Process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents and uses thereof

a technology of unsaturated heterocycloalkyl and reagents, which is applied in the field of new heteroaryl and unsaturated heterocycloalkylmagnesium reagents, can solve the problems of unattractive use of large-scale synthesis, and achieve the effect of less deleterious and greater yield

Inactive Publication Date: 2006-06-22
AVENTIS PHARMA INC +1
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0137] In the present invention, it is often beneficial to consider of functional group / reagent compatibility. In some embodiments, functional groups that are incompatible with particular reagents or conditions can be protected prior to reaction, using well known protecting groups. Alternatively, one of skill in the art can select equivalent reagents to be used, for example, in oxidation procedures that are mild, less deleterious to the reactants and products, or generally provide greater yields.

Problems solved by technology

As discussed above, the current synthesis of these reagents makes their use in large-scale synthesis unattractive.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents and uses thereof
  • Process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents and uses thereof
  • Process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of (S)-2-amino-1-benzoxazol-2-yl-propan-1-ol hydrochloride

[0221]

Step 1

[0222] To a solution of benzoxazole (28.6 g, 240 mmol) in toluene (150 mL) was added during ca 20 min., at ca −4° C. a 2M solution of isopropyl-magnesium chloride in THF (120 mL, 240 mmol). The red-brown mixture was stored at ca −4° C. and used as needed.

Step 2

[0223] To a solution of (S)-2-Boc-aminobutanol (50 g; 264 mmol) in dichloromethane (500 mL) and water (350 mL) were added at 20° C. TEMPO (0.01 eq), sodium bromide (1 eq) and sodium hydrogencarbonate (3 eq). The reaction mixture was stirred at 0° C. and diluted bleach (1.3 eq, 450 mL) was added over 40 min. The reaction mixture was stirred for 30 min. at 0° C. and then quenched with aq. thiosulfate. After decantation and extractions (dichloromethane), the organic phase was washed with brine, dried and concentrated in vacuo to dryness, giving (S)-2-(tert-butoxycarbonyl)-amino-butyraldehyde as a low-melting solid (38.1 g; yield: 77%). C9H17NO3;...

example 2

Synthesis of (S)-2-(tert-butoxycarbonyl)amino-1-(oxazolo[4,5-b]pyridin-2-yl)propan-1-ol

[0226]

Step 1

[0227] A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate (80 ml) and p-toluenesulfonic acid (61 mg) was heated at 140° C. for 8 hours. Excess triethylorthoformate was removed under vacuum and oxazolo[4,5-b]pyridine was crystalized from ethyl acetate (9 g).

Step 2

[0228] In a clean roundbottom flask equipped with stir bar was placed oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in 30 mL THF and the reaction mixture was cooled to 0° C. under N2 atomosphere. Isopropylmagnesium chloride (2M in THF, 2.5 ml, 5 mmol ) was added. After stirring for 1 h at 0° C., (S)-2-(tert-butoxycarbonyl)aminobutyraldehyde (573 mg, 3 mmol) in 20 ml THF was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was e...

example 3

Synthesis of N-[1-(R)-(1S-benzoxazol-2-ylcarbonylpropylcarbamoyl)-2-cyclopropylmethylsulfonylethyl]morpholine-4-carboxamide

[0230]

Step 1

[0231] L-Cysteine (100 g, 0.825 mol) was suspended in ethanol (850 mL). A solution of sodium hydroxide (1.65 mol) in ethanol (650 mL) was added during 40 min at 20-25° C. To the solution was added bromomethylcyclopropane (0.907 mol) at 25-30° C. The reaction mixture was stirred at ambient temperature overnight, the neutralized with 2N HCl (300 mL). The suspension was concentrated under vacuum to 400 mL, then water (750 mL) was added, and pH was adjusted to 6.5 with 2N HCl. The mixture was stirred for 2 h at 0-5° C., the precipitate was filtered, washed with water and dried under vacuum to give (R)-2-amino-3-cyclopropyl-methylsulfanylpropionic acid as a white crystalline solid (128.2 g; yield=88.6%). C7H13NO2S; MW=175.3; Tmelt=209° C.; NMR (DMSO, ppm): 0.20 (m, 2H), 0.50 (m, 2H), 0.94 (m, 1H), 2.50 (m, 2H), 2.78 (dd, J=14.5 and 8.5 Hz, 1H), 3.08 (d...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
temperaturesaaaaaaaaaa
temperatureaaaaaaaaaa
temperatureaaaaaaaaaa
Login to view more

Abstract

The present invention is directed to a novel process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents that are useful in the synthesis of a variety of pharmaceuticals, in particular certain cysteine protease inhibitors.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] The present application claims priority to U.S. Provisional Application Ser. No. 60 / 373,176, filed on Apr. 17, 2002, the disclosure of which is incorporated herein by reference in its entirety.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] NOT APPLICABLE REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK. [0003] NOT APPLICABLE BACKGROUND OF THE INVENTION [0004] 1. Field of the Invention [0005] The present invention is directed to a novel process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents that are useful in the synthesis of a variety of pharmaceuticals, in particular certain cysteine protease inhibitors. [0006] 2. State of the Art [0007] Heteroaryl and unsaturated heterocycloalkylmagnesium reagents are useful in the synthesis of a variety of pharmaceuticals, such as renin inhibitors and cystein...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(United States)
IPC IPC(8): C07F3/02C07D263/56C07D277/64C07D498/04
CPCC07D263/56C07D277/64C07F3/02
Inventor LI, JIAYAOLINK, JOHN O.COLLADANT, COLETTE
Owner AVENTIS PHARMA INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap