Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
W O 93/22269 2 1 3 `'~ O ~ 3 PCT/US9~/00726
5PROCESS FOR THE PREPARATION OF 3 (S)-METHYLHEPTANOIC ACID :
AND INTERMEDIATES THEREFOR``
. ~
Backqround of the Invention
The present invention is directed to a process and intermediates for the
10manufacture of 3~S)-methylheptanoic acid of the absolute stereochemical formula (I)
C H 3~"~H
15~ COOH `,~
;
() I ~
which is a useful interrnediate for the preparation of immunoregulatory agents of the !
20 formula (Il)
CH~ H o H ooR4 H OCH~<H
~N4~,N~N ~2R5;
- -H o H
j~ 25 S -- D`-- - D ``
I!!)
wherein R4 and R5 are each hydrogen oc one of R4 and Rs j5 hydrogen and the other
is (Cl-C6)alkyl or (C0-C3)cycloalkylmethyl as described in copending, commonly owned
30 United States Patent Applications Seriai Nos. 07/346,118, filed February 21, 1989 and
07/3411350 filed February 21, 1989, -which. are herein incorporated by reference.
A procedure used to prepare 3(S)-methylheptanoic acid is described by U.S. I:
Serial No. 07/341,350 as show~beiow.................................... I .
_
WO 93/~2269 P(~/US93/~0~26
21;3i0~3
-2 -
- TBDMSC 1
Imldazole
~ ~ ...s ~ OH ~p `OTBD115
3 -. _
CH2C12/MeOH ~ ~ Ph3PCH3Br
DMS 1~ OTBDMS "BuL i
d THF
Pd-C~H2 ~ H2CrO4
C 0 2 H ' E i o H ~I C 2 R C e t o n e
. .
25 U. S. Serial No-. û7/346,118 describes the synthesis of S-3 -alkylheptanoic acids from a
.
trans~alken 3-ol of the fomlula (111)
R
.
30 :
_ ~ ~OH
(111)
2.~ .093
WO 93/22269 PCr/US93/0072S :
-3-
wherein R is methyl or ethyl which is converted to a compound of the formula (IV)
~.
~H
~"'0 H
(IV)
by the action of t-butyl hydroperoxide, in a reaction inert soivent in the presence of
titanium tetraisopropoxide and L-(+)-diisopropyl tartrate, in an amount sufficient to
oxidize the Sffnantiomer and in a second step, the product of the above reaction is
stereospecifically condense~ with a tri~(C,-C3)-alkyl]orthoacetate and, without isolation, ¦
the intermediate allyl-enol ether rearranged, in the presence of an acid in a reaction
inert solv~nt, to yield a (Ct-C3)alkyl 3(R)-alkyl~hepenoate of the absolute
stereochemical formula (V)
R H -;
Jl ~ ~ C O O H
.. - ._ .
.
which may be hydrogenated to the desiréd S-~alkylheptanoic acid.
i Optically pure 3(S)-methylheptanoic acid (l) has been prepared from the
corresponding racamate in unspecified yield by- multiple (eight) crystallizations of the
quinine salt at an inconvenlently low temperature ot -15C. ~Levene et al., J. Biol.
Chem. 95, pp. 1 24, 1932, at page 18, tliere c~lied 2-n-butylbutyric acid4]. Optically
- ac~ve ~methylheptanoic acid has subsequently been produced by a number of other
35 methods ~Soai et al., J. Chem. Soc., Chem. Commun. 1985, pp. 496470; Oppolzer et
al., Helv. Chim. Acta. 68, pp. 212-215 (1985); Ohno e~ al., U.S. Patent 4,564,620 (1986);
Mori st al., Synthesis 1982, pp. 752-753; Oppolzer et al., Helva. Chim. Acta. 64, pp.
WO g3/222~9 PCI`/US93/~0726
~ 1 3 ~ O ~ 3
2808-2811 (1981); Mukaiyama et al., Chem. Lett. 1981, pp. 913-916; Posner et al., J.
Am. Chem. Soc 103, pp. 2886-2888 (1981); Mukaiyama et al., Bull. Chem. Soc. Japan,
51, pp. 3368-3372 (1978); Meyers et al., J. Am. Chem. Soc. 98, pp. 2290-2294 (1976)].
The above described preparations generally suffer from one or more
5 disadvantages: the product acid is not optically pure, the reaction temperatures are
inconveniently low, between -78C and -30C, use of organometallic reagents, which
are dfflicult to handle on a large scale, is required, overall yields are low; and/or the
required reagents are not readily available.
Summarv of the Invention
This invention relates to a novel process for the preparation of 3~S)-
rnethylheptanoic acid which comprises the sequential steps of;
(a) reaction of racemic 3-methylheptanoic acid with (S)--methylbenzyl
amine to form a mixtura of diastereomeric salts;
(b) separation of the diastereomeric salts from step (a) by recrystallization
to yield (S)--methylbenzylammonium 3~S)-methylheptanoate;
(c) conversion of said (S)-~-rnethylbenzylammonium 3(S)-methyl heptanoate
of step (b) to 3(S)-methylheptanoic acid by treatment with acid.
In another aspect, this invention relates to the use of acetonitrile as the
recrystallizing solvent in step (b).
In yet ~another~ aspect this invention relates to the compound (S)- -
methylbenzylammonium 3(S)-methylheptanoate.
In yet another-aspect this invention comprises a process for preparation of 3(S)-
methylheptanoic acid- from an~ enriched mixture of 3R and 3S-methylheptanoic acid
which contains a preponderance of the (S) isomer. Such an enriched mixture
containing about 70h 3(S)-methylheptanoic acid is available from the procedure of
Meyers,- at al., J. ~m. Chem. Soc., 98, 2290-2294, (1976).
.
- ~ _ ~ Detailed DescriDtion of the Invention
30 As used here, the expression ~reaction inert solvent~ refers to a solvent system
in which the components do not react with starting materials, reagents, intermediates
or products in a manner which adversely affects the yield or purity of the desired
product.
wo g3/2æ69 ~ ~ 3 i ~ n ~ Pcr/uss3/on72~
~ acemic 3-methylheptanoic acid is readily available by the procedure of Organic
Synthesis, Coll. Vol. 5, 762-766, (John Wiley ~ Sons, 1973) which is herein incorporated
by reference.
(S~- ~ rrlethylbenzyiamine is available from the Aldrich Chemical Co., Milwaukee,
5 Wl 53233.
Racemic 3-methylheptanoic acid is dissolved in a reaction inert solvent and an
approximate molar amount of (S)- methylbenzylamine is added slowly. The choiceof solvent is not critical, but it was found that the diastereomeric salt readily precipitates
from acetonitrile which is the preferred solvent. The temperature of the salt formation
10 is not critical, but rorm temperature was found to be convenient and is preferred.
The diastereomeric salt of race~,nic 3-methylheptanoic acid and (S)- -
methylbenzylamine is purified by recrystallization to isolate the desired (S)- -
methylbenzy.ammonium (S)-3-methylheptanoate which is generally less soluble than the
other diastereomzric sa~t i.e., R-acid/S-amine. ~ ~tonitrile is the preferred solvent for
15 recrystallization. Multiple recrystallizations may be required to obtain the required
optica purity and three crystallizations were found to yield a 98% optically pure product.
It was found to be convenient to dissolve the sal$ in boiling solvent and cool slowly over
several hours until the product has precipitated. 3(S)-methylheptanoic acid is obtained
from the salt by acidification of a solution of the salt with strong acid at room
20 temperature. The temperature, solvent and acid are not critical. Any strong mineral
acid is effective; hydrochloric acid is preferred. The preferred solvent is a tv.~o phase
system employing n~hexanes or ethylacetate and wate.-, but any reaction inert solvent
system wou.ld be acceptable. -
The fr.llowing examples are provided solely for the pwpose of~fu.ther illustration
25 and are not intended to limit the invention which is defined by the claims.
.,
Example~
Preparation of the Diastereomeric Sa.t of 3-Methylheptanoic Acid and (S)--Methyl .
Benzylamine _ ~ - F--
30 A solution of racemic 3-methylheptarloic acid (3.1 g, 21.5 mmol) in acetonitrile (20 mL)
was treated with dropwise addition of (S)--methylbenzylamine (2.8 mL, 21.5 mmol).
White solid was obsen~ed to precipitate, and the resulting white suspension was stirred
at room temperature for 3.5 hours. The white solid was collected by suction filtration
WO 93/22269 PCI~US93~0~726
213 Ll ~ 9 3
-6-
and dried in vacuum (house vacuum, 48C) overnight. 4.65 g of the diastereomericsalt was obtained (82% yield).
Example 2
5 Recrystallization of the Diastereomeric Salt; (S)- -methylbenzylammonium 3(S)-
methylheDtanoate _ _ _
A slurry of the 3-methylheptanoic acid/(S)--methylbenzylamine salt (30 9) from
Example 1 in acetonitrile (300 mL) was stirred mechanically under nitrogen and heated
with an oil bath until complete dissolution was observed. The solution was allowed to
10 cool slowly as white solid precipitated. The resulting suspension was stirred overnight
and the white solid was collected by suction filtration. After drying in a vacuum oven,
20.77 g of salt was obtained (37% ee by rotation, [ ~ 11.27, C-5.05,CHCI3). The
above procedure was repeated twice to provide 10.98 g of the salt (73% yield of '
theoretical). The optical purity was judged to be 97%ee ([1~ =-13.66, C=5.05,
15 CHCI3) by comparing the rotations of diastereomeric salts from optically pure acid
prepared by the method of U.S. Serial No. 07/341,350 and the title compound.
Example 3
3(S)-Methvlheptanoic Acid
20 A. The salt from Example 2 (1.59 g, 5.99 mmol) in a mixture of ethyl acetate (20
- mL) and water-(-10 mL)-was treated with 1N HCI (10 mL) and stirred at room
temperature for 1.25 hours. The aqueous layer was separated from the organic andextracted with ethyl acetate ~2QmL). The organic layer and extract were combined, I
washed with water (1 Q m'L)'and then brine. After drying over sodium sulfate, the solvent
25 was removed to provide the acid as a colorless oil in quantitative yield.
B. I The salt from Exarnple 2 (1.0 9, 3.77 mmol) in a mixture of n-hexanes (10 mL)
and water (5 mL) was treated with 1 N HCI (5 mL) and stirred at room temperature for
3.5 hours. The aqueous layer (pH-1) was separated from the organic and extractedwith n-hexanes (2x20'rnL). The organic layer and extracts were combined, washed with '
30 water (10 mL) and then brine. After drying over sodium sulfate, the solvent was
removed to provide the acid as a colorless oil (0.54 9, 99.4% yield). '
