CA2269910A1 - New process for the preparation of morphinans - Google Patents
New process for the preparation of morphinans Download PDFInfo
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- CA2269910A1 CA2269910A1 CA002269910A CA2269910A CA2269910A1 CA 2269910 A1 CA2269910 A1 CA 2269910A1 CA 002269910 A CA002269910 A CA 002269910A CA 2269910 A CA2269910 A CA 2269910A CA 2269910 A1 CA2269910 A1 CA 2269910A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/18—Bridged systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Abstract
A process for the preparation of 14-alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans is disclosed. The process facilitates the preparation of a large variety of 14-alkoxy substituted indolomorphinans and benzofuranomorphinans in which a 3-hydroxy substituent is present.
Description
NEW PROCESS FOR THE PREPARATION OF MORPHINANS
Field of the invention s The present invention is directed to a new process for the preparation of 14-alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans.
Background of the invention io Opioid antagonists have been indispensable as tools in opioid research. For example, the chief criterion for the classification of an agonist effect as being opioid receptor mediated is the ability of known opioid antagonists naioxone or naltrexone to reversibly antagonize this effect in a competitive fashion. The usefulness of naloxone and naltrexone for this purpose is stems from the fact that they are universal opioid antagonists; that is, they are capable of antagonizing the agonist effects mediated by multiple opioid receptor types.
In addition to their uses as pharmacological tools, selective, non-peptide opioid antagonists have been described as having potential clinical applications in the treatment of a variety of zo disorders where endogenous opioids play a modulatory role. These include for instance disorders of food intake, shock, constipation, mental disorders, CNS injury, alcoholism, and immune function (P.S. Portoghese at al., J. Med. Chem., Vol. 34: 1757-1762, l991).
Non-peptide, competitive, S-selective opioid antagonists have been found to have zs immunosuppressive potency and less toxicity than the presently used immunosuppressive compound cyclosporin (EP 45b 833; EP 485 636; EP 614 898; K. Arakawa et al., Transplantation, Vol. 53: 951-953, l992; K. Arakawa et al., Transplant Proc., Vol. 24:
696-697, 1992; K. Arakawa et al., Transplant Proc., Vol. 25: 738-740, 1993).
Such immunosuppressive agents can be used after organ transplantation to suppress the rejection SUBSTITUTE SHEET (RULE 26) WO 98I22467 PCT/SE96/01497 _
Field of the invention s The present invention is directed to a new process for the preparation of 14-alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans.
Background of the invention io Opioid antagonists have been indispensable as tools in opioid research. For example, the chief criterion for the classification of an agonist effect as being opioid receptor mediated is the ability of known opioid antagonists naioxone or naltrexone to reversibly antagonize this effect in a competitive fashion. The usefulness of naloxone and naltrexone for this purpose is stems from the fact that they are universal opioid antagonists; that is, they are capable of antagonizing the agonist effects mediated by multiple opioid receptor types.
In addition to their uses as pharmacological tools, selective, non-peptide opioid antagonists have been described as having potential clinical applications in the treatment of a variety of zo disorders where endogenous opioids play a modulatory role. These include for instance disorders of food intake, shock, constipation, mental disorders, CNS injury, alcoholism, and immune function (P.S. Portoghese at al., J. Med. Chem., Vol. 34: 1757-1762, l991).
Non-peptide, competitive, S-selective opioid antagonists have been found to have zs immunosuppressive potency and less toxicity than the presently used immunosuppressive compound cyclosporin (EP 45b 833; EP 485 636; EP 614 898; K. Arakawa et al., Transplantation, Vol. 53: 951-953, l992; K. Arakawa et al., Transplant Proc., Vol. 24:
696-697, 1992; K. Arakawa et al., Transplant Proc., Vol. 25: 738-740, 1993).
Such immunosuppressive agents can be used after organ transplantation to suppress the rejection SUBSTITUTE SHEET (RULE 26) WO 98I22467 PCT/SE96/01497 _
2 of the foreign organ and also in the treatment of autoimmune diseases (e.g.
rheumatoid arthritis).
In US 5 223 507 and US 5 225 417 the synthesis of 14-O-substituted indolomorphinans and s benzofuranomorphinans have been disclosed. According to the process used for preparing the compounds claimed and disclosed in US 5 223 507, only a 3,14-dimethoxy substituted benzofuranomorphinan was prepared. According to the process used for preparing compounds claimed and disclosed in US 5 225 417, two 14-O-alkyl substituted benzofuranomorphinans have been prepared. According to the methods used for preparing ~ o the compounds of both the two mentioned prior art documents, the 3-hydroxy group was protected by a methyl group which is not easily removed without having a loss in yield.
According to the processes known from the prior art, the variations of the substituents at the oxygen in position 14 are very much limited when a 3-hydroxy group is supposed to be ~ s present in the molecule. It is for instance not possible to prepare compounds with a substituent at the oxygen in 14-position, as this position is labile to the conditions used for the cleavage of the 3-methoxy group.
Thus, the object of the present invention was to find a new process which would facilitate 2o the preparation of 14-O-substituted indolomorphinans and benzofuranomorphinans.
The present patent application discloses a process whereby naloxone, naltrexone or oxymorphone is used as the starting material, whereby the 14-alkoxy group is introduced after the protection of the oxygen in 3-position with an easily removable protecting group, is preferably benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, thereby providing a process enabling the synthesis of compounds involving 14-O-substitution.
SUBSTITUTE SHEET (RULE 26) WO 98I22467 PCT/SE96/01497 _
rheumatoid arthritis).
In US 5 223 507 and US 5 225 417 the synthesis of 14-O-substituted indolomorphinans and s benzofuranomorphinans have been disclosed. According to the process used for preparing the compounds claimed and disclosed in US 5 223 507, only a 3,14-dimethoxy substituted benzofuranomorphinan was prepared. According to the process used for preparing compounds claimed and disclosed in US 5 225 417, two 14-O-alkyl substituted benzofuranomorphinans have been prepared. According to the methods used for preparing ~ o the compounds of both the two mentioned prior art documents, the 3-hydroxy group was protected by a methyl group which is not easily removed without having a loss in yield.
According to the processes known from the prior art, the variations of the substituents at the oxygen in position 14 are very much limited when a 3-hydroxy group is supposed to be ~ s present in the molecule. It is for instance not possible to prepare compounds with a substituent at the oxygen in 14-position, as this position is labile to the conditions used for the cleavage of the 3-methoxy group.
Thus, the object of the present invention was to find a new process which would facilitate 2o the preparation of 14-O-substituted indolomorphinans and benzofuranomorphinans.
The present patent application discloses a process whereby naloxone, naltrexone or oxymorphone is used as the starting material, whereby the 14-alkoxy group is introduced after the protection of the oxygen in 3-position with an easily removable protecting group, is preferably benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, thereby providing a process enabling the synthesis of compounds involving 14-O-substitution.
SUBSTITUTE SHEET (RULE 26) WO 98I22467 PCT/SE96/01497 _
3 Outline of the invention The present invention is directed to a new process for the preparation of compounds of the general formula (I) s wherein R1 represents allyl, cyclopropylmethyl or methyl;
io R2 represents C 1-C6 alkoxy, C 1-C6 alkenyloxy, C~-C 16 arylalkyloxy wherein aryl is C6-C ~ p aryl and alkyloxy is C ~ -C6 alkyloxy, C~-C I 6 arylalkenyloxy wherein aryl is C6-C 1 p aryl and alkenyloxy is C 1-C6 alkenyloxy, C 1-C6 alkanoyloxy, C~-C 16 arylalkanoyloxy wherein aryl is C6-Clp aryl and alkanoyloxy is C1-C6 alkanoyloxy;
R3 represents hydroxy, C 1-C6 alkoxy) C~-C I 6 arylalkyloxy wherein aryl is C6-C ~ p aryl and alkyloxy is C ~ -C6 alkyloxy, C ~ -C6 alkenyloxy) C I -C6 alkanoyloxy, C~-C 16 arylalkanoyloxy wherein the aryl is C6-C 1 p aryl and the alkanoyloxy is C 1-C6 alkanoyloxy, C2-C ~ p alkyloxyalkoxy wherein alkyloxy is C ~ -C4 alkyloxy and alkoxy is C 1-C6 alkoxy; and X represents O, NH or NR4 wherein R4 is C 1-C6 alkoxy, C I -Cb alkenyloxy, C7-C; 6 arylalkyloxy wherein aryl is C6-C 1 p aryl and alkyloxy is C 1-C6 alkyloxy, C~-arylalkenyloxy wherein the aryl is C6-C 1 p aryl and alkenyloxy is C 1-C6 alkenyloxy, C 1-C6 alkanoyloxy, C~-C 16 arylalkanoyloxy wherein aryl is C6-C 1 p aryl and alkanoyoloxy is C1-C6 alkanoyloxy.
SUBSTITUTE SHEET (RULE 26) WO 98/22467 PCT/SE96/01497 _
io R2 represents C 1-C6 alkoxy, C 1-C6 alkenyloxy, C~-C 16 arylalkyloxy wherein aryl is C6-C ~ p aryl and alkyloxy is C ~ -C6 alkyloxy, C~-C I 6 arylalkenyloxy wherein aryl is C6-C 1 p aryl and alkenyloxy is C 1-C6 alkenyloxy, C 1-C6 alkanoyloxy, C~-C 16 arylalkanoyloxy wherein aryl is C6-Clp aryl and alkanoyloxy is C1-C6 alkanoyloxy;
R3 represents hydroxy, C 1-C6 alkoxy) C~-C I 6 arylalkyloxy wherein aryl is C6-C ~ p aryl and alkyloxy is C ~ -C6 alkyloxy, C ~ -C6 alkenyloxy) C I -C6 alkanoyloxy, C~-C 16 arylalkanoyloxy wherein the aryl is C6-C 1 p aryl and the alkanoyloxy is C 1-C6 alkanoyloxy, C2-C ~ p alkyloxyalkoxy wherein alkyloxy is C ~ -C4 alkyloxy and alkoxy is C 1-C6 alkoxy; and X represents O, NH or NR4 wherein R4 is C 1-C6 alkoxy, C I -Cb alkenyloxy, C7-C; 6 arylalkyloxy wherein aryl is C6-C 1 p aryl and alkyloxy is C 1-C6 alkyloxy, C~-arylalkenyloxy wherein the aryl is C6-C 1 p aryl and alkenyloxy is C 1-C6 alkenyloxy, C 1-C6 alkanoyloxy, C~-C 16 arylalkanoyloxy wherein aryl is C6-C 1 p aryl and alkanoyoloxy is C1-C6 alkanoyloxy.
SUBSTITUTE SHEET (RULE 26) WO 98/22467 PCT/SE96/01497 _
4 -The process for the preparation of the compounds of the general formula (I) comprises the following steps:
s (i) Naloxone (II), naltrexone (III} or oxymorphone (IIIa) of the formula (ll): R = allyl (III): R = cyclopropylmethyl (111a): R = methyl HL J
is reacted with phenylhydrazine hydrochloride in the presence of an acid, preferably to methanesulfonic acid, sulfuric acid or hydrochloric acid, giving naloxindole (NLI)) naltrindole (NTI) or oxymorphindole (OMI), PS. Portoghese et al., J. Med.
Chem. Vol. 31:
281-282) l988) of the following formula:
NCR
OH NLI: R = allyl, X = NH
NTI: R = cyclopropylmethyl, X = NH
,,,~~~ , OMI: R = methyl, X = NH
or;
HO O
naloxone (II), naltrexone(III) or oxymorphone is reacted with O-phenyl-hydroxyl amine hydrochloride in the presence of an acid, preferably methanesulfonic acid, sulfuric acid or 2o hydrochloric acid, giving the benzofurane derivatives NLB, naltriben (NTB;
P. S.
SUBSTITUTE SHEET (RULE 26) .
Portoghese et al., J. Med. Chem., Vol. 34: 1715-1720, 1991 ) or OMB (US 5 223 507) of the formula NLB: R = allyl, X = O
NTB: R = cyclopropylmethyl, X = O
OMB: R = methyl, X = O
s (ii) the 3-hydroxy group is protected by alkylation with benzyl bromide, methoxymethyl bromide) ethoxymethyI bromide, trityl chloride or a silylating agent, preferably dimethyl isobutyl-silyl chloride, trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride or tri-i-propylsilyl chloride, in a solvent, preferably N,N-dimethylformamide, dichloromethane or tetrahydrofurane, in the presence of a base which may not be a weak ~ o base, preferably potassium carbonate, potassium hydroxide, sodium hydride, sodium amide or diisopropyl ethylamine, giving a compound of the formula (IV) JiR~
OH
~ s wherein o~ uo> ,~~, ., R1 is allyl, cyclopropylmethyl or methyl;
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, preferably dimethyl isobutyl silyl, 2o trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl;
and SUBSTITUTE SHEET (RULE 26j H(~ ,-WO 98I22467 PCT/SE96/01497 _ X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl or N-silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl;
(iii) the compound of the formula (IV ) is treated with C 1-C2 dialkyl sulfates, C t -C~, alkyl halides, C 1-C6 alkenyl halides, C~-C 16 aralkyl halides wherein the aryl is C6-C 1 p aryl and s the alkyl is C 1-C6 alkyl, C7-C 16 arylalkenyl halides wherein the aryl is C6-C 1 p aryl and the alkenyl is C2-C6 alkenyl, C2-C6 alkanoyl halides, C~-C ~ 6 arylalkanoyl halides wherein the aryl is C6-C ~ p aryl and the alkanoyl is C2-C~, aIkanoyl, in a solvent, preferably N,N- -dimethyl formamide or tetrahydrofurane, using a strong base, preferably sodium hydride, potassium hydride or sodium amide, giving a compound of the formula (V) io o~ ,~o> ~~
wherein R ~ is allyl or cyclopropylmethyl;
is R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and R3 is C 1-C6 alkyl, C I -C6 alkenyl; C~-C 16 arylalkyl wherein the aryl is C6-C 1 p aryl and the zo alkyl is C 1-C6 alkyl; C7-C ~ 6 arylalkenyl wherein the aryl C6-C 1 p aryl and the alkenyl is C 1-C6 alkenyl; C 1-C6 alkanoyl, C~-C 16 arylalkanoyl wherein the aryl is C6-C I p aryl and the alkyl is C t -C6 alkyl;
X is as defined in the formula (IV) above; and is SUBSTITUTE SHEET (RULE 26) WO 98I22467 PCTlSE9610149? _ optionally the following step (iv) whereby (iv) the compound of the formula (V) wherein X is NH, O, N-benzyl, N-methoxymethyl, N
ethoxymethyl, N-trityl or silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, s t-butyldimethylsilyl or tri-i-propylsilyl;
is hydrolized in diluted acids, preferably hydrochloric acid or sulfuric acid, optionally in the presence of a solvent, preferably an alcohol, and in particular methanol, ethanol or n-propanol, giving a compound of the formula (VI) ~n1 o~ ,~o> ,~~, HO \O ,, wherein R ~ , and R3 are as defined above in formula ( V ), and X is NH, O ar N-benzyl; and is (v) the compound of the formula (VI) is alkylated or acylated, giving a compound of the formula (I).
Detailed description of the invention 2o The invention will now be described in more detail by the following examples.
SUBSTITUTE SHEET (RULE 26) EXAMPLES
Example 1 Synthesis of 17-(CycIopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-hydroxy-3-s (methoxymethoxy)-6,7-2',3'-benzo[b)furanomorphinan (compound 1).
Sodium hydride (426 mg, 17.7 mmol; obtained from 710 mg of sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of naltriben methanesulfonate (2.0 g, 3.9 mmol) in 30 ml of anhydrous N,N-dimethyl formamide at 0~ C. The resulting i o mixture was stirred at 0~ C for 20 min and then at room temperature for another 60 min.
After cooling to 0~ C, methoxymethyl bromide (653 pl, 8 mmol) was added and stirnng was continued for 15 min at 0~ C and then for additional 120 min at room temperature. Excess sodium hydride was destroyed by addition of methanol and H20. The resulting mixture was extracted with ethyl acetate (4 x 50 ml), the combined organic layers were washed with is H20 (2 x 50 ml) and brine, dried over Na2S04 and evaporated to give an oil which was crystallized from MeOH to yield 1.0 g (56%) of compound 1. M. p. l29-130~ C.
~ H-NMR (CDC13): S 7.45 (d, J = 8.3 Hz, I atom. H), 7.37 (d, J = 8.3 Hz, 1 atom. H), 7.25 (m, 1 arom.H), 7.l6 (m, 1 atom.), 6.86 (d, J = 8.3 Hz, 1 atom. H), 6.60 (d, J
= 8.3 Hz, I
2o atom. H), 5.63 (s, H-C(5)), 5.17 and 5.06 (2 d, J = 6.6, 6.6 Hz, OCH20), 3.42 {s, CH30).
Analysis calculated for C2gH29N05. 0.2 MeOH {465.95): C 72.69, H 6.45, N 3.01;
found:
72.58, H 6.28, N 3.00.
zs Example 2 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-hydroxy-3-(methoxymethoxy)-6,7-2',3'-(N-methoxymethylindolo)morphinan (compound 2).
Sodium hydride (492 mg, 20.5 mmol; obtained from 820 mg of 60% dispersion in oil by 3o washings with n-hexane) was added to a solution of naltrindole hydrochloride ( 1.5 g, 3.3 SUBSTITUTE SHEET (RULE 26) mmol) in 30 m1 of anhydrous N,N-dimethyl formamide at 0~ C. After stirring at 0~ C for 15 min and additional 30 min at room temperature, the mixture was cooled again to 0~ C and methoxymethyl bromide ( 1.27 g) 10.2 mmol) was added. After stirring at 0~ C
for 30 min, stirring was continued for another 120 min at room temperature. Methanol and H20 were s added to destroy excess of sodium hydride. The mixture was extracted with ehtyl acetate (3 x 60 ml), the combined organic layers were washed with H20 (2 x 50 ml) and brine (2 x 50 ml) and evaporated to give a yellowish oil which was purified by column chromatography (silica gel, elution with CH2C12/MeOH/conc. NH40H 245:10:1) to afford 500 mg (30%) pure compound 2 as a colorless foam.
~o ~H NMR (CDC13): S 7.44 (m, 2 arom. H), 7.20 (m, 1 arom. H), 7.07 (m, 1 arom.
H)) 6.82 (d, J = 8 Hz, 1 arom. H), 6.58 (J = 8 Hz), 5.81 (s, H-C(5)), 5.79 and 5.50 (2 d, J = 10.8, 10.8 Hz, NCH2O) 5.12 and 5.50 (2 d, J = 6.4, 6.4 Hz, OCH20), 3.41 and 3.33 (2 s, CH30).
Analysis calculated for C3pH34N205 (502.61): C 7l.69, H 6.82, N 5.57; found: C
71.92, H
6.94, N 5.34.
Example 3 zo Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-14-(2',6'-dichlorobenzyloxy)-4,5a epoxy-3-(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 3).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 zs mmol) in 8 ml of anhydrous N,N-dimethylformamide at 0~ C. After stirring at 0~ C for 15 min, stirring was continued for another 30 min at room temperature and the mixture was cooled again to 0~ C. 2,6-Dichlorobenzyl bromide (240 g, 1 mmol) was added at once and stirring was continued for 15 min at 0~ C and then for 3 h at room temperature. Excess sodium hydride was destroyed with MeOH and H20 and the mixture was extracted with so ethyl acetate (3 x 30 ml). The combined organic layers were-washed with H20 (2 x 30 ml) SUBSTITUTE SHEET (RULE 26) and brine (2 x 30 ml), dried over Na2S04 and evaporated. The residue (400 mg colorless oil) was crystallized from MeOH to yield 300 mg (75%) of compound 3. M. p. l80-182~ C.
1H NMR (CDC13): 8 7.41 (d, J = 8.3 Hz, 1 atom. H), 7.33 (d, J = 8.3 Hz, 1 atom. H), 7.23 s (m, 1 atom. H), 7.14 (m, 2 atom. H), 7.03 and 7.01 (2 d, J = 7.3, 7.3 Hz, 2 atom. H), 6.84 (d, J = 8.3 Hz, 1 atom. H), 6.59 (d, J = 8.3 Hz, 1 atom. H), 5.56 (s, H-C(5)},
s (i) Naloxone (II), naltrexone (III} or oxymorphone (IIIa) of the formula (ll): R = allyl (III): R = cyclopropylmethyl (111a): R = methyl HL J
is reacted with phenylhydrazine hydrochloride in the presence of an acid, preferably to methanesulfonic acid, sulfuric acid or hydrochloric acid, giving naloxindole (NLI)) naltrindole (NTI) or oxymorphindole (OMI), PS. Portoghese et al., J. Med.
Chem. Vol. 31:
281-282) l988) of the following formula:
NCR
OH NLI: R = allyl, X = NH
NTI: R = cyclopropylmethyl, X = NH
,,,~~~ , OMI: R = methyl, X = NH
or;
HO O
naloxone (II), naltrexone(III) or oxymorphone is reacted with O-phenyl-hydroxyl amine hydrochloride in the presence of an acid, preferably methanesulfonic acid, sulfuric acid or 2o hydrochloric acid, giving the benzofurane derivatives NLB, naltriben (NTB;
P. S.
SUBSTITUTE SHEET (RULE 26) .
Portoghese et al., J. Med. Chem., Vol. 34: 1715-1720, 1991 ) or OMB (US 5 223 507) of the formula NLB: R = allyl, X = O
NTB: R = cyclopropylmethyl, X = O
OMB: R = methyl, X = O
s (ii) the 3-hydroxy group is protected by alkylation with benzyl bromide, methoxymethyl bromide) ethoxymethyI bromide, trityl chloride or a silylating agent, preferably dimethyl isobutyl-silyl chloride, trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride or tri-i-propylsilyl chloride, in a solvent, preferably N,N-dimethylformamide, dichloromethane or tetrahydrofurane, in the presence of a base which may not be a weak ~ o base, preferably potassium carbonate, potassium hydroxide, sodium hydride, sodium amide or diisopropyl ethylamine, giving a compound of the formula (IV) JiR~
OH
~ s wherein o~ uo> ,~~, ., R1 is allyl, cyclopropylmethyl or methyl;
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, preferably dimethyl isobutyl silyl, 2o trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl;
and SUBSTITUTE SHEET (RULE 26j H(~ ,-WO 98I22467 PCT/SE96/01497 _ X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl or N-silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl;
(iii) the compound of the formula (IV ) is treated with C 1-C2 dialkyl sulfates, C t -C~, alkyl halides, C 1-C6 alkenyl halides, C~-C 16 aralkyl halides wherein the aryl is C6-C 1 p aryl and s the alkyl is C 1-C6 alkyl, C7-C 16 arylalkenyl halides wherein the aryl is C6-C 1 p aryl and the alkenyl is C2-C6 alkenyl, C2-C6 alkanoyl halides, C~-C ~ 6 arylalkanoyl halides wherein the aryl is C6-C ~ p aryl and the alkanoyl is C2-C~, aIkanoyl, in a solvent, preferably N,N- -dimethyl formamide or tetrahydrofurane, using a strong base, preferably sodium hydride, potassium hydride or sodium amide, giving a compound of the formula (V) io o~ ,~o> ~~
wherein R ~ is allyl or cyclopropylmethyl;
is R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and R3 is C 1-C6 alkyl, C I -C6 alkenyl; C~-C 16 arylalkyl wherein the aryl is C6-C 1 p aryl and the zo alkyl is C 1-C6 alkyl; C7-C ~ 6 arylalkenyl wherein the aryl C6-C 1 p aryl and the alkenyl is C 1-C6 alkenyl; C 1-C6 alkanoyl, C~-C 16 arylalkanoyl wherein the aryl is C6-C I p aryl and the alkyl is C t -C6 alkyl;
X is as defined in the formula (IV) above; and is SUBSTITUTE SHEET (RULE 26) WO 98I22467 PCTlSE9610149? _ optionally the following step (iv) whereby (iv) the compound of the formula (V) wherein X is NH, O, N-benzyl, N-methoxymethyl, N
ethoxymethyl, N-trityl or silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, s t-butyldimethylsilyl or tri-i-propylsilyl;
is hydrolized in diluted acids, preferably hydrochloric acid or sulfuric acid, optionally in the presence of a solvent, preferably an alcohol, and in particular methanol, ethanol or n-propanol, giving a compound of the formula (VI) ~n1 o~ ,~o> ,~~, HO \O ,, wherein R ~ , and R3 are as defined above in formula ( V ), and X is NH, O ar N-benzyl; and is (v) the compound of the formula (VI) is alkylated or acylated, giving a compound of the formula (I).
Detailed description of the invention 2o The invention will now be described in more detail by the following examples.
SUBSTITUTE SHEET (RULE 26) EXAMPLES
Example 1 Synthesis of 17-(CycIopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-hydroxy-3-s (methoxymethoxy)-6,7-2',3'-benzo[b)furanomorphinan (compound 1).
Sodium hydride (426 mg, 17.7 mmol; obtained from 710 mg of sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of naltriben methanesulfonate (2.0 g, 3.9 mmol) in 30 ml of anhydrous N,N-dimethyl formamide at 0~ C. The resulting i o mixture was stirred at 0~ C for 20 min and then at room temperature for another 60 min.
After cooling to 0~ C, methoxymethyl bromide (653 pl, 8 mmol) was added and stirnng was continued for 15 min at 0~ C and then for additional 120 min at room temperature. Excess sodium hydride was destroyed by addition of methanol and H20. The resulting mixture was extracted with ethyl acetate (4 x 50 ml), the combined organic layers were washed with is H20 (2 x 50 ml) and brine, dried over Na2S04 and evaporated to give an oil which was crystallized from MeOH to yield 1.0 g (56%) of compound 1. M. p. l29-130~ C.
~ H-NMR (CDC13): S 7.45 (d, J = 8.3 Hz, I atom. H), 7.37 (d, J = 8.3 Hz, 1 atom. H), 7.25 (m, 1 arom.H), 7.l6 (m, 1 atom.), 6.86 (d, J = 8.3 Hz, 1 atom. H), 6.60 (d, J
= 8.3 Hz, I
2o atom. H), 5.63 (s, H-C(5)), 5.17 and 5.06 (2 d, J = 6.6, 6.6 Hz, OCH20), 3.42 {s, CH30).
Analysis calculated for C2gH29N05. 0.2 MeOH {465.95): C 72.69, H 6.45, N 3.01;
found:
72.58, H 6.28, N 3.00.
zs Example 2 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-hydroxy-3-(methoxymethoxy)-6,7-2',3'-(N-methoxymethylindolo)morphinan (compound 2).
Sodium hydride (492 mg, 20.5 mmol; obtained from 820 mg of 60% dispersion in oil by 3o washings with n-hexane) was added to a solution of naltrindole hydrochloride ( 1.5 g, 3.3 SUBSTITUTE SHEET (RULE 26) mmol) in 30 m1 of anhydrous N,N-dimethyl formamide at 0~ C. After stirring at 0~ C for 15 min and additional 30 min at room temperature, the mixture was cooled again to 0~ C and methoxymethyl bromide ( 1.27 g) 10.2 mmol) was added. After stirring at 0~ C
for 30 min, stirring was continued for another 120 min at room temperature. Methanol and H20 were s added to destroy excess of sodium hydride. The mixture was extracted with ehtyl acetate (3 x 60 ml), the combined organic layers were washed with H20 (2 x 50 ml) and brine (2 x 50 ml) and evaporated to give a yellowish oil which was purified by column chromatography (silica gel, elution with CH2C12/MeOH/conc. NH40H 245:10:1) to afford 500 mg (30%) pure compound 2 as a colorless foam.
~o ~H NMR (CDC13): S 7.44 (m, 2 arom. H), 7.20 (m, 1 arom. H), 7.07 (m, 1 arom.
H)) 6.82 (d, J = 8 Hz, 1 arom. H), 6.58 (J = 8 Hz), 5.81 (s, H-C(5)), 5.79 and 5.50 (2 d, J = 10.8, 10.8 Hz, NCH2O) 5.12 and 5.50 (2 d, J = 6.4, 6.4 Hz, OCH20), 3.41 and 3.33 (2 s, CH30).
Analysis calculated for C3pH34N205 (502.61): C 7l.69, H 6.82, N 5.57; found: C
71.92, H
6.94, N 5.34.
Example 3 zo Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-14-(2',6'-dichlorobenzyloxy)-4,5a epoxy-3-(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 3).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 zs mmol) in 8 ml of anhydrous N,N-dimethylformamide at 0~ C. After stirring at 0~ C for 15 min, stirring was continued for another 30 min at room temperature and the mixture was cooled again to 0~ C. 2,6-Dichlorobenzyl bromide (240 g, 1 mmol) was added at once and stirring was continued for 15 min at 0~ C and then for 3 h at room temperature. Excess sodium hydride was destroyed with MeOH and H20 and the mixture was extracted with so ethyl acetate (3 x 30 ml). The combined organic layers were-washed with H20 (2 x 30 ml) SUBSTITUTE SHEET (RULE 26) and brine (2 x 30 ml), dried over Na2S04 and evaporated. The residue (400 mg colorless oil) was crystallized from MeOH to yield 300 mg (75%) of compound 3. M. p. l80-182~ C.
1H NMR (CDC13): 8 7.41 (d, J = 8.3 Hz, 1 atom. H), 7.33 (d, J = 8.3 Hz, 1 atom. H), 7.23 s (m, 1 atom. H), 7.14 (m, 2 atom. H), 7.03 and 7.01 (2 d, J = 7.3, 7.3 Hz, 2 atom. H), 6.84 (d, J = 8.3 Hz, 1 atom. H), 6.59 (d, J = 8.3 Hz, 1 atom. H), 5.56 (s, H-C(5)},
5.32 and 4.68 (2 d, J = 8.7, 8.7 Hz, OCH2Ph), 5.16 and 5.05 (2 d, J = 6.6, 6.6 Hz, OCH20), 3.41 (s, CH30).
~o Example 4 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-14-(2',6'-dichlorobenzyloxy)-4,5a-epoxy-3-hydroxy-6,7-2',3'-benzo[b]furanomorphinan (compound 4).
A solution of compound 3 ( 150 mg, 0.24 mmol) in MeOH (4 ml) and 1 N HCl (2 ml) was i s refluxed for 1 h. After cooling, the solution was alkalized with cone.
NH40H, extracted wiht ethyl acetate (3 x 15 ml), the combined organic layers were washed with H20 (2 x 15 ml) and brine ( 10 ml), dried over Na2S04 and evaporated to give an oily residue which was crystallized from MeOH to yield 70 mg (51 %) of compound 4. M. p. l93-l95~ C
(dec.}.
1H NMR (CDC13): 8 7.42 (d, J = 8.3 Hz, 1 atom. H), 7.33 (d, J = 8 Hz, 1 atom.
H), 7.24 (m, 1 atom. H), 7.14 (m, 2 atom. H), 7.03 and 7.01 (2 d, J = 7.3 Hz, 1 atom.
H), 6.64 (d, J
= 8.1 Hz, 1 atom. H), 6.56 (d, J = 8.1 Hz, 1 atom. H), 5.58 (s, H-C(5)), 5.32 and 4.68 (2 d, J = 8.6 Hz, OCH2Ph).
is Analysis calculated for C33H29C12N04 (574.51 ): C 68.79, H 5.09, N 2.44;
found: C 68.97, HS.OS,N2.44.
SUBSTITUTE SHEET (RULE 26) Example 5 Synthesis of 17-(Cyclopropylmethyl) -6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-(3'-nitrobenzyloxy)-6,7-2',3'-benzojb]furanomorphinan (compound 5).
s Sodium hydride {36 mg, 1.5 mmol; obtained from 60 mg of 60~lo sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 6 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 0~ C for 15 min and then at room temperature for another 30 min.
After cooling to 0~ C, 3-nitrobenzyl bromide (216 mg, 1 mmol) was added and stirring was continued first i o at 0~ C for 15 min and then at room temperature for 3 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine (2 x 20 ml), dried over Na2S04 and evaporated to give 380 mg of a brown oil which was purified by column chromatography {silica gel, elution with CH2Cl2/MeOH/conc.
~ s NH40H 240:10:1 ) to afford I00 mg (26% ) of compound 5 as colorless foam.
1H NMR (CDC13): b 8.25 (s, 1 arom. H), 7.99 (m, 1 arom. H), 7.55 (d, J = 7.8 Hz, 1 arom.
H), 7.47 (d) J = 8.3 Hz, 1 arom. H), 7.28 (m, 4 arom. H), 7.15 (m, 1 arom. H),
~o Example 4 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-14-(2',6'-dichlorobenzyloxy)-4,5a-epoxy-3-hydroxy-6,7-2',3'-benzo[b]furanomorphinan (compound 4).
A solution of compound 3 ( 150 mg, 0.24 mmol) in MeOH (4 ml) and 1 N HCl (2 ml) was i s refluxed for 1 h. After cooling, the solution was alkalized with cone.
NH40H, extracted wiht ethyl acetate (3 x 15 ml), the combined organic layers were washed with H20 (2 x 15 ml) and brine ( 10 ml), dried over Na2S04 and evaporated to give an oily residue which was crystallized from MeOH to yield 70 mg (51 %) of compound 4. M. p. l93-l95~ C
(dec.}.
1H NMR (CDC13): 8 7.42 (d, J = 8.3 Hz, 1 atom. H), 7.33 (d, J = 8 Hz, 1 atom.
H), 7.24 (m, 1 atom. H), 7.14 (m, 2 atom. H), 7.03 and 7.01 (2 d, J = 7.3 Hz, 1 atom.
H), 6.64 (d, J
= 8.1 Hz, 1 atom. H), 6.56 (d, J = 8.1 Hz, 1 atom. H), 5.58 (s, H-C(5)), 5.32 and 4.68 (2 d, J = 8.6 Hz, OCH2Ph).
is Analysis calculated for C33H29C12N04 (574.51 ): C 68.79, H 5.09, N 2.44;
found: C 68.97, HS.OS,N2.44.
SUBSTITUTE SHEET (RULE 26) Example 5 Synthesis of 17-(Cyclopropylmethyl) -6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-(3'-nitrobenzyloxy)-6,7-2',3'-benzojb]furanomorphinan (compound 5).
s Sodium hydride {36 mg, 1.5 mmol; obtained from 60 mg of 60~lo sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 6 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 0~ C for 15 min and then at room temperature for another 30 min.
After cooling to 0~ C, 3-nitrobenzyl bromide (216 mg, 1 mmol) was added and stirring was continued first i o at 0~ C for 15 min and then at room temperature for 3 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine (2 x 20 ml), dried over Na2S04 and evaporated to give 380 mg of a brown oil which was purified by column chromatography {silica gel, elution with CH2Cl2/MeOH/conc.
~ s NH40H 240:10:1 ) to afford I00 mg (26% ) of compound 5 as colorless foam.
1H NMR (CDC13): b 8.25 (s, 1 arom. H), 7.99 (m, 1 arom. H), 7.55 (d, J = 7.8 Hz, 1 arom.
H), 7.47 (d) J = 8.3 Hz, 1 arom. H), 7.28 (m, 4 arom. H), 7.15 (m, 1 arom. H),
6.87 (d, J =
8.3 Hz, 1 arom. H), 6.62 (d, J = 8.3 Hz, 1 arom. H), 5.66 (s, H-C(5)), 5.17 and S.07 (2 d, J
20 = 6.6 Hz) OCH20, 4.92 and 4.44 (2 d, J = 11.5 Hz, OCH2Ph), 3.42 (s, CH30).
Example 6 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(3'-nitrobenzyloxy)-6,7-2',3'-benzojb]furanomorphinan Hydrochloride (compound 6).
zs A solution of compound 5 (80 mg, 0.13 mmol) in MeOH (4 ml) and 1N HCl (2 ml) was refluxed for 1 h. After cooling, the solution was alkalized with conc. NH40H, extracted with ethyl acetate (3 x 20 ml), the combined organic layers were washed with H20 (2 x 15 ml) and brine (15 ml), dried over Na2S04 and evaporated. The oily residue was dissolved in SUBSTITUTE SHEET (RULE 26)
8.3 Hz, 1 arom. H), 6.62 (d, J = 8.3 Hz, 1 arom. H), 5.66 (s, H-C(5)), 5.17 and S.07 (2 d, J
20 = 6.6 Hz) OCH20, 4.92 and 4.44 (2 d, J = 11.5 Hz, OCH2Ph), 3.42 (s, CH30).
Example 6 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(3'-nitrobenzyloxy)-6,7-2',3'-benzojb]furanomorphinan Hydrochloride (compound 6).
zs A solution of compound 5 (80 mg, 0.13 mmol) in MeOH (4 ml) and 1N HCl (2 ml) was refluxed for 1 h. After cooling, the solution was alkalized with conc. NH40H, extracted with ethyl acetate (3 x 20 ml), the combined organic layers were washed with H20 (2 x 15 ml) and brine (15 ml), dried over Na2S04 and evaporated. The oily residue was dissolved in SUBSTITUTE SHEET (RULE 26)
7 PCT/SE96/OI497 -acetone and transformed into the hydrochloride salt (compound 6) by addition of ethereal HCI. Yield 50 mg (66%). M. p. > 230~ C (dec.).
1 H NMR (DMSO-d6): S 9.40 (s, OH), 9.15 (broad s, +NH), 7.84 (s, 1 atom. H), 7.60 (d, J
s = 8.8 Hz, 1 atom. H), 7.53 (d, J = 7.6 Hz, 1 atom. H), 7.45 (d, J = 8 Hz, 1 atom. H), 7.23 (d, J = 7.6 Hz, 1 atom. H), 7.19 (d, J = 7.6 Hz, 1 atom. H), 6.98 (m, 1 atom.
H), 6.88 (d, J
= 7.6 Hz, 1 atom. H), 6.69 (d, J = 8.3 Hz, 1 atom. H), 6.66 (d, J = 8.3 Hz, 1 atom. H), 6.03 (s, H-C(5)), 4.98 and 4.87 (2 d, J = 14, 14 Hz, OCH2Ph).
~ o Analysis calculated for C33H3pN206 x HCl (587.08): C 67.52, H 5.32, N.
4.77; found: C
67.78, H 5.25, N 4. 76.
Example 7 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,Sa-epoxy-3-(methoxymethoxy)-14-(2-~ s naphthylmethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 7).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 5 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 20 0~ C for 15 min and then at room temperature for another 30 min. After cooling to 0~ C, 2-(bromomethyl)naphthalene (22l mg) 1 mmol) was added and stirring was continued at first at 0~ C for 1 S min and then at room temperature for 2 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20 ml) and 2s brine (2 x 10 ml), dried over Na2S04 and evaporated to give a crystalline residue which was recrystallized to yield 285 mg (73%) of compound 7. M. p. 198-201~ C.
1H NMR (CDC13): 8 7.72-7.08 (m, 11 atom. H), 6.86 (d, J = 8.3 Hz, 1 atom. H), 6.62 (d, J
= 8.3 Hz, 1 atom. H), 5.68 (s, H-C(5)), 5.17 and 5.07 (2 d, J = 6.6, 6.6 Hz, OCH20), 5.01 so and 4.57 (2 d, J = 11.2) 11.2 Hz, OCH2Ar), 3.42 (s, CH30):
SUBSTITUTE SHEET (RULE 26) Analysis calculated for C39H3~N05 x 0.2 EtOAc (C4Hg02~ (617.35): C77.43, H
6.30, N
2.27; found: C 77.40, H 6.27, N 2.27.
s Example 8 Synthesis of 17-(Cyclopropyimethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(2'-naphthylmethoxy)-6,7-2',3'-benzo[b]furanomorphinan hydrochloride(compound 8).
A solution of compound 7 ( 180 mg, 0.3 mmol) in MeOH (5 ml) and 1N HCl (3 ml) was ~ o refluxed for 30 min, cooled and kept in the refrigerator overnight. The crystals formed were isolated and washed with small amounts of MeOH and ether to yield 150 mg (84%) of compound 8. M. p. > 215~ C.
~ H NMR (DMSO-d6): 8 9.42 (s, OH), 9.00 (broad s, +NH), 7.68-6.85 (m, 11 arom.
H), is 6.71 (d, J = 8 Hz, 1 arom. H), 6.67 (d, J = 8 Hz, 1 arom. H), 6.04 (s, H-C(5)), 4.92 (s, OCH2Ar).
Analysis calculated for C3~H33N04 x HCI. 0.3 MeOH (60l.75): C74.45, H 5.90, N
2.33;
found: C 74.47, H 5.76, N 2.3S.
2o Example 9 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,Sa-epoxy-14-(2'-fluorobenzyloxy)-3-(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 9}.
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion 2s in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 5 ml of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 0~ C for 10 min and the at room temperature for another 30 min.
After cooling to 0~ C, 2-flourobenzyl bromide ( 120 ~.1, 1 mmol) was added and stirring was continued at first at 0~ C for 15 min and then at room temperature for 2 h. Excess sodium hydride was 3o destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl SUBSTITUTE SHEET (RULE 26) acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine (2 x 20 ml), dried over Na2S04 and evaporated to give an oil which purified by column chromatography (silica gel, elution with ethyl acetate/n-hexane 1 ) 1:3 2) 1:1 ) to afford 215 mg (58%) of compound 9 as colorless foam.
s io I H NMR (DMSO-d6): b 7.56 (d, J = 8 Hz, 1 atom. H), 7.49 (d, J = 8 Hz, 1 atom.
H), 7.31 (m, 1 atom. H), 7.21 (m, 1 atom. H), 6.8l (d, J = 8.4 Hz, 1 atom. H), 6.67 (d, J = 8.4 Hz), 5.72 (s, H-C(5}), 5.06 and 5.01 (2 d, J = 6.4, 6.4 Hz, OCH20), 4.89 and 4.57 (2 d, J =
11.6, 11.6 Hz, OCH2Ph), 3.33 (s, CH30).
Analysis calculated for C35H34NO5 (5b7.66): C 74.06, H 6.04, N 2.47; found: C
73.7l, H
5.92, N 2.42.
Example 10 is Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-(2'-fluorobenzyloxy)-3-hydroxy-6,7-2',3'-benzo[b)furanomorphinan Hydrochloride (compound 10).
A solution of compound 9 ( 160 mg, 0.28 mmol) in MeOH (3 ml) and 1 N HCI (3 ml) was refluxed for 20 min, then cooled and kept in the refrigerator overnight. The crystals formed zo were isolated and washed with small amounts of MeOH and ether to yield 110 mg (70%) of compound 10. M. p. > 215~ C.
1 H NMR (CDC13): 8 9.45 (s, OH), 9.04 (broad s, +IVH), 7.54 (d, J = 8.4 Hz, 1 atom. H, 7.31-6.73 (m, 7 atom. H), 6.71 (d, J = 8.2 Hz, 1 atom. H), 6.66 (d, J = 8.2 Hz, 1 atom. H), zs 5.98 (s, H-C(5)), 4.81 and 4.84 (2 d, J = 12 Hz, OCH2Ph).
Analysis calculated for C33H3pFNO4 x HCI. 1.4 H20 (585.29): C 67.72, H 5.82, N
2.39;
found: C 67.63, H 5.56, N 2.51.
SUBSTITUTE SHEET (RULE 26) WO 98l22467 PCT/SE96/01497 Example 11 Synthesis of 14-(Cinnamyloxy)-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 11 ).
s Sodium hydride {36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 5 mi of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 0~ C for 15 min and then at room temperature for another 30 min.
After cooling to 0~ C, cinnamyl bromide ( 197 mg, 1 mmol) was added and stirring was continued first at 0~
i o C for I O min and then at room temperature for 2 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 30 ml)> the combined organic layers were washed with H20 (2 x 20 ml) and brine ( I x 20 ml), dried over Na2S04 and evaporated to give a crystalline residue which was treated with boiling methanol to afford 200 mg (53%) of compound I I. M. p. I56-159~ C.
~s zo 1H NMR (CDCl3): 8 7.47 (d, J = 8 Hz, I arom. H), 7.33 (d, J = 8 Hz, 1 arom.
H), 7.28-7.07 (m, 7 arom. H), 6.84 (d, J, 8.4 Hz, 1 arom. H), 6.59 (d, J = 8.4 Hz, I
arom. H), 6.38 (d, 3 = 16 Hz, I olef. H), 6.13 (m, 1 olef. H), 5.68 (s, H-C(5)), 5.I6 and 5.06 (2 d, J = 6.4, 6.4 Hz) OCH20), 4.46 and 4.11 (2 m, CH20-C( 14)), 3.42 (s, CH30).
Analysis calculated for C3~H3~NOg. 0. I EtOAc (584.52): C 76.85, H 6.52, N
2.40; found:
C 76.70, H 6.48, N 2.41.
Example 12 is Synthesis of 14-(Cinnamyloxy)-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-hydroxy-6,7-2',3'-benzo[b]furanomorphinan Salicylate (compound 12).
A solution of compound 11 (160 mg, 0.28 mmol) in MeOH (3 ml) and 1N HCl (3 ml) was refluxed for 1 h. After cooling, the solution was alkalized with conc. NH40H, extracted 3o with ethyl acetate (3 x 15 ml), the combined organic layers were washed with H20 (2 x 15 SUBSTITUTE SHEET (RULE 26) ml) and brine ( 10 ml), dried over Na2S04 and evaporated to give a colorless foam ( 100 mg). To a solution of this foam in a small amount of methanol 30 mg of salicyclic acid were added, the crystals formed collected and washed with cold methanol to yield 100 mg (53%) ~
of compound 12. M. p. > 170 C.
s 1 H NMR (CDCl3): 8 7.94 (d, J = 8 Hz, 1 arom. H), 7.35 (d, J = 8 Hz, 1 arom.
H), 7.30-6.73 (m, 12 arom. H), 6.56 {d, J = 8 Hz, 1 arom. H), 5.96 (s, 2 olef. H), 5.55 (s, H-C(5)), 4.33-4.02 (m, CH20-C(14)).
io Analysis calculated for C35H33N0~. Salicyclic acid (C~H~03). I MeOH
(701.82): C 73.57, H 6.18, N 2.00; found: C 73.56, H S.96, N 2.06.
Example 13 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-methoxy-3-is (methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 13).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound I (300 mg, 0.65 mmol) in 5 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was 2o stirred at 0~ C for 15 min and the at room temperature for another 30 min.
After cooling to 0~ C, dimethyl sulfate ( 100 ~.1, 1 mmol) was added and stirring was continued at first at 0~
C for 15 min and then at room temperature for 2 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine (2 x 20 2s ml), dried over Na2S04 and evaporated to give a colorless foam (280 mg) of compound 13 which was pure by TLC and NMR.
SUBSTITUTE SHEET (RULE 26) WO 98l22467 PCT/SE96/01497 , 1H NMR (DMSO-d6): 8 7.56 (d, J = 8 Hz, 1 atom. H), 7.S2 (d, J = 8 Hz, 1 atom.
H), 7.32 (dd, J = 8, 8 Hz, 1 atom. H), 7.23 (dd, J = 8, 8 Hz, I atom. H), 6.79 (d, J =
1 H NMR (DMSO-d6): S 9.40 (s, OH), 9.15 (broad s, +NH), 7.84 (s, 1 atom. H), 7.60 (d, J
s = 8.8 Hz, 1 atom. H), 7.53 (d, J = 7.6 Hz, 1 atom. H), 7.45 (d, J = 8 Hz, 1 atom. H), 7.23 (d, J = 7.6 Hz, 1 atom. H), 7.19 (d, J = 7.6 Hz, 1 atom. H), 6.98 (m, 1 atom.
H), 6.88 (d, J
= 7.6 Hz, 1 atom. H), 6.69 (d, J = 8.3 Hz, 1 atom. H), 6.66 (d, J = 8.3 Hz, 1 atom. H), 6.03 (s, H-C(5)), 4.98 and 4.87 (2 d, J = 14, 14 Hz, OCH2Ph).
~ o Analysis calculated for C33H3pN206 x HCl (587.08): C 67.52, H 5.32, N.
4.77; found: C
67.78, H 5.25, N 4. 76.
Example 7 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,Sa-epoxy-3-(methoxymethoxy)-14-(2-~ s naphthylmethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 7).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 5 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 20 0~ C for 15 min and then at room temperature for another 30 min. After cooling to 0~ C, 2-(bromomethyl)naphthalene (22l mg) 1 mmol) was added and stirring was continued at first at 0~ C for 1 S min and then at room temperature for 2 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20 ml) and 2s brine (2 x 10 ml), dried over Na2S04 and evaporated to give a crystalline residue which was recrystallized to yield 285 mg (73%) of compound 7. M. p. 198-201~ C.
1H NMR (CDC13): 8 7.72-7.08 (m, 11 atom. H), 6.86 (d, J = 8.3 Hz, 1 atom. H), 6.62 (d, J
= 8.3 Hz, 1 atom. H), 5.68 (s, H-C(5)), 5.17 and 5.07 (2 d, J = 6.6, 6.6 Hz, OCH20), 5.01 so and 4.57 (2 d, J = 11.2) 11.2 Hz, OCH2Ar), 3.42 (s, CH30):
SUBSTITUTE SHEET (RULE 26) Analysis calculated for C39H3~N05 x 0.2 EtOAc (C4Hg02~ (617.35): C77.43, H
6.30, N
2.27; found: C 77.40, H 6.27, N 2.27.
s Example 8 Synthesis of 17-(Cyclopropyimethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(2'-naphthylmethoxy)-6,7-2',3'-benzo[b]furanomorphinan hydrochloride(compound 8).
A solution of compound 7 ( 180 mg, 0.3 mmol) in MeOH (5 ml) and 1N HCl (3 ml) was ~ o refluxed for 30 min, cooled and kept in the refrigerator overnight. The crystals formed were isolated and washed with small amounts of MeOH and ether to yield 150 mg (84%) of compound 8. M. p. > 215~ C.
~ H NMR (DMSO-d6): 8 9.42 (s, OH), 9.00 (broad s, +NH), 7.68-6.85 (m, 11 arom.
H), is 6.71 (d, J = 8 Hz, 1 arom. H), 6.67 (d, J = 8 Hz, 1 arom. H), 6.04 (s, H-C(5)), 4.92 (s, OCH2Ar).
Analysis calculated for C3~H33N04 x HCI. 0.3 MeOH (60l.75): C74.45, H 5.90, N
2.33;
found: C 74.47, H 5.76, N 2.3S.
2o Example 9 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,Sa-epoxy-14-(2'-fluorobenzyloxy)-3-(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 9}.
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion 2s in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 5 ml of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 0~ C for 10 min and the at room temperature for another 30 min.
After cooling to 0~ C, 2-flourobenzyl bromide ( 120 ~.1, 1 mmol) was added and stirring was continued at first at 0~ C for 15 min and then at room temperature for 2 h. Excess sodium hydride was 3o destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl SUBSTITUTE SHEET (RULE 26) acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine (2 x 20 ml), dried over Na2S04 and evaporated to give an oil which purified by column chromatography (silica gel, elution with ethyl acetate/n-hexane 1 ) 1:3 2) 1:1 ) to afford 215 mg (58%) of compound 9 as colorless foam.
s io I H NMR (DMSO-d6): b 7.56 (d, J = 8 Hz, 1 atom. H), 7.49 (d, J = 8 Hz, 1 atom.
H), 7.31 (m, 1 atom. H), 7.21 (m, 1 atom. H), 6.8l (d, J = 8.4 Hz, 1 atom. H), 6.67 (d, J = 8.4 Hz), 5.72 (s, H-C(5}), 5.06 and 5.01 (2 d, J = 6.4, 6.4 Hz, OCH20), 4.89 and 4.57 (2 d, J =
11.6, 11.6 Hz, OCH2Ph), 3.33 (s, CH30).
Analysis calculated for C35H34NO5 (5b7.66): C 74.06, H 6.04, N 2.47; found: C
73.7l, H
5.92, N 2.42.
Example 10 is Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-(2'-fluorobenzyloxy)-3-hydroxy-6,7-2',3'-benzo[b)furanomorphinan Hydrochloride (compound 10).
A solution of compound 9 ( 160 mg, 0.28 mmol) in MeOH (3 ml) and 1 N HCI (3 ml) was refluxed for 20 min, then cooled and kept in the refrigerator overnight. The crystals formed zo were isolated and washed with small amounts of MeOH and ether to yield 110 mg (70%) of compound 10. M. p. > 215~ C.
1 H NMR (CDC13): 8 9.45 (s, OH), 9.04 (broad s, +IVH), 7.54 (d, J = 8.4 Hz, 1 atom. H, 7.31-6.73 (m, 7 atom. H), 6.71 (d, J = 8.2 Hz, 1 atom. H), 6.66 (d, J = 8.2 Hz, 1 atom. H), zs 5.98 (s, H-C(5)), 4.81 and 4.84 (2 d, J = 12 Hz, OCH2Ph).
Analysis calculated for C33H3pFNO4 x HCI. 1.4 H20 (585.29): C 67.72, H 5.82, N
2.39;
found: C 67.63, H 5.56, N 2.51.
SUBSTITUTE SHEET (RULE 26) WO 98l22467 PCT/SE96/01497 Example 11 Synthesis of 14-(Cinnamyloxy)-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 11 ).
s Sodium hydride {36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 1 (300 mg, 0.65 mmol) in 5 mi of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 0~ C for 15 min and then at room temperature for another 30 min.
After cooling to 0~ C, cinnamyl bromide ( 197 mg, 1 mmol) was added and stirring was continued first at 0~
i o C for I O min and then at room temperature for 2 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 30 ml)> the combined organic layers were washed with H20 (2 x 20 ml) and brine ( I x 20 ml), dried over Na2S04 and evaporated to give a crystalline residue which was treated with boiling methanol to afford 200 mg (53%) of compound I I. M. p. I56-159~ C.
~s zo 1H NMR (CDCl3): 8 7.47 (d, J = 8 Hz, I arom. H), 7.33 (d, J = 8 Hz, 1 arom.
H), 7.28-7.07 (m, 7 arom. H), 6.84 (d, J, 8.4 Hz, 1 arom. H), 6.59 (d, J = 8.4 Hz, I
arom. H), 6.38 (d, 3 = 16 Hz, I olef. H), 6.13 (m, 1 olef. H), 5.68 (s, H-C(5)), 5.I6 and 5.06 (2 d, J = 6.4, 6.4 Hz) OCH20), 4.46 and 4.11 (2 m, CH20-C( 14)), 3.42 (s, CH30).
Analysis calculated for C3~H3~NOg. 0. I EtOAc (584.52): C 76.85, H 6.52, N
2.40; found:
C 76.70, H 6.48, N 2.41.
Example 12 is Synthesis of 14-(Cinnamyloxy)-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-hydroxy-6,7-2',3'-benzo[b]furanomorphinan Salicylate (compound 12).
A solution of compound 11 (160 mg, 0.28 mmol) in MeOH (3 ml) and 1N HCl (3 ml) was refluxed for 1 h. After cooling, the solution was alkalized with conc. NH40H, extracted 3o with ethyl acetate (3 x 15 ml), the combined organic layers were washed with H20 (2 x 15 SUBSTITUTE SHEET (RULE 26) ml) and brine ( 10 ml), dried over Na2S04 and evaporated to give a colorless foam ( 100 mg). To a solution of this foam in a small amount of methanol 30 mg of salicyclic acid were added, the crystals formed collected and washed with cold methanol to yield 100 mg (53%) ~
of compound 12. M. p. > 170 C.
s 1 H NMR (CDCl3): 8 7.94 (d, J = 8 Hz, 1 arom. H), 7.35 (d, J = 8 Hz, 1 arom.
H), 7.30-6.73 (m, 12 arom. H), 6.56 {d, J = 8 Hz, 1 arom. H), 5.96 (s, 2 olef. H), 5.55 (s, H-C(5)), 4.33-4.02 (m, CH20-C(14)).
io Analysis calculated for C35H33N0~. Salicyclic acid (C~H~03). I MeOH
(701.82): C 73.57, H 6.18, N 2.00; found: C 73.56, H S.96, N 2.06.
Example 13 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-14-methoxy-3-is (methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 13).
Sodium hydride (36 mg, 1.5 mmol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound I (300 mg, 0.65 mmol) in 5 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was 2o stirred at 0~ C for 15 min and the at room temperature for another 30 min.
After cooling to 0~ C, dimethyl sulfate ( 100 ~.1, 1 mmol) was added and stirring was continued at first at 0~
C for 15 min and then at room temperature for 2 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine (2 x 20 2s ml), dried over Na2S04 and evaporated to give a colorless foam (280 mg) of compound 13 which was pure by TLC and NMR.
SUBSTITUTE SHEET (RULE 26) WO 98l22467 PCT/SE96/01497 , 1H NMR (DMSO-d6): 8 7.56 (d, J = 8 Hz, 1 atom. H), 7.S2 (d, J = 8 Hz, 1 atom.
H), 7.32 (dd, J = 8, 8 Hz, 1 atom. H), 7.23 (dd, J = 8, 8 Hz, I atom. H), 6.79 (d, J =
8.2 Hz, I atom.
H), 6.64 (d, J = 8.2 Hz, 1 atom. H), 5.64 (s, H-C(5)), 5.05 and 5.00 (2 d, J =
6.4, 6.4 Hz, OCH20), 3.32 (CH30).
s Analysis calculated for C29H31 N05. 0.2 MeOH (479.98): C 73.07, H 6.68, N
2.92; found:
C 72.94, H 6.60, N 2.92.
Example 14 ~o Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-methoxy-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound 14).
A solution of compound 13 ( 160 mg, 0.28 mmol) in MeOH (3 ml) and 1 N HCI (2 ml) was refluxed for 20 min, then cooled and kept in the refrigerator overnight. The crystals formed i s were isolated and washed with small amounts of MeOH and ether to yield 70 mg (36%) of compound 14. M. p. > 240~ C.
I H NMR (DMSO-db): 8 9.47 (s, OH), 9.17 (broad s, ~NH), 7.61 (d, J = 8 Hz, 1 atom. H), 7.53 (d, J = 8 Hz, 1 atom. H), 7.36 (dd, J = 8, 8 Hz, 1 atom. H), 7.27 (dd, J
= 8, 8 Hz, I
2o atom. H), 6.72 (d, J = 8.4 Hz, 1 atom. H), 6.65 (d, J = 8.4 Hz, 1 atom. H), 5.90 (s, H-C(5)), 3.35 (s, CH30).
Analysis calculated for C2~H2~N04 x HCI. 1.5 HZO (493.00): C 65.78, H 6.34, N
2.84;
found: C 65.89, H 6.20, N 2.85.
SUBSTITUTE SHEET (RULE 26) Example 15 Synthesis of 17-(Cyclopropylmethyl)-14-(2'-chlorobenzyloxy}-6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-6,7-2',3'-(N-methoxymethylindolo)morphinan (compound 15).
s Sodium hydride (36 mg, 1.5 mxnol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 2 (327 mg, 0.65 mmol) in 5 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 0~ C for 1 S min and then at room temperature for another 30 min.
After cooling to 0~ C, 2-chlorobenzyl bromide (205 mg, 1 mmol) was added and stirring was continued first i o at 0~ C for 15 min and then at room temperature for 3 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 40 ml) and brine (2 x 30 ml), dried over Na2S04 and evaporated to give 370 mg of compound 15 as colorless foam which was pure by TLC and NMR.
is 1H NMR (CDC13): 8 7.56 (m, 1 arom. H), 7.44 (m, 1 arom. H), 7.37-7.17 (m, 3 arom. H), 7.01 (m, 1 arom. H), 6.9l (m, 1 arom. H), 6.83 (d, J = 8.2 Hz, 1 arom. H), 6.59 (d, J = 8.2 Hz, 1 arom. H), 5.90 (s, H-C(5)), 5.82 and 5.55 (2 d, J = 11.2, 11.2 Hz, NCH20), 5.l3 and 5.03 (2 d, J = 6.4, 6.4 Hz, OCH20), 4.98 and 4.56 (2 d, J = 13, 13 Hz, OCH2Ph), 3.40 and zo 3.26 (2 s, 2 CH30).
Example 16 Synthesis of 17-(Cyclopropylmethyl)-14-(2'-chlorobenzyloxy)-6,7-dehydro-4,5a-epoxy-3-hydroxy-6,7-2',3'-indolomorphinan Hydrochloride (compound 16).
zs A solution of compound 15 (300 mg, 0.48 mmol) in MeOH (5 ml) and IN HCl (3 ml) was refluxed for 1 h. After cooling, the solution was alkalized with conc. NH40H, extracted with ethyl acetate (3 x 20 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine (20 ml), dried over Na2S04 and evaporated to give a colorless oil. To a so solution of this foam in a small amount of methanol ethereal HCl was added, the crystals SUBSTITUTE SHEET (RULE 26) formed collected and washed with cold methanol to yield l20 mg (43%) of compound 16.
M. p. > 250~ C (dec.).
1 H NMR (DMSO-d6): 8 11.38 (s, NH), 9.38 (s, OH), 8.76 (broad s, ~NH), 7.34-6.85 (m, 8 s atom. H), 6.72 (d, J = 8 Hz, 1 atom. H), 6.64 (d, J = 8 Hz, I atom. H), 5.93 (s, H-C(5)), 4.80 and 4.67 (2 d, J = 13, 13 Hz, OCH2Ph).
Analysis calculated for C33H31N2O3 x HCI. (575.S4): C 68.87, H 5.60, N 4.87;
found: C
68.81, H 5.59, H 4.77.
io Example 17 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-3,14-dimethoxy-4,5a-epoxy-6,7-2',3'-benzo[b]furanomorphinan (compound 17).
i s Sodium hydride ( l44 mg, 6 mmol; obtained from 240 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of naltriben methane-sulfonate (500 mg, 0.97 mmol) in 10 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 0~ C for 15 min and then at room temperature for another 30 min.
After cooling to 0~ C, dimethyl sulfate (380 pl, 4 mmol) was added and stirring was 2o continued first at 0~ C for 30 min and then at room temperature for 3 h.
Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 40 ml), the combined organic layers were washed with H20 (2 x 30 ml) and brine (2 x 30 ml), dried over Na2SOq and evaporated to give a crystalline residue which was recrystallized from MeOH to afford 320 mg (74%) of compound 17. M.
p. 221-zs 224~ C (dec.).
~H NMR (CDCI3): S 7.47-7.14 (m, 4 atom. H), 6.64 (d, J = 8.4 Hz, 1 atom. H), 6.S9 (d, J
= 8.4 Hz, 1 atom. H), 5.62 (s, H-C(5)), 3.78 (s, CH30-C(3)), 3.31 (s, CH30-C( 14)).
SUBSTITUTE SHEET (RULE 26) Analysis calculated for C2gH29N04. 0.3 MeOH (453.16): C 75.01, H 6.72, N 3.09;
found:
C 74.97, H 6.68) N 3.05.
Example 18 s Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(3'-chlorobenzyloxy)-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound 19).
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) in anhydrous N,N-dimethyl formamide ( 10 ml) was added sodium hydride (60% dispersion in oil, 60 mg, 1.5 ~ o mmol) at 0~ C. The solution was stirred for 1 h at 20~ C and then cooled to 0~ C prior to addition of bromomethyl methyl ether ( 125 mg, 1.0 mmol). The mixture was warmed up to room temperature during 1 h and cooled again to 0~ C before sodium hydride (60%
dispersion in oil, l00 mg, 2.5 mmol) was added. After 1 h, 3-chlorobenzyl bromide (308 mg, 1.5 mmol) was added to the solution and the resulting mixture was stirred for 4 h at 20~
~ s C, and then 5 m1 of methanol and 5 ml ethyl acetate were slowly added at 0~ C, followed by addition of saturated aqueous NH4C1 solution (20 ml). The mixture was extracted with ethyl acetate (3 x 50 ml), the combined organic layers were washed with brine, dried over MgS04; and evaporated to give crude 17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-14-(3'-chlorobenzyloxy)-6,7-2', 3'-benzo[b]furanomorphinan 20 (compound 18). This crude product was dissolved in 5 m1 of ethanol and 1.5 ml of 1 N
hydrochloric acid and refluxed for 1 h. The reaction mixture was alkalized with 1N aqueous NH40H solution) extracted with ethyl acetate (3 x 50 ml), the combined organic layers were washed with brine, dried over MgS04, and concentrated to give a crude product which was purified by silica gel column chromatography (hexane: CHCl3 zs (75:25-Q50:50-~25:75~ l00:0) -~CHCI3:AcOEt {80:20-Q50:50--Q0:100) to afford the title compound as the free base (colorless oil; 232 mg, 86%). 1 H NMR (CDCl3): 8 7.50-7.05 (m, 8 arom. H), 6.69 (d, J = 8.4 Hz, 1 arom. H), 6.58 (d, J = 8.4 Hz, 1 arom.
H), 5.68 (s, H-C(5)), 4.81 and 4.35 (2 d, J = 11.6, 11.6 Hz, OCH2(3'-CIPh)). A solution of this free base in anhydrous diethyl ether (5 ml) was treated with HCl/ether solution (1M, 2 ml) at 0~
so C. Isolation of the precipitate provided the title compound 19 as a solid.
M. p. >230~ C
SUBSTITUTE SHEET (RULE 26) WO 98I22467 PCTlSE96/01497 , (dec.). IH NMR (DMSO-d6): 8 9.40 (s, OH), 8.59 (broad s, +NH), 7.53-6.90 (m, 8 atom.
H), 6.65 (s, 2 atom. H) 6.03 (s, H-C(5)), 4.74 and 4.62 (2 d, J = 13.6, l3.6 Hz, OCH2(3'-C1PH)). Analysis calculated for C33H3pCIN04. HCI. 1.5 H20: C 65.67, H 5.68, N
2.32;
found: C 65.31, H 5.37, N 2.33.
Example 19 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(2'-chlorobenzyloxy)-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound 21).
i o To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) in anhydrous N,N-dimethyl formamide ( 10 mI) was added sodium hydride (60% dispersion in oil, I00 mg, 2.5 mmol) at 0~ C. The solution was stirred for 1 h at 20~ C and then cooled to 0~
C prior to addition of bromomethyl methyl ether ( 125 mg, 1.0 mmol). The mixture was warmed up to room temperature during 1 h and cooled again to 0~ C before sodium hydride (60%
i s dispersion in oil, 100 mg, 2.5 mmol) was added. After 1 h, 2-chlorobenzyl bromide (205 mg, 1.0 mmol) was added to the solution and the resulting mixture was stirred for 12 h at 20~ C, and then 5 m1 of methanol and 5 ml ethyl acetate were slowly added at 0~ C, followed by addition of saturated aqueous NH4Cl solution (20 ml). The mixture was extracted with ethyl acetate (3 x 50 ml)) the combined organic layers were washed with 2o brine, dried over MgS04, and concentrated to give crude 17-(cyclopropylmethyl)-'6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-14-(2'-chlorobenzyloxy)-6,7-2', 3'-benzo[b]furanomorphinan (compound 20). This crude product was dissolved in 5 m1 of ethanol and 2 m1 of 1 N hydrochloric acid and refluxed for 2 h. The reaction mixture was alkalized with 1N aqueous NH40H solution, extracted with ethyl acetate (3 x 50 ml), the is combined organic layers were washed with brine, dried over MgS04, and evaporated to give a crude product which was purified by silica gel column chromatography (hexane:
CHC13 (75:25-~50:50~25:75--~ 100:0) to afford the title compound as the free base (colorless oil; 236 mg, 87%). 1H NMR (CDC13): 8 7.45-6.90 (m, 8 atom. H), 6.72 (d, J =
8.4 Hz, 1 atom. H), 6.68 (d, J = 8.4 Hz, 1 atom. H), 5.72 (s, H-C(5)), 4.96 and 4.55 (2 d, J
so = 11.6, 11.6 Hz, OCH2(2'-CIPh)). A solution of this free base in (5 ml) of anhydrous SUBSTITUTE SHEET (RULE 26) WO 98/22467 PCT/SE96/01497 _ diethyl ether was treated with HC1/ether solution (1M, 2 ml) at 0~ C.
Isolation of the precipitate provided the title compound as a solid. M. p. >220~ C.
IH NMR (DMSO-d6): 8 9.40 (s, OH), 8.59 (broad s, +NH), 7.56-6.90 (m, 8 arom.
H), 6.66 s (s, 2 arom. H) 6.03 (s, H-C(5)), 4.74 (s, OCH2(2'-CIPh)).
Analysis calculated for C33H3pC1NOq x HCI. 1.5 H20: C 65.67, H 5.68, N 2.32;
found: C
65.72, H 5.48, N 2.25.
i o Example 20 Synthesis of 14-Allyloxy-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-I'-allyl-6,7-2',3'-indolomorphinan Hydrochloride (compound 22).
Dimethyl isobutylsilyl chloride ( 114 mg, 0.75 mmol) was added at 0~ C to a stirred solution ~ s of naltrindole methanesulfonate (255 mg, 0.5 mmol) and diisopropyl ethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide ( 10 ml). The resulting solution was stirred at 20~ C for 1 h and then cooled to 0~ C prior to the addition of sodium hydride (60%
dispersion in oil, l20 mg, 3.0 mmol). After I h, dimethyl isobutylsilyl chloride ( 1 I 4 mg, 0.75 mmol) was added to the mixture. The resulting mixture was stirred for I h at 20~ C
2o and then cooled to 0~ C before adding sodium hydride (60% dispersion in oil, 120 mg, 3.00 mmol). After 1 h allyl bromide ( 1.51 mg, 1.25 mmol) was added. The reaction mixture was stirred for 2 h at 20~ C and then quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with brine, dried over MgS04, and evaporated to give a yellow oil which was dissolved in 2s methanol (6 ml) and 1 N hydrochloric acid (2 ml) and refluxed for 6 h. The reaction mixture was alkalized with 1N NH4OH solution, extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with brine, dried over MgS04, and evaporated. This crude product was purified by silica gel column chromatography (hexane: CHC13 (75:25-Q50:50) ~CHCI3:AcOEt-~ (75:25-Q50:50--~AcOEt) to give the title compound as so the free base (colorless oil; l06 mg).
SUBSTITUTE SHEET (RULE 2fi) WO 98/22467 PCT/SE96/01497 , 1H NMR (CDC13): S 7.40 (d, J = 8.4 Hz, 1 arom. H), 7.24 (m, 1 arom. H), 7.15 (m, 1 arom. H), 7.03 (m, 1 arom. H), 6.S7 (d, J = 8.4 Hz, 1 arom. H), 6.50 (d,J =
8.4 Hz, 1 arom.
H), 6.08 (m, 1 olef. H), 5.76 (m, 1 olef. H), 5.72 (s, H-C(S)), 5.15-4.75 (m, 6 H, CH2N, 2 s CH2 = C), 4.24 and 3.92 (2 dd, J = 12.4, 4.8 Hz, CH20).
The free base was dissolved in diethyl ether (S ml) and treated with HCl/ether solution ( 1M, 2 ml) at 0~ C. Isolation of the precipitate provided the title compound 22 as a solid.
~ o Example 21 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,Soc-epoxy-3-hydroxy-I4-allyloxy-6,7,2',3'-indolomorphinan Hydrochloride (compound 23) To a stirred solution of naltrindole hydrochloride (220 mg, 0.5 mmol) in anhydrous N,N-i s dimethyl formamide ( 10 ml) was added sodium hydride (60% dispersion in oil, l60 mg, 4.0 mmol) at 0~C. The solution was stirred for 1 h at 20~ C, and then cooled to 0~
C prior to addition of bromomethyl methyl ether (2S0 mg, 2.0 mrnol). The mixture was warmed up to r.t. during one hour and cooled again to 0~ C before sodium hydride (60%, 100 mg, 2.5 mmol) was added. After 1 h allyl bromide (242 mg, 2.0 mmol) was added to the solution zo and the resulting mixture was stirred for 4 h at 20~ C, and then 5 ml methanol and S ml ethyl acetate were slowly added at 0~ C, followed by addition of saturated aqueous NH4C1 solution (20 mI). The mixture was extracted with ethyl acetate (3x50 ml), the combined organic layers were washed with brine, dried over MgS04, and evaporated to give crude product, which was dissolved in 5 ml ethanol/1 ml 6N hydrochloric acid and refluxed for 2 is hrs. The reaction mixture was alkalized with 1 N aqueous NH40H solution, extracted with ethyl acetate (3.50 ml), the combined organic layers were washed with brine) dried over MgS04, and concentrated to give a crude product, which was purified by silica gel column chromatography (Hexane: CHC13 {75:2S-Q50:50-Q25:75--Q0:100) ~CHCl3: AcOEt (75:2S--Q50:50-Q0:100)) to afford compound 23 (S3 mg, 23%) as the free base (colorless SUBSTITUTE SHEET (RULE 26) oil). 1 H NMR (CDC13): 8 7.50-7.00 (m, 4 arom. H), 6.65-6.45 (m, 2 arom. H), 5.80 (m, 1 H, CH=C), 5.75 (s, H-C(5)), 5.18-4.85 (m, C=CH2), 4.25 & 3.95 (m, OCH2).
A solution of this free base (53 mg) in anhydrous ethyl ether (5 ml) was treated with s HCl/ether solution ( 1M, 1 ml) at 0~ C. Isolation of the precipitate provided the title compound 23 as a solid (hydrochloride salt). M.p. 270-28S~ C (dec.). IR (HCl salt, KBr) 3087 (m), 2846 (m), 1623 (s), 1505 (s), l462 (s), l330 (s), 1166 (s), 922 (s) cm 1.
Example 22 io Synthesis of 17-Cyclopropylmethyl-6,7-dehydro-4,5oc-epoxy-3-hydroxy-14-benzyloxy-6,7,2',3'-benzo[b]foranomorphinan Hydrochloride (compound 24):
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) and N,N-diisopropylethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide ( 10 ml) is was added triisopropylsilyl chloride (l45 mg, 0.75 mmol) at 0~C. The solution was stirred for 1 h at 20~ C, and then cooled to 0~ C prior to addition of sodium hydride (60%, 120 mg, 3.0 mmol) was added. After 1 h, benzyl bromide ( 171 mg, 1.0 mmol) was dropwise added to the solution. The resulting mixture was stirred for 2 h at 20~ C, and then 5 m1 methanol and 5 ml ethyl acetate were slowly added at 0~ C. After 30 min the mixture was 2o extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgS04, and concentrated to a yellow oil, which was purified by silica gel column chromatography {Hexane: CHCl3 (75:25--Q60:40)--Hexane: AcOEt (75:25-Q50:50)) to afford compound 24 (206 mg, 82%) as the free base (colorless oil). 1 H
NMR (CDC13): S 7.60-7.05 (m, 9 arom. H), 6.80-6.60 (m, 2 arom. H), 5.72 (s, H-C(5)), is 4.95 and 4.52 (2 d, J=11.6) 11.6 Hz, OCH2Ph).
A solution of this free base in anhydrous ethyl ether (5 ml) was treated with HCl/ether solution (1M, 1 ml) at 0~ C. Isolation of the precipitate provided the title compound 24 as a solid (hydrochloride salt). M.p. 255-270~ C (dec.). IR (HCl salt, KBr) 3642 (m), 3l74 (s), so 293b {s), 1616 (s), 1500 (s)) 1457 (s), 1309 (s), 1068 (s), 932 (s) cm 1.
Analysis calculated SUBSTITUTE SHEET (RULE 26) WO 98I22467 PCTlSE96/0149? _ _ 25 for C33H31 N04. HC1. 0.80 H20: C 71.23, H 6.09, N, 2.52. Found: C 71.32; H
5.78, N
2.35.
Example 23 s Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-allyloxy-6,7,2',3'-benzo(b]foranomorphinan Hydrochloride (compound 25) To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) and N,N-diisopropylethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide ( 10 ml) ~ o was added triisopropylsilyl chloride ( l45 mg, 0.75 mmol) at 0~C. The solution was stirred for 1 h at 20~ C) and then cooled to 0~ C prior to addition of sodium hydride (60%, 120 mg, 3.0 mmol) was added. After 1 h, allyl bromide (363 mg, 3.0 mmol) was dropwise added to the solution. The resulting mixture was stirred for 2 h at 20~ C, and then 5 m1 methanol and 5 ml ethyl acetate were slowly added at 0~ C. After 30 min the mixture was extracted i s with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgS04, and concentrated to a yellow oil, which was dissolved in MgSOq, and concentrated to a yellow oil, which was dissolved in 10 m1 ethanol/2.0 ml 1 N
hydrochloric acid and refluxed for 5 hrs. The reaction mixture was alkalized with 1 N
aqueous NH40H
solution, extracted with ethyl acetate (3x50 ml). The combined organic layers were washed zo with brine) dried over MgSOq., and concentrated to give a crude product, which was purified by silica gel column chromatography (Hexane: CHC13 (75:2y50:50)-~CHCl3:
AcOEt (75:25--Q50:50-~AcOEt)) to afford compound 25 ( 106 mg, 46%) as the free base (colorless oil). 1H NMR (CDCl3): 8 7.50-7.08 (m, 4 arom. H), 6.70-6.45 (m, 2 arom. H), 5.75 (m, 1 H, CH=C) 5.65 (s, H-C(5)), 5.18-4.82 (m, 2H), 4.81 (br s, OH), 4.25 and 3.90 2s (m, OCH2).
A solution of this free base in anhydrous ethyl ether (5 ml) was treated with HCl/ether solution ( 1M, 1 ml) at 0~ C. Isolation of the precipitate provided the title compound 25 as a solid (hydrochloride salt). M.p. 280-290~ C (dec.), IR (HCl salt, KBr) 3642 (m), 2948 (s), SUBSTITUTE SHEET (RULE 26) WO 98l22467 PCT/SE96/01497 - -1641 (s), l500 (s), 1375 (s), 1315 (s), 996 (s) 920 (s) cm 1. Analysis calculated for C29H29N04~ HCI. 1.1 H20: C 68.05, H 6.34, N, 2.74. Found: C 67.94, H 5.95, N
2.S3.
Example 24 s Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-crotyloxy-6,7,2',3'-benzo[b]foranomorphinan Hydrochloride (compound 26) To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) and N,N-diisopropylethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide ( 10 ml) io was added triisopropylsilyl chloride (145 mg, 0.75 mmol) at 0~C. The solution was stirred for 1 h at 20~ C, and then cooled to 0~ C prior to addition of sodium hydride {60%, l20 mg, 3.0 mmol} was added. After 1 h, crotyl bromide (405 mg, 3.0 mmol) was dropwise added to the solution. The resulting mixture was stirred for 2 h at 20~ C, and then 5 ml methanol and 5 m1 ethyl acetate were slowly added at 0~ C. After 30 min the mixture was i 5 extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgS04, and concentrated to a yellow oil, which was dissolved in 10 m1 ethanol/2 ml 1 N hydrochloric acid and refluxed for 5 hrs. The reaction mixture was alkalized with 1 N aqueous NH40H solution, extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgS04, and concentrated to 2o give a crude product, which was purified by silica gel column chromatography (Hexane:
CHCl3 (75:25~50:50)~CHC13: AcOEt (75:2y50:50-~AcOEt)) to afford compound 26 (45 mg, 19%) as the free base (colorless oil). 1 H NMR (CDCl3): 8 7.48-7.08 (m, 4 arom.
H), 6.66-6.48 (m, 2 arom. H), 5.62 (s, H-C{5)), 5.40 (m, 2H, CH=CH), 4.20 and 3.82 (m, OCH2), 1.48 & 1.52 (m, 3H, Me).
A solution of the free base in anhydrous ethyl ether (5 ml) was treated with HCl/ether solution (1M, 1 ml) at 0~ C. Isolation of the precipitate provided the title compound 26 as a ~
solid in form of its hydrochloride salt. Mp. 245-260 C (dec.). IR (Hcl salt, Kbr): 3642 {m), 3024 (s), l640 (s), l503 (s), 1325 (s), 927 (s) cm 1.
3a SUBSTITUTE SHEET (RULE 26)
H), 6.64 (d, J = 8.2 Hz, 1 atom. H), 5.64 (s, H-C(5)), 5.05 and 5.00 (2 d, J =
6.4, 6.4 Hz, OCH20), 3.32 (CH30).
s Analysis calculated for C29H31 N05. 0.2 MeOH (479.98): C 73.07, H 6.68, N
2.92; found:
C 72.94, H 6.60, N 2.92.
Example 14 ~o Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-methoxy-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound 14).
A solution of compound 13 ( 160 mg, 0.28 mmol) in MeOH (3 ml) and 1 N HCI (2 ml) was refluxed for 20 min, then cooled and kept in the refrigerator overnight. The crystals formed i s were isolated and washed with small amounts of MeOH and ether to yield 70 mg (36%) of compound 14. M. p. > 240~ C.
I H NMR (DMSO-db): 8 9.47 (s, OH), 9.17 (broad s, ~NH), 7.61 (d, J = 8 Hz, 1 atom. H), 7.53 (d, J = 8 Hz, 1 atom. H), 7.36 (dd, J = 8, 8 Hz, 1 atom. H), 7.27 (dd, J
= 8, 8 Hz, I
2o atom. H), 6.72 (d, J = 8.4 Hz, 1 atom. H), 6.65 (d, J = 8.4 Hz, 1 atom. H), 5.90 (s, H-C(5)), 3.35 (s, CH30).
Analysis calculated for C2~H2~N04 x HCI. 1.5 HZO (493.00): C 65.78, H 6.34, N
2.84;
found: C 65.89, H 6.20, N 2.85.
SUBSTITUTE SHEET (RULE 26) Example 15 Synthesis of 17-(Cyclopropylmethyl)-14-(2'-chlorobenzyloxy}-6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-6,7-2',3'-(N-methoxymethylindolo)morphinan (compound 15).
s Sodium hydride (36 mg, 1.5 mxnol; obtained from 60 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of compound 2 (327 mg, 0.65 mmol) in 5 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 0~ C for 1 S min and then at room temperature for another 30 min.
After cooling to 0~ C, 2-chlorobenzyl bromide (205 mg, 1 mmol) was added and stirring was continued first i o at 0~ C for 15 min and then at room temperature for 3 h. Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with H20 (2 x 40 ml) and brine (2 x 30 ml), dried over Na2S04 and evaporated to give 370 mg of compound 15 as colorless foam which was pure by TLC and NMR.
is 1H NMR (CDC13): 8 7.56 (m, 1 arom. H), 7.44 (m, 1 arom. H), 7.37-7.17 (m, 3 arom. H), 7.01 (m, 1 arom. H), 6.9l (m, 1 arom. H), 6.83 (d, J = 8.2 Hz, 1 arom. H), 6.59 (d, J = 8.2 Hz, 1 arom. H), 5.90 (s, H-C(5)), 5.82 and 5.55 (2 d, J = 11.2, 11.2 Hz, NCH20), 5.l3 and 5.03 (2 d, J = 6.4, 6.4 Hz, OCH20), 4.98 and 4.56 (2 d, J = 13, 13 Hz, OCH2Ph), 3.40 and zo 3.26 (2 s, 2 CH30).
Example 16 Synthesis of 17-(Cyclopropylmethyl)-14-(2'-chlorobenzyloxy)-6,7-dehydro-4,5a-epoxy-3-hydroxy-6,7-2',3'-indolomorphinan Hydrochloride (compound 16).
zs A solution of compound 15 (300 mg, 0.48 mmol) in MeOH (5 ml) and IN HCl (3 ml) was refluxed for 1 h. After cooling, the solution was alkalized with conc. NH40H, extracted with ethyl acetate (3 x 20 ml), the combined organic layers were washed with H20 (2 x 20 ml) and brine (20 ml), dried over Na2S04 and evaporated to give a colorless oil. To a so solution of this foam in a small amount of methanol ethereal HCl was added, the crystals SUBSTITUTE SHEET (RULE 26) formed collected and washed with cold methanol to yield l20 mg (43%) of compound 16.
M. p. > 250~ C (dec.).
1 H NMR (DMSO-d6): 8 11.38 (s, NH), 9.38 (s, OH), 8.76 (broad s, ~NH), 7.34-6.85 (m, 8 s atom. H), 6.72 (d, J = 8 Hz, 1 atom. H), 6.64 (d, J = 8 Hz, I atom. H), 5.93 (s, H-C(5)), 4.80 and 4.67 (2 d, J = 13, 13 Hz, OCH2Ph).
Analysis calculated for C33H31N2O3 x HCI. (575.S4): C 68.87, H 5.60, N 4.87;
found: C
68.81, H 5.59, H 4.77.
io Example 17 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-3,14-dimethoxy-4,5a-epoxy-6,7-2',3'-benzo[b]furanomorphinan (compound 17).
i s Sodium hydride ( l44 mg, 6 mmol; obtained from 240 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of naltriben methane-sulfonate (500 mg, 0.97 mmol) in 10 m1 of anhydrous N,N-dimethylformamide at 0~ C. The resulting mixture was stirred at 0~ C for 15 min and then at room temperature for another 30 min.
After cooling to 0~ C, dimethyl sulfate (380 pl, 4 mmol) was added and stirring was 2o continued first at 0~ C for 30 min and then at room temperature for 3 h.
Excess sodium hydride was destroyed by addition of MeOH and H20. The resulting mixture was extracted with ethyl acetate (3 x 40 ml), the combined organic layers were washed with H20 (2 x 30 ml) and brine (2 x 30 ml), dried over Na2SOq and evaporated to give a crystalline residue which was recrystallized from MeOH to afford 320 mg (74%) of compound 17. M.
p. 221-zs 224~ C (dec.).
~H NMR (CDCI3): S 7.47-7.14 (m, 4 atom. H), 6.64 (d, J = 8.4 Hz, 1 atom. H), 6.S9 (d, J
= 8.4 Hz, 1 atom. H), 5.62 (s, H-C(5)), 3.78 (s, CH30-C(3)), 3.31 (s, CH30-C( 14)).
SUBSTITUTE SHEET (RULE 26) Analysis calculated for C2gH29N04. 0.3 MeOH (453.16): C 75.01, H 6.72, N 3.09;
found:
C 74.97, H 6.68) N 3.05.
Example 18 s Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(3'-chlorobenzyloxy)-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound 19).
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) in anhydrous N,N-dimethyl formamide ( 10 ml) was added sodium hydride (60% dispersion in oil, 60 mg, 1.5 ~ o mmol) at 0~ C. The solution was stirred for 1 h at 20~ C and then cooled to 0~ C prior to addition of bromomethyl methyl ether ( 125 mg, 1.0 mmol). The mixture was warmed up to room temperature during 1 h and cooled again to 0~ C before sodium hydride (60%
dispersion in oil, l00 mg, 2.5 mmol) was added. After 1 h, 3-chlorobenzyl bromide (308 mg, 1.5 mmol) was added to the solution and the resulting mixture was stirred for 4 h at 20~
~ s C, and then 5 m1 of methanol and 5 ml ethyl acetate were slowly added at 0~ C, followed by addition of saturated aqueous NH4C1 solution (20 ml). The mixture was extracted with ethyl acetate (3 x 50 ml), the combined organic layers were washed with brine, dried over MgS04; and evaporated to give crude 17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-14-(3'-chlorobenzyloxy)-6,7-2', 3'-benzo[b]furanomorphinan 20 (compound 18). This crude product was dissolved in 5 m1 of ethanol and 1.5 ml of 1 N
hydrochloric acid and refluxed for 1 h. The reaction mixture was alkalized with 1N aqueous NH40H solution) extracted with ethyl acetate (3 x 50 ml), the combined organic layers were washed with brine, dried over MgS04, and concentrated to give a crude product which was purified by silica gel column chromatography (hexane: CHCl3 zs (75:25-Q50:50-~25:75~ l00:0) -~CHCI3:AcOEt {80:20-Q50:50--Q0:100) to afford the title compound as the free base (colorless oil; 232 mg, 86%). 1 H NMR (CDCl3): 8 7.50-7.05 (m, 8 arom. H), 6.69 (d, J = 8.4 Hz, 1 arom. H), 6.58 (d, J = 8.4 Hz, 1 arom.
H), 5.68 (s, H-C(5)), 4.81 and 4.35 (2 d, J = 11.6, 11.6 Hz, OCH2(3'-CIPh)). A solution of this free base in anhydrous diethyl ether (5 ml) was treated with HCl/ether solution (1M, 2 ml) at 0~
so C. Isolation of the precipitate provided the title compound 19 as a solid.
M. p. >230~ C
SUBSTITUTE SHEET (RULE 26) WO 98I22467 PCTlSE96/01497 , (dec.). IH NMR (DMSO-d6): 8 9.40 (s, OH), 8.59 (broad s, +NH), 7.53-6.90 (m, 8 atom.
H), 6.65 (s, 2 atom. H) 6.03 (s, H-C(5)), 4.74 and 4.62 (2 d, J = 13.6, l3.6 Hz, OCH2(3'-C1PH)). Analysis calculated for C33H3pCIN04. HCI. 1.5 H20: C 65.67, H 5.68, N
2.32;
found: C 65.31, H 5.37, N 2.33.
Example 19 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-(2'-chlorobenzyloxy)-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound 21).
i o To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) in anhydrous N,N-dimethyl formamide ( 10 mI) was added sodium hydride (60% dispersion in oil, I00 mg, 2.5 mmol) at 0~ C. The solution was stirred for 1 h at 20~ C and then cooled to 0~
C prior to addition of bromomethyl methyl ether ( 125 mg, 1.0 mmol). The mixture was warmed up to room temperature during 1 h and cooled again to 0~ C before sodium hydride (60%
i s dispersion in oil, 100 mg, 2.5 mmol) was added. After 1 h, 2-chlorobenzyl bromide (205 mg, 1.0 mmol) was added to the solution and the resulting mixture was stirred for 12 h at 20~ C, and then 5 m1 of methanol and 5 ml ethyl acetate were slowly added at 0~ C, followed by addition of saturated aqueous NH4Cl solution (20 ml). The mixture was extracted with ethyl acetate (3 x 50 ml)) the combined organic layers were washed with 2o brine, dried over MgS04, and concentrated to give crude 17-(cyclopropylmethyl)-'6,7-dehydro-4,5a-epoxy-3-(methoxymethoxy)-14-(2'-chlorobenzyloxy)-6,7-2', 3'-benzo[b]furanomorphinan (compound 20). This crude product was dissolved in 5 m1 of ethanol and 2 m1 of 1 N hydrochloric acid and refluxed for 2 h. The reaction mixture was alkalized with 1N aqueous NH40H solution, extracted with ethyl acetate (3 x 50 ml), the is combined organic layers were washed with brine, dried over MgS04, and evaporated to give a crude product which was purified by silica gel column chromatography (hexane:
CHC13 (75:25-~50:50~25:75--~ 100:0) to afford the title compound as the free base (colorless oil; 236 mg, 87%). 1H NMR (CDC13): 8 7.45-6.90 (m, 8 atom. H), 6.72 (d, J =
8.4 Hz, 1 atom. H), 6.68 (d, J = 8.4 Hz, 1 atom. H), 5.72 (s, H-C(5)), 4.96 and 4.55 (2 d, J
so = 11.6, 11.6 Hz, OCH2(2'-CIPh)). A solution of this free base in (5 ml) of anhydrous SUBSTITUTE SHEET (RULE 26) WO 98/22467 PCT/SE96/01497 _ diethyl ether was treated with HC1/ether solution (1M, 2 ml) at 0~ C.
Isolation of the precipitate provided the title compound as a solid. M. p. >220~ C.
IH NMR (DMSO-d6): 8 9.40 (s, OH), 8.59 (broad s, +NH), 7.56-6.90 (m, 8 arom.
H), 6.66 s (s, 2 arom. H) 6.03 (s, H-C(5)), 4.74 (s, OCH2(2'-CIPh)).
Analysis calculated for C33H3pC1NOq x HCI. 1.5 H20: C 65.67, H 5.68, N 2.32;
found: C
65.72, H 5.48, N 2.25.
i o Example 20 Synthesis of 14-Allyloxy-17-(cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-I'-allyl-6,7-2',3'-indolomorphinan Hydrochloride (compound 22).
Dimethyl isobutylsilyl chloride ( 114 mg, 0.75 mmol) was added at 0~ C to a stirred solution ~ s of naltrindole methanesulfonate (255 mg, 0.5 mmol) and diisopropyl ethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide ( 10 ml). The resulting solution was stirred at 20~ C for 1 h and then cooled to 0~ C prior to the addition of sodium hydride (60%
dispersion in oil, l20 mg, 3.0 mmol). After I h, dimethyl isobutylsilyl chloride ( 1 I 4 mg, 0.75 mmol) was added to the mixture. The resulting mixture was stirred for I h at 20~ C
2o and then cooled to 0~ C before adding sodium hydride (60% dispersion in oil, 120 mg, 3.00 mmol). After 1 h allyl bromide ( 1.51 mg, 1.25 mmol) was added. The reaction mixture was stirred for 2 h at 20~ C and then quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with brine, dried over MgS04, and evaporated to give a yellow oil which was dissolved in 2s methanol (6 ml) and 1 N hydrochloric acid (2 ml) and refluxed for 6 h. The reaction mixture was alkalized with 1N NH4OH solution, extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with brine, dried over MgS04, and evaporated. This crude product was purified by silica gel column chromatography (hexane: CHC13 (75:25-Q50:50) ~CHCI3:AcOEt-~ (75:25-Q50:50--~AcOEt) to give the title compound as so the free base (colorless oil; l06 mg).
SUBSTITUTE SHEET (RULE 2fi) WO 98/22467 PCT/SE96/01497 , 1H NMR (CDC13): S 7.40 (d, J = 8.4 Hz, 1 arom. H), 7.24 (m, 1 arom. H), 7.15 (m, 1 arom. H), 7.03 (m, 1 arom. H), 6.S7 (d, J = 8.4 Hz, 1 arom. H), 6.50 (d,J =
8.4 Hz, 1 arom.
H), 6.08 (m, 1 olef. H), 5.76 (m, 1 olef. H), 5.72 (s, H-C(S)), 5.15-4.75 (m, 6 H, CH2N, 2 s CH2 = C), 4.24 and 3.92 (2 dd, J = 12.4, 4.8 Hz, CH20).
The free base was dissolved in diethyl ether (S ml) and treated with HCl/ether solution ( 1M, 2 ml) at 0~ C. Isolation of the precipitate provided the title compound 22 as a solid.
~ o Example 21 Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,Soc-epoxy-3-hydroxy-I4-allyloxy-6,7,2',3'-indolomorphinan Hydrochloride (compound 23) To a stirred solution of naltrindole hydrochloride (220 mg, 0.5 mmol) in anhydrous N,N-i s dimethyl formamide ( 10 ml) was added sodium hydride (60% dispersion in oil, l60 mg, 4.0 mmol) at 0~C. The solution was stirred for 1 h at 20~ C, and then cooled to 0~
C prior to addition of bromomethyl methyl ether (2S0 mg, 2.0 mrnol). The mixture was warmed up to r.t. during one hour and cooled again to 0~ C before sodium hydride (60%, 100 mg, 2.5 mmol) was added. After 1 h allyl bromide (242 mg, 2.0 mmol) was added to the solution zo and the resulting mixture was stirred for 4 h at 20~ C, and then 5 ml methanol and S ml ethyl acetate were slowly added at 0~ C, followed by addition of saturated aqueous NH4C1 solution (20 mI). The mixture was extracted with ethyl acetate (3x50 ml), the combined organic layers were washed with brine, dried over MgS04, and evaporated to give crude product, which was dissolved in 5 ml ethanol/1 ml 6N hydrochloric acid and refluxed for 2 is hrs. The reaction mixture was alkalized with 1 N aqueous NH40H solution, extracted with ethyl acetate (3.50 ml), the combined organic layers were washed with brine) dried over MgS04, and concentrated to give a crude product, which was purified by silica gel column chromatography (Hexane: CHC13 {75:2S-Q50:50-Q25:75--Q0:100) ~CHCl3: AcOEt (75:2S--Q50:50-Q0:100)) to afford compound 23 (S3 mg, 23%) as the free base (colorless SUBSTITUTE SHEET (RULE 26) oil). 1 H NMR (CDC13): 8 7.50-7.00 (m, 4 arom. H), 6.65-6.45 (m, 2 arom. H), 5.80 (m, 1 H, CH=C), 5.75 (s, H-C(5)), 5.18-4.85 (m, C=CH2), 4.25 & 3.95 (m, OCH2).
A solution of this free base (53 mg) in anhydrous ethyl ether (5 ml) was treated with s HCl/ether solution ( 1M, 1 ml) at 0~ C. Isolation of the precipitate provided the title compound 23 as a solid (hydrochloride salt). M.p. 270-28S~ C (dec.). IR (HCl salt, KBr) 3087 (m), 2846 (m), 1623 (s), 1505 (s), l462 (s), l330 (s), 1166 (s), 922 (s) cm 1.
Example 22 io Synthesis of 17-Cyclopropylmethyl-6,7-dehydro-4,5oc-epoxy-3-hydroxy-14-benzyloxy-6,7,2',3'-benzo[b]foranomorphinan Hydrochloride (compound 24):
To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) and N,N-diisopropylethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide ( 10 ml) is was added triisopropylsilyl chloride (l45 mg, 0.75 mmol) at 0~C. The solution was stirred for 1 h at 20~ C, and then cooled to 0~ C prior to addition of sodium hydride (60%, 120 mg, 3.0 mmol) was added. After 1 h, benzyl bromide ( 171 mg, 1.0 mmol) was dropwise added to the solution. The resulting mixture was stirred for 2 h at 20~ C, and then 5 m1 methanol and 5 ml ethyl acetate were slowly added at 0~ C. After 30 min the mixture was 2o extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgS04, and concentrated to a yellow oil, which was purified by silica gel column chromatography {Hexane: CHCl3 (75:25--Q60:40)--Hexane: AcOEt (75:25-Q50:50)) to afford compound 24 (206 mg, 82%) as the free base (colorless oil). 1 H
NMR (CDC13): S 7.60-7.05 (m, 9 arom. H), 6.80-6.60 (m, 2 arom. H), 5.72 (s, H-C(5)), is 4.95 and 4.52 (2 d, J=11.6) 11.6 Hz, OCH2Ph).
A solution of this free base in anhydrous ethyl ether (5 ml) was treated with HCl/ether solution (1M, 1 ml) at 0~ C. Isolation of the precipitate provided the title compound 24 as a solid (hydrochloride salt). M.p. 255-270~ C (dec.). IR (HCl salt, KBr) 3642 (m), 3l74 (s), so 293b {s), 1616 (s), 1500 (s)) 1457 (s), 1309 (s), 1068 (s), 932 (s) cm 1.
Analysis calculated SUBSTITUTE SHEET (RULE 26) WO 98I22467 PCTlSE96/0149? _ _ 25 for C33H31 N04. HC1. 0.80 H20: C 71.23, H 6.09, N, 2.52. Found: C 71.32; H
5.78, N
2.35.
Example 23 s Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-allyloxy-6,7,2',3'-benzo(b]foranomorphinan Hydrochloride (compound 25) To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) and N,N-diisopropylethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide ( 10 ml) ~ o was added triisopropylsilyl chloride ( l45 mg, 0.75 mmol) at 0~C. The solution was stirred for 1 h at 20~ C) and then cooled to 0~ C prior to addition of sodium hydride (60%, 120 mg, 3.0 mmol) was added. After 1 h, allyl bromide (363 mg, 3.0 mmol) was dropwise added to the solution. The resulting mixture was stirred for 2 h at 20~ C, and then 5 m1 methanol and 5 ml ethyl acetate were slowly added at 0~ C. After 30 min the mixture was extracted i s with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgS04, and concentrated to a yellow oil, which was dissolved in MgSOq, and concentrated to a yellow oil, which was dissolved in 10 m1 ethanol/2.0 ml 1 N
hydrochloric acid and refluxed for 5 hrs. The reaction mixture was alkalized with 1 N
aqueous NH40H
solution, extracted with ethyl acetate (3x50 ml). The combined organic layers were washed zo with brine) dried over MgSOq., and concentrated to give a crude product, which was purified by silica gel column chromatography (Hexane: CHC13 (75:2y50:50)-~CHCl3:
AcOEt (75:25--Q50:50-~AcOEt)) to afford compound 25 ( 106 mg, 46%) as the free base (colorless oil). 1H NMR (CDCl3): 8 7.50-7.08 (m, 4 arom. H), 6.70-6.45 (m, 2 arom. H), 5.75 (m, 1 H, CH=C) 5.65 (s, H-C(5)), 5.18-4.82 (m, 2H), 4.81 (br s, OH), 4.25 and 3.90 2s (m, OCH2).
A solution of this free base in anhydrous ethyl ether (5 ml) was treated with HCl/ether solution ( 1M, 1 ml) at 0~ C. Isolation of the precipitate provided the title compound 25 as a solid (hydrochloride salt). M.p. 280-290~ C (dec.), IR (HCl salt, KBr) 3642 (m), 2948 (s), SUBSTITUTE SHEET (RULE 26) WO 98l22467 PCT/SE96/01497 - -1641 (s), l500 (s), 1375 (s), 1315 (s), 996 (s) 920 (s) cm 1. Analysis calculated for C29H29N04~ HCI. 1.1 H20: C 68.05, H 6.34, N, 2.74. Found: C 67.94, H 5.95, N
2.S3.
Example 24 s Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5a-epoxy-3-hydroxy-14-crotyloxy-6,7,2',3'-benzo[b]foranomorphinan Hydrochloride (compound 26) To a stirred solution of naltriben methanesulfonate (256 mg, 0.5 mmol) and N,N-diisopropylethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide ( 10 ml) io was added triisopropylsilyl chloride (145 mg, 0.75 mmol) at 0~C. The solution was stirred for 1 h at 20~ C, and then cooled to 0~ C prior to addition of sodium hydride {60%, l20 mg, 3.0 mmol} was added. After 1 h, crotyl bromide (405 mg, 3.0 mmol) was dropwise added to the solution. The resulting mixture was stirred for 2 h at 20~ C, and then 5 ml methanol and 5 m1 ethyl acetate were slowly added at 0~ C. After 30 min the mixture was i 5 extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgS04, and concentrated to a yellow oil, which was dissolved in 10 m1 ethanol/2 ml 1 N hydrochloric acid and refluxed for 5 hrs. The reaction mixture was alkalized with 1 N aqueous NH40H solution, extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgS04, and concentrated to 2o give a crude product, which was purified by silica gel column chromatography (Hexane:
CHCl3 (75:25~50:50)~CHC13: AcOEt (75:2y50:50-~AcOEt)) to afford compound 26 (45 mg, 19%) as the free base (colorless oil). 1 H NMR (CDCl3): 8 7.48-7.08 (m, 4 arom.
H), 6.66-6.48 (m, 2 arom. H), 5.62 (s, H-C{5)), 5.40 (m, 2H, CH=CH), 4.20 and 3.82 (m, OCH2), 1.48 & 1.52 (m, 3H, Me).
A solution of the free base in anhydrous ethyl ether (5 ml) was treated with HCl/ether solution (1M, 1 ml) at 0~ C. Isolation of the precipitate provided the title compound 26 as a ~
solid in form of its hydrochloride salt. Mp. 245-260 C (dec.). IR (Hcl salt, Kbr): 3642 {m), 3024 (s), l640 (s), l503 (s), 1325 (s), 927 (s) cm 1.
3a SUBSTITUTE SHEET (RULE 26)
Claims (15)
1. A process for the preparation of a compound of the formula (I) wherein R1 represents allyl, cyclopropylmethyl or methyl;
R2 represents C1-C6 alkoxy, C1-C6 alkenyloxy, C7-C16 arylalkyloxy wherein aryl is C6-C10 aryl and alkyloxy is C1-C6 alkyloxy, C7-C16 arylalkenyloxy wherein aryl is C6-C10 aryl and alkenyloxy is C1-C6 alkenyloxy, C1-C6 alkanoyloxy, C7-C16 arylalkanoyloxy wherein aryl is C6-C10 aryl and alkanoyloxy is C1-C6 alkanoyloxy;
R3 represents hydroxy, C1-C6 alkoxy, C7-C16 arylalkyloxy wherein aryl is C6-C10 aryl and alkyloxy is C1-C6 alkyloxy, C1-C6 alkenyloxy, C1-C6 alkanoyloxy, C7-C10 arylalkanoyloxy wherein the aryl is C6-C10 aryl and the alkanoyloxy is C1-C6 alkanoyloxy, C2-alkyloxyalkoxy wherein alkyloxy is C1-C4 alkyloxy and alkoxy is C1-C6 alkoxy;
and X represents O, NH or NR4 wherein R4 is C1-C6 alkoxy, C1-C6 alkenyloxy, C7-C16 arylalkyloxy wherein aryl is C6-C10 aryl and alkyloxy is C1-C6 alkyloxy, C1-arylalkenyloxy wherein the aryl is C6-C10 aryl and alkenyloxy is C1-C6 alkenyloxy, C7-C16 alkanoyloxy, C7-C16 arylalkanoyloxy wherein aryl is C6-C10 aryl and alkanoyoloxy is C1-C6 alkanoyloxy;
comprising the following steps:
(i) naloxone (II), naltrexone (III) or oxymorphone (IIIa) of the formula (II): R = allyl (III): R = cyclopropylmethyl (IIIa): R = methyl is reacted with phenylhydrazine hydrochloride in the presence of acid, giving naloxindole (NLI), naltrindole (NTI) or oxymorphindole (OMI), of the formula NLl: R = allyl, X = NH
NTI: R = cyclopropylmethyl, X = NH
OMI: R = methyl, X = NH
or naloxone (II), naltrexone (III) or oxymorphone (IIIa) is reacted with O-phenyl-hydroxyl amine hydrochloride in the presence of acid, giving the benzofurane derivatives NLB, naltriben (NTB) or OMB of the formula NLB: R = allyl, X = O
NTB: R = cyclopropylmethyl, X = O
OMB: R = methyl, X = O
(ii) the 3-hydroxy group is protected by alkylation with benzyl bromide, methoxymethyl bromide, ethoxymethyl bromide, trityl chloride, or a silylating agent, in the presence of a solvent and a base, giving a compound of the formula (IV) wherein R1 is allyl, cyclopropylmethyl or methyl;
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl; and X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl or N-silyl;
(iii) the compound of the formula (IV) is treated with C1-C2 dialkyl sulfates, C1-C6 alkyl halides, C1-C6 alkenyl halides, C7-C16 aralkyl halides wherein the aryl is C6-C10 aryl and the alkyl is C1-C6 alkyl, C7-C16 arylalkenyl halides wherein the aryl is C6-C10 aryl and the alkenyl is C2-C6 alkenyl, C2-C6 alkanoyl halides, or C7-C16 arylalkanoyl halides wherein the aryl is C6-C10 aryl and the alkanoyl is C2-C6 alkanoyl, in a solvent, preferably N, N-dimethyl formamide or tetrahydrofurane, using a base, giving a compound of the formula (V) wherein R1 is allyl, cyclopropylmethyl or methyl;
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl; and R3 is C1-C6 alkyl, C1-C6 alkenyl; C7-C16 arylalkyl wherein the aryl is C6-C10 aryl and the alkyl is C1-C6 alkyl; C7-C16 arylalkenyl wherein the aryl C6-C10 aryl and the alkenyl is C1-C6 alkenyl; C1-C6 alkanoyl, C7-C16 arylalkanoyl wherein the aryl is C6-C10 aryl and the alkyl is C1-C6 alkyl;
X is as defined in the formula (IV) above; and optionally the following step (iv) whereby (iv) the compound of the formula (V) wherein X is as defined in formula (IV) above, is hydrolized in diluted acids, optionally in the presence of a solvent, giving a compound of the formula (VI) wherein R1, and R2 are as defined above in formula (V), and X is NH, O or N-benzyl; and (v) the compound of the formula (VI) is alkylated or acylated, giving a compound of the formula (I).
R2 represents C1-C6 alkoxy, C1-C6 alkenyloxy, C7-C16 arylalkyloxy wherein aryl is C6-C10 aryl and alkyloxy is C1-C6 alkyloxy, C7-C16 arylalkenyloxy wherein aryl is C6-C10 aryl and alkenyloxy is C1-C6 alkenyloxy, C1-C6 alkanoyloxy, C7-C16 arylalkanoyloxy wherein aryl is C6-C10 aryl and alkanoyloxy is C1-C6 alkanoyloxy;
R3 represents hydroxy, C1-C6 alkoxy, C7-C16 arylalkyloxy wherein aryl is C6-C10 aryl and alkyloxy is C1-C6 alkyloxy, C1-C6 alkenyloxy, C1-C6 alkanoyloxy, C7-C10 arylalkanoyloxy wherein the aryl is C6-C10 aryl and the alkanoyloxy is C1-C6 alkanoyloxy, C2-alkyloxyalkoxy wherein alkyloxy is C1-C4 alkyloxy and alkoxy is C1-C6 alkoxy;
and X represents O, NH or NR4 wherein R4 is C1-C6 alkoxy, C1-C6 alkenyloxy, C7-C16 arylalkyloxy wherein aryl is C6-C10 aryl and alkyloxy is C1-C6 alkyloxy, C1-arylalkenyloxy wherein the aryl is C6-C10 aryl and alkenyloxy is C1-C6 alkenyloxy, C7-C16 alkanoyloxy, C7-C16 arylalkanoyloxy wherein aryl is C6-C10 aryl and alkanoyoloxy is C1-C6 alkanoyloxy;
comprising the following steps:
(i) naloxone (II), naltrexone (III) or oxymorphone (IIIa) of the formula (II): R = allyl (III): R = cyclopropylmethyl (IIIa): R = methyl is reacted with phenylhydrazine hydrochloride in the presence of acid, giving naloxindole (NLI), naltrindole (NTI) or oxymorphindole (OMI), of the formula NLl: R = allyl, X = NH
NTI: R = cyclopropylmethyl, X = NH
OMI: R = methyl, X = NH
or naloxone (II), naltrexone (III) or oxymorphone (IIIa) is reacted with O-phenyl-hydroxyl amine hydrochloride in the presence of acid, giving the benzofurane derivatives NLB, naltriben (NTB) or OMB of the formula NLB: R = allyl, X = O
NTB: R = cyclopropylmethyl, X = O
OMB: R = methyl, X = O
(ii) the 3-hydroxy group is protected by alkylation with benzyl bromide, methoxymethyl bromide, ethoxymethyl bromide, trityl chloride, or a silylating agent, in the presence of a solvent and a base, giving a compound of the formula (IV) wherein R1 is allyl, cyclopropylmethyl or methyl;
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl; and X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl or N-silyl;
(iii) the compound of the formula (IV) is treated with C1-C2 dialkyl sulfates, C1-C6 alkyl halides, C1-C6 alkenyl halides, C7-C16 aralkyl halides wherein the aryl is C6-C10 aryl and the alkyl is C1-C6 alkyl, C7-C16 arylalkenyl halides wherein the aryl is C6-C10 aryl and the alkenyl is C2-C6 alkenyl, C2-C6 alkanoyl halides, or C7-C16 arylalkanoyl halides wherein the aryl is C6-C10 aryl and the alkanoyl is C2-C6 alkanoyl, in a solvent, preferably N, N-dimethyl formamide or tetrahydrofurane, using a base, giving a compound of the formula (V) wherein R1 is allyl, cyclopropylmethyl or methyl;
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl; and R3 is C1-C6 alkyl, C1-C6 alkenyl; C7-C16 arylalkyl wherein the aryl is C6-C10 aryl and the alkyl is C1-C6 alkyl; C7-C16 arylalkenyl wherein the aryl C6-C10 aryl and the alkenyl is C1-C6 alkenyl; C1-C6 alkanoyl, C7-C16 arylalkanoyl wherein the aryl is C6-C10 aryl and the alkyl is C1-C6 alkyl;
X is as defined in the formula (IV) above; and optionally the following step (iv) whereby (iv) the compound of the formula (V) wherein X is as defined in formula (IV) above, is hydrolized in diluted acids, optionally in the presence of a solvent, giving a compound of the formula (VI) wherein R1, and R2 are as defined above in formula (V), and X is NH, O or N-benzyl; and (v) the compound of the formula (VI) is alkylated or acylated, giving a compound of the formula (I).
2. A process according to claim 1, wherein R1 is allyl or cyclopropylmethyl;
R2 is C1-C6 alkoxy, C1-C6 alkenyloxy, C7-C16 arylalkyloxy, C7-C16 arylalkenyloxy;
R3 is hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy.
R2 is C1-C6 alkoxy, C1-C6 alkenyloxy, C7-C16 arylalkyloxy, C7-C16 arylalkenyloxy;
R3 is hydroxy, C1-C6 alkoxy, C1-C6 alkanoyloxy.
3. A process according to claim 1, whereby the acid used in step (i) is selected from methanesulfonic acid, sulfuric acid and hydrochloric acid.
4. A process according to claim 1, whereby the protection of the 3-hydroxy group in step (ii) is performed by alkylation with dimethyl isobutyl-silyl chloride, trimethylsilyl chloride) triethylsilyl chloride, t-butyldimethylsilyl chloride and tri-i-propylsilyl chloride.
5. A process according to claim 1, whereby the solvent in step (ii) is selected from N, N-dimethylformamide, dichloromethane and tetrahydrofurane.
6. A process according to claim 1, whereby the base in step {ii) is selected from potassium carbonate, potassium hydroxide, sodium hydride, sodium amide and diisopropyl ethylamine.
7. A process according to claim 1, whereby the solvent in step (iii) is selected from N, N-dimethylformamide and tetrahydrofurane.
8. A process according to claim 1, whereby the strong base in step (iii) is selected from sodium hydride, potassium hydride and sodium amide.
9. A process according to claim 1, whereby the diluted acid in step (iv) is hydrochloric acid or sulfuric acid.
10. A process according to claim 1, whereby step (iv) is performed in the presence of a solvent.
11. A process according to claim 10, whereby the solvent is an alcohol.
12. A process according to claim 11, whereby the solvent is selected from methanol, ethanol and propanol.
1 CLAIMS:
14. A compound according to formula (IV) wherein R1 is allyl, cyclopropylmethyl or methyl;
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl, silyl, dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl, N-silyl, dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl;
and with the proviso that:
(i) when R1 is cyclopropylmethyl and R2 is methoxymethyl, X is not O or N-methoxymethyl.
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl, silyl, dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl, N-silyl, dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl;
and with the proviso that:
(i) when R1 is cyclopropylmethyl and R2 is methoxymethyl, X is not O or N-methoxymethyl.
15. A compound according to the formula (V) wherein R1 is allyl or cyclopropylmethyl;
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl; and R3 is C1-C6 alkyl, C7-C6 alkenyl; C7-C16 arylalkyl wherein the aryl is C6-C10 aryl and the alkyl is C1-C6 alkyl; C1-C16 arylalkenyl wherein the aryl C6-C10 aryl and the alkenyl is C1-C6 alkenyl; C1-C6 alkanoyl, C7-C16 arylalkanoyl wherein the aryl is C6-C10 aryl and the alkyl is C1-C6 alkyl;
X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl, N-silyl, dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and with the proviso that:
(j) when R1 is cyclopropylmethyl, R2 is methoxymethyl and R3 is methyl, X is not O.
R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl; and R3 is C1-C6 alkyl, C7-C6 alkenyl; C7-C16 arylalkyl wherein the aryl is C6-C10 aryl and the alkyl is C1-C6 alkyl; C1-C16 arylalkenyl wherein the aryl C6-C10 aryl and the alkenyl is C1-C6 alkenyl; C1-C6 alkanoyl, C7-C16 arylalkanoyl wherein the aryl is C6-C10 aryl and the alkyl is C1-C6 alkyl;
X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl, N-silyl, dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and with the proviso that:
(j) when R1 is cyclopropylmethyl, R2 is methoxymethyl and R3 is methyl, X is not O.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/SE1996/001497 WO1998022467A1 (en) | 1996-11-19 | 1996-11-19 | New process for the preparation of morphinans |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2269910A1 true CA2269910A1 (en) | 1998-05-28 |
Family
ID=20402270
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002269910A Abandoned CA2269910A1 (en) | 1996-11-19 | 1996-11-19 | New process for the preparation of morphinans |
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| Country | Link |
|---|---|
| EP (1) | EP0946564A1 (en) |
| JP (1) | JP2001504829A (en) |
| AU (1) | AU1402497A (en) |
| CA (1) | CA2269910A1 (en) |
| WO (1) | WO1998022467A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19939044A1 (en) * | 1999-08-18 | 2001-03-15 | Gruenenthal Gmbh | Use of morphine derivatives as drugs |
| ES2666404T3 (en) * | 2010-06-11 | 2018-05-04 | Rhodes Technologies | Transition metal catalyzed processes for the preparation and use of N-allyl compounds |
| US10800516B2 (en) | 2017-06-02 | 2020-10-13 | The Boeing Company | Semi-levered shrink landing gear |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE3412727A1 (en) * | 1984-04-04 | 1985-10-17 | Helmut Dr. Innsbruck Schmidhammer | 14-Alkoxy-N-methylmorphinan-6-ones, process for their preparation, and medicaments containing these compounds |
| US5223507A (en) * | 1992-01-21 | 1993-06-29 | G. D. Searle & Co. | Method of using opioid compounds as delta opioid selective agonist analgesics |
| US5354863A (en) * | 1992-01-21 | 1994-10-11 | G. D. Searle & Co. | Opioid agonist compounds |
| US5225417A (en) * | 1992-01-21 | 1993-07-06 | G. D. Searle & Co. | Opioid agonist compounds |
| SE9401728D0 (en) * | 1994-05-18 | 1994-05-18 | Astra Ab | New compounds II |
-
1996
- 1996-11-19 AU AU14024/97A patent/AU1402497A/en not_active Abandoned
- 1996-11-19 WO PCT/SE1996/001497 patent/WO1998022467A1/en not_active Application Discontinuation
- 1996-11-19 JP JP52353998A patent/JP2001504829A/en active Pending
- 1996-11-19 CA CA002269910A patent/CA2269910A1/en not_active Abandoned
- 1996-11-19 EP EP96944151A patent/EP0946564A1/en not_active Withdrawn
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| EP0946564A1 (en) | 1999-10-06 |
| WO1998022467A1 (en) | 1998-05-28 |
| AU1402497A (en) | 1998-06-10 |
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