D-p-hydroxyphenylglycine derivatives and their preparation methods and applications

A technology of p-hydroxyphenylglycine and derivatives, which is applied in the field of drug synthesis and can solve the problem of less research on D-p-hydroxyphenylglycine derivatives

Active Publication Date: 2017-06-23
SOUTHWEST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few studies on D-p-hydroxyphenylglycine derivatives at home and abroad.

Method used

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  • D-p-hydroxyphenylglycine derivatives and their preparation methods and applications
  • D-p-hydroxyphenylglycine derivatives and their preparation methods and applications
  • D-p-hydroxyphenylglycine derivatives and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] The synthesis of embodiment 1 intermediate IM1 and IM2

[0097]

[0098] In a 2L round bottom flask, add SM 83.55g (499.84mmol) and 2mol / L K 2 CO 3 300mL aqueous solution, stirred and dissolved under ice-bath cooling, then added 200mL of Z-OSu 130.11g (522.07mmol) acetone solution, and used 2mol / L K 2 CO 3 Adjust the pH of the aqueous solution to 8-9, stir and react at ambient temperature (15-35° C.), keep the pH constant during the reaction, and monitor the reaction progress by thin-layer chromatography (TLC). After the reaction is over, adjust pH=7 with 3mol / L hydrochloric acid, remove acetone by rotary evaporation, and saturate K 2 CO 3 The aqueous solution was adjusted to pH=9, ethyl acetate (EtOAc) was added for extraction (2×150 mL), the aqueous phase was cooled in an ice bath, concentrated hydrochloric acid was adjusted to pH=3-4, a large amount of solids precipitated, and EtOAc was added for extraction (3×250 mL), collected and The organic phases were co...

Embodiment 2

[0107] The synthesis of embodiment 2 intermediate IM3

[0108]

[0109] Add appropriate amount of IM2, acetonitrile, finely ground anhydrous K to a round bottom flask of appropriate size 2 CO 3 , stirred, and then added 1,3-dibromopropane (IM2:K 2 CO 3 :1,3-dibromopropane molar ratio is 1:4:6), heated in an oil bath at 50°C, and monitored the reaction progress by TLC. After the reaction, suction filtration and rotary evaporation of the filtrate gave a brownish-yellow oily product. Silica gel column chromatography, the eluent was concentrated by rotary evaporation, natural cooling for crystallization, suction filtration, and vacuum drying to obtain the intermediate IM3.

[0110] Table 2 Synthetic data of intermediate IM3

[0111]

[0112] IM3-a (R)-methyl 2-(((benzyloxy)carbonyl)amino)-2-(4-(3-bromopropoxy)phenyl)acetate: white solid; m.p.: 84-85°C ; 1 H NMR (600MHz, DMSO-d 6 )δ:2.21-2.25(m,2H,-CH 2 -),3.61(s,3H,OCH 3 ),3.66(t,2H,J=6.6Hz,-CH 2 Br), 4.07(t, 2H, J...

Embodiment 3

[0116] The synthesis of embodiment 3 compound TM1

[0117]

[0118] Add aromatic compound A and 5-15mL N,N-dimethylformamide (DMF) into a round bottom flask, stir to dissolve, then add powdered K 2 CO 3 After stirring for 30 minutes, IM3 was added, and the reaction was stirred at ambient temperature (15-35° C.), and the progress of the reaction was monitored by TLC. After the reaction, pour into ice water, extract with EtOAc, collect the organic phase, wash with water, anhydrous Na 2 SO 4 Dry, filter with suction, concentrate the filtrate by rotary evaporation under reduced pressure, and perform silica gel column chromatography to obtain the target compound TM1.

[0119] Table 3 Synthetic data of compound TM1

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126] TM1-1a (R)-methyl 2-((benzyloxycarbonyl)amino)-2-(4-(3-(3-formylphenoxy)propoxy)phenyl)acetate: white solid; m.p. :87-88℃; 1 H NMR (300MHz, CDCl 3 )δ: 9.97 (1H, s, CHO), 7.17-7.46 (...

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PUM

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Abstract

The invention discloses a D-hydroxy phenylglycine derivative. Please see the formula of the D-hydroxy phenylglycine derivative in the specification. D-hydroxy phenylglycine serves as a parent body, amino groups and carboxyl groups of the D-hydroxy phenylglycine are reasonably modified, a phenolic hydroxyl group is connected with an aromatic nucleus type hydrophobic group through a connector, the D-hydroxy phenylglycine derivative which is novel in structure is constructed, compounds capable of promoting the secreting activity of GLP-1 and / or inhibiting the activity of Nav1.7 are screened out, the preparation method of the compounds is simple and can be used for preparing GLP-1secernent and / or Nav1.7 inhibitors, and the D-hydroxy phenylglycine derivative has potential application prospects in the fields of diabetes treatment drugs and / or neuropathy pain treatment drugs. Please see the formula in the specification.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a new class of compounds, their preparation methods and their application in pharmacy. Background technique [0002] D-p-Hydroxyphenylglycine (D-PHPG), as a pharmaceutical intermediate, is currently mainly used in the production of β-lactam semi-synthetic antibiotics, such as amoxicillin (amoxicillin), cefadroxil (European Italian ), cefaclor (Pioneer IV), cefoperazone, cefurozil, cefadroxol, cefaclor, cephradine (Pioneer VI), ceftriaxone, ceftrixin and other broad-spectrum antibiotics synthetic production, D- Hydroxyphenylglycine is an essential side chain acid. But there are few studies on D-p-hydroxyphenylglycine derivatives at home and abroad. Contents of the invention [0003] In view of this, the object of the present invention is to use D-p-hydroxyphenylglycine as a parent, by protecting and modifying it, to synthesize a class of novel D-p-hydroxyphenylglycine der...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C269/06C07C271/22C07D311/46C07D263/58C07D235/28C07D285/135C07D239/56A61P29/00A61P25/04A61P5/50
Inventor 杨大成曹园范莉杨龙刘晓华蒋佳黄亚兰叶晶晶吴晓霞曹丽君周围
Owner SOUTHWEST UNIV
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