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Method for synthesizing (1R, 2R)-1-p-methyl sulfone phenyl-2-amino-1,3-propanediol

A technology for the synthesis of thiamphenylphenyl and its method, which is applied in the field of synthesis of 1-p-thiamphenylphenyl-2-amino-1,3-propanediol (I), and can solve the problems of lengthy steps and large dosage , to achieve the effect of short route, easy operation and high yield

Inactive Publication Date: 2014-07-09
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses asymmetric hydroxycyanation and asymmetric induction to construct two chiral centers successively, and the reaction temperature is suitable, and the yield and selectivity are high; Larger dosage

Method used

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  • Method for synthesizing (1R, 2R)-1-p-methyl sulfone phenyl-2-amino-1,3-propanediol
  • Method for synthesizing (1R, 2R)-1-p-methyl sulfone phenyl-2-amino-1,3-propanediol
  • Method for synthesizing (1R, 2R)-1-p-methyl sulfone phenyl-2-amino-1,3-propanediol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1 Put p-thymphenylbenzaldehyde (18.42 g, 0.10 mol), diphenylmethylamine (18.33 g, 0.10 mol), dichloroethane (200 mL), anhydrous magnesium sulfate (40.00 g) in a dry In the reaction bottle, react at room temperature for 12 hours. After the reaction was completed, filter and recover the solvent under reduced pressure to obtain a colorless oil, which was recrystallized with 95% ethanol and dried to obtain white crystals, namely compound (III) (9.60 g, 95%), mp: 139~140°C.

[0033] 1H NMR (CDCl 3 , ppm): δ=3.06 (s, 3H, CH 3 ), 5.67 (s, 1H, CH), 7.26 (m, 2H, ArH), 7.24-7.41 (m, 8H, ArH), 8.02 (m, 4H, ArH) 8.49 (s, 1H, NH).

[0034] ESI-MS: (m / z)=350.6 (M + ).

[0035] Two, (2 S , 3 S )-1-Benzhydryl-2-ethoxycarbonyl-3-sulfonylphenylacridine (IV).

Embodiment 21

[0036] Example 21 Under nitrogen protection, (2 R )-(+)-3,3'-diphenyl-[2,2'-binaphthyl]-1,1'-diol (4.39 g, 0.01mol), triphenyl borate (11.60 g, 0.04 mol) in a dry reaction flask, add 50 ml of toluene, heat to 80°C for 1 hour, recover the toluene under reduced pressure, keep it at 80°C for 0.5 hour under vacuum, cool to room temperature, dissolve with 50ml of anhydrous toluene, and Add to the suspension of compound (III) (69.8 g, 0.20 mol) in anhydrous toluene (700 ml), stir at room temperature for 5 minutes, cool down to -20°C, add ethyl diazoacetate (25.08 g, 0.22 mol) dropwise ), and continue to react for 6 hours. Then the solvent was recovered under reduced pressure, and the crude product was recrystallized twice with ethanol and water to obtain a colorless crystal which was compound (IV) (59.52 g, 68.3%), mp: 122~123°C, optical rotation [α] 25 D = -20.9° (1.05, CHCl 3 ), the ee value is 99.7%.

[0037] 1 H NMR (CDCl 3 , ppm): δ=1.00(t, 3H, J =7.0, CH 3 ), 2.77 (d...

Embodiment 22

[0039] Example 22 Under nitrogen protection, (3 R )-(+)-2,2'-diphenyl-[3,3'-diphenanthrene]-4,4'-diol (5.38 g, 0.01 mol), triphenyl borate (11.60 g, 0.04 mol ) in a dry reaction flask, add 50 ml of toluene, heat to 80 ° C for 1 hour, recover the solvent under reduced pressure, and keep it at 80 ° C for 0.5 hours under vacuum, cool to room temperature, dissolve with 50 ml of anhydrous toluene, and Add to the suspension of compound (III) (69.8 g, 0.20 mol) in anhydrous toluene (700 ml), stir at room temperature for 5 minutes, cool down to -20°C, add ethyl diazoacetate (25.08 g, 0.22 mol) dropwise ), and continue to react for 6 hours. Then the solvent was recovered under reduced pressure, and the crude product was recrystallized twice with ethanol and water to obtain a colorless crystal which was compound (IV) (58.20 g, 66.8%), melting point, optical rotation, 1 H NMR and MS consistent with Example 21.

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Abstract

The invention belongs to the technical field of chemical medicines, and specifically relates to a synthesis method of (1R,2R)-1-p-thiamphenylphenyl-2-amino-1,3-propanediol (I). The method comprises: 1. Compound (III) is prepared by condensing p-thymphenylbenzaldehyde (II) with primary amine. 2. Under the action of a catalyst, compound (III) undergoes acridinization reaction with ethyl diazoacetate to generate compound (IV). 3. Compound (IV) is reduced to obtain compound (V). 4. Under the action of acid, compound (V) undergoes a one-pot ring-opening reaction and deprotection reaction to obtain (1R,2R)-1-p-thiamphenylphenyl-2-amino-1,3-propanediol ( I). The method of the invention has the advantages of novel design, short route, mild conditions, simple operation, good enantioselectivity, high yield and good industrialized production prospect.

Description

technical field [0001] The invention belongs to the technical field of chemical medicines, in particular to a kind of (1 R ,2 R )-1-p-thiamphenylphenyl-2-amino-1,3-propanediol (I) synthesis method. Background technique [0002] (1 R ,2 R )-1-p-thiamphenicolphenyl-2-amino-1,3-propanediol is a key chiral intermediate in the synthesis of antibiotics such as Thiamphenicol and Fluorfenicol. Its structural formula is as shown in formula (I): [0003] [0004] (Ⅰ). [0005] US Patent US3927054 describes the desired (I) obtained from p-sulfone benzaldehyde through condensation, esterification, D-tartaric acid resolution, and reduction, as shown in the figure below. However, this method adopts a resolution strategy. Although the L-configuration product can be utilized through racemization or configuration inversion, it has the disadvantages of lengthy steps and low yield. [0006] [0007] Hajra et al. (Tetrahedron, 62, 2006, 8959–8965) reported that N-p-methylmercapto...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C317/32C07C315/04
Inventor 陈芬儿汪忠华李峰
Owner FUDAN UNIV
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