NZ730827B2 - Improved method of manufacturing buprenorphine and analogues thereof from oripavine - Google Patents

Abstract

The invention relates to an improved method of preparing buprenorphine, a salt thereof, analogues of buprenorphine and their salts. In particular, the invention relates to a method of preparing buprenorphine and related products and salts in economic and ecologic ways having increased yields. The buprenorphine and analogues are produced by the reaction of formula (I) to produce formula (II) as shown in the abstract figure, wherein the formation of the tertiary alkyl alcohol at position 7 is carried out using essentially tert-butylmethylether, 2-methyl-tetrahydrofuran, dimethoxymethane or mixtures thereof. prenorphine and analogues are produced by the reaction of formula (I) to produce formula (II) as shown in the abstract figure, wherein the formation of the tertiary alkyl alcohol at position 7 is carried out using essentially tert-butylmethylether, 2-methyl-tetrahydrofuran, dimethoxymethane or mixtures thereof.

Description

Improved Method of Manufacturing Buprenorphine and Analogues thereof from Oripavine Field of the invention The present invention relates to an improved method of preparing buprenorphine, analogues of buprenorphine or salts thereof, as well as a product produced by the method of the invention and the use of the product in a pharmaceutical formulation as well as the pharmaceutical formulation.

In particular, the invention relates to a novel efficient method having economic and ecologic ages.

State of the art Buprenorphine (cyclopropylmethyl[(S)—3,3-dimethylhydroxybutanyl]methoxy-4,5-epoxy- 6,14-ethanomorphinanol), generally administered in the form of its hydrochloride salt, is a potent semi-synthetic opiate sic, for the relief of moderate, chronic and acute pain, as well as in the therapy of opioid addiction. Since its approval it has been ed as injectable solution, various types of tablets or s. Buprenorphine can be administered as sole active ingredient or in combination with other substances such as naloxone, for example. 18,19-dihydroetorphine, an analogue of buprenorphine, can be used as strong analgesic. |ts clinical properties indicate administration as sublingual tablet or transdermal patches. Main appli- cation fields are the treatment of very e pains and to treat addicts. Even though the y of 18,19-dihydroetorphine is several thousand times higher than that of morphine, the observed side effects are mild. orphine and dihydroetorphine can be shown by the following formula (II) wherein R’ is methylcyclopropyl, R" is tert-butyl and R’" is H in case of orphine, and wherein R’ is methyl, R" is n-propyl and R’" is H in case of 18,19-dihydroetorphine.

(Formula II) It is desirable to develop economic and ecologic methods to manufacture such substances and their pharmaceutically acceptable salts.

Several s for synthesizing buprenorphine from compounds isolated from the opium poppy or compounds d therefrom are known. The most conventional ones use thebaine as starting material, which is shown in Formula | below wherein R is a methyl group and R’" is methyl. synthesis from thebaine to buprenorphine and to analogues thereof. The synthetic route is a series of chemical reaction steps, ing (i) adding methyl vinyl ketone to thebaine, (ii) hydrogenation of the 18,19 etheno group, (iii) addition of the tertiary butyl group by a rd reaction, (iv) 17-N-demethylation and ucing of a cyano group (2 steps), (v) 3-O-de- ation, (vi) hydrolysis of 17-N-cyano group, and (vii) addition of a cyclopropyl methyl group.

The number of steps, the low yield in some critical steps and the restriction to thebaine as starting material are serious drawbacks of this method. which is shown in formula I below wherein R is a methyl group and R’" is H, and which also shows the numbering of carbon atoms in the structure of oripavine and analogues as well as products derived therefrom. The process comprises a series of 8 chemical reactions, following along the conventional route as described when using thebaine as starting nce. Drawback of this route is the need to t the hydroxyl group in position 3 when using oripavine as starting material. Reported yield over all steps is calculated to less than 11.5 %.

(Formula I) Werner et al. (Werner, L.; Machara, A.; Adams, D. R.; Cox, D. P.; ky, T.; J. Org.

Chem. 2011, 76, 4628-4634) describe a synthesis starting from oripavine. However, only a low yield can be obtained or a need for further reaction steps arises for obtaining high yields of buprenorphine.

Also particular steps have been disclosed. describes the hydrogenation of the 18,19 etheno group.

A problem of the actual known methods of preparing buprenorphine is that the preparation still requires many steps, a long s time and includes rather complicate and also critical steps. Further, each step reduces yield, and therefore has an impact on economic and ecologic factors. There is a need for new routes for the synthesis of buprenorphine and analogues f.

In on, there is further a need to optimize the process for synthesizing buprenorphine and analogues thereof from an economic and ecologic point of view.

Thus, an object of the present invention is to provide an ed, more efficient, method of obtaining buprenorphine or a salt thereof, an analogue of buprenorphine or salts thereof.

Summary of the invention In one aspect there is provide a method of preparing a compound of Formula II, or a salt f, from a compound of Formula I, wherein in Formula II R’ represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms, and R’’ represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms, comprising: (Formula II) (Formula I) (i) replacing the group R in the compound of Formula I, wherein R is H or , by a group R’ being a , branched and/or cyclic alkyl group having 1 to 10 carbon atoms; (ii) addition of methyl vinyl ketone to obtain 1-[(5α,7α)alkyl-4,5-epoxy hydroxymethoxy-6,14-ethenomorphinanyl]ethanone or 1-[(5α,7α)alkyl-4,5- epoxyalkoxymethoxy-6,14-ethenomorphinanyl]ethanone; (iii-a) converting the acetyl group in position 7 into a tertiary alkyl alcohol having a general ure –C-(OH)-(CH3)-R", wherein R’’ represents a linear, branched and/or cyclic alkyl group with 1 to 10 carbon atoms; and (iv-a) reducing the etheno group in position 18,19 to form the compound of Formula II; and (v) optionally converting the product from step (iv-a) into an addition salt, preferably a pharmaceutically acceptable salt, wherein introducing and later releasing protecting groups is avoided; and wherein R’’’ is H, wherein step (iv-a) is carried out after step (iii-a), wherein step (iii-a) is carried out using ially tert-butylmethylether, 2-methyl-tetrahydrofuran, dimethoxymethane or mixtures thereof as solvent, n other solvents are contained in a solvent e with less than 10 wt.%, based on the total weight of all ts used in step (iii-a).

The current invention offers a novel method for manufacturing buprenorphine, 18,19- dihydroetorphine and other analogues thereof, as well as acid addition salts. An economic and ecologic way is presented to manufacture the desired substances using a novel ce of reaction steps [next page is page 4] delivering a satisfying yield and without the known and explained drawbacks of actual proce- dures.

The ors found that such substances or salts f can easily be produced by choosing a novel series of reactions and thus avoiding some of the conventional reaction steps, mainly the protection of a side chain. In addition, an t way of substituting the N-methyl group by any alkyl group has been found. Further, an increased yield can be obtained with the novel method.

Additionally, it was found out that it is effective to carry out the steps with low yield earlier in a on sequence in order to reduce production cost and ecological impact, as the amount of e.g. solvents and energy can be reduced. The inventors found out that it is possible to carry out the production of buprenorphine and analogues thereof with an increasing yield in the steps by carrying out first the conversion of the acetyl group in position 7 into a tertiary alkyl alcohol and then reducing the etheno group in position 18,19 of the buprenorphine structure, ry to the route commonly applied in the state of the art. Furthermore, the amount of an expensive catalyst used can be reduced when carrying out the reducing step (iv-a) after the step of converting the acetyl group in position 7 (iii-a), i.e. in a later step, compared to carrying out the reducing step (iii- b) before the conversion step of the acetyl group in position 7 , thus also reducing inevitable losses of such catalyst as well as ng further waste material.

In one aspect, the present ion relates to a method of preparing a compound of Formula II, or a salt thereof, from a compound of formula I, wherein in Formula II R’ represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms, R" represents a linear, ed and/or cyclic alkyl group having 1 to 10 carbon atoms, and R’" represents H or a linear, branched and/or cyclic alkyl group having one to 6 carbon atoms, comprising: (Formula II) (Formula I) (i) optionally replacing the group R in the compound of Formula I, wherein R is H or methyl, by a group R’ being a linear, ed and/or cyclic alkyl group having 1 to 10 carbon atoms; (ii) addition of methyl vinyl ketone to obtain 1-[(50L,70c)alkyl-4,5-epoxy-3—hydroxy methoxy-6,14-ethenomorphinanyl]ethanone or 1-[(50c,70c)—17-alkyl-4,5-epoxyalkoxy methoxy-6,14-ethenomorphinanyl]ethanone; (iii-a) converting the acetyl group in position 7 into a ry alkyl alcohol having a general structure —C-(OH)—(CH3)-R", wherein R" represents a linear, branched and/or cyclic alkyl group with 1 to 10 carbon atoms; and (iv-a) reducing the etheno group in position 18,19 to form the compound of Formula II; (v) optionally converting the product from step (iv-a) or step (iv-b) into an addition salt, preferably a pharmaceutically acceptable salt.

In another aspect the present invention relates to a compound of Formula II, OCH3 (Formula II) n in a II R’ represents a , branched and/or cyclic alkyl group having 1 to 10 carbon atoms, R" ents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms, and R’" represents H or a linear, branched and/or cyclic alkyl group having one to 6 carbon atoms, obtained by the method according to the invention.

Also described is a pharmaceutical formulation comprising the compound of Formula II obtained by the method according the invention.

Also described is the pharmaceutical formulation comprising the compound of Formula II obtained by the method according the invention for use in a medicine.

In addition, described is the use of the compound of Formula II ed by the method according the invention in a pharmaceutical formulation.

Further embodiments are disclosed in the dependent claims and can be taken from the following description and examples, t being limited thereto.

Detailed description of the t invention All ranges disclosed herein are to be considered to be supplemented by the term "about", unless y defined to the contrary or otherwise clear from the context.

All s or percentages relating to amounts of a substance within this application are given in wt.%, unless clearly defined to the contrary or otherwise clear from the context.

In regard to this invention, a reference to a , branched and/or cyclic alkyl group refers to linear alkyl groups, branched alkyl groups, cyclic alkyl groups, cyclic alkyl groups with linear or branched alkyl groups attached, i.e. lkylalkyl groups, and linear or branched alkyl groups with a cyclic alkyl group attached, i.e. alkylcycloalkyl groups, wherein the cyclic alkyl group in the alkylcycloalkyl groups can also have linear or branched alkyl groups attached.

The present invention relates in a first aspect to a method of preparing a compound of Formula II, or a salt f, from a compound of Formula I, wherein in Formula II R’ ents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms, R" represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms, and R’" represents H or a linear, branched and/or cyclic alkyl group having 1 to 6 carbon atoms, comprising: (Formula II) (Formula I) (i) optionally replacing the group R in the compound of Formula I, wherein R is H or methyl, by a group R’, being different from R, selected from H or a , branched and/or cyclic alkyl group having 1 to 10 carbon atoms; (ii) addition of methyl vinyl ketone to obtain 1-[(50L,70c)alkyl-4,5-epoxy-3—hydroxy methoxy-6,14-ethenomorphinanyl]ethanone or 1-[(50c,7oc)alkyl-4,5-epoxyalkoxy methoxy-6,14-ethenomorphinanyl]ethanone; (iii-a) converting the acetyl group in position 7 into a tertiary alkyl alcohol having a l structure —C-(OH)—(CH3)—R", wherein R" represents a linear, branched and/or cyclic alkyl group with 1 to 10 carbon atoms; and (iv-a) reducing the etheno group in position 18,19 to form the compound of Formula II; (v) optionally converting the product from step (iv-a) or step (iv-b) into an addition salt, preferably a pharmaceutically able salt.

Further described is a method of preparing a compound of a II, or a salt thereof, from a compound of Formula I, wherein in Formula II R’ represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms, R" represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms, and R’" ents H or a linear, branched and/or cyclic alkyl group having 1 to 6 carbon atoms, comprising: (Formula II) (Formula I) (i) optionally replacing the group R in the compound of Formula I, n R is H or methyl, by a group R’, being different from R, selected from H or a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms; (ii) addition of methyl vinyl ketone to obtain 1-[(50L,70c)alkyl-4,5-epoxy-3—hydroxy methoxy-6,14-ethenomorphinanyl]ethanone or c,7oc)alkyl-4,5-epoxyalkoxy methoxy-6,14-ethenomorphinanyl]ethanone; (iii-b) reducing the etheno group in position 18,19; and (iv-b) converting the acetyl group in position 7 into a tertiary alkyl alcohol having a general structure —C-(OH)—(CH3)—R", n R" represents a , branched and/or cyclic alkyl group with 1 to 10 carbon atoms, to form the compound of Formula II; and (v) optionally converting the product from step (iv-a) or step (iv-b) into an addition salt, preferably a pharmaceutically acceptable salt.

In Formulas I and II, R, R’, R" and R’" can be the same or different.

According to certain aspects, the present invention relates to a method of preparing a nd of Formula IV, or a salt thereof, from oripavine, wherein in Formula IV R’ ents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms and R" represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms comprising: OC‘H3 (Formula IV) (i) optionally replacing the 17-N methyl group in oripavine by a group R being a , branched and/or cyclic alkyl group having 2 to 10 carbon atoms to obtain a compound of Formula III,17-N-alkyl nororipavine; OCH3 (Formula III) (ii) addition of methyl vinyl ketone to obtain 1-[(50L,70c)alkyl-4,5-epoxy-3—hydroxy methoxy-6,14-ethenomorphinanyl]ethanone; (iii-a) converting the acetyl group in position 7 into a tertiary alkyl alcohol having a general structure —C-(OH)—(CH3)-R", wherein R" represents a linear, branched and/or cyclic alkyl group with 1 to 10 carbon atoms; and (iv-a) reducing the etheno group in position 18,19 to form the compound of Formula IV; (iii-b) reducing the etheno group in position 18,19; and (iv-b) converting the acetyl group in on 7 into a tertiary alkyl alcohol having a general structure —C-(OH)—(CH3)-R", wherein R" represents a linear, branched and/or cyclic alkyl group with 1 to 10 carbon atoms, to form the compound of Formula IV; and (v) ally converting the product from step (iv-a) or step (iv-b) into an addition salt, preferably a pharmaceutically acceptable salt.

According to n aspects, the present invention s to a method of preparing a compound of Formula IV, or a salt thereof, from oripavine, wherein in Formula IV R’ represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms and R" represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms comprising: 013113 (Formula IV) (0 optionally replacing the 17-N methyl group in oripavine by a group R being a , branched and/or cyclic alkyl group having 2 to 10 carbon atoms to obtain a compound of a |||,17-N-alkyl nororipavine; @0113 la III) (ii) addition of methyl vinyl ketone to obtain 1-[(50L,70c)alkyl-4,5-epoxy-3—hydroxy methoxy-6,14-ethenomorphinanyl]ethanone; (iii-a) converting the acetyl group in position 7 into a tertiary alkyl alcohol having a general structure —C-(OH)—(CH3)-R", wherein R" represents a linear, branched and/or cyclic alkyl group with 1 to 10 carbon atoms; and (iv-a) reducing the etheno group in position 18,19 to form the compound of Formula IV; (v) ally converting the product from step (iv-a) or step (iv-b) into an addition salt, preferably a pharmaceutically acceptable salt.

In addition, described is a method of preparing a compound of Formula IV, or a salt thereof, from oripavine, n in Formula IV R’ represents a linear, ed and/or cyclic alkyl group having 1 to 10 carbon atoms and R" represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms comprising: OCH?), (Formula IV) (i) optionally replacing the 17-N methyl group in oripavine by a group R being a , branched and/or cyclic alkyl group having 2 to 10 carbon atoms to obtain a compound of Formula |||,17-N-alkyl nororipavine; \"'5 , OH '0‘ (Formula III) (ii) addition of methyl vinyl ketone to obtain 1-[(50L,70c)alkyl-4,5-epoxy-3—hydroxy y-6,14-ethenomorphinanyl]ethanone; (iii-b) reducing the etheno group in position 18,19; and (iv-b) converting the acetyl group in position 7 into a tertiary alkyl alcohol having a l structure —C-(OH)—(CH3)-R", wherein R" represents a linear, branched and/or cyclic alkyl group with 1 to 10 carbon atoms, to form the compound of Formula IV; and (v) optionally converting the product from step (iv-a) or step (iv-b) into an addition salt, preferably a pharmaceutically acceptable salt.

In Formulas III and IV, R, R’, and R" can be the same or different.

It is understood that all these reaction steps (i) to (v) work under different conditions. In general, there are no limitations in the choice of the solvents, temperature, reaction time, or gas re.

The optional step (i) is a nucleophilic substitution, not particularly limited, and can be suitably d out as known from general synthesis methods. Step (i) consists of two eps to replace a 17-N-R group by a different 17-N-alkyl group. First the alkyl group R’ is introduced and R is released. For example, the compound of Formula |, e.g. oripavine or thebaine, can react with an alkyl R’-X’ wherein R’ represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms and X’ ents a suitable leaving group like halogenide, leading to an addition of alkyl and uently the 17-N-methyl group or the H in position 17 can be removed to obtain 17-N- alkyl nororipavine in case R"’ is H. Depending on starting and target molecule, step (i) needs to be carried out or not. Preferably R is a methyl group and R’ can be a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms.

In certain embodiments, the reaction of step (i) can be d out at a temperature between 0 and 100°C, e.g. 50 to 90 °C, preferably 70 to 85 °C, for a total time of less than 24 hours, wherein e.g. the addition step of an alkyl group can be carried out in less than 20 hours and the elimination of the methyl group or H in less than 4 hours. A t can be suitably selected for the reaction and is not particularly limited in step (i). It can be e.g. DMF (dimethylformamide) in the addition of an alkyl group and DMSO (dimethylsulfoxide) in the elimination step from the quaternary amine.

Oripavine or thebaine, serving as possible and preferred starting materials, can thereby be obtained from known sources. Preferably oripavine and thebaine are ted from the latex of certain types of papaveraceae. It is also possible to use synthetic or semi-synthetic oripavine or thebaine in the present .

In certain embodiments a different starting al than oripavine can be used and thus the substitution of the original alkyl group to the tertiary amine in step (i) by a different one is not limited to the substitution of methyl by methyl cyclopropyl. |n contrary, all kinds of linear, or branched alkyl groups having a total of 3 to 10 carbon atoms as well as alkyl groups having a ring structure can be used. In case the alkyl group ns a ring the ring may have 3 to 7 carbon atoms. Preferably oripavine or ne is used as educt and converted to buprenorphine or 18,19- dihydroetorphine. r preferably oripavine or thebaine is converted to buprenorphine, and according to certain aspects oripavine is converted to buprenorphine.

In preferred embodiments, the group R’ is a linear, branched and/or cyclic alkyl group having 1 to carbon atoms, e.g. a methyl group. In embodiments wherein R’ contains a cyclic group, e.g. an alkyl cycloalkyl group, R’ has preferably 3 to 10 carbon atoms, further preferably 3 to 7 carbon atoms, more preferably 3 to 5 carbon atoms. A le and preferred example is e.g. a methylcyclopropyl group.

The addition of methylvinylketone in step (ii) can be suitably carried out using e.g. a Diels-Alder- reaction. The addition in step (ii) can be an addition of methyl vinyl ketone (MVK) by a Diels-Alder reaction to introduce an etheno group n the atoms in position 6 and 14. While adding the etheno group n the atoms in position 6 and 14, an acetyl group is attached in on 7 in such a reaction.

In certain embodiments, the reaction can be carried out at a temperature between 0 and 100°C, e.g. 50 to 90 °C, for a total time of less than 24 hours, e.g. less than 15 hours. A t for the reaction can be suitably selected and is not particularly limited in step (ii).

The educt in step (ii) can be either the compound of Formula |, e.g. oripavine or thebaine, if the optional step (i) is not d out, or can be e.g. the 17-N-alkylated product of the compound of formula (I) if step (i) is carried out.

Step (iii-a), respectively step (iv-b) represent the conversion of the acetyl group in position 7 of the ring structure by a suitable reaction, e.g. by a Grignard reaction with R"MgX, wherein R" represents a , branched and/or cyclic alkyl group with 1 to 10 carbon atoms, and X ents a halogen to form the l. Step (iii-a), tively step (iv-b) can also be seen as a conversion of the acetyl group in position 7 into a 18,19-dehydrobuprenorphine derivative/analogue having different groups R’ and/or R" and/or R’", wherein R’, R" and R’" can be the same or different, e.g. by reaction with R"MgX, wherein R" represents a linear, branched and/or cyclic alkyl group with 1 to 10 carbon atoms, and X represents a halogen.

In certain embodiments, the Grignard reaction in step (iii-a), respectively step (iv-b) can be conducted with any suitable substance to convert the acetyl group in position 7 to an alcohol. For e tertiary butyl magnesium chloride can be used to form a desired di-methyl butanol group (e-g- a 3-(2,2-dimethylbutanol group), or n-propyl magnesium chloride is used to form the desired 2-pentanol group. It is understood that all kinds of linear, branched and/or alkyl groups having a total of1 to 10 carbon atoms, preferably 3 to 10 carbon atoms, further preferably 3 to 7 carbon atoms as well as alkyl groups having a ring structure can be used. In case the alkyl group ns a ring the ring may have e.g. 3 to 7 carbon atoms. For example, R" can be a tert-butyl group or an n-propyl group, wherein R’" can be e.g. H or CH3, e.g. H.

In certain ments, the reaction can be carried out at a temperature n 0 and 100°C, e.g. 50 to 90 °C, preferably 55 to 80°C, for a total time of less than 24 hours, e.g. less than 15 hours.

A t for the reaction in step (iii-a), respectively step (iv-b), can be suitably selected and is not particularly limited. According to preferred ments, the solvent in step (iii-a) or (iv-b) comprises an ether or is an ether.

Further ably the solvent in step (iii-a) or (iv-b) comprises an ether like tert-butylmethylether, 2-methyl-tetrahydrofuran, diethylether, dimethoxyethane, dimethoxymethane or mixtures thereof, particularly tert-butylmethylether, 2-methyl-tetrahydrofuran, dimethoxymethane or es thereof. The solvent used in (iii-a) or (iv-b) can further comprise solvents like dioxane, tetrahydrofuran or cylcopentyl-methyl-ether, which are less preferable as sole ts, though.

In certain aspects, the solvent in step (iii-a) or (iv-b) comprises an ether like tert-butylmethylether, yl-tetrahydrofuran, diethylether, dimethoxyethane, dimethoxymethane or mixtures thereof with a least 30 wt.%, preferably at least 40 wt.%, with regard to all solvents used in step (iii-a) or (iv-b), ularly tert-butylmethylether, 2-methyl-tetrahydrofuran, dimethoxymethane or es thereof. In this regard, other solvents like dioxane, tetrahydrofuran or cylcopentyl- methyl-ether can be contained in the solvent mixture. ably, step (iii-a) or (iv-b) is carried out using essentially tert-butylmethylether, 2-methyl- tetrahydrofuran, diethylether, dimethoxyethane, dimethoxymethane or mixtures thereof, particularly tert-butylmethylether, 2-methyl-tetrahydrofuran, dimethoxymethane or mixtures thereof, as solvent. In this regard, other solvents like dioxane, tetrahydrofuran or cylcopentyl- methyl-ether can be contained in the solvent mixture with less than 10 wt.%, based on the total weight of all solvents used in step (iii-a) or (iv-b).

According to certain embodiments, a linear ,branched and/or a ring containing reagent R"MgX is used in step (iii-a) or (iv-b) for the conversion of the acetyl group into the hydroxyalkyl group, wherein R" represents a linear, ed and/or cyclic alkyl group with 1 to 10 carbon atoms, and X represents a halogen.

Step (iv-a), respectively step (iii-b) represents a reduction of the 18,19 etheno group bond to form the desired substance as free base, e.g. a ion of the etheno group in position 18,19 to get buprenorphine or the desired analogue thereof. In n embodiments the hydrogenation of the -carbon double bound as disclosed to be step (iv) can be executed with any known technology. In certain embodiments conventional hydrogenation is indicated, in certain other embodiments the use of a hydrogen transfer agent is indicated. In the second case both an external and an internal hydrogen source can be used. Preferably this step is carried out with hydrogen gas and any appropriate catalyst. A preferred reaction system is hydrogen gas and a palladium on carbon as catalyst.

The reaction can be carried out using e.g. a hydrogenation reaction with a suitable st like palladium on carbon, e.g. Pd/C with 5 % Pd, or any other suitable catalyst. The pressure for the hydrogen in the hydrogenation reaction can be suitably selected and can be e.g. between 4 and bar. Also different pressures can be used in step (iv-a) and step (iii-b). For example, a suitable pressure in step (iii-b) can be between 4 — 10 bar, whereas a suitable pressure in step (iv-a) can be between 11 and 20 bar. Further, a solvent in step (iv-a), tively step (iii-b), can be suitably selected and can be e.g. an l like methanol, ethanol, propanol like n-propanol or i-propanol, or l, etc. In addition, the reaction time in step (iv-a) or step (iii-b) is not particularly limited, and also not the reaction time. Au le reaction temperature can be e.g. n 10 and 100 °C, preferably between 40 and 80 °C.

In this regard it has been found that steps (iii-b) and (iv-b) can be swapped while maintaining all advantages of the method. It has further been found that step (iv-b) can be conducted prior step (iii-b) t losing performance, yield or other advantages of the actual invention, resulting in a reaction with steps (iii-a) and (iv-a). When ng out steps (iii-a) and , the reaction with the generally lower reaction yield is carried out first, e.g. in case of a Grignard reaction being between 50 and 65%, with a conversion between 75 and 85%. In contrast, the hydration step (iv-a) generally has 100% conversion with yields between 75 to 90%, as can be seen e.g. in the Examples. This way solvent amount and energy consumption in the l process can be reduced, as will be shown for the Examples below.

The substance obtained after step (iv-a) or step (iv-b) that way can be transferred into an addition salt, preferably into a pharmaceutically acceptable acid addition salts, using standard procedures as dissolving the substance in an appropriate solvent, adding the acid and crystallizing.

In certain embodiments, the optional step (v) can be suitably carried out with e.g. the compound of a (II) and a suitable, preferably pharmaceutical acceptable, inorganic acid like HCl, HBr, H3PO4, H2504, HNO3, or a suitable, preferably pharmaceutical acceptable, organic acid like maleic acid, malic acid, malonic acid, methanesulfonic acid, or 4-toluenesulfonyl acid. The solvent and reaction conditions like temperature and pressure are not particularly limited and can be suitably determined based on the compound of Formula (II) to be reacted and the acid. In certain embodiments, buprenorphine can be d with an acid to produce a buprenorphine salt, for example buprenorphine hydrochloride. The production of a buprenorphine salt, e.g. buprenorphine HCl, can be accomplished, and is not limited to, by any known reaction routes after buprenorphine base has been formed.

According to certain embodiments, R’" represents a linear, branched and/or cyclic alkyl group having1 to 6 carbon atoms in the compound of Formula |, e.g. thebaine. In such embodiments R’" can be converted to H at any suitable time during the present method, i.e. before step (i), after step (i), after step (ii), after step (iii-a) or ) or step (iv-a) or (iv-b) or after step (V). In certain embodiments, R’" is converted to H before step (i) or after step (i) or after step (ii), preferably before step (i). The conversion of the alkoxy group in position 3 into a hydroxy group in position 3 is known in the art and can be suitably carried out using known methods (see e.g. Andre, J-D et al., "O-Demethylation of Opioid Derivatives with Methane Sulfonic ethionine: Application to the sis of Naloxone and Analogues", Synthetic Comm., , 327 .

According to certain embodiments R’" is H. In this case normally R’" is not converted anymore. ing to certain ments, R’ represents methylcyclopropyl and R" represents tert-butyl or R’ represents methyl and R" represents yl in formula II, with R’" being H in both cases. r disclosed is a product obtained by the present method.

According to r aspect, the present invention relates to a compound of Formula II, OCH3 (Formula II) wherein in Formula II R’ represents a , branched and/or cyclic alkyl group having 1 to 10 carbon atoms, R" represents a linear, ed and/or cyclic alkyl group having 1 to 10 carbon atoms, and R’" represents H or a linear, branched and/or cyclic alkyl group having 1 to 6 carbon atoms, obtained by the method of the present invention. ing to certain embodiments the present invention relates to a compound of Formula IV, (Formula IV) wherein in Formula IV R’ represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms and R" represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms, which is obtained by the method of the present invention.

In addition, a pharmaceutical formulation comprising the compound of the present ion is described. Apart from that, the pharmaceutical formulation is not limited. The pharmaceutical formulation can be e.g. in the form of an injection solution, a transdermal patch or for sublingual application.

The ceutical formulations can further comprise one or more pharmaceutically acceptable excipients, e.g. water, stabilizers or ngal.

These excipients are well-known to the skilled , e.g. from Remington, The Science and Practice of Pharmacy, 22nd Edition, 2012, which is incorporated herein by reference in regard to pharmaceutical excipients, ularly volume 1: "The Science of Pharmacy", pages 1049-1070 or from Rowe, R.C., Sheskey, P.J., Quinn, M.E., Cook, W.C.., Fenton, M.E., ook of Pharmaceutical Excipients", 7th Edition, 2012, which is incorporated herein by reference in regard to pharmaceutical excipients.

The pharmaceutical formulation can be used in medicine. Also described is the use of the compound described above in a ceutical formulation.

With regard to this invention, an analogue of buprenorphine is a compound with the same ring structure as shown in formula II. Such analogues of buprenorphine or of another nd can be obtained by choosing the riate substituents R’ and/or R" and/or R’".

In an exemplary reaction, the following steps can be included: (i) optionally the addition of alkyl to the tertiary amine of the compound of Formula |, e.g. oripavine or thebaine, to form a tertiary or quaternary amine, and removing the 17-N-methyl group or hydrogen at the 17-N to get 17-N- alkyl nororipavine or an analogue thereof with different R’", (ii) addition of methyl vinyl ketone by a Diels-Alder on to introduce the etheno group between the positions 6 and 14, (iii) conversion of the acetyl group by a Grignard reaction to form an alcohol, and (iv) reduction of the 18,19 etheno group to get buprenorphine or analogues f. It has also been found that step (iv) can be conducted prior step (iii). The product can then easily be transformed into an addition salt.

A general reaction scheme for the production of buprenorphine is shown below, which shows how exemplified orphine is formed from oripavine. A whole exemplary route of synthesis according to the present ion is disclosed starting from oripavine to buprenorphine. This sequence of reactions is shorter and more efficient as conventional synthesis: The following reaction scheme shows exemplified both le routes of synthesis for 18,19 di- hydroetorphine from oripavine.

Examples The present invention will now be described in detail with reference to several examples f.

However, these examples are illustrative and do not limit the scope of the invention.

Buprenorphine from Oripavine An exemplary stepwise on scheme for producing orphine from oripavine in 4 steps is given in the following Examples 1 to 4.

Example1 N-cyclopropyl methyl nororipavine was synthetized using procedures as known from ture.

For example the route proposed by Werner et al. (Werner, L.; Machara, A.; Adams, D. R.; Cox, D.

P.; Hudlicky, T.; J. Org. Chem. 2011, 76, 4628-4634) is convenient and has a yield between 2770 (chloride as halogenide) up to 55 % (bromide as halogenide).

Example 2 1-[(5oc,7oc)—17-(cyclopropy| methyl)—4,5-epoxy—3-hydroxymethoxy—6,14-ethenomorphinan-7—yl]— N-cyclopropyl methyl nororipavine from e 1 (10.0 g, 29.64 mmol) was dissolved in ethanol (60 mL). Hydroquinone (65 mg, 0.593 mmol) and methyl vinyl ketone (5.19 mL, 63.72 mmol) were added. The reaction mixture was stirred at 88 °C for 16 hrs. Thereafter, thin layer chromatography indicated no starting material. The mixture was partially distilled to give 15.0 g of distillate. The solution was cooled slowly to 0 °C during 12 hrs. and filtrated to give the desired product (8.45 g, 70%). The es were in agreement with literature data.

Example 3 dehydrobuprenorphine A on of tertiary butyl magnesium chloride (2 molar) in diethyl ether (3.1 mL) was added to tertiary butyl methyl ether (MTBE) (3.5 g). The solution was distilled to give 1.5 g of distillate. Tert- butyl methyl ether (3.5g) was added, and the resulting mixture was distilled to give 1.5g of distillate. This step was repeated with 2 g of tert-butyl methyl ether to give 2 g of distillate. 1-[(5oc, 70c)(cyclopropylmethyl)—4,5-epoxyhydroxymethoxy-6,14-ethenomorphinanyl]ethanone (0.5 g, 1.223 mmol) from example 2, dissolved in dioxane (2.5 g), was added slowly during 15 minutes at 20°C to 22° C. The resulting white e was stirred during 4 h at 60°C and then cooled to 0°C. The reaction was quenched with a saturated NH4Cl solution (10 mL). After separation, the aqueous layer was extracted twice with ethyl acetate (AcOEt, 2 times 10.0 mL).

The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (ethyl acetate / e : 3 / 2) to give 18,19- dehydrobuprenorphine (conversion: 72 %, yield: 54 %, 0.199 g).

Table 1: Conversions and yields in Example 3 using different ts Solvent Conversion /% Yield /% MTBE 72 4 yl-tetrahydrofuran 75 diethylether 68 dimethoxyethane 66 oxymethane 73 dioxane <20 cyclopentyl-methyl-ether <20 Example 4 Buprenorphine 18,19-dehydrobuprenorphine from example 3 (2.0 g, 4.296 mmol) was dissolved in methanol (100.0 g). Palladium catalyst on carbon (, 5 % Pd, 0.4 g) was added. The black mixture was stirred at 65°C under 15 bar of hydrogen. After 60 hrs. of heating the reaction solution was cooled to22 °C. The mixture was filtered, washed with methanol (100.0 g) and trated. The crude buprenorphine was purified by flash chromatography (ethyl acetate / heptane : 1 / 1) to give 1.475 g buprenorphine (80 %). 1H-NMR and 13C-NMR analyses were in agreement with literature data.

The reaction scheme for the reactions of examples 1 to 4 can be shown as follows: Ma tabutoxide t~dudecanethial tertfiuMgCl The disclosed route of synthesis gives a total yield of 16.2 % for buprenorphine. This figure is an increase of about 40 % compared to similar routes of sis. 18,19-dihydroetorphine from Oripavine Exemplary reaction schemes for producing 18,19-dihydroetorphine from oripavine are given in the ing Examples 5 to 9.

Example 5 1-[(5oc,7a)—17-|methyl-4,5-epoxyhydroxymethoxy—6,14-ethenomorphinanyl]ethanone.

Oripavine (200 g, 0.672 mol) was ded in ethanol (1260 mL) with hydroquinone (1.5 g, 0.0134 mol) and methyl vinyl ketone (117.3 mL, 1.439 mol) was added. The reaction mixture was stirred at 88C for 22 h. The resulting solution was concentrated partially (350 g of solvent was evaporated). The mixture was cooled to 0°C overnight. After filtration, the product was dried.

Yield: 85 %. The analyses were in agreement with the literature.

Example 6 Etorphine A solution of n-propyl magnesium chloride in diethyl ether (2 molar, 6.5 mL) was added to ry butyl methyl ether (7.0 g). The solution was distilled to give 3.0g of distillate. Tertiary butyl methyl ether (7.0 g) was added, the resulting mixture was distilled to give 3.0 g of late. This step was repeated with 5 g of tert-butyl methyl ether to give 5 g of distillate. 1-[(5oc, 70c)methyl- 4,5-epoxyhydroxymethoxy-6,14-ethenomorphinanyl]ethanone (0.964 g, 2.61 mmol) dissolved in dioxane (5.0 g) was added slowly during 15 min at 22 °C. The resulting white e was stirred during 4 hrs. at 60°C and then cooled to 0° C. The reaction was quenched with a saturated NH4Cl solution (10.0 mL). After tion, the aqueous layer was ted twice with ethyl acetate (2 times 10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (ethyl acetate / heptane :

Claims (4)

Claims:

1. A method of preparing a compound of Formula II, or a salt thereof, from a compound of Formula I, wherein in Formula II R’ represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms, and R’’ represents a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms, comprising: (Formula II) (Formula I) (i) replacing the group R in the compound of Formula I, wherein R is H or methyl, by a group R’ being a linear, branched and/or cyclic alkyl group having 1 to 10 carbon atoms; (ii) addition of methyl vinyl ketone to obtain 1-[(5α,7α)alkyl-4,5-epoxy hydroxymethoxy-6,14-ethenomorphinanyl]ethanone or 1-[(5α,7α)alkyl-4,5- epoxyalkoxymethoxy-6,14-ethenomorphinanyl]ethanone; 32 (iii-a) converting the acetyl group in position 7 into a tertiary alkyl alcohol having a general structure –C-(OH)-(CH3)-R”, wherein R’’ represents a linear, branched and/or cyclic alkyl group with 1 to 10 carbon atoms; and (iv-a) reducing the etheno group in position 18,19 to form the compound of Formula II; and (v) optionally converting the product from step (iv-a) into an addition salt, preferably a pharmaceutically acceptable salt, wherein introducing and later releasing protecting groups is avoided; and wherein R’’’ is H, wherein step (iv-a) is carried out after step (iii-a), wherein step (iii-a) is carried out using essentially tert-butylmethylether, 2-methyl-tetrahydrofuran, dimethoxymethane or mixtures thereof as solvent, wherein other solvents are contained in a solvent mixture with less than 10 wt.%, based on the total weight of all solvents used in step (iii-a).

2. The method according to claim 1, wherein in step (iii-a) for the conversion of the acetyl group into the tertiary hydroxyalkyl group a linear, a branched and/or a ring containing reagent R’’MgX is used, wherein R’’ represents a linear, branched and/or cyclic alkyl group with 1 to 10 carbon atoms, and X represents a halogen.

3. The method according to claim 1 or 2, wherein in formula II R’ represents methylcyclopropyl and R’’ represents tert-butyl or R’ represents methyl and R’’ represents n-propyl.

4. The method according to any one of claims 1 to 3, wherein in step (i) the alkyl group introduced in the 17-N position has 3 to 10 carbon atoms and has a linear, a branched and/or a ring structure.