GB2438401A

GB2438401A - Preparation of morphinan derivatives comprising N-demethylation, reductive amination and O-demethylation steps

Info

Publication number: GB2438401A
Application number: GB0610388A
Authority: GB
Inventors: Anne Mette Nyg Rd; Ole Heine Kvernenes; Harald Halvorsen; Audun Heggelund
Original assignee: Alpharma ApS
Current assignee: Xellia Pharmaceuticals ApS
Priority date: 2006-05-25
Filing date: 2006-05-25
Publication date: 2007-11-28
Also published as: GB2471801B; GB2471801A; GB0610388D0; GB201017989D0

Abstract

A process for the preparation of a compound of formula (I) wherein R is a cyclopropyl, cyclobutyl or vinyl group, X is O or an optionally linked diC1-4alkoxy group comprises N-demethylating a compound of formula (II) by reaction with a -chloroethylchloroformate to form a compound of formula (III). The residue CH2-R shown in formula (I) is then introduced by reacting the compound of formula (III) with an aldehyde RCHO to form an intermediate with an iminium ion double which is reduced to form a compound of formula (IV), i.e. CH2-R is introduced by reductive amination.. The compound of formula (IV) is then reacted with BBr3 or other reagents capable of demethylating an aryl methyl ether to form a compound of formula (I). Preferably R is cyclopropyl and X is O, the compound of formula (I) then being naltrexone. N-Demethylation may be carried out in an aprotic solvent, e.g. 1,2-dichloroethane or acetonitrile and the reductive amination may be carried out in tetrahydrofuran, ethanol, isopropanol, dimethylformamide, dimethylsulfoxide, dichloromethane or 1,2-dichlorethane with reduction being carried out using a triacetoxyborohydride, a cyanoborohydride or hydrogen and a catalyst, e.g. palladium. The O-demethylation may be carried out in an aprotic solvent, e.g. toluene, tetrahydrofuran, chloroform, dichloromethane or 1,2-dichloroethane.

Description

PROCESS USEFUL IN

THE PREPARATION OF MORPHINE ANTAGONISTS

The present invention relates to a process for the preparation of naltrexone or naloxone or derivatives thereof.

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 and naloxone.

HO

NALTREXONE HOTh

NALOXON E $

* , S -* S * S APUKO6O64. $ -s * . *s S S S * S I 5 5 S *s P *S * lSs Numerous reaction sequences are known for the preparation of naltrexone and naloxone but these generally involve numerous steps and can lead to low overall yields. It is still desirable to find a method of producing naltrexone and naloxone which can start from readily commercially available compounds and lead to good yields of naltrexone and naloxone by processes that do not involve too many individual reactions. A reaction sequence that commences from oxycodone and leads to the desired compounds in an effective manner is now provided. The route employed offers the potential advantage of requiring fewer steps.

The present invention provides a process for the preparation of a compound of the formula (I):

HO /

-CH2 R X (I) wherein R is a cyclopropyl, cyclobutyl or vinyl group and X is 0 or diCi4alkoxy group (optionally linked), which process comprises: (i) the N-demethylation of a compound of the formula (II): a * a * S A r)I IL Lf% A 5 * I I S 5 5 I S I I S S. I S * * s * a

S

Is S e Is. CH3O1 o N-CH3

x (Il) wherein X is as defined in relation for formula (I) by reaction with a-chloroethylchloroformate to yield a compound of the formula (Ill):

C /J 0' I

NH

OH

X (Ill) wherein X is as defined in relation to formula (I), followed by (ii) reaction of the compound of formula (Ill) with a compound of the formula R-CHO where R is as defined in relation to formula (I), followed by reduction of the iminium ion double bond of the resulting intermediate to form a compound of the formula (IV): * * S -* S APUKO6O64: : * *. * : : S. S S ** * . . S * S * S * S S S. * **S * S.. H3CO

N-CH2R X (IV) wherein X and R as defined in relation to the compound of the formula (I); followed by: (iii) reaction of the compound of formula (IV) with BBr3 or other reagents capable of demethylating an aryl methyl ether.

Favourably X is 0 or a OCH2CH2O group. Preferably X is 0.

Favourably R is cyclopropyl or a vinyl group. Preferably R is cyclopropyl.

If the final product which is required is one which contains the 6-keto group, the preceding reaction sequence can be performed on compounds wherein X is 0.

Alternatively, the preceding reaction sequence can be performed on compounds wherein X is diC1..6alkoxy (optionally liked), for example a OCH2CH2O group, which can be converted to the 6-keto group by standard methods, for example hydrolysis under mildly acidic conditions.

N-demethylation Reaction The N-demethylation reaction results in an easily hydrolysable carbamate intermediate. Hydrolysis of the carbamate intermediate, for example with MeOH, results in the N-demethylated product.

* S S S S APUKO6O64: : : *:. . : : I S 55 * S * * * I S S S S S I I.. * 5*5 The N-demethylation reaction is most suitably performed in an aprotic solvent such as dichloromethane, I,2-dichloroethane, d imethylformamide, acetonitrile tetrahydrofuran or the like. A favoured solvent is dichloromethane.

Surprisingly, a most preferable solvent is acetonitrile.

The N-demethylation is preferably carried out in the presence of a proton acceptor such as carbonates or bicarbonates. A particularly suitable proton acceptor is anhydrous sodium carbonate.

The temperature of the N-demethylation reaction is generally non-extreme, for example commencing at an ambient temperature (about 20-25 C) and progressing to about 40 C, for example under reflux in dichloromethane.

It is preferred to exclude water, for example by carrying out the reaction under nitrogen.

N-alkylation Reaction The conversion of the compound of the formula (Ill) into a compound of the formula (IV) may be best effected at a depressed temperature especially when X is 0. Somewhat higher temperatures may be employed when X is a protected CO group. When X is 0 the reaction temperature of the reduction may be below -20 , for example at -30 C, although in the initial phase when the carboxaldehyde reacts with the secondary amine the temperature may be higher, for example at ambient temperature.

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 S S * S * APUKO6O64: : : : : * :. * : * S. S S 55 S S * S 5 0 * * * S. S *IS * S..

other hydride reducing agents such as lithium aluminium hydride. Other suitable reducing agents include triethylsilane and phenylsilane.

The reaction may be carried out in a solvent such as tetrahydrofuran, ethanol, isopropanol, d imethylformamide, d imethylsulfoxide, dichloromethane, 1,2-dichloroethane or the like. A preferred solvent is I,2-dichloroethane.

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

0-demethylation Reaction The reaction of the compound of formula (IV) with BBr3 may take place in an aprotic solvent such as toluene, tetrahydrofuran, chloroform, dichloromethane, 1,2-dichloroethane or the like. The BBr3 is generally added at a depressed temperature for example 0 C. Generally, an ambient temperature, for example 20-30C , is employed thereafter. After the reaction is complete, which generally takes from 2 to 4 hours, it is quenched by using water containing a base such as ammonium hydroxide, preferably at a depressed temperature, for example by using ice. The desired compound of formula (I) may be obtained from the organic phase.

The preceding compounds may be in form of salts if required, for example ethanoic, lactic, benzoic, methanesulphonic, toluenesulphonic, mandelic, malic, hydrochloric, sulphuric, phosphoric or the like.

The following examples illustrate the invention.

Example I

N-Demethylation of Oxycodone Oxycodone free base (1.19 g) was dissolved in 6 ml DCM and Na2CO3 (1.60 g) was added. ACE-Cl (1.56m1) was added drop-wise to the stirred suspension at room temperature (RT) and the reaction mixture was heated to reflux and stirred for 24 hours. The reaction mixture was filtered and the precipitate was * S * S * APUKO6O64:::: :.:. *:: ** I S SS S S I S * * S S S S I 4I I *IS I 155 washed with DCM. The filtrate was evaporated to dryness. MeOH (20 ml) was added and the mixture stirred for I h at RI. The solution was again evaporated to dryness and added water (25 ml) and conc. HCI (1 ml). The aqueous phase was washed twice with DCM and then added ammonia until pH 11. The aqueous phase was extracted five times with DCM:MeOH mix (80:20). The combined phases from the last extraction was dried and evaporated. Crude noroxycodone was obtained as a white foam (0.73 g, 64%), purity 90 % by HPLC.

Example 2

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 crude 3-methyl-naltrexone (0.100 g).

Example 3

0-Demethylation of N-Cyclopropylmethyl noroxycodone N-Cyclopropylmethyl noroxycodone (0.20 g, 0.56 mmol) is dissolved in toluene (3 ml) under nitrogen and the reaction flask is immersed in an ice-water bath.

Boron tribromide (2.7 eq, 1.5 ml of a I M solution in DCM) is added slowly with stirring. The reaction flask is left in the ice-water bath and the temperature is allowed to rise slowly to RT. The reaction mixture is left stirring at RI for 3 hours, after which all of the starting material is consumed. Water (3 ml) is added and the reaction mixture is refluxed for 7 hours. The reaction mixture is basified (NH4OH, pH 10) and extracted 4 times with DCM. The combined organic extracts are dried (Na2SO4), filtered and concentrated under reduced pressure to yield crude naltrexone as a beige solid.

* * * . * APUKO6O64: : : * *:. * : : a. a * *s S 0 * S * a * 0 I * I I. S **S S **I ExamDle 4 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.

APUKO6O64

Claims

Claims 1. A process for the preparation of a compound of the formula

(I): -CH2 R x () wherein R is a cyclopropyl, cyclobutyl or vinyl group and X is 0 or diC1alkoxy group (optionally linked), which process comprises: (i) the N-demethylation of a compound of the formula (II): CH3O /J N-CH3 X (II) wherein X is as defined in relation for formula (I) by reaction with a-chloroethylchloroformate to yield a compound of the formula (Ill): APUKO6O64 /L 0' I

NH

OH

x (Ill) wherein X is as defined in relation to formula (I), followed by (ii) reaction of the compound of formula (Ill) with a compound of the formula R-CHO where R is as defined in relation to formula (I), followed by reduction of the iminium ion double bond of the resulting intermediate to form a compound of the formula (IV): H3CO,2 / N-CH2R X (IV) wherein X and R as defined in relation to the compound of the formula (I); followed by: (iii) reaction of the compound of formula (IV) with BBr3 or other reagents capable of demethylating an aryl methyl ether.

2. A process as claimed in claim 1 wherein X is OCH2CH2O.

* * * I I APUKO6O64:::: :.:. *:: ** I S ** * * * S * S I I I I * * * *** * III 3. A process as claimed in claim I wherein X is 0.

4. A process as claimed in any of claims I to 3 wherein step (i) is performed in an aprotic solvent, preferably 1, 2-dichloroethane or acetonitrile.

5. A process as claimed in claim 4 wherein a carbonate or bicarbonate proton acceptor is present.

6. A process as claimed in any preceding claim wherein step (ii) employs an a-chloroethylchoroformate followed by hydrolysis of the resulting intermediate to effect N-demethylation.

8. A process as claimed in any preceding claim wherein step (ii) is performed at a depressed temperature for example 5 C to -30 C.

9. A process as claimed in claims 3 to 8 wherein the reducing agent used in step (ii) may be a triacetoxyborohydride, a cyanoborohydride, for example sodium cyanoborohydride or hydrogen and a catalyst, for example palladium.

10. A process as claimed in any preceding claim wherein step (ii) is performed a solvent such as tetrahydrofuran, ethanol, isopropanol, dimethylformamide, dimethylsulfoxide, dichloromethane or I,2-dichloroethane 11. A process as claimed in claim 10 wherein wherein step (ii) is performed in I,2-dichloroethane.

12. A process as claimed in any preceding claim wherein R is cyclopropyl.

13. A process as claimed in any preceding claim wherein step (iii) is effected using BBr3.

14. A process as claimed in any preceding claim wherein step (iii) is performed in an aprotic solvent, such as toluene, tetrahydrofuran, chloroform, dichioromethane or I,2-dichloroethane.

* * S S * APUKO6O64:::: :.:. *:: *S I S IS S S * S S S S S I S. S 55. * 55 r2.

15. A process as claimed in claim 14 wherein BBr3 is added at a depressed temperature.

06064sp * I S I I * I I APUKO6O64.: : : .. : : : * * S. . Se * III