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Structure of Ethyl 2-chloroacetoacetate
CAS No.: 609-15-4
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 609-15-4 |
Formula : | C6H9ClO3 |
M.W : | 164.59 |
SMILES Code : | O=C(C)C(Cl)C(OCC)=O |
MDL No. : | MFCD00009141 |
InChI Key : | RDULEYWUGKOCMR-UHFFFAOYSA-N |
Pubchem ID : | 11858 |
GHS Pictogram: |
![]() ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H225-H302-H315-H318-H335-H412 |
Precautionary Statements: | P280-P305+P351+P338 |
Class: | 8(3) |
UN#: | 2920 |
Packing Group: | Ⅱ |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.67 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 37.24 |
TPSA ? Topological Polar Surface Area: Calculated from |
43.37 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.68 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.06 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.75 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.64 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.18 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.06 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.26 |
Solubility | 8.96 mg/ml ; 0.0544 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.56 |
Solubility | 4.51 mg/ml ; 0.0274 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.35 |
Solubility | 7.3 mg/ml ; 0.0444 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.55 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.31 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | at 100℃; for 48 h; Molecular sieve | Example 1A Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate 25 g (124.8 mmol) of 2-amino-3-benzyloxypyridine were dissolved in 781 ml of ethanol, 102.7 g (624.2 mmol) of ethyl 2-chloroacetoacetate and two tablespoons of 4 A molecular sieve were added, and the reaction mixture was then heated at reflux (bath temperature 100° C.) for 2 days. The mixture was concentrated, and excess ethyl 2-chloroacetoacetate was removed on a rotary evaporator with dry ice cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate gradient 9:1, 4:1). This gave 20.81 g of the target compound (54percent of theory, purity 99percent). LC-MS (Method 2): Rt=1.12 min MS (ESpos): m/z=311 (M+H)+ 1H NMR (400 MHz, DMSO-d6): δ=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H). |
54% | at 100℃; for 48 h; Molecular sieve | Example 29A Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate 25 g of 2-amino-3-benzyloxypyridine (124.8 mmol, 1 equivalent) were dissolved in 781 ml of ethanol, and 102.7 g of ethyl 2-chloroacetoacetate (624.2 mmol, 5 equivalents) and 15 g of 4 Å molecular sieve were added. The mixture was heated at reflux for 2 d (bath temperature 100° C.). The mixture was then concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator with dry ice-cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate 9:1, 4:1). This gave 20.81 g of the title compound (54percent of theory). LC-MS (Method 1): Rt=1.12 min MS (ESpos): m/z=311 (M+H)+ 1H NMR (400 MHz, DMSO-d6): δ=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H). |
54% | at 100℃; for 48 h; Molecular sieve | Example 23A Ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate 25 g (124.8 mmol) of 2-amino-3-benzyloxypyridine were dissolved in 781 ml of ethanol, 102.7 g (624.2 mmol) of ethyl 2-chloroacetoacetate and two table spoons of 4 A molecular sieve were added and the reaction mixture was then heated at reflux (bath temperature 100° C.) for 2 days. The mixture was concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator using dry ice cooling. The residue was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient-9/1, 4/1). This gave 20.81 g of the target compound (54percent of theory, purity 99percent). LC-MS (Method 2): Rt=1.12 min MS (ESpos): m/z=311 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): δ=1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H), 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H). |
54% | at 100℃; for 48 h; Molecular sieve | 25 g of 2-amino-3-benzyloxypyridine (124.8 mmol, 1 equivalent) were dissolved in 781 ml of ethanol, 102.7 g of ethyl 2-chloroacetoacetate (624.2 mmol, 5 equivalents) and 15 g of 4 A molecular sieve were added and the mixture was heated at reflux (bath temperature 100° C.) for 2 d. Then, the mixture was concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator using dry ice cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate=9:1, 4:1). This gave 20.81 g of the title compound (54percent of theory).10693] LC-MS (Method 2): R=1.12 mm10694] MS (ESpos): mlz=311 (M+H)10695] ‘H-NMR (400 MHz, DMSO-d5): ö=1.35 (t, 3H),2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H),7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.39% | With sodium carbonate; In ethanol; ethyl acetate; at 45 - 65℃; | 200 ml of 25% ethyl acetate in ethanol was added to the four-necked bottle, 30.4 g of thiourea, 1.5 g of sodium carbonate were added, and the temperature was raised to 45 C.33 g of ethyl 2-chloroacetoacetate was added dropwise, and the mixture was added dropwise over 20 to 30 minutes. The temperature was raised to 65 C for 5 hours, and most of the solvent was distilled off under normal pressure and then cooled to room temperature.The unreacted thiourea was removed by filtration, the filtrate was added to 500 ml of water, and the pH was adjusted to 9-10 with 30% liquid alkali, and stirred for 0.5 h.After suction filtration and vacuum drying for 2 hours, the product was 36.7 g, and the yield was 98.39%. |
97.34% | In ethanol; at 20℃; for 12h;Reflux; | To a stirred solution of ethyl 2-chloro-3-oxobutanoate (1) (20 g, 121.51 mmol, 1 eq) in EtOH (200 mL), thiourea (2) (46.24 g, 607.55 mmol, 5 eq) was added at RT. The reaction mixture was refluxed for 12 h. The progress of the reaction was monitored by TLC (M.Ph: 70% EtOAc in n-hexane; RfSM: 0.5, RfRM: 0.4). After completion of reaction, the reaction mixture was cooled to RT. The resulting precipitate so formed was filtered and dried to afford 3 (22 g, 97.34%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (br. s, 1H), 4.23 (q, J = 6.8 Hz, 2H), 2.43 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H). LCMS: 187.20 (M+H)+, Rt = 1.25 min. |
91.4% | In ethanol;Reflux; | The 11.3 g, 84 mmol of thionyl chloride was added dropwise over 30 minutes previously cooled to 0 C containing 10 g, 76.9mmol of ethyl acetoacetate in 100 ml methylene chloride solution. After completion of stirring at room temperature overnight, thereaction solution respectively saturated sodium bicarbonate and saturated sodium chloride solution, the organic layer wascollected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 12.4 g of pink oil of ethyl 3-acetyl VII chloroacetate, 98.4% yield, 3- acetyl acid ethyl ester VII prepared by the amount corresponding scaled up or down thevolume of the reaction vessel according to the corresponding scaled up or down, a commercially available compound VII havethe same effect; in 100 ml round-bottomed flask, 40 ml of ethanol and thiourea 2.0 g, 33.5 mmol, stirred and heated to refluxthiourea dissolved, add 5.5 g, 33.5 mmol 3- acetyl acid ethyl ester VII, after reflux overnight and concentrated under reducedpressure to remove ethanol to give a yellow solid, saturated with carbonate after filtration and washing soda solution of 5.3 g of2-amino-4-methyl-5-ethyl thiazole VIII, a yield of 91.4%, 2-amino-4-methyl-5-ethyl thiazole VIII prepared by the amountcorresponding scaled up or down the volume of the reaction vessel according to the corresponding scaled up or down, acommercially available compound VII have the same effect. |
91% | at 70 - 80℃; for 0.25h; | In anhydrous ethanol (100 mL), thiourea (0.098 M) was added and stirred at room temperature. To this solution ethyl-2-chloro acetoacetate (0.097 M) was added dropwise under constant stirring at room temperature. Once addition of ethyl-2-chloro acetoacetate is complete, reaction mixture was heated at 70-80C for 15 min. Then reaction mass was cooled to room temperature and the solid precipitate was isolated, washed with 100 mL of ethanol and further washed with saturated sodium bicarbonate solution to obtain white solid which was finally dried under vacuum at 50C for 8 h Yield: 91%; m.p.: 170-174C; IR (KBr v max): 3357, 3055, 1741, 1680 1492, 1388, 913, 728 cm-1; 1H-NMR (300 MHz, DMSO-d6, δ, ppm): 1.37 (d, 3H, J = 7.2 Hz, CH3), 2.49 (s, 3H, CH3), 4.38 (q, 2H, J = 7.2 Hz, CH2CH3), 5.18 (bs, 2H, D2O exchangeable NH2); 13C-NMR (75 MHz, CDCl3, δ, ppm): 13.91, 17.32 (CH3), 61.71, 119.06, 157.47, 163.55 (C=O), 170.95 (C-NH2, thiazole); ESI-MS: m/z 187.19 (M+H); Analysis: calcd. for C7H10N2O2S: C,45.15; H,5.41; N,15.04%; found: C, 45.14; H, 5.43; N, 15.07%. |
90% | In ethanol; at 70℃; | To a solution of thiourea (0.013 mole) in absolute ethanol(15 mL), 2-chloroethylacetoacetate (1 equivalent) wasadded dropwise with continuous stirring at room temperature(Ali et al. 2016). After the complete addition of 2-chloroethylacetoacetate, the reaction mixture was warmedon a water bath and the completion of the reaction wasmonitored by using TLC. After the completion of thereaction, the reaction mixture was cooled at room temperature,the solid crystalline product so obtained waswashed with 10 mL of ethanol and then treated with saturatedsodium hydrogen carbonate to obtain white precipitatesof ethyl 2-amino-4-methylthiazole-5-carboxylate.The characterization data for ethyl 2-amino-4-methylthiazole-5-carboxylate are as follows:Yield: 90%, mp: 170-174 C. 1H NMR (CDCl3,300 MHz, δ, TMS= 0): 4.12 (2H, q, J = 7.2 Hz), 2.05 (2H,s), 1.69 (2H, bs), 1.23-1.28 (3H, m) (14-09-2016). 13CNMR (CDCl3, 75 MHz, δ, TMS = 0): 16.81, 19.28, 63.26,160.04, 165.01, 172.14 (28-10-2016). Anal. Calcd. MS:186.0463; Found m/z: 187.0495 (M+ + 1). Anal. Calcd. ForC7H10N2O2S: C, 45.15; H, 5.41; N, 15.04; O, 17.18; S,17.22; Found: C, 45.22; H, 5.35; N, 15.22; S, 17.12. |
84% | In ethanol; for 24h;Reflux; | A mixture of ethyl 2-chloroacetoacetate (20 g, 0.125 mol), thiourea (11.09 g, 0.145 mol) in EtOH (100 mL) was heated under reflux for 24 h (monitored by TLC). The EtOH was evaporated under reduced pressure and the residue was stirred in ice-water mixture. The resultant precipitate was subjected to filtration, dried and recrystallized from EtOH to give 2 as white solid, yield 84%; mp 175 C. IR (ATR, cm-1): = 3373 (NH2), 1673 (C=O, ester); 1H NMR (DMSO-d6, δ, ppm): 7.70 (bs, 2H, NH2), 4.17- 4.10 (q, J = 7.1 Hz, 2H, CH2), 2.37 (s, 3H, CH3), 1.24-1.19 (t, J = 7.1 Hz, 3H, CH3); MS m/z (%): 185.43 (M-1), 186.05 (100.0), 187.05 (8.6), 188.04 (4.5); Anal. Calcd (%) for C7H10N2O2S: C, 45.15; H, 5.41; N, 15.04. Found: C, 45.37; H, 5.48; N, 15.12 |
82% | In ethanol; for 15h; | Ethyl 2-chloro-3-oxobutanoate (2.38 g, 14.45 mmol) was added to a solution of thiourea (1 g, 13.14 mmol) in ethanol (40 mL) at room temperature. The mixture was stirred for 15 h at 80 C. The reaction was monitored with TLC (EtOAc:PET 1:2). After the reaction was completed, ethanol was removed, and the crude product was washed with cold ethanol and crystallized from ethanol. m. p. 173-175 C [28], yield 82%. |
64% | In ethanol; for 3h;Reflux; | To a solution of 2-chloro-3-oxo-butyric acid ethyl ester (5 g, 0.030 mol, 1 eq) in ethanol (25 mL) was added thiourea (2.55 g, 0.033 mmol, 1.1 eq) at 25 C, and the reaction mixture was heated at reflux for 3 h. Then reaction mixture was gradually cooled to 25 C with stirring to precipitate the product as a white solid. The precipitated solid was collected by filtration using a Buckner funnel and dried under vacuum to obtain ethyl 2-amino-4- methylthiazole-5-carboxylate (4.8 g, 64%) as a fine white powder. |
64.8% | Step; 1 Preparation of ethyl 2-amino-4-methyl-l,3-thiazoIe-5-carboxylateTo a solution of 2-chloro-ethyl acetoacetate (0.82g, 5mmol) in EtOH (25ml) was added thiourea (0.38gm, 5mmol) and the reaction mixture was stirred for 5 minutes at 3O0C. Pyridine (0.08g, lOmmol) was later added to the reaction mixture at 3O0C and the stirring was continued at reflux temperature for 6 hours. Subsequently the reaction mixture was diluted with ethyl acetate: hexane mixture (1:1, 10OmL) and filtered. After washing with diethyl ether (5OmL x 3), the crude material was purified by column chromatography using 1% MeOH in dichloromethane as an eluent to give the product (0.61g, 64.8% yield) as a white colored solid. Remaining steps were all performed according to the procedure given in example 1 to afford the title compound. | |
38% | With sodium carbonate; In tetrahydrofuran; acetonitrile; at 120℃; for 0.5h;Microwave irradiation; | To a stirred solution of ethyl 2-chloroacetoacetate (6.0 mL, 43.35 mmol) in MeCN (24 mL) and THF (6 mL) was added thiourea (3.0 g, 39.41 mmol) and Na2CO3 (0.417 g, 39.41 mmol). The reaction mixture was heated at 1200C under microwave irradiation for 30 minutes, cooled to r.t., partitioned between EtOAc and water, and the organic fraction was dried (MgSO4), filtered and concentrated in vacuo to give the title compound (2.76 g, 38%) as a cream solid. δH (CDCl3) 5.47 (2H, br. s), 4.27 (2H, q, J 7.2 Hz), 2.53 (3H, s), 1.33 (3H, t, J 7.2 Hz). MS (ES+) 187.0 (M+H)+. |
In ethanol; for 4h;Reflux; | Intermediate 1: 2-Iodo-4-methyl-l,3-thiazole-5-carboxylic acid; Prepared as per the procedure described inJ. Chem. Soc. Perkin Trans. -1, (1982), 159-164. Stepl: Ethyl 2-amino-4-methyl-l,3-thiazole-5-carboxylate; To a solution of ethyl 2-chloro acetoacetate (10 g, 60.75 mmoles) in ethanol (50 rnL) was added thiourea (1 eq) and refluxed the reaction mixture for 4 h. The reaction mixture was cooled, and then added crushed ice, .neutralized with ammonia. The precipitate was then filtered and dried under vacuum to give 11.5 g of the desired product. 1H NMR (DMSO-d6) δ 7.69 (s, 2H), 4.16-4.09 (q, J= 6.6 Hz, 2H), 2.36 (s, 3H), 1.22 (t, J= 6.9 Hz, 3H). MS (m/z): 185.40 (M-H)+. | |
In ethanol; at 70℃; for 0.25h; | Preparation of ethyl 2-amino-4-methylthiazole-5-carboxylate Thiourea (30 gm/0.3947 moles) was stirred in 150 ml ethanol at room temperature. To the reaction mass ethyl-2-chloroacetoacetate (64 gms/0.389 moles) was added drop wise under constant stirring at room temperature. The reaction mass was heated to 70C and stirred for 10-15 minutes at same temperature. The reaction contents was brought to 25-30C, the solid obtained was isolated by filtration, washed with 100 ml ethanol, and dried under vacuum at 45-50C for 10 hours to yield 68.0 gms of the titled compound. Efficiency: 93% | |
In ethanol;Reflux; | In 200 ml of absolute ethanol,Ethyl 2-chloroacetoacetate (25 g, 150 mmol) was added.Thiourea (22.8 g, 2.0 eq), refluxed overnight,Cool to room temperature,Unscrew the solvent under reduced pressure.Add 500ml of water,2N NaOH solution adjusted to pH 10,Precipitating a white solid,Continue stirring for 10 minutes, suction filtration, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sulfuric acid; In 1,4-dioxane; at 60℃; for 4h; | General procedure: To an ice-cold solution of resorcinol (2.0 g, 18.2 mol) in dioxane, conc. H2SO4 (0.5mL) was added dropwise under 25 C. After the addition of conc. H2SO4, ethyl acetoacetate (2.8 g, 21.8 mmol) was added, and the mixture was heated to 60 C for 4 h. Then, the mixture was poured into cold water, and the precipitate was filtered and dried under reduced pressure. The resulting mixture was recrystallized from methanol to give 6a as white needle crystals. |
79% | With sulfuric acid; In water; at 0 - 5℃; for 24h; | A mixture of dry resorcinol (0.2 mol) and ethyl-2-chloroacetoacetate (0.2 mol) was cooled to 0-5 C and Conc. sulphuric acid (25 mL) added gradually with constant shaking. The reaction mixture was then kept in a refrigerator for 24 h. and poured into crushed ice with stirring. The separated solid was filtered and washed with water. Finally, recrystallized using ethanol to get a pure compound. Yield: 79%; Melting Point: 240-243 C. |
74% | With sulfuric acid; at 0 - 20℃; for 12h; | General procedure: A solution of 1,3-dihydroxybenzene (11.0 g, 100 mmol) in substituted ethyl acetoacetate (100 mmol)was added dropwise to stirring H2SO4 kept at 0 C. After completion of the addition, the reactionmixture was kept stirring for 12 h at room temperature and then poured onto ice-water. The crudeproducts were filtrated and recrystallized from ethanol [18]. |
With sulfuric acid; In 1,4-dioxane; at 60℃; for 4h; | General procedure: Resorcinol (1.50 g,13.62 mmol) was dissolved with 1,4-dioxane in a two-necked flask equipped with a thermometer. The flask was cooled with a surrounded ice bath and concentrated sulfuric acid (0.60 mL, 98%, 11.03 mmol) was added dropwise under magnetic stirring powerfully to keep the temperature of mixture under 10 oC, and then the commercially available appropriate ethyl carboxylate derivative (ethyl 2-methylacetoacetate for 5a, ethyl 2-chloroacetoacetate for 5d and ethyl benzoylacetate for 5h, 14.98 mmol) was dropped. After all needed reagents were added, the ice bath was removed and the reactor was placed in an oil bath and heated at 60 oC. Thin layer chromatography was used to check the reaction progress. When the reaction was ended, the mixture in flask was quenched by pouring onto crushed ice (about 200 mL) cautiously and the further resulting precipitate was filtered, dried under reduced pressure and then purified by crystallized from methanol, or by column chromatography ( petroleum ether/ethy actate ,5 : 1 to 3 : 1) to obtain the pure intermediates of 5a, 5d and 5h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In ethanol; at 0℃; for 16h;Reflux; | General procedure: A solution of 24a-f (1 equiv) and ethyl 2-chloroacetoacetate (1.2 equiv) in ethanol (25mL) was heated to reflux for 6h, then the mixture was allowed to stand at 0C for 10h, and a white needle crystal was precipitate out. The reaction mixture was filtered and the filter cake was washed with 10mL of ethanol, dried in vacuum to give the desired product. |
68% | In ethanol; for 6h;Reflux; | General procedure: A solution of 5a-h (1 equiv) and ethyl 2-chloroacetoacetate (1.2 equiv) in ethanol (25mL) was heated to reflux for 6h, then the mixture was allowed to stand at 0C for 10h, and a white needle crystal was precipitate out. The reaction mixture was filtered and the filter cake was washed with ethanol (10mL), dried to give the title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In 1,2-dimethoxyethane; at 90℃; for 6h; | 4.1.1 Preparation of ethyl 2-methylimidazo[1,2-a]pyridine-3-carboxylate (2) 2-aminopyridine (4.00 g, 42.50 mmol) and 2-chloroethylacetoacetate (7.08 mL, 51.00 mmol) were taken in 1,2-dimethoxyethane (40 mL) and heated at 90 C for 6 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (80 mL), washed the organic layer with H2O (3 * 30 mL). The separated organic layer was dried over anhy Na2SO4 and concentrated under vacuo to get crude compound. The crude compound was purified by column chromatography using 15% EtOAc in hexanes as eluent to get ethyl 2-methylimidazo[1,2-a]pyridine-3-carboxylate (2) (5.40 g, 62%) as an off-white solid. ESI-MS showed 205 [M+H]+ and carried to next step. |
46% | In ethanol;Heating / reflux; | Dissolved 2-aminopyridine (2.0 g, 21.2 mmol) in absolute ethanol (100 mL) and added ethyl 2-chloro-3-oxobutanoate (2.7 mL, 19.5 mmol). Refluxed reaction overnight, then concentrated solvent and brought up residue in dichloromethane. Extracted with water twice, followed by a wash with saturated aqueous sodium chloride. Dried over magnesium sulfate and concentrated. Purified by silica gel chromatography on a 0-7% of 2N methanolic ammonia in dichloromethane to afford 2.0 g (46% yield) of ethyl 2- methylimidazo[1 ,2-a]pyridine-3-carboxylate. 1H NMR (400 MHz, DMSO-D6) δ 1.32 (t, <n="75"/>3H), 2.56 (s, 3H), 4.32 (q, 2H), 7.13 (t, 1H), 7.48 (t, 1H), 7.63 (d, 1H), 9.17 (d, 1H); MS m/z 205 (M+1). |
With sodium hydrogencarbonate; In 1,1-dichloroethane; at 22℃;Reflux; | Intermediate 11: 2-[(E)-2-(2-(2,2-Dimethylpropoxy)-3-methoxyphenyl)vinyl]imidazo[1,2-c]pyridine-3-carboxylic acid; Step 1 Ethyl 2-methylimidazo[1,2-a]pyridine-3-carboxylate: To a stirred solution of 2-aminopyridine (15.0 g. 159.00 mmol) in dimethoxyethane (150 mL) was added NaHCO3 (14.72 g, 175 mmol) followed by ethyl 2-chloroacetoacetate (39.34 g, 239 mmol) at room temperature. After refluxing for 16 h the solvent was removed under reduced pressure. The residue was taken up in water (200 mL) and extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), and dried over anhydrous Na2SO4. Evaporation of solvents under reduced pressure afforded crude product which was further purified by column chromatography to give 20 g of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.44 (t, J=6.9 Hz, 3H), 2.72 (s, 3H), 4.43 (q, J=7.2 Hz, 2H), 6.98 (t, J=6.6 Hz, 1H), 7.38 (t, J=8.7 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 9.31 (d, J=6.9 Hz, 1H); ESI-MS (m/z) 205.13 (MH)+. |
With sodium hydrogencarbonate; In 1,2-dimethoxyethane; at 20℃;Reflux; | Step 1 Ethyl 2-methylimidazo[l,2-a]pyridine-3-carboxylate: To a stirred solution of 2-aminopyridine (15.0 g. 159.00 retool) in dimethoxyethane (150 mE) was added NaHCO3(14.72 g, 175 retool) followed by ethyl 2-chloroacetoacetate (39.34 g, 239 retool) at roomtemperature. After refluxing for 16 h the solvent was removed under reduced pressure.The residue was taken up in water (200 mL) and extracted with dichloromethane (2 x 200mE). The combined organic layers were washed with water (100 mE), brine (100 mE),and dried over anhydrous NazSO4. Evaporation of solvents under reduced pressureafforded crude product which was further purified by column chromatography to give 20g of the product as an off-white solid; H NMR (300 MHz, CDC13) 8 1.44 (t, J= 6.9 Hz,3H), 2.72 (s, 3H), 4.43 (q, J = 7.2 Hz, 2H), 6.98 (t, J = 6.6 Hz, 1H), 7.38 (t, J = 8.7 Hz,1H), 7.62 (d, J= 8.7 Hz, 1H), 9.31 (d, J= 6.9 Hz, 1H); ESI-MS (m/z) 205.13 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | 100 g (0.81 mol) of the starting material (3) was added to 400 ml of water at room temperature,To the reaction solution was added dropwise 270 ml (3.24 mol) of concentrated hydrochloric acid.After the dropwise addition, 115 g (1.62O1) of a mixed solution of sodium nitrite and 460 ml of water was added dropwise to the reaction solution, and the temperature control was carried out at -5 to 10C.Drop control, control the temperature at -5 ~ -10 ° C reaction 30min.Then, 135 ml (0.97 mol 1) of the reaction solution was added dropwise to the reaction solution,A mixed solution of ethyl dichloroacetoacetate and 135 ml of methanol,The temperature during the dropwise process is controlled at -5 to 10 ° C.After completion of the reaction, a mixed solution of 207 g (2.43 mol) of anhydrous sodium acetate and 514 ml of water was added dropwise to the reaction solution,The temperature is maintained at -5 to 10 ° C during the dropwise addition. Drop finished, temperature control at _10 ° C, reaction 2h.Then transferred to room temperature, allowed to stand overnight, with a brown solid precipitated, filtered and the filter cake was washed with anhydrous methanol (2 x 300ml).To give 186.9 g of a yellow solid (theoretical yield of 208. lg) in a yield of 89percent | |
85.0% | General procedure: Commercially available substituted aniline (63.4mmol) was portionwise added to a solution of concentrated HCl (13mL), ethanol (20mL) and water (7mL). To the above mixture was added dropwise a solution of NaNO2 (4.69g, 69.7mmol) in water (15mL) at 0?5°C. After the completion of addition, the reaction mixture was stirred at this temperature for 30min, and then added into a mixture of ethyl 2-chloroacetoacetate (10.88g, 63.4mmol), anhydrous sodium acetate (15.60g, 190.10mmol), and water (90mL) at 0°C. The reaction mixture was stirred at 0°C for 10min and then at room temperature for 4h. The solid which precipitated was collected by filtration and recrystallized from ethanol to afford light yellow solids (21a?21m) in 75.2?90percent yields. 6.3.4 Ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (21d) Yellow solid; Yield: 85.0percent; M.p.: 96.6-98.5 °C; MS (ESI) m/z(percent):279.1 [M+Na]+, 535.1 [2M+Na]+. | |
73.6% | In 250 mLTo a three-necked flask was added p-methoxyaniline (13.5 g, 0.11 mol) Water (56 ml), concentrated hydrochloric acid (28 ml),Stirred and dissolved, cooled to -5°C ,NaNO2 (7.9g, 0.12mol) aqueous solution was added dropwise, the temperature was controlled below 0°C ,Reaction below 0 °C for 30min. A 500 mL three-necked flask was charged with ethyl 2-chloroacetoacetate (18 g, 0.11 mol) Ethanol 270mL,Water 30mL, cooled to -5°C ,Sodium acetate (13.5 g, 0.16 mol) was added.Then make the above prepared diazonium salt solution into the anti-drop Should be the system, the control temperature is below 0°C . After dropping at room temperature for 4h. The reaction mixture was poured into 1 L of water and stirred until a large amount of solid was obtained After the precipitation was filtered off to give the product, a yellow solid, 20.6g, m. p. 106-109 °C, yield 73.6percent. |
50.4% | With hydrogenchloride; sodium acetate; sodium nitrite; In ethanol; water; at -5 - 20℃; for 7h; | Under room temperature, will be sequentially 4-methoxyaniline (30.0 g, 244 mmol) and water (100 ml) added to a reaction flask. Stirring of the obtained mixture, the lower the temperature to -5 to 0 °C. Then to the adding concentrated hydrochloric acid (35 ml) and sodium nitrite solution (50 ml). After the completion of the dropping, preserving heat and stirring the obtained mixture of 0.5 hours, then dropwise 2-chloro-3-oxo butyric acid ethyl ester (40.2 g, 244 mmol) of ethanol solution (200 ml), and sodium acetate (60.0 g, 732 mmol) aqueous solution (500 ml). After the completion of the dropping, at -5 to 0 °C, to the stirring mixture of 0.5 hours. Furthermore, the obtained mixture to room temperature, stirring for 6 hours. After the reaction, filtration, vacuum drying, silica gel column chromatography (PE:EA=10:1) to obtain 31.6 g product, in other words 2-chloro-2 - (2 - (4-methoxyphenyl) hydrazono) ethyl acetate (yield 50.4percent). |
19% | 4-methoxy-aniline (2k) (24.6 g, 0.2 mol) was dissolved in hydrochloric acid (50 mL, 0.2mol, 12N) of water (100 mL) was cooled to 0 ° C, was slowly dropwise sodium nitrite (16.6 g, 0.24 mol) in water (80 mL) solution, after the addition was complete, 0 ° C for 30 minutes, then was added sodium acetate (328 g, 0.40 mol) adjusting the reaction solution pH = 5 ~ 6, maintaining 0 ° C, was added dropwise ethyl 2-chloroacetoacetate (32.9 g, 0.2 mol) in methanol (80 mL) solution, after the addition was complete, maintaining 0. C for 1 hour. To the reaction solution was added ethyl acetate (200 mL x 2) and the combined organic phases, the organic phase was washed with saturated brine QOO mL xl), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the residue was purified by silica gel column chromatography ( ethyl acetate / petroleum ether (v / v) = 1: 50-1: 10) to give the title compound 2-chloro-2- (2- (4-methoxyphenyl) hydrazone yl) acetate (21) , as a yellow solid (19.5 g, 19percent yield). | |
Example 3. Synthesis of a compound of formula (IV): Chloro[(4- methoxyphenyl)hydrazono] acetic acid ethyl ester (IV)IV p-anisidine (31.02 g, 0.252 mol) in 100 ml of H2O is suspended in a 250 ml 4-necked flask equipped with coolant, thermometer, dropping funnel and magnetic stirrer, and cooled to 0°C in an ice bath. 60 ml of 37percent HC1 is added, followed by a solution of NaNO2 (20.95 g, 0.307 mol) in 50 ml of H2O, through a dropping funnel, maintaining the temperature below 5°C. After the addition the mixture is left under stirring at between 0 and 5°C for lh, and the solution obtained is added at 0°C to a solution containing ethyl-2- chloroacetoacetate (41.65 g, 0.254 mol), AcONa (47.84 g, 0.583 mol), AcOEt (200 ml) and H2O (100 ml). The biphasic system is stirred at between 0 and 5°C for lh, and then at about 25 °C for 16h. The phases are then separated and the organic phase is washed with a saturated solution of NaHCO3 (4x80 ml), anhydrified on Na2SO4, filtered and evaporated under low pressure. The compound of formula (IV) is obtained as a solid (about 57 g), which is used for the next stage without further purification.1H NMR (300 MHz, CDC13): 68.24 (1H, s, N-H), 7.16 (2H, dd, Jo=9.0Hz, Ar-H),6.88 (2H, dd, Jo=9.0 Hz, Ar-H), 4.37 (2H, q, J=7.2 Hz, COOCH2CH3), 3.79 (3H, s, Ar-OCH3), 1.39 (3H, t, J=7.2 Hz, COOCH2CH3). | ||
105 g | Example 5Preparation of ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetateStep-i: Water (600 ml) was added to p-anisidine (100 g) at room temperature and the resulting mixture was cooled to 10°C, followed by the addition of concentrated hydrochloric acid (133.5 g). The resulting mixture was cooled to ?5°C to 0°C, followed by portion-wise addition of 40percent aqueous sodium nitrite solution (67.2 g in 175 ml of water) over a period of 45 minutes to 1 hour. The resulting mass was stirred for 1 hour 30 minutes at ?5°C to0°C, followed by slow addition of 11percent sulfamic acid solution (35 g in 325 ml of water) over a period of 1 hour to 1 hour 30 minutes to produce a reaction mass (first part).Step-2:Sodium acetate (146 g) was added to water (300 ml) at room temperature and then stirred for 10 minutes to 15 minutes, followed by the addition of ethyl 2-chloroacetoacetate (160.4g) and acetone (300 ml) at room temperature to form a reaction mixture. The resulting mixture was cooled to 0°C (second part). The resulting mixture (second part) was added to the reaction mass (first part) obtained in step-i at ?5°C to 0°C and then stirred for 1 hour at the same temperature. Acetone (200 ml) was added to the resulting mass and then stirred for 30 minutes at ?5°C to 0°C. The resulting mass was settled for 5 hours at ?5°C to 0°Cand then filtered the solid. Methanol (150 ml) was added to the resulting solid at room temperature and then stirred for 2 hours at the same temperature. The separated solid was filtered, washed with methanol (50 ml) and then dried the material at 25°C for 24 hours to produce 105 g of ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (Purity by HPLC: 96percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
133 mg | In tert-butyl alcohol; at 20℃; for 48h; | To a mixture of 2 , 2 , 2-trifluoroethanethioamide (200 mg) and t-BuOH (10 mL) was added ethyl 2-chloro-3-oxqbutanoate (0.217 mL) at room temperature. The mixture was refluxed for 2 days. After cooling, EtOAc was poured into the mixture, and the mixture was washed successively with water and brine, dried over a2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (133 mg) . XH NMR (300 MHz, CDC13) delta 1.39 (3H, t, J = 7.16 Hz), 2.79 (3H, s) , 4.38 (2H, q, J = 6.91 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | 1) The Preparation of 4-hydroxyl-5-chloro-6-methylpyrimidine 8.80 g (0.16 mol) of CH3ONa in methanol was added slowly to a solution of 11.30 g (0.11 mol) of formimidamide in 50 mL of methanol at room temperature under stirring, the mixture was stirred for another 2 h after addition at room temperature. Followed by addition of 11.17 g (0.068 mol) of ethyl 2-chloro-3-oxobutanoate, the mixture was continued stirring for another 5-7 h at room temperature. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure and pH was adjusted to 5-6 with HCl, and then filtered to afford orange-yellow solid, the water phase was extracted with ethyl acetate (3*50 ml), dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was dissolved to 50 ml of ethyl acetate, stand overnight to obtain 6.48 g as orange-yellow solid with yield of 66%, m.p, 181184 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | The preparation of 4-hydroxyl-5-chloro-6-methylpyrimidine ;8.80g (0.16mol) of CH3ONa in methanol was added slowly to a solution of 11.30g (0.11mol of formimidamide in 50 mL of methanol at room temperature under stirring, the mixture was stirred for another 2 hrs after addition at room temperature. ;Followed by addition of 11.17g ( 0.068mol ) of ethyl 2-chloro-3-oxobutanoate, the mixture was continued stirring for another 5-7 hrs at room temperature. ;After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure and pH was adjusted to 5-6 with HCl, and then filtered to afford orange-yellow soilid, the water phase was extracted with ethyl acetate (3x50mL), dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. ;The residue was dissolved to 50ml of ethyl acetate, stand overnight to obtain 6.48g as orange-yellow soilid with yield of 66%. m.p. 181~184C. | |
66% | 1) Preparation of 4-hydroxy-5-chloro-6-methylpyrimidineStirring at room temperature to a solution of methanol 50ml 11.30g (0.11mol) of formamidine acetate was added slowly dropwise 8.80g (0.16mol) of sodium methoxide methanol solution was dropwise completed stirring was continued at room temperature 2h. To the above solution was then added dropwise 11.17g (0.068mol) of 2-chloroacetyl ethyl acetate, the reaction was stirred for 5-7 hours at room temperature continued, monitored by TLC after completion of the reaction, the solvent was distilled off under reduced pressure, adjusted to pH = 5 with hydrochloric acid 1-6, orange solid was suction filtered, the aqueous phase with (3 × 50ml) and extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and desolvation. The residue was dissolved in 50ml of ethyl acetate and allowed to stand overnight, and filtered to give an orange solid 6.48g. Yield 66%, m.p. 181 ~ 184 . | |
66% | With stirring at room temperature, to 11.30g (0.11mol) of formamidine acetate in 50ml of methanol was slowly added dropwise 8.80g (0.16mol) of methanol solution of sodium methoxide, after dropwise addition, at room temperature and stirring was continued for 2h. To the above solution was then added dropwise 11.17g (0.068mol) of intermediate ethyl 2-chloroacetoacetate, continued stirring for 5-7 hours at room temperature. After completion of the reaction monitored by TLC, the solvent was distilled off under reduced pressure, adjusted with hydrochloric acid pH = 5 ~ 6, orange solid was suction filtered, the aqueous phase was extracted with ethyl acetate (3 × 50ml), dried over anhydrous magnesium sulfate, filtered, removing solvent. The residue was dissolved in 50ml of ethyl acetate and allowed to stand overnight, and filtered to give an orange solid 6.48g. Yield 66%, m.p. 181 ~ 184 deg. C. |
66% | Stirring at room temperature to a solution of methanol 50ml 11.30g (0.11mol) of formamidine acetate was added slowly dropwise 8.80g (0.16mol) of sodium methoxide in methanol, stirring was continued at room temperature completion of dropwise 2h. Then added dropwise 11.17g (0.068mol) ethyl 2-chloroacetoacetate intermediate to the above solution, the reaction was stirred for 5-7 hours at room temperature continued. After completion of the reaction was monitored by TLC, the solvent was distilled off under reduced pressure, adjusted to pH = 5 with hydrochloric acid to 6, orange solid was suction filtered, the aqueous phase with (3 × 50ml) and extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered off solution. The residue was dissolved in 50ml of ethyl acetate and allowed to stand overnight, and filtered to give an orange solid 6.48g. Yield 66% | |
66% | To a solution of 11.30 g (0.11 mol) methylhydrazine acetate in 50 ml of methanol was slowly added dropwise 8.80 g with stirring at room temperature.(0.16 mol) of sodium methoxide in methanol, and the mixture was stirred at room temperature for 2 h. Then 11.17 g (0.068 mol) was added dropwise to the above solution.Ethyl 2-chloro-acetoacetate was stirred at room temperature for 5-7 hours. After TLC monitoring was completed, the solvent was distilled off under reduced pressure and salt was used.The pH was adjusted to 5-6, and the orange solid was filtered by suction. The aqueous phase was extracted with ethyl acetate (3×50 ml), dried over anhydrous magnesium sulfate, and dissolved.The combined product was dissolved in 50 ml of ethyl acetate, allowed to stand overnight and filtered to give 6.48 g of an orange-yellow solid. Yield 66.0% | |
66% | A solution of 8.80 g (0.16 mol) of sodium methoxide in methanol was slowly added dropwise to a solution of 11.30 g (0.11 mol) of methylacetoacetate in 50 ml of methanol at room temperature with stirring, and the mixturewas stirred at room temperature for 2 hours. Then, 11.17 g (0.068 mol) of the intermediate 2-chloroacetoacetic acid ethylacetate was added dropwise to theabove solution, and the reaction was continued for 5-7 hours while stirring at room temperature. After the TLCmonitoring reaction was completed, the solvent was evaporated under reduced pressure, and the pH wasadjusted to 5-6 with hydrochloric acid. The orange solid was collected by suction filtration, and the aqueousphase was extracted with ethyl acetate (3×50 ml), dried over anhydrous magnesium sulfate, filtered and shaken.Dissolved. The residue was dissolved in 50 ml of ethyl acetate, allowed to stand overnight and filtered to give 6.48g of an orange-yellow solid. The yield of 66%. | |
66% | 10343] A solution of 8.80 g (0.16 mol) of CH3ONa in methanol was added slowly to a solution of 11.30 g (0.11 mol) of formimidamideacetate in 50 mL of methanol at room temperature under stirring, the mixture was stirred for another 2 h after addition at room temperature. Followed by addition of 11.17 g (0.068 mol) of ethyl 2-chloro-3-oxobu- tanoate, the mixture was continued stirring for another 5-7 h at room temperature. Afier the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure and pH was adjusted to 5-6 with HC1, and then filtered to afford orangeyellow solid, the water phase was extracted with ethyl acetate (3x50 mL), dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was dissolved to 50 ml of ethyl acetate, stand overnight to obtain 6.48 g as orange-yellow solid with yield of 66%. m.p. 181-184 C. | |
66% | To a solution of 11.30 g (0.11 mol) of formamidine acetate in 50 ml of methanol, a solution of 8.80 g (0.16 mol) of sodium methoxide in methanol was slowly added dropwise with stirring at room temperature.Stirring was continued for 2 h at room temperature.Then, 11.17 g (0.068 mol) of an intermediate ethyl 2-chloroacetoacetate was added dropwise to the above solution, and the reaction was further stirred at room temperature for 5-7 hours.After the TLC monitoring reaction was completed, the solvent was evaporated under reduced pressure, and the mixture was adjusted to pH 5 to 6 with hydrochloric acid, and filtered to give an orange-yellow solid.The aqueous phase was extracted with (3 × 50ml) of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, desolventized.The residue was dissolved in 50ml of ethyl acetate, allowed to stand overnight, and filtered to give an orange-yellow solid 6.48g. Yield 66%, | |
66% | To a solution of 11.30 g (0.11 mol) formamidine acetate in 50 ml of methanol under stirring at room temperature, 8.80 g (0.16 mol) of sodium methoxide in methanol was slowly added dropwise, and stirring was continued at room temperature for 2 h.Then, 11.17 g (0.068 mol) of intermediate ethyl 2-chloroacetoacetate was added dropwise to the above solution, and the reaction was continued to be stirred at room temperature for 5-7 hours.After the reaction was monitored by TLC, the solvent was distilled off under reduced pressure, and the pH was adjusted to 5-6 with hydrochloric acid.Filtration with suction yielded an orange-yellow solid, and the aqueous phase was extracted with (3 × 50 ml) ethyl acetate, dried over anhydrous magnesium sulfate, filtered and desolvated.The residue was dissolved in 50 ml of ethyl acetate, left overnight, and filtered to obtain 6.48 g of orange solid. The yield is 66%, | |
66% | To a solution of 11.30 g (0.11 mol) formamidine acetate in 50 ml of methanol under stirring at room temperature, 8.80 g (0.16 mol) of sodium methoxide in methanol was slowly added dropwise, and stirring was continued at room temperature for 2 h. Then, 11.17g (0.068mol) of intermediate ethyl 2-chloroacetoacetate was added dropwise to the above solution, and the reaction was stirred at room temperature for 5-7 hours. After the reaction was monitored by TLC, the solvent was distilled off under reduced pressure, and the pH was adjusted to 5 with hydrochloric acid. 6, suction filtration to obtain orange-yellow solid, the aqueous phase was extracted with (3 × 50ml) ethyl acetate, dried over anhydrous magnesium sulfate, filtered and desolvated. The residue was dissolved in 50 ml of ethyl acetate, left overnight, and filtered to obtain 6.48 g of orange solid. 66% yield | |
With sodium methylate; In methanol; at 5 - 20℃; | General procedure: A solution of formamidine acetate (0.70 mol) in methanol (150 mL)was stirred at 5-10 C, and then CH3ONa (1.20 mol) in methanol(150 mL) newly prepared was added slowly under stirring, followed byaddition of M-1 (0.50 mol) in methanol (100 mL). The mixture wascontinued stirring for another 3-4 h at room temperature and thenconcentrated under reduced pressure. The residue was adjusted to pH5-6 with diluted HCl, the precipitated solid was filtered to afford M-2 asa white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In ethanol; at 120℃; for 0.5h;Microwave irradiation; | General procedure: A 35-mL microwave process vial was charged with 1a (1.08 g,10 mmol), 2a (1.64 g, 10 mmol) and EtOH (20 mL). The reaction mixture was stirred for 20 min at 120 °C. After cooling to room temperature, the mixture was poured into cold water (100 mL) and stirred for another 1 h. The precipitate was filtered out and dried in vacuum to give the title compound 3a (1.64 g,75percent). For 7-11, 13, 18, 19, 22 and 24, after the reaction completed, the mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (eluted with petroleum ether : EtOAc = 4:1) to get the corresponding title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | The 2,3-Dihydrobenzofuran-5-amine (1A) (2.0g, 14 . 80mmol) is added to the hydrochloric acid in (14.6 ml, 3N), cooling to -5 °C, dropping sodium nitrite (1.2g, 17 . 80mmol) of water (8 ml) solution, after dripping, in 0 °C reaction 30 minutes, slowly adding sodium acetate (2.1g, 25 . 6mmol), adjusting reaction solution pH=5-6, in 0-5 °C lower, dropping ethyl 2-chloroacetoacetate(2.4g, 14 . 80mmol) methanol (5 ml) solution, to reaction at room temperature 2 hours. Adding ethyl acetate to the reaction solution (20 ml), liquid, organic phase with saturated salt water (30 ml) washing, dry anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue is purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1:99-1:9) to obtain the title compound ethyl 2-chloro-2-(2-(2,3-dihydrobenzofuran-5-yl)hydrazono)acetate(1B), yellow solid (200 mg, yield 5percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium methylate; In methanol; at 20℃; | A solution of 8.80 g (0.16 mol) of CH3ONa in methanol was added slowly to a solution of 11.30 g (0.11 mol) of formimidamide acetate in 50 mL of methanol at room temperature under stirring, the mixture was stirred for another 2 h after addition at room temperature. Followed by addition of 11.17 g (0.068 mol) of ethyl 2-chloro-3-oxobutanoate, the mixture was continued stirring for another 5-7 h at room temperature. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure and pH was adjusted to 5-6 with HCl, and then filtered to afford orange-yellow solid, the water phase was extracted with ethyl acetate (3×50 mL), dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was dissolved to 50 ml of ethyl acetate, stand overnight to obtain 6.48 g as orange-yellow solid with yield of 66%. m.p. 181184 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | n a solution of <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> (1.4958, 7.211111101) in ethanol (1311 ^), cesium carbonate(2.58 g, 7.92 mmo 1) in ethanol (33 mL) was added and the mixture was stirred at room temperature for half an hour,Ethyl 2-chloroacetoacetate (1.4 g, 8.43 mmo 1) was added and stirred at 50 C.The mixture was cooled to room temperature,Column chromatography (petroleum ether / ethyl acetate = 60: 1) gave 1.4 g of colorless oil, yield 54% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.8% | 10L glass reactor with mechanical stirring, thermometer and constant pressure dropping funnel,Under nitrogen protection, 1 mole of raw material phosphorus pentasulfide was added,Ethylene glycol dimethyl ether 6kg,While stirring, 5 moles of formamide were added dropwise,Reaction 2h,5 moles of ethyl 2-chloroacetoacetate was added dropwise,The reaction at 60 8h, cooled to 10 , filtered to give a white solid,The solid was added to 4 times the weight of water, neutralized to pH 7-8 with 20percent sodium hydroxide solution at 0-5 ° C and filtered to give 4-methylthiazole-5-carboxylic acid ethyl ester as a white solid product, Purity 99percent, molar yield 95.8percent. |
Tags: 609-15-4 synthesis path| 609-15-4 SDS| 609-15-4 COA| 609-15-4 purity| 609-15-4 application| 609-15-4 NMR| 609-15-4 COA| 609-15-4 structure
A216236 [86728-85-0]
Ethyl (S)-4-chloro-3-hydroxybutanoate
Similarity: 0.67
A216236 [86728-85-0]
Ethyl (S)-4-chloro-3-hydroxybutanoate
Similarity: 0.67
A216236 [86728-85-0]
Ethyl (S)-4-chloro-3-hydroxybutanoate
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P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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