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Preparation method for 2-aryl-2-glycollic acid esters

A technology of glycolic acid ester and aryl group, which is applied in the field of medicine, can solve the problems of unsuitability for industrial production, difficulty in purification, and many by-products, and achieve the effects of mild conditions, reduced side reactions, and increased yield

Inactive Publication Date: 2015-12-30
SHANDONG CHENGCHUANG PHARMA R&D
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] For the synthesis of 2-aryl-2-hydroxyacetates, use NaBH 4 When -MeOH-AcOH-DMF is used as the reducing system, the yield is low, only 23.6%, the main reason is that the ester group is destroyed at the same time
In addition, since the system contains acetic acid, sodium borohydride reacts preferentially with acetic acid, which consumes a large amount of sodium borohydride, resulting in higher cost, more by-products, and difficult purification, which is not suitable for industrial production

Method used

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  • Preparation method for 2-aryl-2-glycollic acid esters
  • Preparation method for 2-aryl-2-glycollic acid esters
  • Preparation method for 2-aryl-2-glycollic acid esters

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Preparation of ethyl 2-(2-fluoro-3-methoxyphenyl)-2-hydroxyacetate

[0030] Ethyl 2-(2-fluoro-3-methoxyphenyl)-2-oxoacetate (69.95g, 0.31mol) was dissolved in 600mL of absolute ethanol, cooled to 0-5°C with ice-water, added Zinc powder (80.6g, 1.24mol) and glacial acetic acid (142mL, 2.25mol) were stirred at 25°C for 4 hours. Use saturated sodium carbonate solution to adjust the pH to 9 (solid sodium carbonate can be added appropriately), filter with suction, wash the filter cake with absolute ethanol, concentrate to remove ethanol, extract the filtrate with ethyl acetate (250mL×3), and use anhydrous Dried over magnesium sulfate and concentrated to dryness yielded 68.81 g of product. Product purity 95.26%, yield: 97.52%; Product characterization: MS (m / z): 229.1 [MH + ]; 1 HNMR (DMSO-d 6 )δ:1.12(t,3H),3.83(s,3H),4.07(q,2H),5.31(d,1H),6.17(d,1H),6.96-7.01(m,1H),7.10-7.13 (m,2H).

Embodiment 2

[0032] Preparation of 2-(2-fluoro-3-methoxyphenyl)-2-hydroxyacetic acid methyl ester

[0033] Methyl 2-(2-fluoro-3-methoxyphenyl)-2-oxoacetate (2.12g, 0.01mol) was dissolved in 30mL of absolute ethanol, cooled to 0-5°C with ice-water, added Zinc powder (1.95 g, 0.03 mol) and acetic acid (2.3 mL, 0.04 mol) were stirred at 25°C for 4 hours. Use saturated sodium carbonate solution to adjust the pH to 9 (solid sodium carbonate can be added appropriately), filter with suction, wash the filter cake with absolute ethanol, concentrate to remove ethanol, extract the filtrate with ethyl acetate (20mL×3), and use anhydrous Dried over magnesium sulfate and concentrated to dryness yielded 2.08 g of product. Product purity 93.63%, yield: 97.19%; Product characterization: MS (m / z): 215.2 [MH + ]; 1 HNMR (DMSO-d 6 )δ: 3.53 (s, 3H), 3.84 (s, 3H), 5.30 (d, 1H), 6.18 (d, 1H), 6.95-7.00 (m, 1H), 7.11-7.13 (m, 2H).

Embodiment 3

[0035] Preparation of Propyl 2-(2-fluoro-3-methoxyphenyl)-2-hydroxyacetate

[0036] Propyl 2-(2-fluoro-3-methoxyphenyl)-2-oxoacetate (2.40g, 0.01mol) was dissolved in 30mL methanol, cooled to 0-5°C with ice-water, and iron powder was added (1.68g, 0.03mol) and glacial acetic acid (2.3mL, 0.04mol), stirred at 25°C for 12 hours. Use saturated sodium carbonate solution to adjust the pH to 9 (solid sodium carbonate can be added appropriately), filter with Celite salt, wash the filter cake with methanol, concentrate the methanol, and extract the filtrate with ethyl acetate (20mL×3), and use the organic phase with Dry over magnesium sulfate and concentrate to dryness to obtain 2.32 g of product. Product purity 93.03%, yield: 95.87%; Product characterization: MS (m / z): 243.2 [MH + ].

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Abstract

The invention discloses a preparation method for 2-aryl-2-glycollic acid esters. The preparation method includes the following steps: dissolving the compound in formula I (refer to the description) in an organic solvent; adding a metal reducing agent and an acid medium; reacting for 4-12 hours at 4-25 DEG C; obtaining the compound in the formula II through aftertreatment after the reaction is finished. A metal-acid-alcohol reduction system is adopted, so that keto carbonyl groups in alpha-ketoester (or alpha- aldehyde-ester) can be successfully reduced into hydroxyl, and other groups in ester groups and aromatic rings are not affected, as a result, a high purity product with relatively high yield can be obtained. Compared with the NaBH4-MeOH-AcOH-DMF reduction system reported in documents, the preparation method has the following benefits: cheap metals are used as the reducing agent, alcohol is used as the organic solvent, and the acid medium is used as a hydrogen supply reagent, the condition is gentle, the operation is simple, side reaction is greatly reduced, reaction yield is effectively improved, the production cost is reduced, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of an elagolix pharmaceutical intermediate, in particular to a preparation method of 2-aryl-2-hydroxyacetate. It belongs to the field of medical technology. Background technique [0002] Orally active non-peptide gonadotropin-releasing hormone (GnRH) antagonist, mainly used for the treatment of endometriosis and uterine leiomyoma. Among them, Elagolix (Elagolix) is an important representative drug, and the key intermediate for the synthesis of the drug is ethyl 2-(2-fluoro-3-methoxyphenyl)-2-hydroxyacetate. [0003] The synthetic method of this compound (compound of formula II) is disclosed in the patent US20110098472: [0004] [0005] For the synthesis of 2-aryl-2-hydroxyacetates, use NaBH 4 When -MeOH-AcOH-DMF was used as the reducing system, the yield was low, only 23.6%, mainly because the ester group was destroyed at the same time. In addition, since the system contains acetic acid, sodium boro...

Claims

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Application Information

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IPC IPC(8): C07C67/31C07C69/734C07C69/732
Inventor 焦培福吕志涛姚松芝刘彬彬
Owner SHANDONG CHENGCHUANG PHARMA R&D
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