Note: Descriptions are shown in the official language in which they were submitted.
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METHODS OF MAKING ( S ) - 3 - ( AMINOMETHYL )
5-METHYLHEXANOIC ACID
a
FIELD OF THE INVENTION
This invention relates to a method of making
(S)-(+)-3-(aminomethyl)-5-methylhexanoic acid. This
invention also relates to the compounds (~)-3-
(carbamoylmethyl)-5-methylhexanoic acid, (R)-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid,(S)-(+)-3-
(carbamoylmethyl)-5-methylhexanoic acid, the (R)-(+)-cx-
phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-
methylhexanoic acid, and the (S)-(-)-«-phenylethylamine
salt of (S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic
acid.
BACKGROUND OF THE INVENTION
(S)-(+)-3-(aminomethyl)-5-methylhexanoic acid,
which is also called l3-isobutyl-y-aminobutyric acid or
isobutyl-GABA, is a potent anticonvulsant. Isobutyl-
GABA is related to the endogenous inhibitory
neurotransmitter y-aminobutyric acid or GABA, which is
involved in the regulation of brain neuronal activity.
It is thought that convulsions can be controlled
by controlling the metabolism of the neurotransmitter
y-aminobutyric acid. When the concentration of GAGA
diminishes below a threshold level in the brain,
' convulsions result (Karlsson A., et. al., Biochem.
Pharmacol., 1974;23:3053-3061), and whenthe GABA level
rises in the brain during convulsions, the seizures
terminate (Hayashi T., Physiol., (London)
1959;145:570-578). The term "seizure" means excessive
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unsynchronized neuronal activity that disrupts normal
function.
Because of the importance of GABA as an inhibitory
neurotransmitter, and :its effect on convulsive states
S and other motor dysfuncC:ions, a variety of approaches
have been taken to increase the concentration of GABA
in the brain.. In one approach, compounds that activate
L-glutamic acid decarboxylase (GAD) have been used, as
the concentrations of GAD and GAGA vary in parallel and
increased GAD concentrations result in increased GAGA
concentrations (Janssens de Varebeke P., et. al.,
Biochem Phazmacol , x.983;32:2751-2755; Loscher W.,
~iQ~hem Pharmacol , x.982;31:837-842; Phillips N.,
et. al., ~iochem PhazmaGO~, 1982;31:2257-2261). For
example, the compound (t)-3-(aminomethyl)-5-
methylhexanoic acid, a. GAD activator, has the ability
to suppress seizures while avoiding the undesirable
side effect of ataxia.
It has been discovered that the anticonvulsant
effect of isobutyl-GAGA is stereoselective. That is,
the S-stereoisomer of isobutyl-GAGA shows better
anticonvulsant activity than the R-stereoisomer. See,
for example, Yuen, et. al., in Bioorganic & Medicinal
Chemistry Letters, 1994;(Vol. 4, No. 6P:823-826. Thus,
it would be beneficial to lave an efficient process for
the synthesis of the S-stereoisomer of isobutyl-GABA.
Presently, (S)-(+)-3-(aminomethyl)-5-methyl
hexanoic acid has been prepared by two synthetic
routes. These routes each use reactions that require
n-butyllithium, and each route contains a step that
must be carried out at low temperatures (s-35°C) under
carefully controlled conditions. These synthetic
routes include the use of (4R,5S)-4-methyl-5-phenyl-2-
oxazolidinone as a chiral auxiliary to introduce the
stereochemical configuration needed in the final
product ( for example sE~e L1. S . Pa ~wents Nos . 5, 608, 090;
5, 684, 189; 5, 563, 1.75; 'i, 599, 973; and 6, 19'7, 819) .
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Although these routes provide the target compound in high
enantiomeric purity, they are difficult to conduct on
large-scale and use reagents which are either expensive
or difficult to handle or both.
The present invention provides an efficient
stereoselective method for making the S-stereoisomer of
isobutyl-GAHA that avoids the above-identified problems
and proceeds with fewer steps.
SUMMARY OF THE INVENTION
The present invention provides a method of making
(S)-(+)-3-(aminomethyl)-5-methylhexanoic acid which
comprises condensing isovaleraldehyde with an alkyl
cyanoacetate to forth a 2-cyano-5-methylhex-2-enoic acid
alkyl ester; reacting the 2-cyano-5-methylhex-2-enoic
acid alkyl ester with a dialkyl malonate to form
3-isobutylglutaric acid; forming the anhydride of
3-isobutylglutaric acid; reacting the anhydride with
ammonia to form (t)-3-(carbamoylmethyl)-5-
methylhexanoic acid; reacting (t)-3-(carbamoylmethyl)-
5-methylhexanoic acid with (R)-(+)-a-phenylethylamine
to obtain the (R)-(+)-a-phenylethylamine salt of
(R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid;
combining the salt with an acid to obtain (R)-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid; and reacting
the (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid
with a Hofmann reagent to obtain (S)-(+)-3-(amino-
methyl)-5-methylhexanoic acid.
The present invention also provides the novel
compounds (t)-3-(carbamoylmethyl)-5-methylhexanoic
acid, (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic
acid,(S)-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid,
the (R)-(+)-a-phenylethylamine salt of (R)-(-)-3
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(carbamoylmethyl)-5-methylhexanoic acid and the
(S) - (-) -a-phenylethylamine salt of (S) - (+) -3-
(carbamoylmethyl)-5-methylhexanoic acid.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with Scheme I below, the present
invention provides an efficient stereoselective method
for malting the S-stereoisomer of isobutyl-GABA.
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Scheme I
a
0
0
cN
o Ro
1. Dialkyl malonate
+ ~CN ~
RO 2. HC1, H O
I II IIa
Acetic anhydride or
OH Acetyl chloride
HG v O O O
III
IV
NH3
---~ (R) - (+) -a,-phenylethyl amine
nv v
V
O '
HzN i., O
H , Hs0+
~ \NH2 ~ \ ~ NH
HO O ~ / HO O
VI VIT_
v
1. NaOBr NHZ
i 2. H30'
HO O
VIII
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The method of Scheme I generally comprises
condensing isovaleraldehyde (I) with an alkyl
cyanoacetate (II) to form a 2-cyano-5-methylhex-2-enoic
acid alkyl ester (IIa); reacting the 2-cyano-5-
a
methylhex-2-enoic acid alkyl ester with a dialkyl
malonate to form 3-isobutylglutaric acid (III); forming
the anhydride of 3-isobutylglutaric acid (IV); reacting
the anhydride with ammonia to form (~)-3-(carbamoyl
methyl)-5-methylhexanoic acid (V); reacting (~)-3-
(carbamoylmethyl)-5-methylhexanoic acid with (R)-(+)-a-
phenylethylamine to obtain the (R)-(+)-a-
phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-
methylhexanoic acid (VI); combining the salt with an
acid to obtain (R)-(-)-3-(carbamoylmethyl)-5-
methylhexanoic acid (VII); and reacting the (R)-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid with.a Hofmann
reagent to obtain (S)-(+)-3-aminomethyl-5-
methylhexanoic acid (VIII).
In one step of the method, isovaleraldehyde is
condensed with an alkyl cyanoacetate to form a 2-cyano-
5-methylhex-2-enoic acid alkyl ester. In general, this
reaction is carried out in the presence of a base such
as di-n-propylamine, diethylamine, diisopropylamine or
piperidine, or an acid and base combination such as
di-n-propylamine and acetic acid, in an inert solvent
such as hexane, heptane, toluene or the like. The term
"inert solvent" means a liquid in which a reaction can
be carried out that does not detrimentally interact
with the starting materials or the products. However,
it is noted that the reaction will proceed in the
absence of a solvent. In addition, the 2-cyano-5-
methylhex-2-enoic acid alkyl ester that is formed can
also contain 2-cyano-5-methylhex-3-enoic acid alkyl
ester.
The alkyl group, R, in Scheme I, of the alkyl
cyanoacetate is preferably a C~-C6 alkyl, branched or
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straight chain, a C3 to C6 cycloalkyl group or benzyl.
Representative examples of C1-C6 alkyl groups include
methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tent-butyl, pentyl and hexyl. Representative examples
of C3 to C6 cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl. Preferably,
the C1-C6 alkyl is ethyl.
In general, isovaleraldehyde and alkyl
cyanoacetate are combined in an inert solvent with a
base and placed under reflux. The water that is
liberated is collected azeotropically. When the
reaction appears to be complete, the solvent may be
removed to yield primarily 2-cyano-5-methylhex-2-enoic
acid alkyl ester. In general, the 2-cyano-5-methylhex-
2-enoic acid alkyl ester that is formed is not isolated
or purified and can be used in the next step in crude
form. It is noted that the reaction will proceed in
the absence of a solvent and that 2-cyano-5-methylhex-
3-enoic acid alkyl ester may also be formed in the
reaction.
3-Isobutylglutaric acid is made from a 2-cyano-5-
methylhex-2-enoic acid alkyl ester by reacting a 2-
cyano-5-methylhex-2-enoic acid alkyl ester with a
dialkyl malonate followed by hydrolysis and
decarboxylation. The alkyl groups of the dialkyl
malonate can be the same or different. Examples of
suitable alkyl groups include C1-C6 alkyl groups and
C3-C6 cycloalkyl groups as defined above and benzyl. A
preferred dialkyl malonate is diethyl malonate.
In general, a 2-cyano-5-methylhex-2-enoic acid
~ alkyl ester is reacted directly with the dialkyl
malonate and a base. That-is, the reaction need not be
~ run in an inert solvent. The reaction mixture can then
be added to an acidic aqueous solution such as aqueous
sulfuric acid, aqueous hydrochloric acid or aqueous
hydrobromic acid, and refluxed to promote hydrolysis
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and decarboxylation. The progress of the reaction may
be monitored by 1H-NMR or other methods well known to
those skilled in the art, and the 3-isobutylglutaric
acid is isolated by methods well known to those skilled
in the art. The reaction can be run in a solvent such
as hexane, ethanol or methanol. Bases that can be used
include, but are not limited to, diethylamine, sodium
methoxide, sodium ethoxide, potassium tert-butoxide and
di-n-propylamine.
3-Isobutylglutaric acid anhydride can be made from
3-isobutylglutaric acid using methods well known to
those skilled in the art for forming the anhydride of
an acid. For example, 3-isobutylglutaric acid
anhydride can be obtained by refluxing acetyl chloride
or acetic anhydride with 3-isobutylglutaric acid and
then distilling the mixture. It is noted that the
3-isobutylglutaric acid anhydride need not be isolated
and purified, but can be used directly, in crude form,
in subsequent steps.
In another step of the method, 3-isobutylglutaric
acid anhydride is reacted with ammonia to form (~)-3-
(carbamoylmethyl)-5-methylhexanoic acid. In this step,
the cyclic anhydride is opened and one of the carbonyl
groups is converted to an amide. (~)-3-(carbamoyl
methyl)-5-methylhexanoic acid can be recrystallized
from a number of solvents including ethyl acetate,
water, chloroform and 2-butanone.
The R-stereoisomer of 3-(carbamoylmethyl)-5-
methylhexanoic acid can be obtained by reacting (t)-3-
(carbamoylmethyl)-5-methylhexanoic acid with (R)-(+)-cx-
phenylethylamine to form the (R)-(-)-3-(carbamoyl
methyl)-5-methylhexanoic acid, (R)-(+)-a-phenylethyl
amine salt, which can be isolated. The salt can be
recrystallized using various solvents such as
chloroform, acetonitrile, ethyl acetate and
tetrahydrofuran.
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(R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid
can be obtained by dissolving the salt in water and
acidifying the solution. Preferably the resolution is
conducted in an organic solvent such as chloroform and
less than 1 molar equivalent of the (R)-(+)-a-
phenylethylamine is used with respect to the (t)-3-
(carbamoylmethyl)-5-methylhexanoic acid.
Alternatively, (R)-(-)-3-(carbamoylmethyl)-5-
methylhexanoic acid can be obtained by combining (~)-3-
(carbamoylmethyl)-5-methylhexanoic acid with (S)-(-)-cY-
phenylethylamine in a solution to give the (S)-(-)-a-
phenylethylamine salt of (S)-(+)-3-(carbamoylmethyl)-5-
methylhexanoic acid, which crystallizes out of the
solution leaving the solution enriched in (R)-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid. (R)-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid can then be
isolated from the solution by methods well known to
those skilled in the art.
In another step of the method, (S)-(+)-3-
0 (aminomethyl)-5-methylhexanoic acid is obtained from
(R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid via a
Hofmann Reaction, which is well known to those skilled
in the art. The conditions under which a Hofmann
Reaction can be carried out are well known to those
skilled in the art, and any such condition known in the
art may be used to obtain (S)-(+)-3-(aminomethyl)-5-
methylhexanoic acid from (R)-(-)-3-(carbamoylmethyl)-5-
methylhexanoic acid. A suitable Hofmann reagent is an
alkali metal hypohalite, which can be prepared by
combining a base such as sodium hydroxide with a
halogen such as bromine. Other alkali metal or
alkaline earth metal bases or other halogens can be
used. Other Hofmann reagents that can be used include,
but are not limited to, I,I-bis(trifluoroacetoxy)-
iodobenzene, iodosobenzene with formic acid,
[hydroxy(tosyloxy)iodo]benzene, I,I-bis(acetoxy)iodo-
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benzene, lead tetraacetate, benzyltrimethylammonium
tribromide, N-bromosuccinimide in basic media (such as
potassium hydroxide solution), and N-bromosuccinimide
in the presence of mercury (II) acetate or silver
acetate.
Isolation of (S)-3-(aminomethyl)-5-methylhexanoic
acid after the Hofmann Reaction is carried out is
easier than isolating the mixture of enantiomers
because sodium chloride or sodium bromide salts tend to
crystallize with the product in the case of a mixture
of enantiomers. In contrast, in the present method,
the chloride or bromide salts do not crystallize with
the product. Halide analysis shows about 11o by weight
halide (calculated as chloride) in the crude product
(unrecrystallized) comprising a mixture of the
enantiomers and about O.lo by weight in the product of
the present method.
Moreover, (S)-(-)-3-(carbamoylmethyl)-5-
methylhexanoic acid can be easily hydrolyzed under
reflux in aqueous hydrochloric acid to give 3-
isobutylglutaric acid, which can be used to produce
additional (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic
acid.
It is contemplated that the compounds of the
present method can be found or isolated in the form of
hydrates or solvates, which are considered to fall
within the scope of the present invention.
The following examples are intended to illustrate
particular embodiments of the invention, and are not
intended to limit the specification, including the
claims, in any manner.
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EXAMPLES
Preparation of 3-Isobutvlcrlutaric acid
A mixture of ethyl cyanoacetate (62.4 g), hexane
(70 mL), isovaleraldehyde (52.11 g), and di-n-
propylamine (0.55 g) is placed under reflux. Water is
collected azeotropically using a water separator. When
no additional water is being collected from the
reaction, the reaction is cooled and subjected to
vacuum distillation to remove the solvent. Diethyl
malonate (105.7 g) and di-n-propylamine (5.6 g) are
added to the remaining oil (primarily 2-cyano-5-
methylhex-2-enoic acid ethyl ester). The mixture is
stirred at 50°C for 1 hour to form 2-cyano-4-
ethoxycarbonyl-3-isobutylpentanedioic acid diethyl
ester and then poured into an aqueous solution of -
hydrochloric acid (300 mL of 6N). The mixture is
placed under reflux. The reaction is maintained under
reflux until 1H-NMR indicates that the hydrolysis and
decarboxylation are complete (approximately 72 hours).
The reaction is cooled to 70-80°C and the aqueous
mixture is extracted with toluene (1 x 250 mL,
1 x 150 mL). The toluene extracts are combined and the
solvent is removed by distillation to give 88_7 g of
3-isobutylglutaric acid as an oil. When purified
3-isobutylglutaric acid is a solid with a melting point
in the range of about 40°C to about 42°C.
1H NMR (CDC13, 200 MHz): b 0.92 (d, 6H, J = 6.6 Hz),
1.23 (dd, 2H, J1 = 6.6 Hz, J~ = 6.5 Hz), 1.64 (m, 1 H),
2.25-2.40 (m, 1 H), 2.40-2.55 (m, 4 H).
13C NMR (CDC13): S 22.4, 25.i, 29.5, 38.4, 43.4, 179.2
' 2R (KBr): 680.7, 906.4, 919.9, 1116.6, 1211.1, 1232.3,
1249.6, 1301.7, 1409.7, 1417.4, 1448.3, 1463.7, 1704.8,
~ 2958.3, 3047.0 cm-1.
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Preparation. of 3 Isobutylglutaric acid anhydride
3-Isobutylglutaric acid (156 g) and acetyl
chloride (130 g) are combined and placed under reflux
for 16 hours. The mixture is distilled at atmospheric
v
pressure until a distillate reflux temperature of 135°C
is reached. The mixture is then cooled and placed
under vacuum distillation to give 129 g of
3-isobutylglutaric acid anhydride (boiling point
127-128°C, 1 mm Hg).
1H-NMR (CDC13, 200 MHz): b 0.91 (d, 6H, J=6.6 Hz),
1.20-1.24 (m, 2H), 1.52-1.78 (m, 1H), 2.10-2.45
(m, 3H), 2.79-2.91 (m, 2H).
13C-NMR (CDC13, 50 MHz): b 166.53, 43.99, 36.48,
26.79, 25.08, 22.57.
IR (neat): 559.3, 592.0, 609.4, 659.5, 837.0, 954.6,
1033.7, 1070.3, 1184.1, 1241.9, 1288.2, 1369.2, 1388.5,
1411.6, 1425.1, 1469.5, 1760.7, 1810.8, 2873.4, 2958.3,
3552.2 cm-1.
Preparation of (+)-3-(Carbamo~lmethyl)-5-methvlhexanoic
acid
Aqueous ammonia ( 3 0 8 g of 2 8 o ammonium hydroxide ,
5.06 mol), water (431 g), and methyl tert-butyl ether
(200 g) are combined and cooled to 15°C.
3-Isobutylglutaric acid anhydride is added and the
reaction mixture is allowed to warm to 50 to 60°C. The
reaction mixture is cooled to 20-25°C. The solvent is
evaporated and the pH of the solution is adjusted to
1.0 with concentrated hydrochloric acid. Water
(200 mL) is added and the mixture is filtered. The
solid is washed with water (200 mL). The solid is
dried under reduced pressure to give 408 g of (~)-3-
(carbamoylmethyl)-5-methylhexanoic acid as an off-white
solid. (t)-3-(Carbamoylmethyl)-5-methylhexanoic acid
has a melting point in the range of about 107.5 to
about 108.5°C.
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1H-NMR (DMSO-d6, 200 MHz): 8 0.84 (d, 6H, J=6.5 Hz),
1.07-1.17 (m, 2H), 1.50-1.72 (m, 1H); 1.98-2.25
(m, 5H) , 6.75 (s, 1H) , 7.30 (s, 1H) , 11.6 (s, 1H) .
IR (KBr): 592.0, 655.7, 700.0, 1010.5, 1133.9, 1214.9,
J
1241.9, 1278.6, 1294.0, 1427.1, 1461.8, 1585.2, 1668.1,
1700.9, 2514.7, 2622.7, 2962.1, 3220.5, 3367.1 cm-1.
Preparation of (+)-3-(Carbamoylmet~l) 5 methylhexanoic
acid (without isolation and purification 3 isobutyl
alutaric acid anhydride)
3-Isobutylglutaric acid (68.8 kg) and acetic
anhydride (44.5 kg) are combined and placed under
reflux for 2.5 hours. The mixture is placed under
atmospheric distillation followed by vacuum
distillation to remove acetic acid and acetic
anhydride. The undistilled 3-isobutylglutaric acid
anhydride is dissolved in methyl tert-butyl ether
(63 kg) and added to a solution of aqueous ammonia
(49 kg of 28o ammonium hydroxide) and water (92 kg) at
a temperature of 25°C or less. The mixture is stirred
for 35 minutes and the layers are separated. The
aqueous layer is placed under vacuum distillation to
remove any remaining volatile nonaqueous solvent.
Concentrated hydrochloric acid (51 kg) is added to the
aqueous mixture to obtain a pH of 1.5. The mixture is
cooled to 0-10°C and filtered. The solid is washed
with water (50 L) and dried under reduced pressure.
The solid is then dissolved in hot (70°C) ethyl acetate
(2z7 kg) a~-f~ltcre-d-:- Tize s-oiution-is cooled to 0-5°C
and the product is collected by filtration. The solid
is washed with cold ethyl acetate (45 kg) and dried
under reduced pressure to give 47.5 kg of (~)-3-
(carbamoylmethyl)-5-methylhexanoic acid as an off-white
solid having a melting point in the range of 106 to
about 108°C.
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Preparation of (R)-(-)-3-jCarbamovlmethy.l)-5-methyl-
hexanoic acid. (R)-(+)-a-phenylethylamine salt
(t)-3-(Carbamoylmethyl)-5-methylhexanoic acid
(17.o g) is placed in chloroform (292 g) and ethanol
(3.2 g) is added. The mixture is heated to 55°C and
(R)-(+)-a-pheriylethylamine (6.0 g) is added. After a
solution forms additional (R)-(+)-a-phenylethylamine
(2.0 g) and (R)-(-)-3-(carbamoylmethyl)-5-
methylhexanoic acid seed crystals (50 mg) are added.
The mixture is cooled to 32°C and filtered. The solid
is washed with chloroform (30 mL). The solid is dried
under reduced pressure to give 10.5 g of the (R)-(+)-a-
phenylethylamine salt of (R)-l-)-3-(carbamoylmethyl)-5-
methylhexanoic acid as a white solid having a melting
point in the range of about 123°C to about 126°C.
1H-NMR (DMSO-d6, 200 Ngiz): b 0.83 (d, 6H, J=6.4 Hz),
1.1-1.4 (m, 2H), 1.32 (d, 3H, 6.6 Hz), 1,50-1.75
(m, 1H), 2.0-2.3 (m, 5H), 4.11 (q, 1H, J=6.6 Hz),
6.0 (s, (broad) , 3H) , 6.72 (s, 1H) , 7.2-7.5 (m, 6H) .
IR (KBr): 700.0, 763.7; 1091.5, 1270.9, 1400.1,
1523.5, 1633.4, 1660.4, 2869.6, 2933.2, 2956.3, 3187.8,
3376.7 cm-1.
Chiral HPLC: (Chiralcel OD-H (Chiral Technologies,
Inc., Exton, PA) Hexane/isopropanol/formic acid,
96:4:0.1) enantiomeric purity >99% (R)-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid
Prer~aration of (Rl - ( - ) - 3 - ( Carbamoylmethyl ) - 5 -
methyihexano~c acid
The (R)-(+)-a-phenylethylamine salt of (R)-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid (10.9 gl is
placed in water (35 mL). The mixture is acidified to
pH 1.7 at 31°C with concentrated hydrochloric acid.
The mixture is cooled to 4°C and filtered. The solid
is washed with cold (4°C) 1 M hydrochloric acid (10 mL)
and dried under reduced pressure to give 6.2 a of
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(R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid as a
white solid having a melting point in the range of
about 130°C to about 133°C.
1H-NMR (DMSO-d6, 200 MHz): b 0.84 (d, 6H, J=6.5 Hz),
1.09-1.15 (m, 2H), 1.50-1.65 (m, 1H), 2.01-2.27
(m, 5H) , 6.76 (s, 1H) , 7.30 (s, 1H) , 12.0 (s, 1H) .
IR (KBr): 624.8, 954.6, 1168.7, 1207.2, 1236.1, 1294.0,
1411.6, 1592.9, 1643.1, 1712.5, 2873.4, 2931.3, 2958.3,
3224.4, 3332.4, 3434.6 cm-1.
Chiral HPLC: (Chiralcel OD-H, Hexane/isopropanol/
formic acid, 96/4/0.1) enantiomeric purity >99%
(R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid
Preparation of (S)-(+)-3-Aminomethyl-5-methylhexanoic
cid
(R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid
(30 g) is dissolved in water (28 g) and 50% sodium
hydroxide solution (12.6 g) and cooled to 5°C. In a
separate flask water (85 g), 50% sodium hydroxide
solution (53 g), and bromine (30.6 g) are combined
while maintaining a temperature of less than 10°C. The
bromine solution is added to the solution of (R)-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid and warmed
until a temperature of 80 °C is reached. The solution
is cooled to 45°C and quenched into 37% hydrochloric
acid solution (42 g). The mixture is heated to 89°C
and then cooled to 3°C. The mixture is filtered and
the solid is washed with water (30 mL). The solid is
dried under reduced pressure to give 16.7 grams of
(S)-(+)-3-aminomethyl-5-methylhexanoic acid.
HPLC enantiomer determination: Derivative with
1-fluoro-2,3-dinitrophenyl-5-L-alanine amide (Hypersil"~
BDS (from Keystone Scientific, Inc., Bellefonte, PA),
0.05 M triethylamine (adjusted to pH 3 with phosphoric
acid)/acetonitrile, 62/38) enantiomeric purity 99.8%
(S)-(+)-3-aminomethyl-5-methylhexanoic acid.
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The solid (16.3 g) is recrystallized from a
mixture of isopropanol (54 g) and water (54 g) to give
14.7 g of recrystallized (S)-(+)-3-aminomethyl-5-
methylhexanoic acid having a melting point in the range
of about 184°C to about 186°C - decomposes.
1H-NMR (D20, 200 MHz): 8 0.88 (d, 3H, J=6_5 Hz),
0.90 (d, 3H, J=6.5 Hz), 1.21 (t, 2H, J=7 Hz), 1.52-1.75
(m, 1H), 2.1-2.4 (m, 3H), 2.89-3.06 (m, 2H).
IR (KBr): 700.0, 823.5, 860.1, 1278.6, 1334_5, 1369.2,
1417.4, 1645.0, 2210.0, 2603.4, 2690.2, 2775.1, 2844.5,
2873.4, 2896.6, 2923.6, 2956.3 cm-1.
Preparation and Resolution of(R)-(-)-3-
~Carbamoylmethyl)-5-methylhexanoic acid followed by
regeneration of 3 - isobut~rlcflutaric acid from ( S ) - ( - ) - 3 -
(carbamoylmethyl)-5-meth~lhexanoic acid
(~)-3-(carbamoylmethyl)-5-methylhexanoic acid
(47 kg, 251 mol) is placed in chloroform (807 kg) and
ethanol (8.8 kg). The mixture is heated to 55°C and
(R)-(+)-a-phenylethylamine (16_7 kg) is added_ After a
solution forms additional (R)-(+)-a-phenylethylamine
(5.5 kg) and (R)-(-)-3-(carbamoylmethyl)-5- .
methylhexanoic acid seed crystals (100 g) are added.
The mixture is cooled to 32°C and filtered. The solid
is washed with chloroform (100 kg) and dried under
reduced pressure to give the (R)-(+)-a-phenylethylamine
salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic
acid. The solid is dissolved in water (138.5 kg) and
concentrated hydrochloric acid (9.4 kg) is added. The
mixture is cooled to 0-10°C and filtered. The solid is
washed with cold water (20 L) and dried under reduced
pressure to give 17.7 kg of (R)-(-)-3-(carbamoyl
methyl)-5-methylhexanoic acid as a white solid.
The chloroform filtrate is extracted with aqueous
sodium hydroxide solution (25 kg 50o sodium hydroxide
dissolved in 106 kg water). The aqueous extract is
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acidified with concentrated hydrochloric acid (94 kg)
and heated under reflux for approximately 24 hours.
l
The aqueous mixture is extracted with methyl tert-butyl
ether (70.5 kg). The methyl tert-butyl ether solution
is concentrated under reduced pressure to give
3-isobutylglutaric acid (27.4 kg).
