Home Cart 0 Sign in  
X

[ CAS No. 930-36-9 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type HazMat fee for 500 gram (Estimated)
Excepted Quantity USD 0.00
Limited Quantity USD 15-60
Inaccessible (Haz class 6.1), Domestic USD 80+
Inaccessible (Haz class 6.1), International USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic USD 100+
Accessible (Haz class 3, 4, 5 or 8), International USD 200+
3d Animation Molecule Structure of 930-36-9
Chemical Structure| 930-36-9
Chemical Structure| 930-36-9
Structure of 930-36-9 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 930-36-9 ]

Related Doc. of [ 930-36-9 ]

Alternatived Products of [ 930-36-9 ]

Product Details of [ 930-36-9 ]

CAS No. :930-36-9 MDL No. :MFCD00144943
Formula : C4H6N2 Boiling Point : -
Linear Structure Formula :- InChI Key :UQFQONCQIQEYPJ-UHFFFAOYSA-N
M.W : 82.10 Pubchem ID :70255
Synonyms :

Calculated chemistry of [ 930-36-9 ]

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.25
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 23.49
TPSA : 17.82 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) : -6.64 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.23
Log Po/w (XLOGP3) : 0.23
Log Po/w (WLOGP) : 0.42
Log Po/w (MLOGP) : -0.06
Log Po/w (SILICOS-IT) : 0.51
Consensus Log Po/w : 0.47

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.11
Solubility : 6.36 mg/ml ; 0.0775 mol/l
Class : Very soluble
Log S (Ali) : -0.16
Solubility : 56.3 mg/ml ; 0.685 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.68
Solubility : 17.1 mg/ml ; 0.208 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 930-36-9 ]

Signal Word:Danger Class:3
Precautionary Statements:P210-P233-P240-P241-P242-P243-P264-P280-P303+P361+P353-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P235-P501 UN#:1993
Hazard Statements:H225-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 930-36-9 ]

* 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 [ 930-36-9 ]
  • Downstream synthetic route of [ 930-36-9 ]

[ 930-36-9 ] Synthesis Path-Upstream   1~33

  • 1
  • [ 930-36-9 ]
  • [ 35852-81-4 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 1313 - 1316
[2] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 1313 - 1316
[3] Synthetic Communications, 2007, vol. 37, # 1, p. 137 - 147
  • 2
  • [ 930-36-9 ]
  • [ 15803-02-8 ]
Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 49, p. 6783 - 6786
[2] Organic Letters, 2015, vol. 17, # 12, p. 2886 - 2889
[3] Synthetic Communications, 2007, vol. 37, # 1, p. 137 - 147
[4] Patent: US5608056, 1997, A,
[5] Patent: US6642237, 2003, B1, . Location in patent: Page/Page column 181
[6] Organic Process Research and Development, 2010, vol. 14, # 4, p. 849 - 858
[7] Justus Liebigs Annalen der Chemie, 1955, vol. 593, p. 200 - 207
[8] Inorganic Chemistry, 2012, vol. 51, # 17, p. 9385 - 9394
[9] Advanced Synthesis and Catalysis, 2018, vol. 360, # 4, p. 626 - 630
  • 3
  • [ 930-36-9 ]
  • [ 39806-90-1 ]
YieldReaction ConditionsOperation in experiment
60% With dihydrogen peroxide; iodine In water at 24℃; A mixture of 1-methyl-1H-pyrazole (7) (37 gm, 0.6090 moles), iodine (57.1 gm,0.225 moles), hydrogen peroxide (9.2 gm, 0.27 moles) and DI water (I 10 ml) were stirred for 24 hour at 20-30°C. Progress of the reaction was monitored by HPLC. The reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with 20percent aqueous sodium bisulfate (100 ml) and stirred for I hour at 5-10°C. The solid obtained was filtered,V washed with cold DI water (100 ml) and dried at 40-45°C to obtain the product, 4-iodo-1-methyl- 1H-pyrazole. VDrywt : 56gmYield : 1.51 w/w(60percent) V
60% With dihydrogen peroxide; iodine In water at 20 - 30℃; for 24 h; Step 1: 4-iodo- 1-methyl-I H-pyrazoleA mixture of 1-methyl-IH-pyrazole (7) (37 gm, 0.6090 moles), iodine (57.1 gm, 0.225 moles), hydrogen peroxide (9.2 gm, 0.27 moles) and DI water (110 ml) were stirred for24 hour at 20-30°C. Progress of the reaction was monitored by HPLC and TLC. The reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with 20percent aqueous sodium bisulfite (100 ml) and stirred for 1 hour at 5-10°C. The solid product obtained was filtered off, washed with cold DI water (100 ml) and dried at 40-45°C to yield the product, 4-iodo-l- methyl-I H-pyrazole.Drywt 56gmYield : 1.51 w/w(60percent)
60% With dihydrogen peroxide; iodine In water at 20 - 30℃; for 24 h; Step 1 : 4-iodo- l -methyl- lH-pyrazole A mixture of 1 -methy 1-1 H-pyrazole (7) (37 gm, 0.6090 moles), iodine (57. 1 gm, 0.225 moles), hydrogen peroxide (9.2 gm, 0.27 moles) and DI water ( 1 10 ml) were stirred for 24 hour at 20-30°C. Progress of the reaction was monitored by HPLC and TLC. The reaction mixture was cooled to 5- 10°C. The reaction mixture was quenched with 20percent aqueous sodium bisulfite ( 100 ml) and stirred for 1 hour at 5-10°C. The solid product obtained was filtered off, washed with cold DI water ( 100 ml) and dried at 40-45°C to yield the product, 4-iodo- l - methyl- 1 H-pyrazole. Dry wt : 56 gm Yield : 1.51 w/w (60percent)
60% With dihydrogen peroxide; iodine In water at 20 - 30℃; for 24 h; A mixture of 1-methyl-1H-pyrazole (7) (37 gm, 0.6090 moles), iodine (57.1 gm, 0.225 moles), hydrogen peroxide (9.2 gm, 0.27 moles) and DI water (110 ml) were stirred for 24 hour at 20-30° C.
Progress of the reaction was monitored by HPLC and TLC.
The reaction mixture was cooled to 5-10° C.
The reaction mixture was quenched with 20percent aqueous sodium bisulfite (100 ml) and stirred for 1 hour at 5-10° C.
The solid product obtained was filtered off, washed with cold DI water (100 ml) and dried at 40-45° C. to yield the product, 4-iodo-1-methyl-1H-pyrazole.

Reference: [1] Heterocycles, 2007, vol. 71, # 9, p. 1967 - 1974
[2] Tetrahedron Letters, 2008, vol. 49, # 25, p. 4026 - 4028
[3] Organic Process Research and Development, 2012, vol. 16, # 8, p. 1329 - 1337
[4] Russian Chemical Bulletin, 1996, vol. 45, # 11, p. 2581 - 2584
[5] Russian Chemical Bulletin, 2014, vol. 63, # 2, p. 360 - 367[6] Izv. Akad. Nauk, Ser. Khim., 2014, # 2, p. 360 - 367
[7] Organic Letters, 2015, vol. 17, # 12, p. 2886 - 2889
[8] Patent: WO2014/2109, 2014, A1, . Location in patent: Page/Page column 132
[9] Patent: WO2014/2110, 2014, A1, . Location in patent: Page/Page column 143
[10] Patent: WO2014/2111, 2014, A1, . Location in patent: Page/Page column 43
[11] Patent: US2015/112063, 2015, A1, . Location in patent: Paragraph 0236
[12] Chemical Communications, 2009, # 42, p. 6433 - 6435
[13] Russian Chemical Bulletin, 2010, vol. 59, # 8, p. 1549 - 1555
[14] Russian Chemical Bulletin, 2013, vol. 62, # 4, p. 1044 - 1051[15] Izv. Akad. Nauk, Ser. Khim., 2013, vol. 62, # 4, p. 1043 - 1050,8
  • 4
  • [ 930-36-9 ]
  • [ 39806-90-1 ]
  • [ 34091-53-7 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1955, vol. 593, p. 200 - 207
  • 5
  • [ 930-36-9 ]
  • [ 68-12-2 ]
  • [ 25016-11-9 ]
YieldReaction ConditionsOperation in experiment
77.7%
Stage #1: at 100℃; for 2 h;
Stage #2: at 20℃;
Stage #3: With sodium hydroxide In water
POCl3 (54.3g, 0.35mol) was added dropwise to a stirred solution of 1 -methyl- lH-pyrazole (29.1g, 0.35mol) in dry DMF (9OmL) at 1000C and the stirring was continued for 2h. Then the reaction mixture was cooled and poured into ice water (35OmL), basified to pH 8 with 2 mol/L of NaOH, extracted with CHCl3, dried over anhydrous Na2 SO4 and concentrated in vacuum to give crude product. It was purified with chromatography to give compound 1 -methyl- lH-pyraozle-4-carboxaldehyde (30g, 77.7percent) as a yellow oil. ES-MS m/z: l l l(M+H+).
66%
Stage #1: at 0 - 80℃; for 1.66667 h;
Stage #2: at 85 - 115℃; for 5.5 h;
1)
1-Methyl-1H-pyrazole-4-carboaldehyde
In an argon atmosphere, phosphorus oxychloride (65.3 mL) was added dropwise to N,N-dimethylformamide (54.2 mL) at 0°C over 30 minutes, and the mixture was stirred at room temperature for 1 hour and 80°C for 10 minutes.
Subsequently, 1-methylpyrazole (25.0 g) was added dropwise to the reaction mixture over 30 minutes.
The reaction mixture was stirred at 85°C for 1 hour, at 100°C for 3 hours, and at 115°C for 1 hour, and then allowed to cool in air.
The reaction mixture was added ice-water (1 L), and the mixture was stirred for 20 hours.
The reaction mixture was partitioned between 1M aqueous sodium hydroxide (2 L) and chloroform, and the organic layer was dried over sodium sulfate anhydrate.
After a filtration step, the solvent was evaporated under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform - methanol), to thereby give 1-methyl-1H-pyrazole-4-carboaldehyde as an oily product (22.1 g, 66percent).
1H-NMR(400MHz,CDCl3)δ:3.97(3H,s), 7.91(1H,s), 7.96(1H,s), 9.85(1H,s).
ESI-MSm/z:111(M+H)+.
66%
Stage #1: at 0 - 80℃; for 1.66667 h;
Stage #2: at 85 - 115℃; for 5.5 h;
Stage #3: at 0℃; for 20 h;
1) 1-Methyl-1H-pyrazole-4-carbaldehyde Under an argon atmosphere, phosphorus oxychloride (65.3 mL) was added dropwise to N, N-dimethylformamide (54.2 mL) at 0°C over 30 minutes, and then the resultant mixture was stirred for 1 hour at room temperature. The reaction solution was stirred for 10 minutes at 80°C, and then 1-methylpyrazole (25.0 g) was added dropwise thereto over 30 minutes. Furthermore, the reaction solution was stirred for 1 hour at 85°C, for 3 hours at 100°C, and for 1 hour at 115°C. After air cooling, the reaction solution was added to ice water (1 L), and stirred for 20 hours. An aqueous 1 M sodium hydroxide solution (2 L) and chloroform were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform-methanol), to obtain 1-methyl-1H-pyrazole-4-carbaldehyde (22.1 g, 66percent) as an oily product. 1H-NMR(400MHz, CDCl3)δ: 3.97(3H, s), 7.91(1H, s), 7.96(1H, s), 9.85(1H, s). ESI-MSm/z: 111(M+H)+.
59%
Stage #1: at 0 - 20℃;
Stage #2: at 80 - 95℃;
Phosphorus oxychloride (6.92 g, 45.1 mmol, 1.50 equiv.) was cooled to 0 0C and then added drop-wise to anhydrous DMF (3.50 mL, 45.2 mmol, 1.50 equiv.) at 0 0C. The mixture was stirred 1 hour at room temperature and was then heated to 80 0C. The compound of formula VIII (2.50 mL, 30.2 mmol) was then added drop-wise to the reaction, and the resulting mixture was stirred 3 hours at 95 0C. The reaction was then quenched by slow addition to ice (40 g). The pH of the resulting solution was 2, and it was raised to 5 by slow addition of 12N aqueous sodium hydroxide solution (11.2 mL). The resulting aqueous solution was extracted with dichloromethane and/or ether (7 x 40 mL), and additional sodium hydroxide was added during extraction, as needed, to maintain a pH of 5. The extracts were then combined, dried over sodium sulfate, filtered and concentrated to yield a brown oil (3.79 g, 59percent yield).
40%
Stage #1: at 100℃; for 2 h;
Stage #2: at 0℃;
Phosphorus oxychloride (181 g, 1.18 mol) was added dropwise to a stirred solution of 1- methylpyrazole (97 g, 1.18 mol) in dry DMF (240 ML) at 100 °C. The reaction mixture was maintained at this temperature for 2 h, cooled to room temperature, poured onto ice water (1 L), and basified to pH 8 by the addition of 2 M aqueous sodium hydroxide solution. The mixture was then extracted with chloroform (4X500 mL), the organic phase dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to a brown oil and the excess DMF distilled away. The crude product was purified (SIO2, diethyl ether) to provide the title compound as a pale yellow oil (52 g, 40percent).
600 mg at 90℃; for 3 h; N-methylpyrazole (1.0 g, 1 eq.) was dissolved in N,N-dimethylformamide (2.8 ml, 3 eq.), phosphorus oxychloride (1.3ml, 1.2 eq.) was added dropwise at 90 °C over about 1 h. The mixture was reacted for another 2 h and then cooled. The reaction liquid was poured into iced water and adjusted with 10percent aqueous sodium hydroxide solution to PH 4∼5, extracted four times with dichloromethane, rinsed with water twice, and separated by column chromatography to give 600 mg product

Reference: [1] Patent: WO2008/144767, 2008, A1, . Location in patent: Page/Page column 117
[2] Patent: EP1762568, 2007, A1, . Location in patent: Page/Page column 62
[3] Patent: EP1785418, 2007, A1, . Location in patent: Page/Page column 78
[4] Patent: WO2008/153870, 2008, A1, . Location in patent: Page/Page column 29
[5] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 471 - 474
[6] Tetrahedron Letters, 2016, vol. 57, # 24, p. 2601 - 2603
[7] Patent: WO2004/58763, 2004, A1, . Location in patent: Page 39
[8] Russian Chemical Bulletin, 2014, vol. 63, # 2, p. 443 - 456[9] Izv. Akad. Nauk, Ser. Khim., 2014, # 2, p. 443 - 456,14
[10] Pharmaceuticals, 2018, vol. 11, # 1,
[11] Journal of the Chemical Society, 1957, p. 3314
[12] Journal of Medicinal Chemistry, 2008, vol. 51, # 13, p. 3777 - 3787
[13] Patent: WO2012/76435, 2012, A1, . Location in patent: Page/Page column 28-29
[14] Patent: WO2013/39854, 2013, A1, . Location in patent: Page/Page column 29
[15] Patent: WO2014/2110, 2014, A1, . Location in patent: Page/Page column 140
[16] Patent: WO2014/2111, 2014, A1, . Location in patent: Page/Page column 33
[17] Patent: WO2014/62454, 2014, A1, . Location in patent: Page/Page column 33
[18] Patent: EP2725024, 2014, A1, . Location in patent: Paragraph 0140; 0141
[19] Patent: US2014/171431, 2014, A1, . Location in patent: Paragraph 0486; 0487
[20] Patent: US2015/112063, 2015, A1, . Location in patent: Paragraph 0191
[21] Patent: EP3239135, 2017, A1, . Location in patent: Paragraph 0130; 0131
  • 6
  • [ 930-36-9 ]
  • [ 25016-11-9 ]
Reference: [1] Patent: WO2014/2109, 2014, A1, . Location in patent: Page/Page column 131
  • 7
  • [ 930-36-9 ]
  • [ 68-12-2 ]
  • [ 10025-87-3 ]
  • [ 25016-11-9 ]
Reference: [1] Journal of the Chemical Society, 1957, p. 3314
  • 8
  • [ 930-36-9 ]
  • [ 67-66-3 ]
  • [ 4513-94-4 ]
  • [ 1722-12-9 ]
  • [ 51269-82-0 ]
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 24, p. 3581 - 3585
[2] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 24, p. 3581 - 3585
  • 9
  • [ 15803-02-8 ]
  • [ 109-72-8 ]
  • [ 60-29-7 ]
  • [ 930-36-9 ]
  • [ 5952-92-1 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1959, vol. 625, p. 55,60
  • 10
  • [ 930-36-9 ]
  • [ 124-38-9 ]
  • [ 16034-46-1 ]
YieldReaction ConditionsOperation in experiment
48.8%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 3 h; Inert atmosphere
Stage #2: at 20℃; for 1.08333 h;
Under room temperature, the 1-methyl -1H-pyrazole (2.0g, 24.4 mmol) dissolved in THF in (30 ml). Under the protection of the nitrogen of the obtained mixture to lower the temperature to -78 °C, then slowly dripping n-BuLi to the (10.72 ml, 26.8 mmol). Then the resulting mixture at -78 ° C stirring 2 hours, to room temperature, then the stirring is performed for 1 hour. Then to the reaction solution to maintain this temperature in drying CO2gas, approximately through 5 minutes. After stirring at room temperature, to 1 hours. To the obtained water is added in the mixture of (30 ml) the reaction quenching and diluting. The resulting mixture is extracted with methylene chloride. After acid aqueous phase precipitating a large amount of solid, filtered. The resulting filter cake is dried to obtain 1.5 g of white solid (yield: 48.8percent).
45.4%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 2 h;
Stage #2: at -78℃; for 0.5 h;
Stage #3: With hydrogenchloride In water at 2 - 3℃;
To a stirred solution of 1 -methyl- lH-pyrazole (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen is added a solution of n-BuLi in hexane (2.6 M, 670 mmol) dropwise at -78°C over a period of Ih. The reaction mixture is then stirred at this temperature for a further 1 h, and then dry carbon dioxide gas is passed through the mixture at -78°C for 30 min. The reaction mixture is then allowed to warm to room temperature and quenched with water (500 mL). The aqueous phase is separated, washed with ether (500 mL) and cooled to 2-3 0C. To the stirred mixture is added concentrated aqueous hydrochloric acid until a pη of 3 is obtained. The resulting precipitate is collected by filtration, washed with ice-cold water (20 mL), dried first in open air, and then in a vacuum desiccator over P2O5 to afford 2-methyl-2H-pyrazole-3-carboxylic acid as a white powder.[00249] Compound wt: 35.3g, 45.4percent yield. 1H NMR (400 MHz, OMSO-d6) δ: 13.31 (IH, bs);7.50 (IH, d); 6.81 (IH, d); 4.07 (3H, s).
45.4%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 2 h;
Stage #2: at -78℃; for 0.5 h;
Stage #3: With hydrogenchloride In water at 2 - 3℃;
To a stirred solution of 1 -methyl- lH-pyrazole (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen is added a solution of n-BuLi in hexane (2.6 M, 670 mmol) dropwise at -78°C over a period of Ih. The reaction mixture is then stirred at this temperature for a further 1 h, and then dry carbon dioxide gas is passed through the mixture at -78°C for 30 min. The reaction mixture is then allowed to warm to room temperature and quenched with water (500 mL). The aqueous phase is separated, washed with ether (500 mL) and cooled to 2-3 0C. To the stirred mixture is added concentrated aqueous hydrochloric acid until a pη of 3 is obtained. The resulting precipitate is collected by filtration, washed with ice-cold water (20 mL), dried first in open air, and then in a vacuum desiccator over P2O5 to afford 2-methyl-2H-pyrazole-3-carboxylic acid as a white powder.[0232] Compound wt: 35.3g, 45.4percent yield. 1H NMR (400 MHz, DMSOi6) δ: 13.31 (IH, bs);7.50 (IH, d); 6.81 (IH, d); 4.07 (3H, s).
45.4%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 2 h;
Stage #2: at -78 - 20℃; for 0.5 h;
Stage #3: With hydrogenchloride In water at 2 - 3℃;
To a stirred solution of 1-methyl-1H-pyrazole (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen was added a solution of n-BuLi in hexane (2.6M, 670 mmol) dropwise at -78oC over a period of 1 h.
The reaction mixture was stirred at this temperature for a further 1 hour, and then dry carbon dioxide gas was passed through the mixture at -78oC for 30 min.
The reaction mixture was then allowed to warm to room temperature and quenched with water (500 mL).
The aqueous phase was separated, washed with ether (500 mL) and cooled to 2-3oC.
To the stirred mixture was added concentrated aqueous hydrochloric acid until a pH of 3 was obtained.
The resulting precipitate was collected by filtration, washed with ice-cold water (20 mL), dried first in open air, and then in a vacuum desiccator over phosphorus pentoxide to afford 2-methyl-2H-pyrazole-3-carboxylic acid as a white powder.
Compound wt: 35.3 g, 45.4percent yield. 1H NMR (400 MHz, DMSO-d6) δ: 13.31(1H, bs); 7.50 (1H, d); 6.81 (1H, d); 4.07 (3H, s).

Reference: [1] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 6, p. 650 - 654
[2] Patent: CN105384739, 2016, A, . Location in patent: Paragraph 0345; 0346; 0347
[3] Patent: WO2009/71705, 2009, A1, . Location in patent: Page/Page column 39
[4] Patent: WO2009/71706, 2009, A1, . Location in patent: Page/Page column 48
[5] Patent: US2008/242661, 2008, A1, . Location in patent: Page/Page column 25
  • 11
  • [ 930-36-9 ]
  • [ 201230-82-2 ]
  • [ 16034-46-1 ]
YieldReaction ConditionsOperation in experiment
27%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h;
Stage #2: at 20℃; for 1 h;
1-Methyl-1H-pyrazole (5.00 g, 60.9 mmol) was dissolved in diethyl ether (anhydrous; 150 mL), n-butyllithium (2.5 M hexane solution, 26.8 mL, 67.0 mmol) was added while cooling to -78°C, and the mixture was stirred for 30 min at -78°C. The reaction mixture was added to finely pulverized dry ice (500 g), the mixture was heated to room temperature, and further stirred at room temperature for 1 hr. To the reaction mixture was added water (200 mL), and the aqueous layer was separated and washed with diethyl ether (3 x 100 mL). The aqueous layer was acidified by adding concentrated hydrochloric acid to pH 3, and the precipitate was collected by filtration, and dried to give the title compound (2.10 g) as a white solid (yield 27percent). 1H NMR (400 MHz, DMSO-d6) δ 4.05 (3H, s), 6.79 (1H, d, J = 2.0 Hz), 7.47 (1H, d, J = 2.0 Hz), 13.29 (1H, s).
Reference: [1] Patent: EP2530078, 2012, A1, . Location in patent: Page/Page column 64
  • 12
  • [ 930-36-9 ]
  • [ 16034-46-1 ]
Reference: [1] Journal of the American Chemical Society, 1958, vol. 80, p. 6271,6273
[2] Justus Liebigs Annalen der Chemie, 1959, vol. 625, p. 55,60
  • 13
  • [ 930-36-9 ]
  • [ 109-72-8 ]
  • [ 60-29-7 ]
  • [ 16034-46-1 ]
Reference: [1] Journal of the American Chemical Society, 1958, vol. 80, p. 6271,6273
[2] Justus Liebigs Annalen der Chemie, 1959, vol. 625, p. 55,60
  • 14
  • [ 930-36-9 ]
  • [ 60-29-7 ]
  • [ 591-51-5 ]
  • [ 16034-46-1 ]
Reference: [1] Journal of the American Chemical Society, 1958, vol. 80, p. 6271,6273
[2] Justus Liebigs Annalen der Chemie, 1959, vol. 625, p. 55,60
  • 15
  • [ 930-36-9 ]
  • [ 34091-51-5 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.25 h;
Stage #2: With iodine In tetrahydrofuran at 20℃; for 1 h;
n-BuLi (2.5M in hexane, 26.8 mL, 67 mmol) was added dropwise over 15 mm to a solutionof 1-methyl-1H-pyrazole (5.0 mL, 61 mmol) in THF (100 mL) at —78 °C. After stirring at—78 °C for 1 h, a solution of ‘2 (17 g, 67 mmol) in THF (20 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 h. The mixture wasquenched with saturated aqueous NH4C1 and poured into H20 (100 mL). The aqueous phase was extracted with Et20. The combined organic phases were washed with saturated aqueous Na2S2O3, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title compound (11.39 g, 90percent).LC-MS: 208.8 [M+Hf, RT 0.94 mm. ‘H NMR (500 MHz, CDC13) ö ppm 3.94 (s, 3H), 6.43 (d, J=1.97 Hz, 1H), 7.48 (d, J=2.00 Hz, 1H)
89%
Stage #1: With (THF)Li(TMP)Zn(tBu)2 In tetrahydrofuran at 25℃; for 1 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran at 25℃; for 1 h; Inert atmosphere
General procedure: [Li(TMP)Zn(tBu)2] 1 was made according to the literature procedure2 on a 0.8 mmol scale in THF solution. To this solution 1-methyl-pyrazole (0.033 mL, 0.4 mmol) was added at room temperature and the solution allowed to stir for 1 hour. Next the solution was quenched with I2 (508 mg, in 1 mL THF) and allowed to stir for 1 hour. A 10percent solution of Na2S2O3 was added until bleaching and the product extracted with DCM (3 x 1 mL). The combined organic extracts were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by SiO2 chromatography eluent heptane:EtOAc (60:40 to 40:60) to give compound 13a as colourless solid 74 mg (89percent yield). 1H NMR (400 MHz,CDCl3) δ ppm 6.30 (dd, 1 H) 7.42 (dd, 1 H).
11.4 g
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5 h; Inert atmosphere; Cooling with ice
Stage #2: With iodine In tetrahydrofuran; hexane at -78 - 20℃;
Production Example 9
5-Iodo-1-methyl-1H-pyrazole
Under a nitrogen atmosphere, n-butyllithium (39.0 mL, 2.6 M hexane solution) was added dropwise to a tetrahydrofuran (120 mL) solution of methylpyrazole (6.00 g) at -78° C., and the obtained solution was then stirred for 30 minutes.
Thereafter, the reaction solution was stirred under cooling in an ice bath for 1 hour.
Thereafter, the temperature of the reaction solution was cooled to -78° C., and a tetrahydrofuran (50 mL) solution of iodine (28.0 g) was then added dropwise to the reaction solution.
Then, the reaction solution was stirred for 1 hour.
Thereafter, the reaction solution was stirred overnight, while increasing the temperature of the solution to a room temperature.
Subsequently, a 30percent sodium thiosulfate aqueous solution was added to the reaction solution, and the solvent was then distilled away under a reduced pressure.
The residue was extracted with ethyl acetate, and the organic layer was then washed with a saturated saline.
The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure.
The obtained solid was washed with n-hexane, so as to obtain the title compound (11.4 g) in the form of a brownish-red solid.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 3.94 (s, 3H) 6.43 (d, J=2.20 Hz, 1H) 7.47 (d, J=1.76 Hz, 1H); MS (ESI pos.) m/z 209 [M+H]+
11.4 g
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5 h; Inert atmosphere; Cooling with ice
Stage #2: With iodine In tetrahydrofuran; hexane at -78 - 20℃;
Production Example 2
5-Iodo-1-methyl-1H-pyrazole
Under a nitrogen atmosphere, n-butyllithium (39.0 mL, 2.6 M hexane solution) was added dropwise to a tetrahydrofuran (120 mL) solution of methylpyrazole (6.00 g) at -78° C., and the obtained solution was then stirred for 30 minutes.
Thereafter, the reaction solution was stirred for 1 hour under cooling in an ice bath.
The reaction solution was cooled to -78° C., and a tetrahydrofuran (50 mL) solution of iodine (28.0 g) was then added dropwise thereto.
The mixed solution was stirred for 1 hour.
Thereafter, the reaction solution was stirred overnight, while increasing the temperature of the solution to a room temperature.
Thereafter, a 30percent sodium thiosulfate aqueous solution was added to the reaction solution, and the solvent was then distilled away under a reduced pressure.
The residue was extracted with ethyl acetate, and the organic layer was then washed with a saturated saline.
The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure.
The obtained solid was washed with n-hexane, so as to obtain the title compound (11.4 g) in the form of a brownish-red solid.
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 3.94 (s, 3H) 6.43 (d, J=2.20 Hz, 1H) 7.47 (d, J=1.76 Hz, 1H); MS (ESI pos.) m/z 209 [M+H]+

Reference: [1] Chemical Communications, 2014, vol. 50, # 85, p. 12859 - 12862
[2] Patent: WO2016/109706, 2016, A1, . Location in patent: Page/Page column 214; 215
[3] Tetrahedron Letters, 2011, vol. 52, # 36, p. 4590 - 4594
[4] Journal of Organic Chemistry, 1984, vol. 49, # 24, p. 4687 - 4695
[5] Patent: US2013/123500, 2013, A1, . Location in patent: Paragraph 0225; 0226
[6] Patent: US2013/137865, 2013, A1, . Location in patent: Paragraph 0274; 0275
  • 16
  • [ 930-36-9 ]
  • [ 92525-20-7 ]
  • [ 92525-19-4 ]
  • [ 34091-51-5 ]
Reference: [1] Journal of Organic Chemistry, 1984, vol. 49, # 24, p. 4687 - 4695
  • 17
  • [ 930-36-9 ]
  • [ 3994-50-1 ]
YieldReaction ConditionsOperation in experiment
74.01% at 35℃; for 6 h; Take 2.7g (0.024mol) of N-nitropyrazole,1g (0.012mol) 1-methylpyrazole spare,8 mL of 98percent concentrated sulfuric acid was added to a 100 mL four-port flask equipped with a mechanical stirrer, a thermometer, and an addition funnel.Add 1-methylpyrazole dropwise to concentrated sulfuric acid at 20°C using a constant pressure dropping funnel.After the feed is completed, the water bath is heated to 35° C. and N-nitropyrazole is added in 10 portions at this temperature.Every time 0.0024mol is added,Constant temperature reaction 6h,While hot, pour the reaction mixture into a beaker with ice cubes and stir it.A white, fine crystalline solid precipitates outAfter the ice melts,Suction filtrationObtained white solid I and filtrate;The filtrate was extracted with ether,Combine solvents,Remove the solvent by vortexing under reduced pressureGet white solid II,The white solid I and white solid II were combined and recrystallized from ethanol to give the desired product.Using the test method in Example 1 to characterize the structure of the target product,The test results obtained are similar to those in Example 1.The target product obtained in Example 3 was proved to be 1-methyl-4-nitropyrazole,The purity of the product is 99.2percent.The product has a melting point of 90-91°C and a yield of 74.01percent
Reference: [1] Patent: CN107629003, 2018, A, . Location in patent: Paragraph 0055; 0070-0074; 0076; 0077 0079; 0080
[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, # 5, p. 778 - 784[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 5, p. 1071 - 1077
  • 18
  • [ 930-36-9 ]
  • [ 1173911-09-5 ]
  • [ 3994-50-1 ]
Reference: [1] Catalysis Communications, 2012, vol. 19, p. 37 - 41
  • 19
  • [ 930-36-9 ]
  • [ 54210-32-1 ]
  • [ 3994-50-1 ]
Reference: [1] Catalysis Communications, 2012, vol. 19, p. 37 - 41
  • 20
  • [ 930-36-9 ]
  • [ 68-12-2 ]
  • [ 27258-33-9 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -20℃; for 2.5 h;
Stage #2: at -20℃; for 1 h;
Example 1.
Synthesis of 2-Methyl-2H-pyrazole-3-carbaldehyde
In a dry 50 ml Vial is placed a solution of 1.642 g (20 mmol) N-Methylpyrazole in 30 ml dry THF.
The mixture is cooled to -20°C and while stirring 8 ml (20 mmol, 2.5M in hexane) n-BuLi-solution is slowly added.
The reaction mixture is stirred for 2.5 h at -20 °C.
With vigorous stirring 4.7 ml (4.39g, 60 mmol) dry DMF is slowly added at -20 °C and the mixture kept at this temperature for 1h.
The reaction mixture is then poured into 100 ml of a 1M acetic acid / sodium acetate buffer (pH: 4.5), 50 ml MTBE is added and the organic layer is separated, washed with 50 ml sat.
Na2CO3-Solution to remove excess acetic acid (extraction with ethyl acetate leads to DMF in the final product).
The organic layer is separated, dried with MgSO4 and the solvent is removed by om a rotary evaporator.
The crude product is purified by vacuum distillation (bp: 67 °C, 21 mbar).
3 preparations which were distilled together yielded 5.969g (54 mmol, 90percent) of the title compound.
1H-NMR (300 MHz, CDCl3): 4.18 (s, 3H, CH3-N), 6.91 (d, 1H, 3J=2.0 Hz, CH=C-N), 7.53 (d, 1H, 3J=2.0 Hz, CH=N), 9.87 (s, 1H, CH=O) ppm.
13C-NMR (100 MHz, CDCl3): 39.31 (CH3-N), 114.78 (CH=C-N), 138.54 (CH=N), 138.98 (CH=C-N), 179.83 (CH=O) ppm.
90%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -20℃; for 2.5 h;
Stage #2: at -20℃; for 1 h;
Example 1.
Synthesis of 2-methyl-2H-pyrazole-3-carbaldehyde
In a dry 50 ml Vial is placed a solution of 1.642 g (20 mmol) N-Methylpyrazole in 30 ml dry THF.
The mixture is cooled to -20 °C and while stirring 8 ml (20 mmol, 2.5M in hexane) n-BuLi-solution is slowly added.
The reaction mixture is stirred for 2.5 h at -20 °C.
With vigorous stirring 4.7 ml (4.39g, 60 mmol) dry DMF is slowly added at -20 °C and the mixture kept at this temperature for 1 h.
The reaction mixture is then poured into 100 ml of a 1 M acetic acid / sodium acetate buffer (pH: 4.5), 50 ml MTBE is added and the organic layer is separated, washed with 50 ml sat.
Na2CO3-solution to remove excess acetic acid (extraction with ethyl acetate leads to DMF in the final product).
The organic layer is separated, dried with MgSO4 and the solvent is removed by om a rotary evaporator.
The crude product is purified by vacuum distillation (bp: 67 °C, 21 mbar).
3 preparations which were distilled together yielded 5.969g (54 mmol, 90percent) of the title compound.
1H-NMR (300 MHz, CDCl3): 4.18 (s, 3H, CH3-N), 6.91 (d, 1H, 3J=2.0 Hz, CH=C-N), 7.53 (d, 1H, 3J=2.0 Hz, CH=N), 9.87 (s, 1H, CH=O) ppm.
13C-NMR (100 MHz, CDCl3): 39.31 (CH3-N), 114.78 (CH=C-N), 138.54 (CH=N), 138.98 (CH=C-N), 179.83 (CH=O) ppm.
Reference: [1] Patent: EP1671953, 2006, A1, . Location in patent: Page/Page column 9
[2] Patent: EP1671968, 2006, A1, . Location in patent: Page/Page column 10
[3] Patent: EP1982987, 2008, A1, . Location in patent: Page/Page column 15; 45
[4] Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6704 - 6713
[5] Patent: EP1186604, 2002, A1, . Location in patent: Page 107
[6] Russian Chemical Bulletin, 2013, vol. 62, # 3, p. 661 - 671[7] Izv. Akad. Nauk, Ser. Khim., 2013, vol. 62, # 3, p. 660 - 670,11
[8] Patent: CN106928143, 2017, A, . Location in patent: Paragraph 0019; 0022; 0023; 0030; 0031
[9] Patent: WO2008/125600, 2008, A2, . Location in patent: Page/Page column 29
  • 21
  • [ 930-36-9 ]
  • [ 143-33-9 ]
  • [ 66121-71-9 ]
  • [ 66121-72-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 2, p. 701 - 702
  • 22
  • [ 930-36-9 ]
  • [ 67-56-1 ]
  • [ 143-33-9 ]
  • [ 66121-71-9 ]
  • [ 66121-72-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 2, p. 701 - 702
  • 23
  • [ 930-36-9 ]
  • [ 108-24-7 ]
  • [ 37687-18-6 ]
YieldReaction ConditionsOperation in experiment
72% at 150℃; for 3 h; Inert atmosphere; Large scale Two identical reactions were carried out in parallel.To a mixture of 1 -methylpyrazole (750 g, 9.16 mol) and acetic anhydride (1.7 kg, 16.67 mol) was added concentrated H2S04 (75 g, 0.75 mol) at about 20° C. The reaction mixture was heated at about 150° C. for about 3 hrs. After cooling, the two mixtures were combined, poured into ice-water (15 L), adjusted to about pH 10 with 20percent aq. NaOH and extracted with DCM (4x10 L). The combined DCM extracts were dried (Na2SO4) and concentrated to afford the title compound as a brown oil (1240 g, 72percent).‘H NMR (400 MHz, CDCl3) δ: 7.86 (s, 1H), 7.84 (s, 1H), 3.92 (s, 3H), 2.40 (s, 3H).GCMS mlz=109.0 [M-CH3]+
69% for 5 h; Inert atmosphere; Reflux General procedure: To a stirred mixture of pyrazole (200 mmol) and the appropriate acid anhydride (350 mmol, 1.75 equiv), concd H2SO4(0.2 mL) was added, and the resulting mixture was stirred under a nitrogen atmosphere in an oil bath until the pyrazole was consumed. For low boiling components, this mixture was heated at reflux. Reaction conditions (temperature and time) are given in Table 2. When the reaction was complete, volatile compounds were removed under reduced pressure and the residue was poured onto 100 mL crushed ice. The reaction mixture was neutralized under vigorous stirring by the addition of 20percent aqueous NaOH or (in the case of fluorinated ketones) solid KHCO3 to adjust pH to 7–8. The ketone was extracted with CH2Cl2(3 × 50 mL) and the combined organic phases were washed with brine (50 mL), dried over MgSO4, and evaporated under reduced pressure. The resulting crude ketone was purified by either distillation or recrystallization from the appropriate solvent.
Reference: [1] Patent: US2017/240552, 2017, A1, . Location in patent: Paragraph 0152; 0153; 0154; 0155; 0156
[2] Synthesis (Germany), 2013, vol. 45, # 15, p. 2188 - 2192
  • 24
  • [ 930-36-9 ]
  • [ 68-12-2 ]
  • [ 84547-61-5 ]
  • [ 84547-62-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 4, p. 961 - 982
  • 25
  • [ 930-36-9 ]
  • [ 68-12-2 ]
  • [ 84547-61-5 ]
  • [ 84547-62-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 4, p. 961 - 982
  • 26
  • [ 930-36-9 ]
  • [ 288148-34-5 ]
YieldReaction ConditionsOperation in experiment
33% at 0 - 110℃; for 3 h; Add 1 -methyl- lη-pyrazole (100 g, 1.18 mol) dropwise to chlorosulfonic acid (325 mL, 4.84 mol) stirring at 0 0C under nitrogen atmosphere. Heat reaction mixture at 110 0C for 3 hr. Cool to room temperature, then pour carefully into crushed ice with stirring. Recover the resulting white solid by vacuum filtration, wash with water, and dry under vacuum. Use the resulting material (72.2 g, 33percent) without further purification.
Reference: [1] Patent: WO2009/29439, 2009, A1, . Location in patent: Page/Page column 24
[2] Patent: US6103708, 2000, A,
[3] Patent: WO2005/97162, 2005, A2, . Location in patent: Page/Page column 432
  • 27
  • [ 930-36-9 ]
  • [ 847818-55-7 ]
Reference: [1] Organic Process Research and Development, 2010, vol. 14, # 4, p. 849 - 858
  • 28
  • [ 930-36-9 ]
  • [ 720702-41-0 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1.5 h;
Stage #2: With Triisopropyl borate In tetrahydrofuran at -78 - 0℃;
Stage #3: With hydrogenchloride; water In tetrahydrofuran
2-Methyl-2H-pyrazole-3-boronic acid: N-methyl pyrazole (25 mL, 0.3 mol) was dissolved in 500 mL of THF.
The solution was then cooled to-78°C in a dry ice/isopropanol bath.
Once the solution reached -78°C, n-BuLi (140 mL, 0.40 mol) was added dropwise by canula.
The reaction mixture was stirred at -78°C for 1.5 hours.
Then, triisopropyl borate (280 mL, 1.2 mol) was added to the above mixture via canula.
While stirring overnight, the reaction temperature was gradually increased from -78δC to 0δC. The pH of the mixture was adjusted to 6 with IN HCI.
THF was removed under reduced pressure, and the aqueous residue was extracted with EtOAc (2 x 100mL).
The solid was then filtered to yield 108 g (100percent) of 2-methyl-2H-pyrazole-3-boronic acid as a yellow solid.
Reference: [1] Patent: WO2005/12254, 2005, A1, . Location in patent: Page/Page column 101
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 5, p. 1923 - 1936
[3] Journal of Heterocyclic Chemistry, 2004, vol. 41, # 6, p. 931 - 939
[4] Patent: WO2004/58722, 2004, A1, . Location in patent: Page 63; 62
  • 29
  • [ 930-36-9 ]
  • [ 5419-55-6 ]
  • [ 720702-41-0 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1.5 h;
Stage #2: at 20℃;
Example 14-(Azetidin-1 -yl)-1 -methyl-3-[1 -methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-1H- pyrazolo[3,4-d]pyrimidine1Step 1: Synthesis of (1-methyl-1H-pyrazol-5-yl)boronic acid (C1) To a solution of 1 -methyl-1 /-/-pyrazole (1 10 g, 1 .34 mol) in anhydrous tetrahydrofuran (2 L), with stirring, was added drop-wise n-butyllithium (2.5 M, 590 imL, 1 .47 mol) at -78 °C. After completion of the addition, the mixture was stirred for 1 .5 hours at -78 °C. Then triisopropyl borate (277 g, 1 .47 mol) was added and the mixture was gradually warmed to room temperature and stirred overnight. Saturated aqueous ammonium chloride solution (1 L) was added drop- wise, while keeping the temperature of the reaction mixture below 10 °C. The resulting mixture was acidified to a pH of approximately 6 with 1 N aqueous hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3 x 1 L). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered; and the solvent was removed under reduced pressure. The residue was washed with petroleum ether (3 x 300 mL) and the resulting solid was dried under vacuum to afford the product as a white solid. Yield: 157 g, 1.25 mol, 93percent. H NMR (400 MHz, DMSO-cf6) δ 3.97 (s, 3H), 6.72-6.74 (m, 1 H), 7.34-7.36 (m, 1 H), 8.35 (br s, 2H).
Reference: [1] Patent: WO2012/168817, 2012, A1, . Location in patent: Page/Page column 44-45
[2] Patent: US2009/62269, 2009, A1, . Location in patent: Page/Page column 54
  • 30
  • [ 930-36-9 ]
  • [ 121-43-7 ]
  • [ 720702-41-0 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 4 h;
Stage #2: at -70℃;
A solution of 1-methylpyrazole (25.0 g, 305 mmol) in tetrahydrofuran (THF) (600 mL) was cooled to 0 °C. n-Butyl lithium (1.6 M in hexanes, 209 mL, 335 mmol) was added drop-wise over 1 h, keeping the temperature below 7 °C. The solution was stirred at room temperature (rt) for 3 h before cooling to −70 °C. B(OMe)3 (44.4 mL, 0.40 mol) was slowly added, keeping the reaction temperature below −65 °C. The resulting mixture was allowed to warm to rt, before it was quenched with 15percent aqueous (aq) NH4Cl (450 mL). The mixture was extracted with THF (3 × 500 mL), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a yellowish solid (15.6 g, 41percent). The aq layer was concentrated in vacuo, and the resulting solid was repeatedly extracted with THF (5 × 250 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo, yielding a yellow solid (20.3 g, 52percent). The combined yield of   (1-methyl-1H-pyrazol-5-yl)boronic acid was 35.9 g (93percent), and 20.3 g (161 mmol) of this material was esterified with   pinacole (28.4 g, 240 mmol) in   THF (200 mL). 4 Å molecular sieves (6.0 g dried in vacuo at 50 °C) were added, and the resulting mixture was stirred at rt for 2 days. The sieves were filtered off, and the filtrate was concentrated in vacuo. The resulting crude product was dissolved in heptane (500 mL) and washed with water (2 × 250 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford a white solid. This material was recrystallized from acetonitrile yielding white   crystals (22.5 g, 67percent). Mp 71.0–71.6 °C (Ivachtchenko et al.,21 74–76 °C). 1H NMR (500 MHz, DMSO-d6): δ, 7.46 (d, J = 1.9 Hz, pyrazole H-3), 6.62 (d, J = 1.9 Hz, pyrazole H-4), 3.98 (s, N-methyl), 1.30 (s, pinacol methyl groups, 12H). 13C NMR (126 MHz, DMSO-d6): δ, 138.3, 115.9, 84.4 (2C), 41.9, 24.9 (4C). Anal. calcd for C10H17BN2O2: C, 57.73; H, 8.24; N, 13.46. Found: C, 57.72; H, 8.08; N, 13.40.
Reference: [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 1, p. 196 - 204
  • 31
  • [ 930-36-9 ]
  • [ 61676-62-8 ]
  • [ 847818-74-0 ]
YieldReaction ConditionsOperation in experiment
77%
Stage #1: With n-butyllithium In tetrahydrofuran at 0 - 20℃; for 1 h;
Stage #2: at -78 - 0℃; for 1.25 h;
Stage #3: With ammonium chloride In tetrahydrofuran
To a solution of 1-methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78°C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78°C, the reaction was allowed to warm to 00C over 1 hour. The reaction <n="32"/>was diluted with saturated NH4CI solution and extracted with DCM. The organic fractions were washed with H2O (2 x 100 ml_), dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77percent) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H).
77%
Stage #1: With n-butyllithium In tetrahydrofuran at 0 - 20℃;
Stage #2: at -78℃;
Preparation 2 Preparation of 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazoleTo a solution of 1-methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78°C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78°C, the reaction was allowed to warm to 00C over 1 hour. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organic fractions were washed with H2O (2 x 100 mL), dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77percent) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H).
76%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 1 h;
Stage #2: at -78 - 0℃; for 1.25 h;
To a solution of 1 -methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78°C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78°C, the reaction was allowed to warm to 00C over 1 hour. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 76percent) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H).
Reference: [1] Patent: WO2009/158372, 2009, A1, . Location in patent: Page/Page column 30; 31
[2] Patent: WO2009/158374, 2009, A2, . Location in patent: Page/Page column 30
[3] Patent: WO2008/98105, 2008, A1, . Location in patent: Page/Page column 36
[4] Patent: US2010/216843, 2010, A1, . Location in patent: Page/Page column 20-21
[5] Patent: WO2008/121786, 2008, A1, . Location in patent: Page/Page column 42-43
[6] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
  • 32
  • [ 930-36-9 ]
  • [ 25015-63-8 ]
  • [ 847818-74-0 ]
Reference: [1] Organometallics, 2018, vol. 37, # 10, p. 1567 - 1574
  • 33
  • [ 930-36-9 ]
  • [ 76-09-5 ]
  • [ 761446-44-0 ]
Reference: [1] Organic Process Research and Development, 2010, vol. 14, # 4, p. 849 - 858
Same Skeleton Products
Historical Records

Related Parent Nucleus of
[ 930-36-9 ]

Pyrazoles

Chemical Structure| 1072-68-0

[ 1072-68-0 ]

1,4-Dimethylpyrazole

Similarity: 0.85

Chemical Structure| 694-48-4

[ 694-48-4 ]

1,3-Dimethyl-1H-pyrazole

Similarity: 0.83

Chemical Structure| 1120-82-7

[ 1120-82-7 ]

(1H-Pyrazol-1-yl)methanol

Similarity: 0.81

Chemical Structure| 288-13-1

[ 288-13-1 ]

1H-Pyrazole

Similarity: 0.79

Chemical Structure| 69843-13-6

[ 69843-13-6 ]

1-Methyl-1H-pyrazol-4-amine

Similarity: 0.78