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CAS No. :94-05-3 MDL No. :MFCD00009136
Formula : C8H11NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :KTMGNAIGXYODKQ-VOTSOKGWSA-N
M.W : 169.18 Pubchem ID :1715183
Synonyms :

Safety of [ 94-05-3 ]

Signal Word:Danger Class:9
Precautionary Statements:P264-P261-P270-P271-P272-P280-P285-P305+P351+P338-P310-P302+P352-P304+P340-P330-P342+P311-P362+P364-P403+P233-P501 UN#:3335
Hazard Statements:H302-H315-H317-H318-H334-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 94-05-3 ]

* 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.

  • Upstream synthesis route of [ 94-05-3 ]
  • Downstream synthetic route of [ 94-05-3 ]

[ 94-05-3 ] Synthesis Path-Upstream   1~43

  • 1
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Reference: [1] European Journal of Organic Chemistry, 2017, vol. 2017, # 3, p. 600 - 608
  • 2
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  • [ 60-34-4 ]
  • [ 31037-02-2 ]
YieldReaction ConditionsOperation in experiment
85% for 72 h; Heating / reflux Example A
5-Amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester
Methylhydrazine (8.6ml, 162mmol) was added to a solution of ethyl (ethoxymethylene)cyanoacetate (24.9g, 147mmol) in ethanol (250ml) and the mixture was heated at reflux for 3 days.
The solvent was removed in vacuo and the residue was purified by recrystallisation from EtOAc/pet. ether to yield a white solid identified as 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (21.1g,85percent).
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8670 - 8692
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 17, p. 4585 - 4589
[3] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 4, p. 749 - 755
[4] Patent: EP1512687, 2005, A1, . Location in patent: Page/Page column 6
[5] Patent: US5498630, 1996, A,
[6] Pakistan Journal of Scientific and Industrial Research, 2005, vol. 48, # 5, p. 318 - 321
  • 3
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YieldReaction ConditionsOperation in experiment
35% With sodium sulfate In ethanol A.
5-Amino-1-methyl-1H-pyrazole-4-carboxylic acid, ethyl ester
Methylhydrazine (25 grams, 0.54 mole) and ethyl(ethoxymethylene)cyanoacetate (92 grams, 0.54 mole) were combined in 150 ml. of ethanol and refluxed for about 16 hours.
The reaction mixture was then cooled and poured over ice water, and the resulting precipitated product was collected by filtration and dried.
The mother liquor was extracted with chloroform, washed with saturated brine, and dried using sodium sulfate and filter paper.
Solvent was removed in vacuo.
Both groups of crystallized product were recrystallized from ethanol, yielding 32.3 grams (35percent) of 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid, ethyl ester, mp=99°-100° C.
Reference: [1] Journal of Organic Chemistry, 2016, vol. 81, # 11, p. 4883 - 4889
[2] Journal of Heterocyclic Chemistry, 2014, vol. 51, # SUPPL. 1, p. E216-E221
[3] Patent: US4620865, 1986, A,
[4] Patent: WO2008/52974, 2008, A1, . Location in patent: Page/Page column 42
[5] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 9, p. 3379 - 3387
[6] Patent: WO2007/62805, 2007, A1, . Location in patent: Page/Page column 68
  • 4
  • [ 60-34-4 ]
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  • [ 21230-43-3 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
[2] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
  • 5
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 17, p. 2979 - 2984
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Reference: [1] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
  • 7
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Reference: [1] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
[2] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
  • 8
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Reference: [1] Patent: WO2004/103975, 2004, A1,
  • 9
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  • [ 21230-43-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1910 - 1918
  • 10
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  • [ 20187-46-6 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1954, vol. 588, p. 45,56
  • 11
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YieldReaction ConditionsOperation in experiment
96% With N-ethyl-N,N-diisopropylamine In ethanol at 85℃; for 12 h; Ethyl-2-cyano-3-ethoxyacrylate (1.5 g, 8.9 mmol. 1 eq.) was dissolved in ethanol (10 mL)withN,N. diisopropylethyiamine (0.74 mL, 9,8 mmoi, 1.1 eq.) and phenylhydrazine (0.96 mL, 9.8 mmol, 1 .1 eq.) and the solution was heated to 85°C with stirring for 12 h. The reaction was condensed to dryness and dissolved in a minimal amount of dichioromethane and chrornatographed on silica gel (2O30percent ethyl acetate in hexane) to give ethy 5-amino-1-phenyl-1H-pyrazole-4-carboxylate (2) as an orange solid (2.0 g, 96percent yield). MS (EI) m/z 232 [M+H]+
90% for 6 h; Heating Ethyl 5-amino-1-phenyl-1H-pyrazole-4-carboxylate (2a)Phenylhydrazine (1 equivalent) in ethanol was added drop wise to ethanolic solution of ethylehoxymethylene cyanoacetate (1 equivalent). The reaction was refluxed at 70 C for 6-7 hours. The reaction mixture was poured in ice cold water and stirred for 15-20 min when a precipitate separates out. The precipitate formed was filtered off and dried. Yield: 90percent; Melting point: 92°C; LC-ESI-MS (m/z): 232.2 (M+1).
90% at 0 - 80℃; for 6 h; A mixture of ethyl 2-cyano-3-ethoxyacrylate (3.00 g, 17.7 mmol) and phenyl hydrazine (1.75 mL, 17.7 mmol) in ethanol (75 mL) was stirred at 0 °C for 1h. Then, the mixture was stirred at 80 °C for 5 h. After cooling the reaction mixture to room temperature, ethanol was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of n-hexane and ethyl acetate (6:1) to give the desired product 2a (3.71 g, 90 percent). 1H NMR (300 MHz, CDCl3): δ=7.79 (s, 1H), 7.52 (m, 4H), 7.40 (m, 1H), 5.30 (br s, 2H), 4.30 (q, J=7.1Hz, 2H), 1.36 (t, J=7.1Hz, 3H) ppm; MS (ESI): m/z: 232 [M+H+].
70% Reflux A mixture of phenylhydrazine (9 mmol) and 10 mL of ethanolwas stirred and allowed to reflux for 1 h. Then, ethyl(ethoxymethylene)cyanoacetate (9 mmol) dissolved in 10 mL ofethanol was slowly added. The reaction mixture was refluxed for20 min. The reaction mixture was poured into 50 mL of ice-coldwater. The precipitate was collected by filtration and washed withwater to afford 13 in 70percent yield.Yield: 70percent. Mp: 98 C. IR (KBr. cm1): 3400–3140; 2995; 2912;1677; 1621; 1552; 1528; 1280; 781–697. 1H NMR (400 MHz,CDCl3, TMS, d in ppm): 1.36 (t, 3H, J = 7.1 Hz; CH2CH3); 4.30 (q,2H, J = 7.1 Hz CH2CH3); 5.31 (s, 2H, NH2); 7.41–7.37 (m, 1H, H40);7.55–7.48 (m, 4H, H20, H30, H50, H60); 7.78 (s, 1H, H3). 13C NMR(100 MHz, CDCl3, TMS, d in ppm): 14.5; 59.6; 96.2; 123.8; 128.1;129.7; 137.6; 140.6; 149.0; 164.6. EI [M1] 230.2.

Reference: [1] Patent: WO2016/49500, 2016, A1, . Location in patent: Paragraph 00217
[2] Cell Chemical Biology, 2018,
[3] Organic Letters, 2013, vol. 15, # 19, p. 5044 - 5047
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4428 - 4433
[5] Tetrahedron, 2017, vol. 73, # 40, p. 5959 - 5973
[6] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
[7] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4492 - 4498
[8] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 3, p. 591 - 599
[9] Heterocycles, 1984, vol. 22, # 11, p. 2513 - 2516
[10] Chemical Biology and Drug Design, 2015, vol. 85, # 5, p. 608 - 622
[11] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3706 - 3710
[12] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 1 - 13
[13] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 1, p. 159 - 167
[14] Patent: CN107880033, 2018, A, . Location in patent: Paragraph 0015-0017
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Reference: [1] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
  • 13
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  • [ 16078-71-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 4, p. 749 - 755
  • 14
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  • [ 16078-71-0 ]
Reference: [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3867 - 3876
  • 15
  • [ 59-88-1 ]
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  • [ 16078-71-0 ]
Reference: [1] Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, vol. 32, # 1, p. 1091 - 1101
  • 16
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YieldReaction ConditionsOperation in experiment
66.78% With hydrazine In ethanol for 4 h; Reflux Ethylmethyloxymethyl nitrile ethyl acetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol; After 100 mL of hydrazine hydrate was added dropwise to the vessel, the vessel was placed in an electrothermal device and gradually heated to 80 ° C over a period of 30 minutes to give a mixture A; The mixture A was heated to reflux and refluxed for 4 hours. The ethanol was distilled off under reduced pressure and the remaining solid was evaporated. The solid was cooled to stand to precipitate a pale yellow solid which was filtered, washed and dried to give the intermediate 5-amino-lH-pyrazole-4-carboxylic acid ethyl ester. The article used in the washing process was cold Anhydrous ethanol. The product The mass of ethyl 5-amino-1H-pyrazole-4-carboxylate was 41.68 g. Yield: 66.78percent
66.78% With hydrazine hydrate In ethanol at 80℃; for 4.5 h; 1.1) ethyl(ethoxymethylene)cyanoacetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol;1.2) 100mL hydrated hydrazine was added to the container,Placing the container in an electric heating device,In the 30-minute range gradually heated to 80°C ,To obtain a mixture A;1.3) The mixture A was heated to reflux,After 4 hours of refluxing,Distillation of ethanol, residual solids;1.4) The solid was cooled to stand to precipitate a pale yellow solid,The light yellow solid was filtered, washed, dried,To give ethyl 5-amino-lH-pyrazole-4-carboxylate;The articles used in the washing process are cold ethanol.The mass of the product 5-amino-lH-pyrazole-4-carboxylate was 41.68 g. Yield: 66.78percent
66.78% With hydrazine hydrate In ethanol at 80℃; for 4.5 h; 1.1) ethyl(ethoxymethylene)cyanoacetate(68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanolin;1.2) After 100 mL of hydrazine hydrate was added to the vessel, the vessel was placed in an electric heating apparatus and gradually heated to 80 ° C over a period of 30 minutes to obtain a mixture A;1.3) The mixture A was heated to reflux and refluxed for 4 hours. The ethanol was evaporated under reduced pressure and the remaining solid was evaporated.1.4) The solid was cooled to stand to precipitate a pale yellow solid which was filtered, washed, dried,To give ethyl 5-amino-lH-pyrazole-4-carboxylate;The articles used in the washing process are cold ethanol.The mass of the product 5-amino-1H-pyrazole-4-carboxylatewas 41.68 g.Yield: 66.78percent
66.78%
Stage #1: With hydrazine hydrate In ethanol at 80℃; for 0.5 h;
Stage #2: for 4 h; Reflux
Ethoxymethylenenitrile ethyl acetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol;100mL of hydrazine hydrate drops into the container, the container is placed in an electric heating device, within a 30-minute range gradually warmed to 80 , to obtain a mixture A;The mixture A was heated to reflux, refluxed for 4 hours, vacuum distillation of ethanol, the remaining solids;The solid was allowed to cool to leave a pale yellow solid which was filtered, washed, dried,To obtain the intermediate ethyl 5-amino-1H-pyrazole-4-carboxylate;The washing process uses cold anhydrous ethanol.The product, 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester, had a mass of 41.68 g. Yield: 66.78percent
66.78%
Stage #1: With hydrazine hydrate In ethanol at 80℃; for 0.5 h;
Stage #2: for 4 h; Reflux
1.1)Ethoxymethylenenitrile ethyl acetate(68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanolin;1.2) 100mL hydrazine hydrate drops into the container, the container is placed in the electric device, gradually within 30 minutesThe temperature was raised to 80 ° C to obtain a mixture A1;1.3) The mixture A1 was heated to reflux, reflux for 4 hours, vacuum distillation of ethanol, the remaining solids;1.4) The solid was allowed to cool to leave a pale yellow solid which was filtered, washed and dried to give5-amino-1H-pyrazole-4-carboxylic acid ethyl ester;The washing process uses cold anhydrous ethanol.The product, 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester, had a mass of 41.68 g. Yield: 66.78percent
66.78% With hydrazine hydrate In ethanol at 80℃; for 4.5 h; 1.1) Ethoxymethylenenitrile ethyl acetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol;1.2) 100mL hydrazine hydrate drops into the container, the container is placed in an electric device,In a 30-minute range gradually warmed to 80 ° C, to obtain a mixture A;1.3) The mixture A was heated to reflux, reflux for 4 hours, vacuum distillation of ethanol, the remaining solids;1.4) The solid was allowed to cool to leave a pale yellow solid which was filtered, washed and dried to give5-amino-1H-pyrazole-4-carboxylic acid ethyl ester; the washing process used cold anhydrous ethanol. The product, 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester, had a mass of 41.68 g. Yield: 66.78percent
52% With hydrazine hydrate In ethanol for 3 h; Reflux Step 2.
Ethyl 5-amino-1H-pyrazole-4-carboxylate
A solution of ethyl 2-cyano-3-ethoxyacrylate (21 g, 86.98 mmol, 1.00 equiv, 70percent) and hydrazine hydrate (11 g, 176.00 mmol, 2.02 equiv, 80percent) in ethanol (150 mL) was heated to reflux for 3 hours.
The resulting mixture was concentrated under vacuum.
The residue was dissolved in 100 mL of dichloromethane.
The organic layer was washed with 3*50 mL of water and dried over sodium sulfate, then concentrated under vacuum.
This resulted in 7.2 g (52percent) of ethyl 5-amino-1H-pyrazole-4-carboxylate as a yellow solid.
LC-MS: (ES, m/z): 156 [M+H]+
1H-NMR (300 MHz, CDCl3, ppm): 7.75 (s, 1H), 6.53 (s, 1H), 4.31-4.26 (q, J=5.4 Hz, 2H), 1.37-1.32 (t, J=5.4 Hz, 3H)

Reference: [1] Patent: CN105949202, 2016, A, . Location in patent: Paragraph 0048-0053
[2] Patent: CN106008517, 2016, A, . Location in patent: Paragraph 0048; 0049; 0050; 0051; 0052; 0053
[3] Patent: CN106008519, 2016, A, . Location in patent: Paragraph 0048; 0049; 0050; 0051; 0052; 0053
[4] Patent: CN105949199, 2016, A, . Location in patent: Paragraph 0047-0052
[5] Patent: CN105949200, 2016, A, . Location in patent: Page/Page column 6; 7; 23
[6] Patent: CN105949201, 2016, A, . Location in patent: Paragraph 0048-0053
[7] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 18
[8] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 8, p. 821 - 826
[9] Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 2338 - 2344
[10] Patent: US2015/65522, 2015, A1, . Location in patent: Paragraph 0429; 0430
[11] Patent: , 2016, , . Location in patent: Paragraph 0031; 0035
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YieldReaction ConditionsOperation in experiment
52% With hydrazine hydrate In ethanol for 3 h; Reflux A solution of (Z)-ethyl 2-cyano-3-ethoxyacrylate (10.5 g, 48.5 mmol) and hydrazine hydrate (5.5 g, 73 mmol) in ethanol (100 mL) was heated to reflux and stirred for 3 h. The resulting mixture was concentrated in vacuo, the residue was diluted with ethyl acetate (100 mL) and washed with water (3 x 20 mL) followed by brine (50 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EA/PE (v/v) = 1/2) to afford the title compound as a yellow solid (7.2 g, 52percent).LC-MS (ESI, pos. ion) m/z: 156.2 [M+H]+; H NMR (400 MHz, CDCls): δ (ppm) 7.73 (s, 1H), 6.58 (br, 3H), 4.28 (q, J= 7.1 Hz, 2H), 1.33 (t, J= 7.1 Hz, 3H).
52% With hydrazine hydrate In ethanol for 3 h; Reflux (Z) -2-cyano-3-ethoxyacrylate (10.5 g, 48.5 mmol)And hydrazine hydrate (5.5 g, 73 mmol)In ethanol (100 mL)Warmed to reflux,Stir for 3 hours.The resulting reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (100 mL), washed sequentially with water (3 × 20 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (EA / PE (v / v) = 1/2) gave the title compound as a yellow solid (7.2 g, 52percent).
14 g With hydrazine hydrate In ethanol at 95℃; To a solution of ethyl (2Z)-2-cyano-3-ethoxyprop-2-enoate (36 g, crude) in ethanol (200 ml) was added N2H4.H2O (11.72 g, 0.23 mol) with stirring overnight at 95°C. The reaction mixture was concentrated in vacuo to give a residue, which was purified by a silica gel chromatography with 2 percent dichloromethane in methanol to afford ethyl 5-amino-lH-pyrazole-4-carboxylate as a light yellow solid (14 g, 40 percent 2 steps).LC/MS (ES, m/z): [M+H]+ 156.0 *H NMR (300 MHz, CDC13) δ 7.77 (s, 1H), 5.65 (s, 3H), 4.27 - 4.34 (m, 2H), 1.34 - 1.39 (t, 7 = 7.2 Hz, 3H)
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4303 - 4307
[2] Patent: WO2015/73267, 2015, A1, . Location in patent: Paragraph 383
[3] Patent: CN104650092, 2017, B, . Location in patent: Paragraph 0745-0746; 0750-0751
[4] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0174 - 0175
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YieldReaction ConditionsOperation in experiment
96% With sodium acetate; acetic acid In water at 130℃; for 0.5 h; Microwave irradiation Synthesis of 155-1. To a mixture of 155-0 (869 mg, 5.1 mmol) and phenylhydrazine (500 mg, 4.6 mmol) in AcOH/H2O (10 mL/2 mL) was added NaOAc·3H2O (1.40 g, 10.0 mmol). The reaction mixture was stirred at 130 °C for 30 min under microwave. The mixture was allowed to cool to room temperature and ice-water was added. The precipitate was collected by filtration and washed with the mixture of Et2O and PE (Et2O : PE = 1 : 1) to give 155-1 (1.03 g, 96 percent) as a yellow solid
Reference: [1] Patent: WO2017/7756, 2017, A1, . Location in patent: Paragraph 207
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Reference: [1] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
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Reference: [1] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 6, p. 1805 - 1808
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3867 - 3876
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Reference: [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3867 - 3876
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  • [ 15001-11-3 ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine In ethanol at 20 - 80℃; for 8 h; General procedure: To ethyl 2-cyano-3-ethoxyacrylate (2.00 g, 11.8 mmol) and 4-methoxyphenyl hydrazine hydrochloride (2.06 g, 11.8 mmol) in ethanol (75 mL) at room temperature was added triethylamine (1.65 mL, 11.8 mmol). The mixture was stirred at 80 °C for 8 h. After cooling the reaction mixture to room temperature, ethanol was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of n-hexane and ethyl acetate (3:1) to give the desired product 2b (2.42 g, 78 percent). 1H NMR (300 MHz, CDCl3): δ=7.76 (s, 1H), 7.42 (d, J=6.9Hz, 2H), 7.01 (d, J=6.9Hz, 2H), 5.19 (br s, 2H), 4.30 (q, J=7.1Hz, 2H), 3.82 (s, 3H), 1.36 (t, J=7.1Hz, 3H) ppm; MS (ESI): m/z: 262 [M+H+].
Reference: [1] Tetrahedron, 2017, vol. 73, # 40, p. 5959 - 5973
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Reference: [1] Organic Letters, 2013, vol. 15, # 19, p. 5044 - 5047
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Reference: [1] Organic Letters, 2013, vol. 15, # 19, p. 5044 - 5047
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Reference: [1] Cell Chemical Biology, 2018,
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YieldReaction ConditionsOperation in experiment
84% at 150 - 160℃; for 5 h; a)
Preparation of 4-(2-cyano-2-ethoxycarbonyl-vinylamino)-benzoic acid ethyl ester
The mixture of triethyl orthoformate (33.3 mL, 0.2 mol) and ethyl cyanoacetate (21.3 mL, 0.2 mol) in acetic anhydride (80 mL) was heated at 150-160° C. for 5 h.
After cooling to room temperature, the solvent was removed under reduced pressure to give ethyl 2-cyano-3-ethoxyacrylate as a yellow solid (28.5 g, 84percent).
76% at 140℃; for 5 h; Preparation of Intermediate 32 2348 Intermediate 32 2349 2350 [0274] A solution of ethyl cyanoacetate (20 g, 176.8 mmol) and triethyl orthoformate 2351 (29.4 mL, 176.8 mmol) in acetic anhydride (100 mL) was heated to 140 °C and allowed to 2352 stir for 5 h. The solvent was then evaporated to afford crude Intermediate 32 (23 g, 76percent) as a 2353 low melting solid. MS: 170 [M + H]+; TLC: 30percent EtO Ac in hexane: Rf: 0.40.
75% at 100℃; for 4 h; General procedure: A mixture of CH-acid (0.1 mol) (malononitrile for 5aand ethyl cyanoacetate for 5b), triethylorthoformate (0.1 mol, 13 ml) and acetic anhydride (50 ml) was stirred at 100 °C for 4 hours. The resulting reaction mixture was cooled to room temperature and concentrated in vacuo. The solid product was recrystallized from ethanol to afford light yellow crystals.Yields of 5a 78percent (mp 65-67 °C)23 and 75percent of 5b (mp. 49-51 °C)24.
47% at 140℃; Step 1.
Ethyl 2-cyano-3-ethoxyacrylate
A solution of ethyl 2-cyanoacetate (22.6 g, 200.00 mmol, 1.00 equiv), triethyl orthoformate (30 g, 202.70 mmol, 1.01 equiv), and acetic anhydride (100 mL) was stirred for overnight at 140° C.
The resulting mixture was concentrated under vacuum.
The resulting solution was diluted with 110 mL of ether/hexane (1:10).
The solids were collected by filtration.
This resulted in 21 g (47percent) of ethyl 2-cyano-3-ethoxyacrylate as a white solid.
LC-MS: (ES, m/z): 170 [M+H]+
200 g at 120℃; for 5 h; A pesticide intermediate pyrazole-4-carboxylate synthesis method, the specific steps are as follows: step one, Synthesis of ethyl ethoxymethylenecyanoacetate: 226 g of ethyl cyanoacetate and 296 g of triethyl orthoformate were placed The flask was charged with 800 ml of acetic anhydride and reacted at 120 ° C for 5 hours, The product after the reaction gave ethanol, a small amount of unreacted starting material and ethyl ethoxymethylcyanoacetate, And then vacuum pump distillation can be obtained 220 g of light yellow ethyl ethoxymethyl cyanoacetate;

Reference: [1] Patent: US2006/4046, 2006, A1, . Location in patent: Page/Page column 35
[2] Patent: WO2014/145986, 2014, A1, . Location in patent: Paragraph 0274
[3] Arkivoc, 2017, vol. 2017, # 3, p. 73 - 86
[4] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 3, p. 591 - 599
[5] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 18
[6] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2824 - 2827
[7] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1970, p. 1420 - 1424[8] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1970, # 7, p. 1504 - 1509
[9] Bulletin de la Societe Chimique de France, 1961, p. 2423 - 2433
[10] Agricultural and Biological Chemistry, 1984, vol. 48, # 1, p. 51 - 54
[11] Agricultural and Biological Chemistry, 1981, vol. 45, # 12, p. 2769 - 2774
[12] Heterocycles, 2004, vol. 64, p. 177 - 191
[13] Chinese Chemical Letters, 2010, vol. 21, # 8, p. 939 - 942
[14] Patent: WO2011/126903, 2011, A2, . Location in patent: Page/Page column 106
[15] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 979 - 984
[16] Chemical Biology and Drug Design, 2015, vol. 85, # 5, p. 608 - 622
[17] European Journal of Medicinal Chemistry, 2015, vol. 103, p. 583 - 593
[18] Patent: CN106518765, 2017, A, . Location in patent: Paragraph 0009
[19] Patent: US2017/326125, 2017, A1, . Location in patent: Paragraph 0434-0435
[20] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 17, p. 2979 - 2984
  • 27
  • [ 105-56-6 ]
  • [ 94-05-3 ]
Reference: [1] Synthesis, 1971, p. 312 - 314
  • 28
  • [ 2986-19-8 ]
  • [ 94-05-3 ]
  • [ 89487-99-0 ]
YieldReaction ConditionsOperation in experiment
65% With potassium carbonate In ethanol for 48 h; Heating / reflux 2-Methyl-2-thiopseudourea (5 mmol) and ethyl ethoxymethylenecyanoacetate (5 mmol) were dissolved in 20 ml EtOH. To this was added K2CO3 (10 mmol). After the mixture was refluxed for 48 h, it was cooled to room temperature and filtered. The solvent was concentrated in vacuo and purified by column chromatography to give 4-hydroxy-2-(methylthio) pyrimidine-5-carbonitrile in a yield of 65percent.
Reference: [1] Patent: US2008/255172, 2008, A1, . Location in patent: Page/Page column 70
  • 29
  • [ 94-05-3 ]
  • [ 89487-99-0 ]
Reference: [1] Patent: US2009/270389, 2009, A1, . Location in patent: Page/Page column 43
  • 30
  • [ 14527-26-5 ]
  • [ 94-05-3 ]
  • [ 89487-99-0 ]
Reference: [1] Patent: US2003/158218, 2003, A1,
  • 31
  • [ 4930-98-7 ]
  • [ 94-05-3 ]
  • [ 69722-29-8 ]
Reference: [1] Patent: US2003/187014, 2003, A1,
[2] Patent: EP1380296, 2004, A1,
[3] Patent: US4631343, 1986, A,
  • 32
  • [ 4930-98-7 ]
  • [ 94-05-3 ]
  • [ 69722-29-8 ]
Reference: [1] Archiv der Pharmazie, 2010, vol. 343, # 11-12, p. 631 - 638
[2] Patent: US4589905, 1986, A,
[3] Patent: US4705558, 1987, A,
[4] Patent: WO2010/85584, 2010, A1, . Location in patent: Page/Page column 45-46
  • 33
  • [ 62437-99-4 ]
  • [ 94-05-3 ]
  • [ 69722-29-8 ]
Reference: [1] European Journal of Medicinal Chemistry, 1989, vol. 24, # 4, p. 435 - 445
  • 34
  • [ 7400-27-3 ]
  • [ 94-05-3 ]
  • [ 112779-14-3 ]
YieldReaction ConditionsOperation in experiment
77% With sodium acetate In ethanol for 16 h; Heating / reflux Step 1.
5-Amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ester
A solution containing t-butylhydrazine hydrochloride salt (10 g, 80.3 mmol), ethyl (ethoxymethylene)-cyanoacetate (13.6 g, 80.4 mmol), and anhydrous sodium acetate (8.2 g, 100 mmol) in 100 mL ethanol was stirred and refluxed for 16 hours.
The solution was poured into ice-water.
The separated aqueous phase was extracted three times with dichloromethane.
The combined organic phases were washed successively with water and saturated brine solution and dried with sodium sulfate.
The solvent was removed in vacuo to give 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ester (13 g, 77percent).
Reference: [1] Patent: US2007/225280, 2007, A1, . Location in patent: Page/Page column 19
  • 35
  • [ 7400-27-3 ]
  • [ 94-05-3 ]
  • [ 112779-14-3 ]
YieldReaction ConditionsOperation in experiment
24 g With sodium acetate In ethanol for 20 h; Reflux (step 1)
A solution of tert-butylhydrazine monohydrochloride (13.9 g, 111.55 mmol), sodium acetate (11.44 g, 139.43 mmol) and ethyl 2-(ethoxymethylene)-2-cyanoacetate (19 g, 112.31 mmol) in ethanol (130 mL) was heated under reflux for 20 hr.
Ethanol was evaporated under reduced pressure, and ethyl acetate was added to the residue.
The solution was washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (solvent gradient; 2→35percent ethyl acetate/hexane) to give ethyl 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylate (24 g, 111.55 mmol, 102percent) as a pale-yellow oil.
1H-NMR(300MHz,CDCl3):δ1.33(3H, t, J=7.16Hz), 1.63(9H, s), 4.26(2H, q, J=7.03Hz), 5.25(2H,br.s.),7.57(1H, s)
Reference: [1] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
[2] Patent: EP2738170, 2014, A1, . Location in patent: Paragraph 0181; 0347
  • 36
  • [ 3530-11-8 ]
  • [ 94-05-3 ]
  • [ 112779-14-3 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 4, p. 749 - 755
  • 37
  • [ 94-05-3 ]
  • [ 138907-73-0 ]
Reference: [1] Patent: EP1176140, 2002, A1,
  • 38
  • [ 38622-91-2 ]
  • [ 94-05-3 ]
  • [ 131341-86-1 ]
Reference: [1] Patent: US5194628, 1993, A,
  • 39
  • [ 823-85-8 ]
  • [ 94-05-3 ]
  • [ 138907-68-3 ]
YieldReaction ConditionsOperation in experiment
72% With triethylamine In ethanol for 2.5 h; Heating / reflux Ethyl(ethoxymethylene)cyanoacetate (20.80 g, 123 mmol) and triethylamine (17.1 ml_, 123 mmol) were added to a solution of 4-fluorophenylhydrazine hydrochloride (20.00 g, 123 mmol). The reaction mixture was refluxed for 2.5 hours and allowed to cool to room temperature. A solid was collected by filtration, washed with small amounts of ethanol and EPO <DP n="37"/>heptane and allowed to dry under reduced pressure to afford the title compound as a beige solid (22.18 g, 72 percent yield). m/z 250 [M+H]+. 1H NMR (300 MHz, CDCI3) 7.80 (1 H, s), 7.58-7.51 (2H, m), 7.27 (2H, m), 5.27 (2H, br s), 4.33 (2H1 q, J=7.2 Hz), 1.39 (2H, t, J=7.2 Hz).
65% With triethylamine In ethanol at 20 - 80℃; for 8 h; General procedure: To ethyl 2-cyano-3-ethoxyacrylate (2.00 g, 11.8 mmol) and 4-methoxyphenyl hydrazine hydrochloride (2.06 g, 11.8 mmol) in ethanol (75 mL) at room temperature was added triethylamine (1.65 mL, 11.8 mmol). The mixture was stirred at 80 °C for 8 h. After cooling the reaction mixture to room temperature, ethanol was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of n-hexane and ethyl acetate (3:1) to give the desired product 2b (2.42 g, 78 percent). 1H NMR (300 MHz, CDCl3): δ=7.76 (s, 1H), 7.42 (d, J=6.9Hz, 2H), 7.01 (d, J=6.9Hz, 2H), 5.19 (br s, 2H), 4.30 (q, J=7.1Hz, 2H), 3.82 (s, 3H), 1.36 (t, J=7.1Hz, 3H) ppm; MS (ESI): m/z: 262 [M+H+].
Reference: [1] Patent: WO2008/53136, 2008, A1, . Location in patent: Page/Page column 35-36
[2] Tetrahedron, 2017, vol. 73, # 40, p. 5959 - 5973
[3] Patent: WO2008/74814, 2008, A1, . Location in patent: Page/Page column 55
[4] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 16, p. 4724 - 4728
[5] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 5, p. 1680 - 1684
[6] Patent: WO2008/777, 2008, A2, . Location in patent: Page/Page column 58
[7] Patent: WO2007/144327, 2007, A2, . Location in patent: Page/Page column 70
[8] Patent: WO2008/138876, 2008, A1, . Location in patent: Page/Page column 103-104
  • 40
  • [ 94-05-3 ]
  • [ 138907-68-3 ]
YieldReaction ConditionsOperation in experiment
74% With potassium carbonate In ethanol; water PREPARATION A
Ethyl-5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate
A stirred mixture of 11.38 g (70.0 mmole) of a commercially available sample of 4-fluorophenylhydrazine hydrochloride, 11.84 g (70.0 mmole) of ethyl (ethoxymethylene)cyanoacetate and 9.67 g (70.0 mmole) of potassium carbonate in 100 ml of ethanol was refluxed overnight and then treated with 300 ml of water.
The precipitate was filtered and dried in vacuo to furnish 12.87 g (74percent yield) of pale yellow crystalline solid.
The sample was recrystallized from ethanol m.p. 151-2° C.
Analysis:
Calculated for C12 H12 FN3 O2: C, 57.82; H, 4.85; N, 16.86percent. Found: C, 57.82; H, 4.78; N, 16.79percent.
Reference: [1] Patent: US5064851, 1991, A,
  • 41
  • [ 371-14-2 ]
  • [ 94-05-3 ]
  • [ 138907-68-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 5, p. 1562 - 1575
[2] Patent: EP1176140, 2002, A1, . Location in patent: Page 45 - 46
  • 42
  • [ 6829-40-9 ]
  • [ 94-05-3 ]
  • [ 853058-40-9 ]
Reference: [1] Patent: US6693193, 2004, B1, . Location in patent: Page column 14
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 218 - 222
  • 43
  • [ 94-05-3 ]
  • [ 1436686-17-7 ]
Reference: [1] Patent: WO2015/73267, 2015, A1,
[2] Patent: CN104650092, 2017, B,
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