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With hydroxylamine hydrochloride; sodium hydrogencarbonate In ethanol for 16 h; Reflux
The title compound is prepared by those skilled in the art according to a literature procedure (Lepage et al, Eur. J. Med. Chem., 1992, 27, 6, 581-93).To a solution of sodium hydrogen carbonate (2.10 g, 25 mmol) and hydroxylamine hydrochloride (1.73 g, 25 mmol) in ethanol (25 mL) is added ethyl trimethyl acetopyruvate (5.00 g, 25 mmol). The mixture is heated at reflux for 16 h. After this time the sodium chloride is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica eluting with 8/2 cyclohexane/ethyl acetate to provide the title compound as a yellow oil (3.2 g, 65percent), m/z 198 [M+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (9 H, s), 1.42 (3 H, t, /=7.15 Hz), 4.44 (2 H, q, /=7.15 Hz), 6.38 (1 H, s).
65%
With hydroxylamine hydrochloride; sodium hydrogencarbonate In ethanol for 16 h; Reflux
Step 1: Synthesis of 5-tert-butyl-isoxazole-3-carboxylic acid ethyl ester The title compound is prepared by those skilled in the art according to a literature procedure (Lepage et al, Eur. J. Med. Chem., 1992, 27, 6, 581-93). To a solution of sodium hydrogen carbonate (2.10 g, 25 mmol) and hydroxylamine hydrochloride (1.73 g, 25 mmol) in ethanol (25 mL) is added ethyl trimethyl acetopyruvate (5.00 g, 25 mmol). The mixture is heated at reflux for 16 h. After this time the sodium chloride is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica eluting with 8/2 cyclohexane/ethyl acetate to provide the title compound as a yellow oil (3.2 g, 65percent), m/z 198 [M+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.3 8 (9 H, s), 1.42 (3 H, t, J=7.15 Hz), 4.44 (2 H, q, J=7.15 Hz), 6.38 (1 H, s).
Reference：
[1] Patent: WO2009/140089, 2009, A2, . Location in patent: Page/Page column 37
[2] Patent: EP2418207, 2012, A1, . Location in patent: Page/Page column 24
[3] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1910, vol. 150, p. 928
2
[ 75-97-8 ]
[ 95-92-1 ]
[ 13395-36-3 ]
Yield
Reaction Conditions
Operation in experiment
93.3%
Stage #1: With sodium ethanolate In ethanol at 20 - 78℃; for 1 h; Stage #2: With hydrogenchloride In ethanol; water
To a solution of sodium ethoxide (740mmol of sodium in 45OmL ethanol), a mixture of methyl tert-bxAy\\ ketone (740mmol) and diethyl oxalate (820mmol) are added dropwise at room temperature and stirred for Ih at 78°C. On complete reaction, the mixture is allowed to cool to room temperature and it is poured onto cold aqueous hydrochloric acid (5M, 800 mL). Following extraction with methyl tert-butyl ether (300 mL x 3), the combined organic phases are washed with saturated aqueous sodium chloride (500 mL) and dried over anhydrous sodium sulfate. After filtration, removal of the solvent under reduced pressure affords the product as a red liquid. Compound wt: 14Og, Yield: 93.3percent.[00292] MS (ES+): 199 (M+l). NMR (1H, CDCl3): 6.5 (IH, s, CH); 4.3 (2H, q, OCH2); 1.35 (3H, t, CH3); 1.15 (9H, s, 3xCH3).
74.6%
With sodium In ethanol at 0 - 20℃;
General procedure: A mixture of ketone 15(0.087 mol), diethyl oxalate 16(0.087mol),thinly sliced sodium (0.047mol) in ethanol (55 mL) was first stirred at 0° and then stirred over night at room temperature. After complication, the mixture was acidified(pH3.0,with 20percent H2SO4), filtered and extracted with dichloromethane.The organic phase was dried and concentrated under vacuum to obtainan yellow or orange liquid 17a-e. The 1,3-diketone 17a-e(0.025mol) was dissolved in methanol (10mL),then added dropwise to a cooled solution(0°C) of hydrazinobenzene(0.025 mol) in methanol (30mL). The reaction was stirred for an hour at room temperature, refluxed for 2h,and the solvent was evaporated under reduced pressure. The residual liguid was purified by column chromatography (a5percent gradient of ethyl acetate in hexanes over a column of silica gel) to afford immediate 18a-e.To obtain the acid 19a-e, a solution of 18a-e(0.007 mol) was saponified through adding7ml 6 mol/L NaOH and stirring at 80°Cfor 2 h.The mixture was acidified (pH1–2) with concentrated hydrochloric acid and filtered to afford 19a-e.To a solution of 19a-e(0.010mol) in 15ml DMF, NCS (0.010mol) was added.The reaction mixture was heated at 90°C for 1hand then added to ice water(50ml), and filtered t oobtain 4-chlorosubstituted carboxylic acids 20a-e. The amide derivatives 21-38 were prepared through the acyl chlorides derived from 19 a-e or 20a-e. A solution of 19a-e or 20a-e(0.004mol) in thionyl chloride(10mL) was refluxed for 5 h and then concentrated under vacuum. The crude acylchloride was added dropwise to a cooled solution(0°C) of substituted aniline (0.004mol) and TEA (0.008mol)in dichloromethane (10mL). The mixture was stirred overnight at room temperature, and then purified on a column of silica using a gradient of ethylacetate in hexanes to afford the pure products.The yields of imtermediate 17a-e, 18a-e, 19a-e and 20a-e are listed intable 1S.
74.6%
With sodium In ethanol at 0 - 20℃;
Pinacolone 1 (0.087 mol) and diethyl oxalate 2 (0.087 mol) were added dropwise to a solution of ethanol (55 mL) containing thinly sliced sodium (0.047 mol) at 0 °C. The mixture was stirred overnight at room temperature. Next morning, the mixture was acidified (pH 3.0, with 20percent H2SO4) and filtered to remove the formed solid. The filtrate was extracted with dichloromethane, dried, and concentrated under vacuum to yield an orange red viscous liquid 3 (12.98 g; 74.6percent y). A solution of the 1,3-diketone 3 (0.025 mol) in methanol (10 mL) was added dropwise to a cooled solution (0 °C) of hydrazinobenzene (0.025 mol) in methanol (30 mL). The mixture was warmed to room temperature by stirring for an hour and then refluxed for 2 h. The resulting cooled mixture was concentrated under vacumm and the pyrazole ester 4 was obtained after purification by column chromatography (a 5percent gradient of ethyl acetate in hexanes over a column of silica gel). To saponify the ester, a solution of 4 (0.007 mol) was combined with an aliquot of 6 mol/L NaOH (aq) (7 mL) and the mixture was stirred at 80 °C. Ice water (50 mL) was added at the end of 2 h and the mixture was acidified (pH 1–2) with concentrated HCl. The formed solid was collected by filtration and the filter-cake was dried. The carboxylic acid was purified by recrystallization (methanol:water, 1:1) to afford 5 (3.57 g; 83.2percent yield). The amide derivatives 6a–p were prepared through the acylchlorides derived from 5. A solution of 5 (0.004 mol) in thionyl chloride (10 mL) was refluxed for 5 h [11] and then concentrated under vacuum. The formed crude acyl chloride was added dropwise to a cooled solution (0 °C) of substituted aniline (0.004 mol) and TEA (0.008 mol) in dichloromethane (10 mL). The resulting mixture was stirred overnight at room temperature to produce the crude product, which was purified on a column of silica using a gradient of ethyl acetate in hexanes to afford the pure products 6a–p.
70%
Stage #1: at 20 - 60℃; for 2 h; Stage #2: With hydrogenchloride In water
A mixture of tert-butyl ketone (499 mmol) and diethyl oxalate (548 mmol) in ethanol(550 mL) is added slowly to the solution of sodium (499 mmol) in ethanol (250 mL) at room temperature. After addition, the reaction mixture is heated to 600C for 2 h. On complete reaction, the ethanol is removed under reduced pressure and aqueous hydrochloric acid (2M, 200 mL) is added to the residue. The aqueous phase is extracted with ethyl acetate (500 mL x 3), washed with water (300 mL), saturated aqueous sodium chloride (300 mL) and it is then dried over anhydrous sodium sulfate. The solvent is then removed under reduced pressure to afford 5,5-dimethyl-2,4-dioxo-hexanoic acid ethyl ester as orange colored liquid (72.5g, 70percent).[0205] 1H NMR (400 MHz, CDCl3) δ: 1.20 (s, 9H), 1.35 (t, 3H), 4.34 (q, 2H), 6.53 (s, IH), 14.75(bs, IH). Mass (m/z): 201 (M+H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4383 - 4388
[2] Journal of Organic Chemistry, 1997, vol. 62, # 17, p. 5908 - 5919
[3] Patent: WO2009/71707, 2009, A1, . Location in patent: Page/Page column 43
[4] Chinese Chemical Letters, 2016, vol. 27, # 4, p. 566 - 570
[5] Chinese Chemical Letters, 2016, vol. 27, # 2, p. 251 - 255
[6] Patent: WO2009/71706, 2009, A1, . Location in patent: Page/Page column 43
[7] Journal of Organic Chemistry, 1991, vol. 56, # 18, p. 5301 - 5307
[8] Helvetica Chimica Acta, 1947, vol. 32, p. 1970
[9] Journal of Medicinal Chemistry, 2004, vol. 47, # 1, p. 14 - 17
[10] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 17, p. 4914 - 4919
[11] Synlett, 2018, vol. 29, # 7, p. 890 - 893
[12] Patent: US2008/242661, 2008, A1, . Location in patent: Page/Page column 24
3
[ 95-92-1 ]
[ 13395-36-3 ]
Yield
Reaction Conditions
Operation in experiment
89.6%
With sodium methylate In methanol; 3,3-dimethyl-butan-2-one; toluene
EXAMPLE 4 116.6 g (2.16 mols) of sodium methylate are suspended in 400 g of toluene. 292 g (2 mols) of oxalic acid diethyl ester are added dropwise at 5°-20° C. in the course of one hour. 200 g of technical grade pinacolin are then allowed to run in rapidly. The mixture is subsequently stirred for 15 minutes; 247 g of a methanol/ethanol/toluene mixture are then distilled off in the course of 4 hours. The bottom temperature rises to 110° C. towards the end of the distillation. The bottom product is cooled to 40° C. and stirred with 506 g of aqueous sulphuric acid (20.9percent strength by weight) for 1 hour. Separation of the phases and subsequent distillation of the organic phase gives 359 g of distillate which consists of pivaloylpyruvic acid ethyl ester to the extent of 92.9percent and of pivaloylpyruvic acid methyl ester to the extent of 6.4percent (89.6percent of the theoretical yield).
Reference：
[1] Patent: US4739104, 1988, A,
4
[ 75-97-8 ]
[ 7664-93-9 ]
[ 95-92-1 ]
[ 42957-17-5 ]
[ 13395-36-3 ]
Yield
Reaction Conditions
Operation in experiment
56.7% and 9.5%
With sodium In methanol; water
EXAMPLE 1 (for comparison) 23 g of sodium are dissolved in 300 ml of absolute methanol according to the instructions in J. Am. Chem. Soc. 67, 1508 (1945). A mixture of 1 mol of oxalic acid diethyl ester and 1 mol of pinacolin is then added dropwise to the sodium methylate solution, which is kept at room temperature by cooling, in the course of 1 hour and with exclusion of atmospheric moisture. The mixture is stirred for a further 6 hours at room temperature and then left to stand overnight at room temperature. An ice-cold solution of 30 g of concentrated sulphuric acid in 200 ml of water is then added to the ice-cooled reaction batch. The mixture is stirred for 10 minutes, poured into 1 liter of water and then extracted with three 100 ml portions of benzene. The combined benzene extracts are washed twice with 100 ml of water each time and then separated by distillation. 127 g of reactions product which, according to analysis by gas chromatography, contains 83percent by weight of pivaloylpyruvic acid methyl ester and 15percent by weight of pivaloylpyruvic acid ethyl ester are obtained. The contents of methyl ester and ethyl ester in the 127 g amount of reaction product correspond to 56.7percent and 9.5percent of the theoretical yield.
To a solution of <strong>[13395-36-3]ethyl trimethylacetopyruvate</strong> (205 mg, 1.02 mmol) in dry EtOH (1 mL) was added O-methylhydroxylamine hydrochloride (90 mg, 1.07 mmol) and 3A mol. sieves. The reaction was stirred at RT for 15 h, then was filtered and washed with EtOH. The filtrated was concentrated in vacuo, and the residue was partitioned between Et2O and sat. aqueous NaHCO3. The Et2O layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo to give Part A compound (176 mg, 75%) as a red-orange oil.
A solution of N-benzhydrylidene-N'-quinolin-6-yl-hydrazine (32 g, 0.099 mol) in EtOH (500 mL) was treated with cone. HC1 (80 ml, 0.96 mmol). After stirring for 10 min, <strong>[13395-36-3]5,5-dimethyl-2,4-dioxo-hexanoic acid ethyl ester</strong> (26 g, 0.15 mol) was added, and the mixture was heated to 80C overnight. The reaction was concentrated in vacuo to give a residue which was washed with Et20 to afford ethyl 5- tert-butyl-l-(quinolin-6-yl)-lH-pyrazole-3-carboxylate hydrochloride (40 g, 0.1 1 mol, 1 12 % yield). MS (ESI) m/z: 324.1 (M+H+).
Hydrazine hydrate (446 mmol) is added dropwise to solution of 5,5-dimethyl-2,4-dioxo- hexanoic acid ethyl ester (360 mmol) in ethanol at room temperature. After addition, the reaction mixture is stirred overnight at room temperature. On completion, the solvent is removed under reduced pressure and the residue obtained is diluted with water (250 mL) and extracted with dichloromethane (250 mL x are3). The combined organic phases are washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to afford 5-tert-butyl-2H- pyrazole-3-carboxylic acid ethyl ester as a white crystalline solid (70%).[0207] 1H NMR (400 MHz, DMSO-d6) delta: 13.21 (bs, IH), 6.45 (s, IH), 4.23 (q, 2H), 1.27 (s,9H,)1.25 (t, 3H). Mass (m/z): 197 (M+H).
11 g
With hydrazine dihydrochloride; In ethanol; for 3h;Reflux;
General procedure: To a stirred solution of appropriate methyl ketone (0.1 mol) in dry toluene (200 mL)was added a suspension of NaH in mineral oil (60%; 0.2 mol) in portions and the mixture was warmed to50 C. At this temperature a solution of diethyl oxalate (0.15 mol) in dry toluene (60 mL) was addeddropwise under stirring. The reaction mixture was refluxed for 1.5 h. Upon cooling to room temperatureacetic acid (0.25 mol) was added dropwise. The reaction mixture was washed with water (200 mL), organicphase was dried over MgSO4 and evaporated to dryness. The obtained crude diketone was dissolved inethanol (250 mL), hydrazine dihydrochloride (0.11 mol) was added and the mixture was refluxed for 3 h.After evaporation of solvent the residue was treated with water (200 mL) and kept under ice-cooling for 1 h.Crystals were filtered off and dried in air to afford the corresponding pyrazole. In some cases thus obtainedsubstance was purified by recrystallization from aqueous ethanol.
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