U.S. patent number 4,521,601 [Application Number 06/477,970] was granted by the patent office on 1985-06-04 for practical total synthesis unnatural enantiomers of opium-derived morphinans.
This patent grant is currently assigned to The United States of America as represented by the Department of Health. Invention is credited to Kenner C. Rice.
United States Patent |
4,521,601 |
Rice |
* June 4, 1985 |
Practical total synthesis unnatural enantiomers of opium-derived
morphinans
Abstract
This invention relates to compounds which may be described as
the unnatural enantiomers of morphine agonists and antagonists,
which are useful as antitussives. The synthesis utilized is capable
of producing all of the unnatural enantiomers of medically
important opium derivatives of the morphinan type, including
thebaine.
Inventors: |
Rice; Kenner C. (Rockville,
MD) |
Assignee: |
The United States of America as
represented by the Department of Health (Washington,
DC)
|
[*] Notice: |
The portion of the term of this patent
subsequent to January 11, 2000 has been disclaimed. |
Family
ID: |
26951226 |
Appl.
No.: |
06/477,970 |
Filed: |
March 23, 1983 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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265469 |
May 20, 1981 |
4410700 |
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165690 |
Jul 3, 1980 |
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Current U.S.
Class: |
546/45; 546/146;
546/149; 546/15; 546/44; 546/74 |
Current CPC
Class: |
C07D
217/20 (20130101) |
Current International
Class: |
C07D
217/00 (20060101); C07D 217/20 (20060101); C07D
489/02 (); C07D 221/28 (); C07D 217/20 () |
Field of
Search: |
;546/44,45,74 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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7107921 |
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Dec 1971 |
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NL |
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1330581 |
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Sep 1973 |
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GB |
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Other References
DeGraw et al., J. Heterocyclic Chem., vol. 11, pp. 363-367 (1974).
.
Beyerman et al., Recl. Trav. Chim Pays-Bas, 95, pp. 184-188,
(1976). .
Beyerman et al., Recl. Trav. Chim Pay-Bas, 97, pp. 127-130, (1978).
.
Beyerman et al., Chemical Abstracts, 91, 74760y (1979). .
Anon., Chemical & Engineering News, Jan. 18, 1971, p. 33. .
Gesson et al., J. Chem. Soc., Chem. Comm. pp. 652-653 (1976). .
Fieser et al., Reagents for Organic Synthesis, vol. 6, John Wiley
Sons, New York, 1977, pp. 617-618. .
Herlem, Pure & Appl. Chem., vol. 49, pp. 107-113 (1977). .
Gesson et al., Chemical Abstracts, vol. 88, 152297g (1978). .
Grewe et al., Chem. Ber., 100, 1550-1558 (1967). .
Friedrichsen, Chem. Ber., 101, 1190-1194 (1968). .
Maeda et al., Chemical Abstracts, vol. 69, 52367u (1968). .
Sawa et al., Chemical Abstracts, vol. 73, 131195x (1970). .
Hellerbach et al., "Synthetic Analgesics, Part IIA, Morphinans,
Pergamon Press, 1966, pp. 1-104. .
Birch et al., "Reduction by Metal-Ammonia Solution and Related
Reagents," Advances In Organic Chemistry, vol. 8,
Wiley-Interscience, 1972, pp. 1-65. .
May et al., "Morphine and Its Modifications," Medicinal Chemistry,
vol. 5, D. Stephens, Analgesics, 1965, pp. 123-174. .
Rice, J. Organic Chem., vol. 45, No. 15, pp. 3135-3137
(07/18/80)..
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Primary Examiner: Rivers; Diana G.
Attorney, Agent or Firm: Roberts, Jr.; John S.
Parent Case Text
This application is a continuation-in-part application of pending
Ser. No. 265,469 filed May 20, 1981, now U.S. Pat. No. 4,410,700,
which is a continuation-in-part of Ser. No. 165,690, filed July 3,
1980, now abandoned, U.S. Pat. No. 4,368,326 describes a process
relating to the natural isomers and stems from the above Ser. No.
165,690, now abandoned.
Claims
I claim:
1. In the preparation of compounds 23 and 24
by a total synthesis method, the steps which comprise:
(a) heating a mixture of an amine compound of the formula 4
##STR4## and pure acid compound, formula 5 R1 ? ? ##STR5## at
200.degree. C. for about 2 hours under argon or other inert gas to
obtain amide compound 6 of the following formula ##STR6## (b)
contacting compound 6 with phosphorous oxychloride to produce the
1,2-dehydro derivative of compound 7 shown below: ##STR7## which
need not be isolated; (c) neutralizing the 1,2-dehydro derivative
of compound 7 with aqueous ammonia and reducing with sodium
cyanoborohydride or sodium borohydride to give racemic 7 which is
then resolved by optically active acids to the compound
tetrahydroisoquinoline (+)-7 to (-)-7 ##STR8## (d) treating of
(-)-7 with lithium or sodium in liquid ammonia as a reducing agent
to give hexahydroisoquinoline, compound (-)-8 ##STR9## and
formylating compound (-)-8 to give 10 ##STR10## and introducing a
protective group for the nitrogen in the subsequent steps of the
reaction where the reagent for formylation of 8 to 10 is
phenylformate chloral or ethyl formate
(e) alternately, N-methylating compound (-)-7 or (-)-8 by treatment
with methyl halides or sulfonate to give the N-methyl derivative of
7 or compound 9 ##STR11## (f) contacting compound 10 with ethylene
glycol in dry methane sulfonic acid in dry tetrahydrofuran to
afford the ketal product, 11 ##STR12## (g) brominating of ketal 11
with N-bromoacetamide (NBA) to give bromo ketal 12 ##STR13## (h)
deketalizing bromo ketal 12 with aqueous formic acid to yield beta,
gamma unsaturated ketone 13 ##STR14## (i) treating beta, gamma
unsaturated bromo ketone 13 with a super acid alone or with
ammonium fluoride HF complex with trifluoromethanesulfonic acid to
give 1-bromo-N-formylnordihydrothebainone (+)-17 ##STR15## (j) acid
hydrolyzing 1-bromo-N-formylnordihydrothebainone (+)-17 with
aqueous acid and methanol to give the intermediate
1-bromonordihydrothebainone, compound (+)-18 ##STR16## (k)
converting intermediate (+)-18, 1-bromonordihydrothebainone, to
dihydrothebainone (+)-19, a codeine precursor by hydrogenation in
the presence of formaldehyde with palladium on carbon catalyst in
2-normal (2N) acetic acid containing sodium acetate; or
(l) treating intermediate (+)-18 with bromine in acetic acid or
chloroform followed by treating with sodium hydroxide to close the
oxide bridge and afford as an intermediate
(+)-1-bromonordihydrocodeinone which need not be isolated but is
hydrogenated in the presence of formaldehyde to give
dihydrocodeinone (+)-22, a codeine precursor or ##STR17## (m)
alternately, converting compound (+)-18 into compound (+)-21,
nordihydrocodeinone ##STR18## by bromination in acetic acid
followed by treating with an aqueous base to close the oxide
bridge, and hydrogenating the unisolated intermediate with
palladium on carbon catalyst in 2-norman (2N) acetic acid
containing sodium acetate.
Description
The present application relates to compounds which may be described
as the unnatural enantiomers of morphine agonists and antagonists,
which are useful as antitussives. The synthesis utilized is capable
of producing all of the unnatural enantiomers of medically
important opium derivatives of the morphinan type, including
thebaine.
Among the advantages of the process is a facile optical resolution
of racemic 7 to give (-)-7a and (+)-7a. The former can then be
converted as described below to the unnatural enantiomers of all
medically valuable-opium derived agonists and antagonists and also
to related derivatives.
Among the advantages emphasized by the present invention are the
utilization of .beta.,.gamma.-unsaturated ketones where in the past
there have been used .alpha.,.beta.-unsaturated ketones. Secondly,
in the step below where .beta.,.gamma.-unsaturated bromoketones (13
or 14) proceed to 1-bromo-N-formylnordihydrothebaine (morphinan)
(17), in this process there are utilized super acids, such as
trifluoromethane sulfonic, polyfluoroethane sulfonic and mixtures
thereof, and also antimony pentafluoride and mixtures of hydrogen
fluoride and antimony pentafluoride. An additional advantage of the
present process is that oxide bridge closure is accomplished in the
N-nor series bromonordihydrothebainone
(18).fwdarw.nordihydrocodeinone (21), thus affording ready access
to either N-nor or N-methyl derivatives from the same intermediate
18. N-nor derivatives are of paramount importance in the synthesis
of unnatural enantiomers of narcotic antagonists and the
agonist-antagonist drugs. The N-methyl derivative,
(+)-dihydrocodeinone(22), is a key intermediate which can be
converted by established methods to unnatural (+)-codeine,
morphine, thebaine and the corresponding enantiomers of all
medically valuable opium derivatives of the morphinan type and
related compounds.
In this specification, morphine-type means alkaloid compounds
generally of the morphinan structure. Specially interesting are
morphine and morphinan agonists and antagonists.
Grewe cyclization is a ring closure method and in the present
disclosure utilizes bromine or other halogens as a blocking group.
The deactivating influence of halogen on the phenolic ring is
overcome by use of super acids in the Grewe cyclization (cf. J.
Het. Chem., June 1974, 363).
Birch reduction of (-)-7a includes reduction with ammonia or lower
amine and lithium (preferred) or other alkali metal.
The introduction of bromine in a 1:1 molar ratio folowed by alkali
metal base served to close the oxide bridge. In a process
proceeding from (+)-1-bromonordihydrothebainone (18) the bridge
head nitrogen may be alkylated using an acid aldehyde, a lower
aldehyde, or ketone such as theyl aldehyde or acetone.
The chart below is a synopsis of the sequence of steps.
##STR1##
PRIOR ART STATEMENT
Rice, J. of Organic Chemistry, Vol. 45(15), July 18, 1980, pp.
3135-3137.
Rice, U.S. Pat. No. 4,368,326
With reference to the use of super acids, the invention encompasses
such acids as trifluoromethane sulfonic, polyfluoroethane sulfonic,
etc., and it is maintained that the use of these very strong acids
overcomes the difficulty of use of acids, such as sulfuric,
phosphoric, etc.
Relative to the compounds produced by alkylating the nitrogen
bridge head, this reaction will work with lower amines and lower
ketones. The utility of the products akin to nordihydrocodeinone
(21) with N-alkylate are morhine agonists or antagonists. These
compounds with the N-alkylate structure are denoted as tertiary
amines and specially where N-methyl, N-ethyl, etc., are produced
and the alkyl chain is C.sub.1 -C.sub.6. Of the ketones, acetone
and methyl ethyl ketone will operate. They are regarded as quite
important for morphine overdose.
In general, as to utility, dihydrothebainone (19) is noted in J.
Med. Chem., 19:1171 (1976) and dihydrocodeinone (22) is a
prescription drug on the market at present produced by
Mallinckrodt, etc., as Hydrocodone.
As a general summary of the above chart, the following general
description is made commencing with codeine (1).
(+)-Dihydrothebainine (19), (+)-nordihydrocodeinone (21) and
(+)-dihydrocodeinone (22) were synthesized in high overall yield
from 3-methoxyphenethylamine (4), via the key intermediate
(+)-1-bromonordihydrothebainone (18); the route utilized
unprotected phenolic intermediates, involved directed Grewe-type
cyclization and for 21 and 22, exploited novel oxide bridge closure
in the N-nor series.
Natural (-)-codeine (1) continues to occupy a position of central
importance among the medically valuable derivatives of the opium
poppy as the most frequently prescribed analgesic-antitussive agent
worldwide. Since the first total synthesis of (-)-codeine (1) and
(-)-morphine (2), other successful routes, including Grewe-type and
biomimetic approaches, have appeared. However, a practical total
synthesis of these drugs has remained elusive. These and continuing
efforts, together with possible shortages, underscore the
desirability of securing a route which could render licit
production of medical opiates independent of the natural and sole
commercial source of these drugs. Since the reports that Grewe-type
electrophilic cyclization of (+)-1-benzylhexahydroisoquinoline (9)
afforded a 3% yield of the codeine precursor dihydrothebainone (19)
(with isomeric 20 as the vastly predominant cyclization product),
several groups have attempted to utilize this approach to codeine
by introduction of a blocking substituent at the 1-position of the
benzyl moiety in order to direct cyclization to the desired
dihydrothebainone oxygenation pattern. Studies utilizing a 1-methyl
substituent were successful in this regard. However, such an
approach must also employ a readily removable group to be of value
in synthesis of codeine and congeners, of course, not the case in
the 1-methyl series. Substitution of bromine for methyl,
unsuccessful hithertofore, would be ideal, since transformation of
4-hydroxymorphinans such as 19 to 22 (with the oxide bridge closed
as in codeine) first involves bromination at C-1 of the morphinan
system and later removal of the C-1 bromine atom by hydrogenolysis.
Recent work describing conversion of (-)-dihydrothebainone [(-)-19]
to (-)-codeine (1) (68% overall), via (-)-dihydrocodeinone,
[(-)-22] and to (-)-thebaine (3), (an important minor opium
alkaloid) in somewhat higher yield, renders any totally synthetic
approach yielding 1-bromodihydrothebainone derivatives still more
attractive. Such an approach which utilizes unprotected phenolic
intermediates is short, experimentally simple, and affords
(+)-dihydrothebainone (19), (+)-nordihydrocodeinone (21) and
(+)-dihydrocodeinone (22) in high overall yield via the key
intermediate (+)-1-bromonordihydrothebainone (18) is included in
this disclosure. The sequence rests essentially on high yield
preparation of .beta.,.gamma.-unsaturated bromoketone 13, that is
converted by directed Grewe-type cyclization into
(+)-1-bromo-N-formylnordihydrothebainone (17), and on the novel
oxide bridge closure in the N-nor series, which optionally provides
ready access to either N-methyl or N-nor derivatives.
Heating a mixture of amine 4 and pure acid 5 at 200.degree. C. for
2 hr. under argon afforded amide 6 (95%, EtOAc). Cyclization of 6
(0.35 mol scale) with phosphorous oxychloride generated an aqueous
solution of the 1,2-dehydro derivative of 7. The conversion of 6 to
the 1,2-dehydro derivative of 7 is carried out under ring closure
conditions in an organic solvent such as acetonitrile or other
lower alkyl nitriles (C.sub.1 -C.sub.6) containing phosphorous
oxychloride. A preferred procedure utilizes a molar ratio of
phosphorous oxychloride to 6 of greater than 1 and employs
refluxing acetonitrile. When the reaction is complete, evaporation
of the solvent and excess phosphorous oxychloride and addition of
water to the residue gives an aqueous solution of the 1,2-dehydro
derivative of 7.
Neutralization of pH 4-5 with concentrated aqueous NH.sub.3 and
reduction with an equimolar quantity of NaCNBH.sub.3 or sodium
borohydride in refluxing 45% MeOH (final concentration) for 1.5 hr.
afforded pure (TLC) 7 (86%), mp 199.5.degree.-201.5.degree. C.
Resolution of racemic tetrahydroisoquinoline 7 is accomplished by
formation and fractional crystallization of diasterisomeric salts
with optically active acids such as tartaric, mandelic and
tartranilic acid, etc. The appropriate optically active base 7 is
then regenerated and subjected the reaction sequence described
herein to afford the corresponding morphinan derivatives with
either the natural or unnatural morphine absolute configuration.
The optically pure (+)-7 obtained showed m.p.
218.5.degree.-220.degree. C., and [.alpha.].sub.D.sup.23
=+38.1.degree. (C 0.27, DMF). The corresponding enantiomer (-)-7
useful for preparing unnatural opiate derivatives showed m.p.
218.degree.-219.5.degree. C., and [.alpha.].sub.D.sup.23
=-37.7.degree. (C 0.26 DMF).
The present invention also encompasses racemization of either
enantiomer of 7 and derivatives so that, if desired, one enantiomer
can be produced to the exclusion of the other by recycle of the
racemate. Racemization can be accomplished by catalytic
hydrogenation of the chiral 1-benzyl-1,2,3,4-tetrahydroisoquinoline
with metal catalysts such as palladium, platinum, nickel and
cobalt. Platinum and palladium catalysts in solvents such as
alkanoic acids, ethers, and hydrocarbons are preferred. Simple
filtration of the catalysts and workup by evaporation of the
solvent affords the racemate in high chemical yield. Also,
oxidation of 1-benzyltetrahydroisoquinolines, lower alkoxy and
acyloxy derivatives with reagents such as N-chlorosuccinamide,
sodium hypochlorite, sodium hypobromite, and lower alkyl
hypochlorites and hypobromites, and treatment with base to give
dehydro intermediate of type 25, followed by reduction with sodium
cyanoborohydride or sodium borohydride, can be used to effect
racemization of either enantiomer of 7. Synthesis of 25 and sodium
cyanoborohydride reduction of 25 to (.+-.)-7 was described
above.
Birch reduction with lithium or sodium in liquid ammonia of 85 mmol
of unpurified 7 with 1.92 g atom of lithium in 450 ml of liquid
NH.sub.3, 225 ml each of dry THF and 6-BuOH at -55.degree. to
-65.degree. C. for 4 hrs., then at -75.degree. C. until no 7
remained by TLC (.about.1.5 h) afforded (90%) essentially pure
(TLC) 8, mp 179.5.degree. C. Refluxing unpurified 8 with 1.5
equivalents of pure PhOCHO, chloral in 10 volumes of EtOAc or in
EtOCHO until TLC showed absence of 8 gave (94%) pure 10, which, as
the N-formyl derivatives described below and others, existed as two
distinct rotomers, as shown by NMR. This N-formyl derivatization
introduces a protective group for the nitrogen in the subsequent
steps of the reaction. Compound 7 or 8 may be N-methylated with
methyl halide or sulfonate to give compound 9. Stirring a solution
of 10 (25.degree. C., 1 h.) in 20 volumes of dry THF containing 1%
(v/v) CH.sub.3 SO.sub.3 H and 3 molar equivalents of ethylene
glycol generated a solution of ketal 11 (quantitatively by TLC)
which was treated at 0.degree.-5.degree. C. during 0.5 h with 1.05
equivalents of recrystallized N-bromoacetamide (NBA) to afford
essentially pure bromoketal 12 after neutralization with NH.sub.3
gas, solvent evaporation and workup with CHCl.sub.3 --H.sub.2 O.
Bromoketal 12 was most efficiently deketalized in 6 volumes of 5:1
88% HCO.sub.2 H--H.sub.2 O (25.degree. C., 1 h) followed by
CHCl.sub.3 -aqueous NaHCO.sub.3 workup to afford 13, IR
(CHCl.sub.3) 1717 (C.dbd.O) and 1665 (NCHO) cm.sup.-1 in 90% yield
from 10.
Bromoketone 13 underwent Grewe-type cyclization to
(+)-1-bromo-N-formylnordihydrothebainone (17), in 60% isolated
yield with dry CF.sub.3 SO.sub.3 H for 24 hrs. at 25.degree. C.
until 13 had essentially disappeared by TLC. Synthetic (+)-17
showed mp 216.5.degree.-218.5.degree. C. and [.alpha.].sub.D.sup.23
=152.degree. (c 0.5, CHCl.sub.3) immediately after dissolving in
chloroform. After standing overnight in chloroform at 25.degree.
C., the compound showed [.alpha.].sub.D.sup.23 =+189.degree. due to
equilibration of the rotamers about the C--N bond of the N-formyl
group. Also, isomerization of 13 occurred during cyclization to
give (TLC) the .alpha.,.beta.-unsaturated bromoketone 16. Pure 16
afforded (TLC) only traces of morphinan 17, and
.beta.,.gamma.-unsaturated ketone 13 under the conditions used to
cyclize 13 to (+)-17. Treatment of pure morphinan (+)-17 under
these conditions gave no 13 or 16 (TLC); the acid catalyzed
equilibrium of 13 and 16 lies nearly exclusively toward the side of
the latter, which undergoes little, if any, morphinan cyclization
under these conditions. Refluxing isolated (+)-17 in 10:1 MeOH-37%
aqueous HCl for 18 h. afforded (+)-1-bromonordihydrothebainone
(18), which was easily isolated as the 1:1 fumarate salt, mp
244.degree. C. (+)-Dihydrothebainone (19), mp
148.degree.-152.degree. C. was obtained directly and quantitatively
from (+)-17 by hydrolysis as above, evaporation to dryness, and
hydrogenation of the residue in 2N AcOH containing 50 mg 10% Pd/C,
0.1 ml of 37% HCHO and 5 mmol of NaOAc per mmol of 17, followed by
workup with CHCl.sub.3 -aqueous NH.sub.3. Bromination (1.1 mol of
Br.sub.2, 25.degree. C., 2H) of an AcOH or CHCl.sub.3 solution of
the dry residue from hydrolysis of 17, evaporation, treatment of
the residue with CHCl.sub.3 -1N NaOH and hydrogenation as above
without addition of HCHO afforded an 80% yield (from (+)-17) of
(+)-nordihydrocodeinone (21), mp 151.degree.-153.degree. C. (as
hydrate from EtOAc-H.sub.2 O). This is the first example of closure
of the oxide bridge in the basic N-nor series and is of potential
interest in the synthesis of narcotic antagonists. When (+ )-17 was
treated as in the preparation of (+)-21, and 0.1 ml of 37%
HCHO/mmol of (+)-17 was added to the hydrogenation medium
(+)-dihydrocodeinone (22), mp 194.degree.-196.degree. C. was easily
isolated in 79% yield from 17.
This straightforward total synthesis of (+)-dihydrothebainone (19),
(+)-nordihydrocodeinone (21), and (+)-dihydrocodeinone (22) in high
overall yields respectively, from readily available
3-methoxyphenethylamine (4) requires isolation of only 6
intermediates. These are directly obtained sufficiently pure for
further transformation. In view of these results, the high yielding
conversion of (-)-19 to (-)-thebaine (3) and (-)-codeine (1)
discussed above and the facile O-demethylation of the latter to
(-)-morphine (2), a practical total synthesis of both enantiomers
of these alkaloids (and the thebaine based drugs) have resulted.
Compounds of the general structures 23 and 24 are prepared by
conventional techniques from process compounds 18, 19, 21 and
22.
The term "super acid" or "super acids" is defined to mean and
include in this specification and claims the following: All protic
acids stronger than 100% sulfuric, thus in this group are
perchloric acid HCLO.sub.4, fluorosulfuric HSO.sub.3 F, and
trifluoromethane sulfonic acid CF.sub.3 SO.sub.3 H, as well as
trifluoroethane sulfonic acid. A convenient review incorporating
this definition is found in Science, Vol. 26, No. 4414, Oct. 5,
1979, pages 13-20.
* * * * *