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Preparation method of chiral pyrazolone compound

A technology of pyrazolone and pyrazolone imine, which is applied in the directions of organic chemistry methods, chemical instruments and methods, organic compounds/hydrides/coordination complex catalysts, etc. Regioselectivity, increasing synthesis steps, etc., to achieve the effect of simple reaction conditions, simplified steps, and small dosage

Pending Publication Date: 2021-12-24
SHANGHAI UNIV OF MEDICINE & HEALTH SCI +1
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

There are still many limitations in the research on chiral quaternary carbon centers substituted by heteroatoms. The reason may be that the reagents containing heteroatoms have nucleophilicity and do not match in electrical properties.
On the other hand, the direct functionalization of simple arylamine compounds is difficult, because aromatic amines have multiple reaction sites in the reaction process, and it is difficult to control the regioselectivity of the reaction by direct functionalization.
The functionalization reaction of the ortho-position of the amino group is realized by using the strategy of preloaded directing group. The introduction of the directing group increases the synthesis steps and limits the application expansion.

Method used

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  • Preparation method of chiral pyrazolone compound
  • Preparation method of chiral pyrazolone compound
  • Preparation method of chiral pyrazolone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of compound 3

[0034]

[0035] Chiral phosphoric acid (0.7mg, 1mol%), nitrogen methyl aniline S1-1 (10.7mg, 0.1mmol, 1.0equiv.), pyrazolone imine S-2 (31.6mg, 0.11mmol, 1.1equiv. ) placed in a dry reaction tube, reacted at room temperature, and monitored with a thin-layer chromatographic plate until the end of the reaction. The reaction solution was spin-dried and purified by column chromatography (PE:EA=20:1) to obtain compound 3 with a yield of 96%.

[0036] Yellow solid.37.8mg,96%yield.96%ee.[α] 20 D +92.71(c 1,CHCl 3 ).m.p.99-101℃.HPLC (Daicel Chiralpak AD-H, hexane / i-PrOH=80:20, 1.0mL / min, 254nm):t R (major)=4.9min,t R (minor) = 7.5min. 1 H NMR (400MHz, Acetone-d 6 ): δ7.83(d, J=8.0Hz, 2H), 7.39(t, J=8.0Hz, 2H), 7.25-7.14(m, 6H), 2.98(s, 3H), 1.89(s, 3H) ,1.33(s,9H). 13 CNMR (100MHz, Acetone-d 6 )δ168.95, 147.07, 138.50, 128.80, 128.50, 127.15, 126.75, 124.24, 118.01, 79.76, 77.59, 36.13, 27.38, 12.95. HRMS (ESI) m / z: [M+Na] + calculated ...

Embodiment 2

[0038] Embodiment 2, the preparation of compound 4

[0039] Chiral phosphoric acid (0.7mg, 1mol%), 4-methylnitromethylaniline S1-2 (12.1mg, 0.1mmol, 1.0equiv.), pyrazolone ketimine S2 (31.6mg, 0.11mmol, 1.1 equiv.) placed in a dry reaction tube, reacted at room temperature, and monitored by a thin-layer chromatographic plate until the end of the reaction. The reaction solution was spin-dried and purified by column chromatography (PE:EA=20:1) to obtain compound 4.

[0040] NMR (400MHz, Acetone-d 6 ):δ7.84(d,J=8.0Hz,2H),7.41-7.37(m,2H),7.18-7.11(m,3H),7.04(d,J=8.0Hz,2H),2.94(s, 3H), 2, 24(s, 3H), 1.89(s, 3H), 1.33(s, 9H). 13 C NMR (100MHz, Acetone-d 6)δ169.96, 157.85, 154.52, 154.32, 145.42, 139.51, 137.50, 130.30, 129.45, 128.03, 125.15, 118.96, 118.82, 80.53, 78.56, 37.16, 28.31, 20.90. Na] + calculated for C 23 h 28 N 4 o 3 Na 431.2059,found 431.2071.

example 3

[0041] Example 3, the preparation of compound 5

[0042] Chiral phosphoric acid (0.7mg, 1mol%), 4-methoxynitromethylaniline S1-3 (13.7mg, 0.1mmol, 1.0equiv.), pyrazolone imine S2 (31.6mg, 0.11mmol, 1.1 equiv.) placed in a dry reaction tube, reacted at room temperature, and monitored by thin-layer chromatography until the end of the reaction. The reaction solution was spin-dried and purified by column chromatography (PE:EA=20:1) to obtain compound 5.

[0043] (m,2H),7.17-7.15(m,3H),6.77(d,J=8.0Hz,2H),3.71(s,3H),2.92(s,3H),1.89(s,3H),1.33( s,9H). 13 C NMR (100MHz, Acetone-d 6 )δ169.96,159.41,158.00,154.39,140.52,139.50,129.44,129.40,125.13,118.94,115.43,114.75,113.72,80.64,78.64,55.59,37.29+,28.341,13. Na] + calculated for C 23 h 28 N 4 o 4 Na447.2008, found447.2019.

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Abstract

The invention provides a preparation method of a chiral pyrazolone compound. The method comprises the following steps: dissolving pyrazolone imine and N-alkyl arylamine in a solvent, and carrying out asymmetric N-alkylation reaction under the action of a chiral phosphoric acid catalyst to prepare a C-4-site diaza quaternary carbon center chiral pyrazolone compound, wherein the chemical structural formula of the chiral pyrazolone compound is defined in the specification. According to the invention, an organic small molecule catalyst is adopted, no metal catalyst is needed, subsequent separation and purification are facilitated, and the derivation step is simplified; and the method has the advantages of simple reaction conditions, small catalyst dosage, high chemical yield and good enantioselectivity, and provides a new idea for synthesis of pyrazolone compounds.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and relates to a pyrazolone compound, especially a preparation method of a chiral pyrazolone compound. Background technique [0002] Molecules with N,N-aminal fragments, that is, two different nitrogen-containing functional groups attached to the same carbon atom, are a very important class of chiral amine molecular compounds, which play an important role in the fields of medicinal chemistry and synthetic chemistry. important role. For example, Bendroflumethiazide is a diuretic widely used clinically. Optically pure imidazolinone compounds are widely used building blocks in organic synthesis, and are often designed as various chiral catalysts and chiral auxiliaries. The N,N-aminal structure of the non-ring system often stabilizes the distribution of charges by introducing electron-withdrawing groups. This type of structure also exhibits many special physiological activities. For example, PMRI f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B53/00C07D231/46C07D231/48C07D403/04C07D487/10B01J31/02
CPCC07B53/00C07D487/10C07D231/46C07D403/04C07D231/48B01J31/0258C07B2200/07
Inventor 孙振亮王林琳孙奇奇
Owner SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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