JP2003261546A - Process for continuous preparation of substituted oxazole - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new process for the continuous preparation of a 5- alkoxy-substituted oxazole in high yield and high space-time yield. <P>SOLUTION: The process for the continuous preparation of a 5-alkoxy- substituted oxazole of formula I (R<SB>1</SB>is a substituted or unsubstituted 1-6C alkyl; and R<SB>2</SB>is H or a substituted or unsubstituted 1-6C alkyl) comprises the conversion of a continuously charged α-isocyanoalkanoic acid ester of formula II to the 5-alkoxy-substituted oxazole of formula I in a reactor at ≥80°C in the presence of an assistant selected from continuously charged alcohols and esters and the continuous discharge of the reaction product from the reactor. <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 synthetic building blocks 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 that α-isocyanoalkanoates can be converted discontinuously into 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 frequent by-products of this reaction are the unconverted reactants (yield: 33-55%) and the rearranged α-cyanopropionate (yield: 1-39%).

Maeda et al., Bull. Chem. Soc. Japan, 1971,
44, 1407-1410, 5-alkoxy at a temperature of 150-180 ℃
Discontinuous thermal cyclizations of various corresponding α-isocyanocarboxylic acid esters to obtain -substituted oxazoles are disclosed. 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 object of the present invention is to provide 5-alkoxys with excellent properties and without the drawbacks of the prior art.
It is an object of the present invention to provide a novel method for producing a 5-alkoxy-substituted oxazole, which produces a -substituted oxazole in a high yield and a high space-time yield.

[0010]

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

[Chemical 11] (Wherein R ₁ is unsubstituted or substituted C ₁ -C _6-
An alkyl group, R ₂ is hydrogen or an unsubstituted or substituted C ₁ -C ₆ -alkyl group)
A process for the continuous production of a 5-alkoxy-substituted oxazole, which comprises: 1) continuously adding formula II

[Chemical 12] Α-isocyanoalkanoic acid ester represented by the formula (wherein R ₁ and R ₂ are as defined above) is continuously added to form an auxiliary agent selected from the group consisting of alcohols and esters. Continuous in the presence of at least 80 ° C. in the presence of the reaction product, into a 5-alkoxy-substituted oxazole of formula I, and 2) continuously discharging the reaction product from the reactor. It has been found to be achieved by the manufacturing method.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The C ₁ -C ₆ -alkyl groups R ₁ and R ₂ are each independently a branched or unbranched, substituted or unsubstituted C ₁ -C _6- Alkyl group is meant, 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,
Examples thereof include 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 may contain up to 6 substituents, depending on the possibility of free bond, which is 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, a C ₁ -C ₆ -alkyl group
R ₁ and R ₂ are 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, more preferably 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, more preferred 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] Are prepared in a manner known per se by reacting them with phosphorus oxychloride or phosgene in the presence of a base.
The usual synthetic methods are Itov et al., Khimiko-Farmatsevtichesk.
ii Zhurnal, 1978, 12, 102-106; Maeda et al., Bull. Che.
m. Soc. Japan, 1971, 44, 1407-1410; Ugi et al., Chem. B.
er. 1961, 94, 2814; Chem. Ber. 1960, 93, 239-248,
Angew. Chem. 1965, 77, 492-504, Chem. Ber. 1975, 1
580-1590, DE 30 29 231 A1 and J. Heterocyclic Chem
istry 1988, 17, 705.

For the purposes of the present invention, auxiliaries are compounds selected from the group consisting of alcohols and esters.

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 using n-butanol as alcohol.

[0022] Preferred esters C ₁ -C ₆ non-substituted or substituted in the - alkanoic acid C ₁ -C ₆ - alkyl can be mentioned, for example, methyl acetate, ethyl acetate, propyl acetate, n- butyl , Tert-butyl acetate, hexyl acetate,
Methyl propionate, ethyl propionate, propyl propionate, n-butyl propionate, tert-propionate
-Butyl, hexyl propionate, methyl butanoate, ethyl butanoate, propyl butanoate, n-butyl butanoate,
There is tert-butyl butanoate, or hexyl butanoate. It is particularly preferred to use n-butyl propionate as the ester.

These auxiliaries can be used as individual compounds or in the form of mixtures. The auxiliaries are preferably used as individual compounds.

No thermal cyclization is observed below 80 ° C. The temperature of the conversion reaction of the present invention is therefore at least 80.
℃.

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

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

In the process of the present invention, the α-isocyanoalkanoic acid ester of formula II and the auxiliary agent are continuously fed to the reactor as a mixture or separately, and the α-isocyanoalkanoic acid ester of formula II is added to the reactor. Is converted to a 5-alkoxy-substituted oxazole of formula I after which the reaction product is continuously withdrawn from the reactor.

Basically, the reactors which can be used are all reactors which can carry out the continuous procedure.

In a preferred embodiment of the process of the present invention, a tubular reactor is used as the reactor. This continuously operated reactor is preferably free of backmixing.

Therefore, a tubular reactor having a Bodenstein number of 50 or more is preferable. This Bodenstein number is, for example, Fitzer
-Fritz, Technische Chemie, 3rd edition, Springer-V
erlag, p. 288 ff, it is determined by a method known per se.

Further, a tubular reactor having a theoretical tank number of 50 or more is preferable.

The pressure and residence time in the tubular reactor are not critical, but the reactor is preferably operated under pressure control and the residence time is also controlled by metering in the reactants. Is preferred.

The pressure in the tubular reactor is preferably 2 bar.
Or more, more preferably 3 to 9 bar, particularly preferably 4 to 7
bar, 5 bar being particularly preferred.

The residence time is preferably 1 to 8 hours, more preferably 2 to 6 hours, particularly preferably 3 to 5 hours, 4 hours being particularly preferred.

In a particularly preferred embodiment of the process using a tubular reactor, the compound of formula II is advantageously only partially converted in the tubular reactor. This partial conversion is preferably 40 to 70%, more preferably 50 to 60%, and particularly preferably 54%.

In this preferred embodiment using a tubular reactor, the effluent from the tubular reactor is fed to a continuously operated column in which a low boiling fraction containing the compound of formula I is contained. It is particularly advantageous to continuously separate by distillation a high-boiling fraction containing the unconverted compound of the formula II and auxiliaries.

As the tower, a reaction tower which is continuously operated as described below is preferable.

In this embodiment, where the column is attached downstream, further conversion takes place in the column attached downstream as described below.

In a further preferred embodiment of this process using a tubular reactor with a downstream column, the unconverted formula II
The high-boiling fraction leaving this column, containing the compounds and auxiliary agents of, is recycled to the reaction. As a result, the formula II
100% conversion of the compound is achieved.

In another preferred embodiment of the continuous process according to the invention, the 5-alkoxy-substituted oxazole of the formula I is withdrawn from the reaction mixture during the conversion reaction in the reactor, ie simultaneously with the conversion reaction. Can be carried out particularly advantageously. It is also preferable that this extraction is also performed continuously.

There are numerous reactor designs useful for this preferred embodiment of the process 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 reactors that can be used are distillation cans with stationary tower sections, extraction towers, bubble cap towers, membrane reactors, Lord reactors, or reaction towers.

As is well known to those skilled in the art, the term "column" means a column structure having a liquid phase unless otherwise specified.

Therefore, "installation tower section" means only a tower structure having no liquid phase.

A reaction column is preferably a column whose internals have a hold-up, for example a column with trays, packed beds, structured packings or random 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 structure and contents of the reaction column can be as desired. It is particularly preferable to use a partition wall column as the reaction column.

The reaction column can be designed differently, but the reactor is designed to 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 simultaneously 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
Is converted to the 5-alkoxy-substituted oxazole on the internals of the reaction column and in the liquid phase, if present, and B) the 5-alkoxy-substituted formula I produced by the conversion The oxazole is continuously withdrawn by the top or side stream of the reaction column, and C) the auxiliary and the high boilers produced in the conversion are also continuously produced by the bottom or side stream of the reaction column. And each of them should be taken out independently.

This is achieved by variously adjusting the rectification parameters, depending on 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 transfer and residence time (especially in the liquid phase), or energy input, which are: Those skilled in the art
It can be optimized by routine tests so that each point of A, B and C is achieved.

At point C, the auxiliaries can also be extracted in particular from the high boilers in the second column sidestream.

By column flow, in the present invention, is meant 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 set so that the temperature of the liquid phase of the column and the temperature of the internal components of the column are at least 80 ° C., preferably
The temperature is adjusted to 100 to 200 ° C, more preferably 120 to 170 ° C.

The pressure at the top of the column is usually adjusted to 5 to 800 mbar, but the pressure at the bottom of the column as a result of the type of the column to be used and the retention vessel of the column internals to be used is approximately 5 mbar 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 oxazoles of formula I are
It may also form an azeotrope with the auxiliaries used, in which case the 5-alkoxy-substituted oxazole of the formula I is taken off as an azeotrope by overhead flow.

In this case, the overhead pressure (and hence also the bottom pressure automatically) depends on the 5-alkoxy-substituted oxazole of the formula I prepared and the auxiliary used, and the azeotrope in the overhead stream. It is advantageous to adjust the proportion of auxiliaries in the mixture to be as low as possible.

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

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

In a further preferred embodiment, the process of the invention is carried out in the presence of an inert solvent. Preferable inert solvent means non-polar and polar aprotic solvent, for example, toluene, xylene or chlorobenzene, dichloromethane, dichloroethane, dichlorobenzene, ethylene carbonate and propylene carbonate, but chlorobenzene is particularly preferable.

If a solvent is used, it is added continuously to the reaction column as a mixture, for example with the auxiliaries and the α-isocyanoalkanoic acid ester of the formula II, or each individual component is added separately. It can be added.

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
Conversion to the 5-alkoxy-substituted oxazole is carried out on the internals of the reaction column and in the liquid phase, if present, and B1) the solvent is the 5-of 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 are continuously withdrawn by a side stream, the solvent is continuously withdrawn by an overhead stream of the reaction column, and C) the auxiliary and the high boilers produced in the conversion are The top stream or side stream of the reaction tower is continuously and independently withdrawn.

The internals used in the reaction tower may be of any design, for example, trays, packed beds, random packings or structured packings.

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

Preferred trays are, for example, valve trays, preferably bubble cap trays or of similar design, for example tunnel cap trays, Lord reactors or other internal organs. Thing, and Th
There are ormann steps.

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 compared to 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.

A further advantage of the method is this continuous process approach. 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 a process for the preparation of pyridoxine derivatives of the formula IX, in which R ₂ is hydrogen or an unsubstituted or substituted C ₁ -C ₆ -alkyl group, This method is as follows: 1) Formula III

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

[Chemical 16] (Wherein R ₁ is unsubstituted or substituted C ₁ -C _6-
2) is converted into an amino acid ester represented by the 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] 4) converting the α-isocyanoalkanoic acid ester of the formula II into a continuous α-isocyanoalkanoic acid ester of the formula II, wherein R ₁ and R ₂ are as defined above; In the process, in the presence of an auxiliary selected from the group consisting of alcohols and esters, at a temperature of 80 ° C. or higher, the 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.

Aside from the novel and advantageous continuous conversion steps of the invention, from the α-isocyanoalkanoic acid esters of the formula II to the 5-alkoxy-substituted oxazoles of the formula I,
All of the above steps are based on Ullmann's Encyclopedia of Industr
ial Chemistry 1996, Vol. A27, pp. 533-537.

The starting material for all 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
Conversion to amino ester of formula IV by esterification with
To be done. This esterification can also be attributed, for example, to the activity of acid functional groups.
And other methods such as esterification and base catalyzed esterification.
It can be done at a much lower cost. Further way is the United States
It is described in Japanese Patent No. 3,227,721.

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

The formamide ester of formula V is then
As described above, it is converted to the α-isocyanoalkanoic acid ester of the formula II by a method known per se.

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.

This step, which contributes to the preferred overall process method, 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 may be carried out downstream of the process of the invention, but by adding the protected diol of formula VI continuously to the reactor of the process of the invention, the α of formula II -
5-Alkoxy-of Formula I from Isocyanoalkanoates
It can also be carried out at the same time as conversion to the substituted oxazole.
The addition can be carried out together with the α-isocyanoalkanoic acid ester of the formula II, the auxiliaries and the solvent as a mixture or as separate components. In this case, the 5-alkoxy-substituted oxazole product is withdrawn directly from the bottom outlet in the form of its Diels-Alder adduct.

The R ₃ and R ₄ groups are each independently a protecting group, preferably an acid labile protecting group of the hydroxyl functional group.

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).

In a preferred embodiment, it is also possible that the R ₃ and R ₄ groups together form one acid labile protecting group with two hydroxyl functional groups. The two hydroxyl functional groups preferably 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 new and advantageous steps contributed by the present invention leads to an improvement in the total yield. The present invention will be described below with reference to examples.

[0086]

Example 1 4-Metric acid in a reaction tower using n-butanol as a cyclization aid
Continuous production of tyl-5-butyloxyoxazole (MOX) Filled with 60 theoretical plates, 3 x 3 mm V ₂ A Raschig ring,
In a continuously operating partition wall tower (4.8mx 64mm) with a 2.4m high partition wall, 30% by weight of n-butyl α-isocyanopropionate and n-butyl from the inlet (A) Butanol 70
A wt% mixture was pumped. N-Butanol was withdrawn at the top with a column top pressure of 300 mbar and a column bottom temperature of 165 ° C.
The liquid phase of the column was maintained at a constant level by using di-n-butyl phthalate as the middle boil. In the tower sidestream,
Purity of 4-methyl-5-butyloxyoxazole (MOX) 97
%, Yield 94%.

Example 2 Reaction tower using n-butyl propionate as cyclization aid
Of 4-methyl-5-butyloxyoxazole (MOX)
Subsequent manufacturing apparatus and experimental operation are the same as in Example 1. 35% by weight of n-butyl α-isocyanopropionate and n-propionate
Example 1 was repeated except that a mixture of 65% by weight butyl was added continuously. N-Butyl propionate was withdrawn at the top with a column top pressure of 300 mbar and a column bottom temperature of 165 ° C. The liquid phase of the column was maintained at a constant level by using di-n-butyl phthalate as the middle boil. In the side stream of the column, 4-methyl-5-butyloxyoxazole (MOX) was obtained with a purity of 95% and a yield of 92%.

Example 3 4-Methyl-5-butyloxyoxazole in a tubular reactor
(MOX) continuous production and subsequent continuous operation of the tower
Purification by distillation (auxiliary agent tri-n-butylamine (TBA)) This equipment consisted of a 100 mL tubular reactor with 120 theoretical tanks. The reactor was operated at 5 bar while controlling the pressure. For feeding, the residence time is 4 while controlling the mass flow rate.
I went on time. The feeds were n-butyl α-isocyanopropionate (ICE) and tri-n-butylamine (TBA).
And a molar ratio of 1: 3 (mol of ICE / mol of TBA). The effluent was collected. The ICE conversion was 54% and the selectivity was 92%, and the MOX yield was 50%. The effluent of the reactor was collected and subjected to distillation in a continuously operated column without a partition wall. The solution was fed from the inlet (nozzle A). At a pressure of 50 mbar and a column bottom temperature of 80-90 ° C, the MOX / amine mixture flows out at the top of the column and the ICE / amine is withdrawn from the column side stream (in the form of gas) one stage above the bottom. Was done. The bottom product contained a high-boiling secondary component. The bottom product was discharged and discarded. The ICE / amine mixture was recycled to the reaction and the MOX overhead effluent was purified to high purity MOX. As a whole process, 100% conversion of ICE was achieved. The selectivity for MOX was 90%. And the rest were high boilers, which were effluent from the continuously operated distillation as column bottoms.

Example 4 4-Methyl-5-butyloxyoxazole in a tubular reactor
(MOX) continuous production and subsequent continuous operation of the tower
Purification by distillation (auxiliary n-butanol) The same conversion was carried out in the same equipment as in Example 3 using n-butanol as auxiliary. The tubular reactor effluent was collected.
MOX yield with 54% ICE conversion and 93% selectivity
50% was obtained. In this example, the tower was operated at 500 mbar with a partition attached. n-Butanol was withdrawn at the top of the tower. MOX with a purity of 98% was obtained in the tower side stream. At the top of the tower, 95% pure ICE was obtained. The liquid phase was kept at a constant level by continuously metered dibutyl phthalate (5% by weight, based on the feed). This overflow contained high boiling material, which was discarded. ICE yield of 100 in all processes
% Has been achieved. The MOX selectivity was 89%. The balance was high boilers, which were discharged as the bottom product of distillation in continuous operation.

[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 FA22 FA34                       FA37                 4C056 AA01 AB01 AC02 AD01 AE03                       AF01 BA03 BB06 BC01                 4D076 AA12 AA16 AA22 AA24 BB05                       BB13 FA03 FA04 FA12 HA11                       JA03 JA04                 4G075 AA14 AA62 BB07 BD15 CA02                       CA05 CA51 EB05 EC09

Claims (14)

[Claims] 1. Formula I: (Wherein R ₁ is unsubstituted or substituted C ₁ -C _6-
An alkyl group, R ₂ is hydrogen or an unsubstituted or substituted C ₁ -C ₆ -alkyl group)
A process for the continuous production of a 5-alkoxy-substituted oxazole, which comprises: 1) continuously adding formula II Α-isocyanoalkanoic acid ester represented by the formula (wherein R ₁ and R ₂ are as defined above) is continuously added to form an auxiliary agent selected from the group consisting of alcohols and esters. A process as described above, comprising in the presence of at least 80 ° C. a temperature, in the reactor, conversion to a 5-alkoxy-substituted oxazole of formula I, and 2) continuously withdrawing the reaction product from the reactor. . 2. The method according to claim 1, wherein a tubular reactor is used as the reactor. 3. The method according to claim 2, wherein the tubular reactor has a Bodenstein number of 50 or more. 4. The method according to claim 2, wherein the number of theoretical tanks in the tubular reactor is 50 or more. 5. The effluent from the tubular reactor is fed into a continuously operated column in which a low boiling fraction containing compounds of the formula I and by distillation of the compound of the formula II which has not been converted. The process according to any one of claims 2 to 4, wherein the high-boiling fraction containing the compound and the auxiliary agent is continuously separated. 6. A process according to claim 5, wherein the high boiler fraction containing the unconverted compound of formula II and the auxiliary is recycled into the reactor. 7. Simultaneously with the conversion, 5-alkoxy-of formula I
The substituted oxazole is withdrawn from the reaction mixture.
The method described in. 8. The process according to claim 7, wherein a reaction column is used as the reactor and the 5-alkoxy-substituted oxazole of formula I is withdrawn from the reaction mixture by rectification simultaneously with the conversion. 9. Adjusting the parameters of said rectification so that 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 present, in the liquid phase of the reaction column, B) the 5-alkoxy-formula of formula I produced in the conversion The substituted oxazole is continuously withdrawn by the overhead or side stream of the reaction column, and C) the auxiliary and the high boilers produced in the conversion are removed by the bottom or side stream of the reaction column. 9. The method according to claim 8, wherein the extraction is performed continuously and independently. 10. 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 present, in the liquid phase of the reaction column, and B1) the solvent is formed of the compound of formula I -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 are continuously withdrawn by a side stream, the solvent is continuously withdrawn by an overhead stream of the reaction column, and C) the auxiliary and the high boilers produced in the conversion are The method according to claim 8 or 9, wherein the bottom stream or the side stream of the reaction column is continuously and independently withdrawn. 11. The method according to claim 8, wherein a partition wall tower is used as the reaction tower. 12. When the auxiliary agent forms an azeotrope with a 5-alkoxy-substituted oxazole of formula I, the top pressure in the column is adjusted to support the azeotrope in the overhead stream. 8. The ratio of the agent should be as low as possible.
The method according to any one of 1. 13. The column top pressure is adjusted to 5-800 mbar and the resulting column bottom pressure is 10 mba, depending on the type of column used and, if used, the type of offal.
The method according to any one of claims 8 to 12, wherein r to atmospheric pressure. 14. Formula IX: A method for producing a pyridoxine derivative represented by the formula: wherein R ₂ is hydrogen or an unsubstituted or substituted C ₁ -C ₆ -alkyl group, wherein: 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 unsubstituted or substituted C ₁ -C
_{A 6} -alkyl group) to give an amino ester of formula 2) 3) converting the formamide ester of formula V to a formamide 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 an auxiliary agent selected from the group consisting of alcohols and esters, at a temperature of 80 ℃ or more,
I [Chemical 8] 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.