GB2444052A - Processes of preparing morphinan derivatives such as naltrexone and naloxone comprising O- and N-demethylation and reductive alkylation steps - Google Patents

Processes of preparing morphinan derivatives such as naltrexone and naloxone comprising O- and N-demethylation and reductive alkylation steps Download PDF

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Publication number
GB2444052A
GB2444052A GB0610385A GB0610385A GB2444052A GB 2444052 A GB2444052 A GB 2444052A GB 0610385 A GB0610385 A GB 0610385A GB 0610385 A GB0610385 A GB 0610385A GB 2444052 A GB2444052 A GB 2444052A
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Prior art keywords
demethylation
formula
compound
reaction
effected
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GB0610385D0 (en
Inventor
Harald Halvorsen
Ole Heine Kvernenes
Audun Heggelund
Anne Mette Nyg Rd
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Xellia Pharmaceuticals ApS
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Alpharma ApS
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Priority to GB1017991A priority Critical patent/GB2471803B/en
Priority to GB0610385A priority patent/GB2444052A/en
Publication of GB0610385D0 publication Critical patent/GB0610385D0/en
Priority to PCT/EP2007/004679 priority patent/WO2007137785A2/en
Priority to US12/300,055 priority patent/US20100022774A1/en
Priority to EP07725575A priority patent/EP2032579A2/en
Priority to AU2007267362A priority patent/AU2007267362B2/en
Priority to CA002652849A priority patent/CA2652849A1/en
Publication of GB2444052A publication Critical patent/GB2444052A/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A process for the preparation of a compound of formula (V), or salt thereof, comprises O-and N-demethylation of a compound of formula (I) followed by reaction of the product with an aldehyde RCHO to produce an intermediate containing an iminium ion which is reduced to give a compound of formula (I). X is O, CH2 or is a diC1-6alkoxy group and R is a cyclopropyl or vinyl group. Where X is a diC1-6alkoxy group, this may be removed to yield a compound of formula (V) wherein X is O. In particular, the compound of formula (V) is naltrexone or naloxone and the starting material of formula (I) is oxycodone. The O- and N-demethylation may be carried out with an aryl or alkyl chloroformate, especially a-chloroethylchloroformate, followed by hydrolysis of the resulting intermediate, e.g. with lithium tri-sec-butylborohydride or the O-demethylation may be carried out with BBr3. The reduction of the iminium-containing intermediate may be carried out with sodium triacetylborohydride or sodium cyanoborohydride. <EMI ID=1.1 HE=131 WI=83 LX=755 LY=1426 TI=CF>

Description

CHEMICAL PROCESS
The present invention relates to a process for the preparation of naltrexone or naloxone.
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.
Some commercial and well known morphinans are shown below. These include naltrexone and naloxone.
HO
NALTREXONE HO NALMEFENE
H H N HO"
NALBUPI-UNE
HO
NALOXONE NALORPHINE
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 * * S * . * * S * S * S S S * * S S S *S * S *e* * * * * S * : * * * S *** . :..
too many individual reactions. A reaction sequence that commences from optionally protected 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.
Therefore, the invention provides a process for the preparation of naltrexone or naloxone or a salt thereof which process comprises: a) the reaction of a compound of the formula (I): H3CO / NCH3 X (I) or a salt thereof wherein X is O,CH2 or X= is a diC16alkoxy group, with a reagent or reagents which result in 0-and N-demethylation to provide a compound of the formula (II):
NH
OH
X (II) or a salt thereof; followed by: * * * * * * * * * * * * S I S * S S S ** S S *SS S S S * I S 5 * * S S S. * S * 5 S *I* b) the reaction with an aldehyde of the formula (Ill): R-CHO (III) wherein R is a cyclopropyl or vinyl group, to yield a intermediate containing the ion of the formula (IV): HO7
NCH-R
)!=.!=J' * OH X (IV) which is reduced to yield a compound of the formula (V): /s> N-CH2R
OH X (V)
wherein X is 0, CH2 or X= is a diC16alkoxy group and removing the keto protecting group if present to yield a compound wherein X is 0.
Most aptly X is 0 or OCH2CH2O. Preferably X is 0. * * *
* S S * * * * S * * S * * S S S ** * * *. : * * * * * S S S * S. 5. S I * 15* The conversion of compound of formula (I) into the compound of formula (II) may be effected in one or two steps.
Thus, for example, the compound of formula (I) may be reacted with a reagent which results in 0-demethylation followed by reaction with a reagent which results in N-demethylation. Alternatively, the compound of formula (I) may be reacted with a reagent which results in Ndemethylation followed by reaction with a reagent which results in 0-demethylation. In one aspect the reagent employed effects both 0-demethylation and N-demethylation.
In some methods of N-demethylation an intermediate carbamate is formed (for example from reaction with a chloroformate) which is then cleaved, for example by the use of L-selectride.
If the chioroformate used is a-chloroethylchloroformate (ACE-Cl), the carbamate formed will be easily hydrolysed. Weak hydrolysing agents, such as MeOH may be used to hydrolyse these carbamates.
If the chloroformate used is C2..6chloroformate, for example ethylchloroformate, the carbamate intermediate will be more stable. A suitable hydrolysing agent that can be used is Lithium selectride (lithium tri-sec-butylborohydride). Another example of a chloroformate is phenyl chloroformate.
A suitable reagent of use in the 0-demethylation and N-deprotection of carbamate intermediates of the compound of the formula (I) is lithium selectride.
An apt reagent for use for the 0-demethylation of a compound of formula (I) is BBr3. An apt reagent for use for the N-demethylation of a compound of formula (I) is a chloroformate, for example a-chloroC1..6alkylchloroformate, preferably a-chioroethylchloroformate. A suitable reagent for use in the 0-demethylation and N-demethylation (via a decarboxymethylation) of a compound of formula (I) is lithium selectride (tri-sec-butylborohyd ride). * S *
* S * * * * I * * * I S * *** I I I ** I * * S I S I S * * S S ** S ** I S I * SIt The reaction of the compound of formula (I) (or its N-demethylated analogue) with BBr3 may take place in an aprotic solvent such as tetrahydrofuran, chloroform, methylene dichloride, 1, 2-dichloroethane or the like. Addition of BBr3 generally takes place at a depressed temperature for example 0 C.
Generally, ambient temperature, for example 20-30 C, is thereafter employed.
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 (II) may be obtained from the aqueous phase (whereas the N-methylated analogue of the compound of formula (II) may be obtained form the organic phase).
The reaction of a compound of formula (I) (or its 0-demethyl analogue) with a chloroformate such as ci-chioroethyichioroformate may be employed to effect N-demethylation.
The N-demethylation of a compound of formula (I) (or its 0-demethylated analogue) into a compound of the formula (II) may be effected at non-extreme elevated temperature, for example at the reflux point of the solvent employed or at about 30-70 C, for example 40-50 C.
The solvent employed may be carried out in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, dichioromethane, I,2-dichloroethane or the like. A favoured solvent is dichioromethane. Surprisingly a most preferably solvent is acetonitrile.
Generally, the reaction is performed under anhydrous conditions, for example under nitrogen. The reaction generally employs a proton abstracting agent, for example carbonate or bicarbonate. Anhydrous sodium carbonate is particularly apt. * . *
* a a * * * * * * a I * * *** S * * S. a * * S * * S * * * * * S S. $ ** S * * * a..
The compound of the formula (I), preferably wherein X is a protected keto group, may be N-demethylated or both N-demethylated and 0-demethylated by reaction with lithium trialkylborohydride following reaction with ACE-Cl.
Suitable lithium trialkylborohydrides include lithium triethylborohydride, lithium tripropylborohydride, lithium tributylborohydride or lithium tripentylborohydride.
A preferred reagent is lithium tri-sec-butylborohydride (sometimes referred to as lithium selectride).
The reaction is carried out in an aprotic solvent such as tetrahydrofuran, diethylether, toluene, dichloromethane, acetonitrile or the like. A non-extreme temperature is generally employed, for example from ambient temperature (about 20-25 C) or an elevated temperature of 50-70 C, for example at reflux.
N-demethylation (via N-decarboxymethylation) may occur first. If the reaction is allowed to proceed, 0-demethylation can then occur to yield the N,O-didemethylated product of the formula (II).
The compound of the formula (II) may be converted to a compound of the formula (V) by reaction with an aldehyde (RCHO) and reduction of the intermediate iminium ion with a suitable reducing agent.
When the 6-keto function is protected, standard hydride reducing agents may be employed. Suitable reducing agents include lithium aluminium hydrides and alkali metal borohydrides. When the 6-keto function is not protected, milder reducing agents are required, for example a triacetylborohyd ride such as lithium or sodium triacetoxyborohydride, sodium cyanoborohydride or even hydrogen gas with a catalyst such as palladium. A preferred reagent is sodium triacetoxyborohydride.
The reductive amination reaction is preferably carried out in a solvent such as tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dichloromethane, 1,2- dichloroethane, ethanol, isopropanol or the like. A preferred solvent is 1,2-dichloroethane.
a a S * S * * S S * * * * I * : : : ** : : : * * *** 5.1:..
The initial reaction between the aldehyde and secondary amine may take place at ambient temperature, for example 20-25C , optionally in the presence of molecular sieves and preferably under anhydrous conditions.
Generally, when X is 0, the reduction reaction is carried out at a depressed temperature, for example -20 C to -30 C. When X is a keto protecting group higher temperatures, for example 0-25 C may be employed.
The compound of formula (II) may be obtained from solution by freeze drying if desired.
Example I
0-demethylation of oxycodone Oxycodone HCI (3.04 g, 8.66 mmol) was suspended in DCM (30 ml) under nitrogen and the reaction flask was immersed in an ice-water bath. Boron tribromide (-3 eq, 25 ml of a I M solution in DCM) was added slowly with stirring. The reaction flask was left in the ice-water bath and the temperature rose slowly to room temperature (RT). Stirring at RT was continued overnight after which HPLC indicated full conversion of starting material. Water (25 ml) was added and the bi-phased reaction mixture was refluxed for 1 hour. The reaction mixture was allowed to cool slowly to RT and a white crystalline solid formed. The solid was filtered off and the resulting filtrate was basified (NH4OH, pH 10). The organic and aqueous phases were separated and the aqueous phase was extracted 5 times using DCM. The combined organic extracts were dried (Na2SO4), filtered and the solvent was removed under reduced pressure.
The residue was dried under vacuum overnight to yield crude oxymorphone as a beige solid 2.34 g (90 % yield), purity <96 % by HPLC.
Example 2
0-Demethylation of noroxycodone Noroxycodone (0.20 g, 0.66 mmol) was suspended in DCM (3 ml) under nitrogen and the reaction flask was immersed in an ice-water bath. Boron tribromide (--3 eq, 2 ml of a 1 M solution in DCM) was added slowly with stirring.
* 0 0 * .0 * * * . 0 * * * * * : : : *. : : : ** 0* * * * 0 * * * *.* The reaction flask was left in the ice-water bath and stirring continued while the temperature rose slowly to RT, after which HPLC showed that all of the starting material had been consumed. Water (3 ml) was added and the reaction mixture was refluxed for 7 hours. The reaction mixture was basified (NH4OH, pH 10) and extracted 4 times with DCM. The product remained in the aqueous phase.
Example 3
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 RT, and the reaction mixture was heated to reflux and stirred for 24 hours. The reaction mixture was filtered and the precipitate was washed with DCM. The filtrate was evaporated to dryness. MeOH (20 ml) was added and the mixture stirred for 1 h at RT. 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 (80:20). The combined organic extracts were dried (Na2SO4), filtered and the solvent was removed under reduced pressure. Crude noroxycodone was obtained as a white foam (0.73 g, 64%), purity 90 % by HPLC.
Example 4
N-cyclopropylmethylation of noroxymorphone Noroxymorphone (0.lOOg) and cyclopropylcarboxaldehyde (0.023 g) are mixed in dichloromethane at room temperature. Also after 30 minutes the solution is cooled to -30 C and NaBH(OAc)3 added. This reaction is left for two days.
HPLC is used to show the presence of naltrexone.
Example 5
N-cyclopropylmethylation of noroxymorphone Noroxymorphone (0.lg) and cyclopropanecarboxaldehyde (0.023g) are mixed in dichoromethane 20m1) at room temperature for 30 minutes. The solution is cooled to -30 C and sodium triacetoxyborohydride (0.07g) is added. The reaction mixture is quenched with sodium bicarbonate solution (20m1) and the * 0 * * *0. a * * I I S * S I * S. * S * S S S I * : : . S.. * **.
phases separated. The solution is adjusted to neutrality. The organic phase is dried (Na2SO4), is filtered and the solvent is removed under reduced pressure to yield naltrexone.
* I * * * * * I I * : : : . :1: : . *t * *** . . . * ***

Claims (16)

  1. Claims 1. A process for the preparation of naltrexone or naloxone or a
    salt thereof which process comprises: a) the reaction of a compound of the formula (I): H3co /J NCH3 X (I) or a salt thereof wherein X is O,CH2 or X= is a diC1..6alkoxy group, with a reagent or reagents which result in 0-and N-demethylation to provide a compound of the formula (II):
    NH
    OH
    X (II) or a salt thereof; followed by: the reaction with an aldehyde of the formula (Ill): I I * * . I * * * * : * * * as a a * * * a a * I a * a a * ** * *.: * * *
    I
    R-CHO (Ill) wherein R is a cyclopropyl or vinyl group, to yield an intermediate containing the ion of the formula (IV): /J
    NCH-R )J'$
    OH
    X (IV) which is reduced to yield a compound of the formula (V):
    HO
    N-CH2R X (V) wherein X is 0, CH2 or X= is a diC16alkoxy group and removing the keto protecting group if present to yield a compound wherein X is 0.
  2. 2. A process as claimed in claim I wherein X is OCH2CH2O.
  3. 3. A process as claimed in claim I wherein X is 0. * *
    * *
  4. 4 * * S * * * I I a a * I * SI I * ** ** S a S * a * I I a ** * *.: * * * 4. A process as claimed in any of claims I to 3 wherein the 0-demethylation is effected using BBr3.
  5. 5. A process as claimed in any of claims I to 3 where the N-demethylation and 0-demethylation is effected using an aryl or alkyl chloroformate, preferably using a-chloroethylchloroformate, followed by hydrolysis of the resulting intermediate, preferably using lithium tri-sec-butylborohyd ride.
  6. 6. A process as claimed in any of claims I to 4 where the N-demethylation is effected using an aryl or alkyl chloroformate followed by hydrolysis of the resulting intermediate.
  7. 7. A process as claimed in claim 6 which employs a-chloroalkyl chloroformate, preferably a-chloroC1..6chloroformate.
  8. 8. A process as claimed in claim 7 wherein the a-chloroC1.6chloroformate is ci-chloroethylchloroformate.
  9. 9. A process as claimed in claim 8 wherein the hydrolysis is effected using an alcohol such as methanol or lithium tri-sec-butylborohydride.
  10. 10. A process as claimed in claim 6 which employs a C2..6chloroformate, for example ethylchloroformate.
  11. 11. A process as claimed in claim 10 wherein the hydrolysis is effected using lithium tri-sec-butylborohydride.
  12. 12. A process as claimed in any preceding claim wherein the reaction solvent in the N-demethylation and 0-demethylation reaction is selected from tetrahydrofu ran, aceton itrile, dimethylformamide, dichloromethane or 1,2-d ichloroethane, preferably d ichloromethane or acetonitrile. *
    * S S S * * * S * * * S S S 5 * * * S. S 5 * * S 5 5 * S S * * S S * S. 4 *** * . * * *S.
  13. 13. A process as claimed in any of claims I to 12 wherein the reduction is effected employing a triacetylborohydride such as sodium triacetylborohydride.
  14. 14. A process as claimed in any of claims I to 12 wherein the reduction is effected by employing a cyanoborohydride such as sodium cyanoborohydride.
  15. 15. A process as claimed in claims 13 or 14 performed at a depressed temperature, for example 5 C to -30 C.
  16. 16. A process as claimed in any preceding claim wherein the reduction is carried out in a solvent such as tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dichloromethane, I,2-dichloroethane, ethanol and isopropanol, preferably I,2-d ichloroethane. S *
    * * S * S * .: : : : *:. * : : * 4 0 * * I S * * *.S * * I * SOS
GB0610385A 2006-05-25 2006-05-25 Processes of preparing morphinan derivatives such as naltrexone and naloxone comprising O- and N-demethylation and reductive alkylation steps Withdrawn GB2444052A (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
GB1017991A GB2471803B (en) 2006-05-25 2006-05-25 Chemical process
GB0610385A GB2444052A (en) 2006-05-25 2006-05-25 Processes of preparing morphinan derivatives such as naltrexone and naloxone comprising O- and N-demethylation and reductive alkylation steps
PCT/EP2007/004679 WO2007137785A2 (en) 2006-05-25 2007-05-25 Process useful in the preparation of morphinan antagonists
US12/300,055 US20100022774A1 (en) 2006-05-25 2007-05-25 Process useful in the preparation of morphinan antagonists
EP07725575A EP2032579A2 (en) 2006-05-25 2007-05-25 Process useful in the preparation of morphinan antagonists
AU2007267362A AU2007267362B2 (en) 2006-05-25 2007-05-25 Process useful in the preparation of morphinan antagonists
CA002652849A CA2652849A1 (en) 2006-05-25 2007-05-25 Process useful in the preparation of morphinan antagonists

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GB0610385A GB2444052A (en) 2006-05-25 2006-05-25 Processes of preparing morphinan derivatives such as naltrexone and naloxone comprising O- and N-demethylation and reductive alkylation steps

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GB2444052A true GB2444052A (en) 2008-05-28

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GB0610385A Withdrawn GB2444052A (en) 2006-05-25 2006-05-25 Processes of preparing morphinan derivatives such as naltrexone and naloxone comprising O- and N-demethylation and reductive alkylation steps

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019009820A1 (en) * 2017-07-04 2019-01-10 Saneca Pharmaceuticals A.S. Process for the preparation of morphinane compounds

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3717643A (en) * 1967-05-04 1973-02-20 Sterling Drug Inc N-substituted-norapomorphines
US3905981A (en) * 1973-10-12 1975-09-16 Research Corp N-dealkylation of tertiary amines
GB2000137A (en) * 1977-06-21 1979-01-04 Warner Lambert Co 7,8-Dihydro-14-hydroxy-normorphine
EP0164290A1 (en) * 1984-05-25 1985-12-11 Sanofi S.A. Process for the dealkylation of alcaloids and intermediates
WO2006035195A1 (en) * 2004-09-30 2006-04-06 Johnson Matthey Public Limited Company Preparation of opiate analgesics by reductive alkylation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3717643A (en) * 1967-05-04 1973-02-20 Sterling Drug Inc N-substituted-norapomorphines
US3905981A (en) * 1973-10-12 1975-09-16 Research Corp N-dealkylation of tertiary amines
GB2000137A (en) * 1977-06-21 1979-01-04 Warner Lambert Co 7,8-Dihydro-14-hydroxy-normorphine
EP0164290A1 (en) * 1984-05-25 1985-12-11 Sanofi S.A. Process for the dealkylation of alcaloids and intermediates
WO2006035195A1 (en) * 2004-09-30 2006-04-06 Johnson Matthey Public Limited Company Preparation of opiate analgesics by reductive alkylation

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Title
Journal of Medicinal Chemistry Vol. 21, No. 4, 1978, pages 398-400 *
Journal of Organic Chemistry Vol. 49, No. 11, 1984, pages 2081-2082 *
Tetrahedron Vol., 48, No. 32, 1992, pages 6709-6716 *
Yaoxue Xuebao Vol. 17, No. 7, 1982, pages 546-548 *
Zhongguo Yaowu Huaxue Zazhi Vol. 8, No. 2, 1998, pages 141-146 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019009820A1 (en) * 2017-07-04 2019-01-10 Saneca Pharmaceuticals A.S. Process for the preparation of morphinane compounds
CN110770237A (en) * 2017-07-04 2020-02-07 萨内卡制药公司 Process for the preparation of morphinan compounds
EA039283B1 (en) * 2017-07-04 2021-12-28 Санека Фармасьютикалс А.С. Process for the preparation of morphinane compounds

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GB2471803A (en) 2011-01-12
GB0610385D0 (en) 2006-07-05
GB2471803B (en) 2011-02-16
GB201017991D0 (en) 2010-12-08

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