MX2008008568A - The use of oripavine as a starting material for buprenorphine - Google Patents

Abstract

There is provided a method for the synthesis of norbuprenorphine, and ultimately buprenorphine, utilizing oripavine as the starting material. Conventional methods of producing buprenorphine utilize thebaine as the starting material, requiring an O-demethylation step, typically a low to moderate yield transformation. The present use of oripavine as a starting material does not require an O-demethylation step, since the oripavine molecule lacks an O-3 methyl group.

Description

USE OF ORIPAVINE AS AN INITIATING MATERIAL FOR BUPRENORPHINE BACKGROUND OF THE INVENTION Buprenorphine acts as a mixed agonist / antagonist and is an important treatment option for opiate addiction and analgesia. The conventional synthesis route used in the world to prepare buprenorphine uses thebaine as the initiator material.

BUPRENORPHINE Through a series of chemical reactions, thebaine is converted to nor-buprenorphine, the immediate precursor to buprenorphine. The final step adds a cyclopropylmethyl group to the nitrogen to form buprenorphine from nor-buprenorphine. A representation of the series of conventional reactions from thebaine to REF is presented below. : 191985 buprenorphine: 1. Thebaine reaction with methyl vinyl ketone to form the reaction product 4 + 2. 2. Hydrogenation of the carbon-carbon double bond. 3. Addition of a tertiary butyl group by means of a Grignard reaction. 4. An N-demethylation, by means of a two-step reaction sequence. 5. An O-demethylation reaction and a hydrolysis of N-cyano. 6. Addition of the cyclopropylmethyl group to form buprenorphine. A drawback of this conventional production scheme is that the O-demethylation stage is considered a low to moderate yield transformation. Therefore, there is a need for a norbuprenorphine / buprenorphine production scheme that does not include a 0-demethylation step.

BRIEF DESCRIPTION OF THE INVENTION One aspect of the present invention is to provide a method for producing norbuprenorphine using oripavine as the initiator material. The method comprises: reacting oripavine according to Formula I with methyl vinyl ketone to form a compound according to with formula II hydrogenation of the compound according to Formula II to form a compound according to Formula III: adding a t-butyl group to the compound according to Formula III to form a compound according to Formula X; Y demethylating the nitrogen of the compound according to Formula X to form norbuprenorphine, Formula VIII.

Another aspect of the present invention is to provide a method for making buprenorphine using oripavine as the initiator material.

DETAILED DESCRIPTION OF THE INVENTION A method using oripavine is provided as the preferred initiator material for the synthesis of norbuprenorphine and optionally buprenorphine. Oripavine is an alkaloid that occurs naturally from Papaver somniferum. The key difference between conventional technology and the present use of oripavine as an initiator material is that the O-demethylation stage, typically a low to moderate yield transformation, is not necessary since the oripavine molecule lacks a methyl group 0-3. In a synthesis involving several stages, it is advantageous to have only high-throughput reactions for the overall transformation to be economical. Since the present oripavine-based synthesis does not require the 0-3 demethylation step, the overall yield of oripavine provides improved performance over that traditionally achieved when thebaine is used as the initiator material. The conversion route of oripavine to produce buprenorphine is convenient and more effective compared to the other synthetic routes. As an illustrative modality of the stages for converting oripavine into norbuprenorphine, and optionally buprenorphine, is as follows: The sequence depicted above is an illustrative embodiment presented to show the required transformations, but is not limited to the order in which the transformations may be employed. In an alternative embodiment, the hydrogenation of the Diels-Alder double bond can also be performed as part of step 7 when the removal of the protective group Y is by means of catalytic hydrogenation.

Stage 1: The first stage involves the reaction of oripavine with methyl vinyl ketone. This addition reaction can be carried out by any conventional method known in the art. An illustrative embodiment in a Diels-Alder reaction in which the oripavine and methyl vinyl ketone are dissolved in a solvent and refluxed until the reaction is substantially complete. Suitable illustrative solvents include isopropyl alcohol, methanol, ethanol, toluene and mixtures thereof. The reaction mixture is then filtered to isolate the Diels-Alder adducts solids. Typical reactions result in at least a yield of about 85% of at least about 98% purity.

Stage 2: The second stage involves the hydrogenation of the double bond C-C. In an illustrative embodiment, the Diels-Alder adduct formed in step 1 was charged with a reaction vessel with Pd / carbon catalyst, then dissolved in a solvent. A presently preferred solvent is methanol, but any solvent, including methanol, ethanol, isopropyl alcohol, acetic acid, and mixtures thereof, can be used. The hydrogenation is carried out under nitrogen at a high pressure and temperature. The temperature and pressure are they select to ensure that the reaction is substantially complete, as is well known in the art. A typical illustrative temperature range of this reaction is about 50-90 ° C, with about 60 ° C being preferred and a typical illustrative pressure range of this reaction is about 20-60 psi (137.88-413.64 kPa), with preferred approximately 35 psi (241.29 kPa). The reaction mixture is filtered to remove the catalyst and the resulting filtrate is reduced in vacuo to produce the product according to Formula III.

Step 3: Optional step 3 describes the addition of a protecting group Y to form a compound according to Formula IV. The preferred method using oripavine as the initiator material for nor-buprenorphine and then buprenorphine uses a 0-3 protecting group. However, the reaction can be carried out without the use of the protecting group, although the overall yield can be compromised. In addition, the protective group can be removed simultaneously with another stage so that a chemical step is eliminated. The addition of a protective group 0-3 can minimize undesired chemical reactions involving the function of deprotected phenol in the 3-position. Suitable illustrative protecting groups include benzyl, O-t-butyl and silyl In an illustrative embodiment, the Diels-Alder adduct reduced according to the crushed formula III and K2C03 are added (non-soluble K2C03) in chloroform and benzyl bromide, heated and refluxed. After cooling to room temperature, the reaction mixture is filtered to remove the K2C03. The filtrate is then reduced in vacuo and aze-dried in toluene.

Step 4: The fourth stage uses the raw material according to Formula IV, formed in step 3, in a Grignard reaction. Under free moisture conditions and also under an inert atmosphere, t-BuMgCl is added, followed by anhydrous toluene. The solution is distilled until a vessel temperature of about 100 ° C is reached and the compound is added according to Formula IV. The reaction is turned off and the temperature of the reaction mixture is lowered. The organic and inorganic layers are separated and the organic layer is concentrated in vacuo to yield an oily residue. The oily residue is then purified resulting in a compound according to Formula V, up to about 93% purity. In an alternative embodiment, the t-butyl group is added using a t-butyl lithium reagent, as is well known in the art. The N-demethylation reaction can be carried out by any suitable method known in the art. In the illustrative embodiment illustrated in steps 5 and 6, the methyl group is first converted to a nitrile in step 5, followed by the reduction of the nitrile group in step 6.

Step 5: In an illustrative embodiment of step 5, the tertiary alcohol initiator material according to formula V is dissolved in a solvent, washed with an inert atmosphere and then K2C03 and cyanogen bromide are added. This reaction mixture is then refluxed until the reaction is substantially complete, cooled to room temperature and filtered to remove K2C03. The reaction mixture is then extracted and the organic layers are reduced and dried under vacuum. The resulting solid is purified to produce up to about 93% clean material after drying.

Step 6: In an illustrative embodiment, potassium hydroxide is dissolved in diethylene glycol and heated. The N-CN compound according to Formula VII is added and the reaction mixture is heated until the reaction is complete substantially. After cooling to room temperature, distilled water is added and the resulting solid is collected and dried, with a yield of up to about 100%.

The N-demethylation can be performed by any method known to those skilled in the art without departing from the present method.

Stage 7: The seventh stage involves the removal of the optional protective group. In the illustrative embodiment, the protecting group Y added in step 3 is removed. In this embodiment, the initiator material of the secondary amine can be catalytically removed by Pd / carbon in an appropriate solvent. Suitable solvents include methanol, ethanol, isopropyl acetate and mixtures thereof. The resulting filtrate is dried under vacuum to produce norbuprenorphine. In another embodiment, the protecting group Y can be removed with an acid, such as HCl, HOAc, HF or an anion of F.

Step 8: Finally, norbuprenorphine is optionally converted to buprenorphine as illustrated in step 8.

In an illustrative embodiment, norbuprenorphine is converted to buprenorphine. In an illustrative mode, a mixture of norbuprenorphine, a moderate base, and cyclopropylmethyl bromide are heated in an oil bath at about 80-100 ° C until the reaction is substantially complete. The reaction mixture is then added for 5 minutes to 160 mL of water, with mechanical stirring, to produce a gum. The mixture is stirred and filtered, and the filter cake is washed with water. The CLAR will show approximately 90% per area of the desired product, and 0.2-0.5% of an impurity substituted with N-butenyl. The resulting product is dried, and then boiled in alcohol, cooled and filtered to yield buprenorphine. In the alternative, norbuprenorphine can be converted to buprenorphine by reductive amination, or by acylation followed by reduction of the amide. In an alternative embodiment, the hydrogenation step 2 is carried out in the crude reaction mixture formed in step 1, whereby a reaction scheme of a container is provided to form a compound according to Formula III.

Oripavine, methyl vinyl ketone and isopropyl alcohol are heated under pressure. Once it cools, it is added the Pd-C catalyst and the reaction mixture is heated under pressure until the reaction is substantially complete. The product is then solubilized and the catalyst is removed by filtration. The filtrate is then concentrated in vacuo. In another alternative embodiment, illustrated below, a method for producing norbuprenorphine and optionally buprenorphine, from oripavine, without the use of a protective group at 0-3. The individual reactions are as described in greater detail below. The method comprises: a) reacting oripavine according to Formula I with methyl vinyl ketone to form a compound according to Formula II: b) hydrogenating the compound according to Formula II to form a compound according to Formula III: c) adding a t-butyl group to the compound according to Formula III to form a compound according to Formula X; Y d) demethylating the nitrogen of the compound according to Formula X to form norbuprenorphine, Formula VIII.

EXAMPLES Example 1 Oripavine (150 g, 505 mmol) was charged to a 1 L 3-neck jacketed flask equipped with a mechanical agitation device, a thermocouple and a reflux condenser. The reagents were dissolved in 750 mL of alcohol Isopropyl (IPA), equivalent to 5 mL / g. Methyl vinyl ketone of 90% technical grade (MVK) was added in two portions. Each portion consisted of 68.0 mL (747 mmol, 1.5 equivalents), with the second addition occurring approximately 8 hours after the first. After the first addition of MVK, the reaction mixture was heated to reflux at about 78 ° C, and the temperature was slowly increased to about 84 ° C as the MVK was consumed. The reaction was allowed to continue overnight after the second addition of MVK and was stopped in the morning by slowly cooling to 5-10 ° C. After stirring for about 2 hours at 5-10 ° C, the reaction mixture was filtered to isolate the solids, washing with cold IPA. After drying, an 85% yield of adduct with a purity of 98-99% per area after correction for the test of the initiator material was recovered.

Example 2 a) A reaction vessel was loaded with 9 g (77% test) of oripavine, 5.6 mL of methyl vinyl ketone and 45 mL of isopropyl alcohol. The container was sealed and the contents heated to 110 ° C resulting in a pressure of 35 psi (241.29 kPa). After 4 hours, the reaction mixture was cooled to room temperature and 0.6 g of Pd-C (10%) was added. The mixture was hydrogenated at 70 ° C and 40 psi (275.6 kPa) for 24 hours. The product was solubilized using methanol, and the catalyst was removed by filtration through a hyflo plug. The filtrate was concentrated in vacuo to provide 8.6 g.

Example 3 The Diels-Alder adduct (13 g, 35 mmol) formed in Example 1 was charged with a reaction vessel with a 5% charge (dry base) of 10% Pd / C catalyst (1.3 g). The adduct was then dissolved / suspended in 10 ml / g methanol (130 mL). After cleaning the vessel eight times with N2 at 40 psi (275.6 kPa) and four times with H2 at 40 psi (275.6 kPa), the pressure was returned to 40 psi of H2 (275.6 kPa). The temperature was raised to 60 ° C where the hydrogenation was carried out for about eight hours in a Parr shaker. Once the consumption of the initiator material was completed, the vessel was flushed with N2 to purge any remaining H2. The reaction mixture was then filtered as a hot solution through a plug of celite to remove the catalyst. The filtrate was then reduced in vacuo to yield 12.9 g (99%) of the expected product.

Example 4 The reduced Diels-Alder adduct (24.0 g, 65 mmol) formed according to Example 4 and ground K2C03 (45.0 g, 326 mmol) was charged to a 500 mL three-necked round bottom flask which was equipped with a mechanical agitation device and a reflux condenser. 200 mL of CHC13 and then benzyl bromide (9.3 mL, 13.4 g, 78.3 mmol) were added to the flask. The reaction mixture was then heated to reflux for six hours. After allowing the reaction mixture to cool to room temperature, it was filtered to remove the K2C03, washing the solids with CHC13 in excess. The filtrate was then reduced in vacuo and aze-dried (3 x 100 mL) with toluene. This raw material is then used directly for the Grignard reaction, Example 5 Before use, all the glassware was dried in an oven overnight at 150 ° C. A 1-liter 4-necked round bottom flask was equipped with a mechanical exhaust, a graduated addition funnel, a distillation head and a thermocouple. The apparatus was mounted while hot and allowed to cool to room temperature under a nitrogen atmosphere. HE 222 mL of t-BuMgCl (222 mmol) were added to the flask followed by 250 mL of anhydrous toluene. The solution was distilled until a container temperature of 100 ° C was reached. To the hot solution was added 20.4 g (44.4 mmol) of benzylated ketone formed according to Example 5 in 50 mL of anhydrous toluene for 15 minutes. The reaction was heated at 100 to 105 ° C for 4 hours then allowed to cool to room temperature. The reaction mixture was cooled below 10 ° C using an ice bath and quenched with 153 mL of 4N NH 4 Cl while keeping the internal temperature below 30 ° C. Concentrated HCl (22 mL) was added to the heterogeneous mixture, so that the pH is decreased to 4. The organic and the accusa layers were separated and the aqueous layer and the reaction vessel were extracted twice with 200 mL portions of water and concentrated in va cuo to provide a oily residue. After working up the reaction, the crude oil was dissolved in about 200 mL of ethyl acetate and charged with about 30 grams of silica gel. The resulting mixture was then reduced in vacuo to yield the solid product bound to silica gel. This material was then purified by flash column chromatography on silica gel using heptanes: ethyl acetate 2: 1 with 1% triethylamine. Fractionation of the eluent yields 13.6 grams of 93% pure product.

Example 6 The initiator material of tertiary alcohol (18.2 g, . 2 mmol) formed according to Example 6 was charged to a 500 mL round bottom flask equipped with a bar magnetic exhaustion. The initiator material was then dissolved in 100 mL of CHC13. After cleaning the flask with N2, K2CO3 (1.7 g, 12.3 mmol) and cyanogen bromide (5.6 g, 52.9 mmol) were added. The reaction mixture was brought to reflux, where it remained for 17 hours. After cooling to room temperature, the mixture was filtered to remove the K2C03. The filtrate was then vigorously stirred with 90 mL of concentrated H2O: NH4OH 2: 1 for 45 minutes. The layers were then separated, washing the aqueous layer with an additional 50 mL of CHC13. The combined organic layers were dried with anhydrous MgSO 4 and reduced in vacuo. This produces a foamed solid after drying additionally to high vacuum. The foamy solid was then dissolved in 25 mL of toluene and 70 mL of heptane. The reaction mixture was placed in a water bath and brought to approximately 90 ° C. After adding an additional volume of 60 mL of heptane, the solution was slowly cooled with a precipitate that forms at about 82 ° C. This reaction mixture was slowly placed at room temperature when the bath was lowered to 10 ° C by means of an ice bath. After 30 minutes, the solids were isolated by vacuum filtration and washed with 40 mL of heptane: toluene 3: 1. This produced 12.4 g (67%) of 93% clean material after drying.

Example 7 A 250 mL round bottom flask was charged with 20.2 g (360 mmol) of potassium hydroxide and 55 mL of diethylene glycol. The reaction mixture was heated to 110 ° C and to the heated solution was added 9.5 g (18 mmol) of the N-CN compound formed according to Example 6. After heating for 27 hours, the reaction was cooled to room temperature and 150 mL of distilled water were added. The solid was collected after 15 minutes of mixing, and washed with 100 mL of distilled water. After drying, 8.9 g of the product corresponding to a crude yield of 100% was obtained.

Example 8 The initiator material of the secondary amine (4.0 g, 8 mmol) formed according to Example 7 and 10% Pd / carbon (0.4 g, 5% w / w in dry basis) were charged to a stirrer reaction bottle Parr. The reagents were suspended in 30 mL of methanol and attached to the Parr agitator apparatus. The reaction mixture was then washed with 40 psi (275.6 kPa) of N2 eight times, and the reaction bottle was filled with H2 at 40 psi (275.6 kPa). The reaction bottle was allowed to run for 2.5 hours at 60 ° C, at which time the LC analysis showed no remaining starter material. The reaction material was then filtered through a plug of celite to remove the catalyst. The filtrate was then reduced in vacuo to produce norbuprenorphine.

Example 9 Formula VIII Formula IX A mixture of 11.5 g of norbuprenorphine, 4.6 g of sodium bicarbonate, 4.85 g of cyclopropylmethyl bromide (1% of butenyl bromide in this by GC) and 46 mL of DMF dry, heat in an oil bath at 80-100 ° C for 4 hours until the reaction is substantially complete. The reaction mixture is transferred to a drip funnel, with a minimum of DMF as a wash. The reaction mixture is added for 5 minutes to 160 mL of water, with mechanical stirring. (Adding water to the reaction produces a gum). The mixture is stirred for approximately 10 minutes and filtered. The filter cake is washed with 20 mL of water. The CLAR will show approximately 90% per area of the desired product, and 0.2-0.5% of an impurity substituted with N-butenyl. The resulting product is dried, yielding approximately 12 g. The resulting product is boiled in 30 mL of methanol for approximately 30 minutes, cooled and filtered to yield approximately 7.3 g of buprenorphine. A new process for the production of norbuprenorphine and buprenorphine has been described. While the process of this invention has been described with reference to the specific reactions and examples, the intent to such a reference is not made to limit the scope of this invention unless otherwise expressly stated. Different modifications may be made in the materials and the sequence of the process steps as well as the process combinations, which are adapted to suit the different process steps without departing from this invention. The The above description is given solely for clarity of understanding and unnecessary limitations should not be understood thereto, since the modifications will be obvious to those skilled in the art. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (15)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Method for producing norbuprenorphine, characterized in that it comprises: a) reacting oripavine according to Formula I with methyl vinyl ketone to form a compound of agreement with Formula II: b) hydrogenating the compound according to Formula II to form a compound according to Formula III: c) adding a t-butyl group to the compound according to Formula III to form a compound according to Formula X; Y d) demethylating the nitrogen of the compound according to Formula X to form norbuprenorphine, Formula VIII.
2. 2. The method according to claim 1, characterized in that it also includes adding a cyclopropylmethyl group to norbuprenorphine to form buprenorphine.
3. 3. The method according to claim 1, characterized in that a) and b) are combined in a single reaction sequence of a single vessel.
4. 4. Method for producing norbuprenorphine, characterized in that it comprises: a) reacting oripavine according to Formula I with methyl vinyl ketone to form a compound according to Formula II: b) hydrogenating the compound according to Formula II to form a compound according to Formula III: c) adding a protecting group Y to the compound according to Formula III to form a compound according to Formula IV: d) adding a t-butyl group to the compound according to Formula IV to form a compound according to Formula V: e) demethylating the nitrogen of the compound according to Formula V to form a compound according to Formula VII; Y f) removing the protecting group Y of the compound according to Formula VII to form norbuprenorphine according to Formula VIII.
5. 5. The method according to claim 4, characterized in that it includes adding a cyclopropylmethyl group to norbuprenorphine to form buprenorphine.
6. 6. The method according to claim 4, characterized in that the demethylation step is comprised of: a) converting the nitrogen in the compound according to Formula V to a nitrile according to a compound according to Formula VI; Y b) reducing the nitrile of the compound according to Formula VI to form a compound according to the Formula
7. 7. The method according to claim 4, characterized in that the protecting group Y is selected from the group consisting of the benzyl, O-t-butyl and silyl groups.
8. 8. The method according to claim 4, characterized in that a) and b) are combined in a sequence of reaction of a single container.
9. 9. Method for producing buprenorphine, characterized in that it comprises: a) reacting oripavine according to Formula I with methyl vinyl ketone to form a compound according to Formula II: b) hydrogenating the compound according to Formula II to form a compound according to Formula III: c) adding a protecting group Y to the compound according to Formula III to form a compound according to Formula IV: d) adding a t-butyl group to the compound according to Formula IV to form a compound according to Formula V: e) demethylating the nitrogen of the compound according to Formula V to form a compound according to Formula VII; f) removing the protecting group Y of the compound according to Formula VII to form norbuprenorphine according to Formula VIII; and g) adding a cyclopropylmethyl group to the norbuprenorphine of Formula VIII to form buprenorphine of formula IX.
10. The method according to claim 9, characterized in that the demethylation step is comprised of: a) converting the nitrogen into the compound in accordance with Formula V to a nitrile according to a compound according to Formula VI; Y b) reducing the nitrile of the compound according to Formula VI to form a compound according to the Formula
11. 11. The method according to claim 9, characterized in that the protecting group Y is selected from the group consisting of the benzyl, O-t-butyl and silyl groups.
12. The method according to claim 9, characterized in that a) and b) are combined in a single-vessel reaction sequence.
13. 13. Method for producing buprenorphine, characterized in that it comprises: a) reacting oripavine according to the Formula I with methyl vinyl ketone to form a compound according to Formula II: b) hydrogenating the compound according to Formula II to form a compound according to Formula III: c) adding a protecting group Y to the compound according to Formula III to form a compound according to Formula IV: d) adding a t-butyl group to the compound according to Formula IV to form a compound according to Formula V: e) converting the nitrogen of the compound according to Formula V to a nitrile according to a compound according to Formula VI; Y f) reducing the nitrile of the compound according to Formula VI to form a compound according to Formula VII: g) removing the protecting group Y of the compound according to Formula VII to form norbuprenorphine according to Formula VIII; Y h) adding a cyclopropylmethyl group to the norbuprenorphine of Formula VIII to form buprenorphine of Formula IX.
14. The method according to claim 13, characterized in that the protecting group Y is selected from the group consisting of the benzyl, O-t-butyl and silyl groups.
15. 15. The method according to claim 13, characterized in that a) and b) are combined in a single-vessel reaction sequence.