JPS58103341A - Substituted valeric ester and its preparation - Google Patents

Abstract

NEW MATERIAL:A substituted valeric ester shown by the formulaI(R<1> is lower alkyl such as methyl, ethyl, etc.; R<2> is H or lower alkyl such as methyl, ethyl, etc.). EXAMPLE:5-Acetoxy-2-acetylvaleric acid ethyl ester. USE:Useful as perfume, an important intermediate for a drug, especially as perfume, and a raw material for synthesizing alpha-acetyl-8-valerolactone, an intermediate for synthesizing pentoxifylline, a remedy for a sequela of cerebral thrombosis. PROCESS:An acetoacetic ester shown by the formula II is reacted with a 3-halogenopropyl ester shown by the formula III (X is halogen such as Cl, Br, I, etc.) in the presence of a basic substance such as potassium carbonate, etc. in an organic solvent such as benzene, etc. optionally in the presence of a catalyst, to give a compound shown by the formulaI. KI is preferable as the catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound represented by the general formula I: (wherein Rg is a lower alkyl group such as a methyl group or an ethyl group, and R1 is a lower alkyl group such as a methyl group or an ethyl group). Substituted valeric acid ester (hereinafter referred to as compound I) and its preparation method Kg41.

It is an important intermediate in the production of such esters and medical products, and is particularly useful in the treatment of cerebral thrombosis sequelae, which will be described later. It is essential as a raw material for the synthesis of a compound that is also an intermediate for the synthesis of the drug pentoxifylline.

The present invention also aims to produce such substituted valeric acid esters in good yields by simple reaction operations using readily available raw materials. The manufacturing method will be explained in detail below.

The substituted valerate ester of the present invention has the general formula II: CHsCOCHtCOOR"(R" is 1
(as described in 1)) (hereinafter sometimes referred to as compound ■), and the general formula III:
(X represents a halogen atom such as C4, Br, I, etc., and V is as described above) It can be easily obtained by reacting with the addition of a catalyst depending on the case. The basicity used is N
a.

Alkali or alkaline earth metals such as K, Ll, Ba, N
ap.

Metal hydroxides such as KH, organic metals such as butylic lithium, methyllithium, methylmagnesium bromide, Na0
M., Alcorado such as NaOgt, KOBut, Na
OH, KOH.

Hydroxide such as Ba(OH), Naz COas'a
Examples include taurate salts such as COs, quaternary ammonium hydroxides such as tetramethylammonium hydroxide, amine organic bases such as DilU (sia V bicyclokundeca 7), DBN (diazapicic I nonane), and triethylamine. , Among these, KI is cheaper and easier to use.
COI, Na1CO1, and NaOH.

KOH is excellent. To the end! ! Potassium is a solvent! M
It is superior to % in that it can be used regardless of IA.

Organic solvents used include L-benzene (swollen hydrogens such as toluene, alcohols such as methanol and ethanol, ethers such as diethyl ether, diisopropyl ether, and dimethoxyethane, cellosolves such as methyl cellosolve and butyl calpitol, calpitols, acetone, Ketones such as methyl ethyl ketone and methyl isobutyl ketone, dimethylformamide (DMF), dimethyl sulfoxide (DM80), hexamethylphosphoric triamide (HMPT), tetramethylethylenediamine (
Examples include so-called aprotic and polar solvents of the TMED type, but as will be described later, the selection of the solvent to be used has a large influence on the yield of the reaction, time, temperature, and the production of aprotic metals. It depends on the salt used and the Class 11 6-balognoprobil ester used, but when using inexpensive potassium carbonate and 6-chloropropyl acetate, the reaction takes a long time when using ashing aqueous substances or ethers. However, if alcohols or pure solvents are used, the rate of impurity formation increases, so it is most desirable to use ketones such as methyl ethyl ketone and methyl isopropyl ketone, and DMF.

When X is ■ in the compound of general formula (■), there is almost no need to use a catalyst, and when X is Br or ct,
Gives better results if used. 1. As a catalyst, it has the same effect as crown ether.

The reaction ffi degree is between room temperature and 200℃.
It may be appropriate to use it depending on the IiMK of the base. For example, compound 1
In ff, when X is ■ and DMF is used as the solvent and potassium cinnabar is used as the base, a temperature of 40° or 50°C from room temperature is sufficient; , 117-118℃ for 1 liter of 4L solvent when using ram
is desirable.

Examples of the acetoacetate represented by the general formula (■) include methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, butyl acetoacetate, isobutyl acetoacetate, 5ee-butyl acetoacetate, t-butyl acetoacetate, amyl acetoacetate, etc. There are many options, but from the viewpoint of price and ease of use, methyl acetoacetate and ethyl acetoacetate are preferred.

Examples of 6-hapgenopropyl esters represented by the general formula: 6-chloropropyl acetate, 3-H-dopropyl acetate, 3-promopyl acetate, 3-chloropropyl formate, 6-chloropropyl propionate, etc. However, as shown later in Reference Examples and Examples, acetic acid 3 which can be easily derived from inexpensive 1-propane, pI:l propane.
It is economically desirable to use -chloropropyl, or vinegar@5-Wl-doprovir. Vinegar M6-chlorobuvir, vinegar, 113-codepropyl can be isolated and purified by #trade if necessary, but in most cases it is sufficient to use the crude product, and the solvent can be used as pyrotechnic I! The reaction solution can be used as is if adjusted accordingly.

The main impurity produced in this reaction is an enol ether conductor (hereinafter referred to as compound 1) as represented by the general formula (2) (in the formula, R'% R is given as described above).

Regarding this, if X is summer, regardless of the reaction
Unless I is increased too much, compound lv will hardly be produced. However, when X is CI and a ketone solvent such as acetone, methyl ethyl ketone, or methyl isobutyl ketone is used, the formation of compound
-Although it can be kept below, it requires a modest reaction time of 20 to 30 hours, and in order to shorten this reaction time, if DMF't- is used instead of a ketone solvent (reaction time is 50 to 60 hours and 5 to 30 hours). 1-2 at 80-90'' for 6 hours
time), at 50 to 60 degrees, 10 or more compounds (2) are formed, and at 80 to 90 degrees, 20 or more compounds (2) are formed, and if KI is not used, the proportion increases further. However, in DMF solvent, X is C
Even in the case of 1, if the tv of K/I of the catalyst is increased, or if the CI is changed to ■ by using compound ■ and an appropriate amount of Kl in the system in advance, and then the reaction is carried out at 40 to 80°, The formation of compound Iv can be suppressed.

Hereinafter, the present invention will be explained in more detail with reference to the following examples, but these examples are not intended to limit the technical scope of the present invention.

Reference Example 500 - In a reaction flask, 1-bromo-6-chloropropa 7157.0p (Imol) and potassium acetate 10A
1 (105 mol) and DMF20011j& were added, the temperature was gradually raised while stirring, and the reaction was carried out at an internal temperature of 70° for 6 hours. After cooling, separate the crystals and perform vacuum distillation, 65
〜dO°lO related property fraction 109. Obtained OIi. 5, 3-chloropropyl acetate is 90s, 3-promobuvir acetate is 10-s, and the yield is 90s.

This fraction 10011't' was further pooled to obtain 850IiY of pure 6-oapropyl acetate. (bp:69～
71°/2931.9)! ! ! Example 1 Ethyl acetoacetate in two reaction flasks. 2.5iQ, 7
1 mol) and 3-chloropropyl acetate 97.0 &
(171 mol) was dissolved in 700-methyl isobutyl ketone and added thereto, 25.6 g of KI, potassium chloride 11 & 9p (Q, 84 m@1) t- were added, and the mixture was stirred.
The mixture was heated to reflux for 30 hours at a temperature of 117 to 118". Cooled to room temperature. 250 yd of water was added to dissolve the precipitate, the organic layer was taken, and the aqueous layer was further extracted with methyl isobutyl ketone. After combining the layers and washing them with water,
The methyl isobutyl ketone was removed to obtain a crude product 1s to IIv (crudeness ratio 9251).

According to analysis such as LIMR, this product is 5-acetoxyV-2-acetylvaleric acid ethyl (in the general formula HE, R1 is an ethyl group and R is a methyl group), and 41 is α-
It can be used as is as a raw material for the synthesis of acetyl-valerolactone. Purification is performed by distillation. JMRa: 4.16 (2H1C, 8Hz), 4.
02 (2H.

t, 8Hz), M8: 230 (M”) Example 2 Methyl acetoacetate 24.4 & (α2111@l), vinegar f
a3-ri pI2I2 Purpil 2 F1 (α20 mol),
KI44N (104mol) VDMPL 25dKf
The solution was dissolved and added to a 50 Qs1 reaction vessel, and 35 IF (α24 mol) of potassium was added thereto, followed by reaction at 50 to 601 for 5 hours. Raw material (methyl acetoacetate) by TLC
After almost no residue remained, the mixture was allowed to cool, water was added to dissolve the precipitate, and the mixture was extracted with ethyl acetate, washed with water, dried, and dried to obtain 45.0 JFtl of oil. The NMR of the crude product is constant, and the main product is methyl 5-acetoxy-2-acetyl blindrate (general formula HC).
cR1 and R8 (methyl groups), about 10-enol ether as non-NIIF, and 111 g of methyl acetoacetate (crudeness ratio: 104.2), which was the raw material for Shoroku.
. 7.0 of the crude product was subjected to column coomadography K, the main product) k5.91. and by-products 1639
was isolated (isolated yield a8*).

(methyl 5-acetoxy-2-acetyl cecolate) b, p
, 106-110°/2 gardens U NMRJ: 5.00 (IH, 8), 4.15 (211,
t, 12.16Hz), S, 82 (2H, t, 12H
s), &61 (5H, 8), 2.26 (SkL, 8)
, 2. os (slL8), 24-19 (21L m),
Clear: 216 (M”) Example 5 Vinegar Jl 15-Chloropropyl IS &8N (1mo
l) VDMF6oo-Km, KIIS1j'(1
mol) and 1j reaction volume fiK were added thereto, and the mixture was reacted at 70° for 3 hours. The reaction was followed by ZLE, and when the peak of vinegar #6-chloropropyl was below 10 and the peak of 6-iotobrovir acetate was between 80 and 85,
11.6-Iotobrovir without isolation from 50 to
600, 1141 g (1 m
・l), potassium carbonate 145-IIi (t05mol
) V was added and reacted for 4 hours. After pmrvm* under reduced pressure, toluene and water were added, and the aqueous layer was extracted with toluene,
Washing with water and forging [obtained oily aIIIJ21 (L4!i). It was confirmed that there was, and the enol form (-organism) was 5- or less.

patent applicant Dainippon Inn Ima Kagaku Kogyo Co., Ltd. Jundo Kukawamura Salt Chemical Research Institute

Claims (2)

[Claims] 1. A substituted valerate ester represented by the general formula I: (wherein R1 is a lower alkyl group such as a methyl group or an ethyl group, and R is H or a lower alkyl group such as a methyl group or an ethyl group). 2. General formula ■: CHsCOCHtCOOR' (in the formula, R1 represents a lower alkyl group such as a methyl group or ethyl group); and the general formula 11 [: X(-C&+0CO1'' (in the formula,
X is Cj, ilr, I etc./%CI Gen Suiko, Bl
is a 3-halogenopropyl ester represented by H or a lower alkyl group such as a methyl group or an ethyl group;
A method for producing a substituted valerate ester represented by the general formula I: (wherein Bl and R1 are as described above), characterized in that the reaction is carried out in the presence of a basic substance in a molten metal.