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Chiral synthesis method for chiral beta-amino acid and synthesis method for medicinal intermediate

A chiral synthesis and amino acid technology, which is applied in the preparation of carbamic acid derivatives, organic chemical methods, chemical instruments and methods, etc., can solve the problems of inconvenient large-scale preparation and storage, high cost of oxidants, and inconvenience of sitagliptin intermediates

Active Publication Date: 2017-12-22
苏州爱玛特生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the preparation of reaction raw material 2,4,5-trifluorophenylacetaldehyde is relatively difficult
It is reported that the method of reducing carboxylic acid to alcohol and then selectively oxidizing it to aldehyde is used, but selective oxidation often has the disadvantages of strict process requirements and high oxidant cost, and aldehyde compounds are relatively unstable, which is not convenient for large-scale preparation and storage
This has brought inconvenience to large-scale production of sitagliptin intermediates

Method used

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  • Chiral synthesis method for chiral beta-amino acid and synthesis method for medicinal intermediate
  • Chiral synthesis method for chiral beta-amino acid and synthesis method for medicinal intermediate
  • Chiral synthesis method for chiral beta-amino acid and synthesis method for medicinal intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] 5-[2-(2,4,5-trifluorophenyl)-1-hydroxyethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione preparation

[0063]

[0064] Under ice bath conditions, into a 2L three-neck reaction flask equipped with 800mL acetonitrile, add 2,4,5-trifluorophenylacetic acid (285.2g, 1.5mol, 1eq), pivaloyl chloride (199.0g, 1.65mol, 1.1eq ), DMAP (1.8g, 0.015mol, 0.01eq), DIPEA (387.6g, 3.0mol, 2.0eq), stirred at room temperature for 45min, added Michaelis acid (237.8, 1.65mol, 1.1eq) and raised the temperature to 45°C to react overnight. TLC detects the progress of the reaction. After the reaction was completed, cool to room temperature, slowly add 1M hydrochloric acid, and a solid was formed. After the obtained solid was washed with water, it was recrystallized from acetonitrile-water to obtain a white solid with a yield of 85%. The NMR results are the same as those reported by F.Xu, J.D.Armstrong, G.X.Zhou, B.Simmons, D.Hughes, Z.Geand E.J.J.Grabowski, J.Am.Chem.Soc., 2004, 126, 13002–13...

Embodiment 2

[0066] (R)-N-[1-(2,2-Dimethyl-4,6-dione-1,3-dioxane-5-ylidene)-2-(2,4,5-tri Preparation of fluorophenyl)ethyl]-2-methylpropane-2-sulfinamide

[0067]

[0068] Under the condition of stirring at room temperature, add the compound (316.2g, 1.0mol, 1eq) obtained in Example 1 into a 2L three-neck reaction flask equipped with 800mL of acetonitrile, and after it is completely dissolved, add (R)- tert-Butylsulfinamide (133.3g, 1.1mol, 1.1eq), after the addition, the system was slowly warmed up to room temperature, stirred overnight at 65°C, and the reaction progress was detected by TLC. After the reaction was completed, most of the solvent was removed, water was added, and Extract with methyl chloride, combine the organic phases, dry over anhydrous sodium sulfate, spin off the solvent, and crystallize from the solution of methanol and dichloromethane to obtain a white solid with a yield of 81%.

Embodiment 3

[0070] (R)-N-[(R)-1-(2,2-Dimethyl-4,6-dione-1,3-dioxane-5-ylidene)-2-(2,4 , Preparation of 5-trifluorophenyl)ethyl]-2-methylpropane-2-sulfinamide

[0071]

[0072] Under the condition of stirring at room temperature, in the 2L three-neck reaction flask equipped with 800mL ethanol, add the compound obtained in Example 2 (209.7g, 0.5mol, 1eq), after it is completely dissolved, slowly add sodium borohydride (56.7 g, 1.5mol, 3eq), after the addition, the system was slowly warmed up to room temperature, after stirring for 3 hours, stirred overnight at 65°C, and the reaction progress was detected by TLC. EA was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, the organic solvent was spun off, and dichloromethane petroleum ether was crystallized to obtain the product (82%).

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Abstract

The invention relates to a chiral synthesis method for chiral beta-amino acid. The chiral synthesis method comprises the following steps: reacting a compound shown in formula (II) with an acylation reagent to prepare anhydride intermediate reaction liquid under the action of alkali; adding Meldrum's acid into the anhydride intermediate reaction liquid, and performing reaction to generate a compound shown in formula (III); reacting the compound shown in formula (III) with a compound shown in formula (IV) to generate a compound shown in formula (V); reducing the compound shown in formula (V) to generate a compound shown in formula (VI); performing acidic hydrolysis on the compound shown in formula (VI) to generate a compound shown in formula (I), i.e., the chiral beta-amino acid. The chiral synthesis method has the advantages of convenience for synthesis, low cost and simple process, and compared with a disclosed preparation method, is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chiral synthesis, and relates to a chiral induction method—using a chiral center in a reactant molecule to induce a new chiral center in a product to selectively generate a chiral isomer, specifically The invention relates to a chiral synthesis method of chiral β-amino acid and a synthesis method of a pharmaceutical intermediate. Background technique [0002] Chiral β-amino acids or their fragments widely exist in nature and pharmaceutical active molecules, and have important application value. Compared with α-amino acids, the synthesis of β-amino acids is relatively difficult. The convenient, concise and industrialized method for synthesizing β-amino acids is still a research hotspot, such as the chiral intermediate of sitagliptin, the preparation method is still the focus of research reports. [0003] The reported synthesis methods of chiral β-amino acids mainly include: chiral catalysis, substrate derivatizati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/34C07C227/20C07C271/22C07C269/04C07D319/06
CPCC07B2200/07C07C227/20C07C269/04C07D319/06C07C229/34C07C271/22
Inventor 汪明中朱明新苏道刘俊鹏
Owner 苏州爱玛特生物科技有限公司
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