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Preparation method for D-pantoic acid

A technology of pantoic acid and dimethylbutyric acid, which is applied in the field of preparation of D-pantoic acid, can solve the problems of complex synthetic route operation, inappropriate preparation conditions, and reduced production costs, so as to achieve high process stability and avoid The use of polluting heavy metals and toxic reagents, and the effect of fewer synthesis steps

Inactive Publication Date: 2020-08-14
NANJING OCEAN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In order to solve the problems such as inappropriate preparation conditions of D-pantoic acid in the prior art, complicated synthetic route operation and high cost, the present invention provides a more economical D-pantoic acid preparation method by realizing compound III(4, 4-dimethyldihydrofuran-2,3-dione) to compound I ((R)-2,4-dihydroxy-3,3-dimethylbutanoic acid) one-step synthesis scheme, not only improves the bottom The utilization rate of the substance, and the enantiomeric excess value of the product can reach more than 99%, which greatly reduces the production cost

Method used

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  • Preparation method for D-pantoic acid
  • Preparation method for D-pantoic acid
  • Preparation method for D-pantoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Add 80mL tetrahydrofuran and 13.01g (0.1mol) of raw material 3-hydroxy-4,4-dimethyldihydrofuran-2-one to a 250mL reaction flask, then add 4.0g NaOH (0.1mol), and control the temperature for -10 below ℃, followed by O3 15 minutes (20g / h), control the temperature at -20°C to 20°C for 12h, and GC (gas chromatography) detects that the reaction of the raw materials is complete. Add concentrated HCl (2M) to the system, adjust the pH to about 7, and continue to add 50mL of water solution. The aqueous phase was extracted twice with 50mLEA (ethyl acetate) (50ml was used for each extraction), the organic phases were combined, dried by adding 10.0g of anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain compound III (12.16g). 95%, HPLC assay purity 98.12%. Compound III carries out proton nuclear magnetic spectrum and carbon nuclear magnetic spectrum analysis, and the data are as follows:

[0039] 1 H NMR (400H Z ,DMSO-d6): δ4.37(s...

Embodiment 2

[0045] Add 80mL tetrahydrofuran and 13.01g (0.1mol) of raw material 3-hydroxy-4,4-dimethyldihydrofuran-2-one to a 250mL reaction flask, then add 20.0g NaOH (0.5mol), and control the temperature for -10 below ℃, followed by O 3 15 minutes (20g / h), control the temperature at -20°C to 20°C for 12h, and GC detects that the reaction of the raw materials is complete. Add concentrated HCl (2M) to the system, adjust the pH to about 7, and continue 50mL of water solution. The aqueous phase was extracted twice with EA (50ml*2, that is, 50ml for each extraction), the organic phases were combined, dried by adding about 10.0g of anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain compound III (12.33g). The yield was 97%, and the purity was 98.5% as determined by HPLC. Compound III carries out proton nuclear magnetic spectrum and carbon nuclear magnetic spectrum analysis, and the data are as follows:

[0046] 1 H NMR (400H Z ,DMSO-d6): δ4...

Embodiment 3

[0052] Add 80mL tetrahydrofuran and 6.5g (0.05mol) of raw material 3-hydroxy-4,4-dimethyldihydrofuran-2-one to a 250mL reaction flask, then add 10.0g NaOH (0.25mol), and control the temperature for -10 below ℃, followed by O 3 36 minutes (20g / h), control the temperature at -20°C to 20°C for 12h, and GC detects that the reaction of the raw materials is complete. Add concentrated HCl (2M) to the system, adjust the pH to about 7, and continue to add 50mL of water solution. The aqueous phase was extracted twice with EA (50ml*2, that is, 50ml for each extraction), the organic phases were combined, dried by adding about 6.0g of anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain compound III (6.15g). The yield was 97%, and the purity was 99.2% as determined by HPLC. Compound III carries out proton nuclear magnetic spectrum and carbon nuclear magnetic spectrum analysis, and the data are as follows:

[0053] 1 H NMR (400H Z ,DMSO-d6...

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Abstract

The invention provides a preparation method for D-pantoic acid, and in particular relates to the technical field of pharmaceutical chemistry. A compound II (3-hydroxy-4,4-dimethyl dihydrofuran-2-ketone) is taken as a raw material and undergoes an oxidation reaction under the action of ozone to obtain a compound III (4,4-dimethyl dihydrofuran-2,3-diketone); then, the compound III undergoes a hydrolysis reaction, and asymmetric reduction occurs under the action of ketoreductase to obtain a racemic crude product containing a compound I [ (R)-2,4-dihydroxy-3,3-dimethyl butyric acid]; and the racemic crude product containing the compound I undergoes a recrystallization step to obtain the high-purity D-pantoic acid. The method has few synthesis steps, mild reaction conditions and high process stability; the enantiomeric excess value of products reaches 99% or more; and the method has broad market prospects, and makes industrial production of the compound I easier.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of D-pantoic acid. Background technique [0002] Pantothenic acid, a B vitamin (vitamin B5), is a key precursor for the biosynthesis of coenzyme A (CoA) and acyl carrier protein (ACP). Both CoA and ACP are essential cofactors for cell growth and participate in many metabolic reactions in key biosynthetic pathways. Both microbes and plants synthesize pantothenic acid, while mammals must obtain it from their diet. Therefore, it is necessary to synthesize D-pantoic acid by a simple and effective method. [0003] There are related literatures (Si D, Urano N, Nozaki S, et al.l-Pantoyl lactonedehydrogenase from Rhodococcus erythropolis: genetic analyzes and application to the stereospecific oxidation of l-pantoyl lactone[J].Applied Microbiology and Biotechnology,2012,95(2):431 -440.) reported the synthesis of D-pantoic acid with 3-hydroxy...

Claims

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Application Information

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IPC IPC(8): C12P41/00C12P7/42
CPCC12P7/42C12P41/002C12P41/003
Inventor 陈本顺江涛何伟杨涛
Owner NANJING OCEAN PHARMA TECH
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