JP2003176272A - Method for producing substituted oxazole - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a 5-alkoxy-substituted oxazole and a method for producing a pyridoxine derivative. <P>SOLUTION: The 5-alkoxy-substituted oxazole is obtained by converting an α-isocyano alkylic acid ester in the presence of a base at >80°C and separating the 5-alkoxy-substituted oxazole from the reaction mixture simultaneously with the converting reaction, and the pyridoxine derivative is obtained by converting an amino acid into an amino acid ester, converting the obtained into a formamido acid ester, converting the obtained into an α-isocyanoalkyl acid ester, converting the obtained into a 5-alkoxy-substituted oxazole in the presence of a base at >80°C and separating the 5-alkoxy-substituted oxazole from the reaction mixture simultaneously with the converting reaction, reacting the obtained 5-alkoxy-substituted oxazole with a protective diol to obtain an Diels-Alder adduct and treating the obtained with an acid and removing the protective group to convert into the pyridoxine derivative. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 5-alkoxy-substituted oxazole, particularly a method for producing a 4-methyl-5-alkoxy-substituted oxazole, and a method for producing a pyridoxine derivative.

[0002]

BACKGROUND OF THE INVENTION 5-Alkoxy-substituted oxazoles are useful synthetic units 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 ).

Therefore, a process for preparing 5-alkoxy-substituted oxazoles which is economical and can be carried out on a large scale, especially 4
The process for preparing -methyl-5-alkoxy-substituted oxazoles is very useful.

It is known to convert α-isocyanoalkyl esters by thermal isomerization into the corresponding 5-alkoxy-substituted oxazoles batchwise.

Itov et al., Khimiko-Farmatsevticheskii Zhu
rnal, 1978, 12, 102-106 and Mishchenlo et al., Khimiko.
-Farmatsevticheskii Zhurnal, 1988, 7, 856-860
The batchwise thermal cyclization of α-isocyanopropionic acid esters at 135 ° C. to the corresponding 4-methyl-5-alkoxy-substituted oxazoles is described. The yield of 4-methyl-5-alkoxy-substituted oxazoles achieved by using various solvents is 4-36%. This method has the disadvantage of low selectivity and thus the production of large amounts of by-products. The most frequent by-products in this reaction were unreacted starting materials (yield: 33-55%) and rearranged α-nitrilopropionate (1-39% production rate).
Is.

Maeda et al., Bull. Chem. Soc. Japan, 1971,
44, 1407-1410 describes the batchwise thermal cyclization of various α-isocyanocarboxylic acid esters to the corresponding 5-alkoxy-substituted oxazoles at temperatures of 150-180 ° C. Depending on the substituents, yields of 5.1-28.2% have been achieved.

JP 54-20493 discloses that in the presence of a tertiary amine,
A batch process for the preparation of 4-methyl-5-alkoxy-substituted oxazoles by thermal cyclization of α-isocyanopropionic acid esters at temperatures of 155-170 ° C is described. After the reaction is complete, the solution is fractionally distilled under reduced pressure at the lowest possible temperature. Although the target selectivity of oxazole was improved (34-91.5%), the yield was not satisfactory because of the low conversion (11.1-49.4%).

All prior art processes have the disadvantage of low conversion and low selectivity, and thus also low yields of 5-alkoxy-substituted oxazoles.

[0009]

The object of the present invention is to obtain 5-alkoxy-, which has the disadvantages of the prior art and has the predominant property of producing 5-alkoxy-substituted oxazoles with high selectivity and high conversion. It is intended to provide a novel method for producing a substituted oxazole.

[0010]

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

[Chemical 11] 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 process for the preparation of an -alkoxy-substituted oxazole comprising a compound of formula II

[Chemical 12] The α-isocyanoalkyl acid ester represented by is converted to a 5-alkoxy-substituted oxazole of the formula I in the presence of a base at a temperature higher than 80 ° C., and at the same time as the conversion, a 5-alkoxy-substituted oxazole of the formula I The present inventors have found that this is achieved by a production method comprising separating an alkoxy-substituted oxazole.

The optionally substituted C ₁ -C ₆ -alkyl group means, independently of the groups R ₁ and R ₂ , a branched or unbranched optionally substituted C group. ₁ ~ C _6-
It is understood to mean 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, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl,
Examples include 1,2,2-trimethylpropyl, 1-ethylbutyl and 2-ethylbutyl.

The nature of these substituents is not an important determinant. The C ₁ -C ₆ -alkyl group may contain up to 6 substituents depending on the likelihood of a free bond, the substituents being
Preferably, aryl, hydroxyaryl, -NO _2, -N
H ₂ , -OH, -CN, -COOH and halogen (especially F or Cl)
Selected from the group consisting of.

In a preferred embodiment, the R ₁ and R ₂ groups are
C ₁ -C ₆ - alkyl group is unsubstituted.

Preferred R ₁ groups are C ₁ -C ₄ -alkyl groups, for example methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl or tert-butyl, particularly preferred n being -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 particularly preferred.

Therefore, in a particularly preferred embodiment of the process according to the invention, n-butyl α-isocyanopropionate is converted into 4-methyl-5-butoxyoxazole.

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

The α-isocyanoalkyl 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, 19
78, 12, 102-106; Maeda et al., Bull. Chem. Soc. Japan,
1971, 44, 1407-1410; Ugi et al., Chem. Ber. 1961, 94, 2
814; Chem. Ber. 1960, 93, 239-248, Angew. Chem. 19
65, 77, 492-504, Chem. Ber. 1975, 1580-1590, DE 30
29 231 A1 and J. Heterocyclic Chemistry 1988, 17,
705.

A base in the process of the invention is understood to mean a compound having the properties of a 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'-tetramethyl-1,3-propanediamine,
Mention may be made of N, N-diethylaniline or N, N-dibutylaniline. It is particularly preferred to use tri-n-butylamine as the base.

Below 80 ° C. no noticeable thermal cyclisation occurs. Therefore, the temperature of the conversion of the present invention is above 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.

The molar ratio of the base to the α-isocyanoalkyl ester of formula II is not as important as left, but is preferably 10:
1 to 0.05: 1.

The process according to the invention can be carried out, inter alia, in batch, semi-batch or continuous mode.

In a preferred embodiment of the method according to the invention, the method is carried out batchwise or semi-batchwise.

Batch-type is understood to mean a batch-type procedure. In this case, preferably the α-isocyanoalkyl acid ester of formula II and a base are introduced into the reactor and the α-isocyanoalkyl acid ester of 5-of the formula I is added at a temperature above 80 ° C.
Conversion to an alkoxy-substituted oxazole, simultaneously with this conversion, the 5-alkoxy-substituted oxazole of formula I is separated from the reaction mixture.

There are numerous examples of suitable reactors for this preferred batch procedure. Preferred reactors are those that have the property of allowing the separation of reaction products upon conversion.

By way of example, backmixing reactors, such as loop reactors, and conventional batch reactors, such as various forms of vessels having an attached column, It can be used as a reactor for the batch procedure described above.

A semi-batch method is understood to mean a semi-batch procedure. In this case, preferably the α-isocyanoalkyl acid ester of the formula II and the base are fed semicontinuously to the reactor and the α-isocyanoalkyl acid ester of the 5-alkoxy- of the formula I at a temperature above 80 ° C. Conversion to the substituted oxazole, simultaneously with this conversion, the 5-alkoxy-substituted oxazole of formula I is separated from the reaction mixture.

There are numerous examples of suitable reactors for this semi-batch procedure. Preferred reactors are those that have the property of allowing the separation of reaction products upon conversion.

Reactors that can be used in this semi-batch procedure are, for example, conventional semi-batch reactors such as loop reactors, membrane reactors, and any form of vessel with an associated reaction column section. It is a reactor.

In a preferred embodiment, the process is carried out in a batch or semi-batch reactor with an associated reaction column section, the conversion of the 5-alkoxy-substituted oxazole of the formula I being carried out by rectification of the reaction mixture simultaneously with the conversion. Separate from.

As is well known to those skilled in the art, the term "tower" will be understood hereinafter as a tower structure having a bottom, if not mentioned.

Correspondingly, the "attached tower part" is
It is understood that it means only the tower structure excluding the bottom.

The reaction column or adjunct reaction column section is preferably a column (ie, for example, plates, fillin) in which the internal fittings of the column have hold-ups.
gs), packings or fillings
It is understood to mean a tower that contains materials).

Column plates which allow a long residence time of the liquid in the column are particularly advantageous, and the residence time in the internal adjunct of the reaction column is preferably at least 30 minutes.

A preferred shelf is, for example, a valve plate (va
lve plates, preferably bubble cap plates
s) or, for example, tunnel plates, Lord
Thing of similar type, such as Lord stages and other internal attachments, or Thormann plate
s).

The packing is preferably structured, but examples include Mellapack® (Sulzer), B
Y (registered trademark) (Sulzer), B1 (registered trademark) (Montz), A3
There are packings with structured packing or similar features, such as the type of Montz®.

The reaction column and attached reaction column section can be designed in any manner depending on its type and internal attachments. It is particularly preferable to use a column having a partition wall as the reaction column.

The reaction column or adjunct reaction column section can be designed in various types, but as a reactor the separation of the 5-alkoxy-substituted oxazole of the formula I from the reaction mixture by conversion of the reactants and rectification It has the property of being able to do both at the same time.

In this preferred embodiment, a batch or semi-batch procedure using a batch or semi-batch reactor with an attached reaction column section, the rectification parameters are further adjusted as follows: Be advantageous.

(D) The conversion of the α-isocyanoalkyl ester of formula II into the 5-alkoxy-substituted oxazole of formula I is carried out in the reactor and / or on the internal adjunct of the adjunct reaction tower section. (E) The 5-alkoxy-substituted oxazole of formula I produced in the conversion is separated by the adjunct reaction tower section.

This is achieved by different adjustments of the rectification parameters, depending on the reactor design, the attached reaction column section and the reactants used. Suitable rectification parameters include, for example, temperature, pressure, reflux ratio in the column, design of the column and its internal adjuncts, heat transfer or energy input, which can be determined by the person skilled in the art according to routine tests D and It can be optimized so that each point of E is achieved.

In batch and semi-batch procedures, the pressure at the top of the adjunct reaction tower section is such that the temperature in the reactor and on its internal adjuncts is at least 80 ° C., preferably 100-200 ° C., particularly preferably 120 ° C. ~ 170 ℃, more preferably 130-170 ℃
Adjust so that

Usually, the column top pressure is adjusted to 5 to 800 mbar and the resulting column bottom pressure is usually 5 mbar to 5 mbar depending on the type of column used and, if applicable, the column internal appendages used. Set to atmospheric pressure.

The 5-alkoxy-substituted oxazole of formula I is
It may form an azeotrope with the base used, in which case the 5-alkoxy-substituted oxazoles of the formula I are separated off as an azeotrope by the auxiliary column section.

In this case, the overhead pressure and thus also the bottom pressure automatically depend on the 5-alkoxy-substituted oxazole of the formula I to be prepared and the base used, and the azeotrope in the azeotrope in the overhead stream. It is advantageous to adjust the proportion of bases to be as low as possible.

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

For example, 4-methyl-5-n-butoxyoxazole produced by the process of the present invention forms an azeotrope with the base tri-n-butylamine. Tower pressure 100 mbar
, The azeotrope in the overhead stream is composed of 91 wt% 4-methyl-5-n-butoxyoxazole and 9 wt% tri-n-butylamine.

The separation of tri-n-butylamine from the azeotrope in this case can be carried out, for example, by a second rectification after a column top pressure of 10 mbar.

Batch and semi-batch procedures can be carried out in the presence or absence of solvent. In a preferred embodiment, the method is performed without solvent.

However, it is also possible to add a solvent or to use the crude mixture in the process according to the invention which already contains a solvent in addition to the α-isocyanoalkyl acid ester of the formula II and a base.

In a further preferred embodiment, the process of the invention is carried out in the presence of an inert solvent. Inert solvents are preferably understood to mean non-polar and polar aprotic solvents, examples being toluene, xylene and chlorobenzene, dichloromethane, dichloroethane,
There are dichlorobenzene, ethylene carbonate and propylene carbonate, and chlorobenzene is particularly preferable.

In this case, in a batch or semi-batch procedure, first the more boiling solvent and then the 5-alkoxy-substituted oxazole of the formula I are separated off by rectification.

In a particularly preferred embodiment of the process according to the invention, the procedure is carried out continuously.

In the continuous procedure, the α-isocyanoalkyl acid ester of formula II and the base are continuously fed to the reactor as a mixture or separately and the α-isocyanoalkyl acid ester of formula II is fed into the reactor. Is converted to a 5-alkoxy-substituted oxazole of formula I, after which the reaction product is continuously withdrawn from the reactor at the same time as the conversion, the 5-alkoxy-substituted oxazole of formula I is continuously extracted from the reaction mixture. To separate.

There are numerous reactor designs suitable for this particularly preferred continuous procedure. Preference is given to reactors which have the property of being able to carry out continuous conversion and at the same time to separate the reaction products.

The reactor which can be used in this continuous procedure is, for example, a distillation can having an auxiliary column section, an extraction column, a bubble cap plate column, a membrane reactor, a Lord reactor, or a reaction column.

As mentioned above, the term tower is understood to mean a tower structure having a bottom, even if it is not stated so.

A reaction column is preferably understood to mean a column whose internal appendages have a hold-up, that is to say, for example, a tray, packing, packing or a column containing packing material.

In a particularly preferred embodiment of the process according to the invention, this continuous procedure is carried out in a reaction column as a reactor, the 5-alkoxy-substituted oxazole of the formula I being converted into the reaction mixture by rectification at the same time. Continuously separated from.

The reactor may be designed in any way with regard to the type of construction and its internal appendages. It is particularly preferable to use a column having a partition wall as the reaction column.

The reaction column can be designed in various forms, but the reactor is designed to simultaneously perform the conversion of the reactants and the separation of the 5-alkoxy-substituted oxazole of the formula I from the reaction mixture by rectification. Have the characteristics that enable it.

In this particularly preferred embodiment in which the reaction column is used in a continuous procedure, it is further advantageous to adjust the rectification parameters as follows.

(A) The conversion of α-isocyanoalkyl esters of formula II to 5-alkoxy-substituted oxazoles of formula I is carried out on the internal appendages of the reaction column and, if applicable, of the reaction column. The expression performed in the bottom and (B) generated by the transformation
5-alkoxy-substituted oxazole of I is continuously separated by overhead or side stream of the reaction column, and (C)
The base, together with the high-boiling components that can be produced in the conversion, are continuously and independently separated by the bottom stream or side stream of the reaction column.

Depending on the design of the reaction column and the reactants used, this is achieved by various adjustments of the rectification parameters. Suitable rectification parameters include, by way of example, temperature, pressure, reflux ratio in the column, design of the column and its internal adjuncts, heat transfer and residence time (especially at the bottom of the column),
There is an energy input, which can be optimized by the person skilled in the art by routine tests so that the points A, B and C are achieved.

At point C, the base can be separated from the high boiling components and specifically separated in the second column side stream.

Column side stream is understood in the present invention to mean continuous discharge of material from the side outlet of the column.

In the continuous procedure of the process according to the invention, the pressure at the top of the column is also such that the temperature at the bottom and the internal adjunct section is at least 80 ° C., preferably 100 to 200 ° C., particularly preferably 120 to 1 ° C.
The temperature is adjusted to 70 ° C, more preferably 130 to 170 ° C.

Usually, the overhead pressure is 5-8 for this continuous procedure.
Adjust to 00 mbar, but ensure that the resulting bottom pressure is approximately 5 mbar to atmospheric pressure, depending on the type of column used and, if applicable, the internal appendages used.

The residence time in the reaction column for this continuous procedure is usually 10 minutes to 7 hours, preferably 30 minutes to 4 hours.

In this continuous procedure, the 5-alkoxy-
The substituted oxazole may also form an azeotrope with the base used, in which case the 5-alkoxy-substituted oxazole of the formula I can be separated off as an azeotrope via the overhead stream.

In this case, the 5-alkoxy-of formula I prepared
Depending on the substituted oxazole and the base used, it is advantageous to adjust the top pressure and thus the bottom pressure automatically so that the proportion of base of the azeotrope in the overhead stream is as low as possible. is there.

The separation of the base from the azeotrope of the overhead stream can be carried out in a manner known per se in this case, for example by a second rectification followed by another pressure (double pressure distillation). it can.

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

In a further preferred embodiment, the continuous procedure of the process according to the invention is carried out in the presence of an inert solvent. Inert solvents are preferably understood to mean nonpolar and polar aprotic solvents, examples being toluene, xylene or chlorobenzene, dichloromethane, dichloroethane, dichlorobenzene, ethylene carbonate,
There is propylene carbonate, but chlorobenzene is particularly preferable.

If a solvent is used, it may be combined with, for example, a base and an α-isocyanoalkyl acid ester of formula II in 1
As a mixture of two or individually as individual ingredients,
The column can be fed continuously.

When using an inert solvent in the continuous procedure of the process of the present invention, the rectification parameters are preferably adjusted as follows.

(A) The conversion of the α-isocyanoalkyl acid ester of the formula II into the 5-alkoxy-substituted oxazole of the formula I is carried out on the internal appendages of the reaction column and, if applicable, at the bottom of the reaction column. (B1) when the solvent has a higher boiling point than the 5-alkoxy-substituted oxazole of formula I produced in the conversion, the 5-alkoxy-substituted oxazole of formula I is continuously passed through the overhead stream. Is separated and the solvent is continuously separated via a side stream or a bottom stream of the reaction column, (B2) the solvent is derived from the 5-alkoxy-substituted oxazole of formula I produced in the conversion. If it also has a low boiling point, the 5-alkoxy-substituted oxazole of the formula I is continuously separated by a column side stream and the solvent is continuously separated by an overhead stream of the reaction column, (C) The base is also combined with the high-boiling components that can be produced in the conversion, The bottom stream or the side stream of the reaction column separates continuously and independently.

The internal appendages of the reaction column can be of any form, such as shelves, packings, packings or structured packing.

Shelf plates with which the residence time of the liquid can be lengthened are particularly advantageous, and the residence time in the internal appendages of the reaction column is preferably longer than 30 minutes.

Preferred shelves are, for example, valve plates, preferably bubble cap plates or of similar construction types, eg tunnel plates, Lord stages or other internal appendages, and Thormann plates. Is.

A preferred structured packing is, by way of example, Me
llapack (registered trademark) (Sulzer), BY (registered trademark) (Sulze
r), B1® (Montz) and A3® (Mont
There are structured packings of type z) or similar packings.

The method of the present invention has the following advantages over the prior art.

Using the method of the present invention, a selectivity of greater than 95% is achieved based on the α-isocyanoalkyl acid ester of formula II.

The conversion is almost 100% and the yield of 5-alkoxy-substituted oxazoles of the formula I is more than 95%, based on the α-isocyanoalkyl acid ester of the formula II used.

The particularly preferred continuous procedure also has the advantage that a much higher space-time yield is obtained than in the previously known processes.

The method of the present invention has the formula IX

[Chemical 14] It is a novel and dominant partial step of the synthesis of the method for producing a pyridoxine derivative represented by the formula (1), particularly the method for producing pyridoxine (vitamin B ₆ ; formula IX, R ₂ = methyl).

The invention therefore also relates to a process for the preparation of pyridoxine derivatives of the formula IX, the formula III

[Chemical 15] The amino acid represented by the formula IV

[Chemical 16] Are converted to amino acid esters represented by

[Chemical 17] To formamide esters of formula II

[Chemical 18] Are converted to α-isocyanoalkyl acid ester represented by
I

[Chemical 19] Is converted to a 5-alkoxy-substituted oxazole represented by the formula, and simultaneously with the conversion, the 5-alkoxy-substituted oxazole of the formula I is separated from the reaction mixture, and the 5-alkoxy-substituted oxazole of the formula I is converted to the formula VI.

[Chemical 20] Wherein R ₃ and R ₄ are independent of each other or R ₃ and R ₄ together are a protecting group for the hydroxyl functionality and are reacted with a protected diol of formula VII

[Chemical 21] Comprising the Diels-Alder adduct of formula (III), which is converted to a pyridoxine derivative of formula IX by acid treatment and removal of the protecting group.

All the steps except this substep of the conversion of this new and superior α-isocyanoalkyl acid ester of formula II to the 5-alkoxy-substituted oxazole of formula I are carried out by Ullmann's
Encyclopedia of Industrial Chemistry 1996, Vol. A
27, pp. 533-537.

The starting material for this overall synthesis is the cheap amino acid of formula III, with alanine (R ₂ = methyl) being preferred. These are, for example, alcohols R ₁ -OH (preferably n-
Acid catalyzed esterification with (butanol)
The amino acid ester of formula IV is converted by a method known per se. This esterification can, however, also be achieved by other methods, such as activation of acid functional groups and esterification with base catalysis. Yet another method is described in US Pat. 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 formula V is then treated with the α of formula II by methods known per se as described above.
-Convert to isocyanoalkyl ester.

The α-isocyanoalkyl acid ester of formula II can be converted to the 5-of formula I using the method of the invention as described above.
Convert to an alkoxy-substituted oxazole.

In a preferred overall process, this partial process is
It is carried out as described in the preferred embodiment above.

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

This substep can be connected to the process of the invention at a later stage, but in the continuous procedure of the process of the invention, the α-isocyanoalkyl acid ester of formula II It can also be carried out by continuous feeding of the protected diol of formula VI to the reactor of the process of the invention simultaneously with the conversion to the -alkoxy-substituted oxazole. This feed is here carried out as a mixture with the α-isocyanoalkyl acid ester of the formula II, a base and, if appropriate, a solvent, or as individual components. In this case, as a product, 5-alkoxy-substituted oxazoles are taken off directly via the bottom effluent in the form of their Diels-Alder adducts.

The R ₃ and R ₄ radicals are taken to mean, independently of one another, protective groups, preferably acid labile protective groups of the hydroxyl function.

Basically, any acid labile protecting group can be used. Preferred acid labile protecting groups are described in the literature (TW Greene, Protective Groups in Organi
c Synthesis, John Wiley & Sons New York, 1981, pp
14-71 ； PJ Kocienski, Protecting Groups, Georg Th
ieme Verlag Stuttgart, 1994, pp 21-94),
It is an acid labile protecting group for the hydroxyl group.

Furthermore, in a preferred embodiment, the R ₃ and R ₄ groups can also be combined to form one acid labile protecting group for 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, for example acetone or isobutyraldehyde.

Subsequent acid treatment of the Diels-Alder adduct of formula VII results in aromatization to the pyridoxine structure, leaving the alcohol R ₁ -OH. Generally by removal of the acid labile protecting group is carried out by aqueous treatment of acidic (one or more), pyridoxine derivatives of the formula IX, in particular pyridoxine (vitamin B _6, R ₂ = methyl) is produced.

The alcohol R ₁ —OH and the protecting groups R ₃ , R ₄ can be recovered and used again in the overall process.

In the whole process, the use of the novel and superior subprocess of the present invention leads to an improvement in the overall yield.

[0104]

The present invention will be described with reference to the following examples.

Example 1 Series of 4-methyl-5-n-butoxyoxazole in a partition wall tower
Continuous production 20.5% by weight of n-butyl α-isocyanopropionate (R ₁ = n-butyl, R ₂ = methyl) and tri-n-butylamine 79.
A mixture consisting of 5% by weight, 3x3mm with 60 theoretical plates
Of V ₂ A-Raschig rings and introduced into a continuously operated partition wall column (4.8 mx 64 mm) with a 2.4 m high partition wall.

4-Methyl-5-n-butoxyoxazole and tri-n-butylamine having a boiling point of 158 ° C. (90: 10% by weight)
Azeotrope of 500 mbar top pressure and bottom temperature 1
Pass the top of the tower at 65 ° C. The high boiling point component and tributylamine are 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 is then added to the same column at the top pressure.
Separated at 10 mbar. As the overhead product, composition 4-methyl-5
-n-butoxyoxazole: tri-n-butylamine = 70:
An azeotrope with 30 was obtained and, at the column side outlet, pure 4-methyl-5-n-butoxyoxazole with a boiling point of 98 ° C. was obtained. The yield of this distillation was 99% (40% pure 4-methyl-5-n-butoxyoxazole and 60% 4-methyl-5-n-butoxyoxazole as an azeotrope, which Returned to first distillation). This pure 4-methyl
The concentration of -5-n-butoxyoxazole was 99.8%.

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, monochlorobenzene 32.2
%, And tri-n-butylamine 50.1% by weight, a mixture of 60 theoretical plates and 3x3 mm V ₂ A-Raschig rings is filled, and a partition with a height of 2.4 m is operated continuously. It was installed in the partition wall tower (4.8mx64mm).

Monochlorobenzene having a boiling point of 90 ° C.
An azeotrope of 4-methyl-5-n-butoxyxazole and tri-n-butylamine (88:12 wt%) was passed through the top at a column top pressure of 300 mbar and a bottom temperature of 169 ° C., and a passing temperature of 15
Obtained at the tower side outlet at 1 ° C. The high boiling point component and tributylamine are withdrawn 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 A mixture consisting of 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. Was continuously fed from the inlet (A) of the column of Example 1 (see FIG. 1) excluding the partition wall.

The solvent was added at a top pressure of 300 mbar and a bottom temperature of 1
Pass through the top outlet (B) at 65 ° C. 4-methyl-5-n-
Butoxyxazole was obtained from the column side outlet (C) in a yield of 99%. The amine is discharged from the bottom outlet (E).

Example 4 Continuous 4-methyl-5-n-butoxyoxazole in a reaction tower
Preparation In Example 3, 13.14% n-butyl α-isocyanopropionate and tris (2-ethylhexyl) amine 86.
A mixture consisting of 86% was continuously fed through the inlet (A).

4-Methyl-5-butoxyoxazole is discharged from the top outlet (D) and the amine is discharged from the bottom outlet (E) at a top pressure of 400 mbar and a bottom temperature of 165 ° C. The yield of 4-methyl-5-n-butoxyoxazole is 98.8.
%Met.

Example 5 Series of 4-methyl-5-isobutoxyoxazole in a reaction tower
Subsequent Production In Example 3, a mixture of 22.7% isobutyl α-isocyanopropionate and 77.3% N, N-dibutylaniline was continuously fed from the inlet (A).

4-Methyl-5-isobutoxyoxazole was discharged from the top outlet (B) at a temperature of 150 ° C. at a column top pressure of 300 mbar and a column bottom temperature of 160 ° C. The amine was obtained at 161 ° C. from the column side outlet (D). The yield of 4-methyl-5-isobutoxyxazole was 91%.

Example 6 Continuous 4-methyl-5-n-butoxyoxazole in a reaction tower
Production In Example 5, a mixture of 11.8% n-butyl α-isocyanopropionate and 88.2% N, N-dibutylaniline was continuously fed from the inlet (A). 4-Methyl-5-n-butoxyoxazole was obtained from the column top outlet (B) and amine was obtained from the column side outlet (D).

[0118]

The method of the invention has the following advantages over the prior art: With the method of the invention, the formula used
95 based on α-isocyanoalkyl ester of II
Selectivities higher than% are 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 the α-isocyanoalkyl ester of
Get higher.

The particularly preferred continuous procedure described above has the further advantage that the space-time yields are much higher than those hitherto known.

[Brief description of drawings]

FIG. 1 shows a reaction tower for continuous production of 5-alkoxy-substituted oxazole.

[Explanation of symbols]

A intake B Tower top exit C Tower side outlet D Tower side outlet E Tower 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 Michael Becker             Germany 67063 Ludwig             Schafen, Schantsstraße 74 F-term (reference) 4C055 AA01 BA02 BA06 CA03 CA16                       CA42 DA16 FA20

Claims (15)

[Claims] 1. Formula I: 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 process for the preparation of an -alkoxy-substituted oxazole, comprising the formula II: The α-isocyanoalkyl acid ester represented by is converted to a 5-alkoxy-substituted oxazole of the formula I in the presence of a base at a temperature higher than 80 ° C., and at the same time as the conversion, a 5-alkoxy-alkoxy group of the formula I is obtained from the reaction mixture. -Separates the substituted oxazole,
The above method comprising: 2. The method of claim 1, wherein the method is performed batchwise. 3. The process is carried out in a batch or semi-batch reactor with an attached reaction column section, at the same time as the conversion, the 5-alkoxy-substituted oxazole of formula I from the reaction mixture by rectification. The method of claim 2, wherein the is separated. 4. Adjusting the parameters of the rectification,
(D) from the α-isocyanoalkyl acid ester of formula II to formula I
To a 5-alkoxy-substituted oxazole in the reactor and / or on an internal adjunct to the adjunct reaction tower section, (E) converting the 5-alkoxy-substituted oxazole of formula I produced in the conversion. The method according to claim 3, wherein the separation is carried out using the attached reaction tower section. 5. The conversion is carried out in the presence of an inert solvent,
The method according to any one of claims 2 to 4. 6. The method according to claim 3, wherein the reaction tower used is a partition wall tower. 7. Adjusting the top pressure of said column to between 5 and 800 mbar and the resulting bottom pressure depending on the type of column used and, if applicable, the internal appendages used. The method according to claim 4, wherein the pressure is 10 mbar to atmospheric pressure. 8. The method according to claim 1, wherein the method is carried out continuously. 9. The process according to claim 8, wherein the process is carried out in a reaction column and, simultaneously with the conversion, the 5-alkoxy-substituted oxazole of the formula I is separated from the reaction mixture by rectification. 10. Adjusting the parameters of the rectification,
(A) from the α-isocyanoalkyl ester of formula II to formula I
Conversion to a 5-alkoxy-substituted oxazole on the internal adjuncts of the reaction column and, if applicable, in the bottom of the reaction column, (B) the 5-alkoxy-formula of formula I formed in the conversion
Substituted oxazole is continuously separated by a top stream or a side stream of the reaction tower. A partial flow is continuously and independently separated.
The method described in 9. 11. The reaction of formula (A) is carried out by carrying out the conversion in the presence of an inert solvent and adjusting the parameters of the reaction.
The conversion of the α-isocyanoalkyl acid ester of II to the 5-alkoxy-substituted oxazole of formula I is carried out on the internal appendages of the reaction column and, if applicable, in the bottom of the reaction column, (B1) When the solvent has a higher boiling point than the 5-alkoxy-substituted oxazole of formula I produced in the conversion, the 5-alkoxy-substituted oxazole of formula I is continuously separated by the overhead stream and the solvent Is continuously separated via a side stream or a bottom stream of the reaction column, (B2) if the solvent has a lower boiling point than the 5-alkoxy-substituted oxazole of formula I produced in the conversion. A 5-alkoxy-substituted oxazole of formula I is continuously separated by a column side stream and the solvent is continuously separated by an overhead stream of the reaction column, (C) the base and the conversion produced A high-boiling point component that can The method according to any one of claims 8 to 10, wherein the separation is performed continuously and independently of each other by a flow. 12. The partition tower is used as the reaction tower.
The method according to any one of claims 9 to 11. 13. When the base forms an azeotrope with a 5-alkoxy-substituted oxazole of formula I, the overhead pressure of the column is adjusted to provide the base in the azeotrope in the overhead stream. The ratio of 1 is set as low as possible.
The method described in the section. 14. Adjusting the top pressure of the column to between 5 and 800 mbar and the resulting bottom pressure depending on the type of column used and, if applicable, the internal appendages used. The method according to any one of claims 9 to 13, wherein the pressure is from 10 mbar to atmospheric pressure. 15. 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, The amino acid represented by the formula IV is (In the formula, R ₁ is an optionally substituted C ₁ -C ₆ -alkyl group) and converted into an amino acid ester, and these are converted to the formula V Are converted to formamidates of the formula: Are converted to α-isocyanoalkyl acid ester represented by
I [Chemical 8] Is converted to a 5-alkoxy-substituted oxazole represented by and at the same time the 5-alkoxy-substituted oxazole of the formula I is separated from the reaction mixture, and the 5-alkoxy-substituted oxazole of the formula I is converted to the formula VI (In the formula, R ₃ and R ₄ are independent of each other, or R ₃ and R ₄
R _{4 taken} together is reacted with a protected diol of the formula (VII) which is a protecting group for the hydroxyl function. Wherein the Diels-Alder adduct of formula (I) is obtained and these are converted to the pyridoxine derivative of formula IX by acid treatment and removal of the protecting group.