* 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] Tetrahedron Letters, 1999, vol. 40, # 4, p. 747 - 748
[2] Synthesis, 1999, # 10, p. 1724 - 1726
[3] Synthetic Communications, 2000, vol. 30, # 16, p. 3047 - 3052
[4] Synthesis, 2001, # 3, p. 373 - 375
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 8, p. 722 - 723
[6] Synthetic Communications, 1999, vol. 29, # 23, p. 4235 - 4239
[7] Journal of Organic Chemistry, 1988, vol. 53, # 10, p. 2166 - 2170
[8] Chemical Communications, 2012, vol. 48, # 91, p. 11247 - 11249
2
[ 536-33-4 ]
[ 1531-18-6 ]
[ 3376-96-3 ]
[ 3376-95-2 ]
[ 1531-16-4 ]
Reference:
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 37, p. 8848 - 8858
3
[ 536-33-4 ]
[ 865-05-4 ]
[ 1531-18-6 ]
[ 3376-96-3 ]
[ 3376-95-2 ]
[ 1531-16-4 ]
Reference:
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 37, p. 8848 - 8858
4
[ 1531-18-6 ]
[ 536-33-4 ]
Yield
Reaction Conditions
Operation in experiment
67%
With sodiumsulfide nonahydrate In N,N-dimethyl-formamide at 130℃; for 2.5 h;
General procedure: Benzonitrile 1a (1 mmol), Na2S*9H2O (1.2 mmol) and DMF (1 mL) were added into a 10 mL bottle. The reactor was placed in a heating magnetic stirrer at 130 °C. After 2.5 h, by adding about 3 mL H2O after the reaction to disperse the solid product, the reaction mixture was extracted with EtOAc (3 x 3 mL), and the mixture was purified by column chromatography.
Reference:
[1] RSC Advances, 2018, vol. 8, # 1, p. 170 - 175
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6572 - 6582
[3] Heterocycles, 2018, vol. 96, # 3, p. 509 - 517
[4] Bulletin de la Societe Chimique de France, 1958, p. 687,691
[5] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 915,918; engl. Ausg. S. 898
5
[ 3376-95-2 ]
[ 536-33-4 ]
Yield
Reaction Conditions
Operation in experiment
35%
With Lawessons reagent In tetrahydrofuran at 20℃; for 48 h; Inert atmosphere
General procedure: THF (5ml/mmol) was added to a flask containing pyridine-4-carboxamide derivative (1 eq) at room temperature under inert atmosphere (argon) and stirring. Lawesson's reagent (1.5 eq) was added to the flask and the solution was stirred at room temperature for 48h-72h. The THF was evaporated under reduce pressure and the residue was partitioned between saturated aqueous NaHCO3 (25ml) and ethyl acetate (25ml) and extracted with ethyl acetate (2×25ml). The organic phase was dried over MgSO4 and eliminated under vacuum. The residue was further purified by flash chromatography (0–3percent MeOH:DCM, puriFlash 15-SI-HC 25G, over 45min). 5.1.3.1.1 2-ethylpyridine-4-carbothioamide (3a) Following general procedure H furnished 3a as a yellow solid, with an isolated yield of 35percent. TLC (CH2Cl2:CH3OH, 90:10 v/v): Rf=0.69; 1H NMR (300MHz, CD3OD): δ 8.47 (dd, J=5.3, 0.8Hz, 1H), 7.65 (dd, J=1.8, 0.8Hz, 1H), 7.58 (dd, J=5.3, 1.8Hz, 1H), 2.86 (q, J=7.6Hz, 2H), 1.32 (t, J=7.6Hz, 3H); 13C NMR (75MHz, CD3OD): δ 200.2, 163.6, 148.5, 148.3, 119.6, 118.6, 30.5, 13.0; IR (neat): 3258.6, 2961.5, 2932.6, 2912.0, 2875.9, 1654.8, 1593.9, 1415.6, 1392.3, 1285.6, 1260.7, 1205.4, 1149.6, 864.4, 808.4, 648.0, 528.8cm−1; HRMS (m/z): [M]+ calcd. for C8H10N2S, 167.0643; found, 167.0643.
Reference:
[1] Journal of Organic Chemistry, 2011, vol. 76, # 6, p. 1546 - 1553
[2] European Journal of Medicinal Chemistry, 2018, vol. 159, p. 35 - 46
[3] Bulletin de la Societe Chimique de France, 1958, p. 687,691
6
[ 100-48-1 ]
[ 536-33-4 ]
Reference:
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6572 - 6582
7
[ 29840-73-1 ]
[ 536-33-4 ]
Reference:
[1] European Journal of Medicinal Chemistry, 2018, vol. 159, p. 35 - 46
8
[ 1531-16-4 ]
[ 536-33-4 ]
Reference:
[1] Bulletin de la Societe Chimique de France, 1958, p. 687,691
9
[ 4104-77-2 ]
[ 536-33-4 ]
Reference:
[1] Bulletin de la Societe Chimique de France, 1958, p. 687,691
10
[ 156761-88-5 ]
[ 536-33-4 ]
Reference:
[1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 915,918; engl. Ausg. S. 898
11
[ 50826-64-7 ]
[ 536-33-4 ]
Reference:
[1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 915,918; engl. Ausg. S. 898
12
[ 4833-24-3 ]
[ 536-33-4 ]
Reference:
[1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 915,918; engl. Ausg. S. 898
13
[ 38594-62-6 ]
[ 536-33-4 ]
Reference:
[1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 915,918; engl. Ausg. S. 898
With sodiumsulfide nonahydrate; In N,N-dimethyl-formamide; at 130℃; for 2.5h;
General procedure: Benzonitrile 1a (1 mmol), Na2S*9H2O (1.2 mmol) and DMF (1 mL) were added into a 10 mL bottle. The reactor was placed in a heating magnetic stirrer at 130 C. After 2.5 h, by adding about 3 mL H2O after the reaction to disperse the solid product, the reaction mixture was extracted with EtOAc (3 x 3 mL), and the mixture was purified by column chromatography.
With Lawessons reagent; In tetrahydrofuran; at 20℃; for 48h;Inert atmosphere;
General procedure: THF (5ml/mmol) was added to a flask containing pyridine-4-carboxamide derivative (1 eq) at room temperature under inert atmosphere (argon) and stirring. Lawesson's reagent (1.5 eq) was added to the flask and the solution was stirred at room temperature for 48h-72h. The THF was evaporated under reduce pressure and the residue was partitioned between saturated aqueous NaHCO3 (25ml) and ethyl acetate (25ml) and extracted with ethyl acetate (2×25ml). The organic phase was dried over MgSO4 and eliminated under vacuum. The residue was further purified by flash chromatography (0-3% MeOH:DCM, puriFlash 15-SI-HC 25G, over 45min). 5.1.3.1.1 2-ethylpyridine-4-carbothioamide (3a) Following general procedure H furnished 3a as a yellow solid, with an isolated yield of 35%. TLC (CH2Cl2:CH3OH, 90:10 v/v): Rf=0.69; 1H NMR (300MHz, CD3OD): delta 8.47 (dd, J=5.3, 0.8Hz, 1H), 7.65 (dd, J=1.8, 0.8Hz, 1H), 7.58 (dd, J=5.3, 1.8Hz, 1H), 2.86 (q, J=7.6Hz, 2H), 1.32 (t, J=7.6Hz, 3H); 13C NMR (75MHz, CD3OD): delta 200.2, 163.6, 148.5, 148.3, 119.6, 118.6, 30.5, 13.0; IR (neat): 3258.6, 2961.5, 2932.6, 2912.0, 2875.9, 1654.8, 1593.9, 1415.6, 1392.3, 1285.6, 1260.7, 1205.4, 1149.6, 864.4, 808.4, 648.0, 528.8cm-1; HRMS (m/z): [M]+ calcd. for C8H10N2S, 167.0643; found, 167.0643.
Raney 2800 nickel; In methanol; at 20 - 60℃; for 18h;
To a solution of 2-ethyl-4-thiopyridylamide (10 g) in MeOH (250 ml) was added Raney 2800 Nickel (5 g, Aldrich) in one portion. The mixture was stirred at RT for 2 days then at 60 C. for 16 h. The mixture was filtered, concentrated to provide the desired compound.
With nickel; In methanol; at 20 - 60℃;
Preparation XLIX-2-Ethyl-4-aminomethyl pyridine To a solution of 2-ethyl-4-thiopyridylamide (10 g) in MeOH (250 mL) was added Raney 2800 Nickel (5 [G,] Aldrich) in one portion. The mixture was stirred at RT for 2 days then at [60 C] for 16 h. The mixture was filtered, concentrated to provide the desired compound.
A mixture of ethyl 5-(2-bromo-acetyl)-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (Example 24c) (0.10 g, 0.33 mmol) and 4-(2-ethylpyridinyl)thioamide (0.07 g, 0.43 mmol) in EtOH (3 ML) was heated at 150 C. by microwave for 7 min.The solid was filtered and triturated with MeOH, filtered and dried by air to give a tan solid. MS (M+1): 370.4. Calc'd for C19H19N3O3S Exact Mass: 369.11. MP: 270 C. (dec).
Example 57 (2S)-1-({2-[2-(2-Ethyl-pyridin-4-yl)-5-methyl-thiazol-4-yl]-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile The title compound was prepared in analogy to example 31 (steps A] and C] as outlined for example 31 and step B] according to example 33) starting from 2-[2-(2-ethyl-pyridin-4-yl)-5-methyl-thiazol-4-yl]-ethanol. This starting material could be prepared from 2-ethyl-4-pyridinecarbothioamide [CAS 536-33-4, commercially available] and methyl-4-bromo-3-oxopentanoate with 4-fluoro-benzamide as described in Collins, J. L. et al. J. Med. Chem. 1998, 41, 5037-5054. The compound was obtained as a yellow gum. MS (ISP): 384.2 (MH+).
With pyridine; In ethanol; at 20℃; for 16h;Reflux;
-Ethyl-2-(2-ethyl-pyridin-4-yl)-thiazol-4-ol: To a stirred solution of 2-ethyl-thioisonicotinamide (0.500 g, 3.01 mmol) and 2-bromo-butyric acid ethyl ester (0.46 mL, 3.61 mmol) in ethanol (15 mL) was added pyridine (0.4 mL, 6.15 mmol) at rt. The mixture was refluxed for 16 h (monitoring by TLC; ethyl acetate-hexane=1:1; Rf ?0.6) before being concentrated under reduce pressure. The crude material was then redissolved in MeOH and diethyl ether which caused the precipitation of pure 5-Ethyl-2-ethyl-pyridin-4-yl-thiazol-4-ol (0.120 g, 17%) that was isolated as a yellow solid. LC-MS: 235 [M+H].
17%
With pyridine; In ethanol; at 20℃; for 16h;Reflux;
To a stirred solution of 2-ethyl-thioisonicotinamide (0.500 g, 3.01 mmol) and 2-bromo-butyric acid ethyl ester (0.46 mL, 3.61 mmol) in ethanol (15 mL) was added pyridine (0.4 mL, 6.15 mmol) at rt. The mixture was refluxed for 16 h (monitoring by TLC; ethyl acetate-hexane=1:1; Rf?0.6) before being concentrated under reduce pressure. The crude material was then redissolved in MeOH and diethyl ether which caused the precipitation of pure 5-Ethyl-2-ethyl-pyridin-4-yl-thiazol-4-ol (0.120 g, 17%) that was isolated as a yellow solid. LC-MS: 235 [M+H].
4-(2-(2-ethylpyridin-4-yl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; diethyl ether;
4-(2-(2-ethylpyridin-4-yl)thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide 45 mg (1.1 eq.) <strong>[536-33-4]ethionamide</strong> are added to a solution of 100 mg (1 eq.) 4-(2-bromoacetyl)-N-(3,3,3-trifluoropropyl)benzamide (46) in 10 mL THF. The mixture is agitated under reflux during 24 h. The formed precipitate is filtrated and then washed using a solution of diethyl ether. The yellow solid thus obtained is then taken over in the ethyl acetate in a separating funnel, washed with a solution saturated with K2CO3 and then using water (2*) and in brine (1*).
With Baeyer-Villiger monooxygenase from the genome of Acinetobacter radioresistens; NADPH; In aq. phosphate buffer; at 30℃; for 0.0833333h;pH 7.4;Enzymatic reaction;Kinetics;
General procedure: The steady state kinetic parameters for 4-phenyl-2-butanone, 2-octanone, 2-decanone and 2-dodecanonewere determined spectrophotometricallyby monitoring the NADPH consumption rates (AU/s) at340 nm with a series of concentrations of substrates. Samples in atotal volume of 0.5 mL contained 0.5 muM enzyme and 150 muM of cosubstrate.Reactions were carried out for 5 min at 30 C in 50 mMpotassium phosphate buffer, pH 7.4.
Take the combination <strong>[536-33-4]ethionamide</strong>(2.0 g, 12 mmol) dissolved in an anhydrous solvent such as ethanol,DMF or ethylene glycol dimethyl ether (20 ml) ethyl bromoacetoacetate (3. 8 g, 18 mmol) was added to the reaction system under nitrogen atmosphere, After heating to 70-100C,After 3 hours, the mixture was cooled to room temperature,After removal of the solvent under reduced pressure,Adjust pH to neutral,Extracted with ethyl acetate,Organic phase by water, After washing with saturated brine, dried over anhydrous sodium sulfate, Concentration under reduced pressure gave the crude product.Purification by column chromatography gave the compound ethyl 2- (2-ethyl-4-pyridyl) -4-methylthiazole-5-carboxylate. A mixture of ethyl 2- (2-ethyl-4-pyridyl) -4-methylthiocar-5-carboxylate (3.0g,Dissolved in 30 ml of anhydrous ether,The reaction was cooled to 0 C,LiAlH4 (618 mg, 16.0 mmol) was then added in portions, 0 C reaction after 1 hour in ice water inactivated,The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product.After purification by column chromatography, the compound 2- (2-ethyl-4-pyridyl) -4-methyl-5-hydroxymethylthiazole (2.5 g, 99%) was obtained.Then 2- (2-ethyl-4-pyridyl) -4-methyl-5-hydroxymethylthiazole (234 mg, was dissolved in 5 ml of dry DMF, sodium hydride (120 mg, 3.0 mmol) was added under cooling in an ice-salt bath and benzyl bromide (257 mg, 1.5 mmol) was added after 30 min at 0 C. The reaction mixture was stirred at 0 C for 1 hour, poured into ice water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product.Purification by column chromatography gave 2- (2-ethyl) -4-pyridyl) -4-methyl-5-benzyloxymethylthiazole (292 mg, yield: 90%)
5-(ethoxycarbonyl)-2-(2-ethyl-4-pyridyl)-4-thiazolyl trifluoromethanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Take compound <strong>[536-33-4]ethionamide</strong> (1.7g, 10mmol0) , diethyl bromomalonate(2.2ml,13.0mmol) and pyridine(2.4 ml, 30 mmol) dissolved in anhydrous ethanol(20ml), heated to reflux under nitrogen gas protection, after 3h, it was cooled to room temperature, solvent was removed under reduced pressure, This intermediate was dissolved in 50 ml of dichloromethane and pyridine(2.4ml,30mmol) was added, into an ice bath added trifluoromethanesulfonicanhydride(2.5ml,15mmol), under room temperature keep the reaction for overnight to obtain 5- (ethoxycarbonyl) -2- (2-ethyl-4-pyridyl) -4-thiazolyltrifluoromethanesulfonate(3.4g,82%), the 5- (ethoxycarbonyl) -2-(2-ethyl-4-pyridyl) -4-thiazolyl trifluoromethanesulfonate(3.4g,8.3mmol) and Morpholine(2.2ml,24.9mmol) in 1,4-dioxane (20 ml) was refluxed for 24h to obtain 2- (2-ethyl-4-pyridyl) -4-morpholinethiazole-Carboxylic acidethyl ester (2.8g,98%). Then using a similar method to the preparation of compound LCZ-003, with replacing benzyl bromide by p-bromobenzyl bromide(375mg,1.5mmol), at last the product was purified by column chromatography to obtain 2-(2-ethyl-4-pyridyl) -4-(morpholine)-5-(4-bromobenzyloxymethyl) thiazole(40.8mg,87%).
2-(2-ethyl-4-pyridyl)-4-methoxythiazole-5-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
Take compound <strong>[536-33-4]ethionamide</strong> (1.7g, 10mmol0) , diethyl bromomalonate(2.2ml,13.0mmol) and pyridine(2.4 ml, 30 mmol) dissolved in anhydrous ethanol(20ml), the heated to reflux under nitrogen gas protection, after 3h, it was cooled to room temperature, solvent was removed under reduced pressure, This intermediate was dissolved in 50 ml of DMF and potassium carbonate (4.2ml,30mmol) was added, at normal temperature added iodomethane(1.9ml,30mmol), keep the reaction for 3h, extraction and column chromatography to obtain 2- (2-ethylpyridine-4-yl) -4-methoxythiazole-5-carboxylate ethyl ester (1.9g,65%). Followed by a similar method for the preparation of the compound LCZ-003, Replacement of benzyl bromide with p-bromobenzyl bromide(2.4g,9.8mmol),at last it was purified by column chromatography to obtain a product of 2-(2-ethyl-4-pyridyl) -4-methoxy-5- (4-bromobenzyloxymethyl) Thiazole (2.6 g,97%).
ETH (50mg, 0.301mmol) and CNB (60.62mg, 0.301mmol) were taken in 25mL beaker and dissolved in 5mL of methanol solvent at room temperature. This clear orange colored solution was then allowed for slow evaporation at room temperature. Block shaped orange colored crystal was obtained in 1:1 molecular stoichiometry after 2days.
ETH (50mg, 0.301mmol) and 2,6HBA (46.39mg, 0.301mmol) were taken in 25mL beaker, dissolved in 10mL of methanol solvent at room temperature. It was left for slow evaporation at ambient temperature. Block shaped orange colored crystal was obtained after 4days with 1:1 stoichiometry in the molecular salt.
ETH (50mg, 0.301mmol) and 2,3HBA (46.39mg, 0.301mmol) were taken in 25mL beaker, dissolved in 10mL of methanol solvent at room temperature. This clear solution was then left for slow evaporation at ambient temperature. Block shaped orange colored crystal was obtained after 4days with 1:1 stoichiometry in the molecular salt.
ETH (50mg, 0.301mmol) and DNB (63.85mg, 0.301mmol) were taken in 25mL beaker, dissolved in 10mL of 5% water in ethanol solvent at 60C temperature. This clear solution was allowed for slow evaporation at room temperature. Block shaped yellow colored crystal was obtained after 6days with 1:1 stoichiometry in the molecular salt.
Ethionamide was purchased from Sigma-Aldrich and usedwithout further purification. All other chemicals, such as nitric acidand ethanol, were from analytical grade. ETHNO3 was obtained bythe reaction of ETH and HNO3 acid. 20 mg of ETH was mechanicallyreacted with excess of HNO3 (14 mol L1). After that the systemsuffer a change in its color and the resultant solid was dissolved inethanol 95% solution and left for slow evaporation at room temperature.Red plate crystals were obtained after a few days uponsolvent evaporation. X-ray powder diffraction was used to verifythe purity of synthesized sample. The experimental powder XRDpattern of ETHNO3 is in good agreement with the calculated indicatingthat the sample presents high purity (Fig. S2).
1-[(2-ethylpyridin-4-yl)methanethioamido]methyl 5-[2-({1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]-N-(3,3,3-trifluoropropyl)formamido}methoxy)ethyl] pentanedioate[ No CAS ]
1-1 Preparation of intermediate 2-(2-ethyl-4-pyridyl)-4-methylthiazole-5-carboxylic acid ethyl ester
Take the compound ethionamide (6.8g, 41mmol) and dissolve it in 50ml of absolute ethanol,Add pyridine (7.5ml, 123mmol) and ethyl 2-chloroacetoacetate (7.3ml, 53mmol) at room temperature, stir at reflux for 7h,Distill under reduced pressure to remove most of the solvent, and extract three times with ethyl acetate and water.The solvent was evaporated to obtain the crude product, ethyl 2-(2-ethyl-4-pyridyl)-4-methylthiazole-5-carboxylate (7.3 g, yield 65%).
Synthesis of 1-[2-(2-ethylpyridin-4-yl)-4-methyl- thiazol-5-yl]ethanone (3)
A mixture of 2-ethyl pyridine- 4-carbothioamide (1) (2 mmol) with 3-chloropentane-2,4- dione (2) (2 mmol) was refluxed in ethanol. The progress of the reaction was monitored by TLC. After completion of the process, ethanol was evaporated under vacuum. The residue thus obtained was dissolved in ethyl acetate (50 mL) and neutralized by ammonia solution. The organic layer was washed with brine and dried over anhydrous sodium sulphate. Ethyl acetate was evaporated under vacuum, and the crude product was purified by column chromatography using ethyl acetate and petroleum ether to give pure compound 3. Yield 92 %, mp 70 - 72 °C. IR spectrum, ν, cm - 1: 3043, 2969, 1642, 1586, 1495, 1360, 1312, 1247, 1027, 949, 896, 728, 665. 1H NMR spectrum, δ, ppm: 1.35 t (3H, J = 7.6 Hz, CH3), 2.58 s (3H, COCH3), 2.79 s (3H, thiazolyl-CH3), 2.90 q (2H, J = 7.6 Hz, CH2), 7.60 d. d (1H, J = 1.6, 5.2 Hz, pyridyl-H), 7.70 s (1H, pyridyl-H), 8.62 d (1H, J = 5.2 Hz, pyridyl-H). 13C NMR spectrum, δ, ppm: 13.92, 18.54, 30.95, 31.55, 118.01, 118.86, 132.57, 139.94, 150.36, 159.82, 165.08, 166.82, 190.50.
2.1 Sample preparation of ETH-BAI cocrystal
270 mg of BAI (1 mmol) and 166 mg of ETH (1 mmol) were ground together in a miniature ball mill machine (15 mL, 35 Hz). A trace of ethanol was added as the assistant ground reagent when milling. After milling for 20 min, a yellow powder was obtained and used as the seed crystal in the following step. 1662mgof ETH (10mmol) and 2702mgof BAI (10mmol) were mixed and dissolved in 350 mL mixed solvent of ethyl acetate and ethanol (v/v=1:4). The solution was stirred for 3 hours at 45°C. Then the solution was filtered when it was cooled down to room temperature. The seed crystal obtained from the liquid-assisted grinding was seeded in the filtrate, and the filtrate was evaporated slowly. Yellow needle crystals were harvested after two days (Fig. S1). The instability phenomenon of thecocrystalwas not observed during the subsequent experimental test and storage at room temperature.