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Preparation method of (3R,5R)-3,5-dihydroxy-6-methyl cyan-caproate

A technology of cyanocaproate and dihydroxy, applied in the field of preparation of -3, 5-dihydroxy-6-cyanocaproate, which can solve the problems of complex operation, harsh reaction conditions, high equipment and labor protection requirements , to achieve high yield, mild reaction conditions and good industrialization prospects

Inactive Publication Date: 2014-05-07
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above synthetic routes all need to use highly toxic cyanide, the reaction conditions are harsh, the requirements for equipment and labor protection are high, and the operation is complicated

Method used

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  • Preparation method of (3R,5R)-3,5-dihydroxy-6-methyl cyan-caproate
  • Preparation method of (3R,5R)-3,5-dihydroxy-6-methyl cyan-caproate
  • Preparation method of (3R,5R)-3,5-dihydroxy-6-methyl cyan-caproate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Step 1: Preparation of (R)-3-tert-butyldiphenylsilyloxy-5-methoxy-5-oxopentanoic acid ( )

[0029] 3--tert-butyldiphenylsilyloxycyclopentanoic anhydride ( )1.1 g (3 mmol, 1.0 eq), methanol 1.2 mL (30 mmol, 10 eq), quinine thiourea catalyst 0.3 mmol (0.1 eq) dissolved in 150 mL methyl tert-butyl ether, 0 o C was reacted for 24 hours, concentrated under reduced pressure, and purified by column chromatography to obtain colorless oily matter 3-tert-butyldiphenylsilyloxy-5-methoxy-5-oxopentanoic acid ( ) (1.16 g, 2.9 mmol), 97% yield. 1 H-NMR (400 MHz, CDCl 3 ) δ 1.04 (s, 9H), 2.55-2.68 (m, 4H), 3.57 (s, 3H), 4.50-4.56 (m, 1H), 7.36-7.47 (m, 6H), 7.68 (d, J = 6.8 Hz, 4H), 10.07 (br s, 1H) ppm. MS (ESI): 399 (M-H + );

[0030] Step 2: Preparation of (R)-dimethyl 2-cyano-3-oxo-5-tert-butyldiphenylsiloxypimelate ( )

[0031] 3-tert-butyldiphenylsilyloxy-5-methoxy-5-oxopentanoic acid ( ) 800 mg (2 mmol, 1.0 eq), 0.29 mL (3 mmol, 1.5 eq) of oxalyl chloride, ...

Embodiment 2

[0037] Step 1: Preparation of (R)-3-tert-butyldiphenylsilyloxy-5-benzyloxy-5-oxopentanoic acid ( )

[0038] 3-tert-butyldiphenylsilyloxycyclopentanoic anhydride ( ) 1.1 g (3 mmol, 1.0 eq), 3.1 mL (30 mmol, 10 eq) of benzyl alcohol, and 0.3 mmol (0.1 eq) of quinine sulfonamide catalyst were dissolved in 150 mL of tetrahydrofuran, and reacted at room temperature for 12 hours under a nitrogen atmosphere. Concentrate under reduced pressure, and purify by column chromatography to obtain colorless oil 3-tert-butyldiphenylsilyloxy-5-benzyloxy-5-oxopentanoic acid ( ) (1.4 g, 2.9 mmol), 97% yield. 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.01 (s, 9H), 2.54-2.69 (m, 4H), 4.49-4.55 (m, 1H), 4.97 (d, J = 12.0 Hz, 1H), 5.03 (d, J = 12.0 Hz, 1H), 7.25-7.44 (m, 11H), 7.64-7.67 (m, 4H) ppm. MS (ESI): 477 (M+H + );

[0039] Step 2: Preparation of methylbenzyl (R)-2-cyano-3-oxo-5-tert-butyldiphenylsiloxypimelate ( )

[0040] 3-tert-butyldiphenylsilyloxy-5-benzyloxy-5-oxopentanoic acid...

Embodiment 3

[0046] Step 1: Preparation of (R)-3-tert-butyldimethylsilyloxy-5-methoxy-5-oxopentanoic acid ( )

[0047] 3-tert-butyldimethylsiloxycyclopentanoic anhydride ( ) 0.73 g (3 mmol, 1.0 eq), 1.2 mL (30 mmol, 10 eq) of methanol, and 0.3 mmol (0.1 eq) of quinine urea catalyst were dissolved in 150 mL of dichloromethane, and reacted at room temperature for 12 hours under a nitrogen atmosphere. Concentrate under reduced pressure, and purify by column chromatography to obtain 3-tert-butyldimethylsilyloxy-5-methoxy-5-oxopentanoic acid as a colorless oil ( ) (0.8 g, 2.9 mmol), yield 97%. 1 H-NMR (400 MHz, CDCl 3 ) δ 0.06 (s, 3H), 0.07 (s, 3H), 0.84 (s, 9H), 2.55-2.69 (m, 4H), 3.68 (s, 3H), 4.51-4.57 (m, 1H), 11.07 ( br s, 1H) ppm. MS (ESI): 275 (M-H + );

[0048] Step 2: Preparation of dimethyl (R)-2-cyano-3-oxo-5-tert-butyldimethylsiloxypimelate ( )

[0049] 3-tert-butyldimethylsilyloxy-5-methoxy-5-oxopentanoic acid ( ) 552 mg (2 mmol, 1.0 eq), 0.29 mL (3 mmol, 1.5 ...

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Abstract

The invention relates to a preparation method of (3R, 5R)-3,5-dihydroxy-6-methyl cyan-caproate (I) and belongs to the technical field of pharmaceutical chemistry. The preparation method concretely comprises the following steps of: firstly, carrying out asymmetric catalysis alcoholysis on 3-siloxy cyclopentane anhydride (II) to prepare (R)-3-siloxy-5-alkoxy-5-oxo-pentanoate (III); secondly, condensing the (R)-3-siloxy-5-alkoxy-5-oxo-pentanoate (III) and methyl cyanoacetate to prepare (R)-2-cyano-3-oxo-5-siloxy diethyl pimelate (IV); thirdly, carrying out decarboxylation on the (R)-2-cyano-3-oxo-5-siloxy diethyl pimelate (IV) to prepare (R)-3-hydroxy-5-oxo-6-benzyl cyanohexanoate (V) by using desilicication protective groups; and fourthly, carrying out asymmetric reduction on the (R)-3-hydroxy-5-oxo-6-benzyl cyanohexanoate to prepare a product of (3R,5R)-3,5-dihydroxy-6-methyl cyan-caproate (I). The preparation method is mild in reaction conditions, simple and convenient to operate, high in stereoselectivity, environment-friendly, and suitable for industrial production; and products have high yield, the used chiral catalyst is small in dosage and can be recovered with fix quantify, raw materials which are easily obtained are low in cost, and particularly hypertoxic cyanides are avoided.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a kind of (3 R , 5 R )-3, the preparation method of 5-dihydroxy-6-cyano hexanoate. Background technique [0002] Compound (3 R , 5 R )-3,5-Dihydroxy-6-cyanocaproate ( ) has the following structural formula: [0003] [0004] where R 1 for C 1 ~C 6 Fatty alkyl, C 3 ~C 6 Cycloalkyl, C 2 ~C 6 Alkenyl, aralkyl or aralkenyl, or optionally substituted derivatives of the above groups. [0005] (3 R , 5 R )-3,5-Dihydroxy-6-cyanocaproate ( ) is a key intermediate for the preparation of blood lipid-lowering drug atorvastatin calcium. Atorvastatin calcium (trade name: Lipitor ? ) is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which can regulate blood lipids, inhibit vascular endothelial inflammation, stabilize atherosclerotic plaques, improve vascular endothelial function, delay the degree of atherosclerosis, and resist It...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C255/20C07C253/30
CPCY02P20/55Y02P20/584
Inventor 陈芬儿陈晓飞何秋琴
Owner FUDAN UNIV