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Method for synthesizing derivatives of chiral pyridyl aminoalcohols, and intermediate products and final products of same

The technology of an aromatic ring amino alcohol and a synthesis method, which is applied in the field of synthesis of derivatives, can solve the problems of low application value, difficult control of splitting conditions, and low purity (ee) value of easy racemic enantiomers of products, and achieves Inexpensive effect

Active Publication Date: 2013-05-15
ASYMCHEM LAB TIANJIN +3
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0004] 1. to As a raw material, use chiral CBS for chiral reduction, and then carry out catalytic hydrogenation debenzylation; but due to the influence of nitrogen atoms, the purity (ee) of the enantiomer of the obtained alcohol is only 50-60 %, little practical value
[0005] 2. to As a raw material, it is reduced with NaBH4 to obtain racemic alcohol, and then resolved, but because it is a benzylic alcohol, it is easy to racemize during the resolution process, and basically has no industrial application value
[0006] The above two types of synthetic methods are difficult to control because of the separation conditions, so that the obtained products are easy to racemize or the purity (ee) value of the enantiomer is not high, so they are not suitable for large-scale production.

Method used

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  • Method for synthesizing derivatives of chiral pyridyl aminoalcohols, and intermediate products and final products of same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (1) Preparation of 1-S-(2-fluoropyridin-3-yl)-1-propanol,

[0033] Add 1.7kg tetrahydrofuran (25mL / g), 34.2g borane dimethyl sulfide (0.9eq.) to the 5L reaction flask, add 8.3gS-methyloxazolidine (0.06eq.) to the system, after the addition is complete, 25 Stir at ~26°C for 30 minutes; start to add 76.6g of 2-fluoro-3-propionylpyridine (1eq) dropwise at a rate of 1 drop / s, after the addition is complete, follow the HPLC until the reaction is complete, add 1.2kg of methanol (20mL / g) Terminate the reaction, shrink the system, add the residue into water, extract with 2.3kg of dichloromethane (23mL / g), shrink the organic phase to obtain 73.7g of product, yield 95%, liquid chromatography purity (HPLC): 98.8%, Enantiomeric purity (ee): 98.5%.

[0034] H-NMR: (300MHZ, CDCl3), δ0.688 (-CH3, t), δ1.352 (H on CH2 connected to CH3, m), δ4.418 (H on CH2 connected to hydroxyl , m), δ5.099 (H on the -OH, d), δ7.425 (H on the 5-position of the pyridine ring, m), δ8.121 (H on the 4-...

Embodiment 2

[0039] (1) Preparation of 1-R-(2-chloropyridin-3-yl)-1-cyclopropylmethanol;

[0040] Add 375.7g 2-methyltetrahydrofuran (30mL / g), 7.3g borane dimethyl sulfide (1.2eq.) to the 1L reaction flask, add 1.5g R-methyloxazolidine (0.07eq.) to the system , after the addition was completed, stir at 29-30°C for 40 minutes; start to add 14.6g of 2-chloro-3-cyclopropylformylpyridine (1eq) dropwise, 1 drop / s, after the addition was completed, follow the HPLC until the end of the reaction, add 172.6g Ethanol (15mL / g) was terminated, the system was shrunk to dryness, the residue was added to water, extracted with 484.2g (25mL / g) of dichloromethane, and the organic phase was dried to obtain 13.4g of the product, with a yield of 91%, liquid chromatography purity (HPLC ): 98%, enantiomeric purity (ee): 99%.

[0041] 1H-NMR: (300MHZ, CDCl3), δ0.561 (cyclopropyl CH2, m), 4.398 (H on the -CH connected to the hydroxyl group, s), δ4.499 (H on the -OH, s), δ7.615 (H, m at the 5-position of the py...

Embodiment 3

[0046] (1) Preparation of 1-S-(2-chloropyridin-3-yl)-1-propanol;

[0047] Add 242.8g diethyl ether (40mL / g) and 1.0g diborane (0.7eq.) to the 1L reaction flask, and add 1.1g S-methyloxazoborane (0.08eq.) to the system. After the addition is complete, 25-26 Stir at ℃ for 35min; start to add 8.5g of 2-chloro-3-propionylpyridine (1eq) dropwise, 1 drop / s, after the dropwise addition is completed, follow the HPLC until the end of the reaction, add 147.7g of methanol (22mL / g) to terminate the reaction, and collect Dry the system, add the residue to water, extract with 229.5g ethyl acetate (30mL / g), shrink the organic phase to obtain 7.6g of product, yield 88%, liquid chromatography purity (HPLC): 98%, enantiomeric Purity (ee): 99%.

[0048] 1H-NMR: (300MHZ, CDCl3), δ0.688 (-CH3, t), δ1.252 (CH2, m), δ4.418 (H connected to hydroxyl, m), δ4.499 (-OH, d ), δ7.425 (H on the 5-position of the pyridine ring, m), δ8.121 (H on the 4-position of the pyridine ring, d), δ8.391 (H on the 6-...

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Abstract

The invention relates to a method for synthesizing the derivatives of chiral pyridyl aminoalcohols, and intermediate products and final products of the same. Initial materials are selected from commercial raw materials on the market or easy-to-prepare raw materials of halogenated pyridine alkyl ketone or aromatic ring ketones, wherein X is F or Cl, R1 is C1 to C8 alkyls or C3 to C8 cycloalkyls; and final products are obtained through a process of chemical reactions under mild conditions, wherein R1 is C1 to C8 alkyls or C3 to C8 naphthene base, R2 is H or C1 to C8 alkyls, or C3 to C8 cycloalkyls or C7 to C9 benzyls, and chiral centers of alcohols have an S or R structure. The method provides a new thought and means for preparing the derivatives of chiral pyridyl aminoalcohols; the intermediate products are that the chiral centers of alcohols have an S or R structure; and the final products are that the chiral centers of alcohols have an S or R structure.

Description

(1) Technical field: [0001] The invention relates to a synthesis method of derivatives of chiral pyridine aromatic ring amino alcohols and some intermediate products and final products thereof. (two) background technology: [0002] Derivatives of chiral pyridine aromatic ring amino alcohols are introduced into peptide drugs to modify the peptide chain structure and enhance their stability and activity in living organisms; in addition, they can also be used as inhibitors or antioxidants to prevent such as Lung cancer, breast cancer, prostate cancer, arteriosclerosis and other malignant proliferative disorders, so as to achieve the purpose of treating cancer and tumor; for example, 1-S-(2-aminopyridin-3-yl)-1-propanol is In the synthesis of kinesin inhibitors for mitosis (drug patent EP1942899), such drug candidates are important drugs for the treatment of cell proliferative diseases. [0003] At this stage, the methods for preparing such compounds mainly include the followin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/72
Inventor 洪浩詹姆斯·盖吉陈朝勇黄海波
Owner ASYMCHEM LAB TIANJIN
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