JP2008538746A - Catalytic production of hydrocodone, hydromorphone and derivatives thereof - Google Patents

Abstract

Wherein, M is an Group VIII transition ^metal; formula _{^{[M (PR 4 R 5 R}} 6) n X m] p R 4, R 5 and ^{R 6} are alkyl, aryl, alkoxyl, phenoxyl and their X is a halide or anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1. A process for the catalytic production of hydrocodone derivatives and hydromorphone derivatives using a transition metal catalyst of

Description

The present invention relates to a process for the catalytic production of hydrocodone derivatives and hydromorphone derivatives.

  Hydrocodone and hydromorphone are opioid analgesics with properties similar to codeine and morphine. The development of new opioid derivatives is desirable to provide a source of new intermediates and potential new analgesics. Conventional methods for producing hydrocodone and hydromorphone typically involve a two-step oxidation / reduction pathway from codeine and morphine. Unfortunately, these methods are expensive and inefficient. Attempts to improve efficiency included the use of catalytic methods. Known methods include the use of metals, typically Ru, Rh, Pd and Pt on activated carbon, and metal complexes. The production of these catalysts is difficult, yields are poor, and product isolation is often cumbersome.

  Other catalytic methods involving the use of finely divided platinum or palladium in acidic media are environmentally undesirable. Enzymatic conversion methods have also been attempted, but like the catalytic methods discussed above, these methods are expensive and difficult to scale.

  Accordingly, there is a need for an improved process for preparing hydrocodone, hydromorphone and their derivatives that is easily scaled up and economical for manufacturing purposes.

式中、Ｒ^１はＨ、アルキル、アリールまたはアシルである。 SUMMARY OF THE INVENTION One aspect of the present invention is to provide a method for catalytic conversion of a compound of formula I to a compound of formula II utilizing at least one transition metal complex as a catalyst;

Where R ¹ is H, alkyl, aryl or acyl.

式中、Ｒ^２は、Ｈ、ベンジル、置換ベンジル、アルキル、アリール、アシル、アリールスルホニル、アルキルスルホニル、カルボキシエステル、カルボキシアミド、トリアルキルシリル、テトラヒドロピラニルおよびテトラヒドロフラニル基から選択されるがこれらに限定されない；そして、
Ｒ^３は、Ｈ、アルキル、アリル、シクロアルキルアルキル、ベンジル、アリールスルホニル、アルキルスルホニル、アリール、アシル基、ホルミル、ヒドロキシル、カルボキシエステルおよびカルボキシアミドから選択されるがこれらに限定されない。 Another aspect of the present invention is to provide a process for catalytic conversion of a compound of formula VI to a compound of formula VII;

Wherein R ² is selected from, but not limited to, H, benzyl, substituted benzyl, alkyl, aryl, acyl, arylsulfonyl, alkylsulfonyl, carboxyester, carboxyamide, trialkylsilyl, tetrahydropyranyl and tetrahydrofuranyl groups. Not limited; and
R ³ is selected from, but not limited to, H, alkyl, allyl, cycloalkylalkyl, benzyl, arylsulfonyl, alkylsulfonyl, aryl, acyl groups, formyl, hydroxyl, carboxyester and carboxyamide.

In one aspect of the present invention, the transition metal complexes are those of the formula _{^{[M (PR 4 R 5 R}} 6) n X m] p; wherein, M is an Group VIII transition ^{metal; R} 4, R ⁵ and R ⁶ are selected from alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is a halide or anion; n is 1, 2, 3 or 4; Or 2; and p is at least 1.

  These are merely exemplary embodiments of the present invention and should not be considered as an enumeration that encompasses all of the myriad aspects related to the present invention. These and other aspects will be apparent to those skilled in the art in light of the following disclosure.

式中、Ｒ^１は、Ｈ、アルキル、アリールまたはアシルである。 DETAILED DESCRIPTION A method for converting a compound represented by Formula I to a compound represented by Formula II is provided;

In which R ¹ is H, alkyl, aryl or acyl.

The method of the invention is particularly useful when R ¹ is methyl or H, ie, codeine or morphine, respectively, leading to the formation of hydrocodone or hydromorphone, respectively.

式中、Ｒ^２は、Ｈ、ベンジル、置換ベンジル、アルキル、アリール、アシル、アリールスルホニル、アルキルスルホニル、カルボキシエステル、カルボキシアミド、トリアルキルシリル、テトラヒドロピラニルおよびテトラヒドロフラニル基から選択されるがこれらに限定されず；そして、
Ｒ^３は、Ｈ、アルキル、アリル、シクロアルキルアルキル、ベンジル、アリールスルホニル、アルキルスルホニル、アリール、アシル基、ホルミル、ヒドロキシル、カルボキシエステルおよびカルボキシアミドから選択されるがこれらに限定されない。 In an alternative embodiment of the invention, there is provided a process for converting a compound represented by formula VI to a compound represented by formula VII;

Wherein R ² is selected from, but not limited to, H, benzyl, substituted benzyl, alkyl, aryl, acyl, arylsulfonyl, alkylsulfonyl, carboxyester, carboxyamide, trialkylsilyl, tetrahydropyranyl and tetrahydrofuranyl groups. Not limited; and
R ³ is selected from, but not limited to, H, alkyl, allyl, cycloalkylalkyl, benzyl, arylsulfonyl, alkylsulfonyl, aryl, acyl groups, formyl, hydroxyl, carboxyester and carboxyamide.

Ｒ^２は、Ｈ、ベンジル、置換ベンジル、アルキル、アリール、アシル、アリールスルホニル、アルキルスルホニル、カルボキシエステル、カルボキシアミド、トリアルキルシリル、テトラヒドロピラニルおよびテトラヒドロフラニル基から選択されるがこれらに限定されない。
Ｒ^８およびＲ^９は、Ｈ、アルキル基、アリル基、ベンジル基、アリール基およびアルキレンシクロアルカンから独立して選択されるがこれらに限定されない。あるいは、Ｒ^８およびＲ^９は、一体となってオキシドを形成している。
Ｘ_１およびＸ_２は、陰イオン、典型的にはＣｌまたはＢｒである。あるいは、Ｘ_１およびＸ_２は、ＢＦ_４、ＰＦ_６、ＣｌＯ_４、ＣＨＯ_２、Ｃ_２Ｏ_４、ＣＦ_３ＣＯ_２、ＣＦ_３ＳＯ_３、ＣＨ_３ＣＯ_２、ＡｒＣＯ_２、ＣＨ_３ＳＯ_３、ｐ−トリルＳＯ_３、ＨＳＯ_４およびＨ_２ＰＯ_４またはこれらの混合物、陰イオン交換の生成物から独立して選択されるがこれらに限定されない陰イオンである。Ｘ_１およびＸ_２は、触媒による交換を受ける。 In other embodiments, the methods of the invention can be utilized with quaternary salts as shown below:

R ² is selected from, but not limited to, H, benzyl, substituted benzyl, alkyl, aryl, acyl, arylsulfonyl, alkylsulfonyl, carboxyester, carboxyamide, trialkylsilyl, tetrahydropyranyl and tetrahydrofuranyl groups.
R ⁸ and R ⁹ are independently selected from, but not limited to, H, alkyl groups, allyl groups, benzyl groups, aryl groups, and alkylenecycloalkanes. Alternatively, R ⁸ and R ⁹ together form an oxide.
X ₁ and X ₂ are anions, typically Cl or Br. Alternatively, X ₁ and X ₂ are BF ₄ , PF ₆ , ClO ₄ , CHO ₂ , C ₂ O ₄ , CF ₃ CO ₂ , CF ₃ SO ₃ , CH ₃ CO ₂ , ArCO ₂ , CH ₃ SO ₃ , p -Tolyl SO ₃ , HSO ₄ and H ₂ PO ₄ or mixtures thereof, anions independently selected from, but not limited to, products of anion exchange. X ₁ and X ₂ undergo catalytic exchange.

In certain embodiments of the invention, the transition metal catalyst of the invention comprises at least one transition metal complex of the formula [M (PR ⁴ R ⁵ R ⁶ ) _n X _m ] _p ; R ⁴ , R ⁵ and R ⁶ are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is a halide or anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1;

In certain embodiments of the present invention, the transition metal catalysts of the present invention comprise a transition metal complex _{^{[M (PR 4 R 5 R}} 6) n X m] p; wherein, M is preferably a Group 8 transition metal R ⁴ , R ⁵ and R ⁶ are independently selected from alkyl, aryl and alkoxyl, phenoxyl groups; X is halogen or anion; n is 1, 2, 3 or 4 And m is 1 or 2. These complexes can be polymerized and therefore p is at least 1. When all three R groups are alkoxyl, phenoxyl, or combinations thereof, the ligand of the complex is referred to as a tertiary phosphite. When at least one of the R groups is not alkoxyl or phenoxyl, the ligand of the complex is called a tertiary phosphine. Preferred metals include Rh, Ru, Pd and Pt. The halide X is typically Cl or Br. The _{anion, BF 4, PF 6, ClO} 4, CHO 2, C 2 O 4, CF 3 CO 2, CF 3 SO 3, CH 3 CO 2, ArCO 2, CH 3 SO 3, p- tolyl SO ₃ , HSO ₄ and H ₂ PO ₄ . Many of these catalysts are commercially available or can be readily manufactured as is known in the art.

In another embodiment of the present invention, the transition metal catalyst of the present invention comprises a transition metal complex of a tertiary phosphine halide [M (PR ⁷ ₃ ) _n X _m ] _p , wherein M is preferably A Group 8 transition metal; R ⁷ is alkyl or aryl; X is a halide or anion; n is 1, 2, 3 or 4; and m is 1 or 2 is there. These complexes can be polymerized and therefore p is at least 1. Preferred metals include Rh, Ru, Pd and Pt. The halide X is typically Cl or Br. The _{anion, BF 4, PF 6, ClO} 4, CHO 2, C 2 O 4, CF 3 CO 2, CF 3 SO 3, CH 3 CO 2, ArCO 2, CH 3 SO 3, p- tolyl SO ₃ , HSO ₄ and H ₂ PO ₄ . R ⁷ is an alkyl or aryl group, preferably phenyl. Many of these catalysts are commercially available or can be readily manufactured as is known in the art. It is noted that the catalyst of formula [M (PR ⁷ ₃ ) _n X _m ] _p is a subgroup of the broader catalyst group [M (PR ⁴ R ⁵ R ⁶ ) _n X _m ] _p .

Complexes of the present invention include, but are not limited to, tertiary phosphines / phosphites supported on polymers, tertiary phosphines / phosphites supported on silica and tertiary phosphines / phosphites bonded to resins. Or a tertiary phosphine / phosphite supported on a solid. As is well known to those skilled in the art, in the case of a tertiary phosphine / phosphite supported on a solid, one of the R groups typically contains a linking group that connects the phosphine / phosphite and the solid phase. Non-limiting examples of solid-supported tertiary phosphines useful in the present invention include copolymers prepared from the monomers p-styryldiphenylphosphine and styrene, also known as diphenyl (p-vinylphenyl) phosphine, or A tertiary phosphine supported on silica made by treating silica with (EtO) ₃ SiCH ₂ CH ₂ PPh ₂ . There are tertiary phosphines / phosphites supported on solids that can be purchased.

In certain embodiments of the invention, the metal is Rh and the complex is of the formula [Rh (PR ⁴ R ⁵ R ⁶ ) _n X _m ] _p ; wherein R ⁴ , R ⁵ and R ⁶ are , Alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is a halide or anion; n is 1, 2, 3 or 4; m is 1 or 2 And p is at least 1.

In another embodiment of the invention, the transition metal is Rh and the metal complex is of the formula [Rh (PR ⁷ ₃ ) _n X] _p , wherein R ⁷ is alkyl or aryl and X is a halide. , N is 1, 2 or 3, and p is at least 1 or the formula [Rh (PR ⁷ ₃ ) _n Y] _p , wherein R ⁷ is alkyl or aryl N is 1, 2 or 3, p is at least 1 and Y is an anion, preferably BF ₄ , PF ₆ , ClO ₄ , CHO ₂ , CF ₃ CO ₂ , CF ₃ SO ₃ , CH ₃ CO ₂ , C ₂ O ₄ , ArCO ₂ , CH ₃ SO ₃ , p-tolyl SO ₃ , HSO ₄ or H ₂ PO ₄ ).

In still another embodiment of the present invention, the transition metal is Ru, metal complexes are those of formula _{^{[Ru (PR 4 R 5 R}} 6) n X m] p; ^wherein, R 4, ^{R 5} And R ⁶ is selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is a halide or anion; n is 1, 2, 3 or 4; 1 or 2; and p is at least 1.

In another embodiment, the transition metal is Ru and the metal complex is of the formula [RuX ₂ (PR ⁷ ₃ ) _n ] _p , where R ⁷ is alkyl or aryl, X is a halide, n Is of 1, 2, 3 or 4; and p is at least 1) or of the formula [RuYX (PR ⁷ ₃ ) _n ] _{p where} R ⁷ is alkyl or aryl Where n = 3, p is at least 1, Y = H and X = Cl; n = 3, Y = H and X = H; n = 4, X = H, Y = H; or , N = 2, 3 or 4, p is at least 1, and X = Y = ClO ₄ , CF ₃ SO ₃ , PF ₆ or BF ₄ , CHO ₂ , CH ₃ CO ₂ , ArCO ₂ , CH ₃ SO ₃ , p-tolyl SO ₃ , HSO ₄ or H ₂ PO ₄ ) The

A suitable method for producing the exemplary Ru complexes of the present invention is to reflux a Ru salt, such as RuCl ₃ xH ₂ O, in an alcohol with excess triphenylphosphine to complex [Ru (P (C ₆ H ₅ )]. ₃ ) forming ₃ Cl ₂ ] _p .

  Exemplary Rh complexes of the present invention can be purchased, or can be prepared by refluxing rhodium trichloride with triphenylphosphine in alcohol, typically methanol or ethanol.

ｐ−スチリルジフェニルホスフィン。 In another exemplary embodiment of the present invention, Rh-, Ru- and / or Ir-complexes are also known as styrene, divinylbenzene and diphenyl (p-vinylphenyl) phosphine (p-styryldiphenylphosphine), May be attached to a tertiary copolymer as illustrated):

p-styryldiphenylphosphine.

In some cases, other monomers may be substituted or added to optimize certain physical properties of the overall polymerizable catalyst. Illustrative examples include ethylene dimethacrylate, p-bromostyrene, and crosslinkers such as divinylbenzene, butadiene, diallyl maleate, diallyl phthalate, glycol dimethacrylate and other di- or triolefins, It is not limited to these. Other phosphines containing monomers attached to the styrene ring may have dialkyl, branched and cyclic dialkyl, dialkoxyl or mixed substitutions in addition to the diaryl substitution. Illustrative examples utilizing styrene are shown in Formulas IV and V.

  The polymerizable complex forms a compound of matter consisting essentially of a solid organic styrene-divinylbenzene copolymer that is inherently porous; the substituent phosphine group is chemically bonded to the carbon atom of the polymer via phosphorus. And the Group 8 metal is chemically bonded to the substituent phosphine, and the compound is substantially insoluble in the solvent.

  In an exemplary embodiment, the polymerizable support is composed of a styrene divinylbenzene copolymer containing 2 to 20 mole percent divinylbenzene, in which a pendant phenyl group from copolymerized styrene has a concentration of 0. 5 to 7 mole percent, preferably 5 to 6 mole percent, contains a diphenylphosphine moiety in the para position. The composition of the polymeric support is 75 to 97.6 mole percent styrene, 2 to 20 percent divinylbenzene and 0.4 to 6 percent p-diphenylphosphenostyrene.

  With respect to the amount of ruthenium complex in the catalyst, typically the Ru / pendant atomic ratio is preferably at least 0.001, more preferably about 0.5 to the point that the polymeric support can no longer incorporate the complex. The upper limit to be set, for example, about 1.2.

The polymerizable complex can be made by contacting a solution of a Group 8 metal salt complex with a polymer support in solution. For practical applications, the metal complex may be water, methanol, ethanol, isopropanol, isobutyl alcohol, t-butyl alcohol, chloroform, dichloromethane, fluorobenzene, chlorobenzene, toluene, N-methylpyrrolidone, N, N-dimethylformamide, N , N-dimethylacetamide, methyl sulfoxide, methyl sulfone, tetrahydrofuran and mixtures thereof. The Group 8 metal complex solution should be at least 10 ⁻⁶ M for ruthenium complexes, but preferably about 10 ⁻³ M for ruthenium complexes.

  In this exemplary embodiment, the polymer portion of the catalyst is inherently porous. The porosity of the polymer portion of the catalyst results in increased activity for the catalyst. A catalyst having an organic polymer portion that is not porous in nature can be used to induce porosity in the polymer portion by solvent swelling. As is well known in the art, combinations of the above solvents can be manipulated to provide varying degrees of swelling of the polymer portion of the catalyst.

  The catalytic conversion of the present invention has the further economic advantage that codeine or morphine salts, such as codeine hydrochloride or morphine hydrochloride, can be converted to hydrocodone or hydromorphone, respectively.

  Furthermore, the catalyst of the present invention facilitates the recovery of high value metals from metal-containing solid catalysts. When recovered by conventional methods known in the art, the metal of the catalyst leads to an improved recovery rate. This further reduces material and labor costs and simplifies processing / post processing. For the purposes of the present invention, the term recovery is intended to encompass metal recovery, reuse and / or regeneration.

  In embodiments where the catalyst is fixed to a support, the catalyst / support can be placed in a column or vessel as part of a loop reactor. In a non-limiting exemplary example, codeine in alcohol heated in the reactor can be pumped or gravity fed through the catalyst bed and returned to the reactor until conversion to the desired hydrocodone takes place. Advantages of this method include the ability to obtain multiple cycles (probably several batches) of product using a given bed. The catalyst noble metal (value) is then easily recovered and sent back to reprocessing. Since no catalyst is present in the solution, purification post-treatment is simplified. For practical reasons, the Group 8 metal concentration should be less than about 10 ppm in the product. Upon cooling, the product crystallizes out of solution with high purity and is recovered by filtration or centrifugation.

As is well known in the art, a number of process designs may be utilized with the method of the present invention.
The reaction of the present invention can be accomplished by any conventional method. Suitable methods include dissolving the reactant of formula I in a suitable solvent in a reaction vessel. Suitable solvents include but are not limited to alcohols, preferably primary and secondary lower alkyl alcohols. The reaction vessel is then flushed with an inert gas, typically nitrogen. The catalyst is added and the reaction mixture is refluxed under an inert atmosphere, typically for at least about 1 hour, until the conversion is essentially complete. The reaction mixture is cooled and the product crystals are recovered. As is well known in the art, the product may be purified by recrystallization in a suitable solvent or by any other suitable conventional purification method.

  In an alternative embodiment, a tertiary amine, such as triethylamine, is added to the reaction mixture when using the preferred Ru complex catalyst. Tertiary amines reduce the formation of by-products, mainly the alkaloid neopine, a potential by-product of the present reaction utilizing the preferred Ru catalyst.

  In another alternative embodiment, the alkaloid compound is added to the reactant that forms the catalyst and the catalyst-forming reaction is performed in the presence of the alkaloid. The ability to form a catalyst and subsequently achieve catalytic conversion in the same reaction vessel further increases the economics of the reaction.

Example Example 1
Codeine 50.00 g was dissolved in 200 ml methanol at room temperature in a three neck flask. The flask was equipped with a condenser and a nitrogen supply tube. One neck was opened and the flask was flushed with nitrogen for 5 minutes. The catalyst RhCl (P (C ₆ H ₅ ) ₃ ) ₃ 0.50 g was added to the solution. The flask was then flushed with nitrogen for an additional 5 minutes and the open mouth was closed. The reaction mixture was stirred under nitrogen and heated to reflux for 4 hours and then cooled to 0 ° C. for 30 minutes. The obtained crystals were removed by filtration. The collected crystals were washed 4 times with 10 ml of cold methanol (5 ° C.) and dried in the air for 1 hour to obtain pale yellow crystals (41.50 g, yield 83%). The filtrate was dried under reduced pressure to obtain 6.14 g of a yellow solid. The solid residue was dissolved in 40 ml of refluxing methanol, cooled to 0 ° C. for 30 minutes and filtered. The collected crystals were washed 4 times with 3 ml each of cold methanol (5 ° C.) and air-dried for 2 hours to obtain 3.41 g (6.8%) of white crystals. HPLC analysis and NMR spectra confirm that the product is pure hydrocodone.

Example 2
50.00 g of morphine was suspended in 500 ml of methanol in a 3-neck flask equipped with a condenser and nitrogen inlet and outlet. After refluxing for 5 minutes under nitrogen, one neck of the flask was opened. 0.50 g of catalyst RhCl (P (C ₆ H ₅ ) ₃ ) ₃ was added to the vessel. The open mouth was closed with a stopper. The reaction mixture was stirred under nitrogen, heated to reflux for 6 hours, cooled to 0 ° C. for 30 minutes and filtered. The collected solid was washed four times with cold methanol (5 ° C.) and dried in air for 20 minutes. The solid was kept under vacuum (15 mmHg) at room temperature for 1 hour to give a white powder (38.83 g, yield 77.7%). The filtrate was distilled under nitrogen leaving only 200 ml of solution. It was cooled to 0 ° C. for 30 minutes and filtered to give a white powder. The product was washed twice with 20 ml portions of cold methanol (5 ° C.), then once with 10 ml and dried in air for 40 minutes to give 3.48 g of white powder product. HPLC analysis and NMR spectra confirm that the product is pure hydromorphone.

Example 3
The ruthenium dimer was prepared by refluxing ₁ g of RuCl ₃ xH ₂ O in 3 equivalents of P (C ₆ H ₅ ) ₃ and EtOH (100 ml) overnight. The resulting catalyst, [Ru (P (C ₆ H ₅ ) ₃ ) ₂ Cl ₂ ] ₂ was obtained as a black precipitate after filtration in 63% yield.

Example 4
The catalyst of Example 3 was reacted with codeine in the presence of triethylamine in MeOH at the rates shown in the table below. The reaction mixture was flushed with N ₂ for 5 minutes, heated to reflux under N ₂ , cooled to 0 ° C. and filtered. The collected crystals were washed twice with 5 ml of MeOH and air-dried to obtain white crystals.

Table 1

Example 5
Codeine 5.0 g and catalyst Ru (P (C ₆ H ₅ ) ₃ ) ₃ Cl ₂ 0.117 g were dissolved in 25 ml EtOH. The mixture was flushed with nitrogen for 5 minutes. After refluxing for 2 hours under nitrogen, the reaction mixture was cooled to 0 ° C. and filtered. The collected crystals were washed twice with 5 ml of MeOH each and dried in air for 1 hour to obtain white crystals of hydrocodone with a yield of 70%.

Example 6
1.0 g of morphine and 80 mg of [Ru (P (C ₆ H ₅ ) ₃ ) ₂ Cl ₂ ] ₂ were suspended in 10 ml of MeOH. The reaction mixture was flushed with N ₂ for 3 minutes, after which 0.25 ml of triethylamine was added and the mixture was flushed with N ₂ for an additional 3 minutes. The reaction mixture was heated to reflux with stirring under N ₂ for 72 hours. The resulting solid was found to be hydromorphone.

Example 7
Codeine 5.09 g, RuCl ₃ xH ₂ O 25.4 mg and P (C ₆ H ₅ ) ₃ 95.9 mg were added to 25 ml of ethanol in a three neck flask. The flask was flushed with N ₂ for 5 minutes. The mixture was heated until the reaction was dissolved and then refluxed overnight under nitrogen. The resulting solution was washed twice with 5 ml of MeOH each and air dried to give 3.31 g of product. Analysis determined the presence of hydrocodone and Ru catalyst.

Example 8
Codeine-HCl 1.1 g and RuCl ₂ (P (C ₆ H ₅ ) ₃ ) ₃ 0.1 g were stirred in 10 ml MeOH and flushed with N ₂ for 5 min. The reaction mixture was refluxed under N ₂ overnight, cooled to room temperature and dried under vacuum to give 1.16 g of a brown solid containing hydrocodone.

Example 9
Conversion to hydrocodone with Ru polymerizable catalyst: 50.00 g of codeine is added to 200 ml of methanol in a three-necked flask equipped with a condenser and nitrogen inlet and outlet. The mixture is refluxed under nitrogen. 5 g (1 mol% Ru) of Ru catalyst fixed in polymeric phosphine is added to the vessel. The reaction mixture is stirred at reflux for several hours under nitrogen. An additional 800 ml of methanol is added and heating is continued for 30 minutes. The polymer catalyst is recovered for reuse by filtration of this hot liquid. About 800 ml of methanol is removed from the filtrate by distillation. The liquid is then cooled to 0 ° C. and maintained at that temperature for at least about 30 minutes. The product is recovered by filtration, washed 4 times with cold methanol (5 ° C.) and air dried. The product is placed under vacuum (<15 mmHg) for at least 1 hour at room temperature. The product is obtained in> 75% yield as a white powder over 38 g. The purity and properties of hydrocodone are confirmed by HPLC, H ¹ and C ¹³ NMR and MS analysis.

コデイン１０ｇ、Ｒｈ（ＰＰｈ_３）_３Ｃｌ０.１ｇ、０.１ｍｍｏｌ、ＰＰｈ_３０.１ｍｍｏｌおよびＡｇＢＦ_４０.１ｇ、０.１ｍｍｏｌを、フラスコに入れ、フラスコをＮ_２で換気した。ＭｅＯＨ１００ｍｌをＮ_２でパージし、次いでフラスコに添加した。反応混合物を室温で撹拌した。１５分でのＨＰＬＣ分析は、反応が９５％以上完了したことを示した。得られた生成物を再結晶し、収率９０％の純粋な生成物を得た。 Example 10

Codeine 10 g, Rh (PPh ₃ ) ₃ Cl 0.1 g, 0.1 mmol, PPh ₃ 0.1 mmol and AgBF ₄ 0.1 g, 0.1 mmol were placed in the flask and the flask was vented with N ₂ . 100 ml of MeOH was purged with N ₂ and then added to the flask. The reaction mixture was stirred at room temperature. HPLC analysis at 15 minutes showed that the reaction was more than 95% complete. The obtained product was recrystallized to obtain a pure product with a yield of 90%.

Example 11
50 g of N-codeine methobromide is dissolved in 200 ml of methanol in a three-necked flask at room temperature. The flask is equipped with a condenser and nitrogen. Open one neck and flush the flask with nitrogen for 5 minutes. 0.50 g of the catalyst RhCl (P (C ₆ H ₅ ) ₃ ) ₃ is added to the solution. The flask was then flushed with nitrogen for an additional 5 minutes and the open mouth was closed. The reaction mixture is stirred under nitrogen, heated to reflux for 6 hours and then cooled. 100 ml of methanol are filtered by distillation. Add 100 ml of ethyl acetate and continue cooling to -10 ° C for 1 hour. The resulting crystals are removed by filtration. The collected crystals are washed 4 times with 10 ml of cold ethyl acetate (5 ° C.) and dried for 1 hour under a stream of nitrogen to give yellow crystals (˜40 g). HPLC analysis and NMR spectra confirm that the product is N-hydrocodone methobromide.

  From the foregoing description, one of ordinary skill in the art will appreciate that an economical and efficient method of catalytic reaction to form hydrocodone and hydromorphone derivatives is provided.

  Having described the invention in detail, those skilled in the art will appreciate that modifications can be made to the invention without departing from the spirit and scope thereof. Accordingly, it is not intended that the scope of the invention be limited to the specific embodiments described. Rather, it is intended that the appended claims and their equivalents determine the scope of the invention.

Claims (21)

A method for converting a compound represented by formula VI into a compound represented by formula VII, wherein the compound represented by formula VI is catalytically converted to a compound of formula VII in the presence of at least one catalyst. the method comprising, the catalyst is at least one compound of formula _{^{[M (PR 4 R 5 R}} 6) n X m] a transition metal complex of _p; wherein, M is an group VIII transition metal; R ⁴ , R ⁵ and R ⁶ are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl, and combinations thereof; X is a halide or anion; n is 1, 2, 3 or 4 M is 1 or 2; and p is at least 1;

Wherein R ² is selected from the group consisting of H, benzyl, substituted benzyl, alkyl, aryl, acyl, arylsulfonyl, alkylsulfonyl, carboxyester, carboxyamide, trialkylsilyl, tetrahydropyranyl and tetrahydrofuranyl groups; And
R ³ is selected from the group consisting of H, alkyl, allyl, cycloalkylalkyl, benzyl, arylsulfonyl, alkylsulfonyl, aryl, acyl group, formyl, hydroxyl, carboxyester and carboxyamide. The method of claim 1, wherein (PR ⁴ R ⁵ R ⁶ ) _n is supported by a solid. (PR ⁴ R ⁵ R ⁶ ) _n supported by a polymer (PR ⁴ R ⁵ R ⁶ ) _n , supported by silica (PR ⁴ R ⁵ R ⁶ ) _n , and bonded to a resin (PR ⁴ R ⁵⁾ The method of claim 1, selected from the group consisting of R ⁶ ) _n and mixtures thereof.   The method of claim 1, wherein the metal complex is bound to a tertiary copolymer selected from the group consisting of styrene, divinylbenzene and diphenyl (p-vinylphenyl) phosphine.   The copolymer is substituted with a monomer selected from the group consisting of ethylene dimethacrylate, p-bromostyrene, divinylbenzene, butadiene, diallyl maleate, diallyl phthalate, glycol dimethacrylate, diolefin and triolefin. The method described in 1. Metal complex is of the formula _{^{[Rh (PR 4 R 5 R}} 6) n X m] p; ^wherein, R 4, ^{R 5} and ^{R 6} are alkyl, aryl, alkoxyl, from phenoxyl and combinations thereof X is a halide or anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1. The method described. n is 1, 2 or 3; p is at least 1; and X is BF ₄ , PF ₆ , ClO ₄ , CHO ₂ , CF ₃ CO ₂ , CF ₃ SO ₃ , CH ₃ CO ₂ , The method of claim 6, which is selected from the group consisting of ArCO ₂ , CH ₃ SO ₃ , p-tolyl SO ₃ , HSO ₄ and H ₂ PO ₄ . Metal complex is Formula ^{[RuXY (PR 4 R 5 R} 6) n] p; ^wherein, R 4, ^{R 5} and ^{R 6} are selected from alkyl, aryl, alkoxyl, from phenoxyl and combinations thereof X is H, halide or anion; Y is H, halide or anion; n is 1, 2, 3 or 4; m is 1 or 2; , P is at least 1. n = 3, p is at least 1, Y = H and X = Cl; or n = 3, p is at least 1, Y = H and X = H; or n = 4, p is at least 1 Or X = H, Y = H; or n = 2, 3 or 4, and X = Y is ClO ₄ , PF ₆ , BF ₄ , CHO ₂ , CF ₃ CO ₂ , CF ₃ SO ₃ , _{CH 3 CO 2, ArCO 2,} CH 3 SO 3, is selected from the group consisting of p- tolyl _SO 3, HSO ₄ and _H 2 PO _4, the method of claim 8. A process for converting a compound represented by formula VIII to a compound represented by formula IX, wherein the compound represented by formula VIII is catalytically converted to a compound of formula IX in the presence of at least one catalyst. the method comprising, the catalyst is at least one compound of formula _{^{[M (PR 4 R 5 R}} 6) n X m] a transition metal complex of _p; wherein, M is an group VIII transition metal; R ⁴ , R ⁵ and R ⁶ are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl, and combinations thereof; X is a halide or anion; n is 1, 2, 3 or 4 M is 1 or 2; and p is at least 1;

Wherein R ² is selected from the group consisting of H, benzyl, substituted benzyl, alkyl, aryl, acyl, arylsulfonyl, alkylsulfonyl, carboxyester, carboxyamide, trialkylsilyl, tetrahydropyranyl and tetrahydrofuranyl groups;
R ⁸ and R ⁹ are independently selected from the group consisting of H, alkyl groups, allyl groups, benzyl groups, aryl groups and alkylenecycloalkanes; and
X ₁ and X ₂ are anions. Wherein, _{X 1} and _{X 2} is Br or Cl, A method according to claim 10. X ₁ and _{X 2, BF 4, PF 6, ClO} 4, CHO 2, C 2 O 4, CF 3 CO 2, CF 3 SO 3, CH 3 CO 2, ArCO 2, CH 3 SO 3, p- tolyl The method according to claim 10, wherein the anion is selected from the group consisting of SO ₃ , HSO ₄ and H ₂ PO ₄ . The method of claim 10, wherein R ⁸ and R ⁹ together form an oxide. _{^{(PR 4 R 5 R 6)}} n is supported by a solid, the method of claim 10. (PR ⁴ R ⁵ R ⁶ ) _n supported by a polymer (PR ⁴ R ⁵ R ⁶ ) _n , supported by silica (PR ⁴ R ⁵ R ⁶ ) _n , and bonded to a resin (PR ⁴ R ⁵⁾ R ⁶⁾ is selected from _n and mixtures thereof the method of claim 10.   11. The method of claim 10, wherein the metal complex is bound to a tertiary copolymer selected from the group consisting of styrene, divinylbenzene and diphenyl (p-vinylphenyl) phosphine.   17. The copolymer is substituted with a monomer selected from the group consisting of ethylene dimethacrylate, p-bromostyrene, divinylbenzene, butadiene, diallyl maleate, diallyl phthalate, glycol dimethacrylate, diolefin, and triolefin. The method described in 1. Metal complex is of the formula _{^{[Rh (PR 4 R 5 R}} 6) n X m] p; ^wherein, R 4, ^{R 5} and ^{R 6} are alkyl, aryl, alkoxyl, from phenoxyl and combinations thereof 11 is selected from the group consisting of: X is a halide or anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1. The method described. n is 1, 2 or 3; p is at least 1; and X is BF ₄ , PF ₆ , ClO ₄ , CHO ₂ , CF ₃ CO ₂ , CF ₃ SO ₃ , CH ₃ CO ₂ , ArCO _{2, CH} 3 _SO 3, is selected from the group consisting of p- tolyl _SO 3, HSO ₄ and _H 2 PO _4, the method of claim 18. Metal complex is Formula ^{[RuXY (PR 4 R 5 R} 6) n] p; ^wherein, R 4, ^{R 5} and ^{R 6} are selected from alkyl, aryl, alkoxyl, from phenoxyl and combinations thereof X is H, halide or anion; Y is H, halide or anion; n is 1, 2, 3 or 4; m is 1 or 2; 11. The method of claim 10, wherein p is at least 1. n = 3, p is at least 1, Y = H and X = Cl; or n = 3, p is at least 1, Y = H and X = H; or n = 4, p is at least 1 Or X = H, Y = H; or n = 2, 3 or 4, and X = Y is ClO ₄ , PF ₆ , BF ₄ , CHO ₂ , CF ₃ CO ₂ , CF ₃ SO ₃ , _{CH 3 CO 2, ArCO 2,} CH 3 SO 3, is selected from the group consisting of p- tolyl _SO 3, HSO ₄ and _H 2 PO _4, the method of claim 20.