GB2392670A

GB2392670A - (+)-Morphine production

Info

Publication number: GB2392670A
Application number: GB0220385A
Authority: GB
Inventors: John Whittall; Paul Mather
Original assignee: Stylacats Ltd
Current assignee: Stylacats Ltd
Priority date: 2002-09-03
Filing date: 2002-09-03
Publication date: 2004-03-10
Also published as: AU2003263301A1; WO2004022564A2; GB0220385D0; AU2003263301A8; WO2004022564A3

Abstract

The invention relates to a process for the production of (+)-morphine from (-)-sinomenine comprising contacting (-)-sinomenine with H2/Pd/C under conditions effective for converting sinomenine to 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof; contacting the resulting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof with polyphosphoric acid or Eatons reagent under conditions effective for converting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof to (+)-dihydrocodeinone; contacting the resulting (+)-dihydrocodeinone with (MeO)3CH followed by TsOH followed by NBA/MeOH under conditions effective for converting (+)-dihydrocodeinone to novel 1,7-dibromodihydrocodeinone dimethylketal, which is useful against pain contacting the resulting 1,7-dibromodihydrocodeinone dimethylketal with t-butoxide followed by acid under conditions effective for converting 1,7-dibromodihydrocodeinone dimethylketal to (+)-1-bromocodeinone; contacting the resulting (+)-1-bromocodeinone with LiA1H4 followed by BBr3 under conditions effective for converting 1,7-dibromodihydrocodeinone dimethylketal to (+)-morphine; and recovering the resulting (+)-morphine as product.

Description

DESCRIPTION

COMPOUND AND PROCESS

The present invention relates to novel intermediate compounds in a process for the production of (+)-morphine from (-)-sinomenine and to the production of the novel intermediate compounds and (-)-sinomenine and to certain intermediate steps in such a process. The function of naturally occurring, (-)-morphine in pain relief is well known. However, recently the properties of its synthetic stereoisomer (+)-morphine have been considered.

Stringer et al, in Neuroscience Letters 295 (2000) 21-24, report that (+)morphine, but not (-)-morphine, has low micro-molar affinity for the site of the N-methyl-D-aspartate (NMDA) receptor in the rat forebrain and suggest the clinical potential for racemic (+)(-)-

morphine in the treatment of neuropathic pain.

Although the clinical potential of (+)-morphine has been postulated, further studies in this area are hindered by the limited commercial availability of (+)-morphine, a problem highlighted in DDT Vol. 6, No. 14 July 2001 in a review article which goes on to suggest (at p746) alternative approaches to achieving NMDA receptor antagonist activity.

The conversion of (-)sinomenine to (+)-morphine has been reported by Iijima et al in J. Org. Chem., Vol. 43, No. 7, 1978, pl462, with reference to earlier work by Goto and

- 2 t Yamamoto, Proc. Jpn. Acad., 30, 769 (1954), 33, 477 (1957) and 34, 60 (1958) and by Weller and Rapoport in J. Med. Chem., 19, 1171 (1976).

It is an object of the present invention to provide an improved synthetic route from (-)-

sinomenine to (+)-morphine and to provide novel intermediate compounds which may be useful for production of a medicament for use in the treatment or prophylaxis of pain.

According to the present invention, there is provided a compound of the formula: MeO,/ Br /\,: NMe 1" MeO;;i \1 MeO I Br or derivative thereof. The compound may be used as an active ingredient in a pharmaceutical preparation. Preferably, the compound or a pharmaceutically active salt thereof may be used in the manufacture of a medicament. The compound or a pharmaceutically active salt thereof, may be used in the manufacture of a medicament for use in the treatment or prophylaxis of pain. It will apparent to those skilled in the art that the medicament may be prepared in a number of formats to allow for different methods of administration, such as oral, intravenous, trans-dermal and suppository for example. It

( - 3 will further be apparent that the medicament may be prepared in a certain manner in order to confer desirable pharmacokinetic or bioavailability properties such as slow release for example.

In accordance with another aspect of the present invention there is provided a process for the production of (+)-morphine (formula 6) from (-) -sinomenine (formula I) comprising at least two reaction steps and at least one intermediate product, the at least one intermediate product comprising 1,7-dibromodihydrocodeinone dimethylketal (formula 4). The chemical formulae I to 6 referred to herein are specified in the reaction scheme below. In one process according to the invention, at least three reaction steps and at least two intermediate products are provided, one of the at least two intermediate products comprising 7(S)-(+)dihydrosinomenine (formula 2) or 7(R)-(+)-dihydrosinomenine or a mixture of both isoforms.

In another process according to the invention, at least four reaction steps and at least three intermediate products are provided, one of the at least three intermediate products comprising (+)-dihydrocodeinone (formula 3).

- 4 In still another process according to the invention, at least five reaction steps and at least four intermediate products are provided, one of the at least four intermediate products comprising (+)- I bromocodeinone (formula 5).

In one preferred process according to the invention, (-)-sinomenine is converted to (+)-

morphine according to the following reaction scheme:

( MeO MeO OH Step I OH Name (2) NMe OMe OMe | Step 2 MeO Br MeO NMe NMe MeO () MeO I Br 1 Sups MeO Br HO / Step 5 / I - 1 . L-----l NMe NMe (5) (6)

- 6 The Preferred reagent for step 1 is H:/Pd/C.

Preferred reagents for step 2 include polyphosphoric acid and Eatons reagent.

Preferred reagents for step 3 include (MeO)3CH followed by TsOH or camphorsulphonic acid followed by NBA/MeOH or N-bromosuccinimide (NBS).

Preferred reagents for step 4 include tBuOK followed by H+.

Preferred reagents for step 5 include LiAIH4 followed by BBr3, BCI3 or trimethylsilyl iodide (TMS-I).

One preferred process according to the invention provides a synthesis of (+)-morphine comprising: a) contacting (-)-sinomenine with HJPd/C under conditions effective for converting (-)-sinomenine to 7(S)-(+)dihydrosinomenine or 7(R)-(+)-dihydrosinomenine; b) contacting the resulting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-

dihydrosinomenine or mixture thereof with polyphosphoric acid or Eatons reagent under conditions effective for converting 7(S)-()dihydrosinomenine or 7(R)-

(+)-dihydrosinomenine to (+)-dihydrocodeinone;

( - 7 c) contacting the resulting (+)-dihydrocodeinone with (MeO)3CH followed by TsOH followed by NBA/MeOH under conditions effective for converting (+)-

d i h y d r o c o d e i n o n e t o 1, 7 - d i b r o m o d i h y d r o c o d e i n o n e d i m e t h y I k e t a I; d) contacting the resulting l, 7-dibromodihydrocodeinone dimethylketal with t-

butoxide followed by acid under conditions effective for converting 1,7-

dibromodihydrocodeinone dimethylketal to (+)-I-bromocodeinone; e) contacting the resulting (+)-I-bromocodeinone with LiAIH4 followed by BBr3 under conditions effective for converting (+)-l-bromocodeinone to (+) -morphine; and f) recovering the resulting (+)-morphine as product.

g) further processing the (+)-morphine into a medicament.

The invention further provides a process for the synthesis of 1,7-

dibromdihydrocodeinone dimethylketal from (-)-sinomenine by steps a) to c) indicated above. Also provided in accordance with the invention is a process for the synthesis of (+)-

morphine from 1,7-dibromdihydrocodeinone dimethylketal by steps d) to f) indicated above. The invention also provides for the (+)-morphine produced by steps a) to f) to be further processed into a medicament. It will be apparent that the medicament may be prepared in a number of formats to allow for different methods of administration and the medicament

- 8 may also be prepared in a certain manner in order to confer desirable pharmacokinetic or bioavailability properties.

The process of the invention will now be more particularly described with reference to the following Example.

Example

A synthesis of (+)-morphine was conducted in accordance with the invention, using the following process steps.

Step I - Preparation of a mixture of 7(R)- and 7(S)-(+)-dihydrosinomenine 25g of (-)-sinomenine.HCI was dissolved in 750g methanol. O.5g Pd/C was then added.

The mixture was then hydrogenated (latm, balloon) with stirring overnight (20hrs). Thin layer chromatography (4:1 CHCI3:MeOH, run up the plate twice) showed the reaction to be complete. The solution was then filtered through Celite and evaporated to dryness to obtain 23.1 g of product. Two further reactions on the same scale have produced 24.5g of product. Step 2(i) - Preparation of (+)-dihydrocodeinone from a mixture of 7(R) and 7(S) -(+) dihydrosinomenine

( - 9 -

Polyphosphoric acid (300g) was added to 1 5g of the mixture of 7(R) and 7(S)-(+)-

dihydrosinomenine obtained from step 1. The mixture was heated to 70 C and stirred for 1.25h. After cooling to room temperature the mixture was poured into a stirred solution of 33% NH3 (200ml), CHCI3 (200ml) and ice, the addition was slow in order to avoid overheating. Occasionally, more ice was added to control the temperature and finally NH3 solution was added to make the solution basic (ca pH 8). The solution was then saturated with NaCI and extracted with CHCI3 (3 x 200ml). The combined extracts were then dried (Nazso4), filtered and evaporated to dryness to provide 7.5g of product as a beige solid.

Step 2(ii) - Alternative preparation of (+)-dihydrocodeinone from a mixture of 7 (R) and 7(S)-(+)-dihydrosinomenine In an alternative method for Step 2, polyphosphoric acid was replaced with Eatons reagent (7% phosphorus pentoxide in methanesulphonic acid). The reaction was complete after 10mins at 70 C, affording the product in near quantitative yield as beige solid. Step 3a- Preparation of (+)-dihydrocodeinone dimethylketal from (+)-dihydrocodeinone (Method derived from that described in JMed Chem, 1976, vol 19, No 10, pl l 74.) 4.5g of (+)-dihydrocodeinone from step 2 was heated with 7.2ml trimethylorthoformate (TMO) to effect solution. 1.4ml cone. H2SO4 was added and the mixture heated to reflux

- 10 (70 ). After 6h a small amount of starting material remained and the mixture was left to stir overnight at room temp (17h). Further portions of TMO (2.5ml) and H2SO4 (0.3ml) were added and the solution heated to reflux again for 2h, after which tic showed only a trace of the starting material. The cooled mixture was poured into 0.5M Na2CO3 solution (I OOml) and extracted with CHC13 (lOOml). The separated organic phase was washed with brine, dried (Na2SO4) and evaporated to yield 5. lg of product.

Step 3b - Preparation of A6-dihydrothebaine from (+)-dihydrocodeinone dimethylketal (Method derived from that described in J Med Chem, 1976, vol 19, No 10, pl 174.) A solution of p-toluenesulphonic acid (2.45g) in dry CHCI3 (I OOml) was added to 4.1 g of (+)-dihydrocodeinone dimethylketal in dry CHC13 (lOOml) and the solution then heated at 1 20 C for 1 5mins, collecting a distillate of ca 1 OOml. The reaction mixture was cooled to 0 C and poured into cold 0.5M Na2CO3 (lOOml). The layers were separated and the aqueous phase washed with CHCI3 (lOOrnl). The combined organic phases were then washed with brine, dried (Na2SO4) and evaporated to give 3.5g of desired enol ether as an oil which solidified on standing.

Step 3c - Preparation of 1,7-dibromodihydrocodeinone dimethylketal 2.1 g of the product enol ether from step 3b was dissolved in CHC13 (200ml) and cooled to -5 C. HBr-H2O (1.13ml of a 6.7mmol solution) was added and the mixture stirred for 2mins. 1 50ml of saturated Nallr solution was added (at 0 C) and the mixture shaken.

The layers were separated and the aqueous phase was washed with 50ml CHCI3. The combined organic phases were dried (Na2SO4) and evaporated. The residue was then dissolved in methanol (80ml), cooled (to 0 C) and treated dropwise with a cooled solution (0 C) of NBA in MeOH over 30mins. The slightly orange solution was evaporated and dissolved by shaking with CHCI3 (150ml) and 2M aqueous NaOH (30ml). After separation, the aqueous phase was extracted with CHCI3 (30ml) and the combined organic phases washed with water (lOOml) and brine (lOOml) then dried (Na2SO4) and evaporated to give 2.5g of a mixture of two compounds by tic. The major compound was the desired dibrominated product and the minor component was the corresponding monobrominated compound, with the Br occupying the 1position on the dihydrocodeinone ring system, as reported by Weller and Rapoport in JMed Chem, 1976, vol19,No10,pll74. Step 4a- Preparation of lbromocodeinone dimethylketal The crude product mixture from step 3b was dissolved in 50ml DMSO together with 1.32g potassium tert-butoxide and the mixture stirred overnight at room temperature. A further portion of potassium tert-butoxide 0.33g was added and the mixture then heated at 60 C for 6h. After cooling, toluene (150rnl) and water (150ml) were added, the layers separated and the aqueous further extracted with toluene (50ml). The combined organics were washed with water (lOOml) and brine (lOOml) then dried (Na2SO4) and evaporated to give 1.85g of crude product.

- 12 Step 4b - Preparation of (+)-1-bromocodeinone The bromoketal product from step 4a was dissolved in dilute aqueous HC1 and heated at 70 C for 30mins. On cooling to 0 C the solution was neutralised to pH 7 with 2M NaOH (0 C) and then extracted with CHCl3 (100ml and 50ml). The combined organic phases were washed with brine and dried (Na2SO4). Evaporation afforded an off-white solid (1.15g). The aqueous phase was Gasified (pH 10) and further extracted with CHC13 to afford more product (0.6g). The two product samples gave similar tic results and were combined. Flash chromatography revealed the presence of two compounds in the combined sample, 1-bromocodeinone and 1-bromodihydrocodeinone.

Step 5a - Preparation of (+)-codeine (Method derived from White et al, Tetrahedron, 1983, 39, 2393, which describes the preparation of (-)codeine.) Product l-bromocodeinone (400mg) from step 4b was taken in 20ml THE and 0.2g LiAlH4 was added. The mixture was heated under reflux for 14h.

After cooling, 1:1 THF:H2O (10ml) was added, followed by saturated aqueous potassium carbonate (5ml). Alternatively, sodium potassium tartrate may be substituted for saturated aqueous potassium carbonate. The mixture was extracted with CH2C12 (lOOml + 50ml) and the combined organic phases were washed with water (100ml) and dried (MgSO4). Flash chromatography of the residue afforded (+)-codeine (240mg) as a white solid.

r! - 1 3 Step Sb(i) - Conversion of (+)-codeine to (+)-morphine (+)codeine (120mg) from step 5a was dissolved in CHCI3 (dry, 2.5ml) and the resulting solution treated under N2 at 20 C with BBr3 solution (2.4ml of a 1.0M solution in CH2CI2), which was added over two minutes. Stirring was continued for 1 5mins and the mixture was then poured into a mixture of ice (leg) and NH40H (28% NH3). Crystalline material formed initially but after 30mins at 0 C, the material dissolved. The aqueous mixture was transferred to a separating funnel (rinsing with 10ml CHCI3, 1 Oml H2O and 2.5ml NH40H), saturated with NaCI and extracted with 3:1 CHCI3:EtOH (2 x 25rnl).

The combined organic phases were dried (MgSO4) and evaporated to give 130mg of crude product.

Step 5b(ii) - Alternative conversion of (+)-codeine to (+)-morphine (+)codeine (70mg) from step 5a was dissolved in CHCI3 (1.5ml) and the resulting solution treated under N2 at room temperature with BBr3 solution (0.94ml of a l.OM solution in CH2CI2), which was added over two minutes. Stirring was continued for 1 5mins and the mixture was then poured into a mixture of ice (8g) and NH.OH (2ml) and stirred for 30mins. Crystalline material formed initially but after 30mins at 0 C, the material dissolved. The lower organic layer had the appearance of an emulsion and was separated. However, tlc revealed the presence only of impurities. The aqueous mixture was extracted with 3:1 CHCI3:EtOH (2 x 20ml). The combined organic phases were dried (MgSO4) and evaporated to give 60mg of crude product.

l - 14 The combined crude products from steps 5b(i) and Sb(ii) were dissolved in a minimum volume of methanol and triturated with distilled water. After standing for 1 Sh (+)-

morphine was afforded as an off-white solid.

Claims

- 15 CLAIMS

1. A compound of the formula: MeOT/ Br /\ NMe | | H MeO MeO | Br (formula 4) or derivative thereof.

2. A pharmaceutical preparation comprising, as an active ingredient, a compound according to claim 1.

3. A compound according to claim I or a pharmaceutically active salt thereof, for use in the manufacture of a medicament.

4. A compound according to claim I or a pharmaceutically active salt thereof, for the use in the manufacture of a medicament for use in the treatment or prophylaxis of pain.

5. A process for the production of a compound according to claim I wherein (+)-

dihydrocodeinone is treated with (MeO)3CH followed by TsOH followed by NBA/MeOH under conditions effective for converting (+)-dihydrocodeinone to 1,7-

dibromodihydrocodeinone dimethylketal.

r - 16

6. A process according to claim 5 wherein the wherein (+)dihydrocodeinone is produced by treating 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof is with polyphosphoric acid or Batons reagent under conditions effective for converting 7(S)-(+)dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof to (+ )-dihydrocodeinone.

7. A process according to claim 6 wherein the 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-

dihydrosinomenine or a mixture thereof is produced by contacting (-)sinomenine with H2/Pd/C under conditions effective for converting (-)sinomenine to 7(S)-(+)-

dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof.

8. A process according to claims 5 to 7 comprising at least two reaction steps and at least one intermediate product, the at least one intermediate product comprising 7(S)-

(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof.

9 À A process according to claims 5 to 7 for the production of a compound according to claim I comprising at least two reaction steps providing at least one intermediate product, the intermediate products comprising (+)dihydrocodeinone.

10. A process according to any one of claims 5 to 9 comprising contacting (-)-sinomenine with H2/Pd/C under conditions effective for converting (-)sinomenine to 7(S)-(+)-

dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof; contacting the resulting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)dihydrosinomenine or a mixture thereof with polyphosphoric acid or Eatons reagent under conditions effective for converting 7(S)-(+)dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof to (+ )-dihydrocodeinone; contacting the resulting (+)-dihydrocodeinone with

( b - 17 (MeO)3CH followed by TsOH followed by NBA/MeOH under conditions effective for converting (+)-dihydrocodeinone to 1,7dibromodihydrocodeinone dimethylketal.

11. A process for the production of (+)-morphine (formula 6) from (-)sinomenine (formula I) comprising at least two reaction steps and at least one intermediate product, the at least one intermediate product comprising 1,7-

dibromodihydrocodeinone dimethylketal (formula 4).

12. A process according to claim 11 comprising at least three reaction steps providing at least two intermediate products, one of the at least two intermediate products comprising 7(S)-(+)-dihydrosinomenine or 7(R)-(+ )-dihydrosinomenine or a mixture thereof.

13. A process according to claim 1 I comprising at least three reaction steps providing at least two intermediate products, one of the at least two intermediate products comprising (+)-dihydrocodeinone.

14. A process according to claim 11 comprising at least three reaction steps providing at least two intermediate products, one of the at least two intermediate products comprising (+)-l-bromocodeinone.

15. A process according to any one of claims 1 I to 14 comprising at least three reaction steps providing at least two intermediate products, one of the at least two intermediate products being selected from 7(S)/(R) -(+)-dihydrosinomenine, (+)-dihydrocodeinone and (+)-I-bromocodeinone.

16. A process according to claim 11 comprising at least four reaction steps providing at least three intermediate products, two of the at least three intermediate products being

( - 18

selected from 7(S)/(R)-(+)-dihydrosinomenine, (+)-dihydrocodeinone and (+) -1-

bromocodeinone.

17. A process according to claim 16 comprising at least five reaction steps providing at least four intermediate products, three of the at least four intermediate products being 7(S)/(R)-(+)dihydrosinomenine, (+)-dihydrocodeinone and (+)-1-bromocodeinone.

18. A process according to any one of claims 1 1 to 17 in which (-)sinomenine is converted to (+)-morphine according to the following reaction scheme:

( ( - 19

MeO if MeO OH'- Step I OH-

NMe NMe O (1) (2) O

OMe OMe 1 Sp2 MeO:Br MeO: Step3 / NNM \1 NMe MeO O MeO I Br 1 s - 4 MeO; Br in 5 HO -: NMe NMe (5) (6)

- 20

19. A process according to any one of claims 1 I to 18 comprising contacting (-) sinomenine with HJPd/C under conditions effective for converting (-) sinomenine to 7(S)-(+)-dihydrosinomenine or 7(R)-(+)dihydrosinomenine or a mixture thereof; contacting the resulting 7(S)-(+)dihydrosinomenine or 7(R)-(+) dihydrosinomenine or a mixture thereof with polyphosphoric acid or Eatons reagent under conditions effective for converting 7(S)-(+)-dihydrosinomenine or 7(R)-(+)-dihydrosinomenine or a mixture thereof to (+)-dihydrocodeinone; contacting the resulting (+)dihydrocodeinone with (MeO)3CH followed by TsOH followed by NBA/MeOH under conditions effective for converting (+) dibydrocodeinone to 1,7dibromodihydrocodeinone dimethylketal; contacting the resulting 1,7dibromodihydrocodeinone dimethylketal with t-butoxide followed by acid under conditions effective for converting 1,7-dibromodihydrocodeinone dimethylketal to (+)-1-bromocodeinone; contacting the resulting (+)-1 bromocodeinone with LiAIH4 followed by BBr3 under conditions effective for converting (+)- I -bromocodeinone to (+)-morphine; and recovering the resulting (+)-morphine as product.