CS233155B1 - Process for the preparation of 1-deoxy-1 - ((3,4-dimethylphenyl) amino) -dibitol - Google Patents

Abstract

Use of Raney nickel catalyst in the production of vitamin Bg. Pressure hydrogenation produces the synthesis intermediate, l-doxy-l-((3,4-dimethylphenyl)amino)-d-ribitol I: The invention enables savings in catalyst compared to previously known production processes and reduces the laboriousness of production. According to the invention, an initial high charge of Raney nickel catalyst is repeatedly used in discontinuous hydrogenations. The ratio of the weight of the wet contact to the weight of ribose is 1 to 7, preferably 2 to 3. Only such high charges of catalyst ensure that the activity decreases only slightly with repeated use, the contact can be used for e.g. for more than 12 hydrogenations in a row and more product is produced per weight unit of catalyst than according to current technologies.

Description

(54) A process for the preparation of 1-deoxy-1 - ((3,4-dimethylphenyl) amino) -d-ribitol

Use of Raney nickel catalyst in the production of vitamin Bg.

Pressurized hydrogenation produces the synthesis intermediate, 1-doxy-1 - ((3,4-dimethylphenyl) amino) -d-ribitol I:

Η Η H

^ò invention allows over the known manufacturing processes of the catalyst savings and reduces labor intensive manufacturing.

According to the invention, an initial high charge of Raney nickel catalyst is used repeatedly in batch hydrogenations.

The ratio of the weight of wet contact to the weight of the ribose is 1 to 7, preferably 2 to 3. Only such high catalyst loads ensure that the activity decreases by repeated use only, the contact can be utilized, for example, for more than 12 consecutive hydrogenations per weight unit. more product is produced than according to current technology.

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The present invention relates to a process for the preparation of a compound of formula I, 1-deoxy-1 - ((3,4-dimethylphenyl) amino) -d-ribitol, an important intermediate of vitamin synthesis

CH ₃ CH ₃

CH ₂ OH

OH OH

H

I c

and

OH

CHgOH

The invention makes it possible to save catalysts compared to the known production processes and to reduce the manufacturing effort.

The preparation of intermediate I, formerly called 3,4-dimethylphenyld-ribamine, is generally known. Starting from d-ribose and 3,4-xylidine, respectively. 4-nitro-o-xylene, or a riboside is prepared beforehand by condensation. The starting materials in the solutions are hydrogenated mostly on Raney nickel catalyst. According to the patents (US 2477560, Oap, 6665 (64), CS 116812, POL, 222287 T), ribose is processed from ribonolac tone reduction, more recently ribose is obtained by epimerizing arabinose (DOS 2923266, 2923268, Eur. Pat, Appl. 20959, 46495).

Catalytic pressure reduction requires relatively high Raney nickel catalyst feedstocks. Depending on the activity and reaction conditions, about 0.2 to 1.0 kg of wet catalyst per kg of ribosil, respectively. a catalyst used or regenerated can be added. Under the conditions described by hydrogenation, the catalysts are considerably deactivated.

There are various general methods of catalyst regeneration known

Raney nickel. According to the patents (DOS 2362255, Oap. Kokai 7466,000, 76,112495, 7486,290) it is regenerated by alkali.

By Oap.pat. 76,112495 also used borohydride.

The catalyst used to hydrogenate the invert sugar was possible

233 155 activated by powdered magnesium in an acidified mixture with sugar (Austr. Pat *, 454,487). Activation by carboxylic acids and alkali metal hydroxides has been proposed (DOS 2147644, t.

US Pat. No. 3796670). Regeneration of the catalyst used can also be achieved by adding it to the starting alloy in the preparation of the catalyst (3ap, U.S. Pat. No. 7684,792).

Known to the dependence of catalyst activity on hydrogen contents, activation of Raney nickel by removal of hydrogen has been suggested (Belg. Pat. 620574).

In the production of vitamin B 4, the catalyst constitutes a considerable part of the production costs. The used catalyst can be regenerated and returned to production, but activation is not complete and there are also handling losses. It is necessary to exclude from the production the necessary replenishment with fresh catalyst and on the other hand part of used Raney nickel. The consumption of Raney nickel (or starting alloy) per unit of production is high. The disadvantage is high laboriousness during regeneration and danger when handling pyrophoric catalyst.

These disadvantages are overcome by the process for the preparation of 1-deoxy-1 ((3,4-dimethylphenyl) amino) -d-ribitol according to the invention, wherein in the discontinuous catalytic hydrogenation condensation of ribose with 3,4-xylidine or 4-nitro-o-xylene , at elevated hydrogen pressure and elevated temperature, utilizes Raney nickel as a catalyst. The process is characterized in that the amount of catalyst is in a weight ratio to ribose of 1 to 7: 1, preferably 2 to 3: 1. The high amount of catalyst ensures that the first batch of it can be reused in subsequent hydrogenations and the catalyst has little activity loss. The process according to the invention is valid for the known and used synthesis conditions of intermediate I.

From the measurement of the reaction rates, it was found that with catalyst feeds of smaller or max. Straight ribose masses, depending on the conditions, the activity loss after one use was one to two thirds of the original value. It has been found that with higher Raney nickel feeds (e.g., a catalyst to ribose weight ratio of 1 to 3, with a conventional ribose concentration up to 10% by weight), activity remains more maintained and decreases only slightly with the number of hydrogenations. In the batches according to the invention, more than 20 hydrogenations can be carried out with one batch of catalyst, for example. No need to add

233 155 fresh or regenerated catalyst. Due to the high number of operations, which is basically made possible by an unusually high Raney nickel charge, a high amount of product is produced per catalyst (or starting alloy). This results in savings of raw materials over the currently known production processes. The used catalyst can be discarded (or regenerated).

The novelty of the process according to the invention is in the use of high Raney nickel batches, thus opening up the possibility of its multiple use. The process is opposed to the known practice in catalysis, where there is a tendency to reduce catalyst feed.

The experimentally established regularity is such that the deactivation degree at a high catalyst to substrate ratio by weight is small, with a decreasing ratio described above being higher, and at a certain small ratio, the catalyst is virtually inadequate.

Particularly preferred is this process for the application of 4-nitro-o-xylene. A high amount of catalyst preferably provides a high reaction rate for the reduction of the nitro group, even with little loss of activity upon repeated use of the catalyst. There are also less undesirable side reactions.

Experiments in a stirred laboratory autoclave showed that deactivation at lower catalyst to substrate ratios was not due to the quality of the substances to be treated. The activities are probably due to the hydrogen state on the catalyst under the influence of the reaction medium.

Known or used conditions for the synthesis of intermediate I mean, for example:

a) 3e raw materials of different qualities and origins can be used (pure ribose, ribose in solution after electronuction of ribonolactone, product from arabinose epimerization, ribosides and their known complex salts can be used eg sulphates, boric acid, 4-nitro- o-xylene.

b) Aqueous, aqueous-organic solutions are used as the reaction medium, or the pH is adjusted in the presence of buffers.

Preferably, aqueous methanolic solutions are used, with a pH of 5 to 9, preferably 6 to 7.

c) it is possible to apply or maintain an excess of one of the reaction components (sugar, xylidine or nitroxylene). A final molar ratio of 1: 1 is preferred,

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d) The concentrations used are given by optimization parameters such as; solubility of the product, methanol recovery, selectivity of reaction, sequencing to the previous and next steps, etc.

Usually, solutions with an initial ribose concentration of up to 10% by weight are processed,

e) Hydrogenation is carried out at temperatures up to 100 ° C, at pressures up to 20 MPa, preferably at 40 to 85 ° C and pressures up to eg 3-6 MPa. Partially adiabatic reaction reaction with nitroderivatives is preferred.

f) Catalyst B ' ey nickel can be of various provenance, preferably the most active, fresh, rapidly settling, prepared from an alloy containing 50% aluminum >

with a grain size below 0.1 mm.

g) The process is monitored, for example, by manometer, the reaction times required depend on the amount of catalyst, the number of operations and the reaction conditions. Times range from, for example, 10 minutes to 3 hours,

Preferably, especially in the presence of acids or acidic salts, times of less than an hour are chosen. Preferably, the catalyst is allowed to sediment in the autoclave and is already with the rest of the reaction solution for the next batch. Small loss of activity can be compensated by addition of fresh or regenerated Raney nickel.

h) The mixing power must be sufficiently dimensioned.

The advantages of the process according to the invention are in the low cost of the catalyst, higher product yields and reduced manufacturing effort.

Further details of the process according to the invention can be seen from the following examples, which are illustrative and not limiting.

Example 1

Ribose solution adjusted to pH 6 after electron reduction of ribonolactone (containing 5.72 g of reducing sugars, of which about 90% was ribose, sodium sulphate, boric acid, sodium ribonate, ribitol and other substances present) of 78.6 ml was preheated to 70 ° C and poured into the autoclave. The Raney / Nickel catalyst feed 15 g was flushed into an autoclave of 65 ml of water and finally a solution of 6 g of xylidine in 56 ml of methanol was added.

The catalyst was prepared from an alloy with half the nickel content, the grain size was below 0.05 mm.

After the addition of the catalyst, hydrogenation was started within 4 min, after a thirty minute process at temperatures up to 85 ° C and pressures.

Raney nickel was left at about 15 to about 6 MPa. in the autoclave to sediment, the solution was withdrawn and filtered (a small amount of entrained catalyst was returned to the autoclave). Within 30 min. after completion of the previous hydrogenation, another started. After 3 hydrogenations, the break was 15 hours (catalyst sediment was under hydrogen pressure) and hydrogenated 3 times again. Hydrogenations lasted 30 to 50 minutes, the catalyst was still usable. The average yield of product I, calculated on the content of reducing sugars, was 77.7

- Example 2

Ribose solutions, similar to Example 1, containing 10.5 g of reducing sugars, 139 ml volumes, were hydrogenated repeatedly with 8.9 g of xylidine in 42 ml of methanol. 20 g of the catalyst of Example 1 were used, but the catalyst age was 2 months,

A total of 13 times were hydrogenated, the reactions lasted 40-75 min.

After the first five batches, the break was 14 hours. After the ninth hydrogenation, 2 g fresh catalyst was added. Reaction yields decreased slightly with the number of repeats. The average yield of product I, calculated from the reducing sugars content, was 74%,

Example 3

Similar to Examples 1 and 2, 139 ml of an aqueous solution of reducing sugars containing 9.6 g, with 3.6 g each, were hydrogenated. xylidine in 55 mL of methanol.

The catalyst was made of an alloy containing about 40% nickel, the grain size was below 0.25 mm. The wet catalyst was weighed 20 g.

A significant decrease in activity was observed only after about 9 hydrogenations. Twelve hydrogenations, including breaks, took

12.5 hours. The other two reductions were paused after 38 hours, the catalyst was still suitable for further use.

The yield of product I, based on the reducing sugars content, was

72.3%.

Example 4

A ribose solution, similar to Example 1, containing 8 g of reducing sugars in 120 ml of solution, was poured (without heating) into an autoclave to 16 g of catalyst having approximately half

233 155 activity than Raney nickel used in the previous examples. This catalyst was made of an alloy with a grain size below 1.3 mm. After pouring 8 g of 4-nitro-o-xylene in 62 ml of methanol, it was hydrogenated for a total of 8 times, similar to the previous examples, for 60 min.

The yield of product I _f, calculated from the content of reducing sugars, was 69%.

Example 5

Aqueous methanolic ribose solutions, similar to Example 1, containing 4 kg of reducing sugars, were preheated repeatedly hydrogenated with equivalent amounts of xylidine after preheating. The reaction slurry volumes were about 100 liters,

24 hydrogenations were carried out with the 12 kg wet Raney Nickel catalyst of Example 4.

The yield of product I, based on the reducing sugars content, was 73

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SUBJECT OF THE INVENTION

Claims (1)

Process for the preparation of 1-deoxy-1 - ((3,4-dimethylphenyl) amino) -d-ribitol of formula I Η Η H I I i C-C-C-CH-OH OH OH OH ( ¹ ) by the intermittent catalytic hydrogenation condensation of a substituted Q-xylene ribose of formula II wherein R is an amino or nitro group at elevated pressure and temperature in the presence of Raney nickel catalyst, characterized in that the amount of catalyst is in a weight ratio to ribose 1 to 7: 1, preferably 2 to 3: 1.