JP2003201283A - Method for continuously producing substituted oxazole - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for continuously producing a 5-alkoxy-substituted oxazole and a method for producing a pyridoxine derivative by using the same. <P>SOLUTION: This method for obtaining a pyridoxine derivative is provided by converting an α-isocyanoalkanoic acid ester expressed by the formula II in the presence of continuously supplied base at ≥80°C temperature to a 5- alkoxy-substituted oxazole I, taking it out from a reactor at the same time with the reaction, performing a reaction of the compound I with a compound VI to make a compound VII, and acid-treating it to obtain a pyridoxine derivative IX (in formulae, R<SB>1</SB>is an alkyl, R<SB>2</SB>is H or an alkyl, R<SB>3</SB>, R<SB>4</SB>are each independently a protection group of hydroxy group). <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a continuous production method of 5-alkoxy-substituted oxazoles, particularly a continuous production method of 4-methyl-5-alkoxy-substituted oxazoles, and a production method of pyridoxine derivatives.

[0002]

BACKGROUND OF THE INVENTION 5-Alkoxy-substituted oxazoles are useful synthons in organic chemistry. 4-methyl-5-alkoxy-- substituted oxazoles are particularly important as a useful precursor for the synthesis and industrial production of vitamin B ₆ (. Turchi et al, Chem Rev. 1975, 75,416).

It is therefore economical and can be implemented on a large scale.
A method for producing a 5-alkoxy-substituted oxazole, particularly a method for producing a 4-methyl-5-alkoxy-substituted oxazole, is very useful.

It is known to convert α-isocyanoalkanoic acid esters discontinuously to the corresponding 5-alkoxy-substituted oxazoles by thermal isomerization.

Itov et al., Khimiko-Farmatsevticheskii Zhu
rnal, 1978, 12, 102-106 and Mishchenlo et al., Khimiko.
-Farmatsevticheskii Zhurnal, 1988, 7, 856-860, at 135 ° C, a discontinuous thermal cyclization of the corresponding α-isocyanopropionate ester to give a 4-methyl-5-alkoxy-substituted oxazole. Is listed. The yields of 4-methyl-5-alkoxy-substituted oxazoles achieved by using different solvents are 4-36%. This method
It has the disadvantage of low selectivity and thus the production of large amounts of by-products. The most representative by-product of this reaction is the unreacted starting material (yield: 33
˜55%) and rearranged α-cyanopropionic acid ester (yield: 1 to 39%).

Maeda et al., Bull. Chem. Soc. Japan, 1971,
44, 1407-1410, at temperatures of 150-180 ° C, various corresponding α-, for obtaining 5-alkoxy-substituted oxazoles.
Discontinuous thermal cyclization of isocyanocarboxylic acid esters is described. Depending on the substituents, yields of 5.1-28.2% are achieved.

JP 54-20493 is a process for the discontinuous production of 4-methyl-5-alkoxy-substituted oxazoles by thermal cyclization of α-isocyanopropionic acid esters in the presence of tertiary amines at temperatures 155 and 170 ° C. Is described. In this case, the selectivity of the desired oxazole was improved (34-9
1.5%), the conversion rate is low (11.1-49.4%), and the yield is still unsatisfactory.

All prior art processes have the disadvantage of low conversion and low selectivity, and thus also low yields of 5-alkoxy-substituted oxazoles. Due to the discontinuous production procedure, the space-time yield in the prior art production method was very low.

[0009]

The problem of the present invention is that it no longer has the disadvantages of the prior art and has the excellent property of producing 5-alkoxy-substituted oxazoles in high yields and high space-time yields. It is to provide a novel method for producing an -alkoxy-substituted oxazole.

[0010]

[Means for Solving the Problem] This problem is represented by the formula I

[Chemical 11] 5-alkoxy represented by the formula: wherein R ₁ is an optionally substituted C ₁ -C ₆ -alkyl group and R ₂ is hydrogen or an optionally substituted C ₁ -C ₆ -alkyl group A method for continuously producing a substituted oxazole, which comprises: 1) continuously supplying formula II

[Chemical 12] Α-isocyanoalkanoic acid ester represented by the formula (wherein R ₁ and R ₂ are as defined above) in a reactor at a temperature of 80 ° C. or higher in the presence of a continuously supplied base. formula
It has been found to be achieved by a continuous process comprising converting I to a 5-alkoxy-substituted oxazole and 2) continuously discharging the reaction product from the reactor.

[0011]

DETAILED DESCRIPTION OF THE INVENTION An optionally substituted C ₁ -C ₆ -alkyl group refers to the groups R ₁ and R ₂ each independently branched or unbranched, optionally substituted. C ₁ -C _6-
Means an alkyl group, for example optionally substituted 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,
Examples include 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl and 2-ethylbutyl.

The nature of the substituents is not particularly critical. The C ₁ -C ₆ -alkyl group is, depending on the possibility of free bonding,
It may contain up to 6 substituents, which are preferably aryl, hydroxyaryl, --NO ₂ , --NH ₂ , --O.
Selected from the group of H, --CN, --COOH and halogen (especially F or Cl).

In a preferred embodiment, the R ₁ and R ₂ groups are
The C ₁ -C ₆ -alkyl group is not substituted.

Preferred R ₁ groups are C ₁ -C ₄ -alkyl groups, such as methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, or tert-butyl, particularly preferred n. -Butyl.

Preferred R ₂ groups are hydrogen and C ₁ -C ₄ -alkyl groups, such as methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl or tert-butyl, with particular preference being given to them. Is methyl.

It is preferred to combine the preferred R ₁ groups with the preferred R ₂ groups, the combination of R ₁ = n-butyl and R ₂ = methyl being especially preferred.

In a particularly preferred embodiment of the process of the invention, therefore, n-butyl α-isocyanopropionate is
Convert to methyl-5-n-butoxyoxazole.

The α-isocyanoalkanoic acid ester of formula II used in the method of the present invention may be of any purity.

The α-isocyanoalkanoic acid ester of formula II has the formula V

[Chemical 13] Can be prepared by a method known per se by reaction with a corresponding formamic acid ester represented by: by reaction with phosphorus oxychloride or phosgene in the presence of base. The usual synthetic methods are Itov et al., Khimiko-Farmatsevticheskii Zhurnal,
1978, 12, 102-106; Maeda et al., Bull. Chem. Soc. Japa.
n, 1971, 44, 1407-1410; Ugi et al., Chem. Ber. 1961, 9
4, 2814; Chem. Ber. 1960, 93, 239-248, Angew. Che
m. 1965, 77,492-504, Chem. Ber. 1975, 1580-1590, D
E 30 29 231 A1 and J. Heterocyclic Chemistry 198
8, 17, 705.

By base in the process of the invention is meant a compound having the properties of Bronsted base. Preferred bases are tertiary amines, such as triethylamine, triisopropylamine, tri-n-butylamine, dimethylcyclohexylamine, tris (2-ethylhexyl) amine, N-methylpyrrolidone, N, N, N'N'-tetra. Methyl-1,
3-propanediamine, N, N-diethylaniline, and N,
Mention may be made of N-dibutylaniline. It is particularly preferred to use tri-n-butylamine as the base.

Below 80 ° C., only slight thermal cyclization occurs. The temperature of the conversion reaction of the present invention is therefore at least 80 ° C.

In a preferred embodiment, the process according to the invention is carried out at a temperature of 100 to 200 ° C, particularly preferably 120 to 170 ° C, more preferably 130 to 170 ° C.

In the process of the present invention, the α-isocyanoalkanoic acid ester of formula II and the base are continuously fed to the reactor as a mixture or separately, and the α-isocyanoalkanoic acid ester of formula II is fed into the reactor. Conversion to the 5-alkoxy-substituted oxazole of formula I is followed by continuous withdrawal of the reaction product from the reactor.

The molar ratio of base to α-isocyanoalkanoic acid ester of formula II is not critical, but is preferably 10: 1.
~ 0.05: 1.

The process according to the invention is carried out during the conversion reaction in the reactor, ie at the same time as the conversion reaction, from the reaction mixture of the formula
It can be carried out particularly advantageously by withdrawing the 5-alkoxy-substituted oxazole of I. It is also preferable that this extraction is also performed continuously.

There are numerous reactor designs suitable for the preferred method of the present invention. The preferred reactor should be equipped with properties that allow for continuous conversion reactions and simultaneous withdrawal of reaction products.

Examples of the reactor that can be used are a boiler having an attached tower section, an extraction tower, a bubble cap column, a membrane reactor, a Lord reactor, or a reaction tower.

As is well known to those skilled in the art, the term "tower" means a tower structure with a bottom unless otherwise specified.

"Attached tower part" therefore only means a bottomless tower structure.

By reaction column is preferably meant a column whose internals show retention, ie, for example, trays, random packings, regular packings, or columns with structured packings. .

In a particularly preferred embodiment of the process according to the invention, the conversion reaction takes place in a reaction column as a reactor.

The design and contents of the reaction column can be as desired. As a reaction tower, 1
It is particularly preferable to use a single partition wall.

The reaction column can be designed differently, but the reactor is designed to simultaneously carry out the conversion reaction of the reactants and the withdrawal of the 5-alkoxy-substituted oxazole of the formula I from the reaction mixture by rectification. It has the characteristics that enable it.

In this preferred embodiment using a reaction column, it is more advantageous to adjust the rectification parameters as follows. That is, A) an α-isocyanoalkanoic acid ester of formula II
Conversion to the 5-alkoxy-substituted oxazole on the internals of the reaction column and, if appropriate, at the bottom of the reaction column, B) the 5-alkoxy-substituted formula I formed in the conversion The oxazole is continuously withdrawn by the overhead or side stream of the reaction column, and C) the base and, if applicable, the high boilers produced in the conversion are also the bottom or side stream of the reaction column. The flow should be continuously and independently extracted.

This can be achieved by variously setting the rectification parameters according to the design of the reaction column and the reactants used. Examples of suitable rectification parameters include temperature, pressure, reflux ratio in the tower, design of the tower and its internals, heat management and residence time (especially at the bottom of the tower), or energy input, which are The contractor
It can be optimized by routine tests so that each point of A, B and C is achieved.

In point C, the base, separately from the high boiler,
It is also possible in particular to withdraw in the second column sidestream.

Column side stream means, in the present invention, the continuous discharge of material from the side outlet of the column.

In the method of the present invention, the pressure at the top of the column is adjusted so that the temperature at the bottom of the column and the temperature at the internal part of the column are at least 80 ° C., preferably
The temperature is adjusted to 100 to 200 ° C, particularly preferably 120 to 170 ° C.

The pressure at the top of the column is usually adjusted to 5 to 800 mbar, but the resulting pressure at the bottom of the column is 5 mbar, depending on the type of column used and optionally the type of internal organs used.
~ Set to atmospheric pressure.

The residence time in the reaction tower is usually 10 minutes to 7 hours,
It is preferably 30 minutes to 4 hours.

The 5-alkoxy-substituted oxazole of formula I is
It may also form an azeotrope with the base used, in which case the 5-alkoxy-substituted oxazoles of the formula I can be taken off as an azeotrope by overhead flow.

In this case, the azeotrope in the overhead stream depends on the overhead pressure (and therefore also automatically on the bottom pressure), the 5-alkoxy-substituted oxazole of the formula I prepared and the base used. It is advantageous to adjust so that the proportion of bases of

The separation of the base from the azeotrope of the overhead stream is carried out in this case in a manner known per se, for example by a subsequent second rectification with different pressures (double pressure distillation).

For example, 4-prepared by the method of the present invention
Methyl-5-n-butoxyoxazole forms an azeotrope with the base tri-n-butylamine. Tower top pressure 100m
At bar, the azeotrope in the overhead stream is 91% by weight of 4
-Methyl-5-n-butoxyoxazole and 9% by weight tri-n-
Composed of butylamine.

The separation of tri-n-butylamine from the azeotrope of the overhead stream can be carried out in the subsequent second rectification, for example with an overhead pressure of 10 mbar.

The method of the present invention can be carried out in the presence or absence of a solvent. In a preferred embodiment, the method of the invention is carried out without solvent.

In a further preferred embodiment, the process according to the invention is carried out in the presence of an inert solvent. By inert solvent is meant preferably non-polar and polar aprotic solvents,
For example, toluene, xylene or chlorobenzene,
Dichloromethane, dichloroethane, dichlorobenzene,
There are ethylene carbonate and propylene carbonate, and chlorobenzene is particularly preferable.

If a solvent is used, it is fed to the reaction column both separately and continuously, for example as a mixture with the base and the α-isocyanoalkanoic acid ester of the formula II, or else in each case. be able to.

When an inert solvent is used in the method of the present invention, the rectification parameters are preferably adjusted as follows. That is, A) an α-isocyanoalkanoic acid ester of formula II
Is converted to a 5-alkoxy-substituted oxazole on the internals of the reaction column and, if appropriate, at the bottom of the reaction column, B1) the solvent being the 5-of the formula I formed in the conversion. Alkoxy-
When it has a higher boiling point than the substituted oxazole, it has the formula I
Of the 5-alkoxy-substituted oxazole is continuously withdrawn by the overhead stream and the solvent is continuously withdrawn by the side stream or the bottom stream of the reaction column, B2) the solvent being the 5- Alkoxy-
When it has a lower boiling point than the substituted oxazole, it has the formula I
Of the 5-alkoxy-substituted oxazole is continuously withdrawn by a side stream, the solvent is continuously withdrawn by the overhead stream of the reaction column, and C) the base, and if applicable, produced in the conversion High-boiling substances are also continuously and independently withdrawn by the bottom stream or side stream of the reaction tower.

Any form of internal organs can be used in the reaction column, such as trays, random packing, regular packing, or structured packing.

A tray with which the residence time of the liquid can be lengthened is particularly advantageous, and the residence time in the internals of the reaction column is preferably at least 30 minutes.

Preferred trays are, for example, valve trays, preferably bubble cap trays or similar trays such as tunnel trays, Lord reactors or other internal organs. There are those of the design, and Thormann Dan.

Preferred structured fillers include, by way of example:
Mellapack (registered trademark) (Made by Sulzer), BY (registered trademark)
(Sulzer), B1 (registered trademark) (Montz) and A3
There are structured fillers of the type (registered trademark) (manufactured by Montz) or fillers of similar design.

The process according to the invention has the following advantages over the prior art: With the process according to the invention, a selectivity higher than 95%, based on the α-isocyanoalkanoic acid ester of the formula II used, is obtained. To be achieved.

The conversion rate is almost 100% and therefore
The yield of 5-alkoxy-substituted oxazole was calculated according to the formula II used.
95% based on α-isocyanoalkanoate
Get higher.

This continuous procedure is a further advantage of the method. Space-time yields are clearly higher than with the previously disclosed methods.

The method of the present invention has the formula IX

[Chemical 14] It corresponds to a novel and advantageous synthetic step that contributes to the method for producing the pyridoxine derivative represented by the formula (3), particularly the method for producing pyridoxine (vitamin B ₆ ; formula IX, R ₂ = methyl).

The invention therefore also relates to pyridoxine derivatives of the formula IX in which R ₂ is hydrogen or optionally substituted C ₁
-C ₆ -alkyl group), which comprises the steps of: 1) Formula III

[Chemical 15] (Wherein, R ₂ is as defined above) an amino acid represented by the formula IV

[Chemical 16] Where R ₁ is an optionally substituted C ₁ -C ₆ -alkyl group, and 2) the amino acid ester of formula IV is converted to the amino acid ester of formula V

[Chemical 17] 3) converting the formamic acid ester of formula V to a formamic acid ester of formula II, wherein R ₁ and R ₂ are as defined above.

[Chemical 18] (In the formula, R ₁ and R ₂ are as defined above) is converted to α- isocyanoalkyl acid esters represented by the 4) α- isocyanoalkyl acid esters of the formula II, in a continuous process, In the presence of a base, at a temperature of 80 ° C or higher, the compound of formula I

[Chemical 19] 5) converting the 5-alkoxy-substituted oxazole of formula I to a 5-alkoxy-substituted oxazole of formula VI, wherein R ₁ and R ₂ are as defined above.

[Chemical 20] (Wherein R ₃ and R ₄ are each independently, or R ₃ and R ₄ together are a protecting group for a hydroxyl group), and reacted with a protected diol represented by the formula VII

[Chemical 21] (In the formula, R ₁ , R ₂ , R ₃ and R ₄ are as defined above.)
A Diels-Alder adduct of formula VII and 6) converting the adduct of formula VII to a pyridoxine derivative of formula IX by acid treatment and removal of the protecting group.

Apart from this new and advantageous process for the continuous conversion of the α-isocyanoalkanoic acid ester of the formula II to the 5-alkoxy-substituted oxazole of the formula I, which contributes to the invention, all the above steps are , Ullmann's Encyclopedia of Ind
ustrial Chemistry 1996, Vol. A 27, pp. 533-537.

The starting material for all of the above synthetic steps is of formula III
An inexpensive amino acid, alanine (R ₂= Methyl)
Good These can be prepared in a manner known per se, for example
R ₁-OH (preferably n-butanol) acid catalyst
By esterification with the amino acid ester of formula IV
Will be replaced. This esterification, for example, is
Such as activation of functional groups and esterification by base catalysis
It can also be achieved in other ways. Further way is rice
No. 3,227,721.

The amino acid ester of formula IV is converted to the formamic acid ester of formula V by methods known per se, for example as described in US Pat. No. 3,227,721.

The formamic acid ester of the formula V is then converted into the α of the formula II by methods known per se as described above.
-Converted to isocyanoalkanoate.

The α-isocyanoalkanoic acid ester of formula II can be prepared continuously by the method of the invention, as described above, by the formula
Convert to the 5-alkoxy-substituted oxazole of I.

The preferred overall process, which contributes to the process, is carried out as described in the preferred embodiment above.

The 5-alkoxy-substituted oxazoles of formula I are
Subsequent reaction with a protected diol of formula VI yields a Diels-Alder adduct of formula VII.

This useful step, which may be carried out after the process of the invention, is carried out by continuously feeding the protected diol of the formula VI to the reactor of the process of the invention to obtain the α-isocyanate of the formula II. It can also be done simultaneously with the conversion of the noalkanoic acid ester to the 5-alkoxy-substituted oxazole of formula I. They are supplied in admixture with the α-isocyanoalkanoic acid ester of formula II, a base, optionally a solvent, or as separate components. In this case, the 5-alkoxy-substituted oxazole is taken off as a product in the form of its Diels-Alder adduct directly from the bottom outlet.

The R ₃ and R ₄ groups, independently of one another, mean protecting groups, preferably acid labile protecting groups of the hydroxyl function.

Essentially any acid labile protecting group can be used. Preferred acid labile protecting groups are the acid labile protecting groups described in the literature for hydroxyl groups (TW Greene, Protective Groups in
Organic Synthesis, John Wiley & Sons New York, 198
1, pp 14-71; PJ Kocienski, Protecting Groups, Geo
rg Thieme Verlag Stuttgart, 1994, pp 21-94).

Another possibility in the preferred embodiment is
The R ₃ and R ₄ groups together form one acid labile protecting group for the two hydroxyl functional groups. For this purpose, it is preferred that the two hydroxyl functional groups form a cyclic acetal with a ketone or aldehyde such as acetone or isobutyraldehyde.

Thereafter, Diels-Alder of formula VII
Alcohol R by acid treatment of the adduct ₁-By removing OH,
Aromatization occurs, resulting in the pyridoxine skeleton. Generally acid
Of acid labile protecting groups carried out by treatment with aqueous solution
Upon removal, pyridoxine derivatives of formula IX, especially pyridoxine
Shin (vitamin B₆, R₂= Methyl) is produced.

The alcohol R ₁ —OH and the protecting groups R ₃ and R ₄ can be recovered and reused.

In the all-step method, the use of the novel and advantageous steps contributed by the present invention leads to an increase in the total yield. The present invention will be described below with reference to examples.

[0073]

Example 1 Example 1 A series of 4-methyl-5-n-butoxyoxazole in a partition wall tower.
Continued production α- isocyanopropionate acid n- butyl (R ₁ = n- butyl, R
₂ = Methyl) 20.5% by weight and tri-n-butylamine 79.5% by weight, filled with a 3 x 3 mm stainless steel Raschig ring with a theoretical plate number of 60. , Continuously operating partition tower (4.8mx 64m
sent to m).

Column top pressure 500 mbar and column bottom temperature 165 ° C.
Then, 4-methyl-5-n-butoxyoxazole was added at a boiling point of 158 ° C.
Effluent as an azeotrope with tri-n-butylamine (90: 10% by weight). High boilers and tributylamine were withdrawn at the bottom of the column. The conversion rate was 98.4% and the selectivity was 99%. The yield of 4-methyl-5-n-butoxyoxazole was 95% based on the n-butyl α-isocyanopropionate used.

The azeotrope obtained was then separated in the same column at a top pressure of 10 mbar. An azeotrope having a composition of 4-methyl-5-n-butoxyoxazole: tri-n-butylamine = 70: 30 was obtained as a product at the top of the column, and a pure product having a boiling point of 98 ° C. was obtained at the column outlet. To give 4-methyl-5-n-butoxyoxazole. The yield of this distillation was 99% (40% pure 4-methyl-5-n-butoxyoxazole and 60% 4-methyl-5-n-butoxyoxazole as an azeotrope The mixture was returned to the first distillation). The purity of this 4-methyl-5-n-butoxyoxazole is 99.8%.
Met.

Example 2 4-Methyl-5-n-butoxyoxy in a partition wall column using a solvent
Continuous production of sazole n-butyl α-isocyanopropionate (R ₁ = n-butyl, R
₂ = methyl) 13.1% by weight, 32.2% by weight of monochlorobenzene and 50.1% by weight of tri-n-butylamine were used to form a 2.4 m high sheet filled with 3 x 3 mm stainless steel Raschig rings with 60 theoretical plates. It was fed into a continuously operated partition wall tower (4.8mx 64mm) with partition walls.

Column top pressure 300 mbar and column bottom temperature 169 ° C.
Then, monochlorobenzene was distilled at a boiling point of 90 ° C, and 4-methyl-5-n-butoxyoxazole was azeotropically mixed with tri-n-butylamine having a boiling point of 151 ° C (88: 12% by weight) on the column side. I got it at the club exit. High boilers and tributylamine were taken off at the bottom of the column. The conversion rate was 99.5% and the selectivity was 99%. The yield of 4-methyl-5-n-butoxyoxazole was 94% based on the n-butyl α-isocyanopropionate used. The azeotrope was separated as in Example 1.

Example 3 4-Methyl-5-n-butoxyoxa in a reaction tower using a solvent
Continuous production of sol 20.6% by weight of chlorobenzene, 5.2% by weight of n-butyl α-isocyanopropionate (R ₁ = n-butyl, R ₂ = methyl),
And 72.60% by weight of tris (2-ethylhexyl) amine were continuously fed from the inlet (A) to the column of Example 1 (see FIG. 1) without the partition wall. At a column top pressure of 300 mbar and a column bottom temperature of 165 ° C., the solvent was taken off at the column top outlet (B). 4-Methyl-5-n-butoxyoxazole was obtained from the column side outlet (C) in 99% yield.
The amine was discharged from the bottom outlet (E).

Example 4 Continuous 4-methyl-5-n-butoxyoxazole in a reaction tower
Manufacture In the same manner as in Example 3, α-isocyanopropionic acid n-
Butyl 13.14% and tris (2-ethylhexyl) amine 8
A mixture consisting of 6.86% was continuously fed through the inlet (A). At a column top pressure of 400 mbar and a column bottom temperature of 165 ° C,
4-Methyl-5-n-butoxyoxazole was taken out from the column top outlet (B) and amine was discharged from the column bottom outlet (E). The yield of 4-methyl-5-n-butoxyoxazole was 98.8%.

Example 5 Series of 4-methyl-5-isobutoxyoxazole in a reaction tower
Subsequent production In the same manner as in Example 3, a mixture of 22.7% isobutyl α-isocyanopropionate and 77.3% N, N-dibutylaniline was continuously fed from the inlet (A). At a column top pressure of 300 mbar and a column bottom temperature of 160 ° C, 4-methyl-5
-Isobutoxyoxazole was withdrawn at a temperature of 150 ° C from the top outlet (B). Take out amine from the tower side (D)
From 161 ° C. The yield of 4-methyl-5-isobutoxyxazole was 91%.

Example 6 Continuous 4-methyl-5-n-butoxyoxazole in a reaction tower
Manufacture In the same manner as in Example 5, α-isocyanopropionic acid n-
A mixture of 11.8% butyl and 88.2% N, N-dibutylaniline was fed continuously from the inlet (A). 4-methyl-5-n-butoxyoxazole is taken out at the top of the tower (B)
Was extracted from the column in a yield of 98.7% to obtain amine from the column side outlet (D).

[Brief description of drawings]

FIG. 1 is a schematic diagram showing a reaction column for continuous production of 5-alkoxy-substituted oxazole.

[Explanation of symbols]

A intake B Top exit C side outlet D side exit E Bottom outlet

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Kirsten Bullcult             Germany 67069 Ludwig             Schafen, Ortwinstraße               Three (72) Inventor Tillman Faust             Germany 67256 Bisen Hai             Mu, Park Weg 4 (72) Inventor Yohim Henkelmann             68165 Mannheim, Germany,             Bassermannstrasse 25 (72) Inventor Alois Kindler             Federal Republic of Germany 67269 Grunsch             Tat, Rosenweg 3 (72) Inventor Christian Knorr             Germany 67141 Neuhofe             N, Otto-Dill-Strasse 4 (72) Inventor André Morley             Germany 50389 Vesselin             Gu, Operner Strasse 12 F-term (reference) 4C055 AA01 BA01 BA02 BA06 CA03                       CA16 CA42 DA16 FA20                 4C056 AA01 AB01 AC02 AD01 AE03                       AF01 BA03 BB06

Claims (9)

[Claims] 1. Formula I: 5-alkoxy represented by the formula: wherein R ₁ is an optionally substituted C ₁ -C ₆ -alkyl group and R ₂ is hydrogen or an optionally substituted C ₁ -C ₆ -alkyl group A method for continuously producing a substituted oxazole, which comprises: 1) continuously supplying formula II Α-isocyanoalkanoic acid ester represented by the formula (wherein R ₁ and R ₂ are as defined above) in a reactor at a temperature of 80 ° C. or higher in the presence of a continuously supplied base. formula
Converting the 5-alkoxy-substituted oxazole of I and 2) continuously discharging the reaction product from the reactor. 2. A process according to claim 1, wherein the 5-alkoxy-substituted oxazole of formula I is withdrawn from the reaction mixture simultaneously with the conversion. 3. The process according to claim 1, wherein the reaction column is used as a reactor and the 5-alkoxy-substituted oxazole of the formula I is withdrawn from the reaction mixture by rectification simultaneously with the conversion. 4. The rectification parameters are adjusted so that A) an α-isocyanoalkanoic acid ester of formula II results in
Conversion to the 5-alkoxy-substituted oxazole on the internals of the reaction column and, if appropriate, at the bottom of the reaction column, B) the 5-alkoxy-substituted formula I formed in the conversion The oxazole is withdrawn continuously by means of the top or side stream of the reaction column, and C) the base and, if applicable, the high boilers produced in the conversion, also the bottom stream or column of the reaction column. The method according to claim 3, wherein the withdrawal is performed continuously and independently by the side flow. 5. The conversion is carried out in the presence of an inert solvent, the parameters of the reaction being adjusted so that A) an α-isocyanoalkanoic acid ester of formula II
Is converted to a 5-alkoxy-substituted oxazole on the internals of the reaction column and, if appropriate, at the bottom of the reaction column, B1) the solvent being the 5-of the formula I formed in the conversion. Alkoxy-
When it has a higher boiling point than the substituted oxazole, it has the formula I
Of the 5-alkoxy-substituted oxazole is continuously withdrawn by the overhead stream and the solvent is continuously withdrawn by the side stream or the bottom stream of the reaction column, B2) the solvent being the 5- Alkoxy-
When it has a lower boiling point than the substituted oxazole, it has the formula I
Of the 5-alkoxy-substituted oxazole is continuously withdrawn by a side stream, the solvent is continuously withdrawn by the overhead stream of the reaction column, and C) the base, and if applicable, produced in the conversion High-boiling substances are also continuously and independently withdrawn by a bottom flow or a side flow of the reaction column.
The method according to any one of 4 above. 6. The method according to claim 3, wherein a partition wall tower is used as the reaction tower. 7. When the base forms an azeotrope with a 5-alkoxy-substituted oxazole of formula I, the top pressure in the column is adjusted to control the azeotrope base in the overhead stream. 7. The method according to claim 3, wherein the ratio is minimized.
The method described in the section. 8. The column top pressure is adjusted to 5-800 mbar and the resulting column bottom pressure is dependent on the type of column used and, optionally, the type of column offal used.
The method according to claim 4, wherein the pressure is 10 mbar to atmospheric pressure. 9. Formula IX A method for producing a pyridoxine derivative represented by the formula: wherein R ₂ is hydrogen or an optionally substituted C ₁ -C ₆ -alkyl group, 1) Formula III The amino acid of formula (wherein R ₂ is as defined above) is represented by the formula IV: Where R ₁ is an optionally substituted C ₁ -C ₆ -alkyl group, 2) converting the amino acid ester of formula IV to a compound of formula V 3) converting the formamic acid ester of formula V into a formamic acid ester of formula II: embedded image wherein R ₁ and R ₂ are as defined above. (In the formula, R ₁ and R ₂ are as defined above) is converted to α- isocyanoalkyl acid esters represented by the 4) α- isocyanoalkyl acid esters of the formula II, in a continuous process, In the presence of a base, at temperatures above 80 ° C., the compound of formula I 5) converting the 5-alkoxy-substituted oxazole of formula I to a 5-alkoxy-substituted oxazole of formula VI, wherein R ₁ and R ₂ are as defined above; (Wherein R ₃ and R ₄ are each independently, or R ₃ and R ₄ together are a protecting group for a hydroxyl group) and are reacted with a protected diol to give a compound of formula VII ] (In the formula, R ₁ , R ₂ , R ₃ and R ₄ are as defined above.)
A Diels-Alder adduct of formula VII and 6) converting the adduct of formula VII to a pyridoxine derivative of formula IX by acid treatment and removal of the protecting group.