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Synthesis method of derivative of chiral Beta-amino-alcohol and part of final products thereof

A synthesis method and technology for final products, which are applied in the field of chemical synthesis methods of chiral beta-amino alcohol derivatives and some final products thereof, can solve the problem of large enzyme requirements, limited application of pharmaceutical intermediates, and unsuitable for large-scale production. And other issues

Inactive Publication Date: 2010-06-23
ASYMCHEM LIFE SCI TIANJIN
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the enzyme resolution method (Tetrahedron: Asymmetry2004, 15, 1335), because of the large amount of enzyme required and the low recycling rate, limits this method to only stay on the level of laboratory preparation
At the same time, the residual traces of biological enzymes in the product are difficult to remove, which limits its application as a drug intermediate
The earliest literature report on chemical resolution (Bull SocChim, 1932, 51, 1277) used tartaric acid as the resolving agent to carry out multiple resolutions, and the chemical purity of the obtained aminocyclohexanol can reach more than 99%, but the disadvantage is that the resolution yield is extremely low , only less than 10%; in addition, sometimes the chemical separation method often has long reaction steps, and sometimes expensive chiral resolving agents are used
[0005] The synthetic method that has been reported above is because the reaction condition is difficult to control, thus the obtained product is easy to racemize or the purity (ee) value of the enantiomer is not high, or because the raw material is not easy to obtain and other reasons, it is not suitable for large-scale production

Method used

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  • Synthesis method of derivative of chiral Beta-amino-alcohol and part of final products thereof
  • Synthesis method of derivative of chiral Beta-amino-alcohol and part of final products thereof
  • Synthesis method of derivative of chiral Beta-amino-alcohol and part of final products thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] (1) Preparation of (R)-2-bromo-1-(4-bromophenyl)ethanol

[0028] Add 1.2L tetrahydrofuran (10mL / g), 32.8g borane dimethyl sulfide (1eq.) to the 2L reaction flask, add 5.9g R-methyloxazolidine (0.05eq.) to the system, after the addition is complete, place on ice Cool the bath to 0°C and stir for 30 min; start to add 120g of 2-bromo-4-bromoacetophenone (1eq) dropwise at a rate of 1 drop / 3s, after the addition is completed, follow the GC until the end of the reaction, add 240mL of methanol (2mL / g ) to terminate the reaction, the heat release is obvious, then add 240mL hydrochloric acid (18%) dropwise, shrink the system, extract with 240mL dichloromethane (2mL / g), wash the organic phase 3 times with saturated sodium bicarbonate solution (360mL*3), Saturated brine was washed 3 times (360mL*3), after drying, the organic phase was shrunk to obtain 112.7g of product, yield 93%, gas chromatography purity (GC): 97.8%, enantiomeric purity (ee) (using manual High performance liq...

Embodiment 2

[0037] (1) Preparation of (R)-2-chloro-1-phenylethanol

[0038] Add 1.5L 4-tetrahydrofuran (15mL / g), 58g borane dimethyl sulfide (1.5eq.) to the 2L reaction flask, add 11.4g R-methyloxazolidine (0.08eq.) to the system, and the addition is complete , cooled to -3°C in an ice bath and stirred for 40min; began to drop 80g of 2-chloro-acetophenone (1eq) at a rate of 1 drop / 2s. ) to terminate the reaction, the heat release is obvious, then add 160mL dilute sulfuric acid (18%) dropwise, shrink the system, extract with 160mL dichloromethane (2mL / g), and wash the organic phase 3 times with saturated potassium bicarbonate solution (150mL*3) , washed with saturated brine 3 times (150mL*3), after drying, the organic phase was concentrated to obtain 75g of product, yield 98.7%, gas chromatography purity (GC): 98.4%, enantiomeric purity (ee): 97.5%.

[0039] HNMR: (300MHz, CDCl3), δ7.333-7.399 (-C6H5, m), δ4.903 (-CH, d), δ3.707 (-CH2, dd), 2.681 (-OH, d).

[0040] (2) Preparation of (...

Embodiment 3

[0047] (1) Preparation of (R)-2-bromo-1-(4-chlorophenyl)ethanol

[0048] Add 1.2L tetrahydrofuran (12mL / g) and 27.9g borane dimethyl sulfide (0.9eq.) to the 2L reaction flask, and add 5.9g R-methyloxazolidine (0.05eq.) to the system. After the addition is complete, Cool down to -5°C in an ice bath and stir for 45 minutes; start to add 100g of 2-bromo-4-chloroacetophenone (1eq) dropwise at a rate of 1 drop / 2s. / g) to terminate the reaction, the heat release is obvious, then add 200mL hydrochloric acid (18%) dropwise, shrink the system, extract with 250mL dichloromethane (2.5mL / g), and wash the organic phase 3 times with saturated sodium carbonate solution (200mL*3 ), washed with saturated brine 3 times (200mL*3), after drying, the organic phase was shrunk to obtain 96.8g of product, yield 96%, gas chromatography purity (GC): 97.8%, enantiomeric purity (ee): 98.9%.

[0049] HNMR: (300MHz, CDCl3), δ7.465 (-C6H4, d), δ7.188 (-C6H4, d), δ4.915 (-CH, m), δ3.752 (-CH2, d), δ3. 6...

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Abstract

The invention relates to a synthesis method of a derivative of chiral Beta-amino-alcohol and part of intermediate products and final products thereof. The method selects a raw material which is commercialized on a market or a raw material of Alpha-halogeno ketone with easy preparation as an initial raw material, wherein X is Br or Cl, the final product with the chemical formula as the accompanying drawing is obtained by reaction or wherein R1=H, 2-Cl, 3-Cl, 4-Cl, 2, 4-Cl, 4-Br, 4-F, 4-CF3 and 4-NO2; R2=H, 2-OMe, 3-OMe, 4-OMe, 4-F, 4-Cl, 4-Br, 3-Br, 3-F, 3-Cl, 2-Br, 2-Cl, 2F, 4-Me, 3-Me and 2-Me, and the chiral center is S or R; the intermediate product with the chemical formula is shown in the accompanying drawing and the chiral center is in S configuration or R configuration; and the final product with the chemical formula is shown in the accompanying drawing and the chiral center is in S configuration or R configuration.

Description

(1) Technical field: [0001] The present invention relates to a chemical synthesis method of chiral β-amino alcohol derivatives and some final products thereof, especially and Synthetic methods and some of their final products. (two) background technology: [0002] The β-aminoalcohol structure is an important pharmacophore in drugs, which has various pharmacological activities. Chiral β-amino alcohol derivatives are widely used in organic synthesis and drug molecule synthesis, such as ephedrine with chiral β-amino alcohol structure extracted from Ephedra plants, which has a refreshing effect, and ephedrine can also be used as a hand Auxiliary reagents are used in asymmetric synthesis; as antibiotics, chloramphenicol also has a chiral β-amino alcohol structure, which is widely used in eye diseases caused by bacterial infections; in addition, chiral amino alcohol derivatives are also used as a good Chiral ligands and chiral auxiliary reagents are widely used in asymmetric ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/28C07C213/04C07C217/84B01J27/135
Inventor 洪浩李新勇
Owner ASYMCHEM LIFE SCI TIANJIN
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