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Methods and compounds useful in the synthesis of fused aminodihydrothiazine derivatives

A technology of aminodihydrothiazine and compounds, which is applied in the field of synthesis and compounding of fused aminodihydrothiazine derivatives, and can solve problems such as undeveloped

Active Publication Date: 2017-05-10
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, Alzheimer's disease is treated only with symptomatic therapy using symptom-improving agents typified by acetylcholinesterase inhibitors, and basic therapy for suppressing the progression of the disease has not yet been developed

Method used

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  • Methods and compounds useful in the synthesis of fused aminodihydrothiazine derivatives
  • Methods and compounds useful in the synthesis of fused aminodihydrothiazine derivatives
  • Methods and compounds useful in the synthesis of fused aminodihydrothiazine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0388] Example 1 : Preparation of 6a-(2-fluorophenyl)-4-(trifluoromethyl)hexahydrofuro-[3,4-c]isoxazole

[0389]

[0390] tert-Butyl 2-(1,1,1-trifluorobut-3-en-2-yloxy)acetate At rt under nitrogen, a reaction vessel was charged with toluene (3.2 L), THF (0.60 L) and propylene Aldehyde (0.40 L, 5.985 mol). (Trifluoromethyl)trimethylsilane (1.003 kg, 7.059 mol) was added at 17°C. The reaction mixture was cooled to 2.5 °C and TBAF (0.01 M in THF, 0.400 L, 0.004 mol) was added over 2 hours. During the addition of TBAF, the temperature of the reaction mixture was raised to 65°C. The reaction mixture was cooled to 0°C and after 2 h, tetra-n-butylammonium bisulfate (0.171 kg, 0.503 mol) was added followed by tert-butyl bromoacetate (0.987 kg, 5.064 mol). Sodium hydroxide (50% wt in water, 4.2 kg, 52.6 mol) was added over 2 h while maintaining the temperature below 10°C. After 2 h at 0-5 °C, water (2.9 L) and methyl tert-butyl ether (6.0 L) were added to the reaction mixture. ...

Embodiment 2

[0414] Example 2 : Preparation of 6a-(2-fluorophenyl)-4-methylhexahydrofuro[3,4-c]isoxazole

[0415]

[0416] tert-Butyl 2-(but-3-en-2-yloxy)acetate: The reactor was charged with tetrabutylammonium bisulfate (0.17 Wt, 0.10 equiv) and toluene (2.6 Wt, 3.0 V). The mixture was stirred and cooled to 0-5°C. While maintaining the internal temperature below 10°C, 50wt% aqueous sodium hydroxide solution (4.5wt, 3.0V, 10.5 equiv; 50%wt sodium hydroxide prepared from 2.25wt sodium hydroxide and 2.25wt water) was added, followed by 3-Buten-2-ol (0.45Wt, 0.53V, 1.20 equiv). The mixture was stirred at 0-10°C for 15 minutes. tert-Butyl bromoacetate (1.0 Wt, 1.00 equiv) was added while maintaining the internal temperature at 0-10 °C. After addition, the mixture was stirred at 0-5°C for 1 h and monitored for complete consumption of t-butyl bromoacetate (target >98% conversion). The reactor was charged with water (3.0Wt, 3.0V) and MTBE (4.4Wt, 6.00V) and warmed to 20-25°C. The biphas...

Embodiment 3

[0453] Example 3 : Preparation of 6a-(2,3-difluorophenyl)-4-((trityloxy)methyl)hexahydrofuro[3,4-c]isoxazole

[0454]

[0455] 1-Morpholino-2-(1-(trityloxy)but-3-en-2-yloxy)ethanone. To the reactor with 1-(trityloxy)but-3-en-2-ol 13 (41.6 g, 0.111 mol, 1.0 equiv) was added toluene (146 mL). The resulting solution was cooled to 0-5°C and tetra-n-butylammonium bisulfate (7.52 g, 0.0222 mol, 0.20 equiv) was added. 4-(Chloroacetyl)morpholine (18.1 g, 0.111 mol, 1.00 equiv) was added at 0-5°C. Sodium hydroxide (50% wt. in water; 88.6 g, 1.10 mol, 10 equiv) was cooled to 15°C and added to the reaction mixture with T99%). 2-Methoxy-2-methylpropane (146 mL) and water (146 mL) were added to the reaction mixture with T<20°C. The organics were washed with 18% aqueous NaCl (73 mL) and saturated aqueous NH4Cl (21 mL). The organics were filtered through celite (10.4 g) to remove particles and rinsed with 2-methoxy-2-methylpropane (83 mL). The solvent was evaporated under vacuum at...

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Abstract

Provided are compounds and methods useful for the preparation of compounds useful as inhibitors of [beta]-site amyloid precursor protein (APP)-cleaving enzyme.

Description

[0001] This application is a divisional application of a Chinese patent with an application date of January 20, 2012, an application number of 201280004193.7, and the title of "Method and Compound for the Synthesis of Condensed Aminodihydrothiazine Derivatives". [0002] Related applications [0003] This application claims the benefit of US Provisional Patent Application No. 61 / 434,849, filed January 21, 2011, under 35 U.S.C. § 119(e). technical field [0004] The present invention relates to compounds and methods for the preparation of compounds useful as beta-site amyloid precursor protein (APP)-lyase inhibitors. Background technique [0005] Alzheimer's disease is a disease characterized by degeneration and loss of neurons and the formation of senile plaques and neurofibrillary degeneration. At present, Alzheimer's disease is treated only with symptomatic therapy using symptom-improving agents typified by acetylcholinesterase inhibitors, and basic treatments for inhibit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04
CPCC07D307/22C07D498/04C07D513/04A61P25/28A61P43/00
Inventor B.米塔塞夫金大式张慧明M.J.施纳德贝克C.N.法兴K.尤施扎瓦
Owner EISIA R&D MANAGEMENT CO LTD
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