CN107540616B - Preparation method of high-enantioselectivity pyrazole amine compound - Google Patents
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Abstract
A preparation method of pyrazole amine compound with high enantioselectivity. The structural formula is as follows:
the new method is adopted to synthesize the pyrazole amine compound with high enantioselectivity so as to
Synthesis of fungicidal pyrazole compounds by four synthetic steps as starting materials with high yields
(CAS: 1845899-33-3). At present, no report is available on the method, and the novel method has the following advantages: the invention can prepare the compound with reasonable general reaction path and simple post-treatment with high efficiency to obtain the pyrazole amine compound with high enantioselectivity.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a pyrazole amine compound with high enantioselectivity.
Background
Pyrazole derivatives are a class of compounds with a wide range of biological activities, some of which have been developed as fungicidesMicrobial agents, pesticides, herbicides and medicinal drugs have become a research hotspot in medicine and agricultural chemistry in the present year. Achiral pyrazole fungicides
(CAS:1845899-33-3, Taggi, A.E., L ong, J.K. PCTInt.appl., WO 2015171392A 120151112,2015) has been successfully synthesized, however, chiral drugs and achiral drugs show different pharmacological activities and toxic and side effects, and the pharmacological action of the chiral drugs is mostly related to chiral matching and molecular recognition capability between the chiral drugs and target molecules in vivo.
At present, asymmetric catalytic reactions have been developed. Chiral pyrazole derivatives have also been developed and challenged, and methods for synthesizing chiral pyrazole amine (CAS:1845899-33-3) compounds have not been reported. Therefore, it has become more important to develop a novel method for synthesizing a pyrazole amine compound having high enantioselectivity (CAS: 1845899-33-3).
Disclosure of Invention
The invention aims to provide a preparation method of a pyrazole amine compound with high enantioselectivity.
A highly enantioselective pyrazole amine compound having the formula:
the synthetic route of the high enantioselectivity pyrazole amine compound is as follows:
the synthesis steps are as follows: (1) dissolving the compound 3 in ether, adding hydrazine hydrate while stirring at room temperature, continuously stirring at room temperature until the reaction is complete, spin-drying the solvent, and performing column chromatography separation to obtain a compound 4;
(2) dissolving a compound 4 in THF, adding NaH into a THF solution of the compound 4 under stirring at 0 ℃, stirring for 10-30 minutes, adding MeI, stirring at room temperature until the reaction is complete, spin-drying the solvent, and performing column chromatography separation to obtain a compound 5;
(3) dissolving the compound 5 and nickel chloride hexahydrate in MeOH, stirring at-40 ℃ for 10-30 minutes, and adding NaBH4Continuing to react at the temperature of minus 40 ℃ until the reaction is complete, filtering, adding water into the filtrate, extracting with ethyl acetate, collecting an ethyl acetate organic phase layer, drying with anhydrous sodium sulfate, spin-drying the solvent, and performing column chromatography separation to obtain a compound 6;
(4) under the argon atmosphere, sequentially adding 2, 6-dimethyl bromobenzene, sodium tert-butoxide, tris (dibenzylideneacetone) dipalladium, 1 '-binaphthyl-2, 2' -bis-diphenylphosphine and a toluene solution of a compound 6, stirring at 90 ℃ for reaction till the reaction is complete, naturally cooling the reaction solution, filtering, washing with tetrahydrofuran, collecting filtrate, spin-drying the solvent, and separating by column chromatography to obtain a compound 7.
Further, the molar ratio of the compound 3a to hydrazine hydrate was 1.0: 1.05.
The molar ratio of compound 4, sodium hydride and methyl iodide was 1.0:5.0: 5.0.
The molar ratio of compound 5, nickel chloride hexahydrate and sodium borohydride was 1.0:1.0: 3.0.
The molar ratio of 2, 6-dimethylbromobenzene, sodium tert-butoxide, tris (dibenzylideneacetone) dipalladium, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine and compound 6 is 1.5:2.0:0.1:0.2: 1.0.
The synthesis of compound 3 is as follows:
further, the molar ratio of compound 1, compound 2, catalyst a and AcONa was 1.0:3.0:0.1: 1.0.
50.0mg per 0.1mmol of Compound 1
And (3) a molecular sieve.
The synthetic route of the catalyst A is as follows:
the specific synthesis steps are as follows:
(1) adding compound C1 into mixed solvent of water and THF at volume ratio of 4: 1, adding Na2CO3、Boc2O, reacting at room temperature until the reaction is finished, adjusting the pH value to 2 in an ice bath after the reaction is finished, adding ethyl acetate for extraction, and using Na for an organic phase2SO4Drying, spin-drying, and separating by column chromatography to obtain compound C2;
(2) adding sodium block at-78 deg.C under nitrogen atmosphere, introducing ammonia gas to form liquid sodium amide, adding THF solution of compound C2, heating to room temperature, adding NH4Quenching the Cl solid, stirring at room temperature until the sodium block is completely consumed, performing suction filtration, and spin-drying the filtrate to obtain a compound C3;
(3) adding a compound C4 and dichloromethane into a round-bottom flask, sequentially adding EDCI, DMAP and a compound C3, reacting completely at room temperature, and performing column chromatography separation to obtain a compound C5;
(4) adding sodium block at-78 deg.C under nitrogen atmosphere, introducing ammonia gas to form liquid sodium amide, adding THF solution of compound C5, heating to room temperature, adding NH4Quenching the Cl solid, stirring at room temperature until the sodium block is completely consumed, performing suction filtration, and spin-drying the filtrate to obtain a compound C6;
(5) dissolving the compound C6 in dichloromethane, adding 3, 5-dichloro phenyl isocyanate, reacting completely at room temperature, and performing column chromatography separation to obtain a compound C7;
(6) dissolving a compound C7 in methanol, dropwise adding AcCl, reacting at room temperature until the reaction is complete, and spin-drying to obtain a compound C8;
(7) under nitrogen atmosphere, Compound C8 was added, followed by Et at 0 deg.C3And N and a dichloromethane solution of the compound C9 are stirred at room temperature until the reaction is completed, and the catalyst A is obtained after column chromatography separation.
Preferably, in the step (1), C1 and Na2CO3And Boc2The molar ratio of O is 1: 1.2; in the step (2), the molar ratio of the compound C2 to the sodium blocks is 50: 1; in the step (3), the molar ratio of the compound C4, EDCI, DMAP and the compound C3 is 1.2: 1.3: 0.2: 1; in the step (4), the molar ratio of the compound C5 to the sodium blocks is 50: 1; in the step (5), the molar ratio of the compound C6 to the 3, 5-dichloro phenyl isocyanate is 1.2: 1; in the step (6), the molar ratio of the compound C7 to AcCl is 10: 1; in the step (7), the compounds C8 and Et3The molar ratio of N to the compound C9 is 1: 2: 1.5.
The invention can efficiently prepare the pyrazole amine compound with high enantioselectivity, and has the advantages that: the reaction efficiency is high, the reaction path is reasonable, the post-treatment is simple, and the compound pyrazole amine compound with high optical purity is obtained.
Drawings
FIG. 1 is a drawing of Compound 31H NMR spectrum;
FIG. 2 shows catalyst A1H NMR spectrum;
FIG. 3 is a drawing of Compound 71H NMR spectrum.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following specific examples, but the scope of the present invention is not limited thereto.
Instruments and primary chemical reagents
Bruker AV-300 nuclear magnetic resonance apparatus (Germany); agilent 1200 high performance liquid chromatograph (usa).
The raw materials and solvents used in the implementation process of the invention are all purchased from commercial sources.
The synthesis of compound 3 in the following example is as follows:
asymmetric aldol condensation reaction: isoxazole 1 and paraformaldehyde obtain isoxazole alcohol compound 3 with high enantioselectivity under the condition that guanidine salt of amino acid derivative urea is used as a phase transfer catalyst, and the synthetic route is as follows:
the synthesis procedure of compound 3 was as follows:
(1) 3-methyl-5-ethyl-4-nitroisoxazole 1(0.1mmol,1.0equiv.), catalyst A (0.01mmol,0.1equiv.), and sodium acetate (0.1 m.)mol,1.0equiv) and
molecular sieves (50mg) were dissolved in 1.0m L cyclopentyl methyl ether and stirred at room temperature for 15 minutes;
(2) paraformaldehyde 2(0.3mmol,3.0equiv.) was added and the reaction continued at room temperature until complete disappearance of starting material 1 was monitored by thin layer plate (T L C) (about 70 h);
(3) the solvent was dried by spin-drying and column chromatography (eluent: petroleum ether and ethyl acetate in a volume ratio of 10:1 to 3:1) gave compound 3 (85% yield).
A colorless oily liquid, 97% ee,
32.7(c 0.8),1H NMR(300MHz,CDCl3)4.06-3.98(m,1H),3.94-3.91(m,2H),2.55(s,3H),1.86(s,1H),1.39(d, J ═ 6.7Hz,3H), as shown in fig. 1;13C NMR(75MHz,CDCl3)176.1,155.8,64.8,36.2,13.8,11.6；HRMS(ESI)m/z 187.0718(M+H+),calc.for C7H11N2O4187.0719.
the ee value of the compound was determined by high performance liquid chromatography (HP L C) using CHIRA L PAK IC (4.6mm × 250 mm. i.d.), n-hexane/isopropanol 80/20(V/V), flow rate 1.0m L/min, 25 deg.C, 254nm, tR5.8min (small peak) and 7.4min (large peak).
Catalyst a was synthesized by the following method:
Step 2: 100ml two-neck bottle is taken, the bottle is baked, vacuum is pumped, nitrogen is exchanged, cut sodium blocks (50.0equiv) are added at-78 ℃, ammonia gas is slowly introduced to form liquid sodium amide (blue), the product C2(741.0g,2.0mmol, 1.0equiv) in the last step is dissolved in THF, and the liquid sodium amide is slowly injected by a syringe and reacted for 4 hours at-78 ℃. Warmed to room temperature and slowly added NH4The Cl solid was quenched and stirred at rt overnight until the sodium cake was completely consumed. Suction filtration and spin drying of the filtrate gave C3 as a white solid (95% yield) which was used directly in the next step.
And 4, step 4: taking a 100ml two-mouth bottle, baking the bottle, vacuumizing, and changing nitrogen. Cut sodium blocks (50.0equiv) were added, placed at-78 ℃ and ammonia gas was slowly bubbled in to form liquid sodium amide, product C5(725.6mg,1.5mmol,1.0equiv.) was dissolved in THF and added slowly to liquid sodium amide with a syringe and reacted for 4 hours at-78 ℃. Warmed to room temperature and slowly added NH4The Cl solid was quenched and stirred at rt overnight until the sodium cake was completely consumed. Suction filtration and spin drying of the filtrate gave C6 as a white solid (95% yield) which was used directly in the next step.
Step 5, the white solid C6(428.4mg,1.3mmol, 1.0equiv) from the previous step was transferred to a 100mL round bottom flask, 5m L DCM was added as a solvent, 3, 5-dichloro phenyl isocyanate (293.4mg,1.56mmol, 1.2equiv) was added, stirred at room temperature for 2 hours, the solvent was dried by spinning, and column chromatography was performed (eluent: dichloromethane to methanol volume ratio from 100:1 to 30:1) to obtain pure white solid C7 (yield 78%).
And 7: taking a 100ml two-mouth bottle, baking the bottle, vacuumizing, and changing nitrogen. The white solid C8(417.4mg,1.0mmol, 1.0equiv) from the previous step was added to a two-necked flask under nitrogen, and Et was added by syringe under ice bath (0 ℃ C.)3N (TEA,0.279m L, 2.0mmol, 2.0equiv) was slowly added, and finally the compound C9 (the specific synthetic steps refer to Ma, T.; Fu, X.; Huang, K.W.; Tan, C.H.J.Am.chem.Soc.2011,133(9),2828-2831) (710.1mg,1.5mmol, 1.5equiv) was dissolved in 5m L DCM and slowly added to the reaction system, and the mixture was stirred at room temperature for 2 hours until the reaction of the raw materials was completed. spin-drying the solvent, and column chromatography was performed (eluent, volume ratio of dichloromethane and methanol was from 100:1 to 50:1) to obtain pure white solid, namely catalyst A (yield 67%).
Catalyst A, M.P.142.3-144.5 ℃;
44.6(c 1.0,CHCl3).1H NMR(300MHz,CDCl3)9.51(s,1H),8.36(s,1H),7.94(d, J ═ 6.0Hz,1H),7.32(d, J ═ 6.0Hz,10H),6.96(s,10H),6.81(s,1H),4.93(d, J ═ 16.0Hz,2H),4.40(s,2H),4.19(d, J ═ 16.0Hz,4H),3.70-3.65(m,2H),2.91(d, J ═ 24.4Hz,1H),2.28(s,2H),1.15(s,9H),0.95(s,9H), as shown in fig. 2 in particular;13CNMR(75MHz,CDCl3)173.1,157.6,155.8,141.8,135.5,134.4,132.6,129.6(two peaks),129.2,128.7,127.5,126.8,121.1,116.3,70.4,65.4,57.8,49.6,45.0,34.2,33.9,27.2,26.8；HRMS(ESI)m/z 875.3352(M+H+),calc.for C48H55N6O2Cl3Na 875.3350.
example 1:
the structural formula of compound 7 is as follows:
(S) -N- (2, 6-dimethylphenyl) -5- (2- (1-methoxypropane)) -1, 3-dimethyl-1H-pyrazol-4-amine
The synthetic route for compound 7 is as follows:
the synthesis procedure of compound 7 was as follows:
(a) dissolving compound 3(52.1mg,0.28mmol) in diethyl ether (1.0m L), stirring at room temperature, adding hydrazine hydrate (0.0143m L, 0.294mmol), stirring at room temperature for an additional 18 hours [ monitoring complete disappearance of starting material 3 by thin layer plate (T L C) ], drying the solvent, and separating by column chromatography (eluent: petroleum ether and ethyl acetate in a volume ratio from 20:1 to 1:1) to give compound 4 (colorless oily liquid, 72% yield);
(b) dissolving compound 4(37.04mg,0.2mmol) in tetrahydrofuran (2.0m L), adding sodium hydride (24.0mg,1.0mmol) with stirring at 0 ℃, continuing to stir for 15 minutes, then adding iodomethane (0.062m L,1.0 mmol) with a syringe, standing at room temperature, continuing to stir for 12 hours [ monitoring the complete disappearance of the starting material 4 by a thin-layer plate (T L C) ], spin-drying the solvent, and separating by column chromatography (eluent: petroleum ether and ethyl acetate volume ratio from 30:1 to 5:1) to obtain compound 5 (colorless oily liquid, 88% yield);
(c) dissolving compound 5(27.7mg,0.13mmol) and nickel chloride hexahydrate (30.85mg,0.13mmol) in methanol (2.0m L) and stirring at-40 ℃ for 10 minutes, adding sodium borohydride (14.8mg,0.39mmol), continuing to stir at-40 ℃ for 3 hours [ monitoring the complete disappearance of the raw material 5 by a thin-layer plate (T L C) ], filtering to remove filter residue, adding water to the filtrate, extracting with ethyl acetate, collecting an ethyl acetate organic phase layer, drying the water with anhydrous sodium sulfate, removing water, and separating by column chromatography (eluent: dichloromethane and methanol volume ratio is from 100:1 to 30:1) to obtain compound 6 (colorless oily liquid, 87% yield);
(d) under argon atmosphere, 2, 6-dimethylbromobenzene (21.78m L, 0.164mmol), sodium tert-butoxide (20.95mg,0.218mmol), tris (dibenzylideneacetone) dipalladium (Pa)2(dba)39.98mg,0.0109mmol) and 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine (BINAP, 13.57mg,0.0218mmol) were added in this order to a round-bottomed flask reaction, compound 6(20.0mg,0.109mmol) was dissolved in toluene (2.0m L) and the toluene solution of the compound was added to the round-bottomed flask the reaction was placed in an oil bath at 90 ℃ for heating for 17 hours [ monitoring the complete disappearance of the raw material 6 by means of a thin-layer plate (T L C) ], the reaction was cooled, filtered, washed with tetrahydrofuran, the filtrate was collected, the solvent was dried by spinning, and column chromatography was performed (eluent: dichloromethane to methanol volume ratio from 100:1 to 30:1) to obtain compound 7 (red oily liquid, 71% yield).
94％ee，
19.3(c 1.11),1H NMR(300MHz,CDCl3)6.94(d, J ═ 6.6Hz,2H),6.75(t, J ═ 6.6Hz,1H),4.98(s,1H),3.68(s,3H),3.48(d, J ═ 6.8Hz,2H),3.30(s,3H),3.08(d, J ═ 6.8Hz,1H),2.07(s,6H),1.79(s,3H),1.25(s, 3H); as shown in particular in fig. 3;13C NMR(75MHz,CDCl3)147.7,142.9,131.9,128.9,127.1,122.6,120.4,78.3,58.7,36.3,31.5,18.8,15.9,8.9；HRMS(ESI)m/z288.2078(M+H+),calc.for C17H26N3O 288.2076.
the ee value of the compound was determined by high performance liquid chromatography (HP L C) using CHIRA L PAK IE (4.6mm × 250 mm. i.d.), n-hexane/isopropanol 90/10(V/V), flow rate 1.0m L/min, 25 deg.C, 254nm, tR7.5min (large peak) and 8.9min (small peak).
Claims (5)
1. A preparation method of a pyrazole amine compound with high enantioselectivity is characterized in that the synthetic route is as follows:
wherein Ar in the catalyst A is 3,5-Cl2Ph，
Dissolving a compound 1, a compound 2, a catalyst A, sodium acetate and a 3 Å molecular sieve in cyclopentyl methyl ether, reacting at room temperature to obtain a compound 3, wherein the molar ratio of the compound 1 to the compound 2 to the catalyst A to the sodium acetate is 1.0:3.0:0.1:1.0, and 50.0mg of 3 Å molecular sieve is added into each 0.1mmol of the compound 1;
(2) dissolving the compound 3 in ether, adding hydrazine hydrate while stirring at room temperature, continuously stirring at room temperature until the reaction is complete, spin-drying the solvent, and performing column chromatography separation to obtain a compound 4;
(3) dissolving a compound 4 in THF, adding NaH into a THF solution of the compound 4 under stirring at 0 ℃, stirring for 10-30 minutes, adding MeI, stirring at room temperature until the reaction is complete, spin-drying the solvent, and performing column chromatography separation to obtain a compound 5;
(4) dissolving the compound 5 and nickel chloride hexahydrate in MeOH, stirring at-40 ℃ for 10-30 minutes, and adding NaBH4Continuing to react at the temperature of minus 40 ℃ until the reaction is complete, filtering, adding water into the filtrate, extracting with ethyl acetate, collecting an ethyl acetate organic phase layer, drying with anhydrous sodium sulfate, spin-drying the solvent, and performing column chromatography separation to obtain a compound 6;
(5) under the argon atmosphere, sequentially adding 2, 6-dimethyl bromobenzene, sodium tert-butoxide, tris (dibenzylideneacetone) dipalladium, 1 '-binaphthyl-2, 2' -bis-diphenylphosphine and a toluene solution of a compound 6, stirring at 90 ℃ for reaction till the reaction is complete, naturally cooling the reaction solution, filtering, washing with tetrahydrofuran, collecting filtrate, spin-drying the solvent, and separating by column chromatography to obtain a compound 7.
2. The process for preparing a highly enantioselective pyrazole amine compound according to claim 1, wherein the molar ratio of the compound 3 to the hydrazine hydrate in the step (2) is 1.0: 1.05.
3. The process for preparing a highly enantioselective pyrazole amine compound according to claim 1, wherein the molar ratio of the compound 4, NaH and MeI in the step (3) is 1.0:5.0: 5.0.
4. The process for preparing a highly enantioselective pyrazole amine compound according to claim 1, wherein in the step (4), the compound 5, nickel chloride hexahydrate and NaBH4Is 1.0:1.0: 3.0.
5. The process for preparing highly enantioselective pyrazole amine compounds according to claim 1, wherein the molar ratio of 2, 6-dimethylbromobenzene, sodium tert-butoxide, tris (dibenzylideneacetone) dipalladium, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine and compound 6 is 1.5:2.0:0.1:0.2: 1.0.
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| CN106458925A (en) * | 2014-05-06 | 2017-02-22 | 杜邦公司 | Fungicidal pyrazoles |
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| CN105473581A (en) * | 2013-06-21 | 2016-04-06 | 齐尼思表观遗传学公司 | Novel substituted bicyclic compounds as bromodomain inhibitors |
| CN106458925A (en) * | 2014-05-06 | 2017-02-22 | 杜邦公司 | Fungicidal pyrazoles |
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