Note: Descriptions are shown in the official language in which they were submitted.
~ 21 76763
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FIELD OF T~E INVENTION
This invention relates to organometallic synthetic
processes and organometallic compounds useful therein. More
specifically, it relates to methods of making organo-copper
compounds which are useful in preparation of pharmaceutically
active synthetic prostaglandin-type compounds.-
~
Ra~R~o~Nn OF ~l~ INVENTION AND PRIOR ART
CAnA~;an Patent 1,040,197 Pappo et. al. describes16-oxygenated prostanoic acid derivatives and processes for
their preparation. At least one of the compounds described in
thispatent,namely(11~,13E)-(+)-11,16-dihydroxy-16-methyl-9-
oxoprost-13-en-1-oic acid, methyl ester, the generic name of
which is misoprostol, has gained significant pharmaceutical
and commercial acceptance as an inhibitor of gastric acid
secretion. It has the following structural chemical formula:
~_"r \/ CO. O. C~13
C~3
~0
OH
The synthetic method for preparing misoprostol and
s;~;lAr compounds disclosed in the aforementioned Pappo et.al.
~' ' 21 767~3 - 2 -
patent involves the preparation of a lower order lithium
cuprate having unsaturated organic radicals associated with
the copper ion, and the reaction of this lower order lithium
cuprate with an appropriately chosen cyclopentenone, which in
the case of misoprostol synthesis is methyl 7-(3RS)-
tetrahydropyran-2-yloxy-5-oxocyclopent-1-ene)heptanoate. The
lower order lithium cuprate used in this process, which in the
ca~e of misoprostol synthesis can be represented by the
formula: .
c~3
CH3 (C~ _C- C ~cl~=cH-c~ C~l C~,3
is made by a relatively complicated, multi-step process. The
process involves reaction of an acetylenic alcohol with a
trialkylsilyl halide to obtain the corresponding trialkylsilyl
ether, addition of diisobutyl alllm;nllm hydride across the
acetylenic bond to produce the corresponding alkenyl all~m;nllm
derivative, reaction of this with iodine to obtain the silyl-
protected l-alkenyl iodide, and contact of this 1-alkenyl
iodide with a lithium alkyl to form 1-alkenyl lithium which
reacts with a cuprous acetylide to form the required lithium
cuprate reagent.
~- ' 2176763
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Canadian patent 1,311,490 Campbell et.al. describes
an improved and simplified process for preparing
prostagl~nA;n~ such as misoprostol, using higher order
cuprates which will undergo -conjugate addition to
cyclopentenones. The higher order cuprates are prepared from
vinyl st~nn~ne compounds, which are much easier to prepare
than the vinyl iodides used in the Pappo ~t. al. patent
process. These higher order cuprates are formed by-reacting a
higher order cuprate complex of formula:
CH3
C~ C ~ Li
C ~l3~
with a st~nn~n~ of general formula Rt.Sn.(R2)3. The group Rt
from the st~nn~ne, which is a carbanion and is normally an
unsaturated group corresponding to the side chain required in
the final prostaglandin compound, exchanges with one of the
methyl groups on the cuprate complex, presumably to form a
15 m; ~PA higher order cuprate of the formula :
Cu - CN Li2
R/
CA 02176763 1998-04-08
Alternative ligands to cyanide suggested in the Campbell et.
al. patent are thiocyanate -SCN, sulfonyl-trifluoromethyl and
thiophenyl, although only cyanide and thiocyanate are
specifically exemplified.
It appears to be essential that the complex with vinyl
group-containing ligands for reaction with enones such as
cyclopentenones in prostaglandin synthesis be a copper
complex. The straightforward reaction sequence to produce
such a complex, where stannanes carrying the required vinyl
group for addition onto the cyclopentenone nucleus are to be
used, would be reaction of the appropriate vinyl stannane
compound with an alkyl lithium such as n-butyllithium to form
a lithium vinyl species. This lithium vinyl compound could
then be reacted with an organometallic copper compound, to
exchange the vinyl group from the lithium compound with an
organic radical from the copper compound, and hence produce
the cuprate complex ready for reacting with the enone.
However, the reaction of the alkyl lithium with the vinyl
stannane will only take place at extremely low temperatures.
The process disclosed in the Campbell et.al. patent overcomes
this problem by first reacting the alkyl lithium with cuprous
cyanide to obtain a first higher order complex, which is
capable of reacting with the vinyl stannane at reasonable
temperatures, to form a higher order cuprate capable of
appropriate reaction with an enone.
-- 2 ~ ~ 6 ~ 6 3
- 5 -
The presence of ligands such as cyanide, with an
empty ~ electronic orbital, on the cuprate complex has
heretofore been believed to be necessary for the formation of
higher order cuprate complexes with lithium alkyls (ref. 1).
According to prior art teachings, copper halides such as
iodides and bromides do not form higher order cuprates, making
necessary the use of copper cyanide and the l~ke as starting
materials (ref. 1 & 2~. This is unfortunate and u~desirable,
because of the highly toxic nature of copper cyanide. This
renders it hazardous to handle, and severely complicates waste
disposal problems of wash waters from a process which involves
its use.
It is an object of the present invention to provide
novel processes for making cuprate complexes capable of
reacting with enone compounds.
It is a further object of the invention to provide
such a process which avoids the use of toxic cyanide
compounds.
S~MMARY OF ~l-n~ INVENTION
According to the present invention, it has been
discovered that organometallic cuprate complexes capable of
reacting with ~no~eR to effect addition of an organic radical
2~ 76763
- 6 -
from the cuprate onto ~he enone, can be prepared by reaction
of an alkyl lithium compound with a cuprous halide and
reaction of the resulting complex with a vinyl stannane,
provided that an excess amount of alkyl lithium is used
initially and is present during the reaction to form the
organometallic cuprate complex. Under such conditions, the
vinyl group from the st~nn~n~ successfully t~ansfers to the
cuprate, to form a complex which readily reacts with an enone
e.g. a cyclopentenone to form a prostaglandin carrying the
vinyl group originally in the stAnn~ne compound, as a
substituent.
The process of the present invention thus not only
adopts a new chemical approach, but also permits the use of
simple and readily available starting materials, e.g. methyl
lithium and a cuprous halide, and avoids the need for the
highly toxic cuprous cyanide or the like. The reactions
proceed smoothly at reasonable temperatures, to give good
yields of intermediate and final products. Cuprous halides
used in the process of the present invention copper (I)
iodide, copper (I) bromide, copper chloride (I) and copper (I)
fluoride, with the fluoride being the least preferred and the
iodide and bromide being the most preferred.
The first stage in the process according to the
invention is the reaction of the alkyl lithium (e.g. methyl
~-' , 217676 3
lithium) with the cuprous halide. This requires a
stoichiometry of two equivalents of methyl lithium and one
equivalent of cuprous halide, to produce the lower order
cuprate. The process of the invention, however, uses more than
two equivalents of alkyl lithium, to provide a small excess of
alkyl lithium in the reaction but not such a large excess as
to promote excessive side reactions. However, if exactly two
equivalents, or less than two equivalents, of alkyl lithium
are used, little or no reaction is observed.
Thus according to one aspect of the present
invention, there is provided a process for preparing an
organometallic cuprate complex carrying an organic unsaturated
ligand, said cuprate complex being capable of reaction with an
enone to effect addition of the organic unsaturated ligand
from the cuprate complex onto the enone, which comprises
reacting from about 2.05 to 4 equivalents of lower alkyl
lithium with one equivalent of a cuprous halide, and reacting
the product thereof with a vinyl st~nn~n~ compound of the
general formula:
R
R,
~ ~ .
2 1 76763
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in which each of R, Rl, and R2 is an independently selected
lower alkyl radical and Y is an optionally substituted vinyl
group.
DESCRIPTION OF THE PREFERRED RMRODIMENTS
The process of the invention is; best further
described and illustrated with reference to the use of methyl
lithium and cuprous iodide as the starting materials, the
preferred embodiments thereof. However, it is not to be
construed as limited thereto. It will be readily apparent that
other lower alkyl (C1 to C6) lithium compounds and other
cuprous halides as outlined above can also be used.
The chemical mechanism by which the process of the
present invention proceeds is not currently fully understood.
The presence of excess alkyl lithium e.g. methyl lithium is
essential for the successful operation of the process
according to the invention. If only the stoichiometric amount
(2 equivalents thereof) is used, no complex able to react with
an enone is formed.
The extent of excess of the methyl lithium needs to
be only small. The reaction proceeds satisfactorily if only a
very small, catalytic amount of methyl lithium is present,
over and above the stoichiometric two equivalents. Suitably
21 76763
~_ g
at least about 2.05 equivalents of methyl lithium per
equivalent of cuprous iodide. The upper limit of methyl
lithium amount is dictated primarily by the need to minimize
side reactions. It is preferred for practical reasons, for
example, to continue with the reaction of the cuprate complex
- with the enone to prepare the prostaglandin, without removing
from the reaction mixture the by-productsj;and unreacted
starting materials from the synthesis of the cuprate complex.
If there is too much residual methyl lithium at this stage,
1,2-addition to the ketone (cyclopentenone) may occur, to
produce unwanted by-products and reduce overall yield.
Preferably, therefore, the amount of methyl lithium does not
exceed about 4 equivalents per equivalent of cuprous halide,
the most preferred range being from about 2.1 : 1 to about
2.25 : 1, and the optimum being about 2.2 equivalents.
The group Y, initially part of the stAnnAne
reactant, can be substantially any vinyl group-containing
radical which is desired to be substituted onto a
cyclopentenone nucleus to form a pharmaceutically active
prostaglandin compound. This group Y in general corresponds
to the formula:
- CH = CH - C - C - R,
l l
R~ R6
21 76763
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in which R3, R4, Rs~ and R6 are independently selected from
hydrogen, C1 to C6 alkyl, Cl to C6 alkoxy, vinyl, hydroxy and
protected hydroxy, and R7 is C2 to C4 straight chain alkyl
optionally interrupted by an ether linkage, or phenoxy.
Preferred groups Y are those in which R7 represents n-butyl
and Rs represents protected hydroxyl. Substantially any of the
chemical groups conventionally used in organic synthetic
chemistry to protect hydroxyl groups from chemical- reaction,
as set out in the standard literature, can be used as the
hydroxyl protectant in the process of the present invention.
Most preferred groups Y are those in which R7 represents n-
butyl, R3 and R4 represent hydrogen, R6 represents methyl and
Rs repre~ents protected hydroxyl, e.g. oxytrimethylsilyl
protected hydroxyl.
The reaction of the excess methyl lithium with
cuprous iodide suitably takes place in solution in an organic
solvent, under strictly anhydrous conditions, since alkyl
lithium compounds are extremely sensitive to water. The time
of the reaction i~ suitably from about 5 minutes to two hours.
The temperature of the reaction is suitably in the range -30~C
- 10~C. Suitable solvents include tetrahydrofuran,
dimethoxyethane, diethoxymethane, diethyl ether, diisopropyl
ether, t-butylmethyl ether and the like.
- CA 02176763 1998-04-08
The vinyl stannane compound, e.g. with R1, R2 and R being
butyl, which is prepared separately, is added to the reaction
mixture from the previous step. The conclusion of this
reaction is signified by the presence of methyltributyl tin
and the disappearance of the vinyl stannane compound and
usually takes from about 5 minutes to about two hours. The
order of addition of methyllithium or vinyl stannane compound
is in general not critical and can be reversed. Methods of
preparation of the appropriate vinyl stannane compounds are
known, and form no part of the invention herein. In the case
of misoprostol preparation using the process of the present
invention, the vinyl stannane compound may have the formula:
fH3
CH3-CH2-CH2-CH2-f-CH2-CH=CH-Sn(C4H7)3
OSi(CH3)3
The vinyl stannane is added to the reaction mixture
resulting from the reaction of the excess methyl lithium with
cuprous iodide or bromide, without separating or isolating the
reaction products and unreacted starting materials therefrom.
The relative amounts of vinyl stannane and other reactants is
relatively unimportant at this stage of the process, but is
preferable about equimolar with the starting amount of cuprous
iodide or bromide. The same organic solvent and generally the
'i 21 76763
~ - 12 - 2176763
same reaction conditions as in the stage of reaction of the
methyl lithium with the cuprous iodide or bromide can be used
in this stage also. After the conclusion of the reaction of
the vinyl stannane with the products of the earlier reaction,
a process which normally takes about 5 minutes to two hours
and the conclusion of which is indicated by the presence of
methyltributyl tin and the disappearance of th~ vinyl stannane
compound, the substituted cyclopentenone for formation of the
prostaglAn~;n can be added directly to the resulting reaction
mixture, without the need to separate the resulting reaction
products from the unreacted starting materials and by-
products.
The preparation of the substituted cyclopentenone is
also known procedure, and constitutes no part of the present
invention. In the case of misoprostol preparation using the
process of the present invention, the cyclopentenone may have
the general formula, where Z is an appropriate protecting
group:
O
~C~ ~.
ZO 3
For preparation of other prostaglandin compounds by
the process of the present invention ~e.g. arbaprostil,
21 ~6~-~3
- 13 -
gemeprost, trimoprostil, rioprostil, enprostil, enisoprost and
viprostol), the substituent at position-1 of the cyclopenten-
one ring will differ from that for preparation of misoprostol,
e.g. in the presence of ethylenic unsaturation in the chain
and/or in the identity of the end group. Such differences do
not alter the course of the reaction of the cuprate complex
made according to the invention, to any significant extent. In
general, the group at the 1-position of the cyclopentenone can
be represented as R8X, where R8represents a C6 - C7 straight-
chain, saturated or unsaturated aliphatic hydrocarbon group,and X represents a carboxyl group, a lower alkyl esterified
carboxyl group, a hydroxy group or a carbonyl-hydroxymethyl
group. Similarly, other protectants may be used for the
hydroxyl group at position-3.
The coupling reaction of the cuprate complex with
the protected enone, which is in effect an addition reaction
across the cyclopentene ring double bond, is effected by
simply adding the protected enone to the reaction mixture in
which the cuprate complex has been formed and is contained.
The temperature of the reaction is suitably in the range from
0~C to -80~C, preferably -50~C to -80~C.
The crude, protected prostaglandin obt~;ne~ can be
deprotected and purified by st~n~rd methods to provide
misoprostol.
21 76763
- 14 -
The invention is further described, for illustrative
purposes, with reference to the following specific examples
DESCRIPTION OF TEE SPECIFIC, MOST PREFERRED EMBODIMENTS
- EXAMPLE 1
To a 1000 ml dried flask under a nitrogen atmosphere was added
74.6g of (E)-trimethyl[[1-methyl-1-[3-(tributylstannyl)-2-
propenyl]pentyl]oxy]silane, 125 ml anhydrous THF and 24.2 g of
copper (I) iodide. The mixture was stirred at room temperature
for 30 minutes and then it was cooled to -25~C to -30~C. 98.8
ml of methyllithium (2.86 M) in DEM was added dropwise and the
resultant solution was stirred at -15~C for 2 hours. Then the
reaction mixture was cooled to -78~C to -80~C and 25g of
methyl 5-oxo-3-[(triethylsilyl)oxy]-1-cyclopentene-1-
heptanoate in 100 ml of THF was added rapidly. After stirring
the mixture for 5 minutes at -78~C, it was quenched into a
mixture of 750 ml of aqueous ~m~o~;um chloride solution and
200 ml of ~mmon;um hydroxide. The resulting mixture was warmed
to room temperature and stirred until a deep blue aqueous
layer was obt~;n~A. Ethyl acetate (2x250 ml) was used for
extraction. Then the combined organic layers were washed with
brine (2x150 ml) and subsequently dried over magnesium
sulfate. After a filtration and concentration under reduced
pressure, an oil (105 g) was obt~;neA. This oil cont~;n;ng the
,
2~ 76763
- 15 -
protected prostaglandin was subjected to acidic deprotection
(cat.PPTS, acetone and water) and purification (chromatography
on silica gel) to provide 15.8 g (60~) of misoprostol. This
product was identical (lH NMR, l3C NMR and IR) to a standard
sample of misoprostol.
EXAMPLE 2
-
To a 300 ml dried flask under a nitrogen atmosphere was added
4.45g of copper (I) iodide and 60 ml of anhydrous THF. The
mixture was cooled to 0~C. 35 ml of 1.4M methyllithium in
diethyl ether was added dropwise and the resultant solution
was stirred at 0~C for 30 minutes. 13.7g of (E)-trimethyl[[1-
methyl-1-[3-(tributylstannyl)-2-propenyl]pentyl]oxy]silanein
5 ml of THF was added and then the mixture was stirred at O C
for 30 minutes. Then an additional 1.5 ml of 1.4M
methyllithium in diethyl ether was added and the mixture was
stirred at 0~C for another 30 minutes. The reaction mixture
was cooled to -78~C and 10 g of methyl 5-oxo-3-[(triethyl-
silyl)oxy]-1-cyclopentene-1-heptanoate in 10 ml of THF was
added rapidly. After stirring the mixture for 5 minutes at -
78~C, it was quenched into 210 ml of basic aqueous ammonium
chloride solution. The resulting mixture was warmed to room
temperature and stirred until a deep blue aqueous layer was
obtA; n~ . Ethyl acetate (2x200 ml) was used for extraction.
Then the combined organic layers were washed with water (10
. 2176763
'_
- 16 -
ml), then with brine (25 ml) and subsequently dried over
magnesium sulfate. After a filtration and concentration under
reduced pressure, an oil (21 g) was obtained. This oil
containing the protected prostaglandin was subjected to acidic
deprotection (cat.PPTS, acetone and water) and purification
(chromatography on silica gel) to provide 4.2 g (40~)
misoprostol. .
' 2~ 76763
- 17 -
REFERENCES
1. "Organometallics in Synthesis: A Manual", Chapter
4, page 283-382; B.H.Lipshutz, Edited by M
Schlosser, John Wiley & Sons, 1994.
2. B.H. Lipshutz, Synthesis, 325 (1987~.
