JPS6248648A - Production of dialkoxyacetic acid ester compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic intermediate for 1,4-dihydropyridine compound which is useful as a medicine, under mild condition in high yield in single step reaction, by using glyoxylic acid as a starting compound and reacting the acid with an ortho ester. CONSTITUTION:Glyoxylic acid of formula or its salt is used as a starting compound and is made to react with an ortho ester of formula II (R is lower alkyl or lower alkoxy-lower alkyl) in a non-aqueous solvent such as methanol under moderate heating or heating at about the boiling point of the solvent to obtain the objective compound of formula III. The amount of the compound of formula II is preferably 3-5mol, especially about 4mol per 1mol of the compound of formula I. the above reaction is carried out preferably in the presence of a catalyst such as hydrogen chloride, sulfuric acid, acetic acid, methanesulfonic acid, etc. The amount of the acid is between catalytic amount and 2mol, preferably about 0.1mol per 1mol of glyoxylic acid used as a raw material.

Description

Detailed Description of the Invention "Industrial Application Field" The present invention relates to a dialkoxy acetate compound represented by the general formula % (in the formula, R means lower alkyl or lower alkoxy lower alkyl) Concerning the manufacturing method.

More specifically, the present invention relates to a method for producing a dialkoxyacetic acid ester compound, characterized in that an orthoester acts on glyoxylic acid, preferably in the presence of an acid catalyst.

The dialkoxyacetic acid ester compound (1) obtained by the production method of the present invention is a 1,4- It is useful as an intermediate for synthesizing dihydropyridine compounds.

1 Conventional technology.

Conventional methods for producing dialkoxyacetic acid ester compounds include, for example, reacting dichloroacetic acid with sodium alkoxide (first step), and reacting the resulting sodium dialkoxyacetate with an alcohol containing hydrogen chloride (second step). For example, 0RGANIC5Y
NTI(ESES, Cot, LEC DIVEVOLt
JME IV, p. 427 (1963) Ko et al.

1. The problem that the invention attempts to solve.

However, in the above conventional method, (1) the first step is a reaction under basic conditions, and step 2 is a reaction under acidic conditions using an acid catalyst, so two reaction steps are required. (2) The reaction with sodium lower alkoxide in the first step is a slurry reaction, which is unsuitable for large-scale synthesis; (3) In the second step, the reaction with hydrogen chloride-containing alcohol, the raw material dichloroacetic acid 2 equivalents of hydrogen chloride must be used, and a long reaction time is required. (4) A large amount of insoluble matter is removed during the neutralization operation to isolate the target product after the reaction. There are problems such as precipitation of the target product, which makes separation and extraction of the target product difficult, and (5) a low yield of 45-50%. .

As a result of intensive research to establish an industrial production method for dialkoxyacetic acid ester compounds, the inventors of the present invention have developed a method for producing dialkoxyacetic acid ester compounds in a single step under mild conditions and in high yield. The present invention was completed by discovering a method for producing the target compound at a high rate.

The production method of the present invention is shown by the following reaction formula.

(In the formula, R has the same meaning as above.) Preferred examples and explanations of the definitions used in this specification will be described in detail below.

Unless otherwise specified, the term ``lower'' refers to carbon atoms of 1
〜6 pieces.

Examples of "lower alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples include linear or branched alkyl groups having 1 to 6 carbon atoms such as butyl, pentyl, tertiary pentyl, hexyl, etc., and preferred examples thereof include 01 to 6 carbon atoms.
More preferred examples of C4 alkyl include methyl, ethyl, propyl, and butyl.

Examples of 1-lower alkoxy-lower alkyl include:
Methoxymethyl, methoxyethyl, methquinpropyl,
Such as methoxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethquinethyl, propoxyprovil, impropoxymethyl, butoxybutyl, pentyloxypentyl, hexyloxyhexyl, etc.
Straight chain or branched alkoxyalkyl having 1 to 6 carbon atoms in each alkyl moiety may be mentioned, and preferred examples thereof include C1 to C4 alkoxy01 to C4
A more preferred example of alkyl is 2-methoxyethyl.

The present invention uses glyoxylic acid (I[) as a raw material compound, preferably orthoester (I[[) in the presence of an acid catalyst.
) to obtain the desired dialkoxyacetic ester (I) in a single step in high yield.

Glyoxylic acid (I
[) can also be used as its hydrate or its salt, and suitable examples of the salt include, for example, quaternary ammonium salt,
Examples include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium, etc.
The monohydrate of the compound (I[) is most preferred in this reaction.

The other raw material compound, orthoester (I[[)
Among these, the compounds in which R is methyl and ethyl are commercially available, and the other compounds are produced by conventional methods.

The amount of orthoester (III) to be used is appropriately selected, but in order to obtain the target compound (I) in a higher yield, it is 3 to 5 times the molar amount of glyoxylic acid (II>), more preferably about 4 times Mol is used.

Examples of acid catalysts used in this reaction include inorganic acids such as hydrogen chloride, sulfuric acid, and hydrogen bromide, acetic acid, trifluoroacetic acid, and! Examples thereof include organic acids such as '-toluenesulfonic acid and methanesulfonic acid, Lewis acids such as borofluoride trifluoride, and notarykyrinlyl halides such as trimethylsilyl chloride.

The amount of acid used is usually 1 to 2 moles of the catalyst based on glyoxylic acid as a raw material, preferably 0.05 to 2 times the mole of the catalyst.
0.5 times the mole, preferably about 0.1 times the mole for awns, can be used.

This reaction is usually carried out in the absence of a solvent under non-aqueous conditions, but it can also be carried out in non-aqueous solvents that do not adversely affect the reaction. Examples of such solvents include methanol, ethanol, propyl alcohol, butyl alcohol, 2-
Examples include methoxyethanol.

Although the reaction temperature is not particularly limited, it is usually carried out with heating or heating to about the boiling point of the solvent.

Compound (I) obtained by this reaction is isolated and purified by a conventional method after neutralizing the reaction solution with a base, but the neutralization reaction may be omitted in some cases. Isolation/
Examples of purification methods include extraction, precipitation, fractional crystallization,
Conventional methods such as recrystallization, chromatography, distillation and the like may be mentioned.

1. Effects of the invention.

Comparing the production method of the present invention with the conventional method described above, the method of the present invention is a single-step reaction, and the desired product is obtained in high yield.
The reaction time can be significantly shortened, only a small amount of acid catalyst is needed, there is less precipitation of insoluble matter due to neutralization during post-reaction treatment, and neutralization can be omitted in some cases, making it easier to separate and remove the target product. It has characteristics such as easy extraction and other operations, making it an excellent industrial manufacturing method.

The dialfoxyacetic acid U ester compound produced according to the present invention can be converted into a dialfoxyacetoacetate ester by the conventional reaction shown below, and further has a vasodilatory effect, and is a 1,4-dihydropyridine compound useful as a pharmaceutical. is converted to

(In the formula, R and R2 each have the same meaning as lower alkyl in R.) Next, the present invention will be explained with reference to Examples.

Production example of orthoester 2-methoxyethanol (112.5 g) and 10 drops of sulfuric acid were added to ethyl orthoformate (54.2 g) at room temperature, and the produced ethanol was distilled off while heating and stirring at -122°C for 70 minutes. (approximately 46ml). 2-Methoxyethanol (2011111) is added and ethanol is similarly distilled off over 30 minutes, and this operation is repeated twice to distill off a total of 65+nQ of ethanol. After the reaction solution was cooled, it was distilled under reduced pressure to obtain orthoformic acid 2-methoxyethyl ester (17.45 g) as a colorless oil.

Boiling point: 125-130℃ (6mmHg>'HNMR&
(ppm, CDCl5): 3.37 (9H,s
), 3.50-3.90 (12H, n+), 5.
33 (LH,s) glyoxylic acid monohydrate (100,
0g), lactate acid methyl ester (461, Ig
), and after dissolving, add concentrated sulfuric acid (10.7 g) at room temperature.
Reflux for an hour. The reaction is cooled and poured into 5% aqueous sodium bicarbonate (aoomu). The aqueous layer is extracted twice with methylene chloride (400 m2). After the methylene chloride layer is foamed, it is washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporation, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain 2,2-dimethoxyacetic acid methyl ester (129.2 g) as a colorless oil.

Boiling point: 75-84℃ (32mmHg) IHNMR &
(ppm, CDCl5): 3.30 <68. s)
, 3.80 (3)! ,s), 4.80 (IH,s
) Example 2 Orthoformic acid ethyl ester (64.4 g) was added to glyoxylic acid monohydrate (10.0 g), and after dissolving, concentrated sulfuric acid (1.06 g) was added at room temperature and stirred at 70° C. for 5 hours. The reaction solution was cooled and diluted with 5% aqueous sodium bicarbonate solution (lQQmu
) Add inside. The aqueous layer is extracted twice with methylene chloride (50 μl). After combining the methylene chloride layers, they are washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was distilled under reduced pressure to obtain 2.2-
>Ethyl quinacetate (16.11 g) was obtained.

Boiling point: 90-95℃ (25mmHg) IHNMRS
(ppm, CDCl5): 1.07-1.
50 <9H, m).

3.63 (4H, q, J=7Hz>, 4.23 <
2H,Q.

J=7Hz＞, 4.87 (LH,5)IRυ""
' 1740cm-1 lLK Fusei±dan glyoxylic acid monohydrate (2,501) and orthoformic acid n
- Add propyl ester (20.6 g) and after dissolving, add concentrated sulfuric acid (0.27 g) and stir at 70°C for 2 hours.
The reaction solution was cooled and diluted with 5% aqueous sodium bicarbonate solution (lQQ
) and extracted twice with methylene chloride (50 mN). After combining the methylene chloride layers, they are washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the residue was distilled under −g pressure to give a colorless oil of 2.2
-di-n-propoxyacetic acid n-propyl ester (4,
56 g) is obtained.

Boiling point: 105-110°C (19mmHg) IHNMR
S (ppm, CDC13)' 0.70-1.17
(9H7m>.

1.33-2.00 (6H, +n), 3.57
(4H, t.

7Hz), 4.13 (28,tj=7Hz),
4.80 (LH, 5) IRυ””: 1760C111-1ax Example 4 Orthoformic acid n in glyoxylic acid monohydrate (4,00g)
-Butyl (40.3g) was added and after dissolving, concentrated sulfuric acid (
The reaction solution was concentrated and then distilled under reduced pressure to obtain 2,2-di-n-butoxyacetic acid n-butyl ester (8.53 g) as a colorless oil.

Boiling point: 120-125℃ (6mm) Ig) 11 (NM
Rδ (ppm, cDcl3>'-0,75-
1,80 (21Lm).

3.57 (4H, t, J=6Hz>, 4.17 (
2H,t.

J=6Hz), 4.80 (LH,5)IRυ""
'1760cm' ax Example 5 Orthoformic acid 2 in glyoxylic acid monohydrate (1,61g)
-Methoxyethyl ester (15.0g) was added and dissolved, then concentrated sulfuric acid (0°17g) was added at room temperature, and the mixture was heated to 70°C for 1 hour.
Time PI1. Stir. The reaction solution was concentrated and then distilled under reduced pressure to obtain a colorless oil of 2,2-bis(2-methoxyethoxy)acetic acid 2.
-Methquin ethyl ester (3.43 g) is obtained.

Boiling point: 140-150℃ (5nu++I(g)IHN
MR& (ppm, cDcl3): 3.40 (9
)1. s), 3.50-4.00 (IOH, m),
4.20 (2)1. 5Hz>.

5.10 (IH, 5) IRL+, 1750cm-1 Film.

ax Example 6 Orthoformic acid methyl ester (46.1'g) was added to glyoxylic acid monohydrate (10.0g), and methanesulfonic acid (1.05g) was added at room temperature with stirring, followed by 1 hour. Reflux. The reaction was cooled and poured into 5% aqueous sodium bicarbonate (80 mQ). The aqueous layer was diluted with methylene chloride (40 m
Extract twice with Ω). After combining the methylene chloride layers, they are washed with saturated brine and dried over anhydrous magnesium sulfate.

After filtration, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain a colorless oil of 2,2-dimethoxyacetic acid methyl ester (t2.sg
).

Orthoformic acid methyl ester (23.0 g) was added to glyoxylic acid monohydrate (5.0 g), and while stirring, trimethylsilyl chloride (11.8 g) was added at room temperature, and the mixture was refluxed for 1 hour. The reaction solution is also cooled and added to saturated aqueous sodium bicarbonate solution (1 oomQ). Suiseki with methylene chloride (50
11IIQ) three times. After combining the methylene chloride layers, they are washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain a colorless oil of 2,2-dimethoxyacetic acid methyl ester (6
, 1g).

Fuyugo 1 Glyoxylic acid monohydrate (50.0g), methyl orthoformate (230.3g) and methanol (300111
After adding and dissolving Q), add concentrated sulfuric acid (5.3 g) at room temperature and reflux for 5 hours. Methanol (approximately 250ml) at normal pressure
) was distilled off, cooled and diluted with 5% aqueous sodium bicarbonate solution (4
00 mQ) and methylene chloride (25 (1 ml)).The organic layer is separated, and the remaining aqueous layer is extracted twice with methylene chloride (125+lLi1).

After the methylene chloride layers are combined, they are washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain 2,2-dimethoxyacetic acid methyl ester (62.9 g) as a colorless oil.

Claims (1)

[Claims] Glyoxylic acid or its salt represented by the general formula OHC-COOH(II) is combined with the general formula HC(OR)_3(III) (wherein, R means lower alkyl or lower alkoxy lower alkyl) ) is reacted with the orthoester represented by the general formula (RO)
A method for producing a dialkoxyacetate compound, which comprises obtaining a dialkoxyacetate compound represented by _2CHCOOR(I) (wherein R has the same meaning as above).