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A kind of method for preparing hydroxyadamantane glycine derivative

A technology of adamantane glycine and its derivatives, which is applied in the field of preparation of hydroxyadamantane glycine derivatives, and can solve the problems of low ee value, high cost and instability of the chemical catalysis method

Active Publication Date: 2017-05-31
上海飞腾医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present invention also provides a synthetic method for a new compound formula III, which can overcome the disadvantages of the prior art, such as expensive and unstable enzyme-catalyzed reaction, low ee value of chemical catalysis method, difficult purification, etc., and is more conducive to industrialization. Production

Method used

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  • A kind of method for preparing hydroxyadamantane glycine derivative
  • A kind of method for preparing hydroxyadamantane glycine derivative
  • A kind of method for preparing hydroxyadamantane glycine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1 Synthesis of (aS)-a-amino-1-adamantane-acetamide (formula III) (S)-1-phenylethylamine resolution

[0018]

[0019] Step 1-1 Add 0.83mol (135.9g) of adamantane-1-carboxaldehyde (Formula II) to a 5000ml four-neck flask, then add 150ml of water, start stirring to obtain a solid-liquid mixture, then add 700ml of methanol, and then add 0.83mol (100.6g) S-phenethylamine, cooled to 5°C in an ice bath; after adding 0.83mol (40.8g) NaCN, add dropwise 0.83mol (86.4g) NaHSO ４ Mixture with 400ml water, control temperature <20℃. Remove the ice bath after dropping, naturally rise to room temperature, stir for about 1 hour, then heat the oil bath to reflux (about 77°C), react for about 17 hours, or track the reaction solution by IPC until S-phenylethylamine <5%, stop heating, and cool down to <30°C. The reaction solution was extracted with DCM, washed with water four times, dried over anhydrous sodium sulfate for 15 min, filtered and concentrated under reduced pressure ...

Embodiment 2

[0022] Example 2 Synthesis of (aS)-a-amino-1-adamantane-acetamide (formula III) (S)-1-(3-chlorophenyl)-ethylamine resolution

[0023]

[0024] In this example, (S)-1-(3-chlorophenyl)-ethylamine was selected as the resolving agent to replace (S)-1-phenylethylamine in Example 1. The amount of (S)-1-(3-chlorophenyl)-ethylamine is 0.85mol (132.3g), the steps are the same as in Example 1, and finally 195.8g (aS)-a-amino-1-adamantane-ethylamine is obtained Amide (compound III) crude.

Embodiment 3

[0025] Example 3 Synthesis of (aS)-a-amino-1-adamantane-acetamide (formula III) (S)-1-(4-methylphenyl)-ethylamine resolution

[0026]

[0027] In this example, (S)-1-(4-methylphenyl)-ethylamine was selected as the resolving agent to replace (S)-1-phenylethylamine in Example 1. The amount of (S)-1-(4-methylphenyl)-ethylamine is 0.81mol (109.5g), the steps are the same as in Example 1, and finally 200.6g (aS)-a-amino-1-adamantane- Acetamide (compound III) crude.

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Abstract

The invention aims to provide a novel and simple synthesis route of a hydroxyadamantylglycine derivative represented by the formula I, namely (aS)-a-[[(1,1-dimethylethoxy)carboxyl]-amino]-1-(3-hydroxyadamantyl)-acetic acid) or salts of the derivative through developing a novel compound. A novel compound namely 2(aS)-a-amino-1-adamantyl-acetamide represented by the formula III is taken as the primary raw material and then is subjected to hydrolysis reactions and hydroxy group introduction so as to obtain the (aS)-a-[[(1,1-dimethylethoxy)carboxyl]-amino]-1-(3-hydroxyadamantyl)-acetic acid) represented by the formula I or salts of the derivative. The invention further provides a synthesis method of the novel compound represented by the formula III. The synthesis method can solve the disadvantages that the cost of enzyme catalyzed reactions is high, the enzyme catalyzed reactions are unstable, the chemical catalysis method has a low ee value, and the reaction product is not easy to purify in the prior art, and thus is more suitable for industrial production.

Description

technical field [0001] The invention relates to a hydroxyadamantane glycine derivative (formula I, (aS)-a-[[(1,1-dimethylethoxy) carboxyl]-amino]-1-(3-hydroxyadamantane) - the preparation method of acetic acid) or its salt. The compound of formula I is an important intermediate for preparing antidiabetic drug Saxagliptin. Background technique [0002] Saxagliptin (Saxagliptin) is a highly effective dipeptidyl peptidase-4 (Dipeptidyl Peptidase 4, DPP-4) inhibitor jointly developed by BMS Company and AstraZeneca. It was launched in 2009 and is used for type II diabetes the treatment. Diabetes is a metabolic disorder characterized by chronic hyperglycemia caused by various etiologies. Type II diabetes is also called adult-onset diabetes. The drug selectively inhibits DPP-4, increases endogenous glucagon-like peptide-1 (Glucagon-like Peptide-1, GLP-1) and glucose-dependent insulinotropic peptide (Glucose-dependent Insulinotropic Peptide, GIP) levels to regulate blood sugar. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/14C07C231/12C07C271/22C07C269/04
Inventor 李祥杨细文文海波宿朝亮
Owner 上海飞腾医药科技有限公司