Methods of O-demethylation

Abstract

There is provided a novel process for the preparation of a compound of formula I, ##STR00001##
wherein R.sup.1, R.sup.2, W, Z and are as described in the description, by demethylation of a corresponding O-methyl derivative with a borohydride-based reagent. This process may be used in the preparation of buprenorphine.

Claims

1. A process for the preparation of a compound of formula I, ##STR00014## or a pharmaceutically acceptable salt thereof; wherein: W and Z independently represent CHR.sup.3 or S, provided that at least one of W and Z represents CHR.sup.3; 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 (which latter four groups are optionally substituted by one or more substituents selected from the list consisting of halogen atoms, phenyl groups and C.sub.3-12 cycloalkyl groups); R.sup.2 represents hydrogen, a halogen atom, —OR.sup.4, —OC(O)R.sup.4, —N(R.sup.4).sub.2, C.sub.1-12 alkyl, C.sub.2-12 alkenyl or C.sub.2-12 alkynyl (which latter three groups are optionally substituted by one or more halogen atoms); each R.sup.3 independently represents hydrogen, —CN, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl or C.sub.3-12 cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from the list consisting of halogen atoms, —OR.sup.5 groups and 5 to 10-membered heteroaryl groups); R.sup.4 independently represents hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl (which latter three groups are optionally substituted by one or more halogen atoms or phenyl groups); R.sup.5 represents hydrogen or C.sub.1-6 alkyl, optionally substituted by one or more halogen atoms; and represents a single or double bond; which process comprises contacting a compound of formula II, ##STR00015## or a salt thereof, wherein R.sup.1a, R.sup.2a, W.sup.a and Z.sup.a are defined according to R.sup.1, R.sup.2, W and Z, respectively, with an alkali metal borohydride and an additional alkali metal salt.

2. The process of claim 1, wherein: (i) R.sup.1 represents methyl, ethyl, propyl, butyl, benzyl or —CH.sub.2-cyclopropyl; or (ii) R.sup.3 represents C.sub.1-6 alkyl optionally substituted by one or more substituents selected from the group consisting of halogen atom, —OR.sup.5 groups, 5-membered heteroaryl groups.

3. The process of claim 1, wherein W and Z independently represent CHR.sup.3, and optionally, wherein W represents CHR.sup.3 and Z represents CH.sub.2.

4. The process of claim 2, wherein R.sup.3 represents C.sub.1-6 alkyl optionally substituted by one or more substituents selected from the list consisting of —OH and thiophenyl.

5. The process of claim 4, wherein R.sup.3 represents: ##STR00016## wherein represents the point of attachment of R.sup.3 to the rest of the compound of formula I.

6. The process of claim 1, wherein: (i) wherein R.sup.2 represents —OR.sup.4; —OC(O)R.sup.4; or a methoxy group; (ii) the alkali metal borohydride and the additional alkali metal salt each comprise the same alkali metal; or (iii) the alkali metal borohydride is a compound of formula III, ##STR00017## wherein each R.sup.6 independently represents C.sub.1-12 alkyl, and X.sup.+ represents an alkali metal cation.

7. The process of in claim 6, wherein the alkali metal borohydride is an alkali metal tri-sec-butylborohydride or an alkali metal trisiamylborohydride; and optionally, wherein (i) the alkali metal borohydride is lithium tri-sec-butylborohydride or (ii) the amount of alkali metal borohydride present is from about 1 to about 10 equivalents relative to the compound of formula II.

8. The process of claim 7, wherein: (i) the amount of alkali metal borohydride present is from about 2 to about 5 equivalents relative to the compound of formula II; or (ii) the additional alkali metal salt is lithium bromide; and optionally, wherein the additional alkali metal salt contains from about 1 to about 6 equivalents of alkali metal cations relative to the compound of formula II.

9. The process of claim 1, wherein: (i) the additional alkali metal salt is lithium bromide; or (ii) wherein the additional alkali metal salt is an alkali metal halide.

10. The process of claim 1, wherein the additional alkali metal salt contains from about 1.5 to about 3 equivalents of alkali metal cations relative to the compound of formula II and optionally, wherein: the reaction is performed in a solvent system comprising 2-methyltetrahydrofuran.

11. The process of claim 1, wherein: (a) wherein the reaction is performed at a temperature of up to about 150° C.; or (b) the compound of formula I is buprenorphine and the process comprises contacting 3-O-methyl-buprenorphine with: (i) an alkali metal borohydride selected from the group consisting of lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, and mixtures thereof; and (ii) an additional alkali metal halide.

12. The process of claim 1, wherein the process further comprises adding an oxidant after the compound of formula I has been formed and optionally, wherein the oxidant is an amine N-oxide, and/or the amine N-oxide is selected from the list consisting of trimethylamine N-oxide and N-methylmorpholine N-oxide.

13. The process of claim 12, wherein the amount of oxidant added is from about 1 to about 10 equivalents relative to the total amount of alkali metal borohydride added to the reaction mixture.

14. The process of claim 13, wherein the amount of oxidant added is from about 3 to about 7 equivalents relative to the alkali metal borohydride.

15. The process of claim 1, wherein the compound of formula II is formed by a process comprising reacting a compound of formula IV, ##STR00018## or a salt thereof, wherein R.sup.2b, W.sup.b and Z.sup.b are defined according to R.sup.2, W and Z, respectively, with a compound of formula V,
R.sup.7—Y  V wherein: R.sup.7 represents C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl or C.sub.3-12 cycloalkyl, which groups are optionally substituted by one or more substituents selected from the list consisting of halogen atoms, phenyl groups and C.sub.3-12 cycloalkyl groups; and Y represents a suitable leaving group and optionally, wherein (i) wherein: R.sup.7 represents methyl, ethyl, propyl, butyl, benzyl or —CH.sub.2-cyclopropyl; and Y represents chloro, bromo, iodo, mesylate or tosylate; or (ii) the reaction between the compound of formula IV and the compound of formula V is conducted in the presence of an inorganic base.

16. The process of claim 15, wherein the compound of formula IV is 3-O-methyl-norbuprenorphine, and the compound of formula II is 3-O-methyl-buprenorphine.

17. A process for preparing a pharmaceutically acceptable salt of a compound of formula I, as defined in claim 1, which process comprises the steps of: (i) preparing a compound of formula I in accordance with a process as claimed in claim 1; (ii) optionally isolating and/or purifying the compound of formula I obtained from that process; (iii) bringing into association the compound of formula I so formed with an acid; (iv) optionally wherein the product of step (iii) is converted into a different salt.

18. A process for preparing a pharmaceutical formulation comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1, which process comprises the steps of: (i) preparing a compound of formula I (or pharmaceutically acceptable salt thereof) in accordance with the process of claim 1; (ii) optionally isolating and/or purifying the compound of formula I (or pharmaceutically acceptable salt thereof) obtained from that process; and (iii) bringing into association the compound of formula I so formed (or pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients, adjuvants, diluents or carriers.

19. A process for the preparation of buprenorphine, or a pharmaceutically acceptable salt thereof, wherein the process comprises the steps of: (i) contacting 3-O-methyl-buprenorphine with an alkali metal borohydride; and (ii) adding an oxidant to the mixture obtained in (i).

Description

EXAMPLES

Example 1

Methylcyclopropylation of 3-O-methyl-norbuprenorphine

(1) A mixture of 3-O-methyl-norbuprenorphine TFA salt (50.0 g, 78 mmol, assay: 85%) and K.sub.3PO.sub.4 (66.6 g, 314 mmol) in MeCN (200 mL) was treated with (bromomethyl)cyclopropane (11.4 mL, 118 mmol). The mixture was stirred and heated to 50±5° C. for at least 24 hr. The reaction was considered complete when the level of 3-O-methyl-norbuprenorphine present was found to be not more than 1% using UPLC/MS.

(2) The mixture was then cooled to 40±5° C. and treated with MTBE (250.0 mL) and water (250 mL), and stirred for 10 min. The resultant phases were allowed to separate and the aqueous phase was discarded. The mixture was treated again with water (250 mL), and stirred for a further 10 min. The phases were allowed to separate and the aqueous phase was discarded. To the organic phase was added 2-MeTHF (250 mL) and approximately 6 volumes were distilled off under atmospheric pressure. The mixture was treated again with 2-MeTHF (250 mL) and approximately 6 volumes (i.e. 6 mL of solvent per gram of starting opioid) were again distilled off under atmospheric pressure. The resultant mixture was used in Example 2 without further purification.

Example 2

Demethylation of 3-O-methyl-buprenorphine

(3) In a separate vessel, LiBr (11.93 g, 137 mmol) was treated with 2-MeTHF (250 mL), and the mixture was stirred at room temperature until the LiBr had dissolved.

(4) The product mixture of Example 1 was added to the LiBr mixture and approximately 6 volumes were distilled off under atmospheric pressure. The mixture was treated with 2-MeTHF (250 mL) and approximately 6 volumes were distilled off under atmospheric pressure. The mixture was further treated with 2-MeTHF (250 mL) and approximately 6 volumes were distilled off under atmospheric pressure.

(5) The mixture was cooled to 50±5° C. and treated with lithium tri-sec-butylborohydride (L-Selectride® 1 M in THF, 220.3 mL, 220 mmol). The mixture was heated under reflux and distilled under atmospheric pressure until the reaction temperature reached 100±5° C. The mixture was heated at 100±5° C. for at least 1 hr. The reaction was considered complete when the 3-O-methyl-buprenorphine level was found to be not more than 0.1% using UPLC/MS. The mixture was then cooled to 60±5° C.

Example 3

Isolation of Buprenorphine

(6) In a separate vessel, TMO dihydrate (80.58 g, 725 mmol) was mixed with MeOH (150 mL). The mixture was stirred at room temperature until the TMO dihydrate had dissolved.

(7) The TMO mixture was added slowly to the buprenorphine mixture of Example 2 and then heated under reflux for 8 hr. Approximately 3 volumes were distilled off under atmospheric pressure and the mixture was then cooled to 25±5° C.

(8) The mixture was treated with water (250 mL) and stirred for at least 1 hr. The mixture was treated dropwise with AcOH (11.78 g) until it reached a pH of between 7 and 8 and stirred for at least 30 min. The resultant precipitate was collected by filtration, rinsed twice with water (2×50 mL) and dried in vacuo at 40±5° C. overnight to afford buprenorphine (34.4 g, 74 mmol, >99.5% purity) as an off-white solid.

Example 4

Methylcyclopropylation of 3-O-methyl-norbuprenorphine

(9) A mixture of 3-O-methyl-norbuprenorphine TFA salt (20.0 g, 31 mmol, assay: 85%) and K.sub.3PO.sub.4 (26.7 g, 126 mmol) in MeCN (80 mL) was treated with (bromomethyl)cyclopropane (4.6 mL, 47 mmol). The mixture was stirred and heated to 50±5° C. for at least 24 hr. The reaction was considered complete when the level of 3-O-methyl-norbuprenorphine present was found to be not more than 0.2% using IPC.

(10) The mixture was then cooled to 40±5° C. and treated with MTBE (100.0 mL) and water (100 mL), and stirred for 10 min. The resultant phases were allowed to separate and the aqueous phase was discarded. The mixture was treated again with water (100 mL), and stirred for a further 10 min. The phases were allowed to separate and the aqueous phase was discarded. To the organic phase was added 2-MeTHF (100 mL) and approximately 6.6 volumes were distilled off under atmospheric pressure. The mixture was treated again with 2-MeTHF (100 mL) and approximately 6.6 volumes were again distilled off under atmospheric pressure. The resultant mixture was used in Example 5 without further purification.

Example 5

Demethylation of 3-O-methyl-buprenorphine

(11) In a separate vessel, LiBr (4.8 g, 137 mmol) was treated with 2-MeTHF (100 mL), and the mixture was stirred at room temperature until the LiBr had dissolved.

(12) The product mixture of Example 4 was treated with the LiBr mixture and approximately 6.6 volumes were distilled off under atmospheric pressure. The mixture was treated with 2-MeTHF (100 mL) and approximately 6.6 volumes were distilled off under atmospheric pressure until the supernatant contained less than 440 ppm of water as determined by volumetric Karl-Fischer titration. The mixture was treated with 2-MeTHF (100 mL) and approximately 6.6 volumes were distilled off under atmospheric pressure.

(13) The mixture was cooled to 50±5° C. and treated with lithium tri-sec-butylborohydride (L-Selectride® 1 M in THF, 88.1 mL, 88 mmol). The mixture was heated under reflux and approximately 6.6 volumes were distilled under atmospheric pressure until the reaction temperature reached 100±5° C. The mixture was heated at 100±5° C. for at least 1 hr. The reaction was considered complete when the 3-O-methyl-buprenorphine level was found to be not more than 0.1% using UPLC/MS. The mixture was then cooled to 60±5° C.

Example 6

Isolation of Buprenorphine

(14) In a separate vessel, TMO dihydrate (32.32 g, 290 mmol) was mixed with MeOH (60 mL). The mixture was stirred at room temperature until the TMO dihydrate had dissolved.

(15) The buprenorphine mixture of Example 5 was added slowly to the TMO mixture at a rate to maintain reflux. The reaction mixture was held at reflux for 8 hr and then cooled to 25±5° C.

(16) The mixture was treated slowly with 10% aqueous AcOH (103.7 mL) until it reached a pH of between 5.2 and 5.4. The phases were allowed to separate and the aqueous phase was discarded. The mixture was treated with water (45.4 mL) and stirred for at least 1 hr. The phases were allowed to separate, the aqueous phase was discarded and approximately 6 volumes were distilled under atmospheric pressure. The mixture was treated with MeCN (75.6 mL) and approximately 5 volumes were distilled under atmospheric pressure. The mixture was treated with water (45.4 mL), approximately 5 volumes were distilled under atmospheric pressure and cooled to 0±5° C. The resultant precipitate was collected by filtration, rinsed with water (45.4 mL) and dried in vacuo at 40±5° C. overnight to afford buprenorphine (13.8 g, 29.5 mmol, >99.5% purity) as an off-white solid.

Example 7

Analysis of Critical Parameters for the Demethylation Reaction

(17) The demethylation of 3-O-methyl-buprenorphine to buprenorphine was investigated using L-Selectride® (or Superhydride®), lithium bromide and 2-methyltetrahydrofuran. Except where specified, the methods used followed the method described in Example 5. See Experiment nos. 1 to 29 in Table 1 below.

(18) Experiment nos. 11 to 17 included a prior step in which 3-O-methyl-norbuprenorphine was alkylated to form 3-O-methyl-buprenorphine using the conditions described in Example 4 (i.e. using approx. 4 equivalents K.sub.3PO.sub.4 and 1.5 equivalents cyclopropylmethylbromide relative to the 3-O-methyl-norbuprenorphine).

(19) Results

(20) Table 1 below shows the results obtained after a reaction time of 24 hrs using different amounts alkali metal borohydride and lithium bromide, and at different reaction temperatures. The L-Selectride®, Superhydride® and lithium bromide quantities are expressed as molar equivalents relative to the amount of the starting buprenorphine derivative used (e.g. the 3-O-methyl-norbuprenorphine or 3-O-methyl-buprenorphine, as appropriate).

(21) TABLE-US-00001 TABLE 1 Demethylation of 3-O-methyl-buprenorphine Exper- 3OMB iment Scale Temp AMBH LiBr area Bup no. (g) (° C.) AMBH (eq) (eq) % area % 1 (part 1) 10 100 LS 2.8 1.75 0 99.6 2 (part 1) 5 87 LS 2.25 3 0.27 99.6 3 (part 1) 10 100 LS 2.80 2.00 0.03 99.97 4 5 100 SH 3.6 2.75 80 20 5 (part 1) 10 100 LS 3 2 ND ND 6 5 80 LS 3 0 30 70 7 (part 1) 5 100 LS 2.6 3.5 1 99 8 5 100 LS 2 1.75 0 76 9 (part 1) 5 100 LS 2.6 3 0.02 99.8 10 (part 1) 5 100 LS 2.8 2 0 100 11 20 100 LS 3.05 1.75 0.9 99.1 12a 5 100 TSBB 2.8 1.75 84.59 12.6 (nor 3OMnB) 12b 5 100 LS.sup.a 2.8 1.75 64.18 33.07 13 (part 1) 50 100 LS 2.8 2 ND 99.7 14 (part 1) 20 100 LS 2.8 2 ND ND 15 (part 1) 20 100 LS 2.8 2 0.07 ND 16 (part 1) 10 100 LS 2.8 2 0.06 99.6 17 (part 1) 70 100 LS 2.8 2 ND 99.9 18 (part 1) 20 100 LS 2.8 1.75 0.15 99.85 19 (part 1) 20 100 LS 2.8 1.75 0.0 100.0 20 (part 1) 20 100 LS 2.8 1.75 0.0 100.0 21 (part 1) 20 100 LS 2.8 1.75 0.0 100.0 22 (part 1) 20 100 LS 2.8 1.75 0.04 99.96 23 (part 1) 20 100 LS 2.8 1.75 0.0 100.0 24 (part 1) 20 100 LS 2.8 1.75 ND ND 25 (part 1) 20 100 LS 2.8 1.75 0.0 99.86 26 (part 1) 20 100 LS 2.8 1.75 0.0 99.79 27 (part 1) 20 100 LS 2.8 1.75 0.0 100.0 28 (part 1) 71 100 LS 2.8 1.75 0.0 100.0 29 (part 1) 1000 100 LS 2.8 1.75 0.03 99.89 .sup.aL-Selectride formed in-situ using the method described by P. Gartner et. al., ARKIVOC, 2001, 2, 9-20. ND: not determined

Example 8

Analysis of Critical Parameters for the Isolation of Buprenorphine

(22) The isolation of buprenorphine was assessed using a mixture of buprenorphine as produced in Example 7, trimethylamine N-oxide as the oxidant, and a suitable solvent using the method described in Example 6.

(23) Results

(24) Table 2 below shows the results obtained after a reaction time of at least 8 hrs, unless states otherwise, using different amounts of trimethylamine N-oxide, with different solvents, different reaction temperatures, and with and without an active nitrogen sweep of the reaction headspace. The quantity of trimethylamine N-oxide is expressed as molar equivalents relative to the amount alkali metal borohydride used in Example 7.

(25) TABLE-US-00002 TABLE 2 Isolation of buprenorphine Iso- Iso- Exper- Temp lation Bup norBup lated iment Scale ° C. Oxidant Sol- area area yield no. (g) (time) (equiv) vent % % % 1 (part 2) 10 10-79 TMO MeOH 99.62 0.19 91 (2 h) (9.24) 2 (part 2) 5 60 TMO MeOH 99.73 0.03 87 (9.24) 3 (part 2) 10 60 TMO MeOH 99.8 0.05 86 (11.76) 5 (part 2) 10 40 TMO AcOH 99.9 ND 86 (6.6) 7 (part 2) 5 60 .fwdarw. TMO MeOH 99.22 0.11 80 reflux (10.8) (2.5 h) 9 (part 2) 5 60-65 TMO MeOH 99.6 0.11 94 (18 h) (11) 10 (part 2) 10 60 — H.sub.2O 99.66 0.35 95 13 (part 2) 50 60 TMO MeOH 99.8 0.05 94 (11.76) 14 (part 2) 20 60 TMO MeOH 99.7 0.05 92 (11.76) 15 (part 2) 20 60 TMO MeOH 99.8 0.06 87 (11.76) 16 (part 2) 10 60 TMO MeOH/ 99.6 0.06 98 (11.76) H.sub.2O 17 (part 2) 70 60 .fwdarw. TMO MeOH 99.9 0.1 85 reflux (9.24) (4.5 h) 18 20 60 .fwdarw. TMO MeOH 98.9 1.13 86 (part 2) .sup.b reflux (9.24) (5 h) 19 20 60-78 TMO IPA >99.9 0.0 not (part 2) .sup.b (7 h) (9.24) iso- lated 20 20 60 .fwdarw. TMO MeOH 99.73 0.06 >100 (part 2) .sup.b reflux (9.24) (25 h) 21 20 60 .fwdarw. TMO MeOH 100 0.0 70 (part 2) .sup.b reflux (9.24) (21.5 h) 22 20 60 .fwdarw. TMO MeOH 99 0.0 64 (part 2) .sup.b reflux (9.24) (22.5 h) 23 20 60 .fwdarw. TMO MeOH 99.7 0.0 80 (part 2) .sup.b,c reflux (9.24) (22 h) 24 20 60 .fwdarw. TMO MeOH 99.82 0.03 83 (part 2) .sup.b,c reflux (9.24) (24.5 h) 25 20 60 .fwdarw. TMO MeOH 99.98 0.02 80 (part 2) .sup.b,c reflux (9.24) (21 h) 26 20 60 .fwdarw. TMO MeOH >99.9 0.00 86 (part 2) .sup.b,c reflux (9.24) (28 h) 27 20 60 .fwdarw. TMO MeOH >99.9 0.00 92 (part 2) .sup.b,c reflux (9.24) (19 h) 28 72 60 .fwdarw. TMO MeOH >99.9 0.00 93 (part 2) .sup.b,c reflux (9.24) (72 h) 29 1000 60 .fwdarw. TMO MeOH 99.96 0.00 91 (part 2) .sup.b,c reflux (9.24) (43 h) .sup.b The reaction was performed by addition of the buprenorphine mixture to the trimethylamine N-oxide mixture, i.e. via inverse addition. .sup.c A nitrogen sweep of the reaction vessel headspace into a HCl (6M aq.) scrubber was used to remove trimethylamine from the reaction mixture.

(26) It was found that the addition of at least about 3 molar equivalents of oxidant relative to the borohydride (which corresponds approximately to about 8 to 10 molar equivalents relative to the compound of formula II) optimised the suppression of impurities and provided buprenorphine at high levels of purity and in high yields. In particular, it was found that by using trimethylamine N-oxide in MeOH, the excess L-Selectride®, and corresponding by-products derived from L-Selectride®, could be quenched. By quenching the boron containing by-products with trimethylamine N-oxide, the suppression of impurities, namely norbuprenorphine, was achieved.

(27) In addition, it was found that a nitrogen sweep of the reaction vessel headspace facilitated removal of trimethylamine, which is a degradation-product of trimethylamine N-oxide.

(28) Removal of trimethylamine in this fashion was found to advantageously achieve consistently high yields of buprenorphine product, with low impurity levels.

Example 9

Demethylation of 3-O-methyl-N-methylbuprenorphine

(29) ##STR00012##

(30) Under a N.sub.2 atmosphere, a mixture of 3-O-methyl-N-methylbuprenorphine (9.2 g, 20.8 mmol) and MeTHF (30 mL) was heated to 40° C. and treated with a mixture of LiBr (3.2 g, 36.5 mmol) in MeTHF (16 mL), followed by lithium tri-sec-butylborohydride (L-Selectride® 1 M in THF, 58 mL, 58 mmol) via syringe. The charge was exothermic reaching 50° C. with gas evolution. The reaction mixture was then heated to 70° C. for 16 h, at which time it was found that 0.1% of the 3-O-methyl-N-methylbuprenorphine remained (according to UPLC). The mixture was heated to 90° C. and 53 mL of solvent was collected. The resultant mixture was cooled to 60° C. and used in Example 10 without further purification.

Example 10

Isolation of N-methylbuprenorphine

(31) The N-methylbuprenorphine mixture of Example 9 was treated with a solution of TMO dihydrate (27.2 g, 245 mmol) in MeOH (30 mL). An exotherm, with gas evolution, was observed. The reaction mixture was then heated under reflux and 30 mL of solvent was distilled off, and then allowed to cool to 25° C. upon which a slurry was formed.

(32) The mixture was treated with water (46 mL), followed by AcOH until the mixture reached pH 7. Phase separation occurred and the two-phase mixture was stirred for 16 h. MTBE (50 mL) was added and the mixture was stirred at 50° C. The phases were separated and the organic phase collected. The aqueous phase was washed with MTBE (25 mL) and the combined organic phases were concentrated and triturated with MTBE. The resultant slurry was treated with NH.sub.4OH (200 mL), and the phases were allowed to separate.

(33) The resultant precipitate in the organic phase was collected by filtration to afford N-methylbuprenorphine (1.10 g, 2.52 mmol, 12% yield). The organic phase was collected and concentrated to afford a second crop of N-methylbuprenorphine (2.40 g, 27% yield).

(34) The solids were analysed by UPLC/MS and .sup.1H NMR.

Example 11

Demethylation of 3-O-methyl-norbuprenorphine

(35) ##STR00013##

(36) Under a N.sub.2 atmosphere, a mixture of 3-O-methyl-norbuprenorphine (2.48 g, 5.8 mmol) and MeTHF (22.5 mL) was heated to 40° C. and treated with LiBr (0.88 g, 10.2 mmol). The mixture was heated to 50° C. and treated with lithium tri-sec-butylborohydride (L-Selectride® 1 M in THF, 16.2 mL, 16.2 mmol) via syringe. The reaction mixture was then heated to 70° C. and stirred for 16 h. UPLC analysis showed that 5.2% of 3-O-methyl-norbuprenorphine remained, and the mixture was treated with further lithium tri-sec-butylborohydride (L-Selectride® 1 M in THF, 1.5 mL, 1.5 mmol) and stirred for 20 h. A sample was obtained and analysed by UPLC showing full conversion to norbuprenorphine. The mixture was cooled to 20° C. and used in Example 12 without further purification.

Example 12

Isolation of Norbuprenorphine

(37) The norbuprenorphine mixture of Example 11 was treated with a solution of TMO dihydrate (7.58 g, 68.0 mmol) in MeOH (9 mL). An exotherm, with gas evolution, was observed. The reaction mixture was then heated at 60° C. for 1 h. The resultant white slurry was cooled to 20° C. After 12 h, the mixture was heated to 80° C. and 14 mL of solvent was distilled off, and then the mixture was allowed to cool to 20° C.

(38) The mixture was treated with water (5 mL), followed by AcOH until the mixture reached pH 7. The phases were separated, and the organic phase was treated with MTBE and sonicated. The resultant precipitate was collected by filtration to afford norbuprenorphine (1.19 g, 2.87 mmol, 50% yield). The solids were analysed by UPLC/MS and .sup.1H NMR.

Example 13

Demethylation of 3-O-methyl-buprenorphine to Buprenorphine Using NMO

(39) Acetonitrile (20 mL) and K.sub.3PO.sub.4 (7.48 g, 35.0 mmol) were charged to a jacketed European flask under N.sub.2 atmosphere. 3-O-methyl-norbuprenorphine (3.35 g, 7.80 mmol) and bromomethylcyclopropane (1.60 g, 12.0 mmol) were subsequently charged to the slurry. The reaction mixture was heated to 60.0° C. for 40 h when a sample was pulled for UPLC/MS analysis. The analysis showed full conversion to 3-O-methylbuprenorphine. The reaction mixture was cooled to 40.0° C. MTBE (25 mL) and water (25 mL) were added and the mixture stirred for 10 minutes. The agitation was stopped and the phases were allowed to separate. The aqueous phase was discarded.

(40) The jacket was incrementally set to 75.0° C. for distillation and 15 mL of distillate was collected. MeTHF (25 mL) was added and the distillation was continued. 15 mL of distillate was collected (pot temperature 70.8° C.), then reaction was cooled to 20° C. and held under a N.sub.2 atmosphere for 22 h. LiBr (1.45 g, 2.13 mmol) and MeTHF (25 mL) were charged to the flask. The mixture was heated for distillation (pot temperature 76° C.) and 25 mL of distillate collected. MeTHF (25 mL) was added, followed by an additional addition of MeTHF (25 mL). The distillation was continued (pot temperature 82.1° C.) and 25 mL of distillate was collected.

(41) The resulting mixture was cooled to 30.0° C. and a 1 M L-Selectride solution in THF (31.5 mL, 31.0 mmol) was added by the means of a syringe to the mixture. The first 10 mL produced off gassing, but no exotherm. The jacket was heated in stages to 110.0° C. to allow for distillation. Distillation was started at a pot temperature of 74.9° C. 35 mL of a distillate had been collected when the pot temperature reached 98.0° C. A sample was pulled and analyzed by UPLC showing that 15.0% of 3-O-methyl-buprenorphine remained. The reaction was further heated for 2 hours at 98.0° C. then a sample was pulled and analyzed by UPLC showing full conversion to buprenorphine.

(42) The reaction mixture was cooled to 15.0° C. and MeOH (3 mL) was added dropwise. The addition produced gas evolution with an initial exotherm. The temperature rose from 15.0 to 20° C. The heater/chiller was turned off and the reaction mixture was stirred at ambient temperature for 16 h. A 50% solution of 4-methylmorpholine N-oxide (24.4 mL, 118.0 mmol) was added slowly by the means of a syringe. The addition produced an exotherm (19.0° C. to 27.0° C.). The exotherm subsided after 5 mL of the 50% solution of 4-methylmorpholine N-oxide had been added. The mixture was heated to 40.0° C. for 18 h. Water (15 mL) was added to the cloudy mixture and the pH was measured to ˜13 by pH paper in the aqueous layer. L-tartaric acid (2.40 g, 16.0 mmol) was added and the resulting mixture stirred for 10 minutes. pH was measured to ˜9 in the lower aqueous layer. The agitation was stopped and the phases were allowed to separate. The aqueous phase was discarded. Water (15 mL) was added to the mixture. Agitation was stopped after 10 minutes and the phases were allowed to separate.

(43) The pH of the discarded aqueous phase was ˜9. The organic phase was treated with water (15 mL), NaCl (1.5 g, 26.0 mmol) and L-tartaric acid (0.12 g, 1.0 mmol). The mixture was stirred for 10 minutes. The agitation was stopped and the phases were allowed to separate. The aqueous phase was discarded.

(44) Acetonitrile (25 mL) was added to the reaction giving a light yellow slurry. The jacket was set to 90° C. for distillation. The distillation started when the pot temperature reached 77.7° C. and 25 mL distillate was collected. Acetonitrile (25 mL) was charged. The pot temperature reached 83.8° C. and 25 mL distillate was collected. Acetonitrile (25 mL) was charged for a third time. The pot temperature reached 83.4° C. and 25 mL of distillate was collected. Acetonitrile (25 mL) was charged for a fourth time. The final pot temperature was 82.8° C. and 20 mL distillate was collected. The jacket was shut off and the reaction slurry held at ambient temperature for 17 h. The jacket was set to 5.0° C. and aged for 1 h.

(45) The solids were filtered off by suction filtration. The wet cake was washed with acetonitrile (25 mL) and suction dried on the filter to give buprenorphine (1.77 g, 3.8 mmol, 48% yield).

(46) The combined solids were analyzed by UPLC/MS and .sup.1H NMR. The purity profile by UPLC/MS is shown in Table 3.

(47) TABLE-US-00003 TABLE 3 purity profile 3-O-methyl-buprenorphine Norbuprenorphine Buprenorphine Others 0.45 0.26 99.07 0.23.sup.1 .sup.10.13% butyl-buprenorphine and 0.10% bupreneorphine-carbinolamine.

Example 14

Demethylation of 3-O-methyl-buprenorphine without any Oxidant Present

(48) 3-O-methyl-norbuprenorphine (10.0 g, 16.0 mmol) and K.sub.3PO.sub.4 (11.7 g, 55.0 mmol) were charged to a jacketed European flask under N.sub.2 atmosphere. Acetonitrile (40 mL)) and bromomethylcyclopropane (3.20 g, 24.0 mmol) were subsequently charged to the slurry. The reaction mixture was heated to 40.0° C. for 19 h when a sample was pulled for UPLC/MS analysis (Table 4, entry 1). The analysis showed 97% conversion to 3-O-methylbuprenorphine. Bromomethylcylopropane (0.64 g, 5.0 mmol) was added to the reaction mixture. The reaction mixture was stirred for an additional 3 h. A sample was pulled for UPLC/MS analysis (Table 4, entry 2) showing 99.0% conversion to 3-O-methylbuprenorphine. Water (50 mL) was charged to the mixture. The circulator was set to 99.0° C. and the flask was equipped with a short path distillation head. 45 mL was distilled off and the mixture was cooled to 30.0° C. The mixture contained a big yellow lump which was dissolved upon treatment with MTBE (50 mL). The agitation was stopped and the phases were allowed to separate. The aqueous phase was discarded. Water (50 mL) was added to the organic phase and the mixture stirred for 5 min. The agitation was stopped and the phases were allowed to separate. The aqueous phase was discarded.

(49) The circulator was set to 70.0° C. and the flask was again equipped with a short path distillation head. 26 mL of distillate was collected, then toluene (30 mL) and LiBr (5.5 g, 63.0 mmol) was added to the flask. The LiBr was observed to be caking on the walls and in the bottom of the flask. The temperature of the circulator was set to 107.0° C. 24 mL distillate was collected at 95.1° C. Toluene (30 mL) was charged to the pot. The pot temperature was gradually raised to 110.9° C. and 31 mL of distillate was collected. Toluene (50 mL) was charged to the pot. The LiBr was now a free-flowing solid in the flask. The distillation was continued and 21 mL was collected. The final pot temperature was 111.0° C. The reaction mixture was cooled to 20.0° C. and held at 20.0° C. for 94 h. Toluene (25 mL) was charged to the reaction mixture. The resulting mixture was heated for distillation and 36 mL was collected. The internal temperature of the mixture was 110.8° C. The reaction mixture was cooled to 23.8° C. and a 1 M L-Selectride solution in THF (2.0 mL, 2.0 mmol) was added by the means of a syringe to the mixture. The temperature rose from 23.8° C. to 24.3° C. and effervescence was observed during the addition. Additional 1 M L-Selectride solution in THF (3.0 mL, 3.0 mmol) was charged. The internal temperature increased to 24.7° C. Additional 1 M L-Selectride solution in THF (2.0 mL, 2.0 mmol) was charged with continued off gassing during the addition. The temperature increased to 25.2° C. Additional 1 M L-Selectride solution in THF was charged (3.0 mL, 3.0 mmol) was charged with no observable exotherm, but effervescence was still observed during the addition. Additional 1 M L-Selectride solution in THF was charged (10.0 mL, 10.0 mmol) was charged with no observable exotherm and effervescence was still observed during the addition. Additional 1 M L-Selectride solution in THF was charged (5.0 mL, 5.0 mmol) was charged with no observable exotherm but effervescence was still observed during the addition. Additional 1 M L-Selectride solution in THF was charged (15.0 mL, 15.0 mmol) and effervescence was still observed during the addition. Additional 1 M L-Selectride solution in THF was charged (6.0 mL, 6.0 mmol) and effervescence was still observed during the addition. Additional 1 M L-Selectride solution in THF was charged (5.0 mL, 5.0 mmol) and effervescence was still observed during the addition. Additional 1 M L-Selectride solution in THF was charged (10.0 mL, 10.0 mmol). No effervescence was observed during the addition. Additional 1 M L-Selectride solution in THF was charged (20.0 mL, 20.0 mmol). The reaction mixture was heated to a gentle reflux at 81.8° C. A sample was pulled after 16 h (Table 4, entry 3) which was analyzed by UPLC/MS showing 98.8% conversion to buprenorphine. A sample was pulled after 21 h (Table 4, entry 4) which was analyzed by UPLC/MS showing 98.8% conversion to buprenorphine, 0.2% remaining 3-O-methylbuprenorphine and 1.0% norbuprenorphine. The reaction was cooled to 15° C. 10% aq. acetic acid (1 mL) was added. The addition was exothermic with considerable effervescence. Additional 10% aq. acetic acid (1 mL) was charged. The addition was exothermic with considerable effervescence. Additional 10% aq. acetic acid was charged in portions, with no observable effervescence but the exotherm remained throughout these additions. In total 28 mL of 10% acetic acid was charged. The pH was ˜14 in the reaction mixture.

(50) The reaction mixture was heated to 40° C. and additional 10% aq. acetic acid (10 mL) was charged in portions. The agitation was stopped and the phases were allowed to separate. The aqueous phase (30 mL) was discarded. A sample was pulled from the organic phase (Table 4, entry 5) which was analyzed by UPLC/MS. Additional water (25 mL) was charged to the organic phase. The phases were stirred for 5 min. The stirring was stopped and the phases were allowed to separate. The aqueous phase (32 mL) was discarded. The pH in the aqueous phase was ˜13.

(51) The reaction flask was equipped with a short path distillation head and heated for distillation. Distillate was starting to collect at an internal temperature of 71.8° C. In total 75 mL was collected when the internal temperature had reached 97° C. The reaction was cooled and kept at 20.0° C. for 17 h. Water (50 mL) was charged and the reaction was heated for distillation. The reaction mixture was refluxing at 81.7° C. and at 84.0° C. a sudden event of off gassing occurred. The off gassing was associated with the formation of a considerable amount of foam. The total volume of distillate collected was 38 mL. Water (50 mL) was added and 40 mL of distillate was collected. The final temperature of the reaction mixture was 98.9° C. The reaction mixture was cooled to 37.1° C. The agitation was stopped and the phases were allowed to separate. The volume of the upper milky layer was 20 mL. The volume of the lower aqueous layer was 20 mL. The pH of the aqueous layer was ˜9. MTBE (50 mL) was added to the reaction mixture. The resulting mixture was stirred for 5 min. The stirring was stopped and the phases were allowed to separate. A sample was pulled from the organic phase (Table 4, entry 6) which was analyzed by UPLC/MS. The milky aqueous layer (60 mL) was discarded. The pH of the aqueous layer was ˜13. Water (50 mL) was added to the organic phase. The resulting mixture was stirred for 15 min. The agitation was stopped and the phases were allowed to separate. The clear aqueous layer (50 mL) was discarded. The pH of the aqueous layer was ˜9. Water (50 mL) was added to the organic phase. The resulting mixture was stirred for 15 min. The agitation was stopped and the phases were allowed to separate. The clear aqueous layer (50 mL) was discarded. The pH of the aqueous layer was ˜7.

(52) Acetonitrile (50 mL) was charged to the reaction mixture. The reaction mixture was heated for distillation. The reaction mixture reached 70.0° C. A total volume of 40 mL of distillate was collected. The reaction mixture reached 70.0° C. Additional acetonitrile (50 mL) was added and the distillation continued. 54 mL of distillate had been collected when the reaction mixture temperature reached 81.5° C. Additional acetonitrile (50 mL) was added and the distillation continued. 60 mL of distillate had been collected when the reaction mixture temperature reached 81.5° C. The reaction mixture was a slurry at this point. The reaction mixture was cooled to 20° C. and held for 16 h. The solids were filtered off to and air dried on a petri dish to give 3.6 g, 7.7 mmol. The solids were analyzed by UPLC/MS (Table 4, entry 7). A sample was pulled from the mother liquor (Table 4, entry 8) which was analyzed by UPLC/MS.

(53) The reaction profile and the purity profile for the wet cake analyzed by UPLC/MS is shown in Table 4.

(54) TABLE-US-00004 TABLE 4 The reaction profile and the purity profile for the wet cake analyzed by UPLC/MS 3-O-Me- Norbuprenor- Buprenor- IPC buprenorphine phine phine Others Entry (h) (Area %) (Area %) (Area %) (Area %) 1 19 97.12 4.88.sup.1 2 24 98.96 1.04.sup.1 3 16 0.22 0.93 98.85 4 21 0.05 0.86 99.09 5 0.94 99.06 6 2.82 96.88 0.30 7 0.33 98.79 0.88 8 10.13 85.55 4.32 .sup.13-O-methylnorbuprenorphine

Example 15

Demethylation of 3-O-methyl-buprenorphine without Initial Oxidant Quench

(55) 3-O-methyl-norbuprenorphine (3.35 g, 7.80 mmol) and acetonitrile (20 mL) were charged to a jacketed European flask under N.sub.2 atmosphere. K.sub.3PO.sub.4 (6.62 g, 31.0 mmol) and bromomethylcyclopropane (1.60 g, 12.0 mmol) were subsequently charged to the slurry. The reaction mixture was heated to 50.0° C. for 42 h when a sample was pulled for UPLC/MS analysis. The analysis showed full conversion to 3-O-methylbuprenorphine. The reaction mixture was cooled to 40.0° C. MeTHF (25 mL) and water (25 mL) were added and the mixture stirred for 10 min. The agitation was stopped and the phases were allowed to separate. Water (25 mL) was added to the organic phase and the mixture stirred for 10 min. The agitation was stopped and the phases were allowed to separate. A sample was pulled from both of the aqueous phases which showed the presence of 3-O-methylbuprenorphine. The aqueous phases were pooled and re-extracted with MTBE (25 mL). The aqueous phase was discarded and the organic phases were pooled.

(56) The jacket was incrementally set to 70.0° C. for distillation and 39 mL of distillate was collected at 61.0° C. MeTHF (25 mL) was added and the distillation was continued. 28 mL of distillate was collected. The pot temperature reached 69.8° C. during this distillation.

(57) MeTHF (25 mL) was added and the distillation was continued. 28 mL of distillate was collected and the pot temperature was 78.7° C. MeTHF (25 mL) was added and the distillation was continued. 20 mL of distillate was collected. The pot temperature reached 79.7° C. during this distillation. The reaction mixture was cooled to 20° C., LiBr (1.40 g, 16.0 mmol) and MeTHF (25 mL) were charged to the flask. The mixture was heated for distillation. The pot temperature reached 80.3° C. and 24.5 mL of distillate was collected.

(58) The resulting mixture was cooled to 25° C. and a 1 M L-Selectride solution in THF (35.5 mL, 35.0 mmol) was added by the means of a syringe to the mixture. The first 10 mL produced off gassing, but no exotherm. The jacket was heated in stages to 105.0° C. to allow for distillation. Distillation was starting when the pot temperature reached 74.5° C. 26 mL of a distillate had been collected when the pot temperature had reached 90.9° C., then a sample was pulled (Table 5, entry 1) which was analyzed by UPLC/MS. The reaction was further heated for 2 hours at 102.0° C., then an additional sample was pulled (Table 5, entry 2) which was analyzed by UPLC/MS showing full conversion to buprenorphine.

(59) The reaction mixture was cooled to 15.0° C. A sample was pulled from the organic phase (Table 5, entry 3) and 20% aq. acetic acid (1 mL) was added dropwise. The addition produced gas evolution and an exotherm evolved from 14° C. to 23.5° C. The remaining 20% aq. acetic acid (9 mL) was added in one portion. No effervescence observed but the temperature rose to 33.0° C. The pH was adjusted to 9 and MTBE (14 mL) was added. The mixture was stirred for 10 min. The agitation was stopped and the phases were allowed to separate. The cloudy aqueous phase was discarded. MTBE (5 mL) was charged to the organic phase, followed by water (25 mL). The mixture was stirred for 5 min, then the agitation was stopped. The phases were allowed to separate and the aqueous phase was discarded. It was observed that the aqueous phase was less cloudy. Water (25 mL) was charged to the organic phase and the resulting mixture was stirred for 4 min. The agitation was stopped and the phases were allowed to separate. The aqueous phase was discarded. A sample was pulled from the organic phase (Table 5, entry 4).

(60) A 50% solution of 4-methylmorpholine N-oxide (25.0 mL, 121 mmol) was added to organic phase. The resulting mixture was heated to 44.0° C. for 1 h. The agitation was stopped and the phases were allowed to separate. The aqueous phase was discarded. Water (25 mL) was charged to the organic phase. The resulting mixture was stirred for 7 min, then the agitation was stopped. The phases were allowed to separate. The aqueous phase was discarded. A sample was pulled from the organic phase (Table 5, entry 5).

(61) Acetonitrile (25 mL) was added to the organic phase and the reaction mixture heated for distillation. 23 mL of distillate was collected. Acetonitrile (25 mL) was added to the mixture. The distillation was continued. Additional acetonitrile (25 mL) was charged when 32 mL of distillate had been collected. Acetonitrile (25 mL) was charged and the distillation continued until 26 mL of distillate had been collected. Acetonitrile (25 mL) was charged for a final time and 24 mL of distillate was collected. The reaction mixture was cooled to 5.0° C. and stirred for 18 h. The formed solids were filtered off and suction dried on the filter. The solids were analyzed by UPLC/MS (Table 5, entry 6).

(62) The reaction profile and the purity profile for the wet cake analyzed by UPLC/MS is shown in Table 5.

(63) TABLE-US-00005 TABLE 5 The reaction profile and the purity profile for the wet cake analyzed by UPLC/MS Norbuprenorphine Buprenorphine Others Entry (Area %) (Area %) (Area %) 1 0.14 98.98 0.88.sup.1 2 0.10 99.90 3 100 4 20.08 78.79 1.13 5 20.19 79.48 0.33 6 19.76 79.58 0.66 .sup.13-O-methylbuprenorphine.

(64) The performance of an initial aqueous quench of the borohydride reaction mixture (using 20% aq. acetic acid) without prior or simultaneous oxidation of the trialkylborane leads to the formation of relatively high levels of norbuprenorphine.

ABBREVIATIONS

(65) AcOH Acetic acid

(66) AMBH Alkali metal borohydride

(67) Aq. Aqueous

(68) Bup Buprenorphine

(69) CPM-Br (Bromomethyl)cyclopropane

(70) Eq. Molar equivalent

(71) Δ Reflux temperature

(72) HPLC High performance liquid chromatography

(73) hr Hours

(74) IPA Isopropyl alcohol

(75) LS L-Selectride®

(76) 2-MeTHF 2-Methyltetrahydrofuran

(77) MeOH Methanol

(78) MeCN Acetonitrile

(79) min Minutes

(80) MTBE tert-Butyl methyl ether

(81) NMO N-Methylmorpholine N-oxide

(82) norBup Norbuprenorphine

(83) 3OMB 3-O-methyl-buprenorphine

(84) 3OMnB 3-O-methyl-norbuprenorphine

(85) ppm parts per million

(86) SH Superhydride

(87) TFA Trifluoroacetic acid

(88) THF Tetrahydrofuran

(89) TMO Trimethylamine N-oxide

(90) TSBB Tri-sec-butyl borane

(91) UPLC/MS Ultra performance liquid chromatography-mass spectrometry