U.S. patent application number 16/020814 was filed with the patent office on 2019-07-18 for processes for the preparation of uracil derivatives.
The applicant listed for this patent is Neurocrine Biosciences, Inc.. Invention is credited to Onorato Campopiano, Shine K. Chou, Donald J. Gallagher, Donald Nicholas Hettinger, Robert Michael Hughes, Michael Allen Ouellette, Laszlo R. Treiber, Peng Wang, Yuxin Zhao.
Application Number | 20190218191 16/020814 |
Document ID | / |
Family ID | 40347871 |
Filed Date | 2019-07-18 |
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United States Patent
Application |
20190218191 |
Kind Code |
A1 |
Gallagher; Donald J. ; et
al. |
July 18, 2019 |
PROCESSES FOR THE PREPARATION OF URACIL DERIVATIVES
Abstract
The present invention relates to processes and intermediates for
preparing Gonadotropin-Releasing Hormone (GnRH) receptor
antagonists of structure (VI); and stereoisomers and
pharmaceutically acceptable salts thereof.
Inventors: |
Gallagher; Donald J.;
(Hopkinton, MA) ; Treiber; Laszlo R.; (San Diego,
CA) ; Hughes; Robert Michael; (San Diego, CA)
; Campopiano; Onorato; (Hayward, CA) ; Wang;
Peng; (Carlsbad, CA) ; Zhao; Yuxin; (San
Diego, CA) ; Chou; Shine K.; (Wildwood, MO) ;
Ouellette; Michael Allen; (San Diego, CA) ;
Hettinger; Donald Nicholas; (Broomfield, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Neurocrine Biosciences, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
40347871 |
Appl. No.: |
16/020814 |
Filed: |
June 27, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15833513 |
Dec 6, 2017 |
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16020814 |
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15406476 |
Jan 13, 2017 |
9868706 |
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15833513 |
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15174774 |
Jun 6, 2016 |
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15406476 |
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14309732 |
Jun 19, 2014 |
9382214 |
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15174774 |
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12741819 |
Jan 13, 2011 |
8765948 |
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PCT/US08/82873 |
Nov 7, 2008 |
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14309732 |
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60986227 |
Nov 7, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 239/54 20130101;
A61K 9/1688 20130101; A61P 15/00 20180101; C07D 239/553 20130101;
A61K 9/146 20130101 |
International
Class: |
C07D 239/54 20060101
C07D239/54; A61P 15/00 20060101 A61P015/00 |
Claims
1.-11. (canceled)
12. Amorphous
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid sodium salt (compound 5-1) having an impurity
profile comprising one or more of the following substances:
heptane, methyl isobutyl ketone, isopropyl acetate, and methyl
ethyl ketone.
13. A pharmaceutical composition comprising amorphous
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid sodium salt (compound 5-1) having an impurity
profile of claim 12, and a pharmaceutically acceptable carrier
and/or diluent.
14.
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-
-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyla-
mino)-butyric acid sodium salt (compound 5-1) having an impurity
profile comprising one or more of the following substances:
heptane, methyl isobutyl ketone, isopropyl acetate, and methyl
ethyl ketone.
15. A pharmaceutical composition comprising
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid sodium salt (compound 5-1) having an impurity
profile of claim 14 and a pharmaceutically acceptable carrier
and/or diluent.
16. A method for treating a condition selected from endometriosis
and uterine fibroids in a subject in need thereof, comprising
administering to the subject a pharmaceutical composition of claim
13.
17. A method for treating a condition selected from endometriosis
and uterine fibroids in a subject in need thereof, comprising
administering to the subject a pharmaceutical composition of claim
15.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to processes for the
preparation of uracil derivatives which may be useful as
gonadotropin-releasing hormone receptor antagonists.
BACKGROUND OF THE INVENTION
[0002] Gonadotropin-releasing hormone (GnRH), also known as
luteinizing hormone-releasing hormone (LHRH), is a decapeptide
(pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2) that plays an
important role in human reproduction. GnRH is released from the
hypothalamus and acts on the pituitary gland to stimulate the
biosynthesis and release of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH). LH released from the pituitary
gland is responsible for the regulation of gonadal steroid
production in both males and females, while FSH regulates
spermatogenesis in males and follicular development in females.
[0003] Due to its biological importance, synthetic antagonists and
agonists to GnRH have been the focus of considerable attention,
particularly in the context of prostate cancer, breast cancer,
endometriosis, uterine leiomyoma (fibroids), ovarian cancer,
prostatic hyperplasia, assisted reproductive therapy, and
precocious puberty (The Lancet 358:1793-1803, 2001; Mol. Cell.
Endo. 166:9-14, 2000). For example, peptidic GnRH agonists, such as
leuprorelin (pGLu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEO, have been
used to treat such conditions. Such agonists appear to function by
binding to the GnRH receptor in the pituitary gonadotropins,
thereby inducing the synthesis and release of gonadotropins.
Chronic administration of GnRH agonists depletes gonadotropins and
subsequently down-regulates the receptor, resulting in suppression
of steroidal hormones after some period of time (e.g., on the order
of 2-3 weeks following initiation of chronic administration).
[0004] In contrast, GnRH antagonists are believed to suppress
gonadotropins from the onset, and thus have received the most
attention over the past two decades. To date, some of the primary
obstacles to the clinical use of such antagonists have been their
relatively low bioavailability and adverse side effects caused by
histamine release. However, several peptidic antagonists with low
histamine release properties have been reported, although they
still must be delivered via sustained delivery routes (such as
subcutaneous injection or intranasal spray) due to limited
bioavailability.
[0005] The present invention relates to synthetic routes to produce
various uracil derivatives including the compounds
4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)-
phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenyle-
thyl]amino]-butanoic acid and its sodium and calcium salts,
4-[[(1R)-2-[5-(2-chloro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)-
phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenyle-
thyl]amino]-butanoic acid and its sodium and calcium salts, and
5-iodo-6-methyl-1-(2-methyl-6-trifluoromethyl-benzyl)-1H-pyrimidine-2,4-d-
ione.
[0006] Uracil derivatives of formula (I) are described as GnRH
antagonists in U.S. Pat. Nos. 6,608,197 and 6,872,728.
##STR00001##
[0007] Additional uracil derivatives of formula (II) are described
in U.S. Pat. No. 7,056,927.
##STR00002##
[0008] Additional uracil derivatives of formula (III) are described
in U.S. Pat. No.
[0009] 7,015,226.
##STR00003##
[0010] Additional uracil derivatives of formula (IV) are described
in U.S. Pat. No. 7,071,200.
##STR00004##
[0011] Additional uracil derivatives of formula (V) are described
in WO2005007164.
##STR00005##
[0012] These patents and application are hereby incorporated by
reference in their entirety.
SUMMARY OF THE INVENTION
[0013] The present invention provides methods amenable to large
scale preparation of substituted uracil derivatives which are
useful as GnRH antagonists. Included are intermediates such as
5-iodo substituted uracils and processes which are useful in
preparing uracils of formulas (I) to (V).
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention provides processes for preparing
compounds of formula (VI):
##STR00006##
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein: [0015] R.sub.1a, R.sub.1b and R.sub.1c are the same or
different and independently hydrogen, halogen, C.sub.1-4alkyl,
hydroxy or alkoxy; [0016] R.sub.2a and R.sub.2b are the same or
different and independently hydrogen, halogen, trifluoromethyl,
cyano or --SO.sub.2CH.sub.3; [0017] R.sub.3 is hydrogen or methyl;
and [0018] R.sub.4 is hydrogen, --C.sub.1-6alkanediyl--COOH, or
--C(.dbd.O)O--(t-butyl).
[0019] As used herein, the above terms have the following
meaning:
[0020] "C.sub.1-4alkyl" means a straight chain or branched,
noncyclic or cyclic hydrocarbon containing from 1 to 4 carbon
atoms. Representative straight chain alkyls include methyl, ethyl,
n-propyl, n-butyl, and the like; branched alkyls include isopropyl,
sec-butyl, isobutyl, tert-butyl, and the like; while cyclic alkyls
include cyclopropyl and the like.
[0021] "C.sub.1-6alkanediyl" means a divalent C.sub.1-6alkyl from
which two hydrogen atoms are taken from the same carbon atom or
from different carbon atoms, such as --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH(CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--, and the like.
[0022] "Halogen" means fluoro, chloro, bromo or iodo, typically
fluoro and chloro.
[0023] "Hydroxy" means --OH.
[0024] "Alkoxy" means --O--(C.sub.1-4alkyl).
[0025] "Cyano" means --CN.
[0026] In an embodiment, the compounds of formula (VI) may be
prepared via intermediate (VII):
##STR00007##
wherein R.sub.2a, R.sub.2b and R.sub.3 are as defined above.
[0027] In an embodiment, a compound of formula (VII) may be reacted
with a compound of formula (VIII):
##STR00008##
[0028] Where R is H or C.sub.1-4alkyl, R' is H or C.sub.1-4alkyl or
R and R' taken together form C.sub.1-6alkanediyl.
[0029] In an embodiment, the compounds of formula VI may be
isolated as crystalline material, amorphic material, or a mixture
of both. In an embodiment, amorphic material may be isolated by
lyophilization, spray drying, co-spraying, precipitation or
co-precipitation.
[0030] In general, the compounds of structure (VI) above may be
made by the following reaction schemes, wherein all substituents
are as defined above unless indicated otherwise.
##STR00009##
[0031] Ureas i may be heated with various acetoacetates ii (such as
t-butyl acetoacetate as shown) with removal of the generated
alcohol to generate an acyclic intermediate which is cyclized to
compound iii with an acid catalyst such as p-toluenesulfonic acid.
The acetoacetate ii provides a procedure which is less hazardous
than diketene. Reaction of iii with an iodinating reagent such as
iodine monochloride results in compound iv in high yield.
##STR00010##
[0032] Compound iv is coupled with an appropriate boronic acid
(such as 2-halo-3-methoxyphenyl boronic acid) or boronic acid ester
under palladium catalysis conditions to generate v. Appropriate
palladium sources include palladium acetate and
tris(dibenzylidene-acetone)dipalladium(0) while
tri-t-butylphosphine and tri-t-butylphosphonium tetrafluoroborate
are acceptable phosphine ligands. Compound v and mesylate vi react
in the presence of a base (such as potassium carbonate or potassium
phosphate) to generate Boc-protected material which is deprotected
under acidic conditions such as trifluoroacetic acid in methylene
chloride or methanesulfonic acid in isopropyl acetate to yield
compound vii.
[0033] Compounds of the present invention may exist as amorphous
solids. An amorphous solid is generally defined as a
non-crystalline solid in which molecules are not organized in a
definite lattice.
4-((R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid sodium salt (compound 5-1) is an example of a
compound of the present invention which may be isolated as an
amorphous solid. Amorphous solids may be isolated from various
procedures such as lyophilization, spray drying, co-spraying,
precipitation or co-precipitation.
[0034] Compounds of the present invention, in particular compound
5-1, may be precipitated as amorphous solids. This precipitation
may involve extraction of a compound of formula (VI), in particular
compound 5-1, from an aqueous mixture into an organic solvent by
adding an appropriate additive (such as sodium chloride, sodium
acetate and sodium hydroxide) to the mixture. Appropriate organic
solvents include methylisobutyl ketone, isopropylacetate and
methylethyl ketone. The compound of interest may then be
precipitated using an appropriate anti-solvent and isolated as an
amorphous solid. Appropriate anti-solvents include nonpolar organic
solvents such as heptane and hexanes.
[0035] These materials may be formulated as amorphous co-solutions
where the co-solution may help stabilize the resulting amorphous
solid.
[0036] Compounds of the present invention may be spray dried by
itself or with other excipients such as PVP (polyvinyl pyrrolidone,
Kollidon's), HPMC (hydroxypropylmethylcellulose), mannitol, or
other suitable carrier.
[0037] These procedures may serve to stabilize amorphic material
via solid solution formation with appropriate polymers (Kollidon,
HPMC, etc.) resulting from evaporation or grinding techniques.
EXAMPLES
Analytical Methods:
HPLC Method 1:
Column: Zorbax SB-C18, 3.5.mu., 3.times.150 mm
[0038] Mobile Phase A=0.1% trifluoroacetic acid in water Mobile
Phase B=0.1% trifluoroacetic acid in acetonitrile Gradient Table
(data collection stops at 13 min):
TABLE-US-00001 Time 0.1% TFA/H.sub.2O 0.1% TFA/CH.sub.3CN Flow Rate
0 70 30 0.75 12.0 10 90 0.75 13.0 2.5 97.5 0.75 13.1 70 30 1.2
15.00 70 30 1.2 15.5 70 30 0.75
Injection Volume: 2.5 .mu.L
Column Temperature: Controlled at 20.degree. C.
[0039] UV Detection: 220 nm and 254 nm (220 nm data used for all
analyses) Diluent: 70:30 CH.sub.3CN:H.sub.2O
Example 1
##STR00011##
[0040] Step 1A:
1-(2-Fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione
(2-Fluoro-6-trifluoromethyl-benzyl)-urea (2.568 g, 10.9 mmol) in
toluene (125 mL) was heated briefly to reflux under a Dean-Stark
trap. T-butyl acetoacetate (5.0 g) was added and the mixture heated
to reflux for 4 hrs. p-Toluenesulfonic acid monohydrate (2.82 g,
14.8 mmol) was added and the reflux was continued for one
additional hour. Toluene was displaced with i-PrOH and the volume
of the solution was reduced to approximately 30 mL. The solution
was stirred overnight at room temp. The crystalline product was
filtered and washed with a few mL of i-PrOH to provide 2.01 g (63%
yield) of
1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione.
LCMS (ESI) m/z 303.0 (MH+) Step 1B:
1-(2-Fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-d-
ione
[0041] To a 250 mL three-neck round bottom flask was charged
1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione
1a (25.0 g) and methanol (250 mL). Iodine monochloride (30.9 g) was
charged over 2.5 min. The mixture was heated at 50.degree. C. for 3
hours. After cooling to ambient temperature, the mixture was
filtered. The cake was re-slurried in methanol (250 mL) and heated
to 50.degree. C. for 3 hours. After cooling to ambient temperature,
the mixture was filtered and the filter cake was washed with
methanol (50 mL). The off-white solid was dried in a vacuum oven at
50.degree. C. to provide
1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-d-
ione 1b (32.5 g, 90% yield). LCMS (ESI) m/z 429.3 (MH+). The
material may be re-slurried in MeOH as needed.
Step 1C:
5-(2-Fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benz-
yl)-6-methyl-1H-pyrimidine-2,4-dione
[0042] To a reactor was charged
1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-d-
ione 1b (20.0 kg), 2-fluoro-3-methoxyphenylboronic acid (8.7 kg),
and acetone (60 L). The mixture was agitated and cooled to
15.degree. C. and a potassium hydroxide/water solution (10.8 kg/64
L) was charged. The reactor contents were degassed for 30 min, then
tri-t-butylphosphonium tetrafluoroborate (142 g) was added to the
reactor and the contents mixed at 45.degree. C. for 20 min.
Palladium (II) acetate (52 g) was charged to the reactor and the
contents were mixed at 55.degree. C. The reaction mixture was
stirred until the reaction was complete. Acetic acid (5.6 kg) was
charged to the reactor over 1 hr, then the mixture was stirred at
55.degree. C. for 30 min. The reactor contents were cooled to
25.degree. C. over 2 hr. The solid was collected by centrifugation
and the cake washed with water (40 L) followed by methanol (80 L).
The solid was dried in a vacuum oven at 50.degree. C. until the
loss-on-drying was less than 1% to provide
5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-met-
hyl-1H-pyrimidine-2,4-dione 1c (16.6 kg, 83% molar yield) as an
off-white solid. LCMS (ESI) m/z 427.1 (MH+).
Alternate Step 1C:
5-(2-Fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethvl-benzyl)-6-met-
hyl-1H-pyrimidine-2,4-dione
[0043] To a reactor was charged
1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-d-
ione 1b (5.0 kg), 2-fluoro-3-methoxyphenylboronic acid (2.58 kg),
and acetone (5.5 L). The mixture was agitated and a potassium
hydroxide/water solution (2.658 kg/19.0 L) was charged. The reactor
contents were degassed for 30-60 min, then the internal temperature
was adjusted to 40.degree. C.
1,1-(bis-di-t-butylphosphino)ferrocene palladium dichloride (11.4
g) was added to the reactor and the contents mixed with jacket
temperature set to 45.degree. C. until the reaction was complete
(2.5 hr). The reaction mixture was cooled to 20-30.degree. C.
Celite (1.25 kg) was charged to the reactor and stirred for more
than one hour and the mixture was filtered through a Celite pad
(0.51 kg). The reactor and Celite cake were washed with
acetone/water/KOH (2.6 L/7.5 L/0.38 kg). The filtered solutions
were passed through a line filter and added over a period of 1-1.5
hr to a mixture of THF/AcOH/Water (15.0 L/7.53 L/5.0 L) maintained
at 62.degree. C. The reactor contents were cooled to 20.degree. C.
over 2-3 hr. The mixture was filtered and the cake washed with
60:40 water/MeOH (2.times.12.6 L) followed by methanol (2.times.16
L). The solid was dried in a vacuum oven at 65.degree. C. for 18 hr
to provide
5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzy-
l)-6-methyl-1H-pyrimidine-2,4-dione 1c (4.312 kg, 87% molar yield)
as an off-white solid. LCMS (ESI) m/z 427.1 (MH+). If necessary,
the material may be solubilized, re-treated with Celite, and
crystallized as above to increase purity.
Step 1D: Methanesulfonic acid
(S)-3-tert-butoxycarbonylamino-3-phenyl-propyl ester
[0044] N-Boc-D-phenylglycinol (17.5 kg), diisopropylethylamine
(11.4 kg), and tetrahydrofuran (79 L) were charged to a reactor,
agitated, and the mixture was cooled to 0.degree. C.
Methanesulfonyl chloride (9.3 kg) was charged while maintaining the
temperature below 10.degree. C. Addition lines were rinsed with 26
L THF. After completion of the reaction, an aqueous 0.5 N HCl
solution (3.6 kg conc. HCl/67 L water) was charged to the reactor
while maintaining temperature below 10.degree. C. After mixing,
agitation was stopped and the layers were allowed to separate. The
aqueous layer was discarded and heptane (175 L) was charged and the
reactor contents were stirred at 0.degree. C. for 1 hour. The
mixture was filtered and the cake was washed with heptane (25 L)
and dried at 40.degree. C. under vacuum to provide methanesulfonic
acid (S)-3-tert-butoxycarbonyl-amino-3-phenyl-propyl ester 1d (21.8
kg, 94% molar yield) as a white solid. LCMS (ESI) m/z 216.0
(M-100(Boc)H+)
Alternate Step 1D: Methanesulfonic acid
(S)-3-tert-butoxycarbonylamino-3-phenyl-propyl ester
[0045] N-Boc-D-phenylglycinol (5.0 kg), triethylamine (3.55 L), and
dimethylformamaide (10.54 L) were charged to a reactor, agitated,
and the mixture was cooled to 0.degree. C. Methanesulfonyl chloride
(1.79 L) was charged through a dip-tube while maintaining the
temperature below 5.degree. C. After completion of the reaction,
acetone (15.0 L) was charged to the reactor while maintaining
temperature below 5.degree. C. Water (12.0 L) was charged to the
mixture over 3 hr, maintaining temperature below 5.degree. C.,
during which time crystallization occurred. An additional portion
of water (18 L) was added while maintaining the temperature below
5.degree. C. The mixture was filtered and the cake was washed with
2:1 (v/v) water:acetone three times (2.times.10 L, 1.times.6600 L)
and dried between 25-40.degree. C. under vacuum to provide
methanesulfonic acid
(S)-3-tert-butoxycarbonyl-amino-3-phenyl-propyl ester 1d (6.278 kg,
94.5% molar yield) as a white solid. LCMS (ESI) m/z 216.0
(M-100(Boc)H+)
Step 1E:
3-((R)-2-Amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(-
2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione
[0046] Methanesulfonic acid
(S)-3-tert-butoxycarbonylamino-3-phenyl-propyl ester 1d (19.7 kg),
5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-met-
hyl-1H-pyrimidine-2,4-dione 1c (16.5 kg), potassium carbonate
(powder, 325 mesh, 13.4 kg) and DMF (101 L) were charged to a
reactor. The mixture was stirred at 55.degree. C. After reaction
completion, the reactor was cooled to 20.degree. C. and isopropyl
acetate (132 L) was charged, followed by water (157 L). After
agitation and settling, the layers were separated and the organic
layer washed with water (87 L). After agitation and settling, the
water layer was removed. To the organic layer was charged
methanesulfonic acid (11.2 kg) and the reactor contents were heated
to 60.degree. C. for 1-2 hours. The reactor contents were cooled to
20.degree. C. and a solution of potassium carbonate/water (26.8
kg/140 L) was added slowly, agitated, and then allowed to settle
prior to separation of layers. The organic layer was treated with a
solution of 85% phosphoric acid/H.sub.2O (22.6 kg/236 kg). The
mixture was agitated, allowed to settle, and the layers were
separated. The aqueous layer was washed with isopropyl acetate
(2.times.167 kg) and the layers were separated. A solution of
potassium carbonate/water (36.1 kg/139 kg) was added slowly to the
aqueous layer. Isopropyl acetate (206 kg) was charged; the mixture
was agitated and then allowed to settle. The aqueous layer was
removed and the organic layer was concentrated to provide a
solution of
3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro--
6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1e in
isopropyl acetate (125.4 kg, 30.7 kg contained, 86% yield) for use
in the next step. LCMS (ESI) m/z 546.2 (MH+)
Alternate Step 1E:
3-((R)-2-Amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro--
6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione
[0047] Methanesulfonic acid
(S)-3-tert-butoxycarbonylamino-3-phenyl-propyl ester 1d (177.54 g),
5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-met-
hyl-1H-pyrimidine-2,4-dione is (160.0 g),
1,1,3,3-tetramethylguanidine (117.72 mL) and DMF (320 mL) were
charged to a reactor. The mixture was stirred at 40.degree. C.
After reaction completion (48 hr), 85% H.sub.3PO.sub.4/water (129.8
g/960 mL) was added followed by isopropyl acetate (960 mL). After
agitation and settling, the layers were separated and the organic
layer washed with 85% H.sub.3PO.sub.4/water (43.27 g/48 mL). After
agitation and settling, the aqueous layer was removed and the
organic layer washed with water (480 mL). After agitation and
settling, the aqueous layer was removed. To the organic layer was
charged water (76 mL) and methanesulfonic acid (108.2 g) and the
reactor contents were heated to 60.degree. C. for 6 hours. The
reactor contents were cooled to 40.degree. C. and a solution of
potassium carbonate/water (259.34 g/1360 mL) was added slowly,
agitated, and then allowed to settle prior to separation of layers.
The organic layer was treated with a solution of 85% phosphoric
acid/H.sub.2O (129.81 g/1360 mL). The mixture was agitated, allowed
to settle, and the layers were separated. The aqueous layer was
washed with isopropyl acetate (2.times.1120 mL) and the layers were
separated. A solution of potassium carbonate/water (259.34 g/480
mL) was added slowly to the aqueous layer. Isopropyl acetate (1360
mL) was charged; the mixture was agitated and then allowed to
settle. The aqueous layer was removed and the organic layer was
washed with water (480 mL) and the layers were separated. The
organic later was filtered through a medium glass frit and the
lines/filter were rinsed with 220 mL i-PrOAc. The organic layer was
concentrated by distillation to approximately 550-750 mL volume.
This solution was heated at 80.degree. C. and heptane (640 mL) was
added over one hour. NBI-54048 crystalline seeds (2.0 g) were
charged after approximately one third of the heptane charge was
complete. After heptane addition the mixture was maintained at
80.degree. C. for 2 hr, then cooled to 10.degree. C. over 180 min.
The mixture was filtered to provide a solid that was dried under
vacuum at 50-60.degree. C. overnight.
3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro--
6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione le
(170.9 g, 84% yield) was obtained as a white solid. LCMS (ESI) m/z
546.2 (MH+)
Example 2
##STR00012##
[0048] Step 2A: Ethyl-2-(2'-fluoro-3'-methoxyphenyl)-glyoxylate
[0049] N,N,N',N',N''-Pentamethyldiethylenetriamine (PMDFT, 36.0 g,
43.5 mL, 208 mmol) and anhydrous tetrahydrofuran (THF, 150 mL) were
charged into a 3-necked 1L round bottom flask purged with N.sub.2.
The solution was chilled to -78.degree. C. with acetone--dry ice.
Under continuous agitation and N.sub.2 purge butyllithium (Bu-Li,
1.6 M solution in hexanes, 130 mL, 208 mmol) was added to the
solution. Over a period of 30-45 min. 2-fluoroanisol (13.1 g, 11.7
mL, 104 mmol) diluted with anhydrous THF (50 mL) was added to the
Bu-Li solution. One hour after the addition of 2-fluoroanisol the
reaction mixture was slowly transferred to another 3-necked 1 L
round bottom flask containing diethyloxalate (100 mL, 107.6 g, 736
mmol) diluted with anhydrous THF (100 mL) at -78.degree. C. under
N.sub.2 purge. Agitation, -78.degree. C. temp. and N.sub.2 purge
were maintained during the transfer and for one hour after. 85%
H.sub.3PO.sub.4 (85 mL) diluted with water (240 mL) was added and
the temperature was allowed to increase to room temp. The layers
were separated and the aqueous phase was extracted with toluene
(400 mL). The organic phases were combined and extracted with
portions of water until the aqueous phase was neutral. The organic
phase was evaporated in vacuo to yield an oily residue 2a
(.about.102 g).
Step 2B: Ethyl-2-fluoro-3-methoxymandelate
[0050] The major portion of the crude 2a (90 g) from step 2A was
dissolved in MeOH (180 mL) and AcOH (30 mL). Under continuous
agitation at room temperature, NaBH.sub.4 (9.5 g, 251 mmol)
dissolved in DMF (95 mL) was slowly added. After completion of the
reduction the solvents were removed by means of vacuum distillation
(e.g. water bath temp. up to 85.degree. C. at 25 mbar vacuum). The
residue was partitioned between water (85 mL) and Et.sub.2O (240
mL). The organic phase was washed with water (3.times.90 mL). The
aqueous phases were extracted again first with Et.sub.2O (250 mL)
then with EtOAc (210 mL) in a "counter current" fashion. The
extracts were concentrated down to oily residues 2b. The
distribution of the product in various extracts is as follows:
TABLE-US-00002 1.sup.st Et.sub.2O extract: 18.35 g, purity: 81.2%*
2.sup.nd Et.sub.2O extract: 2.39 g, purity: 100%* EtOAc extract:
0.68 g, purity: 65.8%* *The "purity" figures are based on the
second Et.sub.2O extract as 100%.
Step 2C:
Ethyl-2-(2'-fluoro-3'-methoxyphenyl)-2-O-mesyl-glycolate
[0051] The crude oily concentrates of the ether extracts of 2b
(20.7 g) were dissolved in a mixture of MeCN (60 mL) and Et.sub.3N
(40 mL). Under continuous stirring at room temperature,
methanesulfonyl chloride (16.7 mL, 24.7 g, 216 mmol) diluted with
MeCN (10 mL) was slowly added to the solution. At the end of the
reaction the sample was partitioned between water (130 mL)
containing Na.sub.2CO.sub.3 (1.5 g) and Et.sub.2O (315 mL). The
aqueous phase was extracted again with Et.sub.2O (100 mL). The
organic phases were combined and evaporated to an oil 2c (24.1
g).
Step 2D: Ethyl-2-bromo-(2'-fluoro-3'-methoxyphenyl)-acetate
[0052] The mesyl ester 2c (24.1 g) was dissolved in MeCN (50.0 mL).
Crystalline Et.sub.4N.sup.+.Br (15.2 g, 72.3 mmol) was added to the
solution and the mixture was stirred at room temperature. The
conversion was ca. 93% complete in five hours and 100% in four
days. The mixture was concentrated to 45-50 mL and water (50 mL)
was added. The resulting two-phase system was vigorously stirred
while loaded onto a Mitsubishi SP207 (brominated cross-linked
polystyrene) column (300 mL, 23 cm high). The column was eluted in
a stepwise gradient manner with mixtures of water/MeCN in the
following ratios: 70:30 (500
mL)-60:40-50:50-40:60-35:65-30:70-25:75 (250 mL each)-20:80 (500
mL)-15:85 and 10:90 (250 mL each). The fractions were evaluated by
TLC first and the fractions containing the product were assayed by
HPLC. Like fractions were combined and the organic component was
removed by distillation in vacuo. The oily phases under the aqueous
residues were extracted with CH.sub.2Cl.sub.2. The organic phases
were dried to yield 2d as a yellow oil. The yield was calculated as
11.45 g from assays based on the best fraction available being used
as a standard.
Step 2E: Ethyl-2-(2'-fluoro-3'-methoxyphenyl)-3-aminocrotonate
[0053] A sample of bromoacetate 2d (3.48 g, ca. 86% pure based on
the purest sample available as standard, 10.3 mmol) was dissolved
in HPLC grade MeCN (10.0 mL). The resulting solution was evaporated
to an oily residue in a stream of N.sub.2 at elevated temperature
(drying block set at 60.degree. C.). Simultaneously, Zn powder
(-100 mesh, 0.714 mg, 10.9 mmol) was suspended in HPLC grade MeCN
(5.0 mL) and was completely dried under the same conditions as
above. All reactants were cooled to room temp. While kept in a
strictly inert atmosphere, 2d sample was re-dissolved in anhydrous
MeCN (10.0 mL) and transferred to the vial containing Zn powder.
Under vigorous agitation the reaction was initiated within the time
interval of 0-10 min. and was complete in 45-60 min. The reaction
mixture was centrifuged to remove excess Zn powder. The supernatant
was partitioned between toluene (100 mL) and water (70 mL)--AcOH
(4.0 mL). The organic phase was washed with water (70 mL) and water
(70 mL)--conc. NH.sub.4OH (2.0 mL). The organic phase was washed
again with water (2.times.70 mL) and evaporated to an oil 2e (3.99
g, .about.69% pure). LCMS (ESI) m/z 254.5 (MH+)
Example 3
##STR00013##
[0054] Step 3A:
(Z)-2-(2-Fluoro-3-methoxy-phenyl)-3-phenoxycarbonylamino-but-2-enoic
acid ethyl ester
[0055] Aminocrotonate 2e (5.0 g, 19.7 mmol), toluene (50 mL),
calcium oxide (powdered, 2.5 g, 44.6 mmol), and phenyl
chloroformate (3.4 g, 21.67 mmol) were combined in a reactor. The
slurry was stirred at 75.degree. C. for 10 hours. The mixture was
cooled to 25.degree. C. and filtered through a #1 filter paper. The
reactor and cake were washed with 50-100 mL of toluene. The toluene
solutions were combined and stripped off under a 10 mm vacuum to
give 7.5 g of carbamate residue 3a.
Step 3B:
N-{(R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-4-methyl-2,6-dioxo-3,6-d-
ihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-2,2-dimethyl-propionamide
[0056] DMF (anhydrous, 70 mL) was added to carbamate residue 3a
(7.5 g, 19.7 mmol) and the mixture was cooled to 0.degree. C.
t-BOC-(1R)-amino-2-amino-1- phenylethane acetate salt (6.41 g, 21.6
mmol) was added followed by K.sub.2CO.sub.3 (4.08 g, 29.6 mmol).
The mixture was stirred for .about.3 hours (all carbamate 3a
(t.sub.R=11.5 minute in HPLC method 1) was converted to urea
intermediate (t.sub.R=10.5 minute in HPLC method 1)). The
temperature was raised to 60.degree. C. to control the CO.sub.2
release. The mixture was heated for 2-3 hours then 210 mL of water
was slowly added over 30-60 minutes maintaining the temperature at
60.degree. C. The slurry was stirred for 30-60 minutes at
50-60.degree. C. and was cooled down to 25.degree. C. over 30-60
minutes. The slurry was filtered and the cake was washed with 210
mL water to remove the residual base. The cake was dried at 10
mm/50.degree. C. to give 6.5 g (70% yield) of off-white fine needle
crystal 3b. Alternately, the cake may be washed with
acetonitrile/water 2:1 before drying.
Step 3C:
3-((R)-2-Amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(-
2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione
[0057] Uracil 3b (14.5 g, 30.9 mmol), sodium carbonate (50.0 g, 106
mmol), sodium bromide (25.0 g, 102.9 mmol), anhydrous DMF (200 mL),
and 2-flouro-6-trifluoromethylbenzyl bromide (12.0 g, 46.7 mmol) in
50 mL toluene were heated at 70-90.degree. C. for 10 hours (HPLC
showed all of the 3b was consumed). The mixture was cooled to room
temperature and was slowly charged with 170 mL of conc. HCl
solution. (Optionally, the solid carbonate and sodium bromide can
be filtered off before the addition of the HCl resulting in the use
of less HCL solution). The solution was heated at 60.degree. C. for
10 hours. The pH of the solution was adjusted to 7-8 by slowly
adding solid sodium carbonate. 600 mL of DI water was added and the
solution was extracted with 2.times.250 mL isopropyl acetate. The
phases were separated and the organic layer was washed with
2.times.100 mL of DI water. The organic layer was concentrated to
150 mL and was extracted with 150 mL 10% phosphoric acid. The
aqueous layer was agitated with 450 mL of isopropyl acetate and the
mixture was neutralized with saturated sodium bicarbonate solution
to pH 7. The phases were separated and the organic layer was washed
with 2.times.100 mL of water then dried over anhydrous sodium
sulfate. The organic layer was filtered and the filtrate was
concentrated at 10 mm and 50-60.degree. C. to give 15.8 g of le as
sticky oil with >98% HPLC peak are at 254 um (t.sub.g=6.61 min,
HPLC method 1). The yield was 91%. The oil can be triturated with
hexane to further remove some of the impurities.
Example 4
##STR00014##
[0058] Step 4A:
4-((R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid ethyl ester
[0059] To a reactor was charged a solution of
3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro--
6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione le in
isopropyl acetate (30.7 kg in 125.4 kg solution). Dimethylformamide
(28.8 kg) was charged and the mixture was distilled under vacuum to
remove the isopropyl acetate. Ethyl-4-bromobutyrate (11.8 kg) was
charged to the reactor followed by diisopropylethylamine (8.87 kg).
The reactor contents were heated to 52.degree. C. and stirred until
completion of reaction. The reactor was cooled to 22.degree. C. and
isopropyl acetate (144 kg) and water (144 kg) were added. The
mixture was agitated and the layers allowed to settle. The water
layer was removed and the organic layer was washed with water (144
kg). The organic layer was treated with a solution of 85%
phosphoric acid/H.sub.2O (15.6 kg/173 kg). The mixture was
agitated, allowed to settle, and the layers were separated. The
organic layer was treated with a solution of 85% phosphoric
acid/H.sub.2O (4.03 kg/28.8 kg). The mixture was agitated, allowed
to settle, and the layers were separated. The aqueous phosphate
layers were combined and washed with isopropyl acetate (28.8 kg).
After layer separation, isopropyl acetate (144 kg) was added to the
aqueous layer, followed by slow addition of a solution of potassium
carbonate/water (35.1 kg/43.2 kg) while mixing. The layers were
separated and the organic layer was concentrated by vacuum
distillation. The solution was passed through a silica gel plug
pre-conditioned with CH.sub.2Cl.sub.2 and the plug eluted using
i-PrOAc/CH.sub.2Cl.sub.2 (31 kg/190 kg) in four portions.
Appropriate portions were combined and the solution was
concentrated initially by atmospheric pressure distillation
followed by vacuum distillation. The concentrated solution of
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid ethyl ester 4a (86.4 kg total, .about.29.8 kg of 4a,
80% yield) was used in the next step. LCMS (ESI) m/z 660.2
(MH+)
Step 4B:
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluorom-
ethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-e-
thylamino)-butyric acid
[0060] To a reactor was charged a solution of
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid ethyl ester 4a (86.4 kg solution, containing
.about.29.8 kg of 4a). The solution was concentrated by vacuum
distillation, followed by addition of ethanol (59.6 kg). The
solution was concentrated by vacuum distillation. After
distillation was complete, ethanol (59.6 kg) was charged to the
reactor, followed by a solution of NaOH/water (4.47 kg/59.6 kg).
The reactor contents were heated at 35.degree. C. for two hours
until reaction completion. The reactor contents were concentrated
using vacuum distillation, water (89.4 kg) was added, and the
reactor contents were concentrated using vacuum distillation. Water
(149 kg) was added and the solution was cooled to 10-15.degree. C.
A solution of conc. HCl/water (8.05 kg/29.8 kg) was added slowly
over .about.1 hr while maintaining the temperature between
10-15.degree. C. until the pH was 6.1. The slurry was stirred at
22.degree. C. for 16 hours and filtered. The reactor and filter
cake were washed with water (2.times.50 kg) and the solid product
was dried under vacuum at 37.degree. C. to provide
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid 4-1 as an off-white solid (26.1 kg, 91% yield). LCMS
(ESI) m/z 632.2 (MH+)
Example 5
##STR00015##
[0061] Step 5A:
4-((R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid ethyl ester
[0062] To a reactor was charged a solution of
3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro--
6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1e in
isopropyl acetate (19.0 kg in 59.6 L solution). Dimethylformamide
(18 L) was charged and the mixture was distilled under vacuum to
remove the isopropyl acetate. Ethyl-4-bromobutyrate (7.83 kg) was
charged to the reactor followed by diisopropylethylamine (5.87 kg).
The reactor contents were heated to 55.degree. C. and stirred until
completion of reaction. The reactor was cooled to 20.degree. C. and
isopropyl acetate (110 L) and water (96 L) were added. The mixture
was agitated and the layers allowed to settle. The water layer was
removed and the organic layer was washed with water (95 L). The
organic layer was treated with a solution of 85% phosphoric
acid/H.sub.2O (10.4 kg/152 L). The mixture was agitated, allowed to
settle, and the layers were separated. The organic layer was
treated with a solution of 85% phosphoric acid/H.sub.2O (2.7 kg/19
L). The mixture was agitated, allowed to settle, and the layers
were separated. The aqueous phosphate layers were combined and
washed with isopropyl acetate (21 L). After layer separation,
dichloromethane (109 L) was added to the aqueous layer, followed by
slow addition of a solution of potassium carbonate/water (23.2
kg/29 L) while mixing. The layers were separated and the organic
layer was concentrated by vacuum distillation. The solution was
passed through a silica gel plug pre-conditioned with
CH.sub.2Cl.sub.2 and the plug eluted using EtOH/CH.sub.2Cl.sub.2 (5
L/469 L). Appropriate portions were combined and the solution was
concentrated by vacuum distillation. Ethanol (80 L) was charged to
provide a concentrated stock solution of
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,
6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid
ethyl ester 4a (82.9 kg total, .about.17.3 kg of 4a, 75% yield)
that was used in the next step. LCMS (ESI) m/z 660.2 (MH+)
Alternate Step 5A:
4-((R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenvl-ethylamino-
)-butyric acid ethyl ester
[0063] To a reactor was charged a solution of
3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro--
6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1e (3000
g) and dimethylfoimamide (4.5 L). The mixture was stirred and
diisopropylethylamine (924 g) and ethyl-4-bromobutyrate (1287 g)
were charged to the reactor and the reactor contents were heated to
80-85.degree. C. After completion of the reaction (4 hr) the
contents were cooled to 25-30.degree. C. and isopropyl acetate
(15.0 L) and water (9.0 L) were added. The mixture was agitated and
the layers allowed to settle. The water layer was removed and the
organic layer was washed with citric acid/water (300 g/6.0 L). The
layers were separated and the organic layer was treated with a
solution of 85% phosphoric acid/H.sub.2O (1055 g/21.0 L). The
mixture was agitated, allowed to settle, and the layers were
separated. The organic layer was treated with a solution of 85%
phosphoric acid/H.sub.2O (422 g/6.0 L). The mixture was agitated,
allowed to settle, and the layers were separated. The aqueous
phosphate layers were combined and washed with isopropyl acetate
(2.times.6.0 L). After layer separation, isopropyl acetate (15.0 L)
was added to the aqueous layer, followed by slow addition of a
solution of potassium carbonate/water (3.04 kg/4.5 L) while mixing.
The layers were separated and the aqueous layer was extracted with
i-PrOAc (6.0 L). After layer separation, the combined organic
layers were washed with sodium bicarbonate/water (1.20 kg/15.0 L).
Reagent alcohol (6.0 L) was added to the organic layer and the
solution concentrated by vacuum distillation until the reactor
volume was .about.9.0 L. Reagent alcohol (12.0 L) was added and
distillation was resumed until the volume was 9.0 L. The
concentrated solution of
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid ethyl ester 4a was used in the next step. LCMS (ESI)
m/z 660.2 (MH+)
Step 5B:
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluorom-
ethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-e-
thylamino)-butyric acid sodium salt
[0064] To a reactor was charged a stock solution of
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid ethyl ester 4a (81.8 kg solution, containing
.about.17.1 kg of 4a). A solution of NaOH/water (2.2 kg/70 L) was
added and the reactor contents were stirred at 20-25.degree. C. for
five hours until reaction completion. The reactor contents were
concentrated using vacuum distillation. Water (124 L) was added and
the solution was passed through a 5 .mu.m line filter. Methyl
isobutyl ketone (120 L) was charged and the mixture heated to
55.degree. C. Separate the layers and add methyl isobutyl ketone
(120 L) to the aqueous layer at ambient temperature. Agitate the
mixture and add 48% aqueous sodium hydroxide (33 kg). Separate the
layers and wash the aqueous layer with methyl isobutyl ketone (51
L). Separate the layers and wash the combined methyl isobutyl
ketone layers with an aqueous brine solution (15.4 kg NaCl/44 L
water). Separate the layers and concentrate the organic layer to
.about.2-3 volumes methyl isobutyl ketone. Filter the concentrated
solution through a 0.2 .mu.m filter. Charge the methyl isobutyl
ketone solution to a well-agitated reactor containing heptane (171
L) cooled to 20.degree. C. The mixture is stirred for two hours,
filtered, and the cake is washed with heptane (10 L) to provide
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid sodium salt 5-1 as an off-white solid (13.2 kg, 78%
yield). LCMS (ESI) m/z 632.2 (MH+)
Alternate Step 5B:
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid sodium salt
[0065] To a reactor was charged a solution of
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid ethyl ester 4a from the previous step. Reagent
alcohol (6.0 L) was added and the temperature adjusted to
20.degree. C. A solution of NaOH/water (440 g/6.0 L) was added and
the reactor contents were stirred at 20-25.degree. C. for two hours
until reaction completion. Water (9.0 L) was added and the reactor
contents were concentrated using vacuum distillation to a volume of
approximately 15.0 L. Water (15.0 L) and methyl isobutyl ketone
(9.0 L) was charged, the mixture was agitated, the layers were
separated, and the aqueous layer was retained. A second wash with
methyl isobutyl ketone may be performed if needed. Methyl isobutyl
ketone (9.0 L) was added and the mixture concentrated by vacuum
distillation to a volume of approximately 30 L and ethanol content
less than 3%. The reactor contents were set to a temperature of
25-30.degree. C. and sodium chloride (4507 g) and methyl isobutyl
ketone (21.0 L) were charged to the reactor and agitated. The
layers were separated and the organic layer was concentrated to
.about.2-3 volumes methyl isobutyl ketone. The concentrated
solution was filtered through Celite and a 0.3 .mu.m line filter.
The filtered solution was charged to a well-agitated reactor
containing heptane (30.0 L) cooled to 10-20.degree. C. The mixture
was stirred for two hours, filtered, and the cake was washed with
heptane (8 L). The product was dried in a vacuum oven for 24-48 hr
at 70-75.degree. C. to provide
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid sodium salt 5-1 as an off-white solid (2.46 kg, 64%
yield). LCMS (ESI) m/z 632.2 (MH+)
Example 6
##STR00016##
[0066] Step 6A:
[0067] To a stock solution of
4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid ethyl ester (=6.55 g, 9.94 mmol) in i-PrOAc (140 mL)
was added conc. HCl (12 N, 0.88 mL, 10.6 mmol) solution in water
dropwise at room temperature over 2 min. Approximately 95 mL of
water and i-PrOAc mixture was removed by distillation under reduced
pressure. Isopropyl alcohol (1.28 mL) was added to provide a
homogeneous solution at 28.degree. C. The reaction mixture was
added dropwise into a vigorously stirred solution of n-heptane (65
mL) at 5.degree. C. A white precipitate was formed immediately and
the mixture became thick upon completion of addition. The white
slurry was stirred for 18 h at room temperature. The white solid
was collected by pressure filtration under nitrogen and dried by
passing nitrogen through the filter cake for 1 h to provide 6.0 g
(87%) of
4-((R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluorom-
ethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-e-
thylamino)-butyric acid ethyl ester HCl salt 4a.HCl as a white
solid, LCMS (ESI) m/z 660.2 (MH+ of free base). Elemental analysis:
Cl, 5.21%
Example 7
##STR00017## ##STR00018##
[0068] Step 7A:
2-(2-Chloro-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
[0069] To a stirred solution of
2-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol
(830 g, 3.26 mol) in dry DMF (4.15 L) was added potassium carbonate
(1126.4 g, 8.15 mol) under an inert atmosphere. Me.sub.2SO.sub.4
(402 mL, 4.24 mol) was added slowly to control the resulting
exotherm (addition over 30 minutes gave a temperature rise from
28.degree. C. to 55.degree. C.) and after complete addition the
reaction was stirred for 10 minutes. The reaction mixture was added
to stirring HCl (5.98 L, 2 N, aq.) very slowly to control
effervescence and the resulting precipitate stirred for 2 hours.
The solids were filtered and washed with water (1 L) and dried in a
vacuum oven over drying agent for 4 days to give
2-(2-chloro-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
7a as a white powder (746.7 g, 2.78 mol, 85%).
Step 7B:
5-(2-Chloro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benz-
yl)-6-methyl-1H-pyrimidine-2,4-dione
[0070] Compound 1b (80 g, 0.19 mol), 7a (60.22 g, 0.22 mol),
HP(t-Bu).sub.3BF.sub.4 (13.01 g, 44.85 mmol), and
Pd.sub.2(dba).sub.3 (13.69 g, 14.95 mmol) were charged to the
reaction vessel and purged with an inert atmosphere. Degassed THF
(560 mL) was added followed by NaOH (31.45 g, 0.56 mol) in degassed
water (128.8 mL) and the reaction warmed to 45.degree. C. After 2
hours acetic acid (56 mL) was added and stirred for 15 minutes.
After settling, the layers were separated and the organic layer was
filtered through celite, rinsing with hot THF (2.times.160 mL). The
filtrate was concentrated in vacuo to a slurry, to which was added
N-acetyl cysteine (15.84 g) as a solution in water (160 mL) and
ethanol (640 mL) and stirred for 2 hours at 75.degree. C. under an
inert atmosphere. The slurry was cooled to RT, and the solids
filtered off, washed with ethanol:water (8:2, 2.times.160 mL) to
give
5-(2-chloro-3-methoxy-phenyl)-1-(2-fluoro-6-methyl-benzyl)-6-methyl-1H-py-
rimidine-2,4-dione 7b as a white solid (58.6 g, 0.13 mol, 70%).
Step 7C:
3-((R)-2-Amino-2-phenyl-ethyl)-5-(2-chloro-3-methoxy-phenyl)-1-(-
2-fluoro-6-methyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione
[0071] 7b (120 g, 0.271 mol), 1d (128.34 g, 0.407 mol) and
K.sub.2CO.sub.3 (93.64 g, 0.407 mol) were charged to the reaction
vessel under an inert atmosphere and suspended in DMF.
[0072] The resulting slurry was warmed to 50.degree. C. and stirred
for 17 hours. The reaction was incomplete so additional 1d (50 g,
0.158 mol) and DMF (300 mL) were added. The reaction was complete
after 32 hours and the mixture was cooled to RT. i-PrOAc (1 L) and
water (1 L) were added and stirred for 30 minutes. The layers were
separated and MeSO.sub.3H (52.8 mL, 0.813 mol) was added slowly to
the organic layer controlling the exotherm (24.4.degree. C. to
41.0.degree. C.). The mixture warmed to 60.degree. C. and was
stirred for 3 hours. The mixture was cooled to RT and was added
slowly to a mixture of K.sub.2CO.sub.3 (186.99 g, 1.35 mol) in
water (975 mL). After stirring for 15 minutes, the organic layer
was separated and extracted with a H.sub.3PO.sub.4 solution (94 g
of 85% H.sub.3PO.sub.4 in 975 mL water). The aqueous layer was
slowly added to K.sub.2CO.sub.3 (186.99 g, 1.35 mol) in water (975
mL), followed by i-PrOAc (1100 mL). The mixture was stirred for 10
minutes and the layers separated. The i-PrOAc layer was dried
(NaSO.sub.4) and concentrated to give
3-((R)-2-amino-2-phenyl-ethyl)-5-(2-chloro-3-methoxy-phenyl)-1-(2-fl-
uoro-6-methyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 7c as a
foaming solid (145.5 g, 0.25 mol, 95% crude yield, uncorrected for
purity).
Step 7D:
4-4-((R)-2-[5-(2-chloro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluor-
omethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-
-ethylamino)-butyric acid ethyl ester
[0073] 7c (145.5 g, 0.259 mol) was dissolved in DMF (146 mL) under
an inert atmosphere. 4-Bromobutyrate (42.6 mL, 0.298 mol) was added
followed by i-Pr.sub.2EtN (58.65 mL, 0.337 mol) and was stirred
overnight at 54.degree. C. The mixture was cooled to RT and i-PrOAc
(620 mL), water (620 mL) were added, and the mixture was stirred
for 30 minutes. After separation, the organic layer was washed with
water (620 mL) and extracted with a H.sub.3PO.sub.4 solution (67.3
g of 85% H.sub.3PO.sub.4 in 1 L water). The organic was extracted a
second time with a H.sub.3PO.sub.4 solution (17.6 g of 85%
H.sub.3PO.sub.4 in 126 mL water). The combined aqueous phosphate
extracts were washed with i-PrOAc (130 mL). CH.sub.2Cl.sub.2 (950
mL) was added to the aqueous phosphate layer followed by a slow
addition of a solution of K.sub.2CO.sub.3 (172 g, 1.24 mol) in
water (188 mL). The mixture was stirred for 30 minutes and after
separation the organic dried (NaSO.sub.4) and concentrated in vacuo
to give
4-((R)-2-[5-(2-chloro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethy-
l-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl-
amino)-butyric acid ethyl ester 7d as a foaming oil (121 g, 0.179
mol, 70%).
Step 7E:
4-((R)-2-[5-(2-chloro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluorom-
ethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-e-
thylamino)-butyric acid sodium salt
[0074] NaOH (338 mL, 169 mmol, 0.5 M aq.) was added to a solution
of 7d (103.9 g, 153.68 mol) in EtOH (472 mL) and the mixture was
stirred for 2 hours. The EtOH was distilled off and water added to
a total volume of 1080 mL (10.5 mL/g). This mixture was passed
through a filter and washed with MIBK (600 mL.times.2). MIBK (700
mL) was added followed by NaOH (289 mL, 50% w/w) and extracted. The
organic layer was separated and the aqueous extracted with MIBK
(250 mL) and the combined organic layers washed with brine (500
mL), dried (NaSO.sub.4) and concentrated in vacuo to give a foam.
This was lyophilized from 300 mL water to give
4-((R)-2-[5-(2-chloro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-ben-
zyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino-
)-butyric acid sodium salt 7-1 as an off white powder (92 g).
Example 8
Spray Drying Compound 5-1
[0075] Compound 5-1 was spray dried in a Buchi Mini Spray Dryer
model B-290. In the B-290, compound 5-1 was dried co-currently with
the drying gas flowing at approximately 30 m.sup.3/hr. The B-290's
spraying chamber was about 5.5 liters. Therefore, the B-290's
average drying residence time was about 0.6 sec. Atomization was
achieved by passing nitrogen gas and feed stream through a two
fluid nozzle atomizer.
[0076] Several drying runs were conducted using different solvents
and adjusting the pH. The following table shows the conditions of
runs. All runs resulted in an amorphous solid with no change in
impurity profile.
TABLE-US-00003 Cmpd Inlet Outlet 5-1 temp temp Run # (g) (.degree.
C.) (.degree. C.) Solvent 1 2 8 v/w 50:50 EtOH:H.sub.2O 2 2 110 55
8 v/w H.sub.2O 3 2 110 64 8 v/w 60:40 H.sub.2O:EtOH 4 2 100 54 8
v/w 50:50 MeOH:H.sub.2O 5 2 70 49 8 v/w MeOH 6 2 100 55 8 v/w 50:50
MeOH:H.sub.2O, XS NaOH 7 2 100 57 8 v/w 50:50 MeOH:H.sub.2O 8 4 110
65 ~12 v/w 50:50 MeOH:H.sub.2O 9 4 110 59 ~6 v/w 50:50
MeOH:H.sub.2O, XS NaOH
[0077] All trials run with N.sub.2 flow of .about.30 m.sup.3/hr,
atomization flow of 0.45 m.sup.3/hr, and solution feed rate of
approx. 5 mL/min
Example 9
Formation of Solid Amorphous Mixtures of Compound 5-1 Using Solvent
Evaporation
[0078] Appropriate amounts of compound 5-1 and polymer were
dissolved by bath sonication in a solvent system comprising
DCM/ethanol 1:1 (w/w), in a 250 mL Quickfit round bottomed flask.
The solvent was then removed as rapidly as possible under vacuum.
The vacuum was maintained until all obvious traces of the solvent
had been removed, and was then transferred to a freeze drier
chamber and left overnight at high vacuum. The dried material was
removed from the flask using a spatula and analyzed for amorphous
content using XRPD and DSC. Compound 5-1 was recovered as an
amorphous solid mixture with polymer.
TABLE-US-00004 Polymer:compound Run # 5-1 ratio Polymer 1 3:1
Kollidon 30 2 3:1 Kollidon 90 F 3 3:1 HPMC 4 3:1 Kollidon 30 5 3:1
Kollidon 90 F 6 3:1 HPMC
[0079] It will be appreciated that, although specific embodiments
of the invention have been described herein for purposes of
illustration, various modifications may be made without departing
from the spirit and scope of the invention. Accordingly, the
invention is not limited except as by the appended claims.
* * * * *