GB2471800A

GB2471800A - Preparation of N-alkylated morphinans by reduction of an iminium group

Info

Publication number: GB2471800A
Application number: GB1017988A
Authority: GB
Inventors: Audun Heggelund; Harald Halvorsen; Ole Heine Kvernenes; Anne Mette Nyg Rd
Original assignee: Alpharma
Priority date: 2006-05-25
Filing date: 2006-05-25
Publication date: 2011-01-12
Anticipated expiration: 2026-05-25
Also published as: GB2438399A; GB2471800B; GB201017988D0; GB0610386D0

Abstract

A process for the preparation of a compound of formula (I) or pharmaceutically acceptable salt thereof wherein R is a hydrocarbon group of 2 to 6 carbon atoms, P is H, CH3or a hydroxyl protecting group and X is 0, CH2or a protected keto group comprises reducing a compound of formula (II). A compound of formula (II) may be prepared by reacting a free amine precursor, i.e. a compound in accordance with fonnula (I) but having H rather than CH2R on the ring nitrogen, with an aldehyde RCHO and the reduction may be performed without isolation or purification of the compound of formula (II). Preferably R is cyclopropyl, X is 0 and P is a methyl group and the compound of formula (I) is therefore 3-methylnaltrexone. Suitable reducing agents include sodium triacetoxyborohydride and sodium cyanoborohydride. The reduction may be performed at below ambient temperature, e.g. at 5 to -30 °C and may be performed in dichloromethane or 1,2-dichloroethane. Where P is methyl, the compound of formula (I) may be demethylated, e.g. with BBr3.

Description

CHEMICAL PROCESS

This invention relates to improved methods of N-alkylation of morphinan derivatives.

It has been known for over 30 years that when suitable substituents are introduced on the nitrogen atom of a morphinan derivative, the resulting compounds are narcotic antagonists that may also have analgesic properties and are not addictive.

Commercial and well known morphinans include naltrexone, nalmefene, nalbuphine, naloxone and nalorphine. HN<

NALTREXONE NALMEFENE

H

HO

NALBUPHINE

O*Th HO

NALOXONE NALORPHINE

The discovery of these improved properties has driven scientists to attempt to produce further N-substituted morphinan derivatives and to improve processes for making them. This invention relates to improved methods of N-alkylation of morphinan derivatives.

Prior art methods of N-alkylation of morphinan derivatives include (1) direct-alkylation, employing an alkyl halide and a base, and (2) acylation followed by reduction of the resulting amide to the corresponding amine.

The direct N-alkylation of morphinans has been known for over 30 years.

There are numerous patented disclosures of the direct alkylation method, some of which are summarised below.

GB Patent 1,108,388, describes the alkylation procedure for preparing N- cyclopropylmethyl-1 4-hydroxydihydromorphinone and N-cyclobutylmethyl-1 4-hydroxydihydronormorphinone by reaction of 14-hydroxydihydromorphinone with cyclopropylmethyl bromide and cyclobutylmethyl bromide, respectively.

GB Patent 939, 287, describes the preparation of N-substituted morphinone and N-substituted codeinone derivatives by reacting morphinone or codienone with an allyl halide or a propargyl halide in the presence of a proton scavenger.

The yields varied between 80.2% and 61.1%.

GB Patent 955,493 describes the preparation of N-allyl-14-hydroxydihydronor-morphinone by reacting allyl bromide with 14-hydroxydihydronormorphinone.

GB Patent 722,571 describes the preparation of an N-allylnormorphine by reacting normorphine with an allyl halide.

GB Patent 1,300,419 describes a method for the preparation of N-substituted derivatives of 14-hydroxydihydrocodeinones by reaction of the 14-hydroxy-dihydronorcodeinones with allyl halide or alkyl halide derivates such as allyl bromide, cyclopropylmethyl bromide and cyclobutylmethyl bromide.

CA913077 shows that dihydroxynorcodeinone can be alkylated with a compound of the formula Y-CO-X, in which Y is cyclobutyl or cyclopropyl and X in a preferred embodiment is a halide such as chloride.

us Patent 4,089,855 describes the process in which N-substituted derivatives of morphinans can be prepared by reaction of the normorphinan compound with an alkyl halide, such as cyclobutylmethyl bromide.

us Patent 4,141,897 describes processes of preparing specific N-allyl and N-alkyl codone and morphone derivatives by reaction of the corresponding allyl halide or alkyl halide with normorphone or norcodone.

These direct N-alkylation processes tend not to have high yields, possibly due to occurrence of side products such as N, N-dialkylated and 14-0-alkylated compounds.

N-Alkylation by N-acylation followed by reduction is also a well known method for N-alkylation of morphinan derivatives, as exemplified by the following.

CA913077 shows that dihydroxynorcodeinone can be alkylated with a compound of the formula Y-CO-X, in which Y is cyclobutyl or cyclopropyl and X can be either the remainder of an ester group, such as -0C2H5, an anhydride group such as -O-CO-Y or a mixed anhydride group, such as -O-CO-0C2H5.

The resulting cycloalkanecarbonyl derivative is then reduced with lithium aluminium hydride, with borane, or preformed borane such as sodium, potassium or lithium borohydride.

GB Patent 1,300,419 describes a method for the preparation of N-substituted derivatives of 14-hydroxydihydrocodeinones. 14-hydroxydihydrocodeinone derivatives are reacted with cyclopropanecarbonyl chloride or cyclobutanecarbonyl chloride into the corresponding N-cyclopropylcarboxyl or N-cyclobutylcarboxyl compound which are subsequently reduced with lithium aluminium hydride.

US Patent 4,089,855 describes the process in which N-substituted derivatives of morphinans can be prepared by reaction of the nor-morphinan compound with an alkyl acid halide such as cyclobutanecarbonyl chloride to give an amide which is then reduced with borane.

GB Patent 1,108,388 and US Patent 3,332,950, describe an alkylation procedure for preparing N-cyclopropylmethyl-14-hydroxydihydromorphinone and N-cyclobutylmethyl-1 4-hydroxydihydronormorphinone by reaction of 14-hydroxydihydromorphinon with cyclopropanecarbonyl chloride and cyclobutanecarbonyl chloride, respectively, which are subsequently reduced by lithium aluminium hydride.

US Patent 4,089,855, describes that N-substituted derivatives of morphinanes can be prepared by reaction of the morphinan with an alkylcarbonylhalide, such as cyclobutanecarbonyl chloride which is then reduced.

GB Patent 1,028,407 describes a process of acylating and then reducing morphinan derivatives. The acylating agent is preferably an acid anhydride or an acid halide. The reducing agent is preferably an alkali metal hydride such as lithium aluminium hydride or sodium borohydride.

In the preceding processes the 6-keto group must be protected prior to the reduction reaction and then be regenerated after the reduction reaction. These protection and deprotection steps increase the number of synthetic stages required.

We have found however, that there are a number of surprising advantages if the N-alkylation step is carried out by reductive amination instead of the traditional alkylation and acylation methods.

One surprising advantage of such a process applied to codeinone derivatives is that the reduction step will selectively reduce the intermediate imine group without interfering with the un-protected carbonyl at the 6-position. This results in a high yield of N-alkylated codeinone and very little (if any) codeine analogue by-product. One example of a commercially important codeinone derivative is 3-methyl-naltrexone. 3-Methyl-naltrexone is an important precursor in the synthesis of naltrexone.

H

HJOH \< 3-methylnaltrexone Eliminating the need to protect the carbonyl group prior to the addition of a reducing agent is advantageous because the overall process is reduced by at least one step and sometimes two steps. A reduction in the number of steps, simplifies the overall process, improves cost, and increases the overall yield.

Furthermore and as described below, N-alkylation by reductive amination of morphinans overcomes a number of disadvantages of the prior art N-alkylation methods.

The presence of a 14-hydroxysubstituent has the potential to result in a number of side reactions with several methods of N-alkylation which do not take place with the process according to the present invention.

Another advantage of carrying out the N-alkylation step by reductive amination is that protection of the 14-hydroxy group is not necessary. If the chosen method of N-alkylation is acylation followed by reduction, it would be expected that an unprotected 14-hydroxy group would also be acylated (see for example GB 1, 028, 407, page 2 lines 21 to 23). Similarily alkylation of the 14-OH group is a potentially unwanted side reaction in the direct alkylation method, when a bromoalkane is used.

Another disadvantage of N-alkylation by the direct alkylation method is that the two alkyl groups can add to the morphinan derivative and produce a quaternized by-product. Such quaternized compounds are disclosed in US Patent 4, 176,186. It is therefore an additional advantage of the reductive amination method that the quaternization reaction will not occur.

In addition, in preferred aspects, it has been found that certain reaction conditions lead to particularly acceptable results. Thus, for example, the use of low temperatures, aprotic solvents and high dilution, individually and accumulatively, can lead to particularly favourable results.

An additional surprising advantage of the present invention is that the N-alkylated products of morphinan derivatives produced by reductive animation are obtainable in high yields and with high purity. The reductive amination method has been shown to produce higher yields than the direct-alkylation method for generating the same N-substituted morphinan.

Accordingly the present invention provides a process for the preparation of a compound of formula (I):-ci I N-OH2 R x (I) or a pharmaceutically acceptable salt thereof, wherein R is a hydrocarbon of 2 to 6 carbon atoms, P is H, CH3 or a hydroxyl-protecting group, and X is 0 or CH2 or a group or groups such that X= represents a protected keto group, of which process comprises the reduction of a compound of the formula (II)

OH x (II)

where R, X and P are as defined in formula (I) and optionally forming a salt.

Suitable protected keto groups X= include ketalised groups such as optionally linked diC14alkyloxy groups especially a -O.CH3CH2O-group.

Preferably X is 0, that is the compounds of formulas (I) and (II) have a 6-keto group.

Most aptly, R is a cyclopropyl, cyclobutyl or vinyl group. Preferably R is a cyclopropyl group.

Suitable groups P include H, CH3, CH3CO or a silyl protecting group such as SiMe3 or TBDMS.

The reducing agent employed may be any which selectively reduces the iminium ion.

Suitable reducing reagents when X is 0 include triacetoxyborohydrides such as sodium triacetoxyborohydride, or a cyanoborohydride such as sodium cyanoborohydride. Hydrogen and a catalyst such as palladium may also be employed.

If X is a protected keto group or a CH2 group more vigorous reducing agents may be employed, for example borohydrides such as sodium borohydride or other hydride reducing agents such as lithium aluminium hydride. Other suitable reducing agents include triethylsilane and phenylsilane.

The reaction is generally carried out in a solvent such as tetrahydrofuran, ethanol, isopropanol, dichloromethane, toluene, dimethylformaldhyde, dimethylsulfoxide, 1-2-dichloroethane or the like. Dichloromethane and 1, 2-dichloroethane are particularly apt.

A particularly favoured solvent is 1, 2-dichloroethane.

The reaction may be performed in high dilution, for example at least 20m1 of solvent per 100mg of starting material.

The reduction is generally effected at below ambient temperature, for example 5°C to -30°C, more aptly at -20°C to -30°C. However, if X= is a protected keto group higher temperatures, for example ambient temperatures, may be employed.

The salts of the compound of formula I may be obtained by reaction with a suitable acid such as a pharmaceutically acceptable organic or inorganic acid, such as ethanoic, citric, lactic, benzoic, methanesulphonic, toluenesulphonic, mandelic, malic, hydrochloric, sulphuric or phosphoric acid.

The compound of formula (II) may be prepared by the reaction of compounds of the formula (III) and (IV): c I

NH

OH

x (III) R-CHO (IV) where R, P and X are as defined in relation to formula (I).

Desirably the compound of formula (II) may be prepared and used without intermediate isolation or purification. Thus the compound of formula (III) can be converted to a compound of formula (I) in a "one pot" process.

The solvent employed is therefore suitably as stated above. The temperature of reaction of the aldehyde and amino compound may be any suitable non-extreme temperature, for example at ambient temperature.

If desired, a dehydrating agent such as molecular sieves may be present.

Once the first step of the reaction is complete, the solution may be cooled prior

to the introduction of the reducing agent.

A particularly preferred moiety X in the preceding reactions is an 0. However, if X has represented a protected keto function, this may be removed by conventional methods, for example hydrolysis, when required.

In a particularly favoured aspect this invention provides a process for the preparation of a compound of the formula (V) H3CO7.

CH2__-< (V) or a salt thereof which comprises the reduction of a compound of the formula

OH (VI)

with a borohydride, for example a triacetoxyborohydride such as sodium triacetoxyborohydride.

The compound of the formula (VI) is preferably prepared by the reaction of noroxycodone with cyclopropanecarboxaldehyde.

In a particularly preferred aspect this invention provides a process for the preparation of the compound of the formula (V) by the reaction of noroxycodone with cyclopropanecarboxaldehyde followed, without isolation or purification of the intermediate iminium ion, by reduction to yield 3-methylnaltrexone.

The reaction conditions for these reactions are as given above in respect of the preparation of the compounds of the formula (I).

The compound to the formula (V) may be converted to naltrexone by methods known in the art, for example, by reaction with BBr3.

The following Examples illustrate the invention:

Example I

N-alkylation of noroxycodone Noroxycodone (0.1 g) and cyclopropanecarboxaldehyde (0.023 g) were mixed in dichloromethane (20 ml) at room temperature for 30 minutes. The solution was cooled to -30°C and sodium triacetoxyborohydride (0.070 g) was added.

The reaction mixture was quenched with sodium bicarbonate solution (20 ml) and the phases were separated. The organic phase was dried (Na2SO4), filtered and the solvent removed under reduced pressure to yield 3-methyl-naltrexone (0.100 g).

Example 2

N-alkylation of noroxycodone Noroxycodone and cyclopropanecarboxaldehyde is dissolved in 1, 2-dichloroethane and stirred for 30 mm at room temperature, before the solution is cooled to -30 °C. Sodium triacetoxyborohydride is added to the solution and the resulting mixture is stirred at -30 °C for 3 days before the reaction is quenched with addition of aqueous sodium carbonate. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phase is dried, filtered and the solvents removed under reduced pressure to yield 3-methylnaltrexone.

Example 3

0-Demethylation of N-cyclopropylmethyl noroxycodone hydrochloride N-cyclopropylmethyl noroxycodone hydrochloride (200 mg, 0.51 mmol) was dissolved in DCM (2 ml) and cooled to 0 °C. Boron tribromide (1 M in DCM, 2.55 ml, 2.55 mmol) was added, and the reaction mixture was stirred under inert atmosphere while the temperature was allowed to reach room temperature. HPLC showed that the reaction was fast. Water was added, and the mixture was stirred for 2 h. Additional water and DCM were added, and the pH was adjusted to 10 with aqueous ammonia. The layers were separated, and the aqueous phase was extracted twice with DCM. Drying (MgSO4) and concentration of the combined organic layers afforded crude Naltrexone (140 mg, 80% yield) as a grey solid.

Claims

Claims 1. A process for the preparation of a compound of the formula (I): ci I OH2 R x (I) or a pharmaceutically acceptable salt thereof, wherein R is a hydrocarbon of 2 to 6 carbon atoms, P is H, CH3 or a hydroxyl-protecting group, and X is 0 or CH2 or a group or groups such that X= represents a protected keto group, which process comprises the reduction of a compound of the formula (II) °yTh )J\cOH x (II)where R, X and P are as defined in formula (I) and optionally forming a salt.
2. A process as claimed in claim I wherein X is 0.
3. A process as claimed in claims I or 2 wherein R is cyclopropyl.
4. A process as claimed in any of claims I to 3 wherein P is a methyl group.
5. A process as claimed in any of claims I to 4 wherein the reducing agent is a triacetoxyborohydride such as sodium triacetoxyborohydride.
6. A process as claimed in any of claims I to 4 wherein the reducing agent is a cyanoborohydride such as sodium cyanoborohydride.
7. A process as claimed in any of claims I to 6 performed at a depressed temperature, for example 5°C to -30°C.
8. A process as claimed in any of claims I to 7 wherein the compound of formula (II) is prepared by the reaction of compounds of the formula (III) and (IV): POy c INHx (III) R-CHO (IV) when R, P and X are as defined in any of claims I to 4.
9. A process as claimed in claim 8 wherein the compound of formula (II) is not isolated or purified prior to reduction.
10. A process as claimed in claims Ito 9 performed in 1,2-dichloroethane.
11. A process as claimed in any of claims I to 10 wherein in the compound of formula (II), P is methyl and the compound of formula (I) is demethylated, forexample with BBr3.AMENDMENTS TO CLAIMS HAVE BEEN FILED AS FOLLOWED1. A process for the preparation of a compound of the formula (I): PoY:Th 0[ I -C H2 R tOH X (I) or a pharmaceutically acceptable salt thereof, wherein R is a hydrocarbon of 2 o to 6 carbon atoms, P is H, CH3 or a hydroxyt-protecting group, and X is 0 or CH2 or a group or groups such that X= represents a protected keto group, -. 10 which process comprises the reduction of a compound of the formula (II) r P0 Ct) qRSOH x (II)where R, X and P are as defined in formula (I) and optionalty forming a salt, with a triacetoxyborohydride or a cyanoborohydride.2. A process as claimed in claim 1 wherein X is 0.3. A process as claimed in claims 1 or 2 wherein R is cyclopropyl.4. A process as claimed in any of claims 1 to 3 wherein F is a methyl group.5. A process as claimed in any of claims I to 4 wherein the reducing agent is sodium triacetoxyborohydride.6. A process as claimed in any of claims I to 4 wherein the reducing agent is sodium cyanoborohydride.7. A process as claimed in any of claims 1 to 6 performed at a depressed temperature, for example 5°C to -30°C. r8. A process as claimed in any of claims I to 7 wherein the compound of o formula (II) is prepared by the reaction of compounds of the formula (Ill) and (1) 20 (IV): /c c INHOHX (Ill)