U.S. patent application number 11/642377 was filed with the patent office on 2007-05-31 for synthesis of cannabinoids.
This patent application is currently assigned to Johnson Matthey Public Limited Company. Invention is credited to Lee Jonathan Silverberg.
Application Number | 20070123719 11/642377 |
Document ID | / |
Family ID | 9915280 |
Filed Date | 2007-05-31 |
United States Patent
Application |
20070123719 |
Kind Code |
A1 |
Silverberg; Lee Jonathan |
May 31, 2007 |
Synthesis of cannabinoids
Abstract
The present invention relates to a process for the production of
compound A comprising reacting compound B with compound C. A
further ring closure reaction may be necessary. The invention
further relates to certain novel compounds of formula B.
##STR1##
Inventors: |
Silverberg; Lee Jonathan;
(Cherry Hill, NJ) |
Correspondence
Address: |
RATNERPRESTIA
P O BOX 980
VALLEY FORGE
PA
19482-0980
US
|
Assignee: |
Johnson Matthey Public Limited
Company
London
GB
|
Family ID: |
9915280 |
Appl. No.: |
11/642377 |
Filed: |
December 19, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10479021 |
Aug 5, 2004 |
7186850 |
|
|
PCT/GB02/02159 |
May 9, 2002 |
|
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11642377 |
Dec 19, 2006 |
|
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Current U.S.
Class: |
549/390 |
Current CPC
Class: |
C07D 311/80
20130101 |
Class at
Publication: |
549/390 |
International
Class: |
C07D 311/80 20060101
C07D311/80 |
Foreign Application Data
Date |
Code |
Application Number |
May 25, 2001 |
GB |
0112752.1 |
Claims
1. A process for the production of a compound of general formula A:
##STR19## wherein R.sup.c, R.sup.d and R.sup.e are independently H,
alkyl, or substituted alkyl; and R.sup.1 to R.sup.4 are
independently H, OH, OR' (R' is alkyl, aryl, substituted alkyl or
aryl, silyl, acyl, or phosphonate), alkyl, substituted alkyl, aryl,
acyl, halide, amine, nitrate, sulphonate or phosphonate; comprising
reacting compound B with compound C: ##STR20## wherein R.sup.a is
H, alkyl, aryl, acyl or silyl; R.sup.b is alkyl, aryl or acyl;
R.sup.c, R.sup.d, R.sup.e and R.sup.1 to R.sup.4 are as
hereinbefore defined.
2. The process according to claim 1, wherein R.sup.a is alkyl, aryl
or acyl.
3. The process according to claim 1, wherein R.sup.b is an acyl
group.
4. The process according to claim 3, wherein OR.sup.b is an ester
group selected from the group consisting of acetate, propionate,
butyrate, trimethylacetate, phenylacetate, phenoxyacetate,
diphenylacetate, benzoate, p-nitrobenzoate, phthalate and
succinate.
5. The process according to claim 1, wherein both of R.sup.a and
R.sup.b are acyl groups.
6. The process according to claim 5, wherein OR.sup.a and OR.sup.b
are ester groups independently selected from the group consisting
of acetate, propionate, butyrate, trimethylacetate, phenylacetate,
phenoxyacetate, diphenylacetate, benzoate, p-nitrobenzoate,
phthalate and succinate.
7. The process according to claim 6, wherein OR.sup.a and OR.sup.b
are diphenylacetate.
8. The process according to claim 1, wherein R.sup.c, R.sup.d and
R.sup.e are methyl.
9. The process according to claim 1, wherein R.sup.1 is OR''
wherein R'' is H, alkyl, substituted alkyl, acyl or silyl.
10. The process according to claim 9, wherein R.sup.1 is OH.
11. The process according to claim 1, wherein R.sup.2 and R.sup.4
are H.
12. The process according to claim 1, wherein R.sup.3 is
C.sub.5H.sub.11.
13. The process according to claim 1, wherein compound A is
.DELTA..sup.9-THC, compound B is an ether or ester of
(+)-p-menth-2-ene-1,8-diol and compound C is olivetol.
14. The process according to claim 1, wherein the reaction of
compound B with compound C is carried out in the presence of an
acid catalyst.
15. The process according to claim 14, wherein the acid catalyst is
nonmetallic.
16. The process according to claim 14, wherein 0.1-1.5 equivalents
of acid catalyst are used.
17. The process according to claim 1, further comprising performing
a ring closure step.
18. The process according to claim 8, wherein R.sup.1 is OH,
R.sup.2 and R.sup.4 are H, and R.sup.3 is C.sub.5H.sub.11.
19. The process according to claim 6, wherein no more than one of
R.sup.a and R.sup.b is acetate.
Description
[0001] This application is a Division of U.S. application Ser. No.
10/479,021, filed Aug. 5, 2004, which is the U.S. National Phase
application of PCT International Application No. PCT/GB02/02159,
which claims priority of GB 0112752.1.
[0002] The present invention relates to a novel process that can be
used to produce (-)-.DELTA..sup.9-tetrahydrocannibinol and related
cannibinoid compounds. The invention further relates to novel
compounds used in the process.
[0003] (-)-.DELTA..sup.9-Tetrahydrocannibinol (.DELTA..sup.9-THC)
is the active ingredient in marijuana. It is used therapeutically
as an inhalant or an oral drug for stimulation of appetite among
AIDS and cancer chemotherapy patients. Related cannibinoid
compounds that show pharmacological activity are also known. In
particular, there have been attempts to produce water soluble
analogues of .DELTA..sup.9-THC (`The Total Synthesis of
Cannibinoids` in The Total Synthesis of Natural Products, Vol 4,
John ApSimon, Wiley, 1981, pp 239-243). ##STR2##
[0004] The chemical synthesis and isolation of .DELTA..sup.9-THC
are both challenging. .DELTA..sup.9-THC is a very high boiling,
viscous liquid. It is very prone to acid-catalysed isomerization to
the thermodynamically more stable .DELTA..sup.8 isomer, it is
easily oxidized by oxygen to inactive cannibinol, and it is
sensitive to light and heat. All of these factors make purification
difficult, especially on an industrial scale, and chromatography
has generally been used. ##STR3##
[0005] Previous syntheses of .DELTA..sup.9-THC have tended to be
either lengthy or low-yielding. Most involve coupling of a chiral
terpene to a resorcinol derivative. The primary difficulty has been
lack of selectivity in the coupling. Acid catalysed couplings have
generally led to mixtures of products (Crombie et al, J Chem Soc.
Perkin Trans. I 1988 1243). Attempts to avoid the selectivity
problem by using base-catalysed coupling reactions have involved
lengthier syntheses overall (Rickards et al, J. Org. Chem. 1984 49
572). Syntheses not using chiral terpenes have yielded racemic
product (Childers et al, J. Org. Chem. 1984 49 5276).
[0006] In seemingly the best known method (U.S. Pat. No.
5,227,537), Stoss claims that acid-catalysed coupling of
(+)-p-menth-2-ene-1,8-diol (1) with olivetol (2) can be stopped at
the intermediate Friedel-Crafts product (3), and then the
intermediate (3) can be isolated and converted in good yield to
.DELTA..sup.9-THC using ZnBr.sub.2 (24 hours, refluxing
CH.sub.2Cl.sub.2). The present inventors have encountered several
problems with this scheme. The initial p-toluenesulfonic acid
catalysed Friedel-Crafts reaction was difficult to stop cleanly at
the intermediate (3) under Stoss' conditions and gave mixtures of
the intermediate (3) and .DELTA..sup.9-THC, the ring-closed
product. Any .DELTA..sup.9-THC formed is likely to isomerize to
.DELTA..sup.8-THC under the disclosed conditions. The use of a
heavy metal such as ZnBr.sub.2 in the last step of an industrial
process is highly undesirable as it may lead to traces of metal in
the product, and this is especially undesirable for
pharmaceuticals. Stoss' method therefore appears to offer no real
advantage in yield or purity of .DELTA..sup.9-THC over a one-pot
coupling that goes directly to .DELTA..sup.9-THC. Razdan has
published a one-pot method for coupling of
(+)-p-menth-2-ene-1,8-diol (1) with olivetol (2) to produce
.DELTA..sup.9-THC (Razdan et al, Tet. Lett. 1983 24 3129). This
also suffers from several problems: it uses nearly 14 equivalents
of ZnCl.sub.2 as the acid, and uses six equivalents of olivetol
(2). Even under these conditions, the yield is still only 28% from
(+)-p-menth-2-ene-1,8-diol (1). ##STR4##
[0007] Thus there is a need for a short, practical, high-yielding
synthesis of .DELTA..sup.9-THC that can be practised on an
industrial scale. This is the problem that the present inventors
have set out to address.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The entire disclosure of U.S. patent application Ser. No.
10/479,021, filed Aug. 5, 2004, is expressly incorporated by
reference herein.
[0009] Accordingly the present invention provides a process for the
production of a compound of general formula A: ##STR5## wherein
R.sup.c, R.sup.d and R.sup.e are independently H, alkyl, or
substituted alkyl; and R.sup.1 to R.sup.4 are independently H, OH,
OR' (R' is alkyl, aryl, substituted alkyl or aryl, silyl, acyl, or
phosphonate), alkyl, substituted alkyl, aryl, acyl, halide, amine,
nitrate, sulphonate or phosphonate; comprising reacting compound B
with compound C: ##STR6## wherein R.sup.a is H, alkyl, aryl, acyl
or silyl; R.sup.b is alkyl, aryl or acyl; R.sup.c, R.sup.d, R.sup.e
and R.sup.1 to R.sup.4 are as hereinbefore defined; and comprising,
when necessary, a ring closure reaction. Preferably the reaction of
compound B with compound C is carried out in the presence of an
acid catalyst.
[0010] A substituted alkyl group may contain substituents such as
halide, hydroxyl, amine and thiol. Alkyl groups may be saturated or
unsaturated, acyclic or cyclic.
[0011] Compound B is similar to the (+)-p-menth-2-ene-1,8-diol used
in the Stoss method. However, compound B is not a diol, and
contains one or more ether or ester groups. R.sup.b is alkyl, aryl
or acyl, and preferably R.sup.a is independently alkyl, aryl or
acyl.
[0012] In a preferred embodiment, R.sup.b is acyl, and OR.sup.b is
an ester group. Suitable ester groups include acetate, propionate,
butyrate, trimethylacetate, phenylacetate, phenoxyacetate,
diphenylacetate, benzoate, p-nitrobenzoate, phthalate and
succinate.
[0013] In an especially preferred embodiment both R.sup.a and
R.sup.b are acyl groups so that compound B is a diester. The two
ester groups are suitably chosen independently from acetate,
propionate, butyrate, trimethylacetate, phenylacetate,
phenoxyacetate, diphenylacetate, benzoate, p-nitrobenzoate,
phthalate and succinate. An especially preferred compound has
OR.sup.a=OR.sup.b=diphenylacetate: ##STR7## R.sup.c, R.sup.d and
R.sup.e can be varied independently of R.sup.a and R.sup.b and will
affect the structure of the product, compound A. R.sup.c is
suitably Me or H, preferably Me. R.sup.d and R.sup.e are suitably
Me or CH.sub.2OH, preferably Me.
[0014] Compound C is a phenolic compound and is preferably a
resorcinol derivative such as olivetol (3).
[0015] R.sup.1 is preferably OR'' wherein R'' is H, alkyl,
substituted alkyl, acyl or silyl. Most preferably R.sup.1 is
OH.
[0016] Preferably, R.sup.2 and R.sup.4 are H.
[0017] R.sup.3 is suitably an alkyl group or substituted alkyl
group. In a preferred embodiment, R.sup.3 is C.sub.5H.sub.11.
R.sup.3 may contain groups that promote water solubility, e.g.
ketone, ester, hydroxyl or amine groups. In one embodiment of the
invention, R.sup.3 contains a thioketal (this can be further
converted to an aldehyde).
[0018] Most preferably, compound C is olivetol (3), wherein R.sup.1
is OH, R.sup.2 is H, R.sup.3 is C.sub.5H.sub.11 and R.sup.4 is
H.
[0019] Suitably, one equivalent of compound B is reacted with
approximately one equivalent of compound C.
[0020] In a preferred embodiment of the invention compound B is an
ether or ester of (+)-p-menth-2-ene-1,8-diol (R.sup.c=Me,
R.sup.d=Me, R.sup.e=Me), compound C is olivetol (R.sup.1=OH,
R.sup.2=H, R.sup.3=C.sub.5H.sub.11, R.sup.4=H) and the product,
compound A, is .DELTA..sup.9-THC. ##STR8## The present invention
therefore provides a novel synthesis of .DELTA..sup.9-THC.
[0021] The present invention provides both a one-step and a
two-step process for the production of compound A. In the one-step
process the reaction of compound B and compound C produces compound
A directly. In the one-step process, suitably about one equivalent
of acid catalyst is used, e.g. between 0.8 to 1.5 equivalents.
Preferably the reaction is carried out below 0.degree. C., most
preferably from -20.degree. C. to 0.degree. C.
[0022] In the two-step process the reaction of compound B and
compound C produces a ring-opened product, compound D: ##STR9## For
the two-step process, suitably less than one equivalent of acid is
used, preferably from 0.1 to 0.5 equivalents. Preferably the
reaction is carried out below 0.degree. C., more preferably below
-10.degree. C. A ring closure step is then carried out. Suitable
reagents for the ring closure step include acids such as
BF.sub.3.(OEt).sub.2 or TsOH. One possible advantage of the
two-step process is that if compound D is a crystalline solid,
purification of the intermediate is straightforward and this may
lead to higher purity in the final product, compound A.
[0023] The present invention provides one-step and two-step
syntheses that can be used to produce .DELTA..sup.9-THC. The
syntheses show improved selectivity and yield compared to prior art
methods. The amount of isomers generated is small and purification
is simple. The phenolic reactant (compound C) is not used in
excess. The process is suitable for scale-up to an industrial
process.
[0024] Preferably the yield of the synthesis of .DELTA..sup.9-THC
is greater than 50%, more preferably the yield is greater than 75%.
The process also provides high purity .DELTA..sup.9-THC. Preferably
.DELTA..sup.9-THC is obtained in greater than 70% purity, more
preferably greater than 90% purity. Methods known in the art can be
used to further purify the products of the reaction.
[0025] The process of the present invention is suitably carried out
in a polar aprotic solvent, preferably methylene chloride.
[0026] Suitable acid catalysts include most Lewis acids.
Non-metallic catalysts such as BF.sub.3.OEt.sub.2 and
toluenesulfonic acid are preferred. Non-metallic catalysts offer
advantages over the zinc catalysts used in the Stoss and Razdan
methods because there is no possibility of a metal residue in the
product. BF.sub.3.OEt.sub.2 is preferred because it is easily
removed from the reaction mixture, and is less prone to causing
isomerisation of .DELTA..sup.9-THC to .DELTA..sup.8-THC than
p-TsOH. Suitably about one equivalent of catalyst or less is used,
e.g. 0.1 to 1.5 equivalents. This offers a clear improvement over
Razdan's method where 14 equivalents of acid are used.
[0027] Procedures for isolating the product, compound A, from the
reaction mixture are well known to those in the art. Chromatography
can be used to purify the product.
[0028] Certain compounds of structure B are novel and are
particularly advantageous when used in the present invention.
Compounds wherein both OR.sup.a and OR.sup.b are chosen
independently from acetate, propionate, butyrate, trimethylacetate,
phenylacetate, phenoxyacetate, diphenylacetate, benzoate,
p-nitrobenzoate, phthalate and succinate (provided that only one of
OR.sup.a and OR.sup.b is acetate) represent a further aspect of
this invention. Preferably the groups are chosen so that compound B
is a solid. Preferably both OR.sup.a and OR.sup.b are
diphenylacetate. Preferably, R.sup.c, R.sup.d and R.sup.e are
Me.
[0029] Compound B can be produced by a variety of methods.
Compounds wherein R.sup.a=H or silyl can be prepared by the
ring-opening of epoxides (5) with an alcohol, a carboxylic acid or
silylated derivatives of alcohols and carboxylic acids. Reactions
of this type are described in a co-pending patent application by
the present inventors. ##STR10##
[0030] Compounds wherein R.sup.a and R.sup.b are both the same can
be produced by base catalysed reaction of the corresponding diol
(6) with anhydrides or chlorides. ##STR11##
[0031] Compounds wherein R.sup.a is not H or silyl and wherein
R.sup.a and R.sup.b are different can be produced by base-catalysed
reaction of mono-ethers or mono-esters (7) with ethers or
chlorides. ##STR12## The following examples are illustrative but
not limiting of the invention.
GENERAL EXPERIMENTAL DETAILS
[0032] Anhydrous solvents were purchased from Aldrich Chemical
Company (Milwaukee, Wis., USA). Samples of .DELTA..sup.9-THC and
.DELTA..sup.8-THC were obtained from RBI/Sigma (Natick, Mass.,
USA). (+)-p-Menth-2-ene-1,8-diol was prepared as described in a
co-pending patent application by the present inventors. TLC plates
(silica gel GF, 250 micron, 10.times.20 cm) were purchased from
Analtech (Newark, Del., USA). TLCs were visualized under short wave
UV, and then by spraying with ceric ammonium nitrate/sulfuric acid
and heating. Column chromatography was carried out using TLC grade
silica gel purchased from Aldrich Chemical Company. NMR spectra
were obtained on a Bruker 300 MHz instrument. HPLC area percentages
reported here are not corrected. HPLCs were run on Shimadzu
LC-10AD.
EXAMPLE 1a
One-step Reaction of Bis(diphenylacetate) Compound (4) with
Olivetol (3) to Produce .DELTA..sup.9-THC
Preparation of Bis(diphenylacetate) Compound (4)
[0033] ##STR13##
[0034] A 25 ml three-necked roundbottom flask with a stir bar was
oven-dried, fitted with septa, and cooled under N.sub.2. Pyridine
(12 ml) was added and the pale yellow solution was stirred.
Diphenylacetyl chloride (5.69 g, 4.2 eq.) was added. The solution
turned brown. N,N-dimethylaminopyridine (0.1435 g, 0.2 eq.) was
added. The mixture was stirred for 1 hour.
(+)-p-Menth-2-ene-1,8-diol (1.00 g) was added. The mixture became a
lighter colour and solids precipitated. The slurry was allowed to
stir overnight at room temperature. The reaction was quenched with
water. The mixture was extracted three times with ethyl acetate.
The organics were combined and washed with 2M HCl, saturated
NaHCO.sub.3, and saturated NaCl (aq.), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to orange oil. The oil was
dissolved in hot methanol and cooled to crystallize. The white
solid was collected and washed twice with cold methanol. After
drying under vacuum, the yield was 3.282 g (76.8% yield). .sup.1H
NMR (CDCl.sub.3): .delta. (ppm) 7.4-7.2 (m, 20H), 5.89-5.84 (dd,
1H), 5.51-5.47 (dd, 1H), 4.90 (s, 2H), 2.7-2.6 (m, 1H), 2.0-1.9 (m,
2H), 1.7-1.6 (m, 1H), 1.43 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H),
1.35-1.2 (m, 1H). .sup.13C NMR: .delta. (ppm) 171.47, 171.44,
139.06, 138.84, 132.38, 128.64, 128.56, 128.51, 128.46, 128.28,
127.11, 127.07, 127.02, 85.12, 80.91, 58.32, 57.86, 44.22, 33.81,
25.41, 23.32, 22.81, 21.41. M.p. 111.degree. C. Elemental Analysis:
81.66% C, 6.59% H. R.sub.f (20% EtOAc/hexane): 0.54.
[.alpha.].sub.D.sup.25=+61.5.degree. (c=1.00, CHCl.sub.3). IR (KBr,
cm.sup.-1): 3061, 3028, 1720.5 (carbonyl stretch).
One-step Reaction
[0035] A 25 ml roundbottom flask with a stir bar was oven-dried,
fitted with septa, and cooled under N.sub.2. The
bis(diphenylacetate) (4) (279 mg, 0.499 mmol) and olivetol (90 mg)
were added. Anhydrous CH.sub.2Cl.sub.2 (8 ml) was added and
stirred. The solution was cooled to -5.degree. C. internal
temperature. BF.sub.3.(OEt).sub.2 (64 .mu.l, 1.0 eq.) was added.
The solution gradually darkened to orange. After 30 minutes, the
reaction was quenched with 10% Na.sub.2CO.sub.3 (10 ml). The layers
were separated and the organic layer was washed with 2.times.5 ml
10% Na.sub.2CO.sub.3. The aqueous washes were combined and
extracted twice with CH.sub.2Cl.sub.2. The organics were combined
and washed with water and saturated NaCl solution, then dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to light
yellow oil. The oil was chromatographed on 5 g TLC mesh silica to
yield 135.2 mg (86.1%) of .DELTA..sup.9-THC. NMR did show a small
amount of solvent present. HPLC showed 96.6 area percent
.DELTA..sup.9-THC. .sup.1H NMR agreed with published reports and
commercial samples. .sup.13C NMR (CDCl.sub.3): .delta. (ppm)
154.81, 154.16, 142.82, 134.41, 123.74, 110.11, 107.54, 77.18,
45.83, 35.47, 33.58, 31.52, 31.17, 30.63, 27.58, 25.03, 23.34,
22.53, 19.28, 13.99. HPLC R.T.: 28.34 min. R.sub.f (10%
MTBE/hexane): 0.30. [.alpha.].sub.D.sup.25=-174.2.degree. (c=1.16,
EtOH).
EXAMPLE 1b
Reaction of Bis(diphenylacetate) (4) Compound with Olivetol to
Produce Ring-open Intermediate
[0036] Bis(diphenylacetate) (4) was prepared as for example 1a.
[0037] A 25 ml 2-neck roundbottom flask with a stir bar was
oven-dried, fitted with septa, and cooled under N.sub.2.
Bis(diphenylacetate) (4) (279 mg, 0.499 mmol) and olivetol (90 mg)
were added. Anhydrous CH.sub.2Cl.sub.2 (8 ml) was added. The
solution was stirred to dissolve the solids and then cooled to
-20.degree. C. internal temperature. BF.sub.3.(OEt).sub.2 (16
.mu.l, 0.25 eq.) was added. The solution was stirred for 12 minutes
and then quenched with 10% Na.sub.2CO.sub.3 (aq.) (6 ml). The
mixture was extracted twice with CH.sub.2Cl.sub.2. The combined
organics were washed with water and saturated NaCl, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to oil.
Chromatography on 10 g TLC mesh silica gel (2% MTBE/hexane-15%)
yielded .DELTA..sup.9-THC (fractions 16-22, 31.4 mg, 20.0% yield),
but the predominant product was the diphenylacetate triol (the ring
open product corresponding to compound D) (fr. 24-37, 160 mg, 60.7%
yield). .sup.1H NMR (CDCl.sub.3): .delta. (ppm) 7.26-71.8 (m, 10H),
6.26 (br s, 1H), 6.04 (br s, 1H), 5.35 (s, 1H), 4.51 (s, 1H), 3.92
(br d, 1H), 2.43-2.36 (m, 3H), 2.1-1.9 (m, 2H), 1.79 (m, 1H), 1.71
(s, 3H), 1.6-1.4 (m, 2H), 1.44 (s, 3H), 1.42 (s, 3H), 1.3-1.2 (m,
4H), 0.85 (t, 3H). .sup.13C NMR (CDCl.sub.3) .delta. ppm 171.56,
142.87, 139.24, 139.08, 128.64, 128.36, 128.31, 126.92, 126.89,
124.93, 115.43, 87.27, 57.53, 45.94, 35.43, 33.46, 31.51, 30.60,
29.96, 24.04, 23.34, 23.20, 23.17, 22.48, 13.97. R.sub.f (20%
EtOAc/hexane): 0.48. [.alpha.].sub.D.sup.25=-45.9.degree. (c=1.298,
CHCl.sub.3). Elemental Analysis: 78.69% C, 8.93% H.
EXAMPLE 2a
One-step Reaction of Monoacetate Compound (8) with Olivetol to
Produce .DELTA..sup.9THC
[0038] ##STR14##
[0039] A 25 ml roundbottom flask with a stir bar was oven-dried,
fitted with septa, and cooled under N.sub.2. The monoacetate (8)
(109 mg) and olivetol (92.5 mg) were added. Anhydrous
CH.sub.2Cl.sub.2 (8 ml) was added and stirred. The solution was
cooled to -5.degree. C. internal temperature. BF.sub.3.(OEt).sub.2
(65 .mu.l, 1.0 eq.) was added. The solution gradually darkened to
orange. After 24 minutes, the reaction was quenched with 10%
Na.sub.2CO.sub.3. The layers were separated and the aqueous layer
was extracted twice with CH.sub.2Cl.sub.2. The organics were
combined and washed with water and saturated NaCl solution, then
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to
oil. HPLC showed 64.0 area percent .DELTA..sup.9-THC. The oil was
chromatographed on 20 g TLC mesh silica to yield 58.7 mg (36.3%) of
.DELTA..sup.9-THC. .sup.1H NMR agreed with published reports and
commercial samples.
EXAMPLE 2b
Reaction of Monoacetate Compound (8) with Olivetol to Produce
Ring-open Intermediate
[0040] A 25 ml 2-neck roundbottom flask with a stir bar was
oven-dried, fitted with septa, and cooled under N.sub.2. The
monoacetate (8) (109 mg, 0.514 mmol) and olivetol (92.5 mg) were
added. Anhydrous CH.sub.2Cl.sub.2 (8 ml) was added. The solution
was stirred to dissolve the solids and then cooled to -20.degree.
C. internal temperature. BF.sub.3.(OEt).sub.2 (16 .mu.l, 0.25 eq.)
was added. The solution was stirred for 45 minutes and then
quenched with 10% Na.sub.2CO.sub.3 (aq.) (4 ml). The mixture was
extracted twice with CH.sub.2Cl.sub.2. The combined organics were
washed with water, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo to a colourless oil. Chromatography on silica
gel yielded 90.5 mg (47.0% yield) of acetyl triol (the ring open
product corresponding to compound D). .sup.1H NMR (CDCl.sub.3):
.delta. (ppm) 6.22 (br m, 2H,), 5.76 (br s, 2H), 5.36 (s, 1H), 4.00
(br d, 1H), 2.67 (dt, 1H), 2.40 (t, 2H), 2.26-2.16 (br m, 2H,),
2.07-1.90 (m, 2H), 1.73 (s, 3H), 1.51 (s, 3H), 1.49 (s, 3H), 1.42
(s, 3H), 1.32-1.24 (m, 4H), 0.85 (t, 3H). .sup.13C NMR
(CDCl.sub.3): .delta. (ppm) 170.83, 142.69, 138.03, 124.99, 115.42,
85.90, 44.29, 35.38, 33.47, 31.49, 30.66, 30.09, 25.16, 24.65,
23.17, 22.57, 22.43, 21.84, 13.95. R.sub.f (20% EtOAc/hexane):
0.37.
EXAMPLE 3a
One-step Reaction of Monomethoxy Compound (9) with Olivetol to
Produce .DELTA..sup.9-THC
[0041] A 25 ml roundbottom flask with a stir bar was oven-dried,
fitted with septa, and ##STR15## cooled under N.sub.2. The
monomethoxy compound (9) (91.9 mg) and olivetol (90 mg) were added.
Anhydrous CH.sub.2Cl.sub.2 (8 ml) was added and stirred. The
solution was cooled to -5.degree. C. internal temperature.
BF.sub.3.(OEt).sub.2 (16 .mu.l, 0.25 eq.) was added. After 1 hour
another 16 .mu.l was added. Two hours later, another 32 .mu.l was
added. The solution gradually darkened to orange. TLC showed a
mixture of .DELTA..sup.9-THC and the ring open product, and two
other major spots. The reaction was quenched with 10%
Na.sub.2CO.sub.3. The layers were separated and the organic was
washed with water and sat. NaCl, then dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo to oil.
EXAMPLE 3b
Reaction of Monomethoxy Compound with Olivetol to Produce Ring-open
Intermediate
[0042] A 5 ml roundbottom flask with a stir bar was oven-dried,
fitted with a septum, and cooled under N.sub.2. The monomethoxy
compound (9) (33.5 mg) in 1.5 ml of anhydrous methylene chloride
was added. Olivetol (32.7 mg) and magnesium sulfate (134 mg) were
added. p-Toluenesulfonic acid monohydrate (34.6 mg) was added. The
slurry was stirred at room temperature for 30 minutes. Solid
NaHCO.sub.3 (100 mg) was added and stirred. The solids were removed
by filtration. The solution was washed once with 5% NaHCO.sub.3
(aq.). The aqueous wash was extracted once with CH.sub.2Cl.sub.2.
The organics were combined, washed with water, and dried over
Na.sub.2SO.sub.4. The solution was concentrated in vacuo and
chromatographed on silica gel. Colourless oil of the methoxy triol
(the ring open product corresponding to compound D) (35.3 mg, 56.0%
yield) was obtained. .sup.1H NMR (CDCl.sub.3): .delta. (ppm) 7.90
(br s, 1H), 6.68 (br s, 1H), 6.33-6.21 (br d, 2H) 5.75 (s, 1H),
3.74 (s, 1H), 3.20 (s, 3H), 2.44 (t, 2H), 2.07 (br s, 2H),
2.00-1.77 (m, 3H), 1.80 (s, 3H), 1.54 (m, 2H), 1.31 (m, 3H), 1.14
(s, 3H, 1.13 (s, 3H), 0.87 (t, 3H). .sup.13C NMR (CDCl.sub.3):
.delta. (ppm) 186.50, 169.63, 166.85,143,41, 140.11, 123.58, 79.32,
48.63, 48.05, 35.51, 32.62, 31.52, 30.63, 27.76, 23.74, 23.01,
22.53, 21.95, 20.39, 13.99. Elemental Analysis: 73.3% C, 8.80% H.
R.sub.f (10% EtOAc/hexane): 0.25.
[.alpha.].sub.D.sup.25=-22.7.degree. (c=0.088, CHCl.sub.3).
EXAMPLE 4
One-step Reaction of Diacetate (10) with Olivetol to Produce
.DELTA..sup.9-THC
Preparation of Diacetate (10)
[0043] ##STR16##
[0044] A 100 ml three-necked roundbottom flask with a stir bar was
oven-dried, fitted with septa, and cooled under N.sub.2.
(+)-p-menth-2-ene-1,8-diol (10.00 g) was added. Triethylamine (68.7
ml, 8.4 eq.) was added and the slurry was stirred.
N,N-dimethylaminopyridine (1.435 g, 0.2 eq.) was added. Acetic
anhydride (23.3 ml) was placed in an addition funnel and added
slowly over 15 minutes. The yellow solution became homogeneous. The
solution was warmed to 35.degree. C. internal temperature and
stirred for 2.5 ours, then raised to 40.degree. C. for another
three hours, then allowed to stir for 13 hours at room temperature.
The reaction was quenched with water while cooling in ice. The
mixture was extracted three times with hexane and once with ethyl
acetate. The organics were combined and washed with saturated NaCl
(aq.), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to an orange oil. Chromatography on 50 g TLC mesh silica
yielded the diacetate (10) as a colourless oil (12.3 g, 82.3%). The
oil was cooled in dry ice to freeze the oil and then the solid was
broken up with a spatula. It was allowed to warm to room
temperature and it remained a white solid. .sup.1H NMR
(CDCl.sub.3): .delta. (ppm): 5.84 (dd, 1H), 5.54 (dd, 1H), 2.70 (m,
1H), 2.05-1.8 (m, 3H), 1.85 (s, 6H), 1.68 (m, 1H), 1.40 (s, 3H),
1.30 (s, 3H), 1.29 (s, 3H). .sup.13C NMR (CDCl.sub.3): .delta.
(ppm) 169.95, 169.89, 132.40, 127.88, 83.79, 79.73, 43.62, 33.85,
25.26, 23.10, 22.74, 22.05, 21.49. m.p. 28-31.degree. C. Elemental
Analysis: 65.26% C, 8.61% H. R.sub.f (20% EtOAc/hexane): 0.52.
[.alpha.].sub.D.sup.25=+73.5.degree. (c=0.99, CHCl.sub.3).
One-step Reaction
[0045] A 25 ml roundbottom flask with a stir bar was oven-dried,
fitted with septa, and cooled under N.sub.2. The diacetate (10)
(126.9 mg, 0.499 mmol) and olivetol (90 mg, 0.499 mmol) were added.
Anhydrous CH.sub.2Cl.sub.2 (8 ml) was added and stirred. The
solution was cooled to -5.degree. C. internal temperature.
BF.sub.3.(OEt).sub.2 (64 .mu.l, 1.0 eq.) was added. The solution
gradually darkened to red. After 15 minutes, the reaction was
quenched with 10% Na.sub.2CO.sub.3. The layers were separated and
the organic layer was washed with 10% Na.sub.2CO.sub.3. The
combined aqueous were extracted once with CH.sub.2Cl.sub.2. The
organics were combined and washed with water and saturated NaCl
solution, then dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo to a tannish oil (0.132 mg). HPLC showed 88.8
area percent .DELTA..sup.9-THC. Chromatography on silica gel
yielded 95.9mg (61.0% yield) of .DELTA..sup.9-THC. HPLC showed 94.9
area percent .DELTA..sup.9-THC.
EXAMPLE 5
One-step Reaction of Dibenzoate (11) with Olivetol to Produce
.DELTA..sup.9-THC
Preparation of Dibenzoate (11)
[0046] ##STR17##
[0047] A 25 ml three-necked roundbottom flask with a stir bar was
oven-dried, fitted with septa, and cooled under N.sub.2.
(+)-p-Menth-2-ene-1,8-diol (1.00 g) was added. Pyridine (6 ml, 12.6
eq.) was added and the pale yellow solution was stirred.
N,N-dimethylaminopyridine (0.1435 g, 0.2 eq.) was added. Benzoyl
chloride (2.73 ml, 4 eq.) was added. After 10 minutes, a solid
precipitated. The slurry was allowed to stir overnight at room
temperature. The reaction was quenched with water. The mixture was
extracted three times with CH.sub.2Cl.sub.2. The organics were
combined and washed with water and saturated NaCl (aq.), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The oil was
chromatographed on 25 g TLC mesh silica to yield a colourless oil.
The oil was cooled in dry ice and froze, but melted on warming to
room temperature. .sup.1H NMR(CDCl.sub.3) .delta. (ppm): 8.0 (dt,
4H), 7.51 (m, 2H), 7.40 (dt, 4H), 6.16 (dd, 1H), 5.88 (dd, 1H),
3.00 (m, 1H), 2.29 (m, 2H), 2.02 (m, 1H), 1.70 (s, 3H), 1.62 (s,
3H), 1.60 (s, 3H), 1.25 (m, 1H). .sup.13C NMR (CDCl.sub.3) .delta.
(ppm): 165.53, 132. 80, 132.53, 132.50, 131.77, 131.63, 129.40,
129.36, 128.39, 128.22, 128.16, 80.64, 44.55, 34.09, 25.81, 23.50,
23.10, 22.59, 21.99, 14.14, 14.05. Elemental Analysis: 76.21% C,
6.97% H. R.sub.f (20% EtOAc/hexane): 0.57.
One-step Reaction
[0048] A 25 ml roundbottom flask with a stir bar was oven-dried,
fitted with septa, and cooled under N.sub.2. The dibenzoate (11)
(189 mg, 0.499 mmol) and olivetol (90 mg) were added. Anhydrous
CH.sub.2Cl.sub.2 (8 ml) was added and stirred. The solution was
cooled to -5.degree. C. internal temperature. BF.sub.3.(OEt).sub.2
(64 .mu.l, 1.0 eq.) was added. The solution gradually darkened to
red. After 15 minutes, the reaction was quenched with 10%
Na.sub.2CO.sub.3. The layers were separated and the organic layer
was washed with water and saturated NaCl solution, then dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to oil. HPLC
showed 78.8 area percent .DELTA..sup.9-THC.
EXAMPLE 6
One-step Reaction of Di-p-nitrobenzoate (12) with Olivetol to
Produce .DELTA..sup.9-THC
Preparation of Di-p-nitrobenzoate (12)
[0049] ##STR18##
[0050] A 25 ml three-necked roundbottom flask with a stir bar was
oven-dried, fitted with septa, and cooled under N.sub.2.
(+)-p-Menth-2-ene-1,8-diol (1.00 g) was added. Pyridine (6 ml, 12.6
eq.) was added and the pale yellow solution was stirred.
N,N-dimethylaminopyridine (0.1435 g, 0.2 eq.) was added.
p-Nitrobenzoyl chloride (4.58 ml, 4.2 eq.) was added. After a few
minutes, tan solid precipitated. More pyridine (12 ml) was added.
The slurry was allowed to stir overnight at room temperature. The
reaction was quenched with water. The mixture was extracted three
times with ethyl acetate. The organics were combined and washed
twice with saturated NaCl (aq.), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to light yellow solid. The solid
was recystallized from isopropyl alcohol and dried under vacuum.
The yield was 3.303 g (120% yield), which clearly still contained
pyridine and isopropyl alcohol by NMR. It was dried more and then
recrystallized from ethyl acetate/hexane to give a lightly coloured
solid (1.89 g, 68.7%). .sup.1H NMR (d.sub.6-acetone) still seemed
to have too many aryl protons. .sup.1H NMR (CD.sub.2Cl.sub.2)
.delta. (ppm): 8.3-8.2 (m, 4H), 8.2-8.1 (m, 4H), 6.14 (dd, 1H),
5.88 (d, 1H), 3.04 (m, 1H), 2.29 (m, 2H), 2.00 (m, 1H), 1.70 (s,
3H), 1.62 (s, 3H), 1.60 (s, 3H0, 1.67-1.65 (m, 2H). .sup.13C NMR
(CD.sub.2Cl.sub.2) .delta. (ppm): 164.275, 164.244, 151.00, 133.00,
131.46, 131.09, 131.04, 129.29, 124.00, 123.96, 87.04, 82.75,
45.00, 34.55, 26.10. 23.83, 23.45, 22.64. m.p >200.degree. C.
(decomposition). Elemental Analysis: 59.68% C, 4.71% H, 6.07% N.
R.sub.f (20% EtOAc/hexane): 0.41.
[.alpha.].sub.D.sup.25=+38.0.degree. (c=0.21, CHCl.sub.3).
One-step Reaction
[0051] A 10 ml roundbottom flask with a stir bar was oven-dried,
fitted with septa, and cooled under N.sub.2. The di-p-nitrobenzoate
(12) (116.5 mg) and olivetol (45 mg) were added. Anhydrous
CH.sub.2Cl.sub.2 (4 ml) was added and stirred. The solution was
cooled to -5.degree. C. internal temperature. BF.sub.3.(OEt).sub.2
(32 .mu.l, 1.0 eq.) was added. The cloudy solution gradually
darkened to orange. After 2 hours, the reaction was quenched with
10% Na.sub.2CO.sub.3. The layers were separated and the organic
layer was washed with water and sat. NaCl, then dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to yellow
oil. HPLC showed 71.5 area percent .DELTA..sup.9-THC.
* * * * *