ITMI20110580A1 - USEFUL INTERMEDIATES FOR THE PREPARATION OF FOSPROPOFOL AND PROCESS FOR THEIR PREPARATION - Google Patents

Description

Patent application for industrial invention entitled:

"Useful intermediates for the preparation of fospropofol and the process for their preparation"

DESCRIPTION

The present invention relates to an intermediate useful for the synthesis of fospropofol and a process for its preparation.

Fospropofol is an intravenously administered sedative-hypnotic prodrug of propofol used as an anesthetic agent. Fospropofol is metabolized in the liver by the alkaline phosphatase enzyme into the active metabolite propofol, which induces the sedative effect by enhancing the activity of the GABAA receptor by slowing the time of channel closure, it also acts as a blocker of sodium channels and recent research has involvement of the endocannabinoid system was also shown. Being water-soluble, fospropofol causes less pain during intravenous administration in the patient, reduced occurrence of hyperlipidemia during long-term administration and low incidence of bacteremia; moreover, the plasma levels of the active metabolite after its administration are lower than an equipotent dose of propofol, also giving a more sustained clinical effect. All these features make it optimal for use in endoscopic procedures, such as esophagogastroduodenoscopy, colonoscopy and bronchoscopy. Often fospropofol is given in combination with an opioid, such as fentanyl.

Fospropofol is a compound of formula (I)

<0> 2Na

chemically known as 2,6-diisopropylphenoxymethyl-phosphoric acid disodium salt, described in US6451776 and marketed under the name of Lusedra <®>. Few methods are known for the preparation of fospropofol.

US6451776 describes some fospropofol preparation processes that involve the use of phosphorylation reagents with environmental problems, not easy to prepare, or in any case obtained in low yields, or using very expensive silver salts (Scheme 1):

O I OBn

NaOH, TBAB

(THE)

US7229978 describes a fospropofol preparation process in which large amounts of bromochloromethane are used in order to obtain adequate conversions and limit the formation of unusable by-products in the synthesis of fospropofol (Scheme 2).

All known processes are also characterized by very laborious and complicated work ups.

We have now found new intermediates for the preparation of fospropofol which allow to obtain fospropofol using easy to prepare, or readily available commercially, low cost and low environmental impact reagents.

The object of the present invention is therefore ammonium salts of 2,6-diisopropylphenol (propofol) of formula (II)

in which Ri, R2, R3 and R4, equal or different from each other, represent hydrogen atoms, linear or branched C1-C20alkyl groups, possibly substituted benzyl or phenyl groups.

Preferably, R1, R2, R3 and R4, equal or different from each other, represent hydrogen atoms, linear or branched C ^ C alkyl groups, benzyl or phenyl groups.

Even more preferably, R1, R2, R3 and R4, the same or different from each other, represent methyl, butyl, benzyl or phenyl groups.

The compounds of formula (II), object of the present invention, are useful intermediates for the synthesis of fospropofol which can be prepared in a simple way and without the use of difficult to find, expensive or high environmental impact reagents.

A further object of the present invention therefore constitutes a process for the preparation of the intermediates of formula (II) which comprises: a) the dissolution of the 2,6-diisopropylphenol of formula (III)

in a polar protic solvent at a temperature between 20 <*> 0 and 40 <<> C;

b) the addition of a quaternary ammonium salt of formula (IV)

wherein R1, R2, R3 and R4, the same or different from each other, represent hydrogen atoms, linear or branched C1-C20alkyl groups, optionally substituted benzyl or phenyl groups; and A <"> represents a suitable anion; to give the ammonium salt of 2,6-diisopropylphenol of formula (II). Preferably, in step a) of the process object of the present invention, the polar protic solvent is water or methanol, more preferably methanol.

Step a) of the process object of the present invention is carried out at a temperature preferably between 25 ° 0 and 30 ° 0. In step b) any known ammonium salt of formula (IV) can be used. Specific examples of usable ammonium (IV) salts are tetra-n-butylammonium hydroxide, tetra-n-butylammonium bromide, benzyltrimethylammonium hydroxide, trimethylphenylammonium hydroxide, etc. Preferably, tetra- / T-butylammonium hydroxide (TBAOH) is used. All the steps of the process object of the present invention are carried out in an inert atmosphere.

In a further aspect, the object of the present invention is a preparation process of 2- (chloromethoxy) -1, 3-diisopropylbenzene of formula (V)

which comprises:

a) the dissolution of the 2,6-diisopropylphenol of formula (III)

in a polar protic solvent at a temperature between 20 * 0 β 40Ό;

b) the addition of a quaternary ammonium salt of formula (IV)

wherein Ri, R2, R3 and R4, the same or different from each other, represent hydrogen atoms, linear or branched CrC2 or alkyl groups, optionally substituted benzyl or phenyl groups; and A <"> represents a suitable anion; to give the ammonium salt of 2,6-diisopropylphenol of formula (II)

c) dissolving the ammonium salt of 2,6-diisopropylphenol of formula (II) in an apolar solvent;

d) the addition of a chlorohalogenomethane of formula CH2CIX in which X is a halogen atom chosen from chlorine, bromine and iodine to give the compound of formula (V).

Preferably, in step a) of the process object of the present invention, the polar protic solvent is water or methanol, more preferably methanol.

Step a) of the process object of the present invention is carried out at a temperature preferably comprised between 25 <*> 0 and 30 <*> 0. In step b) any known ammonium salt of formula (IV) can be used. Specific examples of usable ammonium (IV) salts are tetra-nbutylammonium hydroxide, tetra- / T-butylammonium bromide, benzyltrimethylammonium hydroxide, trimethylphenylammonium hydroxide, etc.

Preferably, tetra- / T-butylammonium hydroxide (TBAOH) is used. In step c) of the process object of the present invention for the preparation of 2- (chloromethoxy) -1, 3-diisopropylbenzene of formula (V) any known non-polar solvent can be used.

Specific examples of apolar solvents that can be used are xylene, tetrahydrofuran, toluene, methyl-tetrahydrofuran, acetonitrile, long-chain alcohols such as for example butanol. Preferably the non-polar solvent used is toluene. In step d) the 2,6-diisopropylphenol ammonium salt of formula (II) is reacted with a chlorohalogenomethane of formula CH2CIX.

Specific examples of chlorohalogenomethane are chlorobromomethane, chloroiodomethane and dichloromethane.

Preferably bromochloromethane is used.

All the steps of the process object of the present invention are carried out in an inert atmosphere.

The compound of formula (V) is a known intermediate in the synthesis of fospropofol which is transformed into fospropofol by phosphorylation according to conventional methods.

The use of quaternary ammonium salts of formula (II), object of the present invention, has the advantage of allowing greater control of the selectivity of the alkylation reaction with chlorohalogenomethane and therefore of obtaining fospropofol with a simpler and more convenient process. All the terms used in the present application, unless otherwise indicated, must be understood in their common meaning as known in the art.

The term "polar solvent" refers to a solvent which tends to provide protons, such as water; an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol; or a polarized solvent, such as, for example, esters, for example, ethyl acetate, butyl acetate; nitriles, for example, acetonitrile; ethers, for example, tetrahydrofuran, dioxane; ketones, for example, acetone, methylbutylketone; and similar.

The term "non-polar solvent" refers to a solvent that does not behave as a proton donor. Examples include, without limitation, hydrocarbons, such as pentane, hexane, heptane, cyclopentane, cyclohexane; aromatic solvents, such as benzene, toluene, o-, m- or p-xylenes; halogenated hydrocarbons, such as methylene chloride, chloroform, and the like; heterocycles, such as tetrahydrofuran, N-methylpyrrolidinone; ethers, such as ethyl ether, dioxolane, etc. Such compounds are known and it is evident to the person skilled in the art that the different solvents or their mixtures can be preferred according to the specific compounds and the reaction conditions, their choice being influenced, for example, by the solubility and reactivity of the reagents, by the preferred temperature ranges.

Further information on non-polar or polar solvents can be found in organic chemistry textbooks or specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., John A. Riddick, et al., Vol. Il, in “Techniques of Chemistry Series”, John Wiley & Sons, NY, 1986.

The term “alkyl” refers to a branched or linear hydrocarbon, containing 1 to 20 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, / r-pentyl, n-hexyl, etc. A preferred alkyl group of the present invention is n-butyl.

A preferred embodiment of the process object of the present invention is the following.

The 2,6-diisopropylphenol (propofol) of formula (III) is dissolved in methanol, at a temperature of about 25'C. To the solution thus obtained, tetra- / T-butylammonium hydroxide (TBAOH) is added to give tetra- / T-butylammonium 2,6-diisopropylphenolate. The tetra - /> butylammonium 2,6-diisopropylphenolate is dissolved in toluene, at a temperature of 25 <*> 0 and bromochloromethane is added to the solution thus obtained. At the end of the reaction, 2- (chloromethoxy) -1, 3-diisopropylbenzene is obtained.

Although the present invention has been described in its characteristic aspects, modifications and equivalents which are evident to the skilled in the art are included in the present invention.

The present invention will now be illustrated by means of some examples, which are not to be seen as limiting the scope of the invention.

Example 1

In a reaction flask, under an inert atmosphere of nitrogen, 1 g of propofol (0.0056 moles) and 10 ml of methanol were charged. 5.6 ml of tetra-n-butylammonium hydroxide solution 1 M in water (0.0056 moles) were added to the solution thus obtained, maintaining the temperature at about 25'C. The reaction mixture was kept under these conditions for 30 minutes. At the end of the reaction, the methanol was distilled under vacuum and toluene (3x10 ml) was added to the solution obtained in order to azeotropically remove all the water present. 2.32 g of tetra - /> butylammonium 2,6-diisopropylphenolate were thus obtained as a solid (quantitative yield).

<1> HNMR (DMSO, 300 Hz): δ 6.50 (d, 2H), 5.73 (t, 1H), 3.32 (m, 2H), 3.20 (m, 8H), 1 , 58 (m, 8H), 1.30 (q, 8H), 0.99 (m, 12H), 0.94 (m, 12H).

Example 2

In a reaction flask, 1 g of propofol (0.0056 moles) and 10 ml of methanol were charged under an inert nitrogen atmosphere. 5.6 ml of tetra - /> butylammonium hydroxide solution 1 M in water (0.0056 moles) were added to the solution thus obtained, maintaining the temperature at about 25'C. The reaction mixture was kept under these conditions for 30 minutes. At the end of the reaction, the methanol was distilled under vacuum and toluene (3x10 ml) was added to the solution obtained in order to azeotropically remove all the water present.

The obtained tetra-n-butylammonium 2,6-diisopropylphenolate was dissolved in 10 ml of toluene and 8.4 g of bromochloromethane (0.065 moles) were then added, maintaining the temperature at about 25 <t> C. The reaction mixture was kept under these conditions for about 3 hours. At the end of the reaction, two extractions were carried out with 10 ml of water; the combined organic phases were concentrated to residue by distillation under vacuum.

The product obtained was distilled at 150 ° C under vacuum, obtaining 1.08 g of 2- (chloromethoxy) -1, 3-diisopropylbenzene as oil (yield 86%).

Claims (10)

CLAIMS 1) An ammonium salt of 2,6-diisopropylphenol of formula (II) in which Ri, R2, R3 and R4, equal or different from each other, represent hydrogen atoms, linear or branched CrCl or alkyl groups, possibly substituted benzyl or phenyl groups. 2) A compound according to claim 1 wherein R1, R2, R3 and R4, equal or different from each other, represent hydrogen atoms, linear or branched C ^ C alkyl groups, benzyl or phenyl groups. 3) A compound according to claim 2 wherein R ^ R2, R3 and R4, equal or different from each other, represent methyl, butyl, benzyl or phenyl groups. 4) A process for the preparation of a compound according to claim 1 which comprises: a) the dissolution of the 2,6-diisopropylphenol of formula (III) in a polar protic solvent at a temperature between 20 * 0 ε 40Ό; b) the addition of a quaternary ammonium salt of formula (IV); wherein Ri, R2, R3 and R4, the same or different from each other, represent hydrogen atoms, linear or branched C-C20alkyl groups, benzyl or phenyl groups optionally replaced; and A <"> represents a suitable anion to give the ammonium salt of 2,6-diisopropylphenol of formula (II). 5) A process of preparation of 2- (chloromethoxy) -1, 3-diisopropylbenzene of formula (V); which includes: a) the dissolution of 2,6-diisopropylphenol of formula (III); in a polar protic solvent at a temperature between 20 ° 0 β 40 °; b) the addition of a quaternary ammonium salt of formula (IV) wherein R1, R2, R3 and R4, equal or different from each other, represent hydrogen atoms, linear or branched CrCl or alkyl groups, possibly substituted benzyl or phenyl groups; and A <"> represents a suitable anion; to give the ammonium salt of 2,6-diisopropylphenol of formula (II) c) dissolving the ammonium salt of 2,6-diisopropylphenol of formula (II) in an apolar solvent; d) the addition of a chlorohalogenomethane of formula CH2CIX in which X is a halogen atom selected from chlorine, bromine and iodine to give the compound of formula (V). 6) A process according to claims 4 and 5 wherein the polar protic solvent is water or methanol. 7) A process according to claims 4 and 5 in which the ammonium salt (IV) is selected from tetra - /> butylammonium hydroxide, tetra-n-butylammonium bromide, benzyl-trimethylammonium hydroxide and trimethylphenylammonium hydroxide. 8) A process according to claim 5 wherein the non-polar solvent is selected from xylene, tetrahydrofuran, toluene, methyl-tetrahydrofuran, vinegar nitrile and butanol. 9) A process according to claim 5 in which the chlorohalogenomethane is selected from chlorobromomethane, chloroiodomethane and dichloromethane. 10) Use of a compound of formula (II) as an intermediate for the preparation of fospropofol.