CN101801915A - Method for synthesizing beta-sodium alanine and calcium pantothenate - Google Patents

Abstract

The present invention provides an improvement in the preparation of sodium beta-alaninate from beta-amino-propionitrile capable of condensing with pantolactone to pantothenate, the improvement comprising carrying out hydrolysis of beta-amino-propionitrile in water followed by solvent replacement from water to alcohol, to obtain sodium beta-alaninate as an alcoholic solution, whereby the final beta-alanine salt mixture contains by-products or by-products only in amounts which do not adversely affect the pantothenate quality.

Description

Method for synthesizing sodium beta-alanine and calcium pantothenate

The invention relates to a method for preparing sodium beta-alanine from beta-amino-propionitrile.

Sodium β-alanine is an intermediate product used in the preparation of sodium D- or DL-pantothenate or calcium D- or DL-pantothenate by reacting alanine salt with L- or DL-pantolactone, respectively.

US 4,258,210 describes a process for the preparation of crystalline sodium D-pantothenate from β-aminopropionitrile, in which β-aminopropionitrile is saponified with aqueous sodium hydroxide to produce a solution of sodium β-alaninate, and water is obtained in a two-step drying process 1% dry sodium beta-alanine, which is dissolved in a lower alkanol solvent and reacted with L-pantolactone to produce crystalline sodium D-pantothenate. However, further crystallization has proven to be necessary in order to obtain sodium D-pantothenate of a purity suitable for human consumption.

In addition to inorganic ions, the main impurity that contaminates the sodium β-alanine obtained according to the background art method comes from the aqueous sodium hydroxide saponification of β-aminopropionitrile, that is, di-(2-carboxyethyl)- Amine (also known as imino-di-propionic acid (IDPA)) and β-alanyl-β-alanine (I and II, respectively). Although amine I does not react with pantolactone, dipeptide II reacts with L-pantolactone to give D(+)-N-(2,4-dihydroxy-3,3-dimethylbutyryl)-β - Alanyl-β-alanine (III).

Considering the increasing demand for high-purity calcium D-pantothenate for human consumption, there is a need to further improve the above method and develop a very economical high-yield synthesis of high-purity crystalline sodium D-pantothenate and calcium D-pantothenate that does not require Additional crystallization.

The present invention therefore relates to an improved process for the preparation of β-alaninate sodium usable for condensation with R-pantolactone to D-pantothenate from β-amino-propionitrile, which method obtains β-alaninate as an alcoholic solution. Sodium Alaninate, whose improvements include:

(a) carry out the hydrolysis of β-amino-propionitrile in alkaline aqueous medium or alcohol/water mixture, then

(b) replacing the solvent with an alcohol such that the final β-alanine salt mixture contains only side-products or by-products in amounts that have no effect on the quality of D-pantothenate Negative Effects.

Saponification can be carried out in water or a mixture of water and one or more alcohols. Water can be removed in a manner known per se by distillation with or without entraining agent, if desired. The term "replacement" includes partial or complete removal of the original solvent. This means that the alcohol solution of sodium β-alanine is finally obtained, which can directly react with L-pantolactone to obtain pure sodium D-pantothenate, which can be converted into calcium D-pantothenate again, and then or meet the specification requirements for use in human food or as a drug. This means more specifically that, for example, calcium pantoate contains less than 0.80% (w/w) and calcium panto-β-alanyl-β-alanine The content of alanyl-β-alaninate) (calcium salt of III) is less than 0.10% (w/w).

More specifically, the improved method of the present invention comprises:

(a) adding β-amino-propionitrile to a solution of excess sodium hydroxide in water or alcohol/water at a temperature of 60-95° C., heating the mixture further and removing water if necessary;

(b) neutralizing excess sodium hydroxide with β-alanine, avoiding a substantial excess of β-alanine, to directly obtain a solution with the desired concentration;

(c) remove water, and

(d) Sodium β-alanine is dissolved in C _1-8 -alcohol to obtain a solution of sodium β-alanine in alcohol with the desired concentration.

It is advantageous to add β-amino-propionitrile to an excess of sodium hydroxide in water (eg about 33 w/w% solution) with stirring. A preferred temperature range for the addition of β-amino-propionitrile is 90-95°C. The ammonia produced can be absorbed by the aqueous mineral acid solution in a known manner in an external scrubber.

The preferred molar amounts of β-amino-propionitrile and sodium hydroxide are in the range of 1:1.01-10, more preferably in the range of 1:1.01-2.0, most preferably in the range of 1:1.03-1.1. After the reaction is complete, the reaction mixture can be further heated, eg, to reflux, and at least part of the water removed by distillation. During this operation, the internal temperature will increase. The reaction can be carried out under atmospheric pressure or under superatmospheric pressure, if desired, under an inert gas.

Excess sodium hydroxide in the remaining reaction mixture was neutralized with β-alanine. According to prior art methods, the beta-alanine is purchased. However, according to the present invention, the β-alanine used to neutralize excess sodium hydroxide in step (b) is obtained by ion exchange from part of the sodium β-alanine obtained in step (a) according to the present invention from The method itself. This side-step makes the whole process more economically attractive. Many suitable ion exchange resins are commercially available and can be used for this purpose.

In a column of appropriate diameter, the resin is regenerated with an aqueous mineral acid after loading the β-alanine salt solution onto the resin and washing the resin with demineralized water. Of course, the β-alanine used for neutralization can also be obtained from its sodium salt by adding an equivalent amount of acid (preferably an aqueous inorganic acid).

During the neutralization step of the method, large excesses of β-alanine should be avoided. This can be achieved by methods known in the art, for example by titration. Preferably, a 60% aqueous solution of sodium beta-alanine is obtained.

Removal of the remaining water from the sodium beta-alanine solution can be achieved at normal or reduced pressure according to methods known in the art, for example by azeotropic distillation using an entrainer or as described in US 4.258.210. If this particular two-step water removal method is used, it is advantageous to use a falling film evaporator in the first step and evaporate under reduced pressure to a residual water content of 5-15% (w/w), and A thin film evaporator is used in the second step at even lower pressure to evaporate to a residual water content of less than 0.5% (w/w), more preferably not more than 0.20% (w/w). The second evaporation step can be accomplished by stripping with nitrogen.

As a result of a two-step water removal process under reduced pressure, a highly pure melt of sodium β-alanine is obtained, which is dissolved in a C _1-8 alkanol (preferably methanol or ethanol after removal of the vacuum) ) to obtain a 1-40% (w/w) solution of sodium beta-alanine in such alkanols containing not more than 0.5%, preferably not more than 0.2% (w/w) of water . The terms "dissolved" and "dissolving" include "dispersed" and "dispersing", respectively.

The sodium beta-alaninate solution thus obtained or capable of being obtained thereby (which itself represents an aspect of the invention) may subsequently be reacted with R-pantolactone to give sodium pantothenate, which is optionally converted to Pantothenic acid or a salt thereof, preferably a calcium salt, does not require an additional crystallization step. The terms "solution" and "dissolution" include "dispersion/dispersion".

Calcium D-pantothenate or sodium D-pantothenate, which can subsequently be converted into calcium D-pantothenate, respectively, is obtained according to methods known per se or methods analogous thereto.

The desired calcium D-pantothenate can be obtained from these solutions in high yields and in a purity meeting specifications for human food applications, human vitamin preparations or preparation of pharmaceutical formulations.

The sodium β-alanine solution and calcium D-pantothenate obtained or obtainable according to the methods described above and in the following embodiments are an aspect of the present invention.

Finally, the use of calcium D-pantothenate obtained according to the methods described herein for the production of human food and animal feed applications, vitamin preparations and pharmaceutical formulations is also an aspect of the present invention.

Methods for the production of such human food and animal feed applications, vitamin preparations and pharmaceutical formulations are well known to those skilled in the art.

The invention is illustrated in more detail by the following examples. All percentages are on a w/w basis unless otherwise stated.

Example 1

Production of β-alanine sodium from β-aminopropionitrile

In a 63L stainless steel reaction tank, 13.34kg of demineralized water (MW=18.02, 740.29 moles, 2.6 equivalents) and 25.12kg of aqueous NaOH (50%) (NaOH: MW=40.00, 314.00 moles, 1.1 equivalents; water: MW=18.02 , 697.00 mol, 2.4 eq) mixture was heated to an internal temperature (IT) of 90°C. To this preheated mixture was added 20.02 g of β-aminopropionitrile (APN) (MW=70.09, 99.0 w/w%, 282.77 moles, 1.0 eq. ). The ammonia produced is absorbed in an external scrubber with 10% aqueous sulfuric acid.

After the addition of APN was complete, the reaction mixture was stirred at 90 °C IT for 45 min. The reaction mixture was then heated to reflux. 6.57 kg of water were distilled off from the reaction mixture under reflux. After 3.5 hours under distillation/reflux of water, the reaction mixture was analyzed by HPLC.

Results: β-alanine: 52.37w/w%; IDPA: 0.68w/w%; dipeptide: 0.02w/w%.

46.45 kg of the reaction mixture were obtained (96.7% yield by the above analysis). The reaction mixture was cooled to 30 °C IT and divided into two parts. Of which 40.88kg (88%) was directly used in the neutralization step, 5.57kg (12%) was diluted with 3.55kg demineralized water and used in the ion exchange step to produce β-alanine.

Example 2

Production of beta-alanine by ion exchange

The diluted reaction mixture (9.0 kg) produced in Example 1 was used in the ion exchange step for generating the β-alanine solution.

Analysis (HPLC): β-alanine: 32.01 w/w %; IDPA: 0.28 w/w %; dipeptide: 0.01 w/w %.

A 2.5m stainless steel column with a diameter of 5.3cm was packed with 4.5L of Rohm&Haas Amberlyst 15 (1.7mole/L, 7.65 mole), and washed with demineralized water before use. The Na-β-Ala feed solution was fed to the column at a flow rate of 300 g/min.

Using this particular apparatus, five cycles were performed with the feed solution. The column was regenerated with 10% sulfuric acid solution after each cycle and washed with water afterwards.

The major fractions containing β-alanine for neutralization from all five cycles were combined to give 9.76 kg. The recovery rate of β-alanine: 95.6%.

Analysis: β-alanine: 28.21 w/w %; IDPA: 0.35 w/w %; dipeptide: 0.01 w/w %; sodium (ion chromatography [IC]): 438 ppm.

Example 3

Precise neutralization of excess NaOH

In a 63 L stainless steel tank, 38.57 kg of the undiluted reaction solution obtained as described in Example 1 was neutralized with the exact amount of 7.12 kg of the β-alanine solution obtained in Example 2 with excess NaOH. The β-alanine solution was added during 30 minutes at IT at <27°C.

The required amount of beta-alanine solution was determined by titrating an aliquot of the reaction solution. Neutralization of β-alanine excess of 2.50% was considered optimal.

After addition of the β-alanine solution, the mixture was stirred for a further 15 minutes. 45.69 kg of neutralized solution were obtained.

Results: β-alanine: 48.26w/w%; IDPA: 0.67w/w%: dipeptide: 0.01w/w%.

As a result, an aqueous solution of 60.19% Na-β-Ala was obtained. The excess of β-alanine in the mixture was 0.22%.

Example 4

Removal of Water from Aqueous Sodium Beta-Alanine Solutions

5.59 kg/h of the sodium β-alaninate solution from Example 3 were fed to the falling film evaporator with circulation. The falling film evaporator operates under the following conditions;

Pressure: 175mbar. Falling film temperature: 150°C. Falling film bottom temperature: 100°C. Falling film cycle temperature: 120°C. Cycle: 20kg/h.

1.65 kg/h of water were distilled from the mixture in the falling film. The concentrate was fed directly to the thin-film evaporator via a sheathed tube (temperature 130°C). The concentrate had the following composition (HPLC for β-Ala and by-products, water in equilibrium):

Analysis: β-alanine: 66.75w/w%; IDPA: 2.11w/w%; dipeptide: 0.01w/w%; water: 14.61w/w%.

3.90 kg/h of concentrate were fed to the thin film evaporator. The thin film evaporator was run with the following parameters:

Pressure: 18mbar; film temperature: 160°C; film bottom temperature: 150°C.

0.55 kg/h of water were distilled from Na-β-Ala in a thin-film evaporator.

The molten sodium β-alanine from the thin-film evaporator was directly fed into a 63 L stainless steel dissolution tank containing 5.78 kg/h methanol. The temperature of the dissolution tank was adjusted to 5°C, resulting in an internal temperature of <25°C during dissolution of the melt.

9.16 kg/h of dried Na-β-Ala methanol solution was obtained from the dissolution tank.

Analysis: β-alanine: 28.67w/w%; IDPA: 1.41w/w%; dipeptide: 0.01w/w%; water: 0.19w/w%.

The calculated recovery for β-alanine was 99.0% for the overall two-step drying process.

This solution was directly used in the condensation reaction of sodium pantothenate.

Preparation of Calpan

100 g of dried Na-β-Ala methanol solution (321.8 mmole) was reacted with 41.9 g (321.8 mmole) of R-pantolactone to obtain a solution of sodium D-pantothenate.

Workup is carried out according to methods known to those skilled in the art, said workup comprising ion exchange from sodium to calcium.

Calpan product: 79.64 g, 163.93 mmole. Yield: 93.6%.

analyze:

Calcium pantothenate 98.09w/w%

Calcium pantothenate 0.59w/w%

pant-β-Ala-β-Ala Calcium 0.02w/w%

Water ad 100w/w%

Example 5

Removal of Water from Aqueous Sodium β-Alanine Solutions Using Nitrogen

This step uses a different aqueous sodium β-alanine solution. The starting material for water removal had an excess of 3.4% neutralization of β-alanine and was analyzed to contain: β-alanine: 46.41 w/w%; IDPA: 1.69 w/w%; dipeptide: 0.06 w/w%.

5.75 kg/h of this solution were fed to a falling film evaporator with circulation. Falling film evaporators operate under the following conditions:

Pressure: 175mbar. Falling film temperature: 150°C. Falling film bottom temperature: 100°C. Falling film cycle temperature: 120°C. Cycle: 20kg/h.

1.86 kg/h of water were distilled from the mixture in the falling film. The concentrate was fed directly to the thin-film evaporator via a sheathed tube (temperature 130°C). The concentrate had the following composition (HPLC for β-Ala and by-products, water in equilibrium):

Analysis: β-alanine: 68.59w/w%; IDPA: 1.94w/w%; dipeptide: 0.09w/w%; water: 11.55w/w%.

3.90 kg/h of concentrate were fed to the thin film evaporator. Thin film evaporators operate under the following conditions:

Pressure: 22mbar; film temperature: 160°C; film bottom temperature: 150°C.

Nitrogen feed at the bottom of the thin film evaporator: 30 L/h.

0.41 kg/h of water were distilled off in the thin-film evaporator. The molten sodium β-alanine from the thin film evaporator was directly added to a 63 L stainless steel dissolution tank containing 5.85 kg/h methanol. The temperature of the dissolution tank was adjusted to 5°C, resulting in an internal temperature of <25°C during dissolution of the melt.

9.27 kg/h of dried Na-β-Ala methanol solution was obtained from the dissolution tank.

Analysis: β-alanine: 28.82w/w%; IDPA: 1.28w/w%; dipeptide: 0.04w/w%; water: 0.09w/w%.

The calculated recoveries for β-alanine are quantitative for the overall two-step drying method. This solution was directly used in the condensation reaction of sodium pantothenate.

Preparation of Calpan

100 g of dried Na-β-Ala methanol solution (323.4 mmole) was reacted with 42.1 g (323.4 mmole) of R-pantolactone to obtain a solution of sodium D-pantothenate.

Workup is carried out according to methods known to those skilled in the art, said workup comprising ion exchange from sodium to calcium.

Calpan product: 79.78 g, 160.68 mmole. Yield: 92.9%.

analyze:

Calcium pantothenate 99.73w/w%

Calcium pantothenate 0.25w/w%

pant-β-Ala-β-Ala Calcium 0.08w/w%

Water ad 100w/w%

Example 6

Overneutralization of excess OH

In a 63 L stainless steel tank, 8.91 kg of β-alanine solution was used to neutralize the excess NaOH of 40.88 kg of the undiluted reaction solution (from the hydrolysis step performed in the same manner as in Example 1) containing: β-alanine, 51.80w/w%; IDPA n.a. and dipeptide, 0.17w/w%; the β-alanine solution was analyzed to contain: β-alanine, 26.91w/w%; IDPA n.a.; dipeptide, 0.03 w/w %; sodium (IC), 380 ppm.

The β-alanine solution was added during 30 minutes at IT at <27°C.

According to the titration, this is the neutralization of 21.5% of the beta-alanine excess.

After addition of the β-alanine solution, the mixture was stirred for a further 15 minutes. 49.49 kg of neutralized solution were obtained.

Results: β-alanine: 47.37w/w%, IDPA: 0.70w/w%, dipeptide: 0.02w/w%.

The excess of β-alanine in the mixture was 2.02w/w%.

Example 7

Removal of Water from Overneutralized Aqueous Sodium Beta-Alanine Solutions

7.29 kg/h of overneutralized sodium β-alaninate solution from Example 6 was fed to a falling film evaporator with circulation. Falling film evaporators operate under the following conditions:

Pressure: 175mbar. Falling film temperature: 150°C. Falling film bottom temperature: 100°C. Falling film cycle temperature: 120°C. Cycle: 20kg/h.

2.23 kg/h of water were distilled from the mixture in the falling film. The concentrate was fed directly to the thin-film evaporator via a sheathed tube (temperature 130°C). The concentrate had the following composition (HPLC for β-Ala and by-products, water in equilibrium):

Analysis: β-alanine: 64.16w/w%; IDPA: 0.34w/w%; dipeptide: 0.05w/w%; water: 13.49w/w%.

5.06 kg/h of concentrate were fed to the thin film evaporator. The thin film evaporator was run with the following parameters:

Pressure: 29mbar; film temperature: 160°C; film bottom temperature: 150°C.

Add nitrogen at the bottom of the thin film evaporator: 40L/h.

0.57 kg/h of water distilled off in the thin-film evaporator. The molten sodium β-alanine from the thin film evaporator was directly fed into a 63 L stainless steel dissolution tank containing 7.39 kg/h methanol. The temperature of the dissolution tank was adjusted to 5°C, resulting in an internal temperature of <25°C during dissolution of the melt.

11.69 kg/h of dried Na-β-Ala methanol solution was obtained from the dissolution tank.

Analysis: β-alanine: 27.02w/w%; IDPA: 0.29w/w%; dipeptide: 0.07w/w%; water: 0.15w/w%.

The calculated recovery for β-alanine was 91.5% for the overall two-step drying process.

This solution was directly used in the condensation reaction of sodium pantothenate.

Preparation of Calpan

100 g of dried Na-β-Ala methanol solution (303.3 mmole) was reacted with 39.5 g (303.8 mmole) of R-pantolactone to obtain a solution of sodium D-pantothenate.

Workup is carried out according to methods known to those skilled in the art, said workup comprising ion exchange from sodium to calcium.

Calpan product: 79.19 g, 160.06 mmole. Yield: 94.3%.

analyze;

Calcium pantothenate 96.32w/w%

Calcium pantothenate 0.14w/w%

pant-β-Ala-β-Ala calcium 0.16w/w% (significantly higher than in Examples 4 and 5)

Water ad 100w/w%

Example 8

Incomplete dipeptide degradation reaction, 1.1 N NaOH is not neutralized

21.7 g of sodium hydroxide pellets (540.2 mmole, 1.1 equiv) were dissolved in 45.1 g of demineralized water (2503.0 mmole, 5.1 equiv) at room temperature. The solution was heated to an IT of 90 °C. At this temperature the addition of 35.0 g of aminopropionitrile (490.5 mmole, 1.0 equiv) was started. The addition of the APN is done within 30 minutes. The reaction mixture was then stirred at 90° C. IT for 10.5 hours.

Analysis: β-alanine: 48.54w/w%; IDPA: 0.15w/w%; dipeptide: 0.21w/w%.

45.11 g of the reaction mixture (from a total of 93.5 g; 246.0 mmol sodium β-alanine) was placed in a rotary evaporator. At an incubation temperature of 60°C and a reduced pressure of 700-600 mbar, the remaining ammonia and most of the water were removed. A total of 147.4 g of n-butanol was added to the aqueous suspension in three portions. The n-butanol/water was azeotropically removed with a rotary evaporator after each n-butanol addition to yield 68.6 g of a waxy solid. The solid was dissolved in 49.5 g methanol.

Analysis: β-alanine: 19.13w/w%; IDPA: 0.05w/w%: dipeptide: 0.07w/w%; water 0.20w/w%. 253.9 mmole β-alanine, yield: 103.2%

Preparation of Calpan

110.5 g of dried Na-β-Ala methanol solution (237.4 mmole) was reacted with 31.2 g (237.3 mmole) of R-pantolactone to obtain a sodium D-pantothenate solution.

Workup is carried out according to methods known to those skilled in the art, said workup comprising ion exchange from sodium to calcium.

Calpan product: 56.71 g, 110.00 mmole. Yield: 83.2%.

analyze:

Calcium pantothenate 92.72w/w%

Calcium pantoate 3.06w/w% (obviously higher than in Examples 4, 5, and 7)

pant-β-Ala-β-Ala calcium 0.19w/w% (obviously higher than in Examples 4 and 5)

Water ad 100w/w%

Claims (7)

1. one kind can be used for being condensed into the R-pantolactone the improving one's methods of Beta-alanine sodium of D-pantothenate by the preparation of beta-amino-propionitrile, and described method obtains the Beta-alanine sodium as alcoholic solution, and its improvement comprises

(a) in alkaline aqueous medium or alcohol/water mixture, carry out the hydrolysis of beta-amino-propionitrile, then

(b) be alcohol with solvent replacing, make final Beta-alanine salt mixture only contain by product or byproduct with the amount that D-pantothenate quality is had no adverse effect.

2. according to the improving one's methods of claim 1, wherein said improvement comprises:

(a) under 60-95 ℃ temperature, in the solution in water or alcohol/water of excessive sodium hydroxide, add beta-amino-propionitrile, further heated mixt also removes and anhydrates when needing;

(b) use in the Beta-alanine and excessive sodium hydroxide, avoid the significantly excessive of Beta-alanine, have the solution of expectation concentration with direct acquisition;

(c) remove water and

(d) Beta-alanine sodium is dissolved in C _1-8In-the alcohol, obtain to have the solution of Beta-alanine sodium in alcohol of expectation concentration.

3. the method for claim 2, it is characterized in that, the neutral Beta-alanine that is used for step (b) is by the following described method self that derives from: the part by the Beta-alanine sodium that obtains in the step (a) obtains by ion-exchange, perhaps obtains by the part with this Beta-alanine sodium of acidifying of equivalent.

4. obtain maybe the Beta-alanine sodium solution that can obtain by each method of claim 1 to 3 by each method in the claim 1 to 3.

5. each method in the claim 1 to 3, wherein Beta-alanine sodium alcoholic solution and the reaction of R-pantolactone according to claim 1 (b) or claim 2 (d) acquisition obtains sodium pantothenate, and described sodium pantothenate randomly is converted into other pantothenate and does not need extra crystallisation step.

6. obtain or can pass through the calcium pantothenate of the method acquisition of claim 5 by the method for claim 5.

7. according to the method acquisition of claim 5 or the purposes of calcium pantothenate in producing people's food and animal-feed application, vitamin preparation and pharmaceutical formulation that can obtain according to the method for claim 5.