Process for preparing hydromorphone and derivatives thereof

Abstract

There is provided a novel process for the preparation of a compound of formula (I), wherein R.sup.1 is as described in the description, by demethylation of a corresponding O-methyl derivative. ##STR00001##

Claims

1. A process for the preparation of a compound of formula I, ##STR00010## or a pharmaceutically acceptable salt thereof; wherein: R.sup.1 represents hydrogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl or C.sub.3-12 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl (which latter four groups are optionally substituted by one or more halogen atoms or phenyl groups; the process comprises contacting a compound of formula II, ##STR00011## or a salt thereof, wherein R.sup.1a is defined according to R.sup.1, with a mixture comprising water, a carboxylic acid, a sulfonic acid, and a sulfide compound; wherein the water is present in the mixture at from about 0.1% to about 70% by weight relative to combined weight of the water and the compound of formula II, and the sulfide compound is selected from the group consisting of cyclic sulfur-containing compounds and sulfides of formula III,
X.sup.1SX.sup.2III wherein X.sup.1 and X.sup.2 each independently represent hydrogen, phenyl, C(O)R.sup.3 or a C.sub.1-12 alkyl group, wherein the phenyl, R.sup.3 and alkyl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, OH, NH.sub.2, phenyl, OC.sub.1-4 alkyl, C(O)R.sup.4 and S(O).sub.mC.sub.1-4 alkyl; R.sup.3 and R.sup.4 independently represent OH, C.sub.1-4 alkyl or OC.sub.1-4 alkyl; and m represents from 0 to 2.

2. The process as claimed in claim 1, wherein R.sup.1 represents methyl, ethyl, propyl, butyl, benzyl or CH.sub.2-cyclopropyl.

3. The process as claimed in claim 1, wherein R.sup.1 represents methyl.

4. The process as claimed in claim 1, wherein the sulfonic acid is a sulfonic acid of formula V,
R.sup.5SO.sub.2OHV wherein R.sup.5 represents a C.sub.1-6 alkyl group that is optionally substituted by one or more halogen atoms, or an aryl group that is optionally substituted by one or more substituents selected from the group consisting of a C.sub.1-4 alkyl group and a halogen atom.

5. The process as claimed in claim 4, wherein the sulfonic acid is selected from the group consisting of methane sulfonic acid, trifluoromethane sulfonic acid, toluenesulfonic acid, and mixtures thereof.

6. The process as claimed in claim 1, wherein the sulfonic acid is present at from about 1 to about 10 equivalents relative to the compound of formula II.

7. The process as claimed in claim 1, wherein the sulfide compound is: (a) a monocyclic aromatic compound containing one or more sulfur atoms within the aromatic ring; (b) a compound of formula IV ##STR00012## wherein n represents from 0 to 3; or (c) a sulfide of formula III,
X.sup.1SX.sup.2III wherein X.sup.1 and X.sup.2 each independently represent hydrogen, phenyl, C(O)R.sup.3 or a C.sub.1-12 alkyl group, wherein the phenyl, R.sup.3 and alkyl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, NH.sub.2, phenyl, C(O)R.sup.4 and S(O).sub.mC.sub.1-4 alkyl); R.sup.3 and R.sup.4 independently represent OH, C.sub.1-4 alkyl or OC.sub.1-4 alkyl; and m represents from 0 to 2.

8. The process as claimed in claim 7, wherein the sulfide compound is selected from the group consisting of dioctyl sulfide, dibutyl sulfide, dipropyl sulfide, diethyl sulfide, dimethyl sulfide, dodecyl methyl sulfide, and mixtures thereof.

9. The process as claimed in claim 1, wherein the sulfide compound is present in an amount of at least 1 equivalent relative to the compound of formula II.

10. The process as claimed in claim 1, wherein the carboxylic acid has a pKa of 5 or below.

11. The process as claimed in claim 1, wherein the carboxylic acid is acetic acid, or a halogenated derivative thereof.

12. The process as claimed in claim 11, wherein the carboxylic acid is selected from the group consisting of trifluoroacetic acid, trichloroacetic acid, difluoroacetic acid, dichloroacetic acid, fluoroacetic acid, chloroacetic acid, and mixtures thereof.

13. The process as claimed in claim 1, wherein the carboxylic acid is present in an amount of from 1 to 20 volumes relative to the compound of formula II.

14. The process as claimed in claim 1, wherein the water is present in an amount ranging from 2% to 50% by weight relative to the combined weight of the water and the compound of formula II.

15. The process as claimed in claim 1, wherein the reaction is performed at a temperature of from about 30 C. to about 70 C.

16. The process as claimed in claim 1, wherein the compound of formula I is hydromorphone or a salt thereof, the compound of formula II is hydrocodone or a salt thereof, and: (i) the carboxylic acid is selected from the group consisting of trifluoroacetic acid, trichloroacetic acid, difluoroacetic acid, dichloroacetic acid, fluoroacetic acid, chloroacetic acid, and mixtures thereof; (ii) the sulfonic acid is selected from the group consisting of methane sulfonic acid, trifluoromethane sulfonic acid, toluenesulfonic acid, and mixtures thereof; and (ii) the sulfide compound is selected from the group consisting of dioctyl sulfide, dibutyl sulfide, dipropyl sulfide, diethyl sulfide, dimethyl sulfide, dodecyl methyl sulfide and mixtures thereof.

17. The process as claimed in claim 2, wherein the compound of formula II is hydrocodone or a salt thereof and wherein the process further comprises a preceding step of converting codeine to the hydrocodone.

18. The process as claimed in claim 1, wherein the compound of formula II is formed by a process comprising reacting a compound of formula VII, ##STR00013## wherein R.sup.1b is defined according to R.sup.1a, with a rhodium complex in an aqueous solvent system; and optionally the compound of formula VII and the rhodium complex are mixed together with an organic additive selected from the group consisting of acetone, isopropanol, tert-butanol and mixtures thereof.

19. The process as claimed in claim 18, wherein the rhodium complex is prepared from a [Rh(COD)(CH.sub.3CN).sub.2](BF.sub.4) and a phosphine derivative, wherein the COD is 1,5-cyclooctadiene.

20. A process for forming hydromorphone, wherein the process comprises: (i) converting thebaine to hydrocodone; and (ii) converting said hydrocodone to hydromorphone according to a process as claimed in claim 1.

21. A process for preparing a salt of a compound of formula I, ##STR00014## wherein: R.sup.1 represents hydrogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl or C.sub.3-12 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are each independently optionally substituted by one or more halogen atoms or phenyl groups; the process comprises the steps of: (i) preparing a compound of formula I in accordance with the process defined in claim 1; (ii) optionally isolating and/or purifying the compound of formula I obtained from the process; (iii) bringing into association the compound of formula I formed from step (i) or (ii) with an acid; and (iv) optionally converting the product from step (iii) into a different salt.

22. A process for preparing a pharmaceutical formulation comprising a compound of formula I, ##STR00015## or a pharmaceutically acceptable salt thereof; wherein: R.sup.1 represents hydrogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl or C.sub.3-12 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are each independently optionally substituted by one or more halogen atoms or phenyl groups; the process comprises the steps of: (i) preparing a compound of formula I or a salt thereof in accordance with a process as defined in claim 1; (ii) optionally isolating and/or purifying the compound of formula I or a salt thereof obtained from the process; and (iii) bringing into association the compound of formula I or a salt thereof formed from step (i) or (ii) with one or more pharmaceutically-acceptable excipients, adjuvants, diluents or carriers.

23. A process for preparing a prodrug of a compound of formula I, ##STR00016## or a pharmaceutically acceptable salt thereof; wherein: R.sup.1 represents hydrogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl or C.sub.3-12 cycloalkyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted by one or more halogen atoms or phenyl groups; the process comprises the steps of: (i) preparing a compound of formula I in accordance with the process as defined in claim 1; (ii) optionally isolating and/or purifying the compound of formula I obtained from the process; and (iii) converting the compound of formula I obtained from step (i) or (ii) into a prodrug of the compound of formula I by reacting with a reagent that is capable to react with a hydroxyl functional group, an enol tautomer, a carboxyl functional group, or an amine group to form the prodrug of the compound of formula I, wherein the product is an ester derivative, a carbamate derivative, an N-acyl derivative, or an N-Mannich base derivative of the compound of formula I.

Description

EXAMPLES

Example 1Demethylation of Hydrocodone Using TCA

(1) To a 5 L jacketed reactor with reflux condenser and vacuum line was added hydrocodone base (651.2 g; equivalent to 323.00 g (18.21 mol) hydrocodone dry base and 328.21 g water), TCA (2632.5 g; 1615.0 mL), dibutylsulfide (315.7 g; 376.7 mL), and MSA (311.1 g, 210.2 mL). The mixture was heated to 40 C. TfOH (404.8 g, 238.7 mL) was added. The mixture was stirred at 485 C. for at least 12 hr. The reaction was considered complete when the hydrocodone level was found to be not more than 4% using UPLC MD-40-14.

(2) The batch was then cooled to 20 C. MEK (780.0 g, 969.0 mL) was then charged slowly to the mixture. The batch was cooled to ca. 20 C. and transferred to a 10 L reactor with bath set to 20 C. iPrOAc (1475.3 g, 1695.8 mL) was added to the 5 L reactor, stirred for 5 min, and then transferred to the 10 L reactor. iPrOAc (4425.9 g, 5087.3 mL) was added and the mixture was stirred at room temperature for at least 48 hr. The batch was filtered, and the cake was washed with IPAc (562.0 g, 646.0 mL). The cake was dried in vacuum at room temperature to give the crude hydromorphone triflate (281.81 g as a white solid).

Example 2Demethylation of Hydrocodone Using TFA

(3) To a 1 L jacketed reactor, was added hydrocodone (22.22 g), TFA (163.8 g, 110.0 mL), dibutylsulfide (21.5 g, 25.7 mL) and MSA (42.4 g, 28.6 mL). Water was added (3.1 g, 3.1 mL), and the mixture was stirred for at least 16 hr at 505 C. The reaction was monitored using UPLC MD-40-14, and was considered completed when the hydrocodone level was found to be less than 2.0% with only hydrocodone and hydromorphone being integrated. After completion, the batch was cooled to 205 C.

(4) The product of the preceding reaction step was added to a source of chloride ions and an anti-solvent, and the resulting mixture furnished a slurry. The solid product was obtained by filtration, washed, and dried in vacuum at 205 C. to give 17.74 g of crude hydromorphone hydrochloride as a white to off-white solid.

Example 3Sulfides

(5) Demethylation reactions using hydrocodone were studied using a range of sulfides.

(6) TABLE-US-00001 HM HC Tot Imp Sulfide Details Area % Area % Area % None MSA (22.6 eq), 30 C. 16 hr 0.0 86.8 13.2 Methionine (3.0 eq) MSA (22.6 eq), , 30 C. 16 hr 38.6 47.8 13.5 Dipropylsulfide(3.0 eq) MSA (22.6 eq), 30 C. 16 hr 61.1 10.8 28.1 Dibutylsulfide (3.0 eq) MSA (22.6 eq), 30 C. 16 hr 50.1 24.0 25.9 Benzylsulfide (3.0 eq) MSA (22.6 eq), 30 C. 16 hr 0.3 0.7 99.0 Thiophene (3.0 e) MSA (22.6 eq), 30 C. 16 hr 0.0 0.0 100.0 Tetrahydrothiophene (3.0 eq) MSA (22.6 eq), 30 C. 16 hr 43.6 6.5 49.9 Diethylsulfide (4 eq) TCA (5 vol), MSA (4.0 equiv), 68.6 21.7 9.7 30 C., 16 hr Ethylpropylsulfide (4 eq) TCA (5 vol), MSA (4.0 equiv), 79.1 19.4 1.5 30 C., 16 hr Dipropylsulfide (4 eq) TCA (5 vol), MSA (4.0 equiv), 69.5 26.0 3.5 30 C., 16 hr Dibutylsulfide (4 eq) TCA (5 vol), MSA (4.0 equiv), 65.4 24.8 9.8 30 C., 16 hr Diisopropylsulfide (4 eq) TCA (5 vol), MSA (4.0 equiv), 37.9 60.2 1.9 30 C., 16 hr Thioanisole (4 eq) TCA (5 vol), MSA (4.0 equiv), 26.6 47.1 26.3 30 C., 16 hr

(7) The following additional sulfides were also screened (conditions: TCA 5 vol, TfOH 2.5 eq, MSA 4.0 eq, 35 C.).

(8) TABLE-US-00002 HM HC Impurity Experiment Sulfide area % area % Area % 1 Trimethylene sulfide 9.4 89.1 1.5 2 Thioacetic acid 8.6 5.4 86.0 3 Dimethyl sulfide 74.2 10.2 15.6 81.0 3.3 15.7 4 Tetrahydrothiophene 70.0 15.0 15.0 75.1 7.9 17.0 5 Diethyl sulfide 75.1 16.2 8.7 88.2 9.1 2.7 83.1 0.0 16.9 6 Ethyl propyl sulfide 71.7 12.2 16.1 75.9 5.6 18.5 77.7 0.0 22.3 7 tert-Butyl methyl sulfide Decomposition 8 Cyclohexene sulfide Decomposition 9 Dipropyl sulfide 81.3 9.3 9.4 84.8 3.9 11.3 10 Diisopropyl sulfide 45.0 48.7 6.3 54.4 39.3 6.3 74.0 5.4 20.6 11 Thioanisole 6.8 0.8 92.4 12 Methyl (methylthio)acetate 54.1 40.6 5.3 54.5 38.1 7.4 13 Dibutyl sulfide 80.2 13.4 6.4 86.3 6.7 7.0 82.9 0.0 17.1 14 sec-Dibutyl sulfide 34.5 62.6 2.9 43.7 53.3 3.0 80.5 14.0 5.5 15 2,2-Thiodiacetic acid 11.0 80.3 8.7 16 S-Phenyl thioacetate Decomposition 17 Phenyl trifluoromethyl 0.8 89.6 9.6 sulfide 18 3,3-Thiodipropionic acid 51.0 23.8 25.2 54.4 13.2 32.4 19 Diphenyl sulfide 5.7 2.5 91.8 20 Dodecyl methyl sulfide 89.1 7.8 3.1 91.5 3.1 5.4 79.1 0.0 20.9 21 Dioctyl sulfide 81.4 14.3 4.3 87.0 7.5 5.5 84.9 0.0 15.1 22 Isopropyl methyl sulfide 71.2 11.0 17.8 23 Pentamethylene sulfide 66.1 17.9 16.0 24 Butyl methyl sulfide 66.5 6.0 27.5 25 Ethyl isopropyl sulfide 57.8 26.7 15.5 26 Bis(methylthio)methane Decomposition 27 Isopropyl propyl sulfide 55.6 24.6 19.8 28 Butyl ethyl sulfide 63.2 11.1 25.7 29 Methyl Decomposition (methylsulfinyl)methyl sulfide 30 tert-Butyl sulfide Decomposition 31 Isobutyl sulfide 76.6 10.9 12.5

Example 4Analysis of Critical Parameters for the Demethylation Reaction Using TfOH

(9) The demethylation of hydrocodone was assessed using a mixture containing hydrocodone, water, TfOH, MSA, dibutylsulfide and TCA.

(10) Method

(11) A scintillation vial was equipped with a magnetic stir bar and hydrocodone (1.00 g), TCA (8.15 g, 5.00 mL), MSA (0.96 g, 0.65 mL) and dibutylsulfide (0.98 g, 1.17 mL) were added.

(12) Water and TfOH were also added in the amounts shown in the table below, and the reaction mixture was heated to 42, 48 or 54 C. (as specified in the results section) overnight.

(13) TABLE-US-00003 Density Amt Amt Mole g/g mL/g Reagent MW (g/mL) Assay (g) (mL) moles Equiv HC HC Hydrocodone 1.00 Content Water Content 18.02 1 0.00% 0.00 0.00 0.000 0.00 0.00 0.00 Hydrocodone 299.36 1 100.00% 1.00 1.00 0.003 1.00 1.00 1.00 Base Water 5% 18.02 1.000 100% 0.05 0.05 0.003 0.83 0.05 0.05 Water 10% 18.02 1.000 100% 0.10 0.10 0.006 1.66 0.10 0.10 Water 15% 18.02 1.000 100% 0.15 0.15 0.008 2.49 0.15 0.15 TfOH 2.0 150.08 1.700 100% 1.00 0.59 0.007 2.00 1.00 11.80 TfOH 2.5 150.08 1.700 100% 1.25 0.74 0.008 2.50 1.25 7.37 TfOH 3.0 150.08 1.700 100% 1.50 0.88 0.010 3.00 1.50 5.90 MSA 3.0 96.11 1.480 100% 0.96 0.65 0.010 3.00 0.96 0.65 Dibutylsulfide 146.29 0.838 100% 0.98 1.17 0.007 2.00 0.98 1.17 2.0 TCA 5.0 163.39 1.630 100% 8.15 5.00 0.050 14.93 8.15 5.00 Hydromorphone 285.34 1 100% 0.95 0.95 0.003 1.00 0.95 0.95 Base
Results

(14) The table below shows the results obtained after a reaction time of 24 hrs using different amounts of water and TfOH, and different reaction temperatures. The water quantity is expressed as % by weight relative to the hydrocodone. The TfOH quantity is expressed as molar equivalents relative to the hydrocodone.

(15) TABLE-US-00004 Temp Water TfOH Impurity Exp ( C.) (%) (eq) HM area % HC area % Area % 1 42 5 2 88.6 1.2 10.2 5 42 5 3 86.2 0.1 13.7 9 42 10 2.5 87.6 1.4 11.0 3 42 15 2 85.3 7.8 6.9 7 42 15 3 88.4 0.9 10.7 11 48 5 2.5 82.9 0.1 17.0 13 48 10 2 86.7 1.1 12.2 17 48 10 2.5 84.8 0.1 15.1 15 48 10 2.5 84.1 0.1 15.8 16 48 10 2.5 84.4 0.1 15.5 14 48 10 3 83.4 0.1 16.5 12 48 15 2.5 86.6 0.8 12.6 2 54 5 2 77.0 0.1 22.9 6 54 5 3 71.8 0.1 28.1 10 54 10 2.5 78.8 0.1 21.2 4 54 15 2 83.0 0.1 16.9 8 54 15 3 79.0 0.1 20.9

(16) It was found that increased levels of water led to an increase in the amount of hydromorphone produced, a decrease in the level of impurities, and a slowing of the conversion of hydrocodone.

Example 5Analysis of Critical Parameters for the Demethylation Reaction Using TfOH

(17) The demethylation of hydrocodone was assessed using a mixture containing hydrocodone, water, TfOH, MSA, dibutylsulfide and TCA.

(18) Method

(19) A scintillation vial was equipped with a magnetic stir bar and hydrocodone (1.00 g), TCA (8.15 g, 5.00 mL), TfOH (1.25 g, 0.74 mL), MSA (0.96 g, 0.65 mL) and dibutylsulfide (0.98 g, 1.17 mL) were added. Water was also added in the amount shown in the table below, and the reaction mixture was heated to 44, 48 or 52 C. (as specified in the results section) overnight

(20) TABLE-US-00005 Density Amt Amt Mole g/g mL/g Reagent MW (g/mL) Assay (g) (mL) moles Equiv HC HC Hydrocodone 1.00 Content Water Content 18.02 1 0.00% 0.00 0.00 0.000 0.00 0.00 0.00 Hydrocodone 299.36 1 100.00% 1.00 1.00 0.003 1.00 1.00 1.00 Base Water 5% 18.02 1.000 100% 0.05 0.05 0.003 0.83 0.05 0.05 Water 10% 18.02 1.000 100% 0.10 0.10 0.006 1.66 0.10 0.10 Water 15% 18.02 1.000 100% 0.15 0.15 0.008 2.49 0.15 0.15 TfOH 2.5 150.08 1.700 100% 1.25 0.74 0.008 2.50 1.25 7.37 MSA 3.0 96.11 1.480 100% 0.96 0.65 0.010 3.00 0.96 0.65 Dibutylsulfide 146.29 0.838 100% 0.98 1.17 0.007 2.00 0.98 1.17 2.0 TCA 5.0 163.39 1.630 100% 8.15 5.00 0.050 14.93 8.15 5.00 Hydromorphone 285.34 1 100% 0.95 0.95 0.003 1.00 0.95 0.95 Base
Results

(21) The table below shows the results obtained after the specified reaction time (20.5 or 44 hrs) using different amounts of water, and different reaction temperatures. The water quantity is expressed as % by weight relative to the hydrocodone.

(22) TABLE-US-00006 20.5 hr 44 hr Added Calculated Temp HM HC Impurity HM HC Impurity Exp Water Water ( C.) area % area % Area % area % area % Area % 1 5% 14.4% 44 88.8 5.9 5.3 87.6 0.4 12.0 7 10% 20.0% 44 86.6 8.8 4.6 91.0 0.8 8.1 2 15% 23.4% 44 82.8 13.4 3.8 90.9 2.9 6.2 5 5% 13.3% 48 91.5 1.4 7.1 87.6 0.1 12.3 9 10% 18.4% 48 89.4 5.8 4.8 90.4 0.5 9.1 10 10% 18.7% 48 89.7 3.9 6.4 89.8 0.3 9.9 11 10% 19.1% 48 90.1 4.0 5.9 90.2 0.2 9.6 6 15% 24.5% 48 88.3 7.0 4.7 91.3 0.6 8.1 3 5% 15.9% 52 90.3 0.7 9.0 85.4 0.0 14.6 8 10% 20.0% 52 89.3 0.8 9.9 86.3 0.1 13.6 4 15% 25.4% 52 88.3 6.3 5.4 90.1 0.6 9.3

(23) It was found that the effect of water on the hydromorphone response changes over time from slowing the reaction down (less area % hydromorphone) to having a preservative effect on hydromorphone. Increasing the levels of water inhibited the formation of by products and inhibited the conversion of hydrocodone.

Example 6Analysis of Critical Parameters for the Demethylation Reaction Using MSA

(24) The demethylation of hydrocodone was assessed using a mixture containing hydrocodone, water, MSA, dibutylsulfide and TFA.

(25) Method

(26) A scintillation vial was equipped with a magnetic stir bar and hydrocodone (1.00 g), TFA (8.94 g, 6.00 mL), and dibutylsulfide (1.222 g, 1.458 mL) were added. Water and MSA were also added in the amount shown in the table below, and the reaction mixture was heated to 45, 50 or 55 C. (as specified in the results section) overnight.

(27) TABLE-US-00007 Density Amt Amt Mole g/g mL/g Reagent MW (g/mL) Assay (g) (mL) moles Equiv HC HC Hydrocodone 1.0 Content Water Content 18.02 1.0 0.00% 0.00 0.00 0.000 0.00 0.0 0.0 Hydrocodone 299.36 1.0 100.00% 1.00 1.00 0.0033 1.00 1.0 1.0 Base Dibutylsulfide 146.29 0.838 100% 0.73 0.875 0.0050 1.50 0.73 0.87 1.5 Dibutylsulfide 146.29 0.838 100% 0.98 1.166 0.0067 2.00 0.98 1.17 2.0 Dibutylsulfide 146.29 0.838 100% 1.22 1.458 0.0084 2.50 1.22 1.46 2.5 TFA 4 114.02 1.49 100% 5.96 4.00 0.052 15.65 5.960 4.00 TFA 5 114.02 1.49 100% 7.45 5.00 0.065 19.56 7.450 5.00 TFA 6 114.02 1.49 100% 8.94 6.00 0.078 23.47 8.940 6.00 MSA 4 96.11 1.48 100% 1.28 0.87 0.0134 4.00 1.28 0.54 MSA 5 96.11 1.48 100% 1.61 1.08 0.0167 5.00 1.61 21.69 MSA 6 96.11 1.48 100% 1.93 1.30 0.0200 6.00 1.93 13.02 Water 1% 18.01 1.000 100% 0.010 0.010 0.001 0.17 0.01 0.01 Water 5% 18.01 1.000 100% 0.050 0.050 0.003 0.83 0.05 0.05 Water 9% 18.01 1.000 100% 0.100 0.100 0.006 1.66 0.10 0.10
Results

(28) The table below shows the results obtained after 24 hrs using different amounts of water and MSA, and different reaction temperatures. The water quantity is expressed as % by weight relative to the hydrocodone. The MSA quantity is expressed as molar equivalents relative to the hydrocodone.

(29) TABLE-US-00008 Exp MSA Water Temperature TFA Dibutylsulfide HM HC Impurity 1 4 1 45 5 2 87.9 8.7 3.4 2 6 1 45 5 2 90.7 3.3 6 3 4 9 45 5 2 83.8 13.7 2.5 4 6 9 45 5 2 88.6 7.9 3.5 5 4 1 55 5 2 89.3 1 9.7 6 6 1 55 5 2 86.7 0.1 13.2 7 4 9 55 5 2 90.1 2.2 7.7 8 6 9 55 5 2 89.7 0.5 9.8 9 5 5 50 5 2 90.6 2.9 6.5 10 5 5 50 5 2 90.6 3 6.4 11 5 5 50 5 2 90.4 3.4 6.2

(30) It was found that the reaction rate is influenced by water, i.e higher water levels slowed the conversion to hydromorphone. Also, less hydrocodone remains when the reaction is conducted at higher temperatures or with greater quantities of MSA. Increased levels of water resulted in lower levels of impurities.

Example 7Analysis of Critical Parameters for the Demethylation Reaction Using MSA

(31) The demethylation of hydrocodone was assessed using a mixture containing hydrocodone, water, MSA, dibutylsulfide and TFA.

(32) Method

(33) A scintillation vial was equipped with a magnetic stir bar and hydrocodone (1.00 g), TFA (7.450 g, 5.000 mL), and dibutylsulfide (0.977 g, 1.166 mL) were added. Water and MSA were also added in the amount shown in the table below, and the reaction mixture was heated to 47, 50 or 53 C. (as specified in the results section) overnight.

(34) TABLE-US-00009 Density Amt Amt Mole g/g mL/g Reagent MW (g/mL) Assay (g) (mL) moles Equiv HC HC Hydrocodone 1.0 Content Water Content 18.02 1.0 0.00% 0.000 0.000 0.000 0.00 0.0 0.0 Hydrocodone 299.36 1.0 100.00% 1.000 1.000 0.0033 1.00 1.0 1.0 Base Dibutylsulfide 2 146.29 0.838 100% 0.977 1.166 0.0067 2.00 0.98 1.17 TFA 5 114.02 1.49 100% 7.450 5.000 0.065 19.56 7.450 5.00 MSA 5 96.11 1.48 100% 1.605 1.085 0.0167 5.00 1.61 0.56 MSA 6 96.11 1.48 100% 1.926 1.302 0.0200 6.00 1.93 65.08 MSA 7 96.11 1.48 100% 2.247 1.518 0.0234 7.00 2.25 37.96 Water 2% 18.01 1.000 100% 0.020 0.020 0.001 0.33 0.02 0.02 Water 4% 18.01 1.000 100% 0.040 0.040 0.002 0.66 0.04 0.04
Results

(35) The table below shows the results obtained after 21 hrs using different amounts of water and MSA, and different reaction temperatures. The water quantity is expressed as % by weight relative to the hydrocodone. The MSA quantity is expressed as molar equivalents relative to the hydrocodone.

(36) TABLE-US-00010 Temperature Exp ( C.) Water MSA HM % HC % Impurity % 1 47 0 5 89.5 5.3 5.2 2 53 0 5 88.5 1.1 10.4 3 47 4 5 88.3 7.4 4.3 4 53 4 5 89.4 1.9 8.7 5 47 0 7 90 2 8 6 53 0 7 85.4 0.5 14.1 7 47 4 7 90.6 2.1 7.3 8 53 4 7 88.5 0.8 10.7 9 47 2 6 90.3 4.8 4.9 10 53 2 6 88.4 0.8 10.8 11 50 0 6 90.6 1.8 7.6 12 50 4 6 90.4 1.9 7.7 13 50 2 5 90.1 3.3 6.6 14 50 2 7 89.7 0.4 9.9 15 50 2 6 90.5 2 7.5 16 50 2 6 90 2 8 17 50 2 6 90.2 1.8 8

(37) It was found that increased levels of water in the reactions led to increased formation of hydromorphone, slower conversion of hydrocodone to hydromorphone and lower levels of impurities. Higher temperatures led to increased degradation of hydromorphone and conversion of hydrocodone. Also, more impurities were formed when the reaction was performed at higher temperatures.

Example 8Analysis of Critical Parameters for the Demethylation Reaction Using MSA

(38) The demethylation of hydrocodone was assessed using a mixture containing hydrocodone, water, MSA, dibutylsulfide and either TFA or TCA.

(39) Method

(40) A scintillation vial was equipped with a magnetic stir bar and hydrocodone (1.00 g) and dibutylsulfide (0.977 g, 1.166 mL) were added along with either TFA (7.450 g, 5.000 mL) or TCA (8.2 g, 5.000 mL). Water and MSA were also added in the amount shown in the table below, and the reaction mixture was heated to 50 C. overnight.

(41) TABLE-US-00011 Density Amt Amt Mole g/g mL/g Reagent MW (g/mL) Assay (g) (mL) moles Equiv HC HC Hydrocodone 1.00 Content Water Content 18.02 1 0.000% 0.000 0.0 0.000 0.00 0.00 0.00 Hydrocodone 299.36 1 100.0% 1.0 1.0 0.003 1.00 1.00 1.00 Base Dibutylsulfide 146.29 0.838 100% 1.0 1.2 0.007 2.00 0.98 1.17 TCA 5 163.39 1.63 100% 8.2 5.0 0.050 14.93 8.15 5.00 TFA 5 114.02 1.489 100% 7.4 5.0 0.065 19.55 7.45 5.00 MSA 5.0 96.11 1.480 100% 1.6 1.1 0.017 5.00 1.61 0.13 MSA 6.0 96.11 1.480 100% 1.9 1.3 0.020 6.00 1.93 0.17 MSA 7.0 96.11 1.480 100% 2.2 1.5 0.023 7.00 2.25 0.95 Water 5% 18.00 1.000 100% 0.1 0.05 0.003 0.83 0.05 0.05 Water 15% 18.00 1.000 100% 0.2 0.15 0.008 2.49 0.15 0.15 Water 25% 18.00 1.000 100% 0.3 0.25 0.014 4.16 0.25 0.25 Hydromorphone 321.80 1.0 100% 1.1 1.1 0.003 1.00 1.07 1.07 HCl
Results

(42) The table below shows the results obtained after the times specified using different amounts of water and MSA, and either TCA or TFA. The water quantity is expressed as % by weight relative to the hydrocodone. The MSA quantity is expressed as molar equivalents relative to the hydrocodone.

(43) TABLE-US-00012 Hydro- Hydro- Sol- morphone codone Impurities Exp Water MSA vent 24 h 43 h 24 h 43 h 24 h 43 h 1 5 5 TFA 88.1 88.2 7.2 0.2 4.7 11.6 2 25 5 TFA 80 89.6 16.9 3.5 3.1 6.9 3 5 7 TFA 90.3 84.6 2.1 0.1 7.6 15.3 4 25 7 TFA 85.7 89.7 10.2 0.9 4.1 9.4 5 5 5 TCA 88.6 91.2 8.5 0.8 2.9 8 6 25 5 TCA 64.2 81.8 34.3 16 1.5 2.2 7 5 7 TCA 91 90 3.9 0.1 5.1 9.9 8 25 7 TCA 80.9 90.6 16.9 4.3 2.2 5.1 9 15 6 TFA 87.8 88.8 7.3 0.7 4.9 10.5 10 15 6 TFA 87.3 89.4 8.3 0.6 4.4 10 11 15 6 TFA 86.7 89.1 9.1 0.6 4.2 10.3 12 15 6 TCA 85.3 91.6 12.1 3.1 2.6 5.3 13 15 6 TCA 83.1 91.5 14.6 3.6 2.3 4.9 14 15 6 TCA 82.3 90.9 15.4 3.9 2.3 5.2

(44) It was found that increased levels of water in the reactions led to a slowing of the reaction initially, but also a slowing of further degradation of hydromorphone. Water gave a slower conversion of hydrocodone throughout the time of the experiment, and increased levels of water led to lower levels of impurities.

ABBREVIATIONS

(45) DMF Dimethylformamide GC Gas chromatography HC Hydrocodone HM Hydromorphone HPLC High performance liquid chromatography hr Hours iPrOAc Isopropyl acetate iPrOH Isopropyl alcohol KF Karl Fischer MEK Methyl ethyl ketone MeOH Methanol MSA Methane sulfonic acid MTBE Methyl-tert-butyl ether MW Molecular weight NMR Nuclear magnetic resonance rt Room temperature TCA Trichloroacetic acid TFA Trifluoroacetic acid TfOH Trifluoromethane sulfonic acid UPLC Ultra performance liquid chromatography