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Structure of 80-48-8 * 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.
22.3 g (250 mmol) of dimethylaminoethanol and 1 L of THF were placed in a four-necked flask (2 L), and the mixture was stirred at room temperature. 250 mL of a THF solution of 51.2 g (275 mol) of methyl tosylate was added dropwise and the mixture was stirred at room temperature for 24 hours. THF was distilled off, and the desired product was purified by recrystallization with 1 L of acetone. Colorless solid Yield 95percent.
Reference：
[1] Russian Chemical Bulletin, 1998, vol. 47, # 8, p. 1547 - 1549
[2] Tetrahedron Letters, 2009, vol. 50, # 28, p. 4092 - 4095
[3] Patent: JP5751578, 2015, B2, . Location in patent: Paragraph 0017
[4] European Journal of Medicinal Chemistry, 2009, vol. 44, # 12, p. 4970 - 4977
[5] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1988, vol. 37, p. 2293 - 2296[6] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1988, # 11, p. 2542 - 2545
37
[ 80-48-8 ]
[ 169205-95-2 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 1999, vol. 35, # 1, p. 84 - 86
38
[ 80-48-8 ]
[ 60832-72-6 ]
[ 169205-95-2 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 1999, vol. 35, # 1, p. 84 - 86
39
[ 80-48-8 ]
[ 160114-16-9 ]
[ 94055-76-2 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 20 - 60℃;
Add 5.0 g (15.95 mmol) of intermediate 3 to the reaction flask at 20~30 °C.5.94 g of p-toluenesulfonic acid methyl ester (31.91 mmol), stir to 50-60 ° C, react for 20-24 h, add 10 mL of acetone for 30 minutes, filter, filter cake and add 20 mL of acetone to recrystallize to obtain metformin. 6.8 g, yield 85.0
Reference：
[1] Patent: CN108440358, 2018, A, . Location in patent: Paragraph 0017; 0020; 0024
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 18, p. 3330 - 3336
40
[ 938058-83-4 ]
[ 80-48-8 ]
[ 77897-02-0 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 73, p. 10180 - 10183
41
[ 3262-72-4 ]
[ 80-48-8 ]
[ 86123-95-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With potassium hydroxide In toluene at 0 - 5℃; for 0.5 h; Stage #2: With tetrabutylammomium bromide In toluene at 0 - 5℃; for 8 h;
In a 1000 mL three-necked flask,400 mL of toluene and 40 g of N-tert-butoxycarbonyl-D-serine (Boc-D-serine)The stirring temperature was lowered to 0-5 ° C,36.5 g of 30percent potassium hydroxide solution was added dropwise.After stirring for 30 minutes,Then 72.65 g of methyl p-toluenesulfonate was added,Tetrabutylammonium bromide 4g,Then 43.68 g of 50percent potassium hydroxide solution was added dropwise.After reaction at 0-5 ° C for 8 hours,Add water 200mL and layered,The aqueous layer was washed with 100 mL of toluene,Discard the organic layer.The combined aqueous layers were then cooled to below 15 [deg.] C and acidified with 50percent phosphoric acid to pH = 2-3.5,Extraction with dichloromethane (200 mL * 3)The combined organic layers were added 30g of anhydrous sodium sulfate and stirred overnight.The next day filterThe filtrate was concentrated to dryness under reduced pressure,42.9 g of light yellow oil,Yield: 100percent, HPLC purity: 98.0percent, Chiral purity: 99.4percent.
Reference：
[1] Patent: CN106699595, 2017, A, . Location in patent: Paragraph 0036; 0037
42
[ 120511-74-2 ]
[ 80-48-8 ]
[ 120511-72-0 ]
Reference：
[1] Organic Preparations and Procedures International, 2008, vol. 40, # 5, p. 487 - 489
43
[ 755039-54-4 ]
[ 80-48-8 ]
[ 755039-55-5 ]
Yield
Reaction Conditions
Operation in experiment
93%
With potassium carbonate In acetone for 2 h; Reflux; Inert atmosphere
Step 11 (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one; (7R)-2-Chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one In (3.50 g, 12.50 mmol) was dissolved in 80 mL of acetone followed by the addition of methyl p-toluenesulfonate (3.40 g, 18.70 mmol) and potassium carbonate (3.45 g, 25 mmol). The resulting mixture was heated to reflux for 2 hours with stirring and then cooled down to room temperature. The reaction mxiture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o (3.40 g, yield: 93.0percent) as a white solid. MS m/z (ESI): 295.4 [M+1]
93%
With potassium carbonate In acetone for 2 h; Reflux
Step 11 (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one (7R)-2-Chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one 1n (3.50 g, 12.50 mmol) was dissolved in 80 mL of acetone followed by the addition of methyl p-toluenesulfonate (3.40 g, 18.70 mmol) and potassium carbonate (3.45 g, 25 mmol). The resulting mixture was heated to reflux for 2 hours with stirring and then cooled down to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o (3.40 g, yield: 93.0percent) as a white solid.MS m/z (ESI): 295.4 [M+1]
With tetrabutylammomium bromide; potassium hydroxide In toluene at -1 - 2℃;
Toluene (820 mL), Intermediate III (50 g), methyl p-toluenesulfonate (63.5 g),Tetrabutylammonium bromide (5.4 g) was added and the mixture was cooled with stirring to -1 to 2 ° C. Potassium hydroxide aqueous solution (40 g / 34 mL) was added at -1 to 2 ° C, and the addition was completed in about 5 minutes. The addition was complete, continue to control the temperature at -1 ~ 2 reaction 4 ~ 4.5 hours (TLC detection or HPLC control) to stop the reaction. After completion of the reaction, water (400 mL) was added to separate the layers. Organic layer followed by 5percent phosphoric acid, saturated sodium bicarbonate, water each200mL wash. Decompression 40 ~ 45 ° C The solvent was evaporated to give an oil, the reaction was used directly for the next step. HPLC purity 95percent, chiral Purity 99.1percent.
60.97g
With tetrabutylammomium bromide; potassium hydroxide In water; toluene at 20℃; for 3 h;
Toluene (330 mL) was added sequentially to the 1 L reaction flask,The compound of formula II (20.00 g, 68 mmol)P-toluenesulfonic acid methyl ester (63.50 g, 340 mmol),Tetrabutylammonium bromide (2.63 g, 8.16 mmol),Stir evenly,An aqueous solution of potassium hydroxide (16.00 g of potassium hydroxide + 16 mL of water) was added at room temperature,Plus complete, room temperature reaction 3 hours.Reaction completed, adding water (160mL), stirring 5min, standing stratification, liquid separation,Organic layer followed by 5percent phosphoric acid(80 mL), water (160 mL x 2), and the organic layer was concentrated at 55 ° C under reduced pressure. The solvent was evaporated to give 60.97 g of an oil.The product of this example was the same as in Example 1 by isolation and identification.
38.5 g
With tetrabutylammomium bromide; sodium hydroxide In water at 20℃; for 3 h;
To a 1L reaction flask were sequentially added toluene (330 mL), Compound II (20.00 g, 68 mmol), methyl p-toluenesulfonate (38.10 g, 204 mmol), tetrabutylammonium bromide (2.63 g, 8.16 mmol), Stir well, add aqueous sodium hydroxide solution (16.00g of sodium hydroxide + 16mL of water) at room temperature, complete the addition, and react at room temperature for 3 hours. After the reaction is complete, add water (160 mL), stir for 5 min, stand for layering, separate the liquid, and use 5percent phosphoric acid in order for the organic layer.(80 mL) and water (160 mL×2) were washed. The organic layer was concentrated under reduced pressure at 55° C., and the solvent was evaporated to give 38.5 g of an oil.
38.5 g
With tetrabutylammomium bromide; sodium hydroxide In water; toluene at 20℃; for 3 h;
Toluene (330 mL) was added sequentially to a 1L reaction flask,Compound II (20.00 g, 68 mmol),Methyl p-toluenesulfonate (38.10 g, 204 mmol),Tetrabutylammonium bromide (2.63 g, 8.16 mmol),Stir well,An aqueous solution of sodium hydroxide (16.00 g of sodium hydroxide + 16 mL of water) was added at room temperature.After the addition, the reaction was carried out at room temperature for 3 hours.After the reaction is complete, add water (160 mL) and stir for 5 min.Static stratification, liquid separation,The organic layer was successively washed with 5percent phosphoric acid (80 mL) and water (160 mL×2), and the organic layer was concentrated under reduced pressure at 55° C.After the solvent was distilled off, 38.5 g of an oil was obtained.
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 17, p. 6875 - 6898
47
[ 80-48-8 ]
[ 400827-68-1 ]
[ 400827-64-7 ]
Yield
Reaction Conditions
Operation in experiment
74.3%
Stage #1: for 12 h; Reflux Stage #2: With pyridine; phosphorus pentachloride In dichloromethane at -10 - -5℃; for 2 h; Stage #3: With hydrogenchloride In dichloromethane; 2-methyl-propan-1-ol; acetone at 25 - 30℃;
A glass round bottom flask was charged with 35g (51,7 mmol) of 5-Thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid, 8-oxo-7-[(2-phenylacetyl)amino]-3-[[4-(4-pyridinyl)-2-thiazolyl]thio]-, diphenylmethyl ester, (6R,7R) and 75 mE of dichloromethane, at 25°C. To the obtained solution were added 48 mE (258,5 mmol) of methyl paratoluenesulphonate and the mixture was heated to reflux and maintained for 12 hours under reflux, then cooled to room temperature. In glass lined reactor were charged 32,3 g (155,1 mmol) of phosphorous pentachloride and 75 mE of dichloromethane. The obtained suspension was cooled to -5÷0°C and 12.3 g (155,1 mmol)of pyridine were added dropwise by maintaining the temperature at -5÷0°C, then the mixture was maintained under stifling for 15 minutes at the same temperature. To the mixture, cooled to -1 0÷-5°C, was carefully added the solution prepared in the round bottom flask, keeping the temperature between -1 0÷-5°C; the mixture thus obtained was maintained under stifling for 2 hours at the same temperature. 105 mE of isobutanol were carefully added, in about 30 minutes, by maintaining the temperature at -5°C0°C; the obtained mixture was heated at 28÷30°C and left to react at the same temperature for 3.5 hours. The mixture was concentrated under vacuum to 1/3 of its volume, diluted with 200 mE of acetone and maintained under stifling for 1 hour at 25÷30°C. 70 mE of 32percent hydrochloric acid were added, keeping the temperature in the range of 25÷30°C, and themixture was maintained under stirring overnight. The obtained suspension was filtered, the cake was washed with acetone (2 x 35 ml). The wet solid was dried under vacuum at 40°C overnight yielding 18.4 g (38,4 mmol) of 4-[2- [[(6R,7R)-7-amino-2-carboxy-8-oxo-5-thia- 1- azabicyclo [4.2.01 oct-2-en-3-yl]thio] -4-thiazolyl] -1 -methyl pyridinium, chloride, hydrochloride (1:1:1) as a crystalline solid. Yield 74,3percent.
5-Bromo-l, 2, 3, 4-tetrahydro-2-methyl-8-nitroisoquinoline (HI); <strong>[63927-23-1]5-Bromo-8-nitroisoquinoline</strong> (II, 5 g, 19.7 mmol) was suspended in anhydrous DMF (20 niL) under nitrogen atmosphere and the mixture was heated until the isoquinoline was dissolved completely. Methyl-p-toluenesulphonate (4 g, 21.5 mmol) was added dropwise, whereafter heated at 85C for 24 hours. After cooling in an ice bath, the solid was collected by filtration and washed with ether and acetone to give the isoquinolinium salt (used without further purification).
In N,N-dimethyl-formamide; at 85℃; for 24h;
<strong>[63927-23-1]5-Bromo-8-nitroisoquinoline</strong> (H, 5 g, 19.7 mmol) was suspended in anhydrous DMF (20 mL) under nitrogen atmosphere and the mixture was heated until the isoquinoline was dissolved completely. Methyl-p-toluenesulphonate (4 g, 21.5 mmol) was added dropwise, 5 whereafter heated at 85C for 24 hours. After cooling in an ice bath, the solid was collected by filtration and washed with ether and acetone to give the isoquinolinium salt (used without further purification)
With triethanolamine; boron tribromide; In methanol; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; acetonitrile;
A. Preparation of 5-(2-chloroethoxy)-2-methylthio-benzothiazole To a 250 mL flask was added <strong>[55690-60-3]2-mercapto-5-methoxybenzothiazole</strong> (5.1 g, 26 mmol), MeCN (63 mL), methyl p-toluenesulfonate (4.8 g, 26 mmol) and TEA (4.4 mL, 31 mmol). After stirring 16 h at ambient temperature, the solution was concentrated under reduced pressure. The crude material was diluted with EtOAc (200 mL), washed with water (2*75 mL), dried over Na2SO4, filtered, and concentrated. The resulting viscous oil was dissolved in DCM (40 mL), and transferred to an argon-purged 250 mL flask. The solution was cooled to -78 C. prior to the addition of a 1.0 M BBr3 solution in DCM (64 mL). The reaction suspension was allowed to warm to room temperature. After 16 h the reaction solution was cooled to -78 C. and quenched by addition of MeOH (100 mL). The resulting precipitates were isolated by vacuum filtration to yield 5-hydroxy-2-methylthio-benzothiazole (3.9 g, 76%) as a white solid.
3-methyl-6-nitrobenzothiazolium p-toluenesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Preparation of 3-methyl-<strong>[2942-06-5]6-nitrobenzothiazol</strong>ium p-toluenesulfonate (2). See FIG. 3A A mixture of 1 g of <strong>[2942-06-5]<strong>[2942-06-5]6-nitrobenzothiazol</strong>e</strong> (1) and 1.2 g of methyl-p-toluenesulfonate was heated to 140 C. for 20 min. The mixture was allowed to cool to room temperature, and the resulting solid was washed with acetone and filtered to provide 1.1 g of 2, as a bluish solid.
Preparation of 3-methyl-<strong>[2942-06-5]6-nitrobenzothiazol</strong>ium p-toluenesulfonate 2 See FIG. 3A. A mixture of <strong>[2942-06-5]<strong>[2942-06-5]6-nitrobenzothiazol</strong>e</strong> (1 g) and methyl-p-toluenesulfonate (1.2 g) was heated to 140 C. for 20 min. The solid was washed with acetone and filtered to provide a bluish solid (1.1 g).
3-methyl-2-(methylthio)-[1,3]benzooxazol-3-ium tosylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetone;
The 2-mercaptobenzoxazole (20 g, 132 mmol) is refluxed in 300 mL of acetone with 18.3 g (133 mmol) of potassium carbonate and 24 g (169 mmol) of methyl iodide for 2 hours to obtain 21 g of 2-methylthiobenzoxazole (2B) which then is heated with 24.5 g (132 mmol) of methyl tosylate at 160 C. for one hour to obtain 32.7 g of 2A.
3-(β-hydroxyethyl)-1-methylpyridinium p-toluenesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
REFERENCE EXAMPLE 16 3-(beta-Hydroxyethyl)-1-methylpyridinium p-toluenesulfonate The procedures of Reference Example 10 were repeated using 1.00 g of 3-pyridinethanol and 1.51 g of methyl p-toluenesulfonate to give 2.51 g of the desired compound. 1 H NMR (DMSO-d6) delta: 2.36 (s, 3H), 3.00 (t, 2H), 3.84 (t, 2H), 4.34 (s, 3H), 7.1-8.8 (m, 8H). IR (KBr) cm-1: 3400, 3050, 2925, 1500, 1300, 1210, 1180, 1120, 1030, 1000, 810, 670.
1,1-dimethyl-2-hydroxymethylpyrrolidinium p-toluenesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetone;
REFERENCE EXAMPLE 3 1,1-Dimethyl-2-hydroxymethylpyrrolidinium p-toluenesulfonate In 10 ml of acetone was dissolved 1.47 g of 1-methyl-2-pyrrolidinemethanol, and 2.38 g of methyl p-toluenesulfonate was added dropwise to the resulting solution. The mixture was stirred at room temperature, heated under reflux, and cooled to precipitate crystals. The crystals were collected by filtration and dried to give 2.67 g of the desired compound. 1 H NMR (DMSO-d6) delta: 1.5-2.2 (m, 4H), 2.28 (s, 3H), 2.94 (s, 3H), 3.17 (s, 3H), 3.3-3.9 (m, 5H), 5.25-5.5 (m, 1H), 6.95-7.6 (m, 4H). IR (KBr) cm-1: 3400, 3050, 2960, 2900, 1475, 1190, 1130, 1040, 1015, 820, 690, 575.
3-(3-hydroxy-1-propenyl)-1-methylpyridinium p-toluenesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetone;
In 30 ml of acetone 710 mg of 3-(3-pyridyl)-2-propen-1-ol and 980 mg of methyl p-toluenesulfonate were heated under reflux for 22 hours. The reaction mixture was subjected by decantation to remove the solvent and then washed with acetone and ether. The residue was dried under reduced pressure to give 1.3 g of the desired compound as an orange-colored oil. 1 H NMR (CD3 OD) delta: 2.34 (s, 3H), 4.28 (d, 2H), 4.34 (s, 3H), 6.7-6.8 (m, 2H), 7.1-8.9 (m, 8H). IR (neat) cm-1: 3350, 3050, 1700, 1500, 1440, 1360, 1290, 1210, 1180, 1115, 1030, 1000, 960, 815, 670.
1,1-Dimethyl-2-hydroxymethylpiperidinium p-toluenesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
REFERENCE EXAMPLE 4 1,1-Dimethyl-2-hydroxymethylpiperidinium p-toluenesulfonate The procedures of Reference Example 3 were repeated using 2.58 g of 1-methyl-2-piperidinemethanol and 3.72 g of methyl p-toluenesulfonate to give 4.95 g of the desired compound. 1 H NMR (CDCl3) delta: 1.3-1.9 (m, 6H), 2.32 (s, 3H), 3.04 (s, 3H), 3.1-3.6 (m, 2H), 3.36 (s, 3H), 3.7-4.0 (m, 2H), 5.34 (t, 1H), 7.0-7.8 (m, 4H). IR (KBr) cm-1: 3325, 2925, 1490, 1470, 1445, 1190, 1125, 1040, 1000, 810, 680, 560.
Step I 3,5-dimethyl-4-nitroanisole <strong>[5344-97-8]3,5-dimethyl-4-nitrophenol</strong> (33.43 g), methyl p-toluene sulfonate (40.97 g) and K2 CO3 (31.79 g) are stirred at reflux in 200 ml of acetone for four and one half hours and then stirred at R.T. overnight. The reaction mixture is filtered to give a dark amber filtrate. The filtrate is concentrated in vacuo to a yellowish brown solid which is dissolved in ethyl acetate washed with saturated aqueous sodium chloride, dried and concentrated in vacuo. The concentrate is distilled (87-104 C./0.10 mm) to give a yellow waxy looking solid. The solid is dissolved in hot ethanol and recrystallized, M.P. 50-52 C.
EXAMPLE 1 1-Methyl-5-nitroimidazole 24.2 G., (0.214 moles) of 4(5)-nitroimidazole is heated with 24.0 g. (0.11 mole) of methyl tosylate for 1 hour at 180-190 C. and cooled to give a hard solid. The mixture is shaken with 175 ml. of 2.5 N aqueous sodium hydroxide until it is dissolved and diluted with 175 ml. of water to give an oily precipitate. The mixture is extracted with ether; the ether extract washed with 2.5 N aqueous hydrochloric acid and water. The aqueous acid wash is treated with excess aqueous sodium hydroxide and extracted with ether. This latter ether extract is evaporated to dryness and recrystallized from petroleum ether to yield 1-methyl-5-nitroimidazole, m.p. 154-155 C.
3-Methyl-2-[(3-methyl-2-thiazolidinylidene)-methyl]-benzoxazolium iodide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; sodium iodide; In water; toluene;
A. 3-Methyl-2- [(3-methyl-2-thiazolidinylidene)-methyl]-benzoxazolium iodide A mixture of 2-methylbenzoxazole (13.3g), 4,5-dihydro-2-(methylthio)-thiazole (20.0g), and methyl p-toluene-sulphonate (55.9g) was heated in an oil-bath at 140 C for five hours. Pyridine (100 ml) was added, and the mixture was refluxed for 30 minutes. The solution was poured, with stirring into a solution of sodium iodide (72g) in water (150 ml), and the mixture was cooled. The resulting solid was filtered off and washed thoroughly with water. After drying, it was warmed with toluene and refiltered, and finally recrystallized from methanol. The product was obtained as pale cream-coloured crystals, m.p. 311-312C (decomp.).
3-Methyl-2-[(3-methyl-2-thiazolidinylidene)-methyl]-5-phenylbenzoxazolium iodide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; hydrogenchloride; sodium iodide; In water; toluene;
Example 2 3-Methyl-2- [(3-methyl-2-thiazolidinylidene)-methyl]-5-phenylbenzoxazolium iodide A mixture of 2-(methylthio)-5-phenylbenzoxazole (14.5 g), <strong>[2346-00-1]4,5-dihydro-2-methylthiazole</strong> (4.75 g), and methyl p-toluenesulphonate (28.0 g) was heated at 140C for four hours. Pyridine (50 ml) was added, and the mixture was refluxed for 40 minutes. The resulting solution was cooled and treated with water (100 ml), and the solid which separated was filtered off. The filtrate was treated with sodium iodide (30 g) and concentrated hydrochloric acid (50 ml). The precipitate was filtered off, washed with water, dried, warmed with toluene, and refiltered; it was finally crystallized from methanol to yield the product as pale yellow crystals, m.p. 262 - 264 C.
Step 2 - Preparation of Intermediate E <strong>[90322-32-0]5-Carboxy-2-methylbenzoxazole</strong> (8.9 g) and methyl- p -toluenesulfonate (11.16 g) were combined and heated to 200C with stirring for 10 minutes. The mixture became a brown liquid and mild boiling occured. The reaction was cooled to room temperature and the liquid solidified. Acetone (50 ml) was added, and with constant heating at reflux, the product was broken up with a spatula. The resulting slurry was heated at reflux for 15 minutes with rapid stirring and the off-white product was collected by filtration. This product was slurried again in refluxing acetone for 30 minutes, filtered, washed with ligroin P950, and dried to yield 9.3 g of 5-carboxy-2,3-dimethylbenzoxazolium p -toluene-sulfonate (Intermediate D).
In acetone;
Step 2 - Preparation of Intermediate H <strong>[90322-32-0]5-Carboxy-2-methylbenzoxazole</strong> (8.9 g) and methyl- p -toluenesulfonate (11.16 g) were combined and heated to 200C with stirring for 10 minutes. The mixture became a brown liquid and mild boiling occured. The reaction was cooled to room temperature and the liquid solidified. Acetone (50 ml) was added, and with constant heating at reflux, the product was broken up with a spatula. The resulting slurry was heated at reflux for 15 minutes with rapid stirring and the off-white product was collected by filtration. This product was slurried again in refluxing acetone for 30 minutes, filtered, washed with ligroin P950, and dried to yield 9.3 g of 5-carboxy-2,3-dimethylbenzoxazolium p -toluenesulfonate (Intermediate H).
PREPARATION 78; 4-Methoxymethyl-oxazole; Oxazol-4-yl-methanol (750 mg) was dissolved in anhydrous THF (38 mL) and the solution cooled to 0 C. Sodium hydride (365 mg, 9.1 mmol) was then added in small portions over 4 minutes, and after complete addition, the reaction was warmed to room temperature for 30 minutes. The reaction was re-cooled to 0 C. and methyltosylate (2.11 g) added in small portions. After complete addition the reaction was warmed to room temperature and stirred for 16 hours. The crude reaction mixture was pre-absorbed onto silica gel and then purified by ISCO combi-flash chromatography (SiO2; gradient elution of MeOH, 2 to 5% in DCM, 1% NH3) to afford the title compound (473 mg) as a pale yellow liquid.1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.41 (s, 3 H), 4.40 (s, 2 H), 7.61 (s, 1 H), 7.85 (s, 1 H)
[0160] A flame-fried three-neck flask (100 mL) was charged with <strong>[155742-48-6]oxazol-4-ylmethanol</strong> (1.0 mmol) and ethyl ether (15 mL). NaH (50 mg, 1.2 mmol) was added portions at 0 OC under nitrogen. After stirred for 30 minutes, methyl tosylate (250 mg, 1.2 mmol) was added. The suspension was stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give 4- (methoxymethyl)oxazoleas. LC/MS = 114 [M+l].
Step 4 (7R)-2-Chloro-7-ethyl-8-isopropyl-5-methyl-7H-pteridin-6-one The crude compound (7R)-2-chloro-7-ethyl-8-isopropyl-5,7-dihydropteridin-6-one 22c (12.10 g, 47.50 mmol) was dissolved in 180 mL of acetone followed by the addition of methyl p-toluenesulfonate (13.28 g, 71.30 mmol) and potassium carbonate (13.11 g, 95 mmol). The reaction solution was heated to reflux for 3 hours with stirring and filtered. The filtrate was concentrated under reduced pressure, added with 100 mL of water and extracted with dichloromethane (100 mL*3). The combined organic phase was washed with saturated sodium chloride solution (100 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-7-ethyl-8-isopropyl-5-methyl-7H-pteridin-6-one 22d (10.80 g, yield: 84.7%) as a white solid.
With potassium carbonate; In acetone; for 3h;Reflux; Inert atmosphere;
Step 4 (7R)-2-Chloro-7-ethyl-8-isopropyl-5-methyl-7H-pteridin-6-one; The crude compound (7R)-2-chloro-7-ethyl-8-isopropyl-5,7-dihydropteridin-6-one 22c (12.10 g, 47.50 mmol) was dissolved in 180 mL of acetone followed by the addition of methyl p-toluenesulfonate (13.28 g, 71.30 mmol) and potassium carbonate (13.11 g, 95 mmol). The reaction solution was heated to reflux for 3 hours with stirring and filtered. The filtrate was concentrated under reduced pressure, added with 100 mL of water and extracted with dichloromethane (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (100 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-7-ethyl-8-isopropyl-5-methyl-7H-pteridin-6-one 22d (10.80 g, yield: 84.7%) as a white solid.
With potassium carbonate; In acetone; for 3h;Reflux;
Step 4 (7R)-2-Chloro-7-ethyl-8-isopropyl-5-methyl-7H-pteridin-6-one The crude compound (7R)-2-chloro-7-ethyl-8-isopropyl-5,7-dihydropteridin-6-one 22c (12.10 g, 47.50 mmol) was dissolved in 180 mL of acetone followed by the addition of methyl p-toluenesulfonate (13.28 g, 71.30 mmol) and potassium carbonate (13.11 g, 95 mmol). The reaction solution was heated to reflux for 3 hours with stirring and filtered. The filtrate was concentrated under reduced pressure, added with 100 mL of water and extracted with dichloromethane (100 mL*3). The combined organic phase was washed with saturated sodium chloride solution (100 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-7-ethyl-8-isopropyl-5-methyl-7H-pteridin-6-one 22d (10.80 g, yield: 84.7%) as a white solid.
With tetrabutylammomium bromide; potassium hydroxide; In toluene; at -1 - 2℃;
Toluene (820 mL), Intermediate III (50 g), methyl p-toluenesulfonate (63.5 g),Tetrabutylammonium bromide (5.4 g) was added and the mixture was cooled with stirring to -1 to 2 ° C. Potassium hydroxide aqueous solution (40 g / 34 mL) was added at -1 to 2 ° C, and the addition was completed in about 5 minutes. The addition was complete, continue to control the temperature at -1 ~ 2 reaction 4 ~ 4.5 hours (TLC detection or HPLC control) to stop the reaction. After completion of the reaction, water (400 mL) was added to separate the layers. Organic layer followed by 5percent phosphoric acid, saturated sodium bicarbonate, water each200mL wash. Decompression 40 ~ 45 ° C The solvent was evaporated to give an oil, the reaction was used directly for the next step. HPLC purity 95percent, chiral Purity 99.1percent.
60.97g
With tetrabutylammomium bromide; potassium hydroxide; In water; toluene; at 20℃; for 3h;
Toluene (330 mL) was added sequentially to the 1 L reaction flask,The compound of formula II (20.00 g, 68 mmol)P-toluenesulfonic acid methyl ester (63.50 g, 340 mmol),Tetrabutylammonium bromide (2.63 g, 8.16 mmol),Stir evenly,An aqueous solution of potassium hydroxide (16.00 g of potassium hydroxide + 16 mL of water) was added at room temperature,Plus complete, room temperature reaction 3 hours.Reaction completed, adding water (160mL), stirring 5min, standing stratification, liquid separation,Organic layer followed by 5percent phosphoric acid(80 mL), water (160 mL x 2), and the organic layer was concentrated at 55 ° C under reduced pressure. The solvent was evaporated to give 60.97 g of an oil.The product of this example was the same as in Example 1 by isolation and identification.
38.5 g
With tetrabutylammomium bromide; sodium hydroxide; In water; at 20℃; for 3h;
To a 1L reaction flask were sequentially added toluene (330 mL), Compound II (20.00 g, 68 mmol), methyl p-toluenesulfonate (38.10 g, 204 mmol), tetrabutylammonium bromide (2.63 g, 8.16 mmol), Stir well, add aqueous sodium hydroxide solution (16.00g of sodium hydroxide + 16mL of water) at room temperature, complete the addition, and react at room temperature for 3 hours. After the reaction is complete, add water (160 mL), stir for 5 min, stand for layering, separate the liquid, and use 5percent phosphoric acid in order for the organic layer.(80 mL) and water (160 mL×2) were washed. The organic layer was concentrated under reduced pressure at 55° C., and the solvent was evaporated to give 38.5 g of an oil.
38.5 g
With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 20℃; for 3h;
Toluene (330 mL) was added sequentially to a 1L reaction flask,Compound II (20.00 g, 68 mmol),Methyl p-toluenesulfonate (38.10 g, 204 mmol),Tetrabutylammonium bromide (2.63 g, 8.16 mmol),Stir well,An aqueous solution of sodium hydroxide (16.00 g of sodium hydroxide + 16 mL of water) was added at room temperature.After the addition, the reaction was carried out at room temperature for 3 hours.After the reaction is complete, add water (160 mL) and stir for 5 min.Static stratification, liquid separation,The organic layer was successively washed with 5percent phosphoric acid (80 mL) and water (160 mL×2), and the organic layer was concentrated under reduced pressure at 55° C.After the solvent was distilled off, 38.5 g of an oil was obtained.
In a 1000 mL three-necked flask,400 mL of toluene and 40 g of N-tert-butoxycarbonyl-D-serine (Boc-D-serine)The stirring temperature was lowered to 0-5 C,36.5 g of 30% potassium hydroxide solution was added dropwise.After stirring for 30 minutes,Then 72.65 g of methyl p-toluenesulfonate was added,Tetrabutylammonium bromide 4g,Then 43.68 g of 50% potassium hydroxide solution was added dropwise.After reaction at 0-5 C for 8 hours,Add water 200mL and layered,The aqueous layer was washed with 100 mL of toluene,Discard the organic layer.The combined aqueous layers were then cooled to below 15 [deg.] C and acidified with 50% phosphoric acid to pH = 2-3.5,Extraction with dichloromethane (200 mL * 3)The combined organic layers were added 30g of anhydrous sodium sulfate and stirred overnight.The next day filterThe filtrate was concentrated to dryness under reduced pressure,42.9 g of light yellow oil,Yield: 100%, HPLC purity: 98.0%, Chiral purity: 99.4%.
1-(2,5-dichlorophenyl)-N,N,N-trimethylmethanaminium 4-methylbenzenesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With sodium hydrogencarbonate; In methanol; at 20℃;
General procedure: A flask was charged with NaHCO3, which was suspended in either MeOH or MeCN. The specified benzylamine was added, followed by methyl toluenesulfonate. After stirring the reaction at r.t. overnight, the solvent was removed and the precipitate was filtered off and washed with CH2Cl2. The combined filtrate and washings were concentrated under reduced pressure, redissolved in a minimum amountof CH2Cl2 and the product was precipitated by addition of Et2O. The precipitate was collected by filtration and washed with further Et2O. If further purification was necessary, it is stated accordingly.
With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; 5-norbornene-2-carbonitrile; caesium carbonate; In acetonitrile; at 20 - 100℃; for 15h;Inert atmosphere; Sealed tube;
Add Pd2 (dba) 3 (9.2 mg, 0.01 mmol, 0.05 equivalent) to a 25.0 mL reaction flask that is dry and equipped with a magnetic stir bar,Tris (furan-2-yl) phosphine (5.2 mg, 0.022 mmol, 0.11 equivalent), cesium carbonate (163 mg, 0.5 mmol, 2.5 equivalent), under the protection of an inert gas,2-cyano-5-norbornene (48 mg, 0.4 mmol, 2.0 equivalents),1-ethyl-2-iodobenzene (92.9 mg, 0.4 mmol, 2.0 equivalents),Methyl p-toluenesulfonate (74.5 mg, 0.4 mmol, 2.0 eq), tert-butyl acrylate (25.6 mg, 0.2 mmol, 1.0 eq) and dry acetonitrile (1.0 mL). The reaction flask was stirred at room temperature for about 5 minutes, after which the mixture was heated to 80 C and stirred for 15 hours. After the reaction vessel was cooled to room temperature, it was filtered through a short silica gel column, rinsed with ethyl acetate (10 mL), and concentrated under vacuum. Purified by column chromatography using petroleum ether: ethyl acetate = 50: 1 (v / v) as eluent to obtain compound I-1 (colorless oily liquid, yield 95%).; The aryl iodide used was <strong>[52522-99-3]5-iodo-2,4-dimethoxypyrimidine</strong> (106.4 mg, 0.4 mmol), the reaction temperature was 100 C, and other conditions were the same as in Example 1. Compound I-8 (yellow solid, Yield 69%)
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