JPH02225451A - 2'-ketopantothenic ester - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula (R is alkyl or aralkyl). EXAMPLE:2'-Ketopantothenic acid methyl ester. USE:An intermediate for D-pantothenic acid ester. PREPARATION:Ketopantolactone and a beta-alanine ester are subjected to aminolysis to give a compound shown by the formula. The reaction is carried out by using methanol, ethyl acetate, hexane, benzene, etc., as a solvent, at room temperature-about the boiling temperature of the solvent. The reaction time is usually one hour to 24 hours. The compound shown by the formula is prochiral derivative of D-pantothenic acid, is reduced with NaBH4 to give D,L-pantothenic ester and is asymmetrically reduced with a microorganism to give D-pantothenic ester.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel intermediate for the synthesis of monobantothenic acid, which is useful as a medicine and as a physiologically important substance, a vitamin.

More specifically, the present invention provides a novel compound represented by the formula % (in which R represents an alkyl group or an aralkyl group), a 2'-ketopantothenic acid ester, i.e., N-(2- Roxycarbonylethyl)
-4-hydroxy-3,3-dimethyl-2-oxobutyramide.

The new substance according to the present invention, 2'-ketopantothenic acid ester, is a prochiral form of D-pantothenic acid ester, and using this substance as a raw material, a reduction reaction is carried out using a general carbonyl reducing reagent such as NaBH. To do this, L
-D-pantothenic acid ester can be obtained, and D-pantothenic acid ester can be obtained by performing an asymmetric reduction reaction using microorganisms. It is extremely useful as a folding intermediate material.

[Disclosure 1 of the Invention The 2'-ketopantothenic acid ester according to the present invention can be obtained by performing amitrisis using ketobantolactone and β-alanine ester.

In this reaction, reaction solvents include alcohols such as methanol, esters such as ethyl acetate, aliphatic hydrocarbons such as hexane, aromatic hydrocarbons such as benzene, halogenated hydrocarbons such as chloroform, and acetone. Ketones, acetonitrile, etc. are used. The reaction temperature at that time is within a range from room temperature to about the boiling temperature of each reaction solvent, and the reaction time is usually from 1 hour to 1 day. After the reaction is completed, the reaction solvent is distilled off, and the target product is extracted with an organic solvent such as ethyl acetate or methylene chloride. If necessary, clean with a dilute acid aqueous solution or dilute alkali aqueous solution. Thus,
A single 2'-ketopantothenic acid ester is obtained in good yield.

The present invention will be described in more detail with reference to Examples below, but the present invention is not limited to these Examples.

Example 1 Preparation of 2'-ketopantothenic acid methyl ester 1.2 g (52 a mol) of sodium metal was added to 200 g of anhydrous methanol.
β-alanine methyl ester hydrochloride 7-39 (5211 mol) and ketopantolactone 6.49 (5011 mol) are added in that order at room temperature. After stirring overnight at room temperature, methanol is distilled off.

The reaction mixture containing by-produced sodium chloride is dissolved in water and extracted with ethyl acetate. After drying the ethyl acetate layer over anhydrous sodium sulfate, it was concentrated under reduced pressure and purified by column chromatography using silica gel.
Obtained as il.

IR(neat)ycm-': 338(L 295
5.2875. 1740°1715, 1680.
1515. 1420°1370, 1260. 12
00. 1180°'H-NMI? (CDCI2S)δ
: 1.28 (6H, S) 2.57 (2H, t) 3.58 (2B, q) 3.72 (5H, s) 7.5 (IH, bs) Example 2 2'-ketopantothenic acid Preparation of ethyl ester 3.69 (52,51 mol) of sodium ethoxide is dissolved in 15 (h++2) of absolute ethanol, and 8-1 g (52,511 mol) of β-alanine ethyl ester hydrochloride and ketopantolactone are dissolved in 15 (h++2) of absolute ethanol. Add 6.49 (50 mmol) in that order. After stirring overnight at room temperature, ethanol is distilled off. After distilling off ethanol, perform the same operation as after distilling off methanol in Example 1, 10.8g of 2'-ketopantothenic acid ethyl ester (yield: 88.1%)
) was obtained as oil.

IR(neat)y cm-”: 3380.298
0.2945.2875°1735, 1680. 15
25. 1480°1380, 1190.1100.1
050′H-N&1R(CDCa3)δ: 1.28
(6H,s) 1.28 (3H,t) 2.57 (2H,t) 3.58 (2H,Q) 3.75 (2H,s) 4.18 (2H,q) 7.5 (1 .
Alanine isopropyl ester aK acid salt 8, 89 (
52,5+ mol) and 6.4 g of ketobantolactone (
50 mmol) are added in that order. After stirring overnight at room temperature, the Impropatool is distilled off. After the impropatol was distilled off, the same operation as after methanol distillation in Example 1 was performed to obtain 3 g (yield: 87.2%) of 2'-ketopantothenic acid isopropyl ester lt as oil.

IR (neat) shicra-' + 3380.298
0.2940.28?5゜1730, 1680. 1
525. 1475.1380, 1270. 120
0. 1105°'H-NMR (CDCL) δ: 1.
28 (6H, s) 1.25 (6H, d) 2.54 (2H, t) 3.57 (2H, q) 3.75 (2H, a) 5.04 (IH, qq) 7.29 ( IH, bs) Example 4 Production of benzyl thenic acid (2'-ketopane) 3-5 g (10 mmol) of β-alanine benzyl ester p-toluenesulfonate was dissolved in 10% sodium carbonate water, and dissolved in ethyl acetate. Extract with This ethyl acetate layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is dissolved in anhydrous methanol, 1.3 g (10+a mol) of ketobantolactone are added thereto, and after boiling under reflux for 6 hours, the methanol is distilled off. After methanol distillation, the same operation as after methanol distillation in Example 1 was performed to obtain 2'-ketopantothenic acid benzyl ester 1.
69 (yield: 52%) was obtained as oil.

IR(neat)ycra-': 3400. 2
975.2940.2875゜1?35. 1680.
1520. 1475°1460, 1390. 1
360. 1260°1180, 1105.1050'H-NMR (CDCI2x) δ: 1.26 (6H
, s) 2.62 (2H, t) 3.58 (2H, q) 3.73 (2B, s) 5.14 (2H, s) 7.35 (5H, s) 2'- An example in which a D-pantothenic acid ester is produced by using a ketopantothenic acid ester and performing asymmetric reduction using a microorganism is listed below as a reference example.

Reference Examples 1 to 6 A liquid medium (pH 7.0) consisting of 5% glucose, 5% cornstarch liquor, and 1% calcium carbonate was dispensed into 6 test tubes at 21 IQ, and 12 IQ was placed in an autoclave.
Heat sterilization was performed at 1° C. for 20 minutes.

One platinum loopful of each strain listed in Table 1 was taken from the slant medium and inoculated into the medium in each test tube, and cultured aerobically with shaking at 28° C. for 2 days. Twenty or nine portions of 2'-ketopantothenic acid ethyl ester were added to the culture solution in each test tube, and the mixture was shaken at 28°C for 2 days. After reaction, HP
LC(Cosmosi15Cra 14.6X
Q loo+lIm, eluent 30% methanol (pH
2,5), the amount of pantothenic acid ethyl ester produced in each test tube was measured at a flow rate of 1 rs (1/111 inch, detection wavelength 230 nm). Furthermore, pantothenic acid ethyl ester was extracted from the reaction solution using ethyl acetate and hydrolyzed with hydrochloric acid.
istry, 112. 9-16 (1981))
Measured at The results are shown in Table 1.

In Table 1, IFO No. indicates the catalog number of the Fermentation Research Institute, and IAM No. indicates the catalog number of the Institute of Applied Microbiology, the University of Tokyo.

Claims (5)

[Claims] (1) Formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R represents an alkyl group or an aralkyl group] A 2'-ketopantothenic acid ester compound represented by (2) Claim 1, wherein R in the above formula (I) is a methyl group.
Compounds described in. (3) Claim 1, wherein R in the above formula (I) is an ethyl group.
Compounds described in. (4) The compound according to claim 1, wherein R in the above formula (I) is an isopropyl group. (5) The compound according to claim 1, wherein R in the above formula (I) is a benzyl group.