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Synthesis method of saxagliptin intermediate

A synthetic method and intermediate technology, applied in the field of synthesis of saxagliptin intermediates, can solve the problems of unfavorable environmental protection production, large amount of acid waste water, low chiral value of compound I, etc.

Active Publication Date: 2021-11-19
济南立德医药技术有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] This synthesis method has been greatly improved than the first generation synthesis method, but there are still two problems below: 1. The amount of acid waste water produced in the synthesis process is very huge: in the step of hydrolysis of -CN into carboxylic acid and oxidation In the single hydroxyl step, huge waste acid water is produced, which is not conducive to environmental protection production; 2. The chiral protecting group is removed prematurely, resulting in a low chiral value of the final product compound I

Method used

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  • Synthesis method of saxagliptin intermediate
  • Synthesis method of saxagliptin intermediate
  • Synthesis method of saxagliptin intermediate

Examples

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Embodiment 1

[0033] Preparation of adamantane formaldehyde (A1)

[0034] Put 1-adamantane methanol (250g, 1.5mol), dichloromethane (1.25L), sodium bicarbonate (63.25g, 0.75mol), water (300g), 2, 2, 6, 6 into a 5.0L four-necked bottle -Tetramethylpiperidinyloxy radical (Tempo, 2.5g, catalytic amount), sodium bromide (20.6g, 0.2mol), start stirring, ice-salt bath to reduce the internal temperature of the system to 0±5°C; add sodium hypochlorite dropwise Solution (10%, 1.8KG), during the dropwise addition, keep the temperature of the system not exceeding 15°C; keep stirring under ice bath for 1.0h. Stand still, separate the lower layer, discard the upper layer, add 800.0 mL of saturated sodium sulfite solution to the lower layer, stir for 15 minutes, let stand, and discard the upper layer; collect the lower layer and concentrate under reduced pressure, the temperature of the water bath shall not exceed 40 ° C, and obtain 232.5 g of yellow oil with a purity of >95 %, the molar yield is 93.8%....

Embodiment 2

[0044] Preparation of adamantane formaldehyde (A1)

[0045] Add 1-adamantane methanol (2.0Kg), dichloromethane (14.0L), sodium bicarbonate (506.0g), water (3.0Kg), 2,2,6,6-tetramethylpiperidine into the 50L reactor Oxygen radicals (20.0g), sodium bromide (200.0g), start stirring, ice-salt bath to reduce the internal temperature of the system to 0±5°C; add 10% sodium hypochlorite solution (13.0kg) dropwise, and keep The temperature of the system does not exceed 15°C; keep stirring in an ice bath for 1.0 h, let stand, separate the lower layer, and discard the upper layer: add 7.0 L of saturated sodium sulfite solution to the lower layer, stir for 15 min, let stand, and discard the upper layer; collect the lower layer and concentrate under reduced pressure, water bath temperature Do not exceed 40°C to obtain 1.86kg of yellow oil with a purity of >95% and a molar yield of 93.6%

[0046] Preparation of compound (A2)

[0047] Put compound A1 (2.0Kg), drinking water (15.0kg), sodiu...

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Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a saxagliptin intermediate. The intermediate is a compound I, and a compound A2 is used as a raw material and is subjected to hydrolytic hydroxylation, hydrogenation and amino protection reaction to obtain the compound I; and 1-adamantane methanol is used as a raw material of the compound A2, and the compound A2 is obtained through oxidation and butt joint. The synthesis route is shortened, so that the production period is shortened, and the production cost is greatly reduced. The compound A2 to a compound A3 are synthesized in one step through hydrolysis and hydroxylation, the amount of waste acid water is greatly reduced, meanwhile, an optical chiral protecting group is reserved and is removed at the end of the synthesis route, and a great role is played in improving the chiral value of the final compound I. The whole reaction process is mild in condition, no harsh anhydrous and anaerobic reaction exists, the amount of wastewater is greatly reduced, and the product is extremely high in optical activity.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthetic method of a saxagliptin intermediate (amantadine compound). Background technique [0002] Saxagliptin was jointly developed by Bristol-Myers Squibb and AstraZeneca. By selectively inhibiting DPP-4, the drug can increase the levels of endogenous glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thereby regulating blood sugar. In May 2011, saxagliptin, a novel dipeptidyl peptidase-IV (DPP-IV, endogenous incretin) inhibitor, was officially approved by SFDA in China. Clinical studies have confirmed that saxagliptin has the advantages of outstanding curative effect and long-lasting effect. Its chemical structure is as follows: [0003] [0004] The chemical structure is synthesized by docking compound I (amantadine compound) and compound II, and the specific route is as follows: [0005] [0006] Therefo...

Claims

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Application Information

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IPC IPC(8): C07C269/04C07C271/12
CPCC07C227/02C07C227/16C07C269/04C07C2603/74C07C229/28C07C271/12Y02P20/55
Inventor 沈建钢陈祝功
Owner 济南立德医药技术有限公司
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