Continuous preparation of substituted oxazoles

Details Continuous preparation of substituted oxazoles Continuous preparation of substituted oxazoles

2002-11-21

2004-03-30

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06713630

ABSTRACT:

The present invention relates to a process for continuously preparing 5-alkoxy-substituted oxazoles, in particular for continuously preparing 4-methyl-5-alkoxy-substituted oxazoles and also a process for preparing pyridoxine derivatives.
5-Alkoxy-substituted oxazoles are valuable synthetic building blocks in organic chemistry. 4-Methyl-5-alkoxy-substituted oxazoles have particular significance as important precursors for the synthesis and industrial production of vitamin B
6
(Turchi et al., Chem. Rev. 1975, 75, 416).
A process which is economically viable and is operable on a large scale for preparing 5-alkoxy-substituted oxazoles, in particular 4-methyl-5-alkoxy-substituted oxazoles, is therefore of great significance.
It is known that &agr;-isocyanoalkanoate esters can be converted batchwise by thermal isomerization into the corresponding 5-alkoxy-substituted oxazoles.
Itov et al., Khimiko-Farmatsevticheskii Zhurnal, 1978, 12, 102 to 106 and Mishchenlo et al., Khimiko-Farmatsevticheskii Zhurnal, 1988, 7, 856 to 860 describe a batchwise thermal cyclization of &agr;-isocyanopropionate esters to give the corresponding 4-methyl-5-alkoxy-substituted oxazoles at 135° C. The yields of 4-methyl-5-alkoxy-substituted oxazoles achieved by the use of various solvents are from 4 to 36%. The process has the disadvantage of low selectivity and thus the disadvantage that large amounts of by-products are formed. The most frequent by-products of this reaction are the unconverted reactant (yield: 33 to 55%) and also the rearranged &agr;-cyanopropionate ester (yield: 1 to 39%).
Maeda et al., Bull. Chem. Soc. Japan, 1971, 44, 1407 to 1410 disclose a batchwise thermal cyclization of various &agr;-isocyanocarboxylate esters to give the corresponding 5-alkoxy-substituted oxazoles at temperatures of from 150 to 180° C. Depending on the substituents, yields of from 5.1 to 28.2% are achieved.
JP 54-20493 describes a batchwise process for preparing 4-methyl-5-alkoxy-substituted oxazoles by thermally cyclizing &agr;-isocyanopropionate esters at temperatures of 155 and 170° C. in the presence of a tertiary amine. Although improved selectivities for the desired oxazoles are achieved (from 34 to 91.5%), the low conversion (from 11.1 to 49.4%) leads to yields which are still unsatisfactory.
All of the prior art processes have the disadvantage of low conversions and low selectivities and thus low yields of 5-alkoxy-substituted oxazoles. Owing to the batchwise processing method, the prior art processes only have low space-time yields.
It is an object of the present invention to provide a further process for preparing 5-alkoxy-substituted oxazoles which has advantageous characteristics, does not have the disadvantages of the prior art and delivers the 5-alkoxy-substituted oxazoles in high yields and high space-time yields.
We have found that this object is achieved by a process for continuously preparing 5-alkoxy-substituted oxazoles of the formula I,
where
R
1
is an unsubstituted or substituted C
1
-C
6
-alkyl radical and
R
2
is hydrogen or an unsubstituted or substituted C
1
-C
6
-alkyl radical, which comprises
converting continuously added &agr;-isocyanoalkanoate esters of the formula II
in the presence of continuously added assistants at temperatures above 80° C. in a reactor to the 5-alkoxy-substituted oxazoles of the formula I and continuously removing the reaction products from the reactor.
The C
1
-C
6
-alkyl radicals R
1
and R
2
are each independently branched or unbranched, substituted or unsubstituted C
1
-C
6
-alkyl radicals, for example, substituted or unsubstituted methyl, ethyl, propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl or 2-ethylbutyl.
The nature of the substituents is not critical. The C
1
-C
6
-alkyl radicals may, depending on the possibility of free bonds, contain up to 6 substituents, preferably selected from the group consisting of aryl, hydroxyaryl, —NO
2
, —NH
2
, —OH, —CN, —COOH, or halogen, in particular F or Cl.
In a preferred embodiment, the C
1
-C
6
-alkyl radicals R
1
and R
2
are unsubstituted.
Preferred R
1
radicals include C
1
-C
4
-alkyl radicals, for example, methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl or tert-butyl, more preferably n-butyl.
Preferred R
2
radicals include hydrogen and C
1
-C
4
-alkyl radicals, for example, methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl or tert-butyl, more preferably methyl.
Preference is given to the combination of the preferred radicals for R
1
and R
2
, and particular preference to the combination of R
1
=n-butyl and R
2
=methyl.
In a particularly preferred embodiment of the process according to the invention, n-butyl &agr;-isocyanopropionate is accordingly converted into 4-methyl-5-n-butoxyoxazole.
The &agr;-isocyanoalkanoate esters of the formula II used in the process according to the invention may be of any desired purity.
The &agr;-isocyanoalkanoate esters of the formula II are prepared in a manner known per se from the corresponding formamido esters of the formula V
by reacting them with phosphorus oxychloride or phosgene in the presence of bases. Common synthetic methods are described in Itov et al., Khimiko-Farmatsevticheskii Zhurnal, 1978, 12, 102-106; Maeda et al., Bull. Chem. Soc. Japan, 1971, 44, 1407-1410; Ugi et al., Chem. Ber. 1961, 94, 2814; Chem. Ber. 1960, 93, 239-248, Angew. Chem. 1965, 77, 492-504, Chem. Ber. 1975, 1580-1590, DE 30 29 231 A1 and J. Heterocyclic Chemistry 1988, 17, 705.
For the purposes of the present invention, assistants are chemical compounds, preferably chemical compounds which accelerate the cyclization reaction or shift the thermodynamic equilibrium in the direction of the desired product. Preferred assistants include cyclizing assistants selected from the group consisting of bases, alcohols and esters.
For the purposes of the present invention, bases are compounds having Brønsted base properties. Preferred bases include tertiary amines, for example, triethylamine, triisopropylamine, tri-n-butylamine, dimethylcyclohexylamine, tris(2-ethylhexyl)amine, N-methylpyrrolidone, N,N,N′N′-tetramethyl-1,3-propanediamine, N,N-diethylaniline or N,N-dibutylaniline. Particular preference is given to the use of tri-n-butylamine as base.
Preferred alcohols are substituted or unsubstituted C
1
-C
6
-alkanols, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol or n-hexanol. Particular preference is given to the use of n-butanol as alcohol.
Preferred esters include substituted or unsubstituted C
1
-C
6
-alkyl C
1
-C
6
-alkanoates, for example, methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate, tert-butyl acetate, hexyl acetate, methyl propionate, ethyl propionate, propyl propionate, n-butyl propionate, tert-butyl propionate, hexyl propionate, methyl butanoate, ethyl butanoate, propyl butanoate, n-butyl butanoate, tert-butyl butanoate, or hexyl butanoate. Particular preference is given to the use of n-butyl propionate as an ester.
The assistants may be used as individual compounds or in the form of mixtures. Preference is given to using the assistants as individual compounds.
Below 80° C., no noticeable thermal cyclization takes place. The temperature of the conversion according to the invention is accordingly at least 80° C.
In a preferred embodiment, the process according to the invention is operated at temperatures of from 100 to 200° C., more preferably at temperatures of from 120 to 170° C., most preferably at temperatures of from 130 to 170° C.
The molar ratio of assistant to &agr;-isocyanoalkanoate ester of the formula II is not critical and is preferably from 10:1 to 0.05:1.
In the process according to the invention, the &agr;-isocyanoalkanoate esters of the formu

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