WO2011032634A1

WO2011032634A1 - Efavirenz salts, method for the production thereof, and method for release from the salt

Info

Publication number: WO2011032634A1
Application number: PCT/EP2010/005230
Authority: WO
Inventors: Andreas Meudt; Michael Nonnenmacher
Original assignee: Archimica Gmbh; Jung, Jörg
Priority date: 2009-09-16
Filing date: 2010-08-26
Publication date: 2011-03-24
Also published as: DE102009041443A1; WO2011032634A8

Abstract

The invention relates to a method for producing compounds according to formula (I), wherein the hydrogen atom bound to the nitrogen is replaced with a metal atom from the series of alkali metals or alkaline-earth metals or with an aluminum atom or a tetraalkylammonium cation and wherein the alkaline-earth metal salts or the aluminum salts of the compound (I) can contain other anions such as fluoride, chloride, bromide, iodide, or sulfate in addition to a deprotonated anion (I).

Description

EFAVIRENZ SALTS, PROCESS FOR THEIR PREPARATION AND RELEASE FROM THE SALT

Object of the invention:

The present invention relates to salts of efavirenz, which can be used as an inhibitor for the reverse transcriptase of the human immunodeficiency virus. The salts described are compounds in which the nitrogen atom bound to hydrogen is replaced by a metal atom. Moreover, this invention relates to the synthesis of the derivatives of efavirenz as well as their purification and crystallization and the use for the preparation of a solution of efavirenz in organic solvents.

Background of the invention:

Efavirenz (Ia) is used as a potent inhibitor of human immunodeficiency virus (HIV) reverse transcriptase. For use as an active ingredient in medicines, high levels of purity, both in terms of organic and inorganic impurities, are required. Many efforts have been made to purify the crude products obtained from various synthetic approaches. Accordingly, crystal structure data of many different modifications have been published (see, for example, WO98 / 33782, WO99 / 64405, WO2006018853, WO2006030299, WO2006040643, WO2006029079, WO2008108630). Most of the cited methods are based on the fact that efavirenz is precipitated or crystallized from a solution in a solvent in which it is readily soluble by adding an "anti-solvent" in which its solubility is low its enantiomerically pure form in almost all solvents is good or at least partially soluble and as "anti-solvent" only very nonpolar hydrocarbons such as hexane, heptane or the like or alternatively water comes into question. It has therefore been of particular interest to develop a new process which has a simplified, reliable and cost-effective cleaning of efavirenz crude product. It has now surprisingly been found that such a simplified, reliable and cost-effective purification can be carried out particularly well over salts of efavirenz. Such a purification process has the particular advantage of being able to remove virtually all contaminants without acidic protons very efficiently. In addition, the release of free efavirenz from the salt is very easy, since it only has to be neutralized with a suitable acid.

The salts according to the invention and the associated inventive method satisfies these claims, since by reacting a crude solution, crude or other solution, suspension or solid modification of efavirenz first a salt of efavirenz is formed by the hydrogen atom on the nitrogen by a metal atom from the series Alkali or alkaline earth metals is replaced or obtained by an aluminum atom or a tetraalkylammonium cation and as a solution, suspension, solid mixture or solid and from which the pure derivative is obtained by crystallization, recrystallization or washing with one or more solvents. Furthermore, the claim to release efavirenz is also met, since by reacting the salt in a suitable solvent with a suitable acid, a solution of efavirenz is formed in this solvent.

In particular, it is advantageous with the new method that only very small losses in yield have to be accepted via the purification steps and that contaminants which can not be separated via the conventional routes can be removed.

Summary of the invention:

Accordingly, the invention relates to derivatives of 6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (I) and (S) -6-chloro -4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (Ia) in which the hydrogen atom bound to the nitrogen atom is represented by a metal atom the series of alkali or alkaline earth metals is replaced or by an aluminum atom or a tetraalkylammonium cation. In addition to deprotonated efavirenz, the alkaline earth metal salts or the aluminum salts of efavirenz may also contain other anions such as fluoride, chloride, bromide, iodide, or sulfate.

Furthermore, the invention relates to the synthesis of derivatives of 6-chloro-4- (cyclopropylethinyl) -1, 4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (I, Ia), in in which the hydrogen atom bound to the nitrogen atom is replaced by a metal atom from the series of alkali or alkaline earth metals or by an aluminum atom or a tetraalkylammonium cation. In addition to deprotonated efavirenz, the alkaline earth metal salts or the aluminum salts of efavirenz may also contain other anions such as fluoride, chloride, bromide, iodide, or sulfate.

The starting point is 6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (I) or (S) -6-chloro-4 - (cyclopropylethynyl) -1, 4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (Ia) in pure form or as a mixture with one or more minor components and or other impurities or from a solution of (S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one or (S) -6-chloro-4- (cyclopropylethynyl ) -1, 4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one in an organic solvent, the additionally may contain minor components and or other impurities.

This raw material is added either directly or after dilution in an organic solvent or solvent mixture with a basic metal salt or other basic compound of the metals lithium, sodium, potassium, magnesium or calcium, forming one of the above-defined derivatives of I or Ia.

The invention further relates to the isolation and purification of the derivatives of efavirenz as defined above, wherein the other constituents of the mixture are removed or substantially removed by distillation and / or washing with a suitable solvent and / or recrystallization and / or drying of the crude product mixture.

Furthermore, the invention relates to the reaction of the above-defined derivatives of efavirenz to a solution of efavirenz in an organic solvent or solvent mixture. In this case, the inventive derivative of efavirenz is suspended or dissolved in the solvent or solvent mixture and mixed at a suitable temperature with a pure or dissolved in a solvent or solvent mixture organic or inorganic Brönstedt acid, wherein Efavirenz and the corresponding metal salt of the acid.

Detailed description of the invention:

In a preferred embodiment, the metal atom of the salt of the invention is 6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (I) or S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (Ia) to an alkali or alkaline earth metal, in one especially preferred embodiment to lithium, sodium, potassium, magnesium or calcium and in a most preferred embodiment to sodium or potassium. In a preferred embodiment, the reagent with which the compound of type I or la is reacted to a basic metal salt or a basic metal compound, in a particularly preferred embodiment to an alkali or alkaline earth metal compound, in a most preferred embodiment an alkali or alkaline earth metal hydride. Furthermore, in a particularly preferred embodiment, it is an alkali metal hydride, in a very particularly preferred embodiment, sodium or potassium hydride. Furthermore, in a preferred embodiment, it is an alkali metal amide. Furthermore, in a particularly preferred embodiment, it is a C 1 to C 10 alkyl or C 6 to C 10 aryllithium compound.

In a preferred embodiment, the compound of type I or la is present before the reaction to the salt according to the invention in a mixture with other substances, wherein the main component or single further component of this mixture is an organic solvent or solvent mixture, in a particularly preferred embodiment, an ether or hydrocarbon and in a most preferred embodiment tetrahydrofuran, methyltetrahydrofuran or toluene. The mixture may contain other organic substances as well as inorganic impurities, in a preferred embodiment these are by-products from the synthesis of efavirenz.

In a preferred embodiment, the salt of the invention is isolated by replacing the organic solvent or solvent mixture in which the salt is soluble with a solvent or solvent mixture in which said salt is sparingly soluble or insoluble. In a particularly preferred embodiment, the solvent is hexane, heptane, methylcyclohexane or toluene or mixtures of two or more of these solvents. In a further preferred embodiment, the salt according to the invention is isolated by filtration after it has been produced in an organic solvent or solvent mixture in which it is insoluble, in a particularly preferred embodiment the solvent is toluene.

In a preferred embodiment, the contaminated salt of the invention is purified from Efavirenz by washing with a solvent, in a particularly preferred embodiment the solvent is C 1 -C 8 alkanes or C 5 -C 8 cycloalkanes, C 6 -C 8 aromatic hydrocarbons, C 6 -C 8 halogenated aromatic hydrocarbons, C1-C3 halogenated hydrocarbons, C1-C4 alkylnitriles, symmetrical or asymmetrical C1-C8 dialkyl ethers, C4-C8 cyclic alkyl ethers or C2-C8 dialkyl ketones, in a very particularly preferred embodiment, hexane, cyclohexane, methylcyclohexane, heptane, dichloromethane, Acetonitrile or toluene.

In a preferred embodiment, the contaminated salt of efavirenz of the invention is purified by recrystallization from a solvent or solvent mixture, in a particularly preferred embodiment the solvent is acetonitrile or dichloromethane.

In a preferred embodiment, the solvent in which the derivative of the invention is suspended or dissolved to protonate by addition of a Bronsted acid is C1-C8 alcohols, symmetrical or asymmetrical C2-C8 dialkyl ethers, C4-C8 cyclic alkyl ethers , C6-C8 aromatic hydrocarbons or C1-C8 halogenated hydrocarbons and in a particularly preferred embodiment to ethanol or methyl tert-butyl ether, in a very particularly preferred embodiment to methyl tert-butyl ether

In a preferred embodiment, the Bronsted acid is hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfuric acid, salts of bisulfate, ammonium chloride, ammonium bromide, ammonium iodide, C1-C8 Monoalkylammonium chloride, bromide, iodide, C1-C8 di- or Trialkylammpniumchlorid, bromide or iodide with the same or mixed alkyl radicals, and in a particularly preferred embodiment to hydrochloric acid or ammonium chloride.

Examples:

Example 1 :

(S) -6-Chloro-4- (cyclopropylethynyl) -1, 4-dihydro-4- (trifluoromethyl) -2H-3, 1-benzoxazin-2-one - sodium salt

A solution consisting of 3.8 g of efavirenz in 57 g of absolute toluene is added in four portions with 500 mg of a 60% suspension of sodium hydride in mineral oil. After completion of the addition, stirring is continued for 1 h and the resulting solid is filtered off with suction. The resulting substance is stirred with 40 g of methylcyclohexane and filtered off again. It is dried to constant weight and receives 3.5 g (86%) of the desired sodium compound.

IR (in cm ^"1 ; s = intense absorption, m = medium absorption, w = weak absorption): 2244.8 (w), 1661, 5 (m), 1627.07 (s), 1588.4 (s) , 1480.5 (s), 1422.0 (w), 1348.6 (w), 1272.0 (w), 1249.7 (m), 1236.4 (m), 1 174, 6 (s), 1094 , 5 (w), 1069.2 (w), 1028.4 (m), 968.87 (m), 928.4 (m), 881, 3 (w), 828.2 (w), 758, 1 (w), 71 1, 7 (w), 698.04 (m), 667.7 (w)

The absence of NH 3 vibration indicates the presence of the desired salt. Example 2:

(S) -6-Chloro-4- (cyclopropylethynyl) -1, 4-dihydro-4- (trifluoromethyl) -2H-3, 1-benzoxazin-2-one - potassium salt

A solution of 4.0 g of efavirenz in 32 g of absolute tetrahydrofuran is mixed in four portions with 1.46 g of a 35% suspension of potassium hydride in mineral oil. After the mixture has been stirred for 1 h, 25 g of the solvent are distilled off and 32 g of n-hexane are added. It is distilled again 25g of the solvent and mixed again with 32 g of n-hexane. The resulting solid is filtered off with suction and washed with 16 g of methylcyclohexane. It is then dried to constant weight and receives 3.27 g (72%) of the desired potassium compound.

Example 3:

Ethanolic solution of (S) -chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one

1.0 g of (S) -chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one sodium salt is suspended in 4.0 g of dry ethanol and cooled to -50 ° C. To the suspension is slowly added dropwise 2.36 ml of a 1, 25M ethanolic hydrogen chloride solution. The resulting sodium chloride is sucked off. This gives 6.78 g of an approximately 13% solution of efavirenz in ethanol. The solution can be converted by distilling off 3.7 g of solvent in an approximately 30% solution.

Example 4:

Solution of (S) -chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one in methyl tert-butyl ether

12 g of (S) -chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazine-2-one sodium salt are suspended in 120 g of methyl tert-butyl ether and washed with 5.7 g of ammonium chloride are added. A total of 90 g of water are added dropwise to the suspension at 0 ° C. and then thawed to room temperature. The phases are separated and the organic phase washed once with 42 g of saturated aqueous sodium bicarbonate solution and once with 40 g of a saturated aqueous sodium chloride solution. The organic phase is dried with sodium sulfate. After filtration of the drying agent is obtained about 90 g of an approximately 10% solution of efavirenz in methyl tert-butyl ether.

Claims

claims

1. A compound of formula I, wherein the hydrogen atom bonded to nitrogen is replaced by a metal atom from the series of alkali or alkaline earth metals or by an aluminum atom or a tetraalkylammonium cation and wherein the alkaline earth metal salts or the aluminum salts of the compound I in addition to deprotonated I may also contain other anions such as fluoride, chloride, bromide, iodide, or sulfate.

2. A compound according to claim 1, wherein the hydrogen atom bound to the nitrogen atom is replaced by sodium or potassium.

3. A compound of the formula Ia, in which the nitrogen atom bound to hydrogen atom is replaced by a metal atom from the series of alkali or alkaline earth metals or by an aluminum atom or a tetraalkylammonium cation and wherein the alkaline earth metal salts or the aluminum salts of the compound la in addition to deprotoniertem la may also contain other anions such as fluoride, chloride, bromide, iodide, or sulfate.

4. A compound according to claim 3, wherein the hydrogen atom bonded to the nitrogen atom is replaced by sodium or potassium.

5. A process for producing any of the compounds recited in claims 1 to 4, wherein I or Ia is reacted with a basic salt or other basic compound of an alkali metal or alkaline earth metal.

6. A process for the preparation of one of the compounds mentioned in claims 1 to 4, in which I or Ia is reacted with an alkali metal hydride or an alkaline earth metal hydride.

7. A process for the preparation of one of the compounds mentioned in claims 1 to 4, in which I or la is reacted with sodium hydride or potassium hydride.

8. A process for the preparation of one of the compounds mentioned in claims 1 to 4, wherein I or Ia is reacted with an alkali metal amide.

9. A process for the preparation of one of the compounds mentioned in claims 1 to 4, in which I or Ia is reacted with a C 1 to C 10 alkyl or a C 6 to C 10 aryllithium compound.

A process according to any one of claims 5 to 9, wherein the target compound is produced in toluene, tetrahydrofuran or methyltetrahydrofuran.

11. A process for purifying the compounds described in claims 1 to 4, wherein these are washed with C1 to C10 saturated hydrocarbons, C4 to C10 unsaturated hydrocarbons, C2 to C10 dialkyl ethers, C1 to C10 halogen or polyhaloalkanes or C1 to C10 alkylnitriles ,

12. A process for the preparation of a solution of efavirenz in an organic solvent, wherein one of the compounds of claims 1 to 4 in said solvent is treated with a Bronsted acid.

13. A process according to claim 12, wherein the solvent is ethanol, MTBE, toluene, THF, methyl THF, diethyl ether or diisopropyl ether.

14. A process according to claim 13 wherein the Bronsted acid is hydrochloric, hydrobromic, hydroiodic, ammonium chloride, ammonium bromide, ammonium iodide, C1-C8 alkylammonium chloride, bromide, iodide, C1-C8 dialkyl ammonium chloride, bromide, iodide having the same or different mixed chain length, trialkylammonium chloride, bromide, iodide having the same or mixed chain lengths, sulfuric acid or a salt of bisulfate.