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Methods and compounds for the synthesis of fused aminodihydrothiazine derivatives

A technology for compounds and mixtures, applied in organic chemistry, drug combinations, neurological diseases, etc., which can solve problems such as undeveloped

Active Publication Date: 2020-12-29
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 for the synthesis of fused aminodihydrothiazine derivatives
  • Methods and compounds for the synthesis of fused aminodihydrothiazine derivatives
  • Methods and compounds for 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 The 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 eq) 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, add 50wt% sodium hydroxide aqueous solution (4.5wt, 3.0V, 10.5 equivalents; 50%wt sodium hydroxide prepared from 2.25wt of sodium hydroxide and 2.25wt of water), 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 the addition, the mixture was stirred at 0-5°C for 1 h and monitored for complete consumption of tert-butyl bromoacetate (target >98% conversion). The reactor was charged with water (3.0Wt, 3.0V) and MTBE (4.4Wt, 6.00V) and raised to 20-25°C. ...

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 eq) 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 while T 99%). 2-Methoxy-2-methylpropane (146 mL) and water (146 mL) were added to the reaction mixture while 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 particulates and rinsed with 2-methoxy-2-methylpropane (83 mL). The solvent was evaporated under vacuum...

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Abstract

Compounds and methods for the preparation of compounds useful as inhibitors of β-site amyloid precursor protein (APP)-lyase are provided.

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 a title of "method and compound for the synthesis of fused aminodihydrothiazine derivatives". [0002] related application [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 inhibitors of beta-site amyloid precursor protein (APP)-lyase. Background technique [0005] Alzheimer's disease is a disease characterized by the degeneration and loss of neurons and the formation of senile plaques and neurofibrillary degeneration. Currently, Alzheimer's disease is treated only with symptomatic therapy using symptom-improving agents typified by acetylcholinesterase inhibitors, and basic therapy for suppressing ...

Claims

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Application Information

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Patent Type & Authority Patents(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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