Category: 5334-39-4

Related Products of 5334-39-4, In the next few decades, the world population will flourish. As the population grows rapidly and people all over the world use more and more resources, all industries must consider their environmental impact. 5334-39-4, name is 3-Methyl-4-nitro-1H-pyrazole belongs to pyrazoles-derivatives compound, it is a common compound, a new synthetic route is introduced below.

To a solution of 3-methyl-4-nitro-lH-pyrazole (1 -1, 398 nig, 3.13 mmol) in DMF (10 niL) was added NaH (125 mg, 3.13 mmol, 60% purity) at 0 C, then the reaction was stirred at 20 C for 1 h. Then, (3-methyl- 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyridin-6-yl) methanesulfonate (604 mg, 2.61 mmol, 70% purity) in DMF (4 mL) was added to the solution at 20 C. Then, the mixture was stirred at 80 C for 12 h. The reaction solution was added with NH4Q solution (20 ml,), extracted with DCM:MeOH (20 mL chi 3, ratio=3: l). The organic layers were combined, dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by prep-TLC (DCM:MeOH = 5: 1) to give a mixture of 3-niethy3~6~(3-methyi-4~nitro^ and 3- methyl-6-(5~methyl-4-nitro-pyra^ as a yellow gum. LCMS: RT 0.925 min, m/z = 263.1 | M – H j ‘ . NMR (400 MHz, CDC13): delta 8.25 (s, 0.6 H), 8.13 (s, 0.3 H), 4.68 – 4.81 (m, 1 H), 4.14 – 4.42 (m, 2 H), 3.02 – 3.31 (m, 2 H), 2.77 (s, 1 H), 2.55 (s, 2 H), 2.44 – 2.53 (m, 4 H), 2.43 (s, 1 1H 1).

In the field of chemistry, the synthetic routes of compounds are constantly being developed and updated. I will also mention this compound in other articles, 3-Methyl-4-nitro-1H-pyrazole, other downstream synthetic routes, hurry up and to see.

Reference:
Patent; DENALI THERAPEUTICS INC.; ESTRADA, Anthony A.; FENG, Jianwen A.; LYSSIKATOS, Joseph P.; SWEENEY, Zachary K.; DE VICENTE FIDALGO, Javier; (271 pag.)WO2017/87905; (2017); A1;,
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Related Products of 5334-39-4, In the next few decades, the world population will flourish. As the population grows rapidly and people all over the world use more and more resources, all industries must consider their environmental impact. 5334-39-4, name is 3-Methyl-4-nitro-1H-pyrazole belongs to pyrazoles-derivatives compound, it is a common compound, a new synthetic route is introduced below.

To a stirred solution of PPh3 (4.28 g, 0.016 mole, 1.1 equiv) and DIAD (3.33 gm,, 0.016 mole, 1.1 equiv) in THF (2mL), was added 4-nitro-lH-pyrazole (1.96 g, 0.004 mmol, 1.0 equiv) The reaction mixture was added l-[2, 4-bis (trifluoromethyl) phenyl] ethanol (4 g, 0.004 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 1 hrs. Product formation was confirmed with TLC and LCMS. After completion of reaction mixture were diluted with EtOAc (50 mL) and washed with water (3×50 mL). Organic layer dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude which was further purified by flash column chromatography to obtain pure product l-(l-(2,4- bis(trifluoromethyl)phenyl)ethyl)-5-methyl-4-nitro-lH-pyrazole (0.5 gm) and l-(l-(2,4- bis(trifluoromethyl)phenyl)ethyl)-3-methyl-4-nitro-lH-pyrazole (1.5 gm). LCMS: 368 [M+H] +.

In the field of chemistry, the synthetic routes of compounds are constantly being developed and updated. I will also mention this compound in other articles, 3-Methyl-4-nitro-1H-pyrazole, other downstream synthetic routes, hurry up and to see.

Reference:
Patent; PRAXIS BIOTECH LLC; ALFARO, Jennifer; BELMAR, Sebastian; NUNEZ VASQUEZ, Gonzalo Esteban; PUJALA, Brahmam; SATHE, Balaji Dashrath; BERNALES, Sebastian; CHAKRAVARTY, Sarvajit; THAKRAL, Pooja; PATIDAR, Rajesh Kumar; (344 pag.)WO2019/195810; (2019); A2;,
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Adding a certain compound to certain chemical reactions, such as: 5334-39-4, name is 3-Methyl-4-nitro-1H-pyrazole, belongs to pyrazoles-derivatives compound, can increase the reaction rate and produce products with better performance than those obtained under traditional synthetic methods. Here is a downstream synthesis route of the compound 5334-39-4, name: 3-Methyl-4-nitro-1H-pyrazole

Intermediate 6B 1-(4-methoxybenzyl)-3-methyl-4-nitro-1 H-pyrazole and 1-(4-methoxybenzyl)-5- methyl-4-nitro- 1 H-pyrazole In analogy to intermediate 4B), 2.5 g (19.7 mmol) 3-methyl-4-nitro-1 H-pyrazole and 3.70 g (23.6 mmol) 1 -(bromomethyl)-4-methoxybenzene were reacted to give after purification of the crude product via a Biotage chromatography system (50g snap KP- Si L column, hexane / 10 – 100% ethyl acetate, then ethyl acetate / 0 – 25% methanol) 4.9 g (100%) of the desired title compounds as a mixture. 1H-NMR (300 MHz, DMSO d6) delta (ppm) = 2.38 / 2.60 (s, 3H), 3.72 / 3.72 (s, 3H), 5.21 / 5.34 (s, 2H), 6.85 – 6.94 (m, 2H), 7.18 / 7.29 (d, 2H), 8.24 / 8.89 (s, 1 H). Intermediate 6C 1-(4-methoxybenzyl)-3-methyl-1 H-pyrazol-4-amine and 1-(4-methoxybenzyl)-5- methyl- 1 H-pyrazol-4-amine 4.94 g (20.0 mmol) 1 -(4-methoxybenzyl)-3-methyl-4-nitro-1 H-pyrazole and 1 -(4- methoxybenzyl)-5-methyl-4-nitro-1 H-pyrazole (intermediate 6B) was dissolved in 78 mL methanol, and 522 mg palladium on carbon (10 wt. %) and 10.1 g (160 mmol) ammonium formiate were added. The reaction mixture was heated for 1 h at 80 C. Afterwards the suspension was filtered through Celite and the filtrate was evaporated. The residue was diluted with 50 mL water and this phase was extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to obtain a crude material which was purified via a Biotage chromatography system (100g snap KP-Sil column, hexane / 20 – 70% ethyl acetate) to give 3.64 g (84%) of the desired title compounds as a mixture. 1H-NMR (400 MHz, DMSO d6) delta (ppm) = 1.96 / 1.98 (s, 3H), 3.55 (s, 2H), 3.70 / 3.71 (s, 3H), 4.94 / 5.05 (s, 2H), 6.83 – 6.88 (m, 2H), 6.90 / 6.94 (s, 1 H), 6.98 – 7.02 / 7.09 – 7.14 (m, 2H).

In the field of chemistry, the synthetic routes of compounds are constantly being developed and updated. I will also mention this compound in other articles, 3-Methyl-4-nitro-1H-pyrazole, other downstream synthetic routes, hurry up and to see.

Reference:
Patent; BAYER PHARMA AKTIENGESELLSCHAFT; BUCHMANN, Bernd; HEISLER, Iring; MUeLLER, Thomas; CLEVE, Arwed; HEROULT, Melanie; NEUHAUS, Roland; PETRUL, Heike; QUANZ-SCHOeFFEL, Maria; (248 pag.)WO2016/12481; (2016); A1;,
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Some common heterocyclic compound, 5334-39-4, name is 3-Methyl-4-nitro-1H-pyrazole, molecular formula is C4H5N3O2, traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route. COA of Formula: C4H5N3O2

A mixture of 2-(l-methyl-lH-pyrazol-3-yl)ethyl methanesulfonate (600 mg, 2.94 mmol), 3-methyl-4-nitro-lH-pyrazole (373 mg, 2.94 mmol), and Cs2C03 (1.92 g, 5.882 mmol) in DMF (20 ml) was stirred at 100 C for 2 h. H20 (20 ml) was added and the resulting mixture was extracted with EtOAc (20 ml x 3). The organic layers were combined, washed with brine (20 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with petroleum ether/ethyl acetate (1/1) to afford the title compound (600 mg, 87%) as a white solid. LC-MS (ESI): m/z = 236 (M+H)+.

These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 5334-39-4, its application will become more common.

Reference:
Patent; F. HOFFMANN-LA ROCHE AG; GENENTECH, INC.; BAKER-GLENN, Charles; BURDICK, Daniel Jon; CHAMBERS, Mark; CHAN, Bryan K.; CHEN, Huifen; ESTRADA, Anthony; SWEENEY, Zachary Kevin; WO2013/164321; (2013); A1;,
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Related Products of 5334-39-4, The chemical industry reduces the impact on the environment during synthesis 5334-39-4, name is 3-Methyl-4-nitro-1H-pyrazole, I believe this compound will play a more active role in future production and life.

To a solution of 3-methyi-4- mtro-lH-pyrazole (40 g, 314.71 mmol) in DMF (700 mL) was added NaH (18.88 g, 472.06 mmol, 60% purity) at 0 C over a period of 30 min under N2. The reaction was then stirred at 25 C for 2 h followed by the addition of methyl 2-bromo-2-methylpropanoate (85.46 g, 472.06 mmol, 61.04 mL) dropwise at 0C. The reaction mixture was warmed to 25 C and stirred at 25 C for another 16 h. TLC (petroleum ether/ethyl acetate = 5: 1) showed the starting material was consumed completely. The reaction was quenched by ice water slowly and then extracted with EtOAc (3 chi 700 mL). The combined organic phase was washed with brine (3 chi 200 mL), dried over anhydrous Na2S(, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 30: 1- 15: 1), to yield the desired product as a light yellow solid. H NMR (400 MHz, C DC M: 5 8.29 (s, 1 H), 3.72 is. 1 1 1). 2.51 (s, I H), 1 .84 (s, 6 H).

In the field of chemistry, the synthetic routes of compounds are constantly being developed and updated. I will also mention this compound in other articles, 3-Methyl-4-nitro-1H-pyrazole, other downstream synthetic routes, hurry up and to see.

Reference:
Patent; DENALI THERAPEUTICS INC.; ESTRADA, Anthony A.; FENG, Jianwen A.; LYSSIKATOS, Joseph P.; SWEENEY, Zachary K.; DE VICENTE FIDALGO, Javier; (271 pag.)WO2017/87905; (2017); A1;,
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Each compound has different characteristics, and only by selecting the characteristics of the compound suitable for a specific situation can the compound be applied on a large scale. 5334-39-4, name is 3-Methyl-4-nitro-1H-pyrazole, This compound has unique chemical properties. The synthetic route is as follows., Safety of 3-Methyl-4-nitro-1H-pyrazole

A solution of 940 mg (2.90 mmol) tert-butyl 4-[(5-methyl-4-nitro-1 H-pyrazol-1 – yl)methyl]piperidine-1 -carboxylate and tert-butyl 4-[(3-methyl-4-nitro-1 H-pyrazol-1 – yl)methyl]piperidine-1 -carboxylate (intermediate 17B) in 5 mL dichloromethane was stirred with 2.2 mL (29.0 mmol) trifluoroacetic acid for three hours. The reaction mixture was filtered over NH2 derivatized silica gel, and the filtrate was evaporated yielding 557 mg of the desired title compounds as crude product which was used without further purification. 1 H NMR (400 MHz, DMSO d6): delta (ppm) = 1.04 / 1.11 (m, 2H), 1.39 (m, 2H), 1.89 (m, 1 H), 2.38 (m, 2H), 2.42 / 2.60 (s, 3H), 2.90 (m, 2H), 3.95 / 4.01 (d, 2H), 8.80 / 8.23 (s, 1 H).

According to the analysis of related databases, 5334-39-4, the application of this compound in the production field has become more and more popular.

Reference:
Patent; BAYER PHARMA AKTIENGESELLSCHAFT; BUCHMANN, Bernd; HEISLER, Iring; MUeLLER, Thomas; CLEVE, Arwed; HEROULT, Melanie; NEUHAUS, Roland; PETRUL, Heike; QUANZ-SCHOeFFEL, Maria; (194 pag.)WO2016/12474; (2016); A1;,
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Related Products of 5334-39-4, These common heterocyclic compound, 5334-39-4, name is 3-Methyl-4-nitro-1H-pyrazole, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.

To a solution of 5-hydroxy-l-methyl-piperidin-2-one (175 nig, 1.35 mniol) , 3 -methyl -4-nitro-lH-pyrazole (5) (205.9 rag, 1.62 mmol) and PPh3 (531.14 mg, 2.03 mmol) in THF (15 mL) was added DIAD (409.48 mg, 2.03 mmol) at 0 C. The mixture was stirred at 25 C for 12 h. The reaction mixture was concentrated under reduced pressure to get a residue, which was purified by prep-TLC (Si02, DCM: MeOH :=: 20: 1) to give a mixture of l-methyl-5-(5-methyl-4-nitro-lH- pyrazol-l-yl)piperidin-2-one and l-methyl-5-(3-methyl-4-iiitro-lH-pyrazol-l-yl)piperidin-2-one as yellow solid, LCMS: RT 0,577 min, m/z = 239.1 [M+H . To a mixture of l-methyl-5-(5-methyl-4-nitro-lH-pyrazol- l-yl)piperidin-2-one and l-methyl-5-(3-methyl-4-nitro-lH-pyrazol-l-yl)piperidin-2-one (180 mg, 755.54 muetaiotaomicron) in MeOH (10 mL) was added Pd/C (10%, 60 mg) under 2. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 C for 4 h. It was filtered over celite, the filter cake was washed wtih MeOH (20 mL chi 2), the filtrate was combined and concentrated under reduced pressure to give a mixture of 5-(4-amino-5-meth}7l-lH-pyrazol-l-yl)-l-methylpiperidin-2- one and 5-(4-amino-3-methyl-lH-pyrazol-l -yl)-l -methylpiperidin-2-one (as yellow oil. LCMS: RT 0.194 mm, m/z = 209.1 [M+H]+. A mixture of 5-(4~amino-5~ methyl- lH-pyrazol-l-yl)-l-methylpiperidm-2-one and 5-(4-amino-3-methyl-lH-pyrazol-l-y])-l- methylpiperidin-2-one (107 mg, 513.78 mupiiotaomicron), 4-cyclopropyl-2-methylsulfonyl-5- (trifluoromethyl)pyrimidine (137 mg, 513.78 muetaiotaomicron) and TsQH.HjQ (49 mg, 256.89 mupiiotaomicron) in 1,4-dioxane (15 mL) was degassed and purged with N2 for 3 times, and then the m ixture was stirred at 100 C for 2 h under N2. It was poured into H20 (15 mL), adjusted to pH = 8 with aq, NaHC03, extracted wtih EtOAc (2 x 30 mL). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure to get a residue, which was purified by prep-HPLC (neutral) first and then it was re- purified by SFC to give 5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-lH- pyrazol-1 -yl)-l -methylpiperidin-2-one (14 mg) and 5-(4-((4-cyc]opropyl-5-(tri£luoromethyl)pyrimidin-2- yl)amino)-3 -methyl- 1 H-pyrazol- 1 -yl)- 1 -methylpiperidin-2-one . 5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-lH-pyrazol-l-yl)-l- methylpiperidin-2-one (A-26): H MR (400 MHz, CDC13): 3 8.39 (s, IH), 7.67 (br, s . 1H), 6.51 (br. s, H), 4.42 – 4.60 (m, IH), 3.91 (dd, J = 1 1.69, 9,92 Hz, 1H), 3.46 (ddd, J = 12.13, 5 ,51 , 1 ,76 Hz, IH), 3.00 (s, 3H), 2.65 (d, J ——- 3.97 Hz, 1H), 2.42 – 2.59 (m, 11 1 ). 2.25 (s, 3H), 2.17 (d. ./ 1.76 Hz, 2H), 1.22 (br. s.,2H), 1.09 (dd, J = 7.72, 3.31Hz, 2H). HPLC: Retention Time: 2.87 min. MS: (M+lT) m/z. 395.2. 5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-lH-pyrazol-l-yl)-l- methylpiperidin-2-one (A-27): MR (400 MHz, CDC13): delta 8.43 (s, IH), 7.86 (br, s,, IH), 6,49 – 6.87 (m, IH), 4.56 id. ./ 6.62 Hz, IH), 3.71 (d, ./ 7.06 Hz, 21 1 ). 3.00 (s, 3H), 2.48 – 2.64 (m, 2H), 2.34 – 2.45 (m, IH), 2.17 ·· 2.34 (m, 4H), 1.22 – 1.30 (m, 21 1 ). 1.15 (br. s., 2H). HPLC: Retention Time: 2.86 m in. MS: ( M l ) m/z: 395.2.

Statistics shows that 3-Methyl-4-nitro-1H-pyrazole is playing an increasingly important role. we look forward to future research findings about 5334-39-4.

Reference:
Patent; DENALI THERAPEUTICS INC.; ESTRADA, Anthony A.; FENG, Jianwen A.; LYSSIKATOS, Joseph P.; SWEENEY, Zachary K.; DE VICENTE FIDALGO, Javier; (271 pag.)WO2017/87905; (2017); A1;,
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Synthetic Route of 5334-39-4, In the chemical reaction process, reaction time, type of solvent, can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product. An updated downstream synthesis route of 5334-39-4 as follows.

To a stirred solution of 3-methyl-4-nitro-lH-pyrazole (1.24 g, 0.009 mol, 1 equiv) in DMF (20 mL) was added K2CO3 (1.86 g, 0.013 mol, 1 equiv) portion wise at 0C and stirred for 10 minutes. l-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (3 gm, 0.009 mol, 1 equiv) was added drop wise 0C. The reaction mixture was allowed to stir for 1 hour at RT. Product formation was confirmed by LCMS. After completion of reaction, reaction mixture was diluted with water and extracted with ethyl acetate (100 mL x 3). Combined organic extracts were washed with water (100 mL x 4), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain mixture of l-(2,4-bis(trifluoromethyl)benzyl)- 3-methyl-4-nitro-lH-pyrazole(peak 1) and l-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-4- nitro-lH-pyrazole(peak 2). obtained crude was sent for separation in prep. LCMS: 353 [M+H] +.

According to the analysis of related databases, 5334-39-4, the application of this compound in the production field has become more and more popular.

Reference:
Patent; PRAXIS BIOTECH LLC; ALFARO, Jennifer; BELMAR, Sebastian; NUNEZ VASQUEZ, Gonzalo Esteban; PUJALA, Brahmam; SATHE, Balaji Dashrath; BERNALES, Sebastian; CHAKRAVARTY, Sarvajit; THAKRAL, Pooja; PATIDAR, Rajesh Kumar; (344 pag.)WO2019/195810; (2019); A2;,
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Researchers who often do experiments know that organic synthesis is a process of preparing more complex target molecules from simple raw materials through one or more chemical reactions. Generally, it requires fewer steps, and cheap raw materials. 5334-39-4, name is 3-Methyl-4-nitro-1H-pyrazole, A new synthetic method of this compound is introduced below., name: 3-Methyl-4-nitro-1H-pyrazole

Procedure B:General Procedure for the Synthesis of 4-Amino-3 -methyl- 1-N-alkylated pyrazolesA solution of 3-methylpyrazole (1.96mL, 24.0mmol) in sulfuric acid (15mL) was cooled to – 5C and potassium nitrate (l . leq) was added portion-wise. The reaction was warmed to rt and stirred for 16h. The mixture was cooled to 0C and neutralized with ammonium hydroxide solution. The resulting solid was filtered and air-dried to give 3-methyl-4-nitro- 1H-pyrazole. To a solution of 3-methyl-4-nitropyrazole (300mg, 2.6mmol), potassium carbonate (2eq) and the alkylating reagent (l. leq) in acetonitrile (lOmL) was heated at 60C for 18h. After cooling to rt the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgSC^) and concentrated in vacuo. The crude residue was dissolved in methanol (lOmL), palladium on carbon (50mg) was added and the reaction was stirred under a balloon of hydrogen for 18h. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give the desired product.Example 23: 2-((6-(l-(2-methoxyethyl)-3 -methyl- 1 H-pyrazo 1-4-ylamino)- 1 H-pyrazo lo [3,4- d]pyrimidin- 1 -yl)methyl)benzonitrileThe following compound was made according to the procedure in Example 1, using l-(2- methoxyethyl)-3 -methyl- lH-pyrazo 1-4-amine. 1 -(2 -methoxyethyl)-3 -methyl- lH-pyrazo 1-4- amine was prepared by Procedure B using l-bromo-2-methoxyethane as alkylating agent:1H NMR (d6-DMSO) delta 9.29-9.36 (m, 1Eta), 8.94 (s, 1Eta), 8.09 (s, 1Eta), 7.89 (d, 1Eta), 7.65 (td, 1Eta), 7.51 (t, 1Eta), 7.28-7.30 (m, 1Eta), 5.68 (s, 2Eta), 4.15 (t, 2Eta), 3.63 (t, 2Eta), 3.18 (s, 3Eta), 2.14 (s, 3H); LC-MS method B, (ES+) 389.1, RT = 7.86min

The basis of chemical reaction formula synthesis, the synthesis route is composed of some specific reactions and combined according to certain logical thinking. We look forward to the emergence of more reaction modes in the future.

Reference:
Patent; CELLZOME LIMITED; RAMSDEN, Nigel; HARRISON, Richard John; OXENFORD, Sally; BELL, Kathryn; PITON, Nelly; DAGOSTIN, Claudio; BOUSSARD, Cyrille; RATCLIFFE, Andrew; WO2011/48082; (2011); A1;,
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Adding a certain compound to certain chemical reactions, such as: 5334-39-4, name is 3-Methyl-4-nitro-1H-pyrazole, belongs to pyrazoles-derivatives compound, can increase the reaction rate and produce products with better performance than those obtained under traditional synthetic methods. Here is a downstream synthesis route of the compound 5334-39-4, COA of Formula: C4H5N3O2

To a solution of cw-3-benzyloxycyclobutanol (17 g, 95 ,4 mmol) and 3-methyl-4-nitro-lH-pyrazole (12.1 g, 95.4 mmol) in THF (350 mL) was added PPh3 (37.5 g, 143 mmol). Then, DIAD (28.9 g, 143 mmol) was added slowly at 0 C, and the mixture was stirred at 15 C for 20 h. The mixture was quenched with H2Q (100 mL), then filtered. The filtrate was then extracted with EtOAc (3 x 70 mL), The organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel colum chromatography (PE:EtOAc = 10: 1 to 7: 1), to give trans- l-(3-benzyloxycyclobutyl)-5-methyl-4-nitro-pyrazole and trans-l-(3- benzyloxycyclobutyl)-3-methyl-4-nitro-pyrazoleTo a solution of /ra>v-l-(3-benzyloxycyclobutyl)-5-methyl-4-nitro-pyrazole and rra?is-l-(3-benzyloxyxyck)butyl)-3-methyl-4-nitro-pyrazole (19.5 g, 67.9 mmol) in DCM (200 mL) was added BC1 (1 M, 26.5 mL) at 0 C, and the mixture was stirred at 0 C for 2 h. The mixture was poured into water (200 mL) slowly, then extracted with DCM (2 x 100 mL). The organic phase was washed with aqueous ai K ()·. (50 mL), brine (40 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc = 2 : 1 to 1 : 1), to give trans-3-[5- methyi-4-nitro-pyrazol- 1 -yl]cyclobutanol and trans-3-[3-methyl-4-nitro-pyrazol-1-yl]cyclobutanol as a mixture as a white soli d . To a mixture of trans-3~[5-methyl-4-nitro- pyrazol- 1 -yl] cyclobutanol and rrav-3-[3-methyl-4-nitro-pyrazol-l-yl]cyclobutanol ( 1.4 g, 7.1 mmol) in CL CN (100 mL) was added Cul (541 mg, 2.84 mmol) and 2,2-difluoro-2-fluorosulfonyl-acetic acid ( 1.9 g, 10.65 mmol) at 15 C, and the mixture was stirred at 55 C for 2 h. The mixture was quenched with water (5 mL), The solvent was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1), to give trans- 1 – [3 -(difluoromethoxy)cyciobutyl] -5 -methy 1-4-nitr o-pyrazole and trans- 1-[3- (difluoroinethoxy)cyclobutyi]~3-methyl-4-nitro~pyrazole as a yellow solid To a mixture of ras-l-[3- (difiuoi methoxy)cyclobutyl |-5~methyl-4″nitro-pyrazoie and ro;/s~l~[3-(difluoromethoxy)cyclobutyl]-3- methyl-4-nitro-pyrazole (350 mg, 1.42 mmol) and NH4CI (379 mg, 7.08 mmol) in EtOH (8,8 mL) and H20 (2.2 mL) was added powder Fe (395 mg, 7.08 mmol) at 15 C, then the mixture was stirred at 80 C for 2 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The mixture was extracted with EtOAc (2 x 30 mL). The organic phase was washed with brine (10 mL), dried over anhydrous Na2S04, filtered and concentrated to give trans-l-[3- (dif]uoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-amine and rranA”-l-[3-(di£luoromethox’)cyclobutyl]-3- methyl-pyrazol-4-amme as a brown oil. LCMS: RT 2.06 min, m/z ==393.1 |M+H]+. To a mixture of trans- 1 – f 3 -(difluoromethoxy )cyclobutyl] -5 -methyl -pyrazol -4-amine and trans- 1 – f 3 – (difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-amine (270 mg, 1.24 mmol) in 1,4-dioxane (10 mL) was added 2~chloro-N-methy3-5~(trifliJoromethyi)pyrimidin-4-amine (262 mg, 1.24 mmol) and TsOH-H20 (236 mg, 1.24 mmol) at 15 C. The mixture was warmed to 90 C and stirred for 2 h. The reaction was quenched with H20 ( 1 mL), then concentrated under reduced pressure. The crude was purified by prep-HPLC (FA) to give trans-N2-[l-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5- (trifluoromethyl)pyrimidine-2,4-diamine (D-25): 1H NMR (400 MHz, CDC13): delta rhorhoiotaeta 8.08 (s, 1 H) 7.71 – 7.98 (br. s., 1 H), 6.23 (t, J =3.2 Hz, 1 H), 5 ,20 (t, .7 =3,2 Hz, 1 H), 4.1 (t, J =3.2 Hz, 1 H), 4 ,75 (br. s., 1 H), 3,03 (s, 3 H), 2.97 – 3.03 (m, 2 H), 2.68 – 2,73 (m, 2 H), 2,20 (s, 3 H); HPLC: RT 2.06 mm; MS: m/z: 393.1 [M+H]+ trans-N2-[l-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-yl]-]N4-methyl-5- (trifluoromethyl)pyrimidine-2,4-diamine (D-26): ‘H NMR (400 MHz, CDCi3): delta rhorhoetaiota 8.21 (s, 1 H), 8.07 (br, s,, 1 ). 7.89 (s, 1 H), 6,22 (t, J =3 ,2 Hz, I H), 5.34 (br. s., 1 H), 4.96-5.02 (m, 1 H), 4,81 – 4.90 (m, 1 H) 3.04 – 3.15 (m, 3 H), 2.84 – 2.96 (m, 2 H), 2.65 – 2.78 (m, 2 H), 2.31 (s, 3 H); HPLC: RT 2.06 min; MS: m/z: 393.1 j M 1 1 ] –

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Reference:
Patent; DENALI THERAPEUTICS INC.; ESTRADA, Anthony A.; FENG, Jianwen A.; LYSSIKATOS, Joseph P.; SWEENEY, Zachary K.; DE VICENTE FIDALGO, Javier; (271 pag.)WO2017/87905; (2017); A1;,
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics