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Product Details of [ 31037-02-2 ]

CAS No. :31037-02-2 MDL No. :MFCD00051652
Formula : C7H11N3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :MEUSJJFWVKBUFP-UHFFFAOYSA-N
M.W : 169.18 Pubchem ID :271299
Synonyms :

Calculated chemistry of [ 31037-02-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.43
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 43.98
TPSA : 70.14 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.86 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.59
Log Po/w (XLOGP3) : 0.66
Log Po/w (WLOGP) : 0.19
Log Po/w (MLOGP) : 0.18
Log Po/w (SILICOS-IT) : -0.21
Consensus Log Po/w : 0.48

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.42
Solubility : 6.51 mg/ml ; 0.0385 mol/l
Class : Very soluble
Log S (Ali) : -1.71
Solubility : 3.31 mg/ml ; 0.0195 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.91
Solubility : 20.7 mg/ml ; 0.122 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.87

Safety of [ 31037-02-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 31037-02-2 ]

* 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 [ 31037-02-2 ]
  • Downstream synthetic route of [ 31037-02-2 ]

[ 31037-02-2 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 94-05-3 ]
  • [ 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
  • 2
  • [ 60-34-4 ]
  • [ 94-05-3 ]
  • [ 31037-02-2 ]
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
  • 3
  • [ 42466-67-1 ]
  • [ 60-34-4 ]
  • [ 31037-02-2 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 5, p. 1045 - 1050
[2] Patent: US5849779, 1998, A,
[3] Helvetica Chimica Acta, 1959, vol. 42, p. 349,358
  • 4
  • [ 42466-67-1 ]
  • [ 22038-72-8 ]
  • [ 31037-02-2 ]
YieldReaction ConditionsOperation in experiment
68% for 2 h; Inert atmosphere; Reflux Ethyl (E)-2-cyano-3-ethoxyacrylate (4) (0.775 g, 4.6 mmol) was stirred in ethanol (5 mL) and 2-hydrazinylpyridine (0.50 mL, 4.6 mmol) was added dropwise and allowed to stir for 2 hours. Solvent was removed and residue was poured onto ice and solid collected by filtration. Recrystallisation from methanol/water afforded the title compound 6 (730 mg, 68percent) as an off-white solid.
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 136, p. 330 - 333
  • 5
  • [ 60-34-4 ]
  • [ 94-05-3 ]
  • [ 31037-02-2 ]
  • [ 21230-43-3 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
[2] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
  • 6
  • [ 38109-77-2 ]
  • [ 60-34-4 ]
  • [ 31037-02-2 ]
Reference: [1] Synlett, 2004, # 4, p. 703 - 707
  • 7
  • [ 105-56-6 ]
  • [ 31037-02-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 17, p. 2979 - 2984
  • 8
  • [ 22038-72-8 ]
  • [ 94-05-3 ]
  • [ 31037-02-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 17, p. 2979 - 2984
  • 9
  • [ 60-34-4 ]
  • [ 94-05-3 ]
  • [ 31037-02-2 ]
  • [ 21230-43-3 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
[2] Organic Letters, 2015, vol. 17, # 12, p. 2964 - 2967
  • 10
  • [ 31037-02-2 ]
  • [ 23000-43-3 ]
Reference: [1] Patent: CN107955008, 2018, A,
[2] Patent: US4124764, 1978, A,
  • 11
  • [ 31037-02-2 ]
  • [ 1192-21-8 ]
YieldReaction ConditionsOperation in experiment
87% With water; sodium hydroxide In ethanol for 2 h; Reflux; Inert atmosphere Carboxylate 62 (20.0 g, 118 mmol) in ethanol (100 mL) was treated with aqueous sodium hydroxide (50 mL, 3 M). The reaction mixture was heated to reflux and allowed to stir for 2 h and the ethanol removed under reduced pressure. The aqueous solution was cooled to 0 °C and acidified with HCl (3 M) to pH 5. The white precipitate was collected by filtration and heated neat to 185 °C in Kugelrohr oven under vacuum (1 mmHg) to afford titled compound 22 (10.0 g, 87percent) as a light brown solid. MP: 73 – 74 °C; IR (Diamond Cell, neat): 3395, 3134, 1643, 1556, 1517, 1431, 1344, 1268, 1207, 999, 928, 758, 632 cm–1; 1H NMR (300 MHz, Chloroform-d) δ 7.21 (d, J = 2.0 Hz, 1H), 5.49 (d, J = 2.0 Hz, 1H), 3.62 (s, 3H), 3.50 (br. s, 2H); 13C NMR (75 MHz, Chloroform-d) δ 144.6 (C), 138.2 (CH), 91.2 (CH), 34.3 (CH3); LRMS (ESI+) m/z: 98 (100, [M + H]+), 120 (50, [M + Na]+). This data matched that previously reported. 3
Reference: [1] Journal of Organic Chemistry, 2016, vol. 81, # 11, p. 4883 - 4889
[2] European Journal of Medicinal Chemistry, 2017, vol. 136, p. 330 - 333
  • 12
  • [ 31037-02-2 ]
  • [ 56984-32-8 ]
  • [ 85290-80-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 6, p. 1545 - 1547
[2] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 6, p. 1545 - 1547
  • 13
  • [ 31037-02-2 ]
  • [ 85290-80-8 ]
Reference: [1] Australian Journal of Chemistry, 1983, vol. 36, # 1, p. 135 - 147
  • 14
  • [ 31037-02-2 ]
  • [ 4058-91-7 ]
Reference: [1] Patent: WO2008/52974, 2008, A1, . Location in patent: Page/Page column 42
[2] Journal of Agricultural and Food Chemistry, 2008, vol. 56, # 20, p. 9535 - 9542
[3] Patent: WO2007/62805, 2007, A1, . Location in patent: Page/Page column 68
  • 15
  • [ 31037-02-2 ]
  • [ 56984-32-8 ]
YieldReaction ConditionsOperation in experiment
75% With tert.-butylnitrite; copper(l) chloride In acetonitrile at 20 - 60℃; for 3 h; To a solution of tBuONO (2.95 mL, 2.46 mmol) in acetonitrile(ACN) was added CuCl (1.76 g, 1.77 mmol), and then added 14 (2.5 g, 1.48 mmol) to the mixture in portions. The reaction was stirred at r.t. for 2 h, and then heated at 60°C for 1 h.After completion as TLC monitored, the reaction mixture was cooled to r.t. and diluted with 2 N aq. HCl, then extracted with DCM (3×). The combined phases were washed withbrine, dried over MgSO4, filtered, concentrated and purifiedby flash column chromatography to give 15 (2.08 g) in 75percentyield. 1H-NMR (300 MHz, CDCl3) δ: 7.90 (1H, s), 4.30 (2H, q,J=5.4 Hz), 3.86 (3H, s), 1.34 (3H, t, J=5.4 Hz).
75% With tert.-butylnitrite; copper(l) chloride In acetonitrile at 20 - 65℃; for 2 h; A solution of tert-butyl nitrite (2.95 ml, 2.46 mmol) in acetonitrile (50 ml) was added cuprous chloride (1.76 g 1.77 mmol) Ethyl 5-amino-1-methylpyrazole-4-carboxylate (2.5 g, 1.48 mmol) was added portionwise After stirring at room temperature for 1 hour, Then 65 ° C for 1 hour, The reaction is completed, until the reaction liquid cooled to room temperature, It was poured into 3N HC1, extracted with dichloromethane, and the organic layer was dried and evaporated to dryness. The product was purified by a rapid preparative column (2.08g) in a yield of 75percent.
64%
Stage #1: With tert.-butylnitrite; copper(l) chloride In acetonitrile at 0 - 65℃; for 2.5 h;
Stage #2: With hydrogenchloride In water; acetonitrile
Step 1.
5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester
To a mixture of t-butyl nitrite (29.5 mL, 248 mmol), cuprous chloride (17.6 g, 177.8 mmol) and anhydrous acetonitrile (490 mL) was added 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (25 g, 148 mmol) in portions over 30 minutes at 0° C.
The reaction mixture was stirred at room temperature for 1 h, then at 65° C. for 1 h.
The mixture was then poured into 6N HCl (600 mL) and extracted with dichloromethane.
The aqueous phase was extracted three times with dichloromethane.
The combined organic phases were concentrated in vacuo, and the crude residue was purified by flash chromatography eluding with a gradient of 0-20percent ethyl acetate/hexanes, then 20percent ethyl acetate/hexanes to give 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (18 g, 64percent).
44.3% With hydrogenchloride; phosphoric acid; acetic acid; sodium nitrite In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water REFERENCE EXAMPLE 2
Ethyl 5-chloro-1-methylpyrazole-4-carboxylate (Compound C)
23.7 g of ethyl 5-amino-1-methylpyrazole-4-carboxylate is dissolved in a mixture of 50 ml of concentrated hydrochloric acid, 34 ml of acetic acid and 28 ml of phosphoric acid.
A solution of 10 g of sodium nitrite in 25 ml of water is added dropwise to the solution while cooling at -4° C. to -6° C. and stirring over a period of 35 minutes to prepare the diazonium salt solution.
While cooling at 3° C. to 4° C., the diazonium salt solution is added dropwise to 140 ml of concentrated hydrochloric acid containing 13.9 g of cuprous chloride over a period of 45 minutes.
The mixture is stirred at the same temperature for 1 hour, poured into 2l of ice water, and extracted with ethyl acetate.
The extract is washed with a saturated aqueous sodium chloride solution, a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution in that order, and dried over anhydrous sodium sulfate.
Ethyl acetate is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent, ethyl acetate:toluene=1:1) to give 11.7 g of the titled compound.
Yield 44.3percent.

Reference: [1] Chemical and Pharmaceutical Bulletin, 2016, vol. 64, # 4, p. 326 - 339
[2] Patent: CN105164112, 2017, B, . Location in patent: Paragraph 0439-0442
[3] Patent: US2007/225280, 2007, A1, . Location in patent: Page/Page column 18
[4] Patent: US4872901, 1989, A,
[5] Patent: US4620865, 1986, A,
  • 16
  • [ 31037-02-2 ]
  • [ 56984-32-8 ]
  • [ 85290-80-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 6, p. 1545 - 1547
[2] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 6, p. 1545 - 1547
  • 17
  • [ 31037-02-2 ]
  • [ 754219-01-7 ]
Reference: [1] Beilstein Journal of Organic Chemistry, 2009, vol. 5,
  • 18
  • [ 31037-02-2 ]
  • [ 105486-72-4 ]
YieldReaction ConditionsOperation in experiment
81% With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 20 - 65℃; for 3.5 h; Intermediate 1: (5-Bromo-1-methyl-1H-pyrazol-4-yl)-(octahydro-quinolin-1-yl)methanone; Step 1. ; 5-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester; To a mixture of t-butyl nitrite (29.5 mL, 221.5 mmol), cupric bromide (39.7 g, 177.5 mmol), and acetonitrile was added 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (25 g, 148 mmol) in portions over 30 minutes. The reaction mixture was stirred at ambient temperature for 2 h, then at 65° C. for 1 h. The mixture was then poured into 6N HCl (400 mL) and extracted with dichloromethane. After concentration in vacuo, the crude residue was purified by flash chromatography with a gradient of 0-20percent ethyl acetate/hexanes to give 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (28 g, 81percent).
68% With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 60℃; for 2 h; Inert atmosphere 5-Amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (5.0 g, 29.6 mmol) was added portionwise to a mixture of tert-butyl nitrite (4.57 g, 44.3 mmol) and copper (II) bromide (7.92 g, 35.5 mmol) in acetonitrile (20 mL). The mixture was heated to 60°C for 2 h. The resulting mixture was poured into 6M HCl (200 mL) and extracted with dichloromethane (3 x 250 mL). The combined organics was dried on magnesium sulfate and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, 0percent to 50percent ethyl acetate in hexanes) to afford 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester as an off-white solid (4.7 g, 68percent). 1H NMR (CDCl3) : 7.93 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H).
66% With tert.-butylnitrite; copper(I) bromide In acetonitrile at 65℃; for 24 h; Step 1.
Synthesis of ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate
Copper(II) bromide (99percent, 20.0 g, 88.6 mmol) and tert-butyl nitrite (90percent, 14.1 mL, 107 mmol) were combined in acetonitrile (65 mL) and heated to 65° C. Ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (10.0 g, 59.1 mmol) was slowly added portion-wise {Caution: gas evolution!} and the reaction was maintained at 65° C. for 24 hours.
The mixture was cooled to room temperature, poured into aqueous hydrochloric acid (3 N, 600 mL), diluted with ethyl acetate (300 mL) and stirred for 10 minutes.
The aqueous layer was extracted with ethyl acetate (150 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo.
The residue was purified via silica gel chromatography (Gradient:
5percent to 100percent ethyl acetate in heptane, with a 5-minute hold at 32percent), affording the product as a pale yellow solid. Yield: 9.10 g, 39.0 mmol, 66percent. LCMS m/z 233.3 (M+1).
1H NMR (500 MHz, CDCl3) δ 1.36 (t, J=7.1 Hz, 3H), 3.92 (s, 3H), 4.32 (q, J=7.1 Hz, 2H), 7.93 (s, 1H).
Reference: [1] Patent: US2006/223852, 2006, A1, . Location in patent: Page/Page column 10
[2] Patent: WO2013/189904, 2013, A1, . Location in patent: Page/Page column 49
[3] Patent: US2012/214791, 2012, A1, . Location in patent: Page/Page column 23
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 1001 - 1018
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