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[ CAS No. 609-15-4 ]

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Chemical Structure| 609-15-4
Chemical Structure| 609-15-4
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Product Details of [ 609-15-4 ]

CAS No. :609-15-4 MDL No. :MFCD00009141
Formula : C6H9ClO3 Boiling Point : 225.5°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :164.59 g/mol Pubchem ID :11858
Synonyms :

Safety of [ 609-15-4 ]

Signal Word:Danger Class:8,3
Precautionary Statements:P280-P305+P351+P338 UN#:2920
Hazard Statements:H225-H302-H315-H318-H335-H412 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 609-15-4 ]

  • Upstream synthesis route of [ 609-15-4 ]
  • Downstream synthetic route of [ 609-15-4 ]

[ 609-15-4 ] Synthesis Path-Upstream   1~41

  • 1
  • [ 77287-34-4 ]
  • [ 609-15-4 ]
  • [ 51605-32-4 ]
Reference: [1] Chemische Berichte, 1958, vol. 91, p. 988,992
[2] Patent: WO2018/64119, 2018, A1, . Location in patent: Paragraph 1357
  • 2
  • [ 77287-34-4 ]
  • [ 609-15-4 ]
  • [ 2510-32-9 ]
YieldReaction ConditionsOperation in experiment
64.5%
Stage #1: at 20 - 120℃;
Stage #2: at 20℃; for 4 h;
Preparation 14: 3- [ (3-Chloropropyl) thio]-4-methyl-5- (4-methyl-1, 3-oxazol-5-yl)-4H- 1,2, 4-triazole; Ethyl-2-chloroacetoacetate (1 wt; 1 eq. , 1000 g) was aged with formamide (0.68 vol ; ca. 2.8 eq. ) and the resulting solution was heated to 120 °C. After 5 hours the mixture was allowed to cool to room temperature and allowed to age under nitrogen over night. The mixture was treated with NaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases allowed to separae. The organic layer was discarded while the aqueous was acidified with conc. (32percent) aqueous HCI to pH 2 (ca. 2.0 vol). A precipitate started to form. The suspension was treated with AcOEt (8 vol) and vigorously stirred until the bulk of the precipitate had dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers distilled to low volume (again a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture evaporated to dryness. The collected solid was placed in the oven at 40 °C over night under reduced pressure to give 4-methyl-1, 3-oxazole-5-carboxylic acid (498 g, 64.5percent).
64.5%
Stage #1: at 20 - 120℃; for 5 h;
Stage #2: at 20℃; for 4 h;
Stage #3: With hydrogenchloride In water
Preparation 5: 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1 ,3-oxazol-5-yl)-4H- 1,2,4-triazole (P5)Ethyl-2-chloroacetoacetate (1 wt; 1 eq., 1000 g) was aged with formamide (0.68 vol; ca. 2.8 eq.) and the resulting solution was heated to 120 0C. After 5 hours the mixture was allowed to cool to room temperature and allowed to age under nitrogen over night. The mixture was treated with NaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases allowed to separae. The organic layer was discarded while the aqueous was acidified with cone. (32percent) aqueous HCI to pH 2 (ca. 2.0 vol). A precipitate started to form. The suspension was treated with AcOEt (8 vol) and vigorously stirred until the bulk of the precipitate had dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers distilled to low volume (again a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture evaporated to dryness. The EPO <DP n="33"/>collected solid was placed in the oven at 40 0C over night under reduced pressure to give 4-methyl-1 ,3-oxazole-5-carboxylic acid (498 g, 64.5percent).This material (498 g, 1 wt) was dissolved in dry tetrahydrofuran (5 vol), under nitrogen, cooled to 0 0C. DCC (1.62 wt, 1 eq) was added portionwise followed by HOBt (1.07 wt, 1 eq). The mixture was warmed to 25+/-2 0C and stirred for 30 min. 4-Methyl-3- thiosemicarbazide (0.83 wt, 1 eq) was then added and the mixture further stirred for 2 h at 25+/-2°C. The mixture was filtered and the cake was washed with fresh tetrahydrofuran (1 vol) and dried on the filter for a few hours. The cake was suspended in 1 M aqueous NaOH (13 vol) and heated to 70 0C for 30 min. After this time, the mixture was cooled to 25+/-2 0C and a solid was removed by filtration. The cake was washed with 1 M aqueous NaOH (10 vol). The combined mother liquors were cooled to 0 0C and acidified to ca. pH 5 with HCI (aqueous, 16percent; NOTE: keep temperature while adding HCI below +10 0C). The suspended product was isolated by filtration washing with water (2x3 vol). The cake was dried at 40 0C for 18 h in high vacuum to obtain 4-methyl-5-(4-methyl-1 ,3-oxazol-5- yl)-2,4-dihydro-3/-/-1 ,2,4-triazole-3-thione (respectively a tautomeric form thereof; 290 g, 37percent).NaOEt (21percent solution in EtOH, 2.08 vol, 1.1 eq) was added to EtOH (20 vol) under nitrogen atmosphere. 4-Methyl-5-(4-methyl-1 ,3-oxazol-5-yl)-2,4-dihydro-3H-1 ,2,4-triazole- 3-thione (respectively a tautomeric form thereof; 290 g, 1 wt) was added in one portion and the resulting mixture stirred at 25+/-2°C until a clear solution was obtained. Then 1- bromo-3-chloropropane (0.54 vol, 1.1 eq) was added and the solution stirred at 40 'C for 24 h then cooled to 25 'C. After filtration, water (20 vol) was added and the ethanolic phase removed by vacuum distillation (internal temperature ~40 'C). The mixture was extracted with EtOAc (41 vol). The aqueous layer was removed and the organic phase was evaporated to dryness. Dichloromethane (4 vol) was added. The organic solution is purified through a short silica gel column (18 wt of silica), eluting with EtOAc (200 vol) to give the title compound as a solid foam (267.64 g, 66percent). NMR (1H, CDCI3): δ 7.90 (s, 1 H), 3.70 (s, 5H), 3.40 (t, 2H), 2.52 (s, 3H), 2.30 (m, 2H).
64.5%
Stage #1: at 20 - 120℃;
Stage #2: at 20℃; for 4 h;
Stage #3: With hydrogenchloride In water
Ethyl-2-chloroacetoacetate (1 wt; 1 eq., 1000 g) was aged with formamide (0.68 vol; ca. 2.8 eq.) and the resulting solution was heated to 120 0C. After 5 hours the mixture was allowed to cool to room temperature and allowed to age under nitrogen over night. The mixture was treated with NaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases allowed to separae. The organic layer was discarded while the aqueous was acidified with cone. (32percent) aqueous HCI to pH 2 (ca. 2.0 vol). A precipitate started to form. The suspension was treated with AcOEt (8 vol) and vigorously stirred until the bulk of the precipitate had dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers distilled to low volume (again a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture evaporated to dryness. The collected solid was placed in the oven at 40 0C over night under reduced pressure to give 4-methyl-1 ,3-oxazole-5-carboxylic acid (498 g, 64.5percent).This material (498 g, 1 wt) was dissolved in dry tetrahydrofuran (5 vol), under nitrogen, cooled to 0 0C. DCC (1.62 wt, 1 eq) was added portionwise followed by HOBt (1.07 wt, 1 eq). The mixture was warmed to 25+/-2 0C and stirred for 30 min. 4-Methyl-3- thiosemicarbazide (0.83 wt, 1 eq) was then added and the mixture further stirred for 2 h at 25+/-2°C. The mixture was filtered and the cake was washed with fresh tetrahydrofuran (1 vol) and dried on the filter for a few hours. The cake was suspended in 1 M aqueous NaOH (13 vol) and heated to 70 0C for 30 min. After this time, the mixture was cooled to 25+/-2 0C and a solid was removed by filtration. The cake was washed with 1 M aqueous NaOH (10 vol). The combined mother liquors were cooled to 0 0C and acidified to ca. pH 5 with HCI (aqueous, 16percent; NOTE: keep temperature while adding HCI below +10 0C). The suspended product was isolated by filtration washing with water (2x3 vol). The cake was dried at 40 0C for 18 h in high vacuum to obtain 4-methyl-5-(4-methyl-1 ,3-oxazol-5-yl)-2,4- dihydro-3H-1 ,2,4-triazole-3-thione (respectively a tautomeric form thereof; 290 g, 37percent). EPO <DP n="37"/>NaOEt (21percent solution in EtOH, 2.08 vol, 1.1 eq) was added to EtOH (20 vol) under nitrogen atmosphere. 4-Methyl-5-(4-methyl-1 ,3-oxazol-5-yl)-2,4-dihydro-3/-/-1 ,2,4-triazole- 3-thione (respectively a tautomeric form thereof; 290 g, 1 wt) was added in one portion and the resulting mixture stirred at 25+/-2°C until a clear solution was obtained. Then 1- bromo-3-chloropropane (0.54 vol, 1.1 eq) was added and the solution stirred at 40 'C for 24 h then cooled to 25 'C. After filtration water (20 vol) was added and the ethanolic phase was removed by vacuum distillation (internal temperature ~40 'C). The mixture was extracted with EtOAc (41 vol). The aqueous layer was removed and the organic phase was evaporated to dryness. Dichloromethane (4 vol) was added. The organic solution is purified through a short silica gel column (18 wt of silica), eluting with EtOAc (200 vol) to give the title compound as a solid foam (267.64 g, 66percent).NMR (1H, CDCI3): δ 7.90 (s, 1 H), 3.70 (s, 5H), 3.40 (t, 2H), 2.52 (s, 3H), 2.30 (m, 2H).
64.5%
Stage #1: at 20 - 120℃;
Stage #2: With sodium hydroxide In water at 20℃; for 4 h;
Stage #3: With hydrogenchloride In water
Preparation 11: 3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazole Ethyl-2-chloroacetoacetate (1 wt; 1 eq. , 1000 g) was aged with formamide (0.68 vol; ca. 2.8 eq. ) and the resulting solution was heated to 120 °C. After 5 hours the mixture was allowed to cool to room temperature and allowed to age under nitrogen over night. The mixture was treated with NaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases allowed to separae. The organic layer was discarded while the aqueous was acidified with conc. (32percent) aqueous HCI to pH 2 (ca. 2.0 vol). A precipitate started to form. The suspension was treated with AcOEt (8 vol) and vigorously stirred until the bulk of the precipitate had dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers distilled to low volume (again a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture evaporated to dryness. The collected solid was placed in the oven at 40 °C over night under reduced pressure to give 4-methyl-1,3-oxazole-5-carboxylic acid (498 g, 64.5percent). This material (498 g, 1 wt) was dissolved in dry tetrahydrofuran (5 vol), under nitrogen, cooled to 0 °C. DCC (1.62 wt, 1 eq) was added portionwise followed by HOBt (1.07 wt, 1 eq). The mixture was warmed to 25No.2 °C and stirred for 30 min. 4-Methyl-3-thiosemicarbazide (0.83 wt, 1 eq) was then added and the mixture further stirred for 2 h at 25No.2°C. The mixture was filtered and the cake was washed with fresh tetrahydrofuran (1 vol) and dried on the filter for a few hours. The cake was suspended in 1 M aqueous NaOH (13 vol) and heated to 70 °C for 30 min. After this time, the mixture was cooled to 25No.2 °C and a solid was removed by filtration. The cake was washed with 1 M aqueous NaOH (10 vol). The combined mother liquors were cooled to 0 °C and acidified to ca. pH 5 with HCI (aqueous, 16percent; NOTE: keep temperature while adding HCI below +10 °C). The suspended product was isolated by filtration washing with water (2x3 vol). The cake was dried at 40 °C for 18 h in high vacuum to obtain 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3- thione (respectively a tautomeric form thereof; 290 g, 37percent). NaOEt (21percent solution in EtOH, 2.08 vol, 1.1 eq) was added to EtOH (20 vol) under nitrogen atmosphere. 4-Methyl- 5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (respectively a tautomeric form thereof; 290 g, 1 wt) was added in one portion and the resulting mixture stirred at 25No.2°C until a clear solution was obtained. Then 1-bromo-3-chloropropane (0.54 vol, 1.1 eq) was added and the solution stirred at 40 'C for 24 h then cooled to 25 'C. After filtration water (20 vol) was added and the ethanolic phase was removed by vacuum distillation (internal temperature -40 'C). The mixture was extracted with EtOAc (41 vol). The aqueous layer was removed and the organic phase was evaporated to dryness. Dichloromethane (4 vol) was added. The organic solution is purified through a short silica gel column (18 wt of silica), eluting with EtOAc (200 vol) to give the title compound as a solid foam (267.64 g, 66percent). NMR ('H, CDC13): No. 7.90 (s, 1 H), 3.70 (s, 5H), 3.40 (t, 2H), 2.52 (s, 3H), 2.30 (m, 2H). MS (m/z): 273 [MH]+.
64.5%
Stage #1: at 20 - 120℃;
Stage #2: With sodium hydroxide In water at 20℃; for 4 h;
Stage #3: With hydrogenchloride In water
Preparation 7: 3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1 ,3-oxazol-5-yl)-4H- 1 ,2,4-triazole; EPO <DP n="36"/>Ethyl^-chloroacetoacetate (1 wt; 1 eq., 1000 g) was aged with formamide (0.68 vol; ca. 2.8 eq.) and the resulting solution was heated to 120 0C. After 5 hours the mixture was allowed to cool to room temperature and allowed to age under nitrogen over night. The mixture was treated with NaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases allowed to separae. The organic layer was discarded while the aqueous was acidified with cone. (32percent) aqueous HCI to pH 2 {ca. 2.0 vol). A precipitate started to form. The suspension was treated with AcOEt (8 vol) and vigorously stirred until the bulk of the precipitate had dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers distilled to low volume (again a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture evaporated to dryness. The collected solid was placed in the oven at 40 0C over night under reduced pressure to give 4-methyl-1 ,3-oxazole-5-carboxylic acid (498 g, 64.5percent). This material (498 g, 1 wt) was dissolved in dry tetrahydrofuran (5 vol), under nitrogen, cooled to 0 0C. DCC (1.62 wt, 1 eq) was added portionwise followed by HOBt (1.07 wt, 1 eq). The mixture was warmed to 25+/-2 0C and stirred for 30 min. 4-Methyl-3- thiosemicarbazide (0.83 wt, 1 eq) was then added and the mixture further stirred for 2 h at 25+/-2°C. The mixture was filtered and the cake was washed with fresh tetrahydrofuran (1 vol) and dried on the filter for a few hours. The cake was suspended in 1 M aqueous NaOH (13 vol) and heated to 70 0C for 30 min. After this time, the mixture was cooled to 25+/-2 °C and a solid was removed by filtration. The cake was washed with 1 M aqueous NaOH (10 vol). The combined mother liquors were cooled to 0 0C and acidified to ca. pH 5 with HCI (aqueous, 16percent; NOTE: keep temperature while adding HCI below +10 0C). The suspended product was isolated by filtration washing with water (2x3 vol). The cake was dried at 40 0C for 18 h in high vacuum to obtain 4-methyl-5-(4-methyl-1 ,3-oxazol-5- yl)-2,4-dihydro-3H-1 ,2,4-triazole-3-thione (respectively a tautomeric form thereof; 290 g, 37percent). NaOEt (21percent solution in EtOH, 2.08 vol, 1.1 eq) was added to EtOH (20 vol) under nitrogen atmosphere. 4-Methyl-5-(4-methyl-1 ,3-oxazol-5-yl)-2,4-dihydro-3H-1 ,2,4-triazole- 3-thione (respectively a tautomeric form thereof; 290 g, 1 wt) was added in one portion and the resulting mixture stirred at 25+/-2°C until a clear solution was obtained. Then 1- bromo-3-chloropropane (0.54 vol, 1.1 eq) was added and the solution stirred at 40 'C for 24 h then cooled to 25 'C. After filtration water (20 vol) was added and the ethanolic phase was removed by vacuum distillation (internal temperature ~40 'C). The mixture was extracted with EtOAc (41 vol). The aqueous layer was removed and the organic phase was evaporated to dryness. Dichloromethane (4 vol) was added. The organic solution is purified through a short silica gel column (18 wt of silica), eluting with EtOAc (200 vol) to give the title compound as a solid foam (267.64 g, 66percent). NMR (1H1 CDCI3): δ 7.90 (s, 1H), 3.70 (s, 5H), 3.40 (t, 2H), 2.52 (s, 3H), 2.30 (m, 2H).
44%
Stage #1: at 20 - 120℃; Inert atmosphere
Stage #2: at 20℃; for 4 h; Inert atmosphere
Stage #3: With hydrogenchloride In waterInert atmosphere
A stirred mixture of ethyl 2-chloro-3-oxobutanoate (16.8 ml, 121.51 mmol) and formamide (13.5 mL, 340.23 mmol) was heated to 120 °C. After 6 hrs the mixture was allowed to cool to RT and stirred under nitrogen O/N. The mixture was treated with 3M NaOH (120 mL, reaction moderately exothermic) and stirred at RT for 4 hours. EtOAc (120 mL) was added and the phases allowed separating. The organic layer was discarded while the aqueous was acidified with 37percent aqueous HCI to pH 2 (~ 40 mL). A precipitate started to form. The suspension was treated with EtOAc (160 mL) and, vigorously shaken until the precipitate had dissolved. Phases were separated and the aqueous one was further extracted with EtOAc twice (120 mL). The combined organic layers were concentrated to low volume. Fresh EtOAc (160 mL) was added and the mixture evaporated to dryness under vacuum. The collected solid was placed in the oven at 45 °C O/N under reduced pressure affording 4-methyl-1 ,3- oxazole-5-carboxylic acid (p53, 8.52 g, y=44percent) as rusty brown solid. MS (/T7/z): 128.0 [MH]+
44%
Stage #1: at 120℃; for 6 h; Inert atmosphere
Stage #2: at 20℃; for 4 h;
A stirred mixture of ethyl 2-chloro-3-oxobutanoate (16.8 mL, 121.51 mmol) and formamide (13.5 mL, 340.23 mmol) was heated to 120 °C. After 6 hrs the mixture was allowed to cool to RT and stirred under nitrogen ON. The mixture was treated with 3 M NaOH (120 mL, reaction moderately exothermic) and stirred at RT for 4 hrs. EtOAc (120 mL) was added and the phases allowed separating. The organic layer was discarded while the aqueous was acidified with37percent aqueous HCI to pH 2 (4O mL). A precipitate started to form. The suspension was treated with EtOAc (160 mL) and, vigorously shaken. Phases were separated and the aqueous one was further extracted with EtOAc twice (120 mL). The combined organic layers were concentrated to low volume. Fresh EtOAc (160 mL) was added and the mixture evaporated to dryness under vacuum. The collected solid was placed in the oven at 45 °C ON under reduced pressure to give8.52 g of title compound (p1, y= 44percent), rusty brown solid. MS (m/z): 128.0 [IVII{]t
44%
Stage #1: at 120℃; for 6 h;
Stage #2: at 20℃; for 4 h; Inert atmosphere
Preparation 1
4-methyl-1,3-oxazole-5-carboxylic acid
A stirred mixture of ethyl 2-chloro-3-oxobutanoate (16.8 mL, 121.51 mmol) and formamide (13.5 mL, 340.23 mmol) was heated to 120° C.
After 6 hrs the mixture was allowed to cool to RT and stirred under nitrogen O/N.
The mixture was treated with 3 M NaOH (120 mL, reaction moderately exothermic) and stirred at RT for 4 hrs. EtOAc (120 mL) was added and the phases allowed separating.
The organic layer was discarded while the aqueous was acidified with 37percent aqueous HCl to pH 2 (˜40 mL).
A precipitate started to form.
The suspension was treated with EtOAc (160 mL) and, vigorously shaken.
Phases were separated and the aqueous one was further extracted with EtOAc twice (120 mL).
The combined organic layers were concentrated to low volume.
Fresh EtOAc (160 mL) was added and the mixture evaporated to dryness under vacuum.
35.3%
Stage #1: at 120℃; for 21 h;
Stage #2: With sodium hydroxide; water In tert-butyl methyl ether; N,N-dimethyl-formamide at 20℃; for 3 h;
Stage #3: With hydrogenchloride In water at 20℃; for 2.16667 h;
Ethyl^-chloroacetoacetate (28.6 g, 24.0 ml.) was dissolved in DMF (28.6 ml_) and formamide (19.5 mL) was added. The resulting solution was heated up to 120 0C (internal temperature) under nitrogen for 21 h. The mixture was allowed to cool down to 200C, diluted with ter-butyl methyl ether (172 mL) and washed with water (115 mL). The aqueous phase was extracted again with 115 mL of fert-butyl methyl ether and the combined organic layers were washed twice with water (86 mL) and treated with NaOH 3 N (86 mL). The resulting mixture was stirred at 200C for 3 hours. The organic layer was discarded while the aqueous was acidified with 20 mL of concentrated HCI (37percent sol.) till pH 2 over 10 minutes. A precipitate started to crush out of solution. The suspension was stirred at 200C for 2 h, filtered and the cake washed with 14.3 mL of cold water (1O0C ca.). The collected solid was dried under high vacuum at 400C for 16 hours. The title compound was obtained in a theoretical yield of 35.3 percent (7.81 g). NMR (1 H, DMSO-d6, δ ppm): 13.5 (bs, 1 H), 8.47 (s, 1 H), 2.38 (s, 3H) MS (m/z): 128[MH]+
35.5%
Stage #1: at 120℃; for 21 h;
Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide at 20℃; for 3 h;
Stage #3: With hydrogenchloride In water; N,N-dimethyl-formamide at 20℃; for 2.16667 h;
Ethyl^-chloroacetoacetate (28.6 g, 24.0 ml.) was dissolved in DMF (28.6 mL) and formamide (19.5 mL) was added. The resulting solution was heated up to 120 0C (internal temperature) under nitrogen for 21 h. The mixture was allowed to cool down to 200C, diluted with ter-butyl methyl ether (172 mL) and washed with water (115 mL). The aqueous phase was extracted again with 115 mL of tert-butyl methyl ether and the combined organic layers were washed twice with water (86 mL) and treated with NaOH 3 N (86 mL). The resulting mixture was stirred at 200C for 3 hours. The organic layer was discarded while the aqueous was acidified with 20 mL of concentrated HCI (37percent sol.) till pH 2 over 10 minutes. A precipitate started to crush out of solution. The suspension was stirred at 200C for 2 h, filtered and the cake washed with 14.3 mL of cold water (1O0C ca.). The collected solid was dried under high vacuum at 400C for 16 hours. The title compound was obtained in a theoretical yield of 35.5 percent (7.8 g).

Reference: [1] Patent: WO2005/80382, 2005, A1, . Location in patent: Page/Page column 47-48
[2] Patent: WO2007/22933, 2007, A1, . Location in patent: Page/Page column 31-32
[3] Patent: WO2007/22980, 2007, A1, . Location in patent: Page/Page column 35; 36
[4] Patent: WO2005/123717, 2005, A1, . Location in patent: Page/Page column 21-22
[5] Patent: WO2006/108700, 2006, A1, . Location in patent: Page/Page column 34-35
[6] Patent: WO2016/67043, 2016, A1, . Location in patent: Page/Page column 108
[7] Patent: WO2017/21920, 2017, A1, . Location in patent: Paragraph 0495; 0496
[8] Patent: US2018/297990, 2018, A1, . Location in patent: Paragraph 0227
[9] Patent: WO2007/22980, 2007, A1, . Location in patent: Page/Page column 131
[10] Patent: WO2008/22994, 2008, A1, . Location in patent: Page/Page column 18
  • 3
  • [ 609-15-4 ]
  • [ 2510-32-9 ]
Reference: [1] Journal of the Chemical Society, 1953, p. 93,95
  • 4
  • [ 77287-34-4 ]
  • [ 609-15-4 ]
  • [ 20485-41-0 ]
YieldReaction ConditionsOperation in experiment
95.8%
Stage #1: With tetraphosphorus decasulfide In 1,2-dimethoxyethane for 2 h; Inert atmosphere; Large scale
Stage #2: at 60℃; for 8 h; Large scale
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.
Reference: [1] Patent: CN105130924, 2017, B, . Location in patent: Paragraph 0021; 0022
  • 5
  • [ 17356-08-0 ]
  • [ 609-15-4 ]
  • [ 5398-36-7 ]
YieldReaction ConditionsOperation in experiment
86.8%
Stage #1: With potassium carbonate In ethylene glycol at 3℃; for 3 h;
Stage #2: With boron tribromide In ethylene glycol for 0.5 h;
In a molar ratio of 1.3:1,Weigh 2-ethyl acetoacetate and thiourea into a three-necked flask.And adding potassium carbonate and ethylene glycol, the molar ratio of potassium carbonate and thiourea is 2:1, the molar ratio of ethylene glycol to ethyl 2-chloroacetoacetate is 5:1, and the three-necked flask is placed in an ice water bath. The reaction was stirred at 3 ° C for 3 h. After the reaction, 3 drops of boron tribromide were added dropwise, and the reaction was further stirred for 30 min. After the reaction, the temperature was raised to room temperature. The reaction liquid in the three-necked flask was mixed with ethyl acetate and distilled water, stirred and allowed to stand. After stratification, the oil phase is collected, washed with water and dried with anhydrous sodium sulfate. After drying, the reaction solution is rotary evaporated to dryness, and the dried product is added to an ethanol solution for recrystallization to obtain a key intermediate of ocotamine hydrochloride 2- Ethyl aminothiazole-4-carboxylate, melting point 173.4 ° C, purity 99.5percent,The yield was 86.8percent.
Reference: [1] Patent: CN108503605, 2018, A, . Location in patent: Paragraph 0020-0025
  • 6
  • [ 115-08-2 ]
  • [ 609-15-4 ]
  • [ 20582-55-2 ]
YieldReaction ConditionsOperation in experiment
58.7% for 3 h; Reflux 3L reaction flask with mechanical stirring,Thermometer and constant pressure dropping funnel,Under ice-water bath, 2.5 L of tetrahydrofuran,135.6 g phosphorus sulfide,Control temperature below 10 ,50g formamide was added dropwise,Warmed to room temperature,The reaction for 2 hours.Concentrate to dryness under reduced pressure.The solid was dissolved with 5percent NaOH solution,Extracted five times with ethyl acetate,Each 300mL.The combined organic layers,Rinse once with saturated brine,Dried over anhydrous sodium sulfate,filter,concentrate,Have a yellow oily liquid 55g.
2L reaction flask with mechanical stirring,Condenser and thermometer,Add 55 g of thiocarboxamide,185g ethyl 2-chloroacetoacetate and 1000mL absolute ethanol,Warmed to reflux,Insulation for 3 hours.Concentrate to dryness under reduced pressure,Add water to dissolve the solid,Extracted three times with ethyl acetate,200mL each.The combined organic layers,Dried over anhydrous sodium sulfate,filter,concentrate,Got a red oily liquid.Vacuum distillation,To the former distillate,Positive fraction plus a small amount of petroleum ether,Frozen crystallization,filter.A white solid 142g,Molar yield: 58.7percent.
Reference: [1] Heterocycles, 1980, vol. 14, # 1, p. 33 - 37
[2] Patent: CN106977471, 2017, A, . Location in patent: Paragraph 0008; 0018; 0022
[3] Journal of Medicinal and Pharmaceutical Chemistry, 1959, vol. 1, p. 577,594
[4] Journal of the Chemical Society, 1939, p. 443,445
[5] Helvetica Chimica Acta, 1945, vol. 28, p. 824,827
[6] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 24, p. 368
[7] Journal of the American Chemical Society, 1935, vol. 57, p. 1879
[8] Tetrahedron Letters, 1990, vol. 31, # 10, p. 1487 - 1490
[9] Patent: EP2039686, 2009, A1, . Location in patent: Page/Page column 28
[10] Patent: US2002/68729, 2002, A1,
[11] Journal of Medicinal Chemistry, 2015, vol. 58, # 17, p. 6909 - 6927
  • 7
  • [ 609-15-4 ]
  • [ 20582-55-2 ]
Reference: [1] Patent: CN101921268, 2016, B,
[2] Patent: WO2006/108701, 2006, A1,
  • 8
  • [ 77287-34-4 ]
  • [ 609-15-4 ]
  • [ 20582-55-2 ]
Reference: [1] Proceedings - Indian Academy of Sciences, Section A, 1945, # 22, p. 362,376
  • 9
  • [ 609-15-4 ]
  • [ 22900-83-0 ]
Reference: [1] Patent: WO2011/73617, 2011, A1,
[2] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1625 - 1629
[3] Patent: WO2017/152032, 2017, A1,
  • 10
  • [ 504-29-0 ]
  • [ 609-15-4 ]
  • [ 21801-79-6 ]
YieldReaction ConditionsOperation in experiment
44%
Stage #1: at 80℃; for 48 h;
Stage #2: With water; sodium hydroxide In ethanol at 70℃; for 1 h;
Stage #3: With hydrogenchloride In ethanol; waterCooling with ice
[001145] (i) Production of 2-methylimidazo[l,2-a]pyridine-3-carboxylic acid [001146] A mixture of pyridin-2-amine (10 g, 106 mmol), ethyl 2-chloro-3-oxobutanoate (16 g, 97 mmol) and ethanol (200 mL) was stirred at 800C for 2 days. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (25 mL), water (75 mL) and ethanol (200 mL) were added to the obtained residue, and the mixture was stirred at 700C for 1 hr. 6N Hydrochloric acid (34 mL) was added dropwise to the reaction mixture under ice-cooling. The resulting precipitate was collected by filtration, washed with water, ethanol and diethyl ether and dried to give the title compound (7.6 g, 44percent) as a pale-pink solid.[001147] 1H-NMR (DMSO-d6, 300 MHz) δ 2.60 (3H, s), 7.14 (IH, dt, J = 1.3, 6.9 Hz), 7.50 (IH, ddd, J = 1.3, 7.0, 8.7 Hz), 7.65 (IH, td, J = 1.0, 9.0 Hz), 9.27 (IH, td, J = Ll, 7.0 Hz), 13.04 (IH, br s).
Reference: [1] Patent: WO2010/90716, 2010, A1, . Location in patent: Page/Page column 321
  • 11
  • [ 609-15-4 ]
  • [ 108-46-3 ]
  • [ 6174-86-3 ]
YieldReaction ConditionsOperation in experiment
92% With sulfuric acid In 1,4-dioxane at 60℃; for 4 h; 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 24 h; 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: 79percent; Melting Point: 240-243 °C.
74% at 0 - 20℃; for 12 h; 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].
Reference: [1] Chemistry - A European Journal, 2012, vol. 18, # 32, p. 9901 - 9910
[2] Synthesis, 2006, # 11, p. 1895 - 1897
[3] Monatshefte fur Chemie, 2008, vol. 139, # 7, p. 805 - 808
[4] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 153 - 165
[5] Tetrahedron Letters, 2006, vol. 47, # 19, p. 3279 - 3281
[6] Australian Journal of Chemistry, 2013, vol. 66, # 2, p. 131 - 144
[7] Journal of Photochemistry and Photobiology B: Biology, 2016, vol. 157, p. 1 - 14
[8] Molecules, 2016, vol. 21, # 6,
[9] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 1, p. 358 - 365
[10] Chemische Berichte, 1901, vol. 34, p. 356
[11] Journal of the Indian Chemical Society, 1931, vol. 8, p. 129,132[12] Journal of the Indian Chemical Society, 1935, vol. 12, p. 536,539
[13] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 272 - 275
[14] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 6, p. 1251 - 1257
[15] Chinese Chemical Letters, 2011, vol. 22, # 6, p. 663 - 666
[16] European Journal of Medicinal Chemistry, 2018, vol. 151, p. 434 - 449
[17] Bioorganic Chemistry, 2018, vol. 81, p. 512 - 528
  • 12
  • [ 2227-79-4 ]
  • [ 609-15-4 ]
  • [ 33763-20-1 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1890, vol. 259, p. 234
  • 13
  • [ 141-97-9 ]
  • [ 1115-30-6 ]
  • [ 623-71-2 ]
  • [ 64-19-7 ]
  • [ 141-78-6 ]
  • [ 609-15-4 ]
  • [ 123-25-1 ]
Reference: [1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, # 1, p. 109 - 112[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 1, p. 125 - 128
  • 14
  • [ 584-08-7 ]
  • [ 609-15-4 ]
  • [ 20485-39-6 ]
YieldReaction ConditionsOperation in experiment
31% With formamide In benzene EXAMPLE 1
Preparation of Ethyl 4-Methyl-5-Oxazolecarboxylate
This compound was prepared according to the procedure described in French Pat. No. 1,543,853.
A mixture of 50.0 g (0.337 moles) of ethyl chloroacetoacetate and 42.0 g (0.933 moles) of formamide was stirred at 120°-135° for 18 hr.
Thereafter, the mixture was cooled using an ice bath to 10° C. 300 ml of 1 N K2 CO3 was added dropwise with gas evolution noted.
After complete addition of K2 CO3 solution, the reaction mixture was stirred with 200 ml of benzene/ether (2:1) and saturated with NaCl.
The insoluble material was filtered and the benzene/ether layer was separated and washed with water, dried (MgSO4) and concentrated under reduced pressure.
The brown residue was distilled on a Kugelrohr to give 14.8 g of white solid, mp 31°-33° C.; yield 31percent; nmr (CDCl3) 8.0 (s,1H,C2 H), 44 (q, J=7 Hz, 2H,CH2), 2.5 (s,3H,CH3), 1.4 (t,3H,CH3).
Reference: [1] Patent: US4303439, 1981, A,
  • 15
  • [ 16712-16-6 ]
  • [ 609-15-4 ]
  • [ 20485-39-6 ]
Reference: [1] Organic Letters, 2006, vol. 8, # 18, p. 4125 - 4128
[2] Patent: US2009/143346, 2009, A1, . Location in patent: Page/Page column 8
  • 16
  • [ 609-15-4 ]
  • [ 20485-39-6 ]
Reference: [1] Patent: US6063778, 2000, A,
  • 17
  • [ 77287-34-4 ]
  • [ 609-15-4 ]
  • [ 20485-39-6 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1998, vol. 35, # 4, p. 859 - 863
[2] Pharmaceutical Chemistry Journal, 1990, vol. 23, # 4, p. 330 - 332
[3] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 2, p. 443 - 445
[4] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 6, p. 1517 - 1520
[5] Patent: US2009/36450, 2009, A1, . Location in patent: Page/Page column 44
  • 18
  • [ 609-15-4 ]
  • [ 20485-39-6 ]
Reference: [1] Pharmaceutical Chemistry Journal, 1990, vol. 23, # 4, p. 330 - 332
  • 19
  • [ 96-50-4 ]
  • [ 609-15-4 ]
  • [ 57626-37-6 ]
YieldReaction ConditionsOperation in experiment
82% at 90℃; for 6 h; 2-Aminothiazole (3.00 g, 29.99 mmol) and 2-chloroethylacetoacetate(4.96 mL, 35.99 mmol) were taken in 1,2-dimethoxyethane(30 mL) and heated at 90 C for 6 h. The reactionmixture was concentrated under reduced pressure, diluted withEtOAc (80 mL), washed the organic layer with H2O (3 30 mL).The separated organic layer was dried over anhyd Na2SO4 and concentratedunder vacuo to get crude compound. The crude compoundwas purified by column chromatography using 20percent EtOAcin Hexanes as eluent to get ethyl 6-methylimidazo[2,1-b]thiazole-5-carboxylate (2a) (5.20 g, 82percent) as an Off-white solid. ESIMSshowed 211 [M+H]+ and carried to next step.
26% at 80℃; for 24 h; [001195] (i) Production of ethyl 6-methylimidazo[2,l-b][l,3]thiazole-5-carboxylate[001196] A mixture of l,3-thiazol-2-amine (10 g, 100 mmol), ethyl 2-chloro-3-oxobutanoate (16 g, 100 mmol) and ethanol (100 mL) was stirred at 800C for 1 day. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80- 50/50) and washed with diisopropyl ether to give the title compound (5.5 g, 26percent) as a colorless solid.[001197] 1H-NMR (DMSO-d6, 300 MHz) 5 1.34 (3H, t, J = 7.2 Hz), 2.51 (3H, s), 4.33 (2H, q, J = 7.2Hz), 7.44 (IH, d, J = 4.3 Hz), 8.08 (IH, d, J = 4.3 Hz).
Reference: [1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 6, p. 1298 - 1307
[2] European Journal of Medicinal Chemistry, 1994, vol. 29, # 12, p. 981 - 983
[3] Patent: WO2010/90716, 2010, A1, . Location in patent: Page/Page column 328
[4] Farmaco, Edizione Scientifica, 1983, vol. 38, # 7, p. 533 - 545
[5] Archiv der Pharmazie, 1976, vol. 309, # 12, p. 959 - 965
[6] Patent: US2010/152192, 2010, A1, . Location in patent: Page/Page column 10
[7] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 24, p. 5916 - 5919
[8] Patent: WO2010/70452, 2010, A1, . Location in patent: Page/Page column 23
  • 20
  • [ 609-15-4 ]
  • [ 14337-43-0 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 50
  • 21
  • [ 609-15-4 ]
  • [ 110-46-3 ]
  • [ 14337-43-0 ]
Reference: [1] Chemische Berichte, 1955, vol. 88, p. 130,133
  • 22
  • [ 7697-37-2 ]
  • [ 609-15-4 ]
  • [ 14337-43-0 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 50
  • 23
  • [ 104-94-9 ]
  • [ 609-15-4 ]
  • [ 27143-07-3 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With hydrogenchloride; sodium nitrite In water at -10 - -5℃; for 0.5 h;
Stage #2: With sodium acetate In water at -10 - -5℃; for 2 h;
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%
Stage #1: With hydrogenchloride; sodium nitrite In ethanol; water at 0 - 5℃; for 0.5 h;
Stage #2: With sodium acetate In ethanol; water at 0 - 25℃;
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%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5 h;
Stage #2: With sodium acetate In ethanol; water at -5 - 20℃; for 4 h;
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 7 h; 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%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5 h;
Stage #2: With sodium acetate In methanol at 0℃; for 1 h;
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).
105 g
Stage #1: With hydrogenchloride; sodium nitrite In water at -5 - 10℃;
Stage #2: With sodium acetate; acetone In water at -5 - 0℃; for 1 h;
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).

Reference: [1] Patent: CN104513239, 2017, B, . Location in patent: Paragraph 0197; 0238; 0243; 0244
[2] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 431 - 446
[3] Patent: CN107400131, 2017, A, . Location in patent: Paragraph 0026; 0031; 0042-0044
[4] Patent: CN105384739, 2016, A, . Location in patent: Paragraph 0391; 0392; 0393
[5] Patent: CN104395312, 2016, B, . Location in patent: Paragraph 0396; 0451-0455; 0501; 0502-0506
[6] Synthesis, 2011, # 11, p. 1799 - 1803
[7] Patent: WO2012/168364, 2012, A1, . Location in patent: Page/Page column 16-17
[8] Patent: WO2015/177801, 2015, A1, . Location in patent: Page/Page column 25; 26
[9] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 10, p. 2800 - 2810
  • 24
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  • [ 4755-81-1 ]
  • [ 609-15-4 ]
Reference: [1] Green Chemistry, 2009, vol. 11, # 2, p. 275 - 278
  • 25
  • [ 141-97-9 ]
  • [ 6134-66-3 ]
  • [ 609-15-4 ]
Reference: [1] Chemistry Letters, 2012, vol. 41, # 4, p. 432 - 434
[2] Synthesis (Germany), 2016, vol. 48, # 9, p. 1359 - 1370
  • 26
  • [ 141-97-9 ]
  • [ 6134-66-3 ]
  • [ 85153-67-9 ]
  • [ 609-15-4 ]
Reference: [1] Journal of applied chemistry of the USSR, 1985, vol. 58, # 111 pt 1, p. 2318 - 2322
[2] Journal of applied chemistry of the USSR, 1985, vol. 58, # 111 pt 1, p. 2318 - 2322
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1988, vol. 37, p. 756 - 757[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1988, # 4, p. 876 - 877
  • 27
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  • [ 6134-66-3 ]
Reference: [1] Journal of the Chemical Society, 1923, vol. 123, p. 1129
  • 28
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  • [ 6134-66-3 ]
  • [ 609-15-4 ]
  • [ 5408-04-8 ]
Reference: [1] Monatshefte fuer Chemie, 1980, vol. 111, p. 771 - 774
  • 29
  • [ 141-97-9 ]
  • [ 1115-30-6 ]
  • [ 623-71-2 ]
  • [ 64-19-7 ]
  • [ 141-78-6 ]
  • [ 609-15-4 ]
  • [ 123-25-1 ]
Reference: [1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, # 1, p. 109 - 112[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 1, p. 125 - 128
  • 30
  • [ 123-73-9 ]
  • [ 609-15-4 ]
  • [ 6555-40-4 ]
YieldReaction ConditionsOperation in experiment
65% With sodium acetate In acetic acid EXAMPLE 1
Preparation of Ethyl 2-Hydroxy-6-methylbenzoate
A stirred mixture of crotonaldehyde (21.0 g, 0.30 mol) and anhydrous sodium acetate (25.0 g, 0.30 mol) in glacial acetic acid is heated to reflux temperature under N2, treated dropwise with ethyl chloroacetoacetate (41.1 g, 95percent, 0.25 mol) over a 2.25 hr. period, heated at reflux temperature for 16 hr., cooled to room temperature and concentrated in vacuo to give a residue.
The residue is partitioned between ethyl acetate and water.
The organic phase is diluted with hexanes, washed sequentially with water and aqueous NaHCO3 and concentrated in vacuo to give the title product as an oil, 41.0 g, 71.4percent purity (65percent yield), characterized by NMR analysis.
Reference: [1] Patent: US6441219, 2002, B1,
  • 31
  • [ 609-15-4 ]
  • [ 100-51-6 ]
  • [ 67354-34-1 ]
Reference: [1] Patent: US2004/147561, 2004, A1, . Location in patent: Page 41
  • 32
  • [ 17356-08-0 ]
  • [ 609-15-4 ]
  • [ 72054-60-5 ]
YieldReaction ConditionsOperation in experiment
93% for 2 h; Heating / reflux Step 2:
Ethyl 2-amino-5-methylthiazole-4-carboxylate
Thiourea (47 g, 616.83 mmol) was added to a solution of ethyl 2-chloro-3-oxobutanoate (100 g, 577.19 mmol) in ethanol (1000 mL).
The resulting solution was allowed to react for 2 h at reflux.
The reaction mixture was cooled in a water/ice bath.
A filtration was performed to afford 105 g (93percent) of ethyl 2-amino-5-methylthiazole-4-carboxylate as a light yellow solid.
Reference: [1] Patent: US2008/139558, 2008, A1, . Location in patent: Page/Page column 51
  • 33
  • [ 504-29-0 ]
  • [ 609-15-4 ]
  • [ 123531-52-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 1870 - 1873
  • 34
  • [ 609-15-4 ]
  • [ 173530-73-9 ]
Reference: [1] Patent: US2014/128386, 2014, A1,
[2] Patent: US2017/217954, 2017, A1,
  • 35
  • [ 24016-03-3 ]
  • [ 609-15-4 ]
  • [ 173530-73-9 ]
Reference: [1] Patent: US2017/57954, 2017, A1,
  • 36
  • [ 609-15-4 ]
  • [ 161797-99-5 ]
YieldReaction ConditionsOperation in experiment
84.2%
Stage #1: With sodium hydroxide; hydrogen sulfide In ethanol at 80℃;
Stage #2: With hydrogenchloride In ethanol
Stage #3: at 70℃; for 2 - 3 h; Heating / reflux
A mixture of 4-Cyanophenol (23.82 g, 0.2 mol), NaOH (8 g, 0.2 mol), and 200 mL ethanol were mixed in a pressure bottle while heated to 80° C. Hydrogen sulfide gas was then introduced and the pressure increased to 30-60 psi until the thioamidation was determined to be complete by HPLC. Without isolating the thioamide product, HCl was added to the bottle until the pH was below 3.5, the H2S gas was removed, and the bottle was placed under a vacuum for 20 minutes at 30-40° C. The reaction was then heated to 70° C. and ethyl 2-chloroacetoacetate(1.1 eq.) was added to the reaction solution. The reaction was mixed under reflux for 2-3 hours, treated with enough H2O to dissolve the NaCl salt in the reaction mixture, cooled to room temperature, treated with enough water to precipitate the product, and the solid was collected by filtration. The precipitate was washed with water and dried at 80° C. with nitrogen bleeding to provide 50.50 g (84.2percent) of desired product
Reference: [1] Patent: US2005/75503, 2005, A1, . Location in patent: Page/Page column 3
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  • [ 609-15-4 ]
  • [ 161797-99-5 ]
YieldReaction ConditionsOperation in experiment
98% at 65 - 70℃; for 3 h; EXAMPLE-2 (preparation of ethyl 2-(4-hydroxyphenyl)-4-methyl-5- thiazolecarboxylate) 0.26 moles of 4-hydroxythiobenzamide suspended in 180 ml of ethanol was taken in the reactor. 0.29 Moles of ethyl-2- chloroacetoacetate was added. The reaction mixture was then heated to 65-70°C and maintained at this temperature for 3 hrs. Ethanol was distilled off and 300 ml water was added to the reaction mass. It was then cooled to 25-30°C and maintained at this temperature for 30 min. The solid obtained was filtered and washed with 70 ml water. The product was dried at 80oC to obtain ethyl 2- (4- hydroxyphenyl)- 4- methyl- 5-thiazolecarboxylate with 98percent yield.
90.7% at 60 - 65℃; for 2.5 h; Example 1 : Synthesis of Ethyl 2-(4-HvdroxyphenvO-4-Methyl-5-Thiazol CarboxylateA mixture of 4-hydroxy thiobenzamide (100 g, 0.653 mol) and ethyl 2- chloroacetoacetate (118.3 g, 0.719 mol) in denatured spirit (DNS) (500 mL) was heated at about 60°C to 65°C for about 2.5 hours. The reaction mixture was cooled to about 0°C to 5°C and stirred for about 1 hour at the same temperature. The solid obtained was filtered, washed with denatured spirit and dried to obtain the title compound. (Yield: 156 g, 90.7percent)
58% at 55 - 85℃; for 3 h; 4-hydroxy thiobenzamide (2) (0.79 g, 5.16 mmol) was dissolved in isopropanol (4 mL) and the reaction mixture was then heated to 55 °C and under this heating condition, 2-chloroacetoacetic acid ethyl ester (1.27 g, 7.74 mmol) was added drop wise to it. After addition, the reaction mixture was heated at 85 °C for 3 h. During this reaction a white solid was found. The reaction mixture was cooled at rt and the resultant solid was filtered and washed with cold isopropanol, dried under rotavapour to afford 2-(4-Hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (3) (1 g, 58percent) as white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.83 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.64 Hz, 2H), 4.28 (q, J = 7.04 Hz, 2H), 2.65 (s, 3H), 1.29 (t, J = 7.08 Hz, 3H). 13C NMR (100 MHz, CDCl3):169.01, 168.70, 162.19, 161.01, 152.65, 130.60, 128.01, 122.26, 121.94, 21.12, 17.48, 14.30. MS (ESI): m/z calc. for C13H13NO3S+: 263.0; found: 264.0 [M+H]+.
38 g With phosphoric acid In ethanol; water at 30 - 80℃; After the sulfonylation reaction is complete,Do not need to separate, continue to the next thiazolyl reaction,In the reaction system was added organic solvent 60g ethanol,Get anhydrous phosphoric acid + alcohol system,Then 30 g of ethyl 2-chloroacetoacetate was slowly added dropwise,Temperature control 30-80 ,Insulation reaction, the reaction time is 3-6 hours,The reaction was complete by HPLC, 60 g of water was added,Slowly cool to 0 filter,Washed with a small amount of ice ethanol (10g)The wet product was dried to give 38 g of ethyl 2- (4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylate (formula III) as a pale yellow solid with a chromatographic purity of ≥99percentTwo-step yield of about 86percent, content of 99.5percent;

Reference: [1] Patent: WO2016/46836, 2016, A2, . Location in patent: Page/Page column 4
[2] Patent: WO2012/14117, 2012, A1, . Location in patent: Page/Page column 12
[3] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 334, p. 1 - 12
[4] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 685 - 695
[5] Patent: WO2012/168948, 2012, A2, . Location in patent: Page/Page column 10
[6] Letters in Organic Chemistry, 2015, vol. 12, # 3, p. 217 - 221
[7] Patent: CN104529935, 2017, B, . Location in patent: Paragraph 0050
  • 38
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  • [ 609-15-4 ]
  • [ 161797-99-5 ]
Reference: [1] Patent: CN106928108, 2017, A, . Location in patent: Paragraph 0068; 0069
  • 39
  • [ 609-15-4 ]
  • [ 161798-01-2 ]
Reference: [1] Patent: WO2012/14117, 2012, A1,
[2] Patent: WO2012/168948, 2012, A2,
  • 40
  • [ 609-15-4 ]
  • [ 161798-03-4 ]
YieldReaction ConditionsOperation in experiment
97% at 60℃; for 4 h; 4. lg of the compound having the formula (VI) dissolved in structure 80mLDMF added ethyl-chloroacetoacetate 3. 89g, 60 ° C for 4 hours, the reaction was stopped by filtration to obtain a solid reaction mixture was cooled, ethyl acetate 4. 5g recrystallized white solid 2- (3-aldehyde-4-isobutyloxyphenyl) -4-methyl-thiazole-5-carboxylate, namely the compound having the formula (VII) structure, to close It was 97percent.
Reference: [1] Patent: CN103880775, 2016, B, . Location in patent: Paragraph 0071; 0079; 0086; 0093; 0100
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  • [ 161798-03-4 ]
Reference: [1] Patent: WO2012/168948, 2012, A2,
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