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Synthesizing method, partial intermediate products and final products of chiral beta-alkamine derivative

A technology for amino alcohols and a synthetic method is applied in the field of synthesis of chiral beta-amino alcohol derivatives, and can solve the problems of being unsuitable for large-scale production, difficult to obtain raw materials, difficult to control reaction conditions and the like

Active Publication Date: 2013-01-23
ASYMCHEM LIFE SCI TIANJIN
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Problems solved by technology

[0007] 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 enantiomer is not high, or raw material is not easy to obtain etc., is not suitable for large-scale production

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  • Synthesizing method, partial intermediate products and final products of chiral beta-alkamine derivative
  • Synthesizing method, partial intermediate products and final products of chiral beta-alkamine derivative
  • Synthesizing method, partial intermediate products and final products of chiral beta-alkamine derivative

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Experimental program
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Effect test

Embodiment 1

[0032] (1) Preparation of R-1-(3-bromoanilino)-3-chloro-propan-2-alcohol,

[0033] Add 100g (R) epichlorohydrin (1eq), 204.6g m-bromoaniline (1.1eq) to a 1L four-necked bottle, add 12.1g stannous chloride dihydrate (SnCl 2 .2H 2 O) (0.05eq), the addition is complete, stirred at 25±1°C, followed by GC until the end of the reaction, 400mL of water was added to terminate the reaction, the system was extracted with 600mL of methyl tert-butyl ether, the organic phase was washed with 150mL of saturated brine, and the The organic phase was dried to obtain 185.9 g of the product, the yield was 65%, the enantiomeric purity (ee): 99.8%, and the gas phase purity (GC): 94%.

[0034] H-NMR: (300MHz, DMSO-d 6 ), δ2.991-3.058 (dd, CH2NH, 1H), δ3.138-3.198 (dd, CH2NH, 1H), δ3.553-3.608 (dd, CH2Cl, 1H), δ3.648-3.699 (dd, CH2Cl , 1H), δ3.800-3.836(m, CH, 1H), δ5.390(b, NH, 1H), δ5.971(b, OH, 1H), δ6.587(d, Ph-H, 1H ), δ6.615 (d, Ph-H, 1H), δ6.772 (s, Ph-H, 1H), δ6.995 (t, Ph-H, 1H).

[0...

Embodiment 2

[0042] (1) Preparation of R-1-(4-fluoroanilino)-3-chloro-propan-2-alcohol,

[0043] Add 150g (R) epichlorohydrin (1eq), 189g p-fluoroaniline (1.05eq) to a 1L four-necked bottle, add 21.9g stannous chloride dihydrate (SnCl 2 .2H 2 O) (0.06eq), the addition is complete, stirred at 26±1°C, followed by GC until the end of the reaction, 400mL of water was added to terminate the reaction, the system was extracted with 800mL of methyl tert-butyl ether, the organic phase was washed with 200mL of saturated brine, and the Dry the organic phase to obtain 358g of crude product, methyl tert-butyl ether:petroleum ether=1:3 recrystallization, obtain product 210g, yield 63.6%, enantiomeric purity (ee): 99.6%, gas phase purity (GC): 96%.

[0044] H-NMR: (300MHz, DMSO-d 6), δ3.032-3.075 (dd, CH2NH, 1H), δ3.158-3.218 (dd, CH2NH, 1H), δ3.576-3.630 (dd, CH2Cl, 1H), δ3.670-3.719 (dd, CH2Cl , 1H), δ3.810-3.846(m, CH, 1H), δ5.503(b, NH, 1H), δ5.998(b, OH, 1H), δ6.501(m, Ph-H, 2H ), δ6.790 (m, ...

Embodiment 3

[0053] (1) Preparation of R-1-(4-bromoanilino)-3-chloro-propan-2-alcohol,

[0054] Add 50g (R) epichlorohydrin and 106.9g 4-bromoaniline (1.15eq) into a 500mL four-necked bottle, add 7.05g lithium bromide (0.15eq) to the system in two batches, after the addition is complete, stir at 27±1°C, GC tracking to the end of the reaction, 300mL of water was added to terminate the reaction, the system was extracted with 600mL of methyl tert-butyl ether, the organic phase was washed with 150mL of saturated brine, and the organic phase was dried to obtain 71g of the product with a yield of 50%. Enantiomer Purity (ee): 99.7%, gas phase purity (GC): 95%.

[0055] H-NMR: (300MHz, DMSO-d 6 ), δ2.701-3.078 (dd, CH2NH, 1H), δ3.158-3.218 (dd, CH2NH, 1H), δ3.532-3.587 (dd, CH2Cl, 1H), δ3.627-3.678 (dd, CH2Cl , 1H), δ3.806-3.847(m, CH, 1H), δ5.270(b, NH, 1H), δ5.983(b, OH, 1H), δ6.560(d, Ph-H, 1H ), δ6.651 (d, Ph-H, 1H), δ6.790 (d, Ph-H, 1H), δ6.974 (d, Ph-H, 1H).

[0056] (2) Preparation of...

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Abstract

The invention relates to a synthesizing method, partial intermediate products and final products of a chiral beta-alkamine derivative. The synthesizing method of the chiral beta-alkamine derivative is characterized by comprising the steps of: selecting commercialized materials in the market and NH2R2 as initial materials, wherein R2 is a Cl-C6 alkyl group, a C3-C6 naphthenic base and an aryl group or an aryloxy; obtaining the intermediate products and the final products through a chemical reaction process with moderate conditions, wherein R1 and R2 are the Cl-C6 alkyl group, the C3-C6 naphthenic base and the aryl group or the aryloxy, and a chiral center is in an S or R shape. The invention has the advantages that the adopted materials are easy to obtain and at low price and can meet the requirements of large-scale production, chiral compounds are used as the initial materials, optical purity is retained in consequent reaction without finding racemization, and committed steps accord with the requirements of the current green chemistry; in addition, the invention has the advantages of simple synthesizing method, good selectivity, high yield coefficient, easy operation and good market benefits.

Description

(1) Technical field: [0001] The present invention relates to a synthesis method of chiral β-amino alcohol derivatives and some intermediate products and final products thereof, especially Synthetic methods and some intermediate products and final products. (two) background technology: [0002] The β-amino alcohol structure is the main pharmacophore of many drugs. Chiral β-amino alcohols have important uses in organic synthesis. They are ideal chiral building blocks and excellent organic catalysts. They are still asymmetric A very important chiral ligand in catalytic reactions, which can coordinate with transition metal ions to form chiral catalysts, catalyze asymmetric hydrogenation and asymmetric hydrogen transfer reactions, etc. In addition, recent studies have found that chiral β-amino alcohols The compounds of the structure are applied to the synthesis of heterocyclic compounds, which help to prevent the absorption of cholesterol and have good biological activity in an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/00C07C213/04C07C215/16C07D303/36C07C217/64
Inventor 洪浩马特·约翰森李康应
Owner ASYMCHEM LIFE SCI TIANJIN
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