* 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] Phosphorus, Sulfur and Silicon and the Related Elements, 1993, vol. 74, # 1-4, p. 249 - 260
[2] ChemMedChem, 2014, vol. 9, # 8, p. 1850 - 1859
[3] Proceedings - Indian Academy of Sciences, Section A, 1945, # 22, p. 362,376
[4] Helvetica Chimica Acta, 1950, vol. 33, p. 306,312
[5] Tetrahedron Letters, 1997, vol. 38, # 12, p. 2085 - 2086
[6] Patent: US5883110, 1999, A,
[7] Patent: US6080772, 2000, A,
[8] Patent: US5798374, 1998, A,
[9] Patent: US5883110, 1999, A,
[10] Russian Journal of General Chemistry, 2010, vol. 80, # 12, p. 2572 - 2589
2
[ 121-66-4 ]
[ 71-41-0 ]
[ 3034-48-8 ]
Reference:
[1] Patent: US6080772, 2000, A,
[2] Patent: US6080772, 2000, A,
[3] Patent: US6080772, 2000, A,
3
[ 121-66-4 ]
[ 3034-47-7 ]
Reference:
[1] Phosphorus, Sulfur and Silicon and the Related Elements, 1993, vol. 74, # 1-4, p. 249 - 260
4
[ 96-50-4 ]
[ 121-66-4 ]
Reference:
[1] Proceedings - Indian Academy of Sciences, Section A, 1945, # 22, p. 362,376
[2] Galenica Acta, 1959, vol. 12, p. 249,252
[3] Journal of Organic Chemistry, 1955, vol. 20, p. 499,505
[4] Tetrahedron Letters, 1997, vol. 38, # 12, p. 2085 - 2086
[5] Russian Journal of General Chemistry, 2010, vol. 80, # 12, p. 2572 - 2589
5
[ 59024-01-0 ]
[ 121-66-4 ]
Reference:
[1] Canadian Journal of Chemistry, 1956, vol. 34, p. 1261,1267
[2] Synthetic Communications, 2001, vol. 31, # 19, p. 2921 - 2927
6
[ 140-40-9 ]
[ 121-66-4 ]
Reference:
[1] Proceedings - Indian Academy of Sciences, Section A, 1945, # 22, p. 362,376
[2] Yakugaku Zasshi, 1952, vol. 72, p. 1020[3] Chem.Abstr., 1952, p. 10286
7
[ 2719-23-5 ]
[ 121-66-4 ]
Reference:
[1] Patent: US2617809, 1950, ,
8
[ 96-50-4 ]
[ 625-58-1 ]
[ 121-66-4 ]
Reference:
[1] Annali di Chimica Applicata, 1948, vol. 38, p. 449,454
9
[ 73430-27-0 ]
[ 17356-08-0 ]
[ 121-66-4 ]
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7414 - 7417
10
[ 121-66-4 ]
[ 108-24-7 ]
[ 140-40-9 ]
Yield
Reaction Conditions
Operation in experiment
91%
With triethylamine In dichloromethane at 20℃;
General procedure: To a solution of 2-amino-5-nitrothiazole (0.3 g, 0.0020 mol) in dichloromethane was added 1.2 molar equiv of triethylamine (TEA). After the reaction mixture was stirred at 5 °C for 15 min, acetic anhydride (0.0100 mol, 5 equiv), or respectively acyl chlorides (0.0022 mol, 1.1 equiv) were added drop-wise. The reaction mixture was stirred at room temperature for 4–24 h. After complete conversion, the solvent was removed in vacuo and the residue was neutralized with saturated NaHCO3 solution. The precipitated solids were recrystallized from a mixture of solvents.
Reference:
[1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 5, p. 1626 - 1633
11
[ 121-66-4 ]
[ 140-40-9 ]
Reference:
[1] Annali di Chimica Applicata, 1948, vol. 38, p. 449,454
[2] Bulletin de la Societe Chimique de France, 1955, p. 1594,1596
[3] Galenica Acta, 1959, vol. 12, p. 249,252
12
[ 121-66-4 ]
[ 5538-51-2 ]
[ 55981-09-4 ]
Reference:
[1] European Journal of Medicinal Chemistry, 1978, vol. 13, # 6, p. 539 - 543
Example 12 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole (SU4390) (Compound 7) The key starting material 2-bromo-5-nitrothiazole was prepared by treating 2-amino-5-nitrothiazole (Aldrich) with sodium nitrite and hydrogen bromide (Fr. Demande 2,015,434, 1970).
With sodium nitrite;
Example 1 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole (Compound 1) The starting material 2-bromo-5-nitrothiazole was prepared by treating 2-amino-5-nitrothiazole (Aldrich) with sodium nitrite and hydrogen bromide (Fr. Demande 2,015,434, 1970).
With sodium nitrite;
Example 1 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole (Compound 7) The starting material 2-bromo-5-nitrothiazole was prepared by treating 2-amino-5-nitrothiazole (Aldrich) with sodium nitrite and hydrogen bromide (Fr. Demande 2,015,434, 1970).
Stage #1: glutaric anhydride,; 2-amino-5-nitro-1,3-thiazole With triethylamine In dichloromethane at 20℃; for 18h; Inert atmosphere;
Stage #2: With sodium hydroxide In dichloromethane; ethyl acetate
Stage #3: With hydrogenchloride In dichloromethane; water; ethyl acetate
3
^/^-BisCS-nitrothiazol^-y^glutaramide (VPC161276). Glutaric anhydride (1.0 g, 8.8 mmol), TEA (1.35 ml, 9.6 mmol) and cat. DMAP were dissolved in CH2Cl2 (7 mL). 2-Amino-5-nitrothiazole (1.4 g, 9.64 mmol) was then added and the solution was held at ambient temperature. After 18 hours, the solution was diluted with EtOAc (50 mL) and extracted with IM NaOH (3 x 30 mL). The combined aqueous layers were washed withEtOAc (20 mL) then acidified with 12M HCl and subsequently extracted with EtOAc (5 x 20 mL). The combined organics were washed with brine (2 x 20 mL), dried (MgSO4), filtered and concentrated to dryness to yield 5-(5-nitrothiazol-2-ylamino)-5- oxopentanoic acid (1.13 g, 54%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 12.59 (bs, 1H), 8.59 (s, 1H), 2.57 (t, J = 7.4 Hz, 2H), 2.28 (t, J = 7.3 Hz, 2H), 1.82 (quint, J = 7.3 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 174.0, 172.8, 161.8, 142.8, 141.7, 34.1, 32.7, 19.6; HRMS (ESI) calcd for [C8H9N3O5S + H]+ 260.0336, found 260.0344.
54%
With dmap; triethylamine In dichloromethane at 20℃; for 18h;
1
Glutaric anhydride (1.0 g, 8.8 mmol), TEA (1.35 ml, 9.6 mmol) and cat. DMAP were dissolved in CH2C12 (7 mE). 2-Amino-5-nitrothiazole (1.4 g, 9.64 mmol) was then addedand the solution was held at ambient temperature. After 18 hours, the solution was diluted with EtOAc (50 mE) and extracted with 1 M NaOH (3x30 mE). The combined aqueous layers were washed with EtOAc (20 mE) then acidified with 1 2M HC1 and subsequently extracted with EtOAc (5x20 mE). The combined organics were washed with brine (2x20 mE), dried (MgSO4), filtered and concentrated to dryness to yield 5-(5-nitrothiazol-2-ylamino)-5-oxopentanoic acid (1.13 g, 54%) as an orange solid. ‘H NMR (300 MHz, DMSO-d5) ö12.59 (bs, 1H), 8.59 (s, 1H), 2.57 (t, J=7.4 Hz, 2H), 2.28 (t,J=7.3 Hz, 2H), 1.82 (quint., J=7.3 Hz, 2H); ‘3C NMR (75 MHz, DMSO-d5) ö 174.0, 172.8, 161.8, 142.8, 141.7, 34.1, 32.7, 19.6; HRMS (ESI) calcd for [C8H9N3O5S+H]260.0336. found 260.0344.
2 General method of synthesis of amides (9-12)
General procedure: To a solution of 2-amino-5-nitrothiazole (0.3 g, 0.0020 mol) in dichloromethane was added 1.2 molar equiv of triethylamine (TEA). After the reaction mixture was stirred at 5 °C for 15 min, acetic anhydride (0.0100 mol, 5 equiv), or respectively acyl chlorides (0.0022 mol, 1.1 equiv) were added drop-wise. The reaction mixture was stirred at room temperature for 4-24 h. After complete conversion, the solvent was removed in vacuo and the residue was neutralized with saturated NaHCO3 solution. The precipitated solids were recrystallized from a mixture of solvents.
81%
With triethylamine In tetrahydrofuran at -15 - 20℃; Reflux;
2.b
General procedure: (b) 2-Amino-5-nitrothiazole (1.5 mmol, 1.0 equiv) was dissolved in dry tetrahydrofuran (5 mL/mmol), and triethylamine (1.8 mmol, 1.2 equiv) was added to the reaction solution. At -15°C, the benzoyl chloride solution prepared in step (a) was added dropwise to the above precooled reaction solution. The reaction solution was returned to room temperature, heated to reflux overnight, reacted until the starting material was completely consumed, and the reaction was quenched by adding water. The reaction solution was extracted with ethyl acetate, the combined organic phases were washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane/methanol gradient elution) to give the title compound.
42%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 20℃; for 24h; Inert atmosphere;
4.6%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;
With triethylamine In tetrahydrofuran at -15℃; Reflux;
With dmap; triethylamine In tetrahydrofuran at 0℃; for 0.5h;
1 Preparation of 3,4-dichloro-N-(5-nitrothiazol-2-yl)benzamide (Formula I)
Synthesized by one-step method. The target compound is synthesized through the reaction of acid chloride and heterocyclic (or aniline) amine compound. Weigh about 3mmol of 2-amino-5-nitrothiazole (Formula III), put it into a 100mL three-necked flask, add 15mL THF (tetrahydrofuran), magnetically stir until completely dissolved, ice-salt bath, after cooling to 0°C , add 1.2 ~ 1.5 eq (equivalent) of triethylamine. 3.6 mmol of 3,4-dichlorobenzoyl chloride (Formula II) was dissolved in 5 mL of THF, and then slowly dropped into the reaction system through a constant pressure dropping funnel. Remove the ice bath after the dripping is completed, add an appropriate amount of DMAP (p-dimethylaminopyridine) after half an hour of reaction. Petroleum ether: ethyl acetate is used as a developing agent, and when the reaction is monitored by thin-layer chromatography until there is no raw material, ice water is added, and after stirring until a yellow substance is precipitated, it is suction filtered to obtain a crude product of an ochre solid, which is dried. Recrystallization from ethanol gave yellow crystals.
With triethylamine In tetrahydrofuran at -15℃; Reflux;
2-Bromo-5-nitrothiazole To 72.5 g of 2-amino-5-nitrothiazole in 300 mL of 48percent hydrobromic acid and 200 mL of water stirred and cooled to about -10° C. was slowly added, in portions, 51.8 g of sodium nitrite dissolved in 80 mL of water from one addition funnel and 250 mL of n-amyl alcohol from a second addition funnel. The addition of both solutions required about 3 hours. The cooling bath was removed and the mixture allowed to warm to about 15° C. overnight and then stirred at room temperature for 2 hours. The solid was collected by vacuum filtration and steam distilled to give 67 g of crude product. The crude product was recrystallized from hot ethanol to give 61 g (60percent yield) of the 2-bromo-5-nitrothiazole as a yellow solid.
60%
In water; hydrogen bromide; sodium nitrite;
2-Bromo-5-nitrothiazole To 72.5 g of 2-amino-5-nitrothiazole in 300 mL of 48percent hydrobromic acid and 200 mL of water stirred and cooled to about -10° C. was slowly added, in portions, 51.8 g of sodium nitrite dissolved in 80 mL of water from one addition funnel and 250 mL of n-amyl alcohol from a second addition funnel. The addition of both solutions required about 3 hours. The cooling bath was removed and the mixture allowed to warm to about 15° C. overnight and then stirred at room temperature for 2 hours. The solid was collected by vacuum filtration and steam distilled to give 67 g of crude product. The crude product was recrystallized from hot ethanol to give 61 g (60percent yield) of the 2-bromo-5-nitrothiazole as a yellow solid.
60%
In water; hydrogen bromide; sodium nitrite;
2-Bromo-5-nitrothiazole To 72.5 g of 2-amino-5-nitrothiazole in 300 mL of 48percent hydrobromic acid and 200 mL of water stirred and cooled to about -10° C. was slowly added, in portions, 51.8 g of sodium nitrite dissolved in 80 mL of water from one addition funnel and 250 mL of n-amyl alcohol from a second addition funnel. The addition of both solutions required about 3 hours. The cooling bath was removed and the mixture allowed to warm to about 15° C. overnight and then stirred at room temperature for 2 hours. The solid was collected by vacuum filtration and steam distilled to give 67 g of crude product. The crude product was recrystallized from hot ethanol to give 61 g (60percent yield) of the 2-bromo-5-nitrothiazole as a yellow solid.
2-(3-methoxyphenyl)-N-(5’-nitrothiazol-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
Stage #1: m-methoxyphenylacetic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 100℃; for 0.333333h;
Stage #2: 2-amino-5-nitro-1,3-thiazole In N,N-dimethyl-formamide at 100℃; for 2.5h;
7
2- (3-Methoxyphenyl)-N- (5-nitro-1, 3-thiazol-2yl) acetamide A solution of 3-methoxyphenylacetic acid (196 mg, 1.18 mmol) and 1, 1'-carbonyldiimidazole (191 mg, 1.18 mmol) in N, N-dimethylformamide (5 mL) was heated at 100 °C for 20 min. 2-Amino-5-nitrothiazole (171 mg, 1.18 mmol) was added, and the reaction mixture was heated at 100 °C for 2.5 h. The mixture was allowed to cool, and was then partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated. Purification on a silica gel column using heptane/ethyl acetate, (65: 35), as the eluent gave 103 mg (30% yield) of the title compound as a yellow solid: IH NMR (DMSO-d6, 400 MHz) 8 13.31 (br s, 1 H), 8.63 (s, 1 H), 7.26 (t, J = 8 Hz, 1 H), 6.92-6. 84 (m, 3 H), 3. 85 (s, 2 H), 3.75 (s, 3 H); 13C NMR (DMSO-d6, 100 MHz) 8 171.00, 161.77, 159.36, 142.72, 141.95, 135.41, 129.59, 121.62, 115.26, 112.52, 55.08, 41.59 ; EIMS m/z 294 (M+).
16%
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 24℃; for 12h; Inert atmosphere;
General synthetic protocol for methoxyphenyl acetamides 36.
General procedure: To a mixture of N,N‘-dicyclohexylcarbodimide (220 mg, 1.08 mmol), DMAP (11.1 mg, 9.03 × 10-5 mmol) and 3-methoxyphenylacetic acid 31 (150 mg, 0.903 mmol) at 0 oC were added the respective amines (b-g) (0.903 mmol) in anhydrous CH2Cl2 (5.0 mL) and the resultant reaction mixture was stirred at 24 oC for 12 h. The suspension was filtered and the eluent concentrated under reduced pressure to yield a solid residue which was purified by flash chromatography (15:85 EtOAc/Hexane) to afford the products described below. The compounds were characterized by NMR spectroscopy (for some compounds HRMS too) and utilized directly in the next reduction step).
Stage #1: 2-fluoronicotinic acid chloride; 2-amino-5-nitro-1,3-thiazole With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 20℃; Inert atmosphere;
Stage #2: With hydrogenchloride In tetrahydrofuran; diethyl ether
3
2-Fluoro-N-(5-iiitrothiazol-2-yl)iiicotmamide (VPC16alO52). 2-Fluoronicotinic acid (100 mg, 0.71 mmol) was dissolved in CH2Cl2 (2 mL) with a drop of DMF (catalytic) and cooled to 0 °C then (COCl)2 (0.18 mL, 2.12 mmol) was added dropwise to the stirring solution. The slurry was allowed to warm to room temperature for 2 hours then concentrated to dryness using hexanes to remove the excess (COCl)2. The resulting acid chloride was dissolved in THF (7 mL) and DIPEA (0.26 mL, 1.49 mmol) was added. The solution was cooled to -78 °C and 2-amino-5-nitrothiazole (108 mg, 0.78 mmol) was then added in one portion and the solution was held at -78 °C for 10 mins then warmed to room temperature and stirred for 2 days until judged complete by TLC analysis. The resulting suspension was quenched with 2M HCl in Et2O (0.78 mL, 1.56 mmol) and concentrated to dryness then purified by flash column chromatography (1%MeOH/CH2Cl2) to obtain the title compound VPC16alO52 (118 mg, 62%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.77 (bs, 1H), 8.70 (s, 1H), 8.54 - 8.44 (m, 1H), 8.41 - 8.35 (m, 1H), 7.63 - 7.50 (m, 1H); 13C NMR (75 MHz, DMSO-(d6) δ 163.0 (d, JCF = 5.9 Hz), 161.5, 159.4 (d, JCF = 242 Hz), 151.3 (d, JCF = 15.2 Hz), 142.4, 142.3, 122.3 (d, JCF = 4.1 Hz), 115.9 (d, JCF = 28.5 Hz); HRMS (ESI) calcd for [C9H5FN4O3S + H]+ 269.0139, found 269.0143.
118 mg
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 20℃; for 48h;
1 2-Fluoro-N-(5-nitrothiazol-2-yl)nicotinamide(VPC16a1O52)
2-Fluoronicotinic acid (100mg, 0.71 mmol) was dissolvedin CH2C12 (2 mE) with a drop of DMF (catalytic) and cooledto 0° C. then (COd)2 (0.18 mE, 2.12 mmol) was addeddropwise to the stirring solution. The slurry was allowed towarm to room temperature for 2 hours then concentrated todryness using hexanes to remove the excess (COd)2. Theresulting acid chloride was dissolved in THF (7 mE) andDIPEA (0.26 mE, 1.49 mmol) was added. The solution wascooled to -78° C. and 2-amino-5-nitrothiazole (108 mg, 0.78mmol) was then added in one portion and the solution washeld at -78° C. for 10 mins then warmed to room temperatureand stirred for 2 days until judged complete by TEC analysis.The resulting suspension was quenched with 2M HC1 in Et20(0.78 mE, 1.56 mmol) and concentrated to dryness then purified by flash column chromatography (1% MeOH/CH2C12) toobtain the title compound VPC16a1O52 (118 mg, 62%) as ayellow solid. ‘H NMR (300 MHz, DMSO-d5) 0 13.77 (bs,1H), 8.70 (s, 1H), 8.54-8.44 (m, 1H), 8.41-8.35 (m, 1H),7.63-7.50 (m, 1H); ‘3C NMR (75 MHz, DMSO-d5) 0 163.0(d, cF= Hz), 161.5, 159.4 (d, JCF=242 Hz), 151.3 (d,JcF=15.2 Hz), 142.4, 142.3, 122.3 (d, JCF=4.1 Hz), 115.9 (d,JcF=28.5 Hz); HRMS (ESI) calcd for [C9H5FN4O3S+H]269.0139. found 269.0143.
EXAMPLE 1: Compound D (2-acetyloxy-3-methyl-N- (5-nitro-2- thiazolyl) benzamide)Compound D is a compound according to formula (I) in which Ri = -OCOCH3, R2= -CH3 and R3, R4 and R5 = -H.Compound D is synthesized from 3-methyl salicylic acid and 2-amino-5-nitro thiazole as shown in the following scheme: EPO <DP n="7"/> in which: Ac2O is acetic anhydride, SOCl2 is thionyl chloride, Et3N is triethylamine, and THF is tetrahydrofuran. Other synthesis methods, reagents and adaptations will readily occur to those of skill in the art, and the compounds of the present invention are not limited by their method of synthesis, which is provided for illustrative purposes only. Throughout this disclosure -OAc and -OCOCH3 are equivalent.Compound D is effective against at least H. Pylori, C. jejuni, Influenza A and B, Herpes VZV, G. intestinalis, P. falciparum and T. vaginalis.
N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium In tetrahydrofuran; hexane at 20℃;
1.) Synthesis of the urea derivatives
General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
In a round bottom-flask fitted with a calcium chloride drying tube, acetic anhydride (756 μL, 8 mmol) and formic acid (302 μL, 8 mmol) are stirred at 55 °C for 2 h. The mixture is cooled to room temperature before addition of 5-nitrothiazol-2-amine (580 mg, 4 mmol) in diethyl ether (10 mL), and stirred overnight at room temperature. The crude mixture is filtered through a short pad of silica gel to afford N-(5-nitrothiazol-2-yl)formamide (465 mg, 67%). 1H NMR (CDCl3, 200 MHz) δ (ppm) 9.40 (brs, 1H), 8.68 (s, 1H), 8.34 (s, 1H).
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 20h; Inert atmosphere;
47.2%
With sodium hydride at 20℃;
4.2.3 Synthesis of compounds 5a-5n
General procedure: General method C: To a solution of compound 4 or 6 in DMF was added compound 2 (1eq) and NaH (1.2eq). After stirring for 8-10h at room temperature. The reaction mixture was diluted with AcOEt and brine. The aqueous layer was extracted with AcOEt, and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography to give the desired compound as a solid.
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 40 - 50℃; for 3h;Inert atmosphere;
General procedure: A mixture of CDI (1.2 equiv) and the proper carboxylic acid in anhydrous solvent under a N2 atmosphere, was stirred at 40-50 C for 3 h. The solution was then cooled at room temperature and 2-amino-5-nitrothiazole and in some cases 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), was added. The mixture was heated at 60 C for 12-18 h, cooled at room temperature and water was added to precipitate the hybrid compounds. The solid was filtered and washed with acetone and water for give the corresponding hybrid compounds.
With 1,1'-carbonyldiimidazole In acetonitrile at 40 - 50℃; for 3h; Inert atmosphere;
General Method for the synthesis of 1-methyl-N-(5-nitro-1,3-thiazol-2-yl)-1H-benzimidazole-6-carboxamides (1-13)
General procedure: A mixture of CDI (1.2 equiv) and the proper carboxylic acid in anhydrous solvent under a N2 atmosphere, was stirred at 40-50 °C for 3 h. The solution was then cooled at room temperature and 2-amino-5-nitrothiazole and in some cases 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), was added. The mixture was heated at 60 °C for 12-18 h, cooled at room temperature and water was added to precipitate the hybrid compounds. The solid was filtered and washed with acetone and water for give the corresponding hybrid compounds.
General procedure: To a solution of 2-amino-5-nitrothiazole (0.3 g, 0.0020 mol) in dichloromethane was added 1.2 molar equiv of triethylamine (TEA). After the reaction mixture was stirred at 5 C for 15 min, acetic anhydride (0.0100 mol, 5 equiv), or respectively acyl chlorides (0.0022 mol, 1.1 equiv) were added drop-wise. The reaction mixture was stirred at room temperature for 4-24 h. After complete conversion, the solvent was removed in vacuo and the residue was neutralized with saturated NaHCO3 solution. The precipitated solids were recrystallized from a mixture of solvents.
2-(2-methyl-5-nitro-1H-imidazol-1-yl)-N-(5-nitrothiazol-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With dmap; diisopropyl-carbodiimide In tetrahydrofuran at 20℃; Inert atmosphere;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)-N-(5-nitrothiazol-2-yl)acetamide (18, C9H8N6O5S)
2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetic acid (11,0.19 g, 1.0 mmol) was dissolved in 5 cm3 dry THF under stirring with 0.13 g N,N'-diisopropylcarbodiimide (DIC, 1.0 mmol) and 0.012 g 4-dimethylaminopyridine (DMAP, 0.1 mmol) under nitrogen. 2-amino-5-nitrothiazole (10,0.15 g, 1.0 mmol) was added and the mixture was stirred overnight at room temperature. Water was then added and the product was extracted with chloroform (5 9 50 cm3). The organic solvent was removed under reduced pressure and the residue was purified by column chromatography (eluent: chloroform) to yield 18. Yield: 0.19 g (61.0 %);m.p.: 132-137 °C; 1H NMR (500 MHz, CDCl3): d = 2.40(s, 3H, CH3), 3.35 (s, 2H, H-10), 8.07 (s, 1H, H-4), 8.50 (s,1H, H-400), 9.24 (s, 1H, H-30) ppm; 13C NMR (125 MHz,CDCl3): d = 14.0 (C2-CH3), 48.5 (C-10), 132.5 (C-500),133.2 (C-4), 141.1 (C-5), 142.3 (C-400), 152.1 (C-2), 164.1(C-100), 165.3 (C=O) ppm; HRMS (ESI): m/z calcd forC9H8N6NaO5S [M?Na]? 335.01746, found 335.01691.
Stage #1: bis(trichloromethyl) carbonate; 4-methoxy-benzylamine With triethylamine In dichloromethane at 0 - 20℃; for 1.25h; Inert atmosphere;
Stage #2: 2-amino-5-nitro-1,3-thiazole With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere;
1 Procedure A: urea formation with triphosgene
General procedure: A solution of triphosgene (0.4 mmol) in dry CH2C12 (2.5 mL) was prepared underargon atmosphere in a dry round bottom flask and cooled to 0 °C. A solution of amine (1.0 mmol) and triethylamine (2.2 - 3.2 mmol) in dry CH2C12 (1.9 mL) which wasprepared under argon atmosphere in a dry round bottom flask was added dropwise to the first solution. The ice bath was removed after 15 minutes and the reaction mixture was stilTed for 1 h at room temperature. In another round bottom flask under argon, triethylamine (1.1 mmol) was added to a solution of thiazole (1.1 mmol) in dry DMF (1.3 mL). This solution was cooled to 0°C and the isocyanate solution was added. The redreaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel column (CH2C12/MeOH 10:0 to 95:5 (v/v) in 30 mm) to afford an oil or a solid, which was triturated in hexanes and CH2C12 and filtered to afford the urea.Obtained according to general procedure A from 4-methoxybenzylamine and2-amino-5-nitrothiazole. Pale yellow solid (0.124 g, 25%). Purity = 100%;tr = 2.50 mm; MS (ESI-): m/z = 307 [M-H1-; HRMS m/z calculated for C12H11N4045 [M-H1- 307.0506, found 307.0507. 1H NMR (DMSO-d6) ö (ppm): 11.7(br s, 1H), 8.52 (s, 1H), 7.37-7.25 (m, 6H), 4.38 (d, 1H, J = 7.5 Hz). 13C NMR (DMSOd 6) ö (ppm): 164.8, 158.9, 153.8, 143.9, 141.4, 131.2, 129.2, 114.3, 55.5, 43.1.
General procedure: A solution of triphosgene (0.4 mmol) in dry CH2C12 (2.5 mL) was prepared underargon atmosphere in a dry round bottom flask and cooled to 0 C. A solution of amine (1.0 mmol) and triethylamine (2.2 - 3.2 mmol) in dry CH2C12 (1.9 mL) which wasprepared under argon atmosphere in a dry round bottom flask was added dropwise to the first solution. The ice bath was removed after 15 minutes and the reaction mixture was stilTed for 1 h at room temperature. In another round bottom flask under argon, triethylamine (1.1 mmol) was added to a solution of thiazole (1.1 mmol) in dry DMF (1.3 mL). This solution was cooled to 0C and the isocyanate solution was added. The redreaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel column (CH2C12/MeOH 10:0 to 95:5 (v/v) in 30 mm) to afford an oil or a solid, which was triturated in hexanes and CH2C12 and filtered to afford the ureaObtained according general procedure A from <strong>[6234-01-1]glutamic acid 5-tert-butyl 1-methyl ester hydrochloride</strong> and 2-amino-5-nitrothiazole. Yellow solid (0.221 g, 36%). MS (ESI-): m/z = 387 [M-H1. To a solution (EtOH/THF 2/1, 1.0 mL) of the previously prepared urea (0.221 g, 0.57 mmol, 1.0 eq.) at 0C was added 1M lithium hydroxideaqueous solution (0.63 mL, 0.026 g, 0.63 mmol, 1.1 eq.). The mixture was stirred for 16 h at room temperature and 60 h at 50 C. The reaction mixture was diluted in CH2C12 and H20. The organic phase was discarded and the aqueous layer was acidified with 1 N hydrochloric acid solution until pH 1 and extracted three times with CH2C12. The combined organic layers were dried over Na2504 and concentrated under reducedpressure to give an orange oil (0.119 g). This oil was precipitated in CH2C12 and solid was filtered affording the monoacid as a white powder (0.03 2 g, 15 %). MS (ESI-): mlz = 373 [M-H1. 1H NMR (DMSO-d6) oe (ppm): 11.54 (br s, 0.5H), 8.53 (s, 1H), 7.20 (d, 1H, J = 7.6 Hz), 4.32-4.28 (m, 1H), 2.30-2.27 (m, 2H), 2.10-2.05 (m, 1H), 1.91-1.84 (m, 1H), 1.40 (s, 9H). The previous prepared monoacid (0.015 g, 0.04 mmol, 1 eq.) wassolubilized in CH2C12 (0.08 mL) and TFA (0.08 mL) at 0 C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was dissolved in Et20 and was evaporated to dryness. This step was done three times affording the urea as a white solid (0.013 g, quantitative yield). Purity = 96%; tr = 0.80 mm; MS (ESI+): m/z = 319 [M+H1 HRMS mlz calculated for C9H11N4075 [M+H1 319.0343, found 319.0331. 1HNMR (DMSO-d6) oe (ppm): 11.54 (br s, 1H), 8.53 (s, 1H), 7.20 (d, 1H, J = 7.5 Hz), 4.30(d, 1H, J = 5.0 Hz), 2.35-2.24 (m, 2H), 2.12-2.05 (m, 1H), 1.92-1.85 (m, 1H). 13C NMR (DMSO-d6) oe (ppm): 173.5, 172.7, 163.8, 153.1, 143.2, 141.1, 52.1, 29.7, 26.7.
2-(4-chlorophenoxy)-2-methyl-N-(5-nitro-1,3-thiazol-2-yl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With dmap; dicyclohexyl-carbodiimide; at 20℃; for 4h;
General procedure: To the corresponding NSAID acid (1 mmol) dissolved in cold CH2Cl2 or CHCl3, 2-amino-5-nitrothiazole (1.1 mmol) and 4-dimethylaminopyridine (DMAP, 0.3 mmol) was added followed by the addition of N,N?-dicyclohexylcarbodiimide (DCC, 1.2 mmol) in the same solvent. The mixture was stirred for 4 hours at room temperature. The reaction progress was monitored by TLC. Upon completion, N,N?-dicyclohexylurea (DCU) was removed by filtration, the solvent was removed in vacuo, and the residue was suspended in acetone. The precipitates were filtered and dried. Crude final compounds were recrystallized from suitable solvents.
(4-((5-nitrothiazol-2-yl)amino)-4-oxobutyl)carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: N-(tert-butoxycarbonyl)-4-aminobutanoic acid With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.5h;
Stage #2: 2-amino-5-nitro-1,3-thiazole In dichloromethane for 11h;
8.1; 16.1 Preparation of Intermediate (4-((5-Nitrothiazol-2-yl)amino)-4-oxobutyl)carbamic acid tert-butyl ester (2-1).
Dissolve N-Boc-γ-aminobutyric acid in 25 mL of anhydrous dichloromethane.EDCI (1.2 mmol) was sequentially passed to the reaction solution at room temperature.HOBT (1.2mmol), DMAP (1mmol),N,N-diisopropylethylamine (1.2 mmol), added,After stirring for 30 min, add 5-nitro-2-aminothiazole (1 mmol) for 11 h.The reaction was detected by TLC, and there was no residue in the starting material, and the reaction was stopped.Add 100 mL of citric acid solution to the reaction solution and wash twice (2×100 mL).Wash once with saturated sodium bicarbonate solution (1 × 100 mL),It was washed once with a saturated sodium chloride solution (1×100 mL) and dried over anhydrous magnesium sulfate.Filtration under reduced pressure, followed by evaporation to give a crude material.The crude product was purified by silica gel column (dichloromethane:methanol=200:1)Obtained a yellow solid,The yield was 80%.
{2-hydroxy-4-methoxy-5-[-(5-nitro-1,3-thiazol-2-yl) diazenyl]phenyl}(phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
General procedure: A facile, low-cost and traditional diazo-coupling method was adapted for the synthesis of azo dyes [18]. 2-Amino-5-nitrothiazole (2 mmol) was dissolved in orthophosphoric acid (5 mL) and was rapidly cooled in an ice bath at 0-5 C for10 min. To the cold solution of sodium nitrite (2 mmol) in sulphuric acid (2 mL), the previously prepared amine solution was added dropwise within 15 min. The reaction mixture was constantly stirred for 2 h, and the excess of nitrous acid was removed by the addition of required quantity of urea and the diazonium salt solution thus prepared was used for coupling reaction. The coupling compounds (2 mmol) were dissolved in acetic acid (5 mL) and placed in an ice bath. To this solution,a cold diazonium salt solution was added dropwise with vigorous stirring for 10 min. The whole reaction mixture was stirred at 0-5 C for 1 h. The pH of the reaction mixture was adjusted in the range of 2-3 by addition of the required volume of saturated bicarbonate solution, and the progress of the reaction was monitored by TLC. Further, the reaction mixture was stirred for 1 h at ambient temperature. The resulting solid product was filtered off, washed with water, dried and recrystallized from ethanol. The synthetic route for the preparation of azo dyes was represented in Scheme 1. {2-Hydroxy-4-methoxy-5-[-(5-nitro-1,3-thiazol-2-yl)diazenyl]phenyl}(phenyl)methanone (N1)This azo compound was afforded as a result of the diazotization reaction between heterocyclic amine with coupling component 2-hydroxy-4-methoxybenzophenone as reddish-orange solid. Yield: 62%, m.p: 220-223 C, FTIR(KBr) (cm-1) max: 3400 (O-H), 3098 (C-H), 1622(C=O), 1595 (C=C), 1526 (N=N), 1441 (NO2). 1H NMR(400 MHz, DMSO-d6, ppm): delta 4.06 (s, 3H, OMe), 6.76(s, 1H, thiazole proton), 7.55-7.75 (m, 5H, Ar-H), 7.93 (s,1H, Ar-H), 8.92 (s, 1H, Ar-H), 12.23 (s, 1H, OH). LC-MS(m/z) = 385 [M+ H]+. Anl.cal (%) for C17H12N4O5S: C(53.12), H (3.15), N (14.58), Found: C (53.03), H(3.18), N (14.63).
{2,4-dihydroxy-5-[-(5-nitro-1,3-thiazol-2-yl)diazenyl] phenyl}(phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
General procedure: A facile, low-cost and traditional diazo-coupling method was adapted for the synthesis of azo dyes [18]. 2-Amino-5-nitrothiazole (2 mmol) was dissolved in orthophosphoric acid (5 mL) and was rapidly cooled in an ice bath at 0-5 C for10 min. To the cold solution of sodium nitrite (2 mmol) in sulphuric acid (2 mL), the previously prepared amine solution was added dropwise within 15 min. The reaction mixture was constantly stirred for 2 h, and the excess of nitrous acid was removed by the addition of required quantity of urea and the diazonium salt solution thus prepared was used for coupling reaction. The coupling compounds (2 mmol) were dissolved in acetic acid (5 mL) and placed in an ice bath. To this solution,a cold diazonium salt solution was added dropwise with vigorous stirring for 10 min. The whole reaction mixture was stirred at 0-5 C for 1 h. The pH of the reaction mixture was adjusted in the range of 2-3 by addition of the required volume of saturated bicarbonate solution, and the progress of the reaction was monitored by TLC. Further, the reaction mixture was stirred for 1 h at ambient temperature. The resulting solid product was filtered off, washed with water, dried and recrystallized from ethanol. The synthetic route for the preparation of azo dyes was represented in Scheme 1
Stage #1: 4-(aminosulfonyl)-benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 25℃; for 0.5h;
Stage #2: 2-amino-5-nitro-1,3-thiazole With dmap In N,N-dimethyl-formamide at 45℃; for 24h;
4.1.2 Synthesis of 2a-3f
General procedure: 4-Carboxybenzenesulphonamide (10.0mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 12.0mmol), and 1-hydroxybenzotriazole (HOBt, 12.0mmol) were added to 10mLN,N-dimethylformamide (DMF) and stirred at room temperature (20-25°C) for 30min. Then, 2-amino-4-ethoxycarbonyl thiazole (12.0mmol) and 4-dimethylaminopyridine (DMAP, 3.0mmol) were added to the solution. The reaction was carried out at 45°C for 24h. The mixture was cooled to room temperature and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane/methanol, 60:1-30:1) to recover compound 2a. The method for synthesising 2b-3f was the same as for 2a.
2-(N,N-dimethylsulfamoyl)-N-(5-nitrothiazol-2-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.22 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 80℃; for 3h;
Stage #1: aspirin With bis(trichloromethyl) carbonate In tetrahydrofuran at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: With 2,4,6-trimethyl-pyridine In tetrahydrofuran for 0.5h; Inert atmosphere;
Stage #3: 2-amino-5-nitro-1,3-thiazole With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 40 - 50℃; for 20h; Inert atmosphere;
General procedure for amide bond formation using triphosgene
General procedure: To a stirred solution of (1.0 mmol) acid, (0.4 mmol) triphosgene were added in dry THF under N2 atmosphere atroom temperature. After 10 min 2.4 mmol of 2,4,6-colidinewere added, and a white precipitate was formed. After30 min, 0.9 mmol of the respective amine and 0.9 mmol ofDIPEA were added. The resulting mixture was stirred atreflux for 12-24 h. The mixture is concentrated to drynessand the crude was dissolved in EtOAc, washed with 5% v/vHCl and a saturated solution of NaHCO3, dried withNa2SO4, filtered and evaporated in vacuo. The crude waspurified by flash chromatography using the correspondingeluent to give the amide.2-[(5-Nitro-1,3-thiazol-2-yl)carbamoyl]phenyl acetate (1)Compound 1 was obtained following the general procedurefor in situ acid chloride formation from 6 (236 mg,1.63 mmol) and acetylsalicylic acid, in 19 mL of dry THF.Reaction was refluxed 6 h and stirred 14 h at 40-50 °C.Yield 42%. Brown powder. Rf = 0.35 using a mixture ofCHCl3:MeOH (3:0.2) as eluent. 1H NMR (400 MHz,DMSO) δ (ppm): 13.61 (ba, 1H), 8.68 (s, 1H), 7.87 (dd,J = 7.9, 1.6 Hz, 1H), 7.67 (td, J = 7.9, 1.7 Hz, 1H), 7.43 (td,J = 7.6, 1.0 Hz, 1H), 7.30 (dd, J = 8.17, 0.9 Hz, 1H), 2.26(s, 3H). 13C NMR (100 MHz, Acetona-d6) δ (ppm): 168.7,164.7, 162.3, 151.3, 148.9, 141.4, 133.7, 129.7, 126.1,124.2, 123.7, 20.0. MS (ESI + ) calcd for C12H9N3O5S,[M + H]+ 308.02, found 308.05.
Stage #1: aspirin With bis(trichloromethyl) carbonate In tetrahydrofuran at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: With 2,4,6-trimethyl-pyridine In tetrahydrofuran for 0.5h; Inert atmosphere;
Stage #3: 2-amino-5-nitro-1,3-thiazole With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 40 - 50℃; for 20h; Inert atmosphere;
General procedure for amide bond formation using triphosgene
General procedure: To a stirred solution of (1.0 mmol) acid, (0.4 mmol) triphosgene were added in dry THF under N2 atmosphere atroom temperature. After 10 min 2.4 mmol of 2,4,6-colidinewere added, and a white precipitate was formed. After30 min, 0.9 mmol of the respective amine and 0.9 mmol ofDIPEA were added. The resulting mixture was stirred atreflux for 12-24 h. The mixture is concentrated to drynessand the crude was dissolved in EtOAc, washed with 5% v/vHCl and a saturated solution of NaHCO3, dried withNa2SO4, filtered and evaporated in vacuo. The crude waspurified by flash chromatography using the correspondingeluent to give the amide.2-[(5-Nitro-1,3-thiazol-2-yl)carbamoyl]phenyl acetate (1)Compound 1 was obtained following the general procedurefor in situ acid chloride formation from 6 (236 mg,1.63 mmol) and acetylsalicylic acid, in 19 mL of dry THF.Reaction was refluxed 6 h and stirred 14 h at 40-50 °C.Yield 42%. Brown powder. Rf = 0.35 using a mixture ofCHCl3:MeOH (3:0.2) as eluent. 1H NMR (400 MHz,DMSO) δ (ppm): 13.61 (ba, 1H), 8.68 (s, 1H), 7.87 (dd,J = 7.9, 1.6 Hz, 1H), 7.67 (td, J = 7.9, 1.7 Hz, 1H), 7.43 (td,J = 7.6, 1.0 Hz, 1H), 7.30 (dd, J = 8.17, 0.9 Hz, 1H), 2.26(s, 3H). 13C NMR (100 MHz, Acetona-d6) δ (ppm): 168.7,164.7, 162.3, 151.3, 148.9, 141.4, 133.7, 129.7, 126.1,124.2, 123.7, 20.0. MS (ESI + ) calcd for C12H9N3O5S,[M + H]+ 308.02, found 308.05.
84 %
With triethylamine; dicyclohexyl-carbodiimide In acetone at 0.5℃; Inert atmosphere;
1
To the same flask containing 2-amino-5-nitrothiazole (1.45g, lOmmol), added acetylsalicylic acid (3.62g, 20mmol) in dry 10ml acetone under argon atmosphere, stirred for about 45 minutes at 0-5 °C, and after 45 minutes, a solution of N-N'-Dicyclohexylcarbodiimide (6.60 g, 32 mmol) in 20 mL of acetone was added. And also, dry triethylamine (40 mmol) in 10 mL acetone was added drop wise and the reaction mass was stirred for 5 hrs. The reaction mixture concentrated to 5 ml under reduced pressure, was poured into water (40 mL) and was extracted with EtOAc (100 mLx4). The combined organic extract was dried over anhydrous Na2SC>4, filtered, and washed with EtOAc. Then 1.5g activated charcoal was added at 50 °C in a hot water bath and colored impurities were removed. The mixture was then filtered while hot and the filtrate was concentrated to 5 mL by removing the solvent under reduced pressure. 20ml of isopropanol was added to the concentrated solution at 0-5 °C to precipitate Nitazoxanide (Formula I) as a light-yellow solid, which on recrystallization with ethanol yielded 84% of the pure form of Nitazoxanide [Figure 1].
84 %
With triethylamine; dicyclohexyl-carbodiimide In acetone at 0.5℃; Inert atmosphere;
1
To the same flask containing 2-amino-5-nitrothiazole (1.45g, lOmmol), added acetylsalicylic acid (3.62g, 20mmol) in dry 10ml acetone under argon atmosphere, stirred for about 45 minutes at 0-5 °C, and after 45 minutes, a solution of N-N'-Dicyclohexylcarbodiimide (6.60 g, 32 mmol) in 20 mL of acetone was added. And also, dry triethylamine (40 mmol) in 10 mL acetone was added drop wise and the reaction mass was stirred for 5 hrs. The reaction mixture concentrated to 5 ml under reduced pressure, was poured into water (40 mL) and was extracted with EtOAc (100 mLx4). The combined organic extract was dried over anhydrous Na2SC>4, filtered, and washed with EtOAc. Then 1.5g activated charcoal was added at 50 °C in a hot water bath and colored impurities were removed. The mixture was then filtered while hot and the filtrate was concentrated to 5 mL by removing the solvent under reduced pressure. 20ml of isopropanol was added to the concentrated solution at 0-5 °C to precipitate Nitazoxanide (Formula I) as a light-yellow solid, which on recrystallization with ethanol yielded 84% of the pure form of Nitazoxanide [Figure 1].
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; ethyl cyanoglyoxylate-2-oxime at 20℃; for 28h; Inert atmosphere; Reflux;
General procedure for amide bond formation usingoxyma pure
General procedure: Oxyma pure (1.2 mmol), EDCI (1.2 mmol), DIPEA(1.2 mmol), 4-DMAP (catalytic) were added to a stirredsolution of the respective acid (1.2 mmol) and amine(1.0 mmol) under N2 atmosphere in dry solvent (CH2Cl2 orTHF) at 0 °C. The resulting mixture was stirred at roomtemperature for 12-48 h and then evaporated in vacuo. Thecrude was dissolved in EtOAc, washed with 5% v/v HCland with a saturated solution of NaHCO3, dried withNa2SO4, filtered, and evaporated in vacuo. The crude waspurified by flash chromatography using the correspondingeluent to give the amide.
68%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; ethyl cyanoglyoxylate-2-oxime at 20℃; for 28h; Inert atmosphere; Reflux;
General procedure for amide bond formation usingoxyma pure
General procedure: Oxyma pure (1.2 mmol), EDCI (1.2 mmol), DIPEA(1.2 mmol), 4-DMAP (catalytic) were added to a stirredsolution of the respective acid (1.2 mmol) and amine(1.0 mmol) under N2 atmosphere in dry solvent (CH2Cl2 orTHF) at 0 °C. The resulting mixture was stirred at roomtemperature for 12-48 h and then evaporated in vacuo. Thecrude was dissolved in EtOAc, washed with 5% v/v HCland with a saturated solution of NaHCO3, dried withNa2SO4, filtered, and evaporated in vacuo. The crude waspurified by flash chromatography using the correspondingeluent to give the amide.