JPS59222485A - 4-oxo-6-methyl-2-pyrone derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The 3-ureidomethylene-4-oxo-6-methyl-3,4-dihydro-2-pyrone derivative of formula I (R and R<1> are H, 1-4C alkyl, 2-4C alkenyl, aromatic group, or aromatic alkyl group). USE:A raw material of 4-hydroxy-6-methyl-niconitic acid and its N-substituted derivative useful as an intermediate of cephalosporin derivatives, etc. It is available easily at a low cost. The above derivatives can be prepared in high yield, in a short step, economically on an industrial scale, without producing the by- products other than the objective intermediate, by the use of the compound of the present invention. PREPARATION:The compound of formula I can be prepared by reacting 4-hydroxy-6-methyl-2-pyrone of formula II with the urea derivative of formula III and a orthoformia acid ester in the presence of a solvent such as methanol, at 30- 180 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula (I): (wherein R and R1 are the same or different, a hydrogen atom,
Alkyl group having 1 to 4 carbon atoms 1. A novel 6-uridomethylene-6-methyl-4- represented by an alkenyl group, an aromatic group or an aromatic alkyl group having lk 2 to 4 carbon atoms.
4-Hydroxy-6-methyl-nicotinic acid and its N-substituted derivatives are useful as pharmaceutical intermediates, especially penicillin and their N-substituted derivatives. It has gained increasing importance in recent years as an intermediate for cepha-tetrasumelin derivatives.

Compound (I) of the present invention is useful as a new, inexpensive and easily available raw material for such 4-hytronic 6-methylnicotinic acid and its N-substituted derivatives. Several methods are known for the production of methylnicotinic acid (1).
6-dimethylaminomethylene-6-methyl-4-oxo-6,4-dihydro-12-2-bipone (hereinafter referred to as compound (
This is a method of reacting A) with ammonia or a primary amine.
Ohem, ), vol. 67, p. 1145 (197
2), hereinafter, this method will be referred to as method (1)) O This method is a method with mild reaction conditions, but the li, N used
- Dimethylformamide dimethyl acetal has the disadvantage of being unstable and being very expensive and not easily available.

(2) is 4-hydroxy6-methyl-2-pyfourine and aniline) is 4(2)-2) tetraaniline, 4
- Aniline derivatives such as chloroaniline and ethyl orthoformate are reacted, and 6-anilinomethylene-6-methyl-4-oxo-6,4-dihydro-0-2-bifourine (hereinafter referred to as
compound CB)) or a corresponding derivative thereof;
Next, compound (4) was synthesized by reacting with dimethylamine [Monato
h, □hem, ), vol. 106, p. 966 (1975)
), a method in which ammonia or a primary amine is applied according to method (1) (hereinafter, this method will be referred to as method (2)).
). Such a method requires a long process and cannot be said to be industrial.
tGf3-(4-nido-panilino)methylene-6-methyl-4-oxo-6,4-dihydro-2-pyrone was hydrolyzed under alkaline conditions to produce 4-hydroxy-6-methyA/-2-bi-pyrone. This is a method in which p-6-carpaldehyde (hereinafter referred to as compound (0)) is prepared and then an amine compound is reacted in the presence of ammonia [JP-A-54-125
678L Hereinafter, this method will be referred to as method <8).

In such a method, it is necessary to isolate compound (0), and the crude 4- and ζ-6-methylnicotinic acid (sol) obtained in rough form contains colored substances that are time-consuming to separate.

(4) can be obtained by reacting compound (B) or a derivative thereof with ammonia.
-oxo-6,4-dihydro-2-bifourne (hereinafter referred to as compound CD)) is then reacted with dimethylamine [Tokugo No. 54-157567 and No. 54-157569, hereinafter referred to as This method is referred to as method (4)] It is said that this method can be operated continuously without isolating compound (1), and compound (B) is often used as a raw material. Method (4) is an industrially advantageous method with shorter steps compared to not only method (1) but also method (2) and method (8). It has the disadvantage of producing as a by-product an N-substituted product of compound (2), such as 1-phenyl-6-methyl-4-pyridone-6-carboxylic acid, derived from compound (B) or its derivative used as a raw material, In addition, method (2) and method (
Similar to 3), it also has the disadvantage that it is difficult to remove harmful anilines that are used as raw materials for compound ① or its derivatives or are inevitably produced as by-products during the reaction process.

The inventors of the present invention have conducted extensive studies while keeping in mind the problems of known production methods for compound (2), and have found that the general formula (■)
: (wherein R and R1 are the same as above) urea or its asymmetric derivative in which at least one of the two nitrogen atoms is unsubstituted is 4-human U represented by the formula:
Compound (I) is converted by reacting with x-6-methyl-2-bipne and orthoformic acid ester, and more surprisingly, compound (I) is converted by reacting with dimethyl-7mine in the presence of ammonia. In this case, 4-human tetraxy-6-methylnicotinic acid (sol) is hydrolyzed with potassium carbonate, the compound (0) is produced, and when reacted with ammonia, the compound φ) is produced, respectively. Furthermore, the compound (1) of the present invention is capable of reacting with ammonia and dimethylamine even if the product is removed from the reaction solution after isolation and purification or without isolation and purification. It has been found that the compound (I) of the present invention can be used directly to produce 4-hydroxy-6-methylnicotinic acid (2) in a high yield. If it is produced directly or indirectly, there is no need to use N,IIT-dimethylformamide dimethyl acetal, which has drawbacks such as those described above, or anilines, which can be harmful in some cases. ), there is no by-product of the N-substituted product, there is no difficulty in removing it, and compound (2), which is a useful pharmaceutical intermediate, can be produced with scales in a short process and in an industrially advantageous manner, and in high yield. I can do it.

An object of the present invention is to provide Compound (1) at low cost as a new raw material for an important pharmaceutical intermediate Compound (1).

The compound represented by the general formula (I) of the present invention: (wherein R and R1 are the same as above) is a known compound. (2): Produced by reacting a urea derivative represented by the formula (wherein R and R1 are the same as above) with an orthoformic acid ester.

The raw material compound (It) used in the present invention is easily available as a fertilizer, agricultural chemical intermediate, pharmaceutical intermediate, and synthetic raw material [
New Experimental Chemistry Course, Volume 14, Page 1628 (edited by the Chemical Society of Japan,
Published by Maruzen (1978)) o Substituents R and R1 of urea derivative (II) include hydrogen atoms 1 methyl, ethyl, n-privyl, isopropyl, n-butyl, 5ea-
Alkyl groups such as butyl, alkenyl groups such as allyl, phenyl groups, alkylbenzyl groups (!
: EGf o-1m- or p-tolyl, alkoxyphenyl such as o-1m-t or p-methoxy(ethoxy)phenyl, 0-lm- or p-chloro or p-bupmphenyl halogenated Phenyl and benzyl groups, 0-lm- or p-hensyl tetragenide, olm- or p-alkylbenzyl, 7
Examples include aromatic alkyl groups such as enethyl, but urea is extremely inexpensive and the reaction proceeds smoothly, so it is economically advantageous for both R and R1 to be hydrogen atoms.

As the orthoformate ester which is another raw material compound, lower alkyl orthoformates 1 are preferred, particularly methyl orthoformate and ethyl orthoformate.

Although the reaction of the present invention proceeds in the absence of a solvent, it is preferable to use an anhydrous solvent. Examples of solvents include alcohols such as methanol, ethanol, purpanol, isoprotetrapanol, various phthanols, and amyl alcohol, aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, and ethers such as isobutylene ether. , tetrahydrofuran, dioxane, diphenyl ether, acetonitrile, and mixed solvents thereof.

The reaction may be stopped in a stream of inert gas, such as nitrogen, helium, etc.

The reaction temperature can range from 60 to 180°C, but is preferably from 50 to 110°C since raw materials and products decompose at high temperatures.

Orthoformic acid ester and compound (II) used in the reaction
The amount of 4-hydroxy-6-methyl-2-pyrone is usually 1 mole or more, but can be adjusted as appropriate, and is preferably 1 to 5 moles.

The reaction proceeds homogeneously or heterogeneously and is generally completed within 20 hours. It usually takes 60 minutes to 6 hours to complete.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is not limited only to these Examples and Reference Examples.

Note that the actual values of melting points in Examples and Reference Examples are uncorrected.

In the examples, the A spectrum analysis was performed using A manufactured by JASCO Corporation.
-102 model, and mass spectrum analysis was performed using a direct introduction method using TMS-D200 manufactured by JEOL Ltd., at an ionization chamber temperature of 20oooa and an ionization voltage of 70e.
I did it with V.

Example 1 [6-Uridomethylene-4-oxo-6-methyl-6
, 4-Dihydro-0-2-pyrone (I) (R=R~Hydrogen atom)] 25 units of 4-human-oxy-6-butyl-2-pyrone (0.2 mol), 12 g of urea ('0. 2 mol), 40 m/(0.24 mol) of ethyl orthoformate and 12 ml of ethanol. After cooling, the crystals were collected and heated to 1 ethanol-At60 m
The target compound 34 was obtained by washing with l and drying with 6ooO
A yield of 87.4% was obtained.

Showing the characteristic values of the compound obtained next〇Melting point 2160
a (decomposition) Elemental analysis value; o s H a N 2 0 4 calculated value (a) + 0 48.98 H 4. 11 N 13
．． 83 actual measurement value) I O 49.11 H 4.56
N 14.28 engineering R spectrum analysis value (ymaz: a
m-1) = (KBr) 667 length 3615, 6210
, 1 720-, 1 708, 1662 Mass spectrum analysis value □ Reference peak (intensity ratio) i 155 (100) molecular ion peak (intensity ratio): 196 (3,1) When the amount was increased to 18 p (0.5 mol) and 80 m/ (0.4 a% mol), 67 g (yield 95%) of the target compound was obtained, and when only ethyl orthoformate was increased to 80 ml, 56.
29 (yield 95.1%) of the target compound was obtained.

Furthermore, when the above reaction was carried out using isofohano, /I/% dioxane, benzene, toluene, or acetonitrile as a solvent instead of ethanol, the target compound was obtained in almost the same yield.

Examples 2 to 14 The corresponding compound (
I got 1). The results are summarized in Table 1.

In addition, the reaction scale was shown in the number of moles of 4-hydroxy-6-methyl-2-pyrone used. In addition, the amounts of ethyl orthoformate and urea derivative (1) are 4-hydroxy-6-
The amount of ethanol is 1.2 times and equimolar to methyl-2-pyrone, respectively, and the amount of ethanol is 4-hydroxy-
The amount of 6-methyl-2-pyrone was 90 m/0-1%. Samples for elemental analysis were recrystallized from acetonitrile.

Reference Example 1 [Production of 4-human tetraxy-6-methyl-2-pyrone-3-carbaldehyde 1 compound 0] Compound (1) (n = nl = hydrogen atom) 5, water 160 m
A mixture of 1 and 8 g of potassium carbonate was heated under reflux for 1 hour. The reaction mixture was adjusted to pH 1 with hydrochloric acid, the precipitated crystals were extracted with dichloromethane, and the solvent was then distilled off to obtain 6 g (yield: 76.5%) of the desired product. Melting point 106~1
07% Obtained object is Monatshe 7te Fairhemy-110
6, p. 966 (1975), and the R spectrum analysis value and melting point were the same as those obtained by the method described in Vol. 6, p. 966 (1975).

Reference example 2 [3-aminomethylene-4-oxo-6-methyl-3,
Production of 4-dihydro*-'l-pyrone, compound 41MD)]
3-Uridomethylene-4-oxo-6-methyl-6,4-dihydro a-'l-bifourne (I) obtained in Example 1
(R=R1=hydrogen atom) 19.6G+ is water 92+nl
The mixture was added to a mixture of 8 ml of 28% aqueous ammonia and stirred for 1 hour. Once the reaction mixture was completely dissolved, crystals were precipitated. This was washed with water and air-dried, yielding 12 g (yield: 78.4%) of the desired product.

Melting point 212-216°a.

The obtained compound had a spectral analysis value and a melting point that matched those of a standard obtained by the method described in Journal Op Organic Chemistry, Vol. 67, p. 1145 (1972).

Reference example 6 [4-hydroxy-6-methylnicotinic acid (IQ (7)
Ma) (a) Compound (I) obtained in Example 1 (R=R
1-Hydrogen atom) 470g to 270ml of 28% ammonia water
/ and 2.08 t of water and stirred for 60 minutes to precipitate crystals. 40% dimethylamine 1 to the reaction mixture
．． After adding 041 and stirring for 2 hours, the reaction mixture became a solution. Excess dimethylamine and ammonia were distilled off under reduced pressure, the pH was adjusted to 1 with hydrochloric acid, and the precipitated crystals were collected, washed with water, and dried. (100qO) 250 objects
g (yield 68.1%). Melting point 263-265
°0 (activated carbon-water) The obtained target product had an XR spectrum analysis value and a melting point that matched the standard obtained by the method described in Journal Op Organic Chemistry, Vol. 67, p. 1145 (1972).

(b) Target compound 2 was prepared in the same manner as in the method of IL, except that 8 ml of thylamine 8 and 17.7 ml of water were used instead of compound (I) (R=R1" hydrogen atom).
．． 66 ml (yield 77.1%) was obtained.

(0) Compound (I) (R = hydrogen atom, R1 = n-butyl) in place of 0.02 mol of each compound (I) (R
= hydrogen atom, R1 = methyl), compound (I) (R = water,
The target compound was prepared in the same manner as in method (a) above except that compound (I) (n = u1 = methyl] or compound (I) (R = 11 = ethyl) was used.
Obtained with a yield of ~67.6%.

(d,) Compound (1) obtained in Example 6 (R=hydrogen atom, R1=benzyl) A mixture of 2.6 ml of 5.769.28% ammonia water and 17.7 ml of water was stirred for 60 minutes.

40% dimethylamine 8.8mj! The mixture was stirred for an additional 3 hours, and the precipitated benzylurea was removed by filtration, and excess ammonia and dimethylamine were distilled off under reduced pressure. The precipitated crystals were adjusted to pH 1 with hydrochloric acid, washed with water, and dried at 100°A to give 2.12 g of the desired product (yield: 75.
7%).

<e>Compound (I) (R=hydrogen atom, R1=benzyl)
in place of compound CI) (R-hydrogen atom, R1=phenyl, 0- or p-)lyl, o- or m-lytetralphenyl, p-bromphenyl or p-methoxyphenyl] or compound (I) (R The desired product was obtained in the same manner as in the method (d) above, except that R1=methyl and R1=phenyl were used.

Reference Example 4 (Production of 1,6-dimethyl=4-pyridone-6-carboxylic acid) Compound +1) (R=R"" hydrogen atom) 19.6
After stirring for 30 minutes, 10 ml of 40% dimethylamine was added and further stirred for 2 hours. The mixture was gradually heated to 98°C while monomethylamine and dimethylamine were distilled off. After cooling, adjust the pH to 2 with hydrochloric acid, remove the resulting crystals, wash with water,
It was dried at 100° CJ to obtain 12 g (yield: 72%) of the desired product. The obtained target product was identical in R spectrum analysis value and melting point to the standard obtained by the method described in Journal of Organic Chemistry, Vol. 67, p. 1148 (1972).

Claims (1)

[Claims] 1 General formula (1): (wherein R and R1 are the same or different, a hydrogen atom,
-6-Uridomethylene-4-oxo-6-methyl- represented by an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an aromatic group, or an aromatic alkyl group)
6,4-dihydro-2-pyrone derivative. 2 R is a hydrogen atom, and R1 is a phenyl group, a substituted 7-enyl group, a phenyl lower alkyl group, or a nuclear-substituted phenyl lower alkyl group, 6-U'ridemethylene-4-oxo- as described in claim si 6-Methyl-6,4-dihydro-2-pyrene derivative. 6. Claim 2, wherein the substituted phenyl group and the nuclear-substituted phenyl lower alkyl group have one substituent, which is a chlorine atom, a bromine atom, a lower alkyl group, or a lower alkoxy group.
6-Uridomethylene-4-oxo-6-methyl-6,4-dihydrocy-2-bifourne derivative as described in 2. 4-hydroxy-6-methyl-2-pyrone and orthoformic acid ester represented by the formula (II): (wherein R and R1 are the same or different, a hydrogen atom, an alkyl having 1 to 4 carbon atoms, group, alkenyl group having 2 to 4 carbon atoms, aromatic group,
6-uridomethylene-4- represented by the general formula (I): (wherein R and R1 are the same as above) Oxo-6-methy-6,4-dihydro a-2-
Method for producing pyrone derivatives. 5. The production method according to claim 4, wherein R is a hydrogen atom and R1 is a phenyl group, a substituted phenyl group, a phenyl lower alkyl group, or a nuclear-substituted phenyl lower alkyl group. 6. The manufacturing method according to claim 5, wherein the substituted phenyl group and the nuclear-substituted phenyl lower alkyl group have one substituent, which is a chlorine atom, a bromine atom, a lower alkyl group, or a lower alkoxy group.