Note: Descriptions are shown in the official language in which they were submitted.
1 333807
HA427
--1-- .
PROCESS FOR PREPARING
(TRANS)-4-PHENYL-L-PROLINE DERIVATIVES
The present invention relates to a process
for preparing trans-4-phenyl-L-proline derivatives
which are intermediates in the preparation of
certain angiotensin-converting enzyme inhibitors.
In accordance with the present invention, a
pr~cess is provided for preparing (trans~-4-phenyl-L-
proline derivatives of the structure I
~ R2
R C2 1
wherein R is a nitrogen protecting group (such as
acetyl, benzoyl, p-anisoyl, p-nitrobenzoyl,
trifluoroacetyl, o-toluoyl, p-toluoyl, p-tosyl,
p-chlorobenzoyl, o-chlorobenzoyl, and the like,
1 333807
.,
-2- HA427
R1 is H, aryl or lower alkyl, and R2 is H,
F, Cl or Br in the o or ~ positions or mixtures,
which process includes the steps of reacting a
proline derivative of the structure II
X ~ ~H
II < >
~N ~
R C2R1
or a lactone of the structure III
III ~ \
\ ~
N O
R
wherein R and R1 are as defined above, and X is a
leaving group (such as a halogen like F, Cl, Br or
I, mesylate, tosylate or triflate), with an aromatic
nucleophile such as benzene, halo-substituted
benzene (e.g., F-, Cl- or Br-substituted benzene~
or phenyltrimethyl silane, in the presence of a
Lewis acid and, if desired, recovering the
trans-4-phenyl-L-proline derivative from the
reaction mixture. However, where the lactone III
is employed, it is preferred that III be reacted
with benzene.
Where the lactone reactant III is employed,
the trans-4-phenyl-L-proline derivative will have
the structure
1 333807
_3_ HA427
_ 2
", / H
IV
N~ "'H
R ~CO2H
The reaction products resulting from using
the lactone starting compound III will include the.
trans-4-phenyl-L-proline derivative I, as well as
the side products
Cl, H
V ~ , .
N --~ H
R C02H
and
H"~ / Cl
VI
N---~""H
R CO2H
Where the proline derivative II is employed
as the starting compound, the reaction products
ob~A;ne~ will include the trans-4-phenyl-L-proline
derivative I as well as the side product V where
the leaving group X in II is mesylate or F. In
- - 1 333807
_4_ HA427
addition, where X in proline derivative II is Cl or
tosylate, then cis-4-phenyl-L-proline may be
obtained as a by-product as well.
The side product V may be converted to the
neutral lactone III by treatment of the mixture of
IV and V with a base such as sodium bicarbonate in
the presence of an inert organic solvent such as
dimethylformamide, at a temperature within the
range of from about 0 to about 100C and preferably
from about 50 to about 80C.
In carrying out the process of the invention,
the proline derivative II or the lactone III will
be employed in a molar ratio to the aromatic
nucleophile of within the range of from about
1:5 to about 1:100 and preferably.from about 1:10
to about 1:40, while the Lewis acid will be
employed in a molar ratio to II or III of within
the range of from about 2:1 to about 10:1 and
preferably from about 3.6:1 to about 4.0:~. The
reaction will be carried out at a reduced
temperature of within the range of from about 5
to about 80C and preferably from about 7 to about
40C, under an inert atmosphere such as argon or
nitrogen, deprn~i ng upon the proline derivatives II
or lactone III that is employed.
The starting lactone III may be prepared
starting with the (trans)-4-hydroxy-L-proline
OH
A
HN ~ ~H
C2H
1 333807
HA427
.
which is treated with a protecting compound
B RCl
S whereïn "R" represents a nitrogen protecting group
such as acetyl, benzoyl, p-anisoyl, p-nitrobenzoyl,
trifluoroacetyl, o- or p-toluoyl, p-tosyl, or p- or
o-chlorobenzoyl to form the protected proline
derivative C
10 C
N ~
lS R CO2H
Proline C is then treated with p-TsOH (that is
p-toluenesulfonic acid monohydrate) in the
presence of methanol and then with p-TsCl and a
base such as triethylamine or pyridine to form the
tosylate D
OTs
D
~ ~
R/ ~ C2CH3
which is treated with strong base such as sodium
- 30 hydroxide to form the acid E
i 333807
-6- HA427
-
-
N
R 2
Acid E is then treated with weak base such as
potassium carbonate in the presence of methylethyl
ketone to form the lactone III.
The starting derivative II when X is
mesyloxy may be prepared by treating lactone III
with methanol in the presence of an acid catalyst
to afford hydroxy ester F
OH
~N~
R C 2 3
Treatment of F with methanesulfonyl chloride and a
base such as triethylamine affords mesyl ester G
OMesyl
G
<~
R/ C2CH3
Treatment of G with lithium hydroxide affords II
where X is mesyloxy.
1 333807
HA427
-7-
The starting proline derivative II wherein
X is F may be prepared by treating a proline
derivative of the structure
scl Q
R C2CH3
with diethylaminosulfur trifluoride and
pyridine at a temperature within the range of from
about -35C to about 25C employing a molar ratio
of trifluoride:C' of within the range of from
about 3:1 to about 1:1 in the presence of an inert
organic solvent such as dichloromethane, to form
the fluoro analog G
F
G
~N
R 2 3
which is subjected to a saponification reaction by
treatment with lithium hydroxide to form proline
25- II where X is F.
Examples of starting lactone compounds
III and starting proline compounds II useful in
carrying out the process of the invention include,
but are not limited to, the following.
1 333807
HA42 7
--8--
o
~0
R
R
C6HSC-
6 5
p-CH30C6H4-C-
CH3S02-
P 2 6 4
CF -C-
p-CH3 -C6H4C-
o-CH -C6H4C-
p-tosyl
p-Cl-C6H4C-
- O
o Cl 6 4
1 33~8~
_9_ ~ 427
X ~H
R C02R
X 1l R Rl
F C6H5 C- H and CH3
Cl C6H5C- H
Cl 6 5 3
Br 6 5 C6H5-
mesylate C6H5C- C6H5 ~
triflate O_ H and CH3
triflate C6H5C- CH3 and H
Cl P ~2 6 4 C6H5-
Br CH3C,o H
CF -C- H
mesylate 6 5 H and CH3
mesylate 1 6 4 CH3 and H
1 333807
- HA427
--10--
X R R
o
tosylateC6H5C H and CH3
S Cl p-tosyl 3 7
O
Br o-Cl-C6H4C n-C4Hg
i
F o-Cl-C6H4C H and
CH3
The trans-4-substituted-4-phenyl-L-proline
derivatives I may be employed to form angiotensin
converting enzyme inhibitors as described in U. S.
Patent No. 4,337,201 to Petrillo which covers
fosinopril which has the following formula:
O
200 ~
(CH2)4-P-CH2CO-N I C02eNaO
0 /OCOCH2CH3
CH
~ CH
25CH3 CH3
Listed below are definitions of the terms
used in this specification. These definitions
apply to the terms as they are used throughout the
specification (unless they are otherwise limited
in specific inst~nces)~ either individually or as
part of a larger group.
1 333807
HA427
--11--
The terms "alkyl'' and "alkoxy" refer to
both straight and branched chain groups. Those
groups having 1 to 10 carbon atoms are preferred.
The terms "cycloalkyl" and "cycloalkenyl"
refer to groups having 3 to 7 carbon atoms.
~ The term "aryl" refers to phenyl or phenyl
substituted with halogen, alkyl, alkoxy,
alkylthio, hydroxy, AlkAnoyl, nitro, amino,
dialkylamino, or trifluoromethyl groups.
The term "alkanoyl" refers to groups having
2 to 9 carbon atoms.
The term "halogen" refers to fluorine,
chlorine, bromine and iodine.
- ` 1 333807
HA427
-12-
The following working Examples represent
preferred embodiments of the present invention.
Unless otherwise indicated, all temperatures are
expressed in degrees Centigrade.
Example l
(trans)-1-Benzoyl-4-phenyl-L-proline
A. l-Benzoyl-allo-hydroxy-L-proline
lactone
A(1) (trans)-1-Benzoyl-4-hydroxy-L-
proline
A 12-liter beaker equipped with an
efficient shaft stirrer, a pH electrode and a
-1-liter dropping funnel was installed in an ice
bath. 4 Liters of water were charged to the
beaker, and 1.31 kg (10.0 moles) of trans-4-
hydroxy-L-proline was added with agitation to
dissolve same. The dropping funnel was then
charged with aqueous lON sodium hydroxide
solution. The pH of the mixture was raised to 8.0
with a little sodium hydroxide solution (about 25
ml). 300 ml of benzoyl chloride was then added
and the agitation speed raised to assure efficient
dispersion. Sodium hydroxide solution was added
- 25 as required to maintain pH 8 and sufficient cooling
was provided to maintain the mixture at about
25C. As soon as most of the benzoyl chloride was
consumed, another 300 ml portion of benzoyl
chloride was added and the benzoylation
continued. Two more 300 ml portions of benzoyl
chloride were added in sequence. The benzoylation
was allowed to come to completion at pH 8 and the
1 333807
-13- HA427
mixture was stirred for an extra half hour while
cooling to about 20C.
A 4-liter separatory funnel was charged
with 1 liter of isobutyl acetate. Part of the
reaction mixture was added and equilibrated. The
lower phase was allowed to settle and drain
through a polish filter. More of the reaction
mixture was added to the funnel until the total
had been extracted. The IBA extract was
discarded. The filtrate was returned to the
12-liter beaker and the dropping funnel was
charged with concentrated hydrochloric acid.
About 0.25 liters acid was added with efficient
agitation to reach pH 4. Product seeds were added
and agitation continued until a thin crystal s~urry
was formed and the pH did not climb anymore.
Dropwise acid addition was resumed until the pH of
the mixture was stable at 2Ø The total acid
consumption was about 0.85 liters.
The crystal slurry was cooled to about 15C
and agitated for an additional half hour.
The sandy crystals were collected on a
R~lch~r filter with most of the mother liquor
being removed by suction. Then the crystals were
washed with cold water until the filtrate was free
of chloride ions. Suction was continued until no
more li~uid emerged. The product was then dried
to constant weight.
A(2) (trans)-1-Benzoyl-4-hydroxy-L-proline,
methyl ester
A 5-liter flask was installed in an oil
bath on a magnetic stirrer, provided with a reflux
1 333807
HA427
-14-
condenser and charged with 3.0 liters of methanol
and 750 g (3.2 moles) of (trans)-1-benzoyl-4-
hydroxy-L-proline. 19 grams of p-toluenesulfonic
acid monohydrate (0.1 moles) were added. The
mixture was heated to reflux and the esterification
followed by T~C. Refluxing was continued until
starting material was no longer detectable. 8
grams (0.1 moles) of sodium acetate was added to
neutralize the catalyst acid. The condenser was
set for distillation and the mixture concentrated
at atmospheric pressure until the pot temperature
reached 80C. The distillate was then discarded.
The clear residue was rapidly diluted with 2 liters
of warm water. The flask was swirled for quick
mixing and to permit the ester to crystallize.
The slurry was cooled to room temperature with
occasional swirling and maintained at room
temperature for at least another hour. The
crystals were collected on a filter and the
filtrate recycled to aid in the transfer. The
cake was pressed down and washed with one liter of
cold water. The cake was sucked dry as possible
and the product dried via a laboratory fluid bed
dryer to constant weight. The combined filtrate
was vacuum concentrated from the first crop to a
small volume and the resulting slurry cooled to
room temperature. A second crop of crystals was
collected on a filter and washed with a minimum of
cold water. The cake was pressed down and suction
applied until no more liquid emerged. The second
crop was dried to constant weight.
1 333807
-15- HA427
A(3) (trans)-1-Benzoyl-4-tosyloxy-L-proline
methyl ester
540 Grams (2.84 moles) of technical
p-toluenesulfonyl chloride were charged to a 5
liter flask. 1.5 Liters of anhydrous pyridine was
added and the flask swirled to dissolve.
Gradu`ally, 600 g (2.40 moles) of (trans)-1-benzoyl-
4-hydroxy-L-proline methyl ester were added and
dissolved by swirling. The clear solution was
maintained at room temperature and the conversion
followed by TLC. After the starting material
completely disappeared, the reaction mixture was
transferred to a 12 liter beaker with an efficient
agitator. 0.8 Liters of ice water and some
tosylate seeds were added. Thick crystal slurry
formed in about 10 minutes. Strong agitation was
- maintained and~another 7 liters of an ice-water
mixture were added over a period of one hour. The
crystals were collected on a filter, the cake
pressed down and washed with cold water until the
effluent was free of chloride ions and suction
applied to the cake until no more liquid emerged.
The filtrate was discarded and the product dried
to constant weight.
A(4) (trans)-1-Benzoyl-4-hydroxy-proline-
tosylate
To a mixture of 6 liters of aqueous NaOH
(81.6 g, 4.15 moles NaOH) and 1.6 liters of
methanol were added Part A(3) tosylate (806.9 g, 2
moles) while holding the temperature between
25-30C. The mixture was stirred for 24 hours
while holding the pH of the mixture between
- ` 1 333807
HA427
-16-
11.0-11.5. The reaction mixture was filtered
clear, the pH adjusted to 2.0 by addition of 37%
aqueous hydrochloric acid (ca 175 ml) and
stirring was continued for 1 hour at 20C. The
product was collected by filtration and the cake
washed with water until Cl test was nearly
negative. Wet weight: 2400 g. The product was
dried at 40C to a water content less than 5% by
K.F.
Yield: 762.6 g = 97.9 % "as is"
= 93.4 % corrected for H2O
A(5) l-Benzoyl-allo-hydroxy-L-proline-
lactone
15 Liters of methyl ethyl ketone were added
to a 50 liter re-actor, followed by 731.6 g Part
A(4) tosylate. 573.2 g K2CO3 were added with
good agitation. The mixture was heated to reflux
and held at reflux until TLC in-process control
showed that reaction was complete. The reaction
mixture was cooled to 15-20C and the undissolved
K2CO3 collected by filtration and washed with 15
liters of methyl ethyl ketone. The product rich
filtrate was concentrated to about 1200-1300 g
under red-lce~ pressure. 2.3 Liters of n-h~Ane
were added within 1 hour and the mixture stirred
for 1 hour at 20C. The precipitated title lactone
was collected by filtration and washed with 700 ml
of n-h~YAne. Wet weight: 532 g. The material was
dried in vacuo to a constant weight of 332.7 g,
79.4%.
- 1 333~07
.
HA427
-17-
B. (cis)-l-Benzoyl-4-hydroxy-L-proline,
methyl ester
A suspension of Part A lactone (100 g,
460.8 mmoles) in 2 liters of methanol was treated
with p-toluenesulfonic acid monohydrate (1.28 g).
The reaction was stirred 2 days at room
temperaturé under argon. The methanol was removed
in vacuo from the resulting solution. The residue
was taken up in 1.4 liters of EtOAc, washed with
saturated NaHCO3 solution (3 x 300 ml), water (100
ml), and brine (100 ml), dried over MgSO4,
filtered, and concentrated in vacuo. The
resulting white solid was recrystallized from
EtOAc (100 ml), filtered, washed with cold EtOAc
and dried in vacuo to yield 81.25 g (71%) of title
compound.
M.P. 102.5-104C
Anal Calcd for C13H15NO4: C, 62.64; H, 6.07;
N, 5.62
Found: C, 62.87; H, 6.03; N, 5.57
C. (cis)-l-Benzoyl-4-[(4-methylsulfonyl)-
- oxy]-L-proline
A solution of Part B proline derivative (80
g, 321.3 mmoles) in 1.6 liters of dichloromethane
was treated with Et3N (67.17 ml, 482 mmoles). The
solution was cooled to -15C in an acetone-dry ice
bath and methAneculfonyl chloride (28.3 ml, 353
mmoles) was added via addition funnel. The
reaction was very exothermic and care had to be
taken to keep the temperature below -5. After
stirring for 30 minutes at -5C to -10C, TLC (9:1
1 333807
HA427
-18-
CH2C12:HOAc) indicated the reaction had gone to
completion. The dichloromethane was removed
in vacuo. The residue was taken up in ethyl
acetate (1.5 liters), wafihed with 2 x 400 ml of
water, 2 x 400 ml of 1 N HCl, 400 ml of saturated
NaHCO3 solution, 400 ml of brinc, dried over
MgSO4, filtered, and concentrated in vacuo to a
vi~cous oil. The oil was treated with 1 liter of
THF (from a fresh bottle) and 200 ml of water.
LiOH-H2o (28.31 g, 674.7 mmoles) was added and the
reaction was stirred for one hour. The THF was
removed in vacuo and the pH wa~ lowered to 1 with
concentrated HCl. The aqueous mi~ture was
e~tracted with 2 x 400 ml of eth~l acetate and the
e~tracts were wa~hed with 250 ml of water and then
brine. At this point the extracts started to
crystallize so they were transferred to an
Erlenmeyer flask and Lc_l~stallized after boiling
off 250 ml of ethyl acetate. The crystals were
collected by filtration, washed with cold ethyl
acetate and h~ane, and dried in vacuo to yield
69.18 g of title compound as white prisms (69%).
M.P. 172-173C (with decomposition)
Anal Calcd for C13HlSNO6S 05 H2O
C, 49.69; H, 4.84; N, 4.46
Found: C, 49.48; H, 4.79; N, 4.42
D. (tranQ)-l-Benzoyl-4-phenyl-L-proline
A dry, 3-necked 21 Morton flask (eguipped
with overhead stirrer, nitrogen inlet, and
temperature probe) was charged with anhydrous
aluminum chloride (124.23 g, 0.93 mole) followed
*Trade-mark
1 333807
HA427
--19--
by thiophene free benzene (810 ml). While
stirring, the flask was cooled (dry ice-acetone)
to an internal temperature of 6C. Part C
compound (powdered) was added (81 g, 0.26 mole) in
portions. A rise in internal temperature to 7C
was noted after the addition of ca. half the solid.
The addition was briefly interrupted until the
internal temperature returned to 6C and was then
continued. The resulting heterogeneous mixture
was vigorously stirred for 4 hours at 7-8C and
1.5 hours at 8-10C. During this time the reaction
became almost totally homogeneous and TLC indicated
the conversion of Part C compound to a mixture of
the title compound and (trans)-1-benzoyl-4-chloro-
L-proline. The reaction was cooled to 7C, and the
mixture was hydrolyzed by the slow addition of 3N
HCl (990 ml) such that the internal temperature did
not rise above 30C. The hydrolyzed mixture was
treated with brine (180 ml), seeded with crystals
of title compound, stirred at room temperature for
45 minutes and then held at room temperature
overnight. The mixture was filtered through a
coarse frit and the solid remaining in the reaction
vessel was transferred to the funnel using lN HCl
(390 ml). The crude product was washed with water
(4 x 500 ml). The last filtrate gave a weakly
positive test for chloride (ethanolic silver
nitrate). After drying on the filter for ca. 20
minutes the product weighed 122 g (159 mole%). The
product was dried in vacuo to a weight of 98 g.
The crude product was suspended in 240 ml of
n-butyl acetate and heated to boiling. When the
product dissolved, a second lower layer (presumably
1 3~
HA427
-20-
residual water) was evident. Boiling was continued
until this layer disappeared. Sodium sulfate was
added, boiling was continued an additional 5
minutes, and the mixture was filtered through
celite (pre-washed with n-butyl acetate). The
celite was washed with hot n-butyl acetate (2
x ca. 50 ml). The filtrate volume was reduced to
240 ml, cooled, was seeded with crystals of title
compound and stirred gently at ambient temperature
overnight. The crystals were filtered and washed
with n-butyl acetate (1 x 50 ml) and h~XAne (1 x
50 ml). The product was dried under high vacuum
at 40C to a constant weight of 57.37 g (75.1 mole
%; corrected for starting material and product HI).
HPLC HI (A218) of 99.03.
M.P. 137-138.5C
[a]D = -62.3 (c=1.0, MeOH)
Anal Calcd for-C18H17NO3: C, 73.20; H, 5.80;
N, 4.74
Found: C, 73.10; H, 5.81;, N, 4.72
Examle lA
(trans)-1-Benzoyl-4-phenyl-L-proline
A suspension of aluminum trichloride (7.456
g, 55.91 mmole) in benzene (150 ml) was stirred
under argon and treated with powdered
(cis)-1-benzoyl-4-mesyloxy-L-proline (5 g, 15.93
mmole). The reaction was stirred at room
temperature for 7 hours, cooled and treated slowly
with lN HCl (55 ml). After stirring 15 minutes,
the mixture was transferred to a separatory funnel
and treated with an additional 55 ml of lN HCl
- ~ ~33~7
-21- HA427
followed by 20 ml of concentrated HCl and 250 ml
of ethyl acetate. The layers were separated and
the aqueous layer was washed with additional ethyl
acetate (2 x 100 ml). The combined organic
extracts were washed with water and brine and
dried. Filtration and concentration in vacuo
afforded 4.74 g of a white foam which was
recrystallized from n-butyl acetate (seeding and
sonication to initiate crystallization). The
product was filtered, washed with n-butyl acetate
and h~YAne ~ and dried in vacuo to 2.168 g of
(trans)-1-benzoyl-4-phenyl-L-proline.
The mother liquor was evaporated and
treated with DMF (50 ml) and potassium bicarbonate
(868 mg). The resulting solution was stirred at
60-65C under argon for 5 hours, treated with
additional potassium bicarbonate (100 mg) and
stirred an additional 2 hours. THe DMF was mostly
removed in vacuo at 35C and the residue was
partitioned between ethyl acetate and water. The
ethyl acetate layer (A) was washed twice with
potassium bicarbonate solution. The combined
aqueous extracts were acidified to pH l.S with
HCl, extracted with ethyl acetate and washed with
lN HCl, water, brine and dried. Filtration and
concentration in vacuo afforded 1.683 g (corrected
for residual solvent) of (trans)-1-benzoyl-4-
phenyl-L-proline. The overall yield for the
experiment was (2.168 g + 1.683 gm) 81%.
The ethyl acetate layer (A) from above was
washed with brine, dried, filtered and
concentrated in vacuo to 312 mg of 1-benzoyl-allo-
hydroxy-L-proline lactone.
~ 3~3~7
HA427
-22-
Example 2
(trans)-l-Benzoyl-4-phenyl-L-proline
A suspension of aluminum trichloride (736
mg, 4.8 mmole) in benzene (5 ml) was treated with
N-benzoyl-allo-hydroxy-L-proline lactone (prepared
as described in Example 1, Part A) (217 mg, 1
mmole) and stirred under argon at 45C for 2
hours. After removal of the heat, the reaction
was allowed to stand at room temperature
overnight. Hydrolysis was effected by pouring the
mixture into cold, agueous HCl followed by
extraction with ethyl acetate. The organic layer
was washed with water and brine, dried, filtered,
and concentrated in vacuo. The residue was
chromatographed on silica gel with 4% acetic
acid-dichloromethane to afford:
(a) (trans)-l-Benzoyl-4-phenyl-L-proline (119 mg,
40%)
(b) (trans)-l-Benzoyl-4-chloro-L-proline (70 mg,
28%)
(c) (cis)-l-Benzoyl-4-chloro-L-proline: present by
TLC in several mixed fraction 1 with (b).
Example 3
(trans)-1-Benzoyl-4-phenyl-L-proline
A. (cis)-1-Benzoyl-4-fluoro-L-proline
methyl ester
A solution of (trans)-l-benzoyl-4-hydroxy-L-
proline methyl ester prepared as described in
Example 1 Part A(2) (6 g, 24.1 mmole) was
dissolved in dichloromethane and cooled to -45C
under an argon atmosphere. To the above solution
diethylaminosulfur trifluoride (5.2 ml, 42 mmole)
1 333807
HA427
-23-
was added dropwise. The resulting solution was
stirred and warmed to -35C. To the above
solution pyridine was added dropwise (9 ml, 116
mmole). The reaction was allowed to stir
overnight while warming to room temperature. The
solvent was removed in vacuo and the oily residue
treated with ethyl acetate and lN HCl. The
mixture was transferred to a separatory funnel,
the aqueous layer removed, and the organic layer
washed with additional lN HCl, then water and
saturated sodium bicarbonate solution. The
organic solution was dried over sodium sulfate,
filtered and concentrated to a yellow oil. The
crude product was chromatographed on silica gel
lS using 1:1 ethyl acetate:hexane as eluent.
Combination and concentration of product
contA~n;ng fractions produced 3.9 gm (64%) of
title compound as an oil.
B. (cis)-l-Benzoyl-4-fluoro-L-proline
To a solution of Part A (cis)-l-benzoyl-4-
fluoro-L-proline methyl ester (3.7 g, 14.74 mmole)
in tetrahydrofuran-water (37 ml-7 ml) was added 31
ml of a lN solution of lithium hydroxide in
water. The reaction was stirred at room
temperature for 2 hours. The tetrahydrofuran was
evaporated, the pH of the residual aqueous
solution was adjusted to 8 and extracted with
ethyl acetate. The organic extracts were
discarded. The aqueous phase was acidified to pH
2 with concentrated HCl and extracted with
dichloromethane. The organic extracts were washed
with brine and dried (sodium sulfate). The
1 333807
HA427
-24-
organic solution was filtered and concentrated to
2.9 g of solid.
The crude product was reGrystallized by
dissolving in ca. 100 ml of boiling ethyl
acetate. The volume was reduced to ca. 75 ml,
cooled and crystalIization was allowed to proceed
at room temperature overnight. The product was
filtered, washed with ethyl acetate and h~xAn~ and
dried in vacuo to 2.32 g (66%). M.P. 195-197C.
Anal Calcd for C12H12NO3F: C, 60.76; H, 5.10;
N, 5.91; F, 8.01
Found: C, 60.62; H, 5.09; N, 5.88; F. 8.23
C. (trans)-1-Benzoyl-4-phenyl-L-proline
A suspension of aluminum trichloride (191
mg, 1.43 mmole) in benzene (5 ml) was stirred
under argon and treated with Part B (cis)-N-
benzoyl-4-fluoro-L-proline (100 mg, 0.42 mmole).
The reaction was stirred at room temperature for
20 hours, cooled to 0C and hydrolyzed with lN
HCl. The layers were separated and the aqueous
layer was extracted with ethyl acetate. The
organic extracts were combined, washed with brine,
dried and concentrated. The residue consisted of
(a) (trans)-1-benzoyl-4-phenyl-L-proline (70%)
(b) (trans)-1-benzoyl-4-chloro-L-prol-ine (30%).
The ratios were determined by spectrodensitometry
at A 260.
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Example 4
(trans)-l-o-Chlorobenzoyl-4-phenyl-L-proline
A. (cis)-l-o-Chlorobenzoyl-4-fluoro-
L-proline
A solution of (cis)-4-fluoro-L-proline
hydrobromide (Biochemistry, 4(11), 2507 (1965);
250 mg, 1.17 mmole) in 4 ml of water was
prepared. The pH was adjusted to 7.8 with aqueous
potassium carbonate. o-Chlorobenzoyl chloride
(155 ~1, 1.23 mmole) was added in three portions
while maintAi ni ng the pH at 7.5-8Ø After the pH
was stabilized, the reaction was transferred to a
separatory funnel and washed with several portions
of ethyl acetate. The aqueous layer was acidified
to pH 2 with concentrated HCl, saturated with
sodium chloride and extracted with ethyl acetate.
The organic extracts were washed with brine, dried
(sodium sulfate), filtered and concentrated to a
solid. The crude product was recrystallized from
ethyl acetate, filtered, washed with cold ethyl
acetate and h~YAne and dried in vacuo to 204 mg
(64%). M.P. 158-160C.
Anal Calcd for C12HllClFNO3: C, 53.05; H, 5.16;
N, 5.16; Cl, 13.05, F, 6.99
Found: C, 53.25; H, 4.12; N, 5.17;, Cl, 12.86;
F, 7.35
B. (trans)-l-o-Chlorobenzoyl-4-phenyl-L-
proline
A suspension of aluminum trichloride (100
mg, 0.75 mmole) in benzene (3.7 ml) was stirred
- under argon and treated with (cis)-l-o-chloro-
benzoyl-4-fluoro-L-proline (60 mg, 0.22 mmole).
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After stirring overnight, the reaction was cooled,
ched with lN HCl and extracted with ethyl
acetate. The combined organic extracts were
washed with brine, dried and concentrated
5 in vacuo. The residue consisted of
Yields
A260 NMR
(a) trans-l-o-chlorobenzoyl-4-phenyl-
L-proline 83% 85%
10 (b) trans-1-o-chlorobenzoyl-4-chloro-
L-proline 17% 15%
Mass spectroscopy confirmed the presence of both
products.
The stereochemistry of the products in this
example was assumed to be trans based on the
result for Example 3.
Example 5
(trans)-l-Benzoyl-4-phenyl-L-proline
A. (cis)-1-Benzoyl-4-chloro-L-proline
(trans)-N-benzoyl-4-hydroxy-L-proline
methyl ester (prepared as described in Example 1
Part A(2) (4.0 g, 16.19 mmoles) was added neat in
several portions to a stirred solution of benzene
(25 ml), carbon tetrachloride (2.19 ml, 22.67
mmoles) and triphenylphosphine (5.95 g, 22.67
mmoles) at room temperature. Acetonitrile (15 ml)
was added and the reaction was stirred for 16 hours.
The solvents were removed in vacuo and the residue
was treated with THF (50 ml) and 32.4 ml of lN
sodium hydroxide solution. The reaction was
stirred at room temperature for 4 hours. The
organic solvent was removed in vacuo and the
y
-
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aqueous solution was extracted with ethyl
acetate. The cooled aqueous solution was
acidified to pH 2 with concentrated hydrochloric
acid, then extracted with ethyl acetate. The
combined organic extracts were washed with brine,
dried and concentrated in vacuo to a white solid.
This solid was recrystallized from ethyl acetate
to yield 2.5 g (61%) of (cis)-1-benzoyl-4-chloro-
L-proline.
M.P. 167.5C.
Anal Calcd for C12H12N03Cl: C, 56.81; H, 4.77;
N, 5.52; Cl, 13.97
Found: C, 56.97; H, 4.82; N, 5.57; Cl, 13.70
B. (trans)-l-Benzoyl-4-phenyl-L-proline
A suspension of aluminum trichloride (452
mg, 3.4 mmole) in benzene (5 ml) was stirred under
argon and treated with (cis)-l-benzoyl-4-chloro-
L-proline (253 mg, 1 mmole). The reaction was
stirred at reflux overnight, cooled and hydrolyzed
with lN HCl. The mixture was extracted with ethyl
acetate. The organic extracts were washed with
water, dried and concentrated in vacuo.
Filtration and concentration in vacuo afforded a
mixture consisting of:
(a) (trans)-l-benzoyl-4-phenyl-L-proline (75%)
(b) (cis)-l-benzoyl-4-phenyl-L-proline (16.5%)
(c) (cis)-l-benzoyl-4-chloro-L-proline (2%)
(d) (trans)-l-benzoyl-4-chloro-L-proline (6.4%)
The yields were determined by spectrodensitometry
at A260.
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Example 6
(trans)-l-Benzoyl-4-phenyl-L-proline
A. (cis)-1-Benzoyl-4-tosyloxy-L-proline,
methyl ester
A solution of (cis)-l-benzoyl-4-hydroxy-L-
proline, methyl ester (1.9 g, 7.63 mmole) in
pyridine (6 ml) was stirred under argon and
treated with p-toluenesulfonyl chloride (1.75 g,
9.16 mmole). The reaction was stirred overnight,
treated with additional p-toluenesulfonyl chloride
(0.145 g, 0.76 mmole) and stirred for 24 hours.
Ice water was added followed by ethyl acetate.
The organic layer was washed with lN HCl, brine,
and dried. Filtration and concentration in vacuo
afforded the title compound as a foam which was
used without purification in the subse~uent step.
B. (cis)-l-Benzoyl-4-tosyloxy-L-proline
A solution of (cis)-l-benzoyl-4-tosyloxy-L-
proline, methyl ester (from the previous step) inTHF-H2O (25 ml - 5 ml) was stirred under argon and
treated with lithium hydroxide mono hydrate (672
mg, 16 mmole). The reaction was stirred for 3
hours, concentrated in vacuo, acidified to pH 1.5
with HCl, and extracted with ethyl acetate. The
organic extracts were dried, filtered and
co~crntrated in vacuo to a white solid which was
recrystallized twice from ethyl acetate to afford
the title compound.
C. (trans)-l-Benzoyl-4-phenyl-L-proline
To a dry flask was added aluminum
trichloride (58 mg, 0.435 mmole) and benzene (3
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ml). While stirring under argon, (cis)-1-benzoyl-4-
tosyloxy-L-proline (50 mg, 0.128 mmole) was
added. After further stirring overnight, the
reaction was cooled to 0C and quenched with lN
HCl. The resulting mixture was extracted with
ethyl acetate and the organic extracts were washed
with brine, dried, and concentrated in vacuo. The
residue consisted of:
% (densito-
metry, A260)
(a) (trans)-1-Benzoyl-4-phenyl-L-proline 66%
(b) (trans)-l-Benzoyl-4-chloro-L-proline 17%
(c) (cis)-1-Benzoyl-4-phenyl-L-proline
or 17%
(d) (cis)-1-Benzoyl-4-tosyloxy-L-proline
or a mixture of (c) and (d) which was not separable
by tlc.
Example 7
(trans)-1-Benzoyl-4-phenyl-L-proline
A suspension of powdered (cis)-1-benzoyl-4-
mesyloxy-L-proline (250 mg, 0.8 mmole) in
1,2-dichlorobenzene (3 ml) was stirred under argon
and treated with phenyltrimethylsilane (1 ml, 5.8
mmole) followed by aluminum trichloride (383 mg,
2.87 mmole). The reaction was stirred overnight
and an aliquot was removed, quenched into lN HCl
and extracted with ethyl acetate. Analysis of the
organic layer by tlc showed the presehce of :
(a) (trans)-1-benzoyl-4-phenyl-L-proline 41%
(b) (trans)-1-benzoyl-4-chloro-L-proline 59%
Yield by densitometry at A260.
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Example 8
(cis)-1-Benzoyl-4-chlorophenyl-L-proline
A suspension of aluminum trichloride (364
mg, 2.72 mmole) in chlorobenzene (10 ml) was
stirred at 0C under argon and treated with
powdered (cis)-1-benzoyl-4-mesyloxy-L-proline. The
reaction was stirred at 0C for 3 hours and room
temperature overnight. The reaction was quenched
at 0C by the addition of lN HCl. The mixture was
diluted with ethyl acetate. The organic layer was
washed with sodium bicarbonate solution. The
aqueous layer was acidified to pH 2 with HCl and
extracted with ethyl acetate. The organic extracts
were washed with brine, dried, filtered and
concentrated in vacuo. Mass spectral analysis
indicated the presence of
(a) (trans)-1-benzoyl-4-chlorophenyl-L-proline and
(b) (trans)-1-benzoyl-4-chloro-L-proline.
Spectrodensitometry of a HC plate showed the ratio
of a:b was 32:68 (A260).
Example 9
Alternative Preparation of (cis)-1-Benzoyl-4-
mesyloxy-L-proline
A solution of (cis)-1-benzoyl-4-hydroxy-L-
proline, methyl ester (169.2 g, 0.679 mole) and
triethylamine (104.2 ml, 0.747 mole) in dichloro-
methane (3.3 liters) was cooled to -10C under
nitrogen and treated dropwise with methAn~sulfonyl
chloride (59.85 ml, 0.74 mole). The reaction was
stirred an additional 30 minutes at -5C to -10C
and the volatiles were removed in vacuo. The
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residue was treated with ethyl acetate and washed
with water, lN HCl, saturated sodium bicarbonate
solution, and brine. The organic solution was
dried, filtered, and concentrated in vacuo. The
residue was dissolved in THF (2.1 liters) and
treated with 3.36 N LiOH solution (423 ml) and
stirred at room temperature for 1 hour. The THF
was removed in vacuo and the aqueous soiution was
acidified to pH 4. The resulting solid was
filtered, washed with ice water, and recrystallized
from 95% ethanol-ethyl acetate to afford 130 g of
the title compound.
Example 10 to 20
Following the procedure of Example 3 except
substituting the (cis)~ -4-fluoro-L-proline
shown in Column I below for the (cis)-l-benzoyl-
4-fluoro-L-proline used in Example 3, the following
products IIx and IIx were obtained.
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Column I Column II* Column III*
F ~, Cl
OH ~ H ~ OH
R R R
Ix IIx IIIx
Ex. TLC (A260)
No. R IIx IIIx % of IIx (PMR)
10. p-anisoyl 34 32 and 2 demethylated
products (15%, 19%).
Required 4.4 equiv
AlC13
11. p-nitrobenzoyl 40 46 and 13.6Z Ix. Used 5
equiv AlC13
12. phenoxycarbonyl 50 50
13. acetyl 53
14. trifluoroacetyl 63
15. o-toluoyl 64 36
16. p-toluoyl 65 35 62
17. p-tosyl 66 34 69
18. benzoyl 70 30
19. p-chlorobenzoyl 74 26 73
20. o-chlorobenzoyl 83 17 84
*Trans stereochemistry confirmed for entry 14 by comparison
with authentic samples.
For examples 12-13 and 16-20, mass spectroscopy confirmed the
presence of IIX and IIIX.
