WO2015097717A2

WO2015097717A2 - AN IMPROVED PROCESS FOR THE PREPARATION OF β-CAROTENE

Info

Publication number: WO2015097717A2
Application number: PCT/IN2014/000795
Authority: WO
Inventors: Satyanarayana Chava; Seeta Rama Anjaneyulu GORANTLA; Venkata Lakshmi Narasimha Rao Dammalapati; Harikrishna MUDDULURU; Munishekar Reddy SANNAREDDY
Original assignee: Laurus Labs Private Limited
Priority date: 2013-12-23
Filing date: 2014-12-23
Publication date: 2015-07-02
Also published as: WO2015097717A3

Abstract

The present invention relates to an improved process for the preparation of β-carotene having pharmaceutically acceptable level of residual solvent content.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF β -CAROTENE

PRIORITY This application claims the benefit under Indian Provisional Application No. 6033/CHE/2013, filed on December 23, 2013, the content of which is incorporated by reference herein.

FIELD OF THE INVENTION

The present invention generally relates to an improved process for preparation of β-carotene having pharmaceutically acceptable level of residual solvent content.

BACKGROUND OF THE INVENTION

Carotenoid compounds are characterized by the conjugated polyene chains and some of the representative examples are β-carotene, lycopene, and astaxanthin etc. β-carotene have found not only in the industrial applications as animal feeds and colorants for foodstuffs but also in the medicinal applications due to its prophylaxis effects on certain cancers by selectively reacting with cancer suspects such as singlet oxygen and radicals. Therefore, β-carotene has been widely utilized as food additives and nutraceuticals.

It is known that carotenoids, such as β-carotene, are prepared inter alia by double Wittig reaction of a Cis phosphonium salt (Ci₅— P) with a symmetrical C[₀ dialdehyde (Carotenoids, Vol. 2, page 89 et seq., Birkhauser Verlag, 1996).

C₁₅-P + Beta Carotene

- Carotenoids have a typical property of incorporating solvents in non-stoichiometric amounts. The thermal stability of carotenoids is, however, critical and therefore the removal of the incorporated traces of solvent is difficult and generally can be realized only at the expense of the commencement of decomposition.

According to the description of U.S. Patent No. 5,654,488, process for the preparation of carotenoids as described in EP05748A2 & several publications i.e. Helv. Chim. Acta 64, 1981 ; cf. pages 2405-18; 2436-46 and 2447-62 involves witting reaction of asta-Ci₅- triarylphosphonium salt with Cio-dial in halohydrocarbon such as methylene chloride or chloroform as a solvent. Further disclosed the possibility of adduct formation by final product with methylene chloride or having higher amount of methylene chloride as a residual solvent. Hence provides alternate process which avoids the usage of methylene chloride and involves the usage of methanol, ethanol or mixtures thereof with water in the aforementioned reaction.

The disclosed process for the synthesis of Astaxanthin in U.S. Patent No. 5,654,488 involves Wittig reaction of symmetrical dialdehyde with two moles of triphenyl phosphonium salt in methanol, ethanol, or mixture of any of these solvents with water and heating the heterogenous reaction mass to obtain a solution before reacting with a base, wherein the product astaxanthin is precipitated by simply adding water. Later US patent No. US 6,150,561 also indicate the possibility of formation higher level of residual solvent when methylene chloride or chloroform used in the witting reaction. To overcome this difficulty of trapping residual solvents, this patent provides a process for the manufacture of carotenoids by Wittig reaction of a symmetrical dialdehyde with two moles of triarylphosphonium salt in a polar reaction medium wherein less than about 10% by weight of the reactants and the carotenoids thus formed are dissolved in the reaction medium during the reaction process, which is at all times substantially heterogeneous.

In general, organic solvents are frequently used during processing of chemical materials and subsequent removal of solvents is one of the key steps for the production of pure chemical products. Drying is typically used, but in some cases it is difficult to remove residual solvents by drying especially if the drying process is hampered by thermal instability of the desired chemical product. It is necessary to avoid the formation or reducing the level of such residual solvents within the limits prescribed by ICH guideline by varying the process parameters.

The processes known in the art such as in US 5,654,488 and US 6,150,561 provides alternate process for the preparation of β-carotene to avoid the formation of residual solvent only by avoiding the solvent itself. There is a need in the art for an improved process for the preparation of β-carotene with a residual solvent content limit that will comply with the ICH guideline with process modifications still using halohydrocarbons such as methylene chloride as a solvent.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for preparation of β-carotene having pharmaceutically acceptable level of residual organic solvents, which comprise of reacting a symmetrical dialdehyde and two equivalents of a Wittig salt in a suitable organic solvent in presence of a base to provide β-carotene of formula (I). In one embodiment, the present invention provides a process for the preparation of β-carotene of formula (I),

comprises of reacting the symmetrical dialdehyde compound of formula (II) and Wittig salt compound of formula (III)

wherein Ri, R₂ and R₃ are same or different and are selected from an alkyl, cycloalkyl, aryl or arylalkyl and X is an anion of strong acid; in the presence of an appropriate base in a suitable solvent selected from esters, ethers, hydrocarbons selected from the group consisting of aromatic hydrocarbons, C_5-8 linear, branched or cyclic hydrocarbons, halogenated hydrocarbons and the like, to obtain β-carotene of formula (I).

In another embodiment, the present invention provides a process for the preparation of β-carotene of formula (I), comprising:

a) reacting symmetrical dialdehyde compound of formula (II) and Wittig salt compound of formula (III) in presence of a suitable base in a suitable organic solvent;

b) separating the organic layer from the reaction mixture;

c) adding the organic layer of step b) to water at about 35°C to about 95 °C and simultaneously removing the organic solvent; and

d) isolating the β-carotene of formula (I).

i) providing a solution of β-carotene in a suitable organic solvent;

ii) adding the step a) solution to water at about 35°C to about 95°C and , simultaneously removing the organic solvent; and

iii) isolating the β-carotene of formula (I).

b) separating the organic layer from the reaction mixture; c) adding the organic layer of step b) to water at about 35°C to about 95°C and simultaneously removing the organic solvent;

d) isolating the β-carotene of formula (I);

e) treating the β-carotene in suitable solvent under nitrogen pressure at temperature of about 100°C to about 140°C, and

f) isolating the trans isomer of β-carotene.

In another embodiment, the present invention provides a process for the preparation of trans β-carotene of formula (I), comprising: treating the β-carotene in suitable solvent under nitrogen pressure at temperature of about 100°C to about 140°C, and isolating the trans isomer of β-carotene.

In another embodiment, the present invention provides a process for preparation of β-carotene, comprising:

a) reacting symmetrical dialdehyde compound of formula (II) and Wittig salt compound of formula (III) in presence of a suitable base in a suitable organic solvent,

b) separating the organic layer from the reaction mixture,

c) adding the organic layer of step b) to water at about 35°C to about 95°C and simultaneously removing the organic solvent,

d) isolating the β-carotene of formula (I),

e) treating the β-carotene in suitable solvent under nitrogen pressure at temperature of about 100°C to about 140°C,

f) isolating the trans isomer of β-carotene, and

g) purifying the trans isomer of β-carotene in ester solvent to obtain pure trans isomer of β-carotene.

In another embodiment, the present invention provides a process for purification of β-carotene, comprising:

a) providing a solution of β-carotene in ester solvent at a suitable temperature, b) stirring the solution at a temperature of about 40°C to about reflux temperature, c) cooling the solution to less than 35°C, and

d) filtering the pure β-carotene.

In another embodiment, the present invention provides β-carotene of formula (I) having relatively low content of one or more organic volatile impurities.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation β-carotene having pharmaceutically acceptable level of residual organic solvents. In one embodiment, the present invention provides a process for the preparation of β-carotene of formula (I),

comprising:

a) reacting symmetrical dialdehyde compound of formula (II) and Wittig salt compound of formula (III)

wherein R_{l s} R₂ and R₃ are same or different and are selected from an alkyl, cycloalkyl, aryl or arylalkyl and X is an anion of strong acid; in presence of a suitable base in a suitable organic solvent;

b) separating the organic layer from the reaction mixture;

d) isolating the crude β-carotene of formula (I).

Examples of the lower alkyl group in the Wittig salt compound of formula (III) include a (C₁-C5) straight or branched chain alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl group, n-pentyl group, i-pentyl group, neo-pentyl group and the like.

Examples of the aryl group in the Wittig salt compound of (III) include substituted or unsubstituted phenyl, tolyl and naphthyl.

Specific examples of the group of formula: PR]R₂R₃ in the Wittig salt compound of formula (III) includes triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine, trihexylphosphine, triphenylphosphine, tri-(o-tolyl)phosphine and the like, preferably triphenylphosphine.

Examples of the anions are those of acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, sulfonic acids, formic acid and acetic acid; particularly chloro. bromo, iodo, methane sulfonyl, ethane sulfonyl, trifluoromethane sulfonyl, benzene sulfonyl, fluoroacetyloxy, trifluoroacetyloxy, more preferably bromo. The starting compound symmetrical dialdehyde compound of formula (II) can be prepared by any known methods, for example the dialdehyde compound may be obtained according to U.S. patent number US 5,107,030 and US 5,276,209. The Wittig salt compound of formula (III) can be prepared by any known methods, for example the Wittig salt may be obtained according to U.S. patent number US 3,347,932 and US 4,182,731.

Step a) of the foregoing process involves reaction of symmetrical dialdehyde compound of formula (II) with Wittig salt compound of formula (III) in presence of a base in an organic solvent, preferably the wittig salt used in formula (III) is triphenylphosphonium bromide.

The organic solvent used herein is selected from but are not limited to an ethers such as diethyl ether, diisopropyl ether and the like; an esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate and the like; aromatic hydrocarbons such as benzene, toluene, chlorobenzene and the like; C_5-8 linear, branched or cyclic hydrocarbons such as pentane, hexane, heptane, cyclohexane and the like; halogenated hydrocarbons such as chloroform, methylene chloride, ethylene chloride, carbon tetrachloride and the like and mixtures thereof; preferably halogenated hydrocarbons; more preferably methylene chloride.

The base used herein is selected from alkali metal alkoxide such as potassium methoxide, potassium ethoxide, potassium n-butoxide, potassium t-butoxide, sodium methoxide, sodium ethoxide, sodium n-butoxide, sodium t-butoxide and the like; an alkali metal hydroxide such as lithium hydroxide, potassium hydroxide, sodium hydroxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like. An epoxide such as an ethylene oxide or 1 ,2-butene oxide may be used instead of the base. Preferably the base is alkali metal alkoxide; more preferably sodium methoxide.

Further the base can be used in an amount of about 0.5 to about 3 equivalents of the starting dialdehyde compound of formula (II), preferably about 2.5 equivalents. It is possible in this connection either to introduce both starting compounds (Wittig salt and dialdehyde) into the solvent and add the base thereto or else add the base to a solution of the Wittig salt, and then add a solution of the aldehyde.

The reaction may be advantageously carried out at a suitable temperature at about 20°C to about reflux temperature. Preferably, the reaction is carried out at about 20°C to about 40°C. The reaction is allowed to stir for a period of time from about 30 min to until completion of the reaction, preferably for 1 hr to 4 hr.

Step b) of the foregoing process involves the separation of organic layer from the reaction mixture and washing the organic layer with water. Preferably, before the separation of organic layer, aqueous ammonium chloride was added to step a) reaction mass, after reaction completion. Then reaction mass optionally filtered through celite bed to remove any extraneous matter. Step c) of the foregoing process involves addition of organic layer to water at a temperature of about 35°C to about 95°C, preferably at about 75°C to about 90°C, taken in a separate flask arranged with downward distillation setup under slow purge of nitrogen. Preferably, the water may be pre-heated to about 60°C to about 90°C before the addition of organic layer.

Preferably, the organic solvent present in the reaction mass may be removed simultaneously during the addition of organic layer to water by distillation under atmospheric pressure or reduced pressure. Preferably, the reaction mass may be further heated to a temperature of about 80°C to about 100°C, more preferably at about 85°C to about 95°C, for removal of traces of organic solvent after completion of organic layer addition step c).

Addition of organic layer to water at about 35°C to about 95°C and simultaneous removal of solvent by distillation avoids the possibility of formation of residual solvent formation or adduct with the final product, as the final product is precipitated out from the water at about 70°C to about 95 °C. This step is the advantageous of the present invention over the prior art process thereby reducing the formation of residual solvent in the final product; preferably, restricting the residual content of methylene chloride in β-carotene.

Step d) of the foregoing process involves isolation of the β-carotene from the step c) by filtration. Prior to filtration, the reaction mass may be diluting with a suitable organic solvents to solubilizing the unwanted by-products, if any formed during the reaction such as triphenylphosphine oxide and other inorganic salt, which are removed along with organic solvent as mother liquors. The obtained solid product may be optionally dried.

Examples of suitable organic solvents used for the removal of triphenylphosphine oxide and other inorganic salts include but are not limited to methanol, ethanol, n-propanol. isopropanol, n-butanol, tert-butanol, acetone, tetrahydrofuran, dimethylformamide and dimethylsulfoxide; preferably methanol.

After addition of suitable organic solvents to step c), the resultant solution may be stirred for about 1 to 4 hours preferably for an hour, at reflux temperature and then allowed to cool to room temperature (about 25 °C to about 35°C). The resultant product may be isolated by techniques known in the art, for example, filtration, to obtain β-carotene. The temperature during the filtration may range from temperature at about 20°C to about 35°C.

The resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 70°C over a period of about 3 hours to about 12 hours, preferably drying can be carried out at a temperature of about 60°C to about 65°C over a period of about 4 hours.

The resultant product, β-carotene obtained by the process of the present invention is having less content of organic solvent, preferably methylene chloride. This is due to the incorporation of step of simultaneous removal of organic solvent used in the reaction, during the step of quenching the reaction mass in to water. Simultaneous removal of organic solvent during the quenching stage avoids the availability of organic solvent for trapping it in to product. β-carotene thus obtained may be isomerized in to Trans isomer by treating it with a suitable solvent.

In another embodiment, the present invention provides a process for the preparation of trans β-carotene of formula (I), comprising: treating the β-carotene in a suitable solvent under nitrogen pressure at temperature of about 100°C to about 140°C, and isolating the trans isomer of β-carotene.

Starting β-carotene may be prepared by any process known in the art or it can be obtained by the process described just as above. The suitable solvent used herein for isomerization is selected from Ci-C₈ alcohols like methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tert-butanol, pentanol, hexanol, heptanol or octanol; hydrocarbons like heptane, hexanes; water and mixtures of these solvents. Preferably the suitable solvent is methanol or mixture of n-butanol and methanol and more preferably methanol. The isomerization step may be carried out under nitrogen pressure at a temperature of about 100°C to about 140°C, preferably at about 120°C to about 130°C. The reaction may be advantageously carried out under a closed vessel at a pressure of about 3 Kg/Cm² to about 10 Kg/Cm².

All trans- -carotene thus obtained may be isolated by methods known in the art; for example, cooling the reaction mass to less than 35°C followed by filtering the product. The resultant product may optionally be further dried by the methods known in the art. The all trans-P-carotene obtained may be optionally purified with a suitable ester solvent.

d) filtering the pure β-carotene. The starting β-carotene may be obtained by any process known in the art or obtained by the process described as above or may be obtained directly from the previous processing steps, preferably β-carotene obtained by the process of the invention.

The suitable ester solvent used herein for purification is include but are not limited to methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate and the like and mixtures thereof.

The suitable temperature for step a) of providing the solution of β-carotene in ester solvent is at about 40°C to about reflux temperature; preferably at about 65°C to about 80°C.

The solution of β-carotene in ester solvent preferably in ethyl acetate is stirred for about 30 min to about 5 hours, preferably for an hour at the same temperature. Then the solution may be allowed cool to less than 35°C to precipitation followed by filtration to obtain pure β-carotene.

It has been observed that when β-carotene was isolated by simply concentrating the organic solvent containing the product as per the reported processes, the residual solvent content of the solvent used is relatively high in comparison to allowable limits setforth in ICH guidelines. Further co-distillation with another solvent also not yielded desired level of residual content. It has been surprisingly found that removal of residual solvent is remarkably enhanced by adding organic solvent containing β-carotene to pre-heated water and simultaneously distilling out the organic solvent. For carotenoids it is all the more surprising, since this class of substance tends to form non-stoichiometric inclusions with organic solvents.

An important advantage of the present invention as compared to known processes for the isolation of β-carotene is the reduction of the residual solvent content. As a consequence, substantially no solvent is incorporated in the crystal lattice of the resulting β-carotene.

In accordance with another embodiment, the present invention provides β-carotene, obtained by the processes described herein, having relatively low content of one or more organic volatile impurities. The present invention provides β-carotene obtained using the process as described herein, may have a residual solvent content that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The guideline solvent level depends on the type of solvent but is not more than about 5000 ppm, or about 4000 ppm, or about 3000 ppm.

The present invention provides a β-carotene, obtained by the process disclosed herein, having less than about 500 parts per million (ppm) methanol, ethanol, preferably less than about 100 ppm; less than about 400 ppm of isopropanol, preferably less than about 200 ppm; less than about 500 ppm of methylene chloride, preferably less than about 200 ppm; less than about 300 ppm of toluene, preferably less than about tOO ppm; less than about 500 ppm of acetone, preferably less than about 100 ppm; less than about 500 ppm of ethyl acetate, preferably less than about 100 ppm; less than about 500 ppm of tetrahydrofuran, preferably less than about 100 ppm; less than about 500 ppm of n-heptane, preferably less than about 100 ppm and having less than about 5000 ppm of n-butanol, preferably less than about 100 ppm.

The present invention further provides β-carotene, obtained by the process disclosed herein, having less than about 85 ppm methanol, less than about 100 ppm isopropanol, less than about 100 ppm methylene chloride, less than about 80 ppm acetone, less than about 100 ppm of n-butanol, less than about 60 ppm of ethyl acetate and less than about 15 ppm of each of tetrahydrofuran, toluene and n-heptane.

In a preferred embodiment, the present provides β-carotene contains less than about 100 ppm methanol; less than about 15 ppm isopropanol; less than about 15 ppm methylene chloride; less than about 15 ppm toluene; less than about 70 ppm acetone; less than 60 ppm ethyl acetate; less than 15 ppm n-heptane, less than 15 ppm tetrahydrofuran or less than 15 ppm n-butanol.

EXAMPLES

The present invention is further illustrated by the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Comparative Example:

[(2E,4E)-3-methyl-5-(2,6,6-trimethyl-l -cyclohexenyl)-2,4-pentadienyl]triphenyl- phosphonium bromide (376 g), 2, 7-dimethyl-2,4,6-octatrien-l, 8-dial (50 g) was added to methylene chloride (2000 mL) at 0°C to -5°C and stirred for 15 min. Sodium methoxide solution (82.3 g) was added to the reaction mass in 30 mins at 0°C to -5°C and reaction mass temperature was raised to 30-35°C then stirred for 2 hr. After reaction completion, 20% ammonium chloride solution (750 mL) was added and stirred for 15 min. The reaction mass was settled; organic and aqueous layers were separated, then organic layer washed with water. Separated organic layer was distilled off; isopropanol (500 mL) was added to the remaining mass and then co-distilled with isopropanol. The reaction mass was cooled to 70°C, isopropanol (250 mL) was added and refluxed for 2 hr. Then the reaction mass was cooled to 25-35°C, filtered off the solid, washed with isopropanol and suck dried. The obtained solid was added to n-butanol (450 ml), heated to 1 14-1 18°C and stirred for an hour. Then the reaction mass was cooled to 48-52°C and methanol (1500 mL) was added in to the reaction mass in 30 min. The reaction was stirred for 30 min at 48-52°C then cooled to 25-35°C. The solid obtained was filtered, washed with methanol and suck dried for an hour.

The above obtained compound was added to DM water (1500 mL), heated to 85-95°C and stirred for an hour at reflux. Then the reaction mass was cooled to 25-35°C, filtered off the solid, washed with water, suck dried for an hour and finally dried under vacuum at 40-45°C for 4 hr to get 65 g of β-carotene.

Total isomer content by HPLC: 98.36%.

Residual solvents:

Methylene chloride: 2374 ppm

n-butanol: 12223 ppm

isopropanol: 3350 ppm

Example 1:

[(2E,4E)-3-methyl-5-(2,6,6-trimethyl-l-cyclohexenyl)-2,4-pentadienyl]triphenyl- phosphonium bromide (182.8 g), 2, 7-dimethyl-2,4,6-octatrien-l , 8-dial (25 g) was added to methylene chloride (1000 mL) at 15-25°C and stirred for 15 min. Sodium methoxide solution (20.53g/82.1 mL) was added to the reaction mass in 2 hr at 15-25°C then stirred

U for 3 hr at 25-35°C. After reaction completion, 10% ammonium chloride solution (500 mL) was added to the reaction mass at 25-35°C and stirred for 15 min. The reaction mass was filtered through celite and washed with methylene chloride. The organic and aqueous layers were separated from filtrate and separated organic layer was washed with water. In another flask arranged with downward distillation, DM water (625 mL) was added and heated to 75-80°C. The above separated organic layer was added into the hot water under slow purge of nitrogen at 75-80°C and simultaneously solvent from the reaction mass was distilled off. The reaction mass was further heated to 85-95°C and maintained for 30 min to remove of methylene chloride traces by distillation under slow nitrogen purging. Then the reaction mass was cooled to 50°C, methanol (1250 mL) was added and stirred for an hour at reflux. The reaction mass was cooled to 25-35°C. The solid obtained was filtered, washed with methanol, suck dried for an hour and finally dried at 60-65°C under vacuum for 4 hr. The above dried material was added into n-butanol (250 mL) at 25-35°C, heated the reaction mass to 100-105°C and stirred for an hour at reflux. The reaction mass was cooled to 45-55°C and methanol (750 mL) was added to it. Then the reaction mass was heated to 65-70°C and stirred at reflux for an hour. Finally the reaction mass was cooled to 25-35°C, filtered off the solid, washed with methanol and suck dried for an hour. The solid was further dried under vacuum at 60-65 °C for 6 hr to get 65 g of β-carotene. Total isomer content by HPLC: 99.22%.

Residual solvents:

"ND" represents Not Detected (15 ppm) Example 2:

[(2E,4E)-3-methyl-5-(2,6,6-trimethyl-l-cyclohexenyl)-2,4-pentadienyl]triphenyl- phosphonium bromide (146.2 g), 2,7-dimethyl-2,4,6-octatrien-l , 8-dial (20 g) was added to methylene chloride (800 mL) at 15-25°C under nitrogen atmosphere and stirred for 15 min. Sodium methoxide solution (16.47 g/ 66 mL) was added to the reaction mass in 2 hr at 15-25°C and stirred for 2 hr at 25-35°C. After reaction completion, 10% ammonium chloride solution (400 mL) was added to the reaction mass at 25-35 °C and stirred for 15 min. The reaction mass was filtered through celite and washed with methylene chloride. The organic and aqueous layers were separated from filtrate and the separated organic layer was washed with water. In another flask arranged with downward distillation, DM water (500 mL) was added and heated to 80-90°C under slow nitrogen purging. The above separated organic layer was added into the hot water under slow purge of nitrogen at 80-90°C and simultaneously solvent from the reaction mass was distilled off. The reaction mass was further heated to 85-95°C and maintained for 30 min to remove of methylene chloride traces by distillation under slow nitrogen purging. Then the reaction mass was cooled to 50°C, methanol (1000 mL) was added and stirred for an hour at reflux. The reaction mass was cooled to 25-35°C. The solid obtained was filtered, washed with methanol, suck dried for an hour and finally dried at 60-65 °C under vacuum for 4 hr.

The above dried material was added to methanol (600 mL) in an autoclave vessel at 25-35°C under nitrogen pressure. The reaction mass was heated to 120-130°C under nitrogen pressure of about 8 Kg/Cm² and maintained for 12 hr. Then the reaction mass was cooled 25-35°C. The solid obtained was filtered, washed with methanol and suck dried for an hour under vacuum under nitrogen atmosphere. The dried material was added to ethyl acetate (160 mL) at 25-35°C under slow nitrogen purging. The reaction mass was heated to 65-75°C and stirred for an hour, then cooled to 25-35°C. The obtained solid was filtered off, washed with ethyl acetate, suck dried for an hour and finally dried at 60-65°C under vacuum for 6 hr to get 54 g of β-carotene.

Total isomer content by HPLC: 98.96%

Residual solvents:

"ND" represents Not Detected ( 15 ppm)

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

Claims

WE CLAIM:

wherein Ri, R₂ and R₃ are same or different and are selected from an alkyl, cycloalkyl, aryl or arylalkyl and X is an anion of strong acid; in the presence of a suitable base in a suitable organic solvent;

b) separating the organic layer from the reaction mixture;

d) isolating the β-carotene of formula (I).

Claim 2: The process of claim 1, wherein the Wittig salt compound of formula (III) is selected from the group consisting of triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine, trihexylphosphine, triphenylphosphine and tri-(o- tolyl)phosphine.

Claim 3: The process of claim 1, wherein the 'X' is selected from the group consisting of chloro, bromo, iodo, methane sulfonyl, ethane sulfonyl, tnfluoromethane sulfonyl, benzene sulfonyl, fluoroacetyloxy and trifluoroacetyloxy.

Claim 4: The process of claim 1 , wherein the Wittig salt is triphenylphosphonium bromide.

Claim 5: The process of claim 1, wherein the organic solvent is selected from the group consisting of ethers, esters, aromatic hydrocarbons, C₅-₈ linear, branched or cyclic hydrocarbons, halogenated hydrocarbons and mixtures thereof.

Claim 6: The process of claim 5, wherein the organic solvent is selected from the group comprising diethyl ether, diisopropyl ether, methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, benzene, toluene, chlorobenzene, pentane, hexane, heptane, cyclohexane, chloroform, methylene chloride, ethylene chloride, carbon tetrachloride and mixtures thereof.

Claim 7: The process of claim 6, wherein the organic solvent is methylene chloride.

Claim 8: The process of claim 1 , wherein the base is selected from the group consisting of alkali metal alkoxide, alkali metal hydroxide, alkali metal hydrides and mixtures thereof.

Claim 9: The process of claim 8, wherein the base is selected from the group consisting of potassium methoxide, potassium ethoxide, potassium n-butoxide, potassium t-butoxide, sodium methoxide, sodium ethoxide, sodium n-butoxide, sodium t-butoxide, lithium hydroxide, potassium hydroxide, sodium hydride and potassium hydride.

Claim 10: The process of claim 9, wherein the base is sodium methoxide.

Claim 1 1 : The process of claim 1, wherein the step a) reaction is carried out at a temperature of about 20°C to reflux temperature.

Claim 12: The process of claim 1 1 , wherein the temperature is about 20°C to about 40°C. Claim 13: The process of claim 1 , wherein the addition of organic layer to water is carried out at a temperature about 75 °C to about 90°C.

Claim 14: The process of claim 1 , wherein the water is pre-heated to about 60°C to about 90°C prior to addition of organic layer.

Claim 15: The process of claim 14, wherein the water is pre-heated to about 75°C to about 90⁶C.

Claim 16: The process of claim 1 , wherein the removal of organic solvent is carried out by distillation.

Claim 17: The process claim 16, wherein the distillation is carried out under atmospheric pressure or reduced pressure. Claim 18: The process of claim 1 , wherein the step d) further comprising: adding suitable organic solvent to the step c), heating to about reflux temperature, cooling to room temperature and filtering the β-carotene. Claim 19: The process of claim 18, wherein the suitable organic solvent is methanol.

Claim 20: An improved process for the preparation of β-carotene of formula (I), comprising:

i) providing a solution of β-carotene in a suitable organic solvent,

ii) adding the step i) solution to water at about 35°C to about 95°C and simultaneously removing the organic solvent; and

iii) isolating the β-carotene of formula (I).

Claim 21 : The process of claim 20, wherein the suitable organic solvent is selected from the group comprising diethyl ether, diisopropyl ether, methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, benzene, toluene, chlorobenzene, pentane, hexane, heptane, cyclohexane, chloroform, methylene chloride, ethylene chloride, carbon tetrachloride and mixtures thereof.

Claim 22: The process of claim 21 , wherein the organic solvent is methylene chloride. Claim 23: The process of claim 20, wherein the addition of step i) solution to water is carried out at a temperature about 75°C to about 90°C.

Claim 24: The process of claim 20, wherein the water is pre-heated to about 75°C to about 90°C.

Claim 25: The process of claim 20, wherein the removal of organic solvent is carried out by distillation.

Claim 26: An improved process for preparation of β-carotene, comprising:

a) preparing β-carotene of formula (I) according to claims 1-25 or obtained by any process,

b) treating the β-carotene in suitable solvent under nitrogen pressure at temperature of about 100°C to about 140°C,

c) isolating the trans isomer of β-carotene, and

d) purifying the trans-isomer of β-carotene in ester solvent to obtain pure trans isomer of β-carotene.

Claim 27: The process of claim 26, wherein the suitable solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tert-butanol, pentanol, hexanol, heptanol, octanol, heptane, hexanes; water and mixtures of these solvents. Claim 28: The process of claim 27, wherein the suitable solvent is methanol.

Claim 29: The process of claim 26, wherein the step b) reaction is carried out in a closed vessel.

Claim 30: The process of claim 29, wherein the reaction is carried out at a

2 2

Nitrogen pressure of about 3 Kg/Cm to about 10 Kg/Cm .

Claim 31 : The process of claim 26, wherein the step b) reaction is carried out at temperature of about 120°C to about 130°C.

Claim 32: The process of claim 26, wherein the isolation is carried out by cooling the solution of step b) to less than 35°C followed by filtration. Claim 33: The process of claim 26, wherein the ester solvent is selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate and mixtures thereof.

Claim 34: A process for purification of β-carotene, comprising:

d) filtering the pure β-carotene. Claim 35: The process of claim 34, wherein the ester solvent is selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate and mixtures thereof.

Claim 36: The process of claim 35, wherein the ester solvent is ethyl acetate.

Claim 37: The process of claim 34, wherein the suitable temperature in step a) is about 40°C to reflux temperature.

Claim 38: The process of claim 37, wherein the temperature is at about 65°C to about 80°C.

Claim 39: A process for the preparation of β-carotene, comprising:

a) reacting symmetrical dialdehyde compound of formula (II) and Wittig salt compound of formula (III) in presence of sodium methoxide in methylene chloride,

b) separating the organic layer from the reaction mixture, c) adding the organic layer of step b) to water at about 35°C to about 95°C and simultaneously removing the methylene chloride,

d) adding methanol to the step c) and stirring at reflux temperature,

e) cooling to about 25°C to about 35°C,

f). filtering the β-carotene of formula (I),

g) treating the β-carotene in methanol under nitrogen pressure at temperature of about 120°C to about 130°C in a closed vessel at 3 Kg/Cm² to about 10 Kg/Cm², h) isolating the trans isomer of β-carotene, and

i) purifying the trans isomer of β-carotene in ethyl acetate to obtain trans isomer of β-carotene.

Claim 40: β-carotene contains less than about 100 ppm methanol; less than about 15 ppm isopropanol; less than about 15 ppm methylene chloride; less than about 15 ppm toluene; less than about 70 ppm acetone; less than 60 ppm ethyl acetate; less than 15 ppm n-heptane, less than 15 ppm tetrahydrofuran or less than 15 ppm n-butanol.