile (50 mL), isocyanate or chloroformate (3.0 eq)were added dropwise. The mixture was stirred for 48 h at 25 C. Afterthat, the solvent was removed. EtOAc (30 mL) and water (30 mL) wereused to extract product. The organic phase was washed with saturatedNaCl solution twice and dried over Na2SO4. After filtration and concentration,the received product was purified by silica gel chromatography.Target compounds were received after purification with silica gelchromatography.1,3-Bis(ethylaminocarbonyl)-2-methyl-2-thioisourea (8a). White oil(510 mg, 98.0% yield).
With N-ethyl-N,N-diisopropylamine In acetonitrile at 25℃; for 48h; Alkaline conditions;
4.1.4. General synthesis steps for 8a 8z
General procedure: To a mixture of 2-methyl-2-thiopseudourea sulfate (1.0 eq), DIPEA(3.0 eq) and acetonitrile (50 mL), isocyanate or chloroformate (3.0 eq)were added dropwise. The mixture was stirred for 48 h at 25 C. Afterthat, the solvent was removed. EtOAc (30 mL) and water (30 mL) wereused to extract product. The organic phase was washed with saturatedNaCl solution twice and dried over Na2SO4. After filtration and concentration,the received product was purified by silica gel chromatography.Target compounds were received after purification with silica gelchromatography.1,3-Bis(ethylaminocarbonyl)-2-methyl-2-thioisourea (8a). White oil(510 mg, 98.0% yield).
62%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 25℃; for 48h; Alkaline conditions;
4.1.4. General synthesis steps for 8a 8z
General procedure: To a mixture of 2-methyl-2-thiopseudourea sulfate (1.0 eq), DIPEA(3.0 eq) and acetonitrile (50 mL), isocyanate or chloroformate (3.0 eq)were added dropwise. The mixture was stirred for 48 h at 25 C. Afterthat, the solvent was removed. EtOAc (30 mL) and water (30 mL) wereused to extract product. The organic phase was washed with saturatedNaCl solution twice and dried over Na2SO4. After filtration and concentration,the received product was purified by silica gel chromatography.Target compounds were received after purification with silica gelchromatography.1,3-Bis(ethylaminocarbonyl)-2-methyl-2-thioisourea (8a). White oil(510 mg, 98.0% yield).
1,3-bis(heptyloxycarbonyl)-2-methyl-2-thioisourea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.9%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 25℃; for 48h; Alkaline conditions;
4.1.4. General synthesis steps for 8a 8z
General procedure: To a mixture of 2-methyl-2-thiopseudourea sulfate (1.0 eq), DIPEA(3.0 eq) and acetonitrile (50 mL), isocyanate or chloroformate (3.0 eq)were added dropwise. The mixture was stirred for 48 h at 25 C. Afterthat, the solvent was removed. EtOAc (30 mL) and water (30 mL) wereused to extract product. The organic phase was washed with saturatedNaCl solution twice and dried over Na2SO4. After filtration and concentration,the received product was purified by silica gel chromatography.Target compounds were received after purification with silica gelchromatography.1,3-Bis(ethylaminocarbonyl)-2-methyl-2-thioisourea (8a). White oil(510 mg, 98.0% yield).
88.9%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 25℃; for 48h; Alkaline conditions;
4.1.4. General synthesis steps for 8a 8z
General procedure: To a mixture of 2-methyl-2-thiopseudourea sulfate (1.0 eq), DIPEA(3.0 eq) and acetonitrile (50 mL), isocyanate or chloroformate (3.0 eq)were added dropwise. The mixture was stirred for 48 h at 25 C. Afterthat, the solvent was removed. EtOAc (30 mL) and water (30 mL) wereused to extract product. The organic phase was washed with saturatedNaCl solution twice and dried over Na2SO4. After filtration and concentration,the received product was purified by silica gel chromatography.Target compounds were received after purification with silica gelchromatography.1,3-Bis(ethylaminocarbonyl)-2-methyl-2-thioisourea (8a). White oil(510 mg, 98.0% yield).