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Us7897763 PDF
Us7897763 PDF
Burgoon et a].
(54)
(75)
8/1993 Notte
1/1999 Preuss
6,916,933 B2
7/2005 Kaplan
7,553,840 B2*
2003/0144541 A1
2005/0096353 A1
5/2005 Ackermann
2005/0282900 A1
12/2005 Kawaguchi
2006/0128956 A1
6/2006 Hocek
2006/0148862 A1
2007/0191370 Al*
7/2006 Clary
8/2007 Devasagayaraj et a1.
2009/0088447 A1
2009/0099206 A1
4/2009 Bednarz
4/2009 Iimura
514/269
514/241
Woodlands, TX (US)
(22)
*Mar. 1, 2011
5,233,111 A
5,859,020 A
NJ (US)
(*)
US 7,897,763 B2
W0
W0
W0 03/104189
W0 03/104200
12/2003
12/2003
OTHER PUBLICATIONS
(2003).
Kuijpers, B.H.M., et al., Organic Let. 6(18):3123-3126 (2004).
Moussebois, C., et al., Helv. ChimicaActa 60(1):237-242 (1977).
Peyrnan, A., et al., Angew. Chemie 39(16):2874-2877 (2000).
Shi, Z. et al. J'. Med. Chem. 51(13):3684-3687 (2008).
Yoburn, J.C. and Van Vranken, D.L., Organic Let. 5(16):2817-2820
(2003).
(65)
May 7, 2009
US 2009/0118505 A1
* cited by examiner
(60)
29, 2005.
(51)
ABSTRACT
Int. Cl.
C07D 239/42
C07D 403/12
A61K 31/506
A61P 9/02
(52)
(58)
(57)
(2006.01)
(2006.01)
(2006.01)
(2006.01)
544/330
(56)
References Cited
U.S. PATENT DOCUMENTS
4,866,181 A
4,916,074 A
9/1989 Brown
4/1990 Yoshida
2 Claims, No Drawings
US 7,897,763 B2
1
4. DETAILED DESCRIPTION
This invention is based on the discovery of a novel process
that can be used to e?iciently prepare compounds of formula
by reference.
1. FIELD OF THE INVENTION
4.1. DEFINITIONS
20
299176 (2003).
The enZyme tryptophan hydroxylase (TPH) catalyZes the
30
(2003).
Because serotonin is involved in so many biochemical
processes, drugs that affect serotonin levels are often attended
by adverse effects. Thus, a need exists for neW methods of
40
eroaryl moiety.
45
cycle moiety.
Unless otherWise indicated, the term alkynyl means a
55
US 7,897,763 B2
3
alkyl moiety.
25
tamyl.
35
an alkyl moiety.
Unless otherWise indicated, the term heterocycloalkyl
refers to a non-aromatic heterocycle.
40
45
50
60
non-toxic acids include, but are not limited to, inorganic and
65
US 7,897,763 B2
6
5
Unless otherwise indicated, the term include has the
same meaning as include, but are not limited to, and the
term includes has the same meaning as includes, but is not
limited to. Similarly, the term such as has the same mean
ing as the term such as, but not limited to.
1(b)
O
01
R3
10
(R1041
I \
R4
OH
V (Rl2)p
NH2
N /N
R7
1(0)
R3
(R1041
I \
R4
OH
V (Rl2)p
NH2
'
N /N
20
R7
I(d)
O
R3
25
I \
R4
OH
""o
NH2
30
1(6)
35
YN
40
NH2
I(a)
0R2
55
R3
R4
US 7,897,763 B2
7
With a compound of formula III:
II(b)
R3
III
R4
OH
(RUM
|\ \
/
under conditions suf?cient for the formation of the compound
of formula I(a), wherein: A is optionally substituted
formula III(a):
20
P3
Yl
NPIPZ
N'YN
25
R7
30
III(b):
P3
Yl
40
NPIPZ
N'YN
NH2
III(b)
0
35
III(a)
45
of formula II(a):
IV
50
Y2
R4
XH
65
US 7,897,763 B2
10
cycloalkyl, aryl, or heterocycle; Y2 is halogen or pseudohalo
gen; and each R is independently hydrogen, optionally sub
stituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or hetero
cycle, or are taken together With the oxygen atoms to Which
they are attached to provide a cyclic dioxaborolane.
VI
O
| \
/
10
iCF3. In another, X is O.
In a particular embodiment, the compound of formula IV is
of formula IV(a):
<
R'O B
)2
/\
"3
NP P
1 2
(R5).
IV(a)
VII
B(OR)2
(RUM
20
25
Qimomz
30
are taken together With the oxygen atoms to Which they are
of formula VI(a):
VI(a)
45
P3
50
VI(b):
VI(b)
V(b)
c1:3
P3
60
0
OH
65
NPIPZ
US 7,897,763 B2
11
12
VH0)
1s l-4.
NP P
\B
1 2
1(0)
HO/
10
0
R3
R4
Y1
I
N
VII(a)
Y3
CF| \,
1s <R11>m/
OH
NI /N
(Rl2)p
R7
M)
R7
20
R3
R4
VII(b):
@f. \
<R11>m/ \a R
l
VIM)
OH
( 12),;
30
NH;
| \
N
/N
C113
NH2
OH
"'0
NH2
bl] / N
Y
formula I:
NHZ
OR;
Schemel
R4
45
P3 +
NPIPZ
m5)
VI
Y
I(b)
O
55
R3
/
(RUM
\ I \
'
(Rl2)p
>
N\ / Z2
Z1
R4
IY| 23
;Y3
OH
\
|
\f
v11
NH2
0
60
R7
HI
US 7,897,763 B2
13
14
-continued
-continued
R3
I \
I
__
(Rmm
R4
OH
(Rl2)p
ll(a)
Y1WY3
P3
JYN
R7
20
25
30
35
40
?nal product:
S cheme 2 (b) :
50
55
65
US 7,897,763 B2
16
15
-continued
on
c1
NI-IBOC
N' /N
NH2
15
R7
C113
20
H3CO
OH
.,Io
NP P
l 2
NYN
25
NH2
3,2-dioxaborolan-2-yl.
In another embodiment, each protecting group is indepen
30
35
aryl-alkoxy.
0
45
C113
OH
OH
"'0
Cl
NP1P2
N' /N
H3CO
NI-IBOC
NY N
50
NH2
NH2
55
60
aryl-alkoxy.
In one embodiment, P 1 is hydrogen. In another, P2 is ben
65
US 7,897,763 B2
19
20
-continued
-continued
O
O
C
OH
OH
Cl
I/O
NHBoc
N' /N
I \
NHZ
NY N
NH2
NH2
OMe
10
Scheme 3(d):
USA).
20
Scheme 3 d
CF3
25
C113
30
Br
C113
Br
OMe
3
40
>
NHBoc
| \
N
OH
C1
lyst
45
/N
NH;
50
(20 g) and Hy?o Super Cel (20 g) and the mixture was
OH
../O I \
NHBoc
60
N /N
NHZ
OMe
9
65
US 7,897,763 B2
21
22
5 .2. (S)-1-(4-Bromophenyl)-2,2,2-tri?uoroethanol
This mixture Was ?ltered hot and Washed With ethyl acetate
(100 ml) and then concentrated to a syrup. This syrup Was
c1:3
7.20 (m, 1H), 7.14 (m, 1H), 6.95 (m, 1H), 5.82 (q, 1:66 HZ,
1H), 3.85 (s, 3H), 2.63 (br s, 1H). 13C NMR (CDCl3): 6 160.3,
142.6,142.2,133.5,130.3,128.3,127.8,124.8(q,J:282 HZ),
NMR (CDCl3): 6 7.38 (d, 1:60 HZ, 2H), 7.25 (d, 1:60 HZ,
25
120.1, 113.4, 113.3, 73.0 (q, 1:32 HZ), 55.7. 19P NMR
(CDCl3): 6-783 (d, 1:64 HZ). Residual palladium: 11 ppm.
Anal. Calcd for Cl5H13F3O2: C, 63.83; hours, 4.64. Found: C,
63.78; hours, 4.60.
30
2H), 5.00 (dq, 11:66 HZ, 12:33 HZ, 1H), 2.49 (d, 1:38 HZ,
1H), 2.42 (s, 3H).
5 .4. (S) -2,2,2-Tri?uoro- 1 -(p-tolyl)ethanol
[(trans)-RuCl2[(S)-Xyl-P-Phos] [(S)-DIAPEN].
5.5. (R)-2,2,2-Tri?uoro-1-(3'-methoxybiphenyl-4-yl)
ethanol (3)
pound 2 (1.00 kg, 1 Wt, 3.92 mol) and ethanol (4.5 L, 4.5 vol).
The mixture Was sparged With nitrogen for 10 minutes and
(Ph3P)2PdCl2 (12.6 g, 0.0126 Wt, Strem) Was added. FolloW
40
Br
45
CF3
The heat Was sWitched off and at 69 C., Water (3.6 vol) Was
added. The reaction mixture Was then ?ltered at 50 C.
OMe
55
60
65
US 7,897,763 B2
23
24
?ltrate Was reduced to 6.7 volumes over 2.5 hours and then
heptane (3.15 vol) Was added. The solution Was further dis
to 6.7 vol at 55 C. over 1.5 hours and then heptane Was added
trated under reduced pressure to 200 ml. This Was diluted With
(CDCl3) 6 7.16 (m, 4H), 4.95 (d, J:7.1 HZ, 1H), 4.53 (m, 1H),
3.64 (s, 3H), 3.10 (dd, 11:57 HZ, 12:13.8 HZ, 1H), 2.97 (dd,
11:63 HZ, 12:13.6 HZ, 1H), 1.34 (s, 9H). 13C NMR (CDCl3)
6172.3, 155.4,149.0,137.4, 131.5, 121.7, 119.1 (q, 1:321
HZ), 80.54, 54.62, 52.7, 38.3, 28.6. 19P NMR (CDCl3) 6-73.4.
5.9. (S)-2-(Tert-butoxycarbonylamino)-3-(4-(4,4,5,5
tetramethyl-1 ,3 ,2-dioxaborolan-2-yl)phenyl)pro -
OMe
30
NHBoc
TfO
35
OMe
0\
NHBOC
40
(tri?uoromethylsulfonyloxy)phenyl)propanoate (5)
OH
0
NHBOC
50
OMe
NHBo 0
HO
55
OMe
NHBo c
60
TfO
65
US 7,897,763 B2
25
26
5.1 1. (S)-3-(4-(2-Amino-6-chloropyrimidin-4-yl)
phenyl)-2-(tert-butoxycarbonylamino)propanoic acid
(8)
3H), 3.13 (m, 2H), 1.44 (s, 9H), 1.36 (s, 12H).
OH
>
NHBoc
\B
/
OH
20
Cl
NH;
30
9H),1.35(s,12H).l3CNMR(CDCl3)6175.8,155.7,139.7,
Compound 7 can optionally isolated by crystallization.
NHBoc
NY N
| \
yield.
toxycarbonylamino)-3-(4-(4,4,5 ,5 -tetramethyl-1,3,2
45
50
Were added to reach the cloudy point and the turbid solution
Was held at ~60 C. for 75 minutes folloWed by cooling to
~10 C. over ~1.5 hrs. After 45 minutes, the mixture Was
biphasic and Was diluted With an additional 30 ml 2-propanol.
The mixture Was stirred under nitrogen at 10 C. overnight
and the resulting White ?ne suspension Was ?ltered. The
collected solids Were Washed With 100 ml 9:1 Water:2-pro
panol and Were dried in vacuo at 50-60 C. to give 39.88 g 7
as a chalky White poWder (78% recovery). The solid Was in
the ?ltrate Was ?ltered and dried to afford 4.51 g of a pale
60
hours. After 1 hours hold, the slurry Was ?ltered, Washed With
isopropanol (150 ml), and dried at 50 C. under vacuum to
give the product 8 as a light pink solid (46.2 g, 37% yield from
65
US 7,897,763 B2
27
28
d6) 6 12.60 (s, 1H), 8.02 (d, 1:83 HZ, 2H), 7.38 (d, J:8.1 HZ,
2H), 7.23 (s, 1H), 7.13 (br s, 2H), 3.09 (dd, 11:44 HZ, 12:13.5
HZ, 1H), 2.91 (dd, 11:10.5 HZ, 12:13.8 HZ, 1H), 1.32 (s, 9H).
13C NMR (DMSO-d6) 6 173.4, 165.8, 163.5, 161.0, 155.4,
141.4, 134.0, 129.4, 126.8, 104.4, 78.0, 54.8, 36.2, 28.1.Anal.
Calcd for C18H2lClN4O4: C, 55.03; hours, 5.39; N, 14.26.
Found: C, 54.76; hours, 5.65; N, 14.09.
HPLC analysis of the above mother liquor against an stan
dard solution of compound 8 shoWed additional 38 g product
8 (30% yield from Boc-Tyr-OMe, 4). Product 8 can be par
29 C. The cake Was Washed With Water (2><2.5 vol) and then
dried at 45-50 C. for 24 hours to provide 720 g of 8 (84%
(8)
A 22-L, round-bottom ?ask equipped With a mechanical
stirrer, a thermocouple attached to a temperature controller,
and a condenser With a nitrogen line Was charged With com
30
45
With Water (300 g). THF (1000 g) and toluene (730 g) Were
then added to the combined aqueous layer and the mixture
Was acidi?ed to pH 2.5~3.5 With 6 N HCl (100 g) at 20~25
C. The layers Were separated and NaCl (500 g) Was added to
solution of PBu3 (212 ml, 0.25 vol, 97%) in EtOAc (3.5 vol)
The vacuum Was released and Water (3 vol) Was added to the
charged EtOH (570 g), THF (1330 g), boronic acid 7 (100 g,
255.6 mmol, 1.0 eq.), 2-amino-4,6-dichloropyrimidine 126 g
(768.3 mmol, 3.0 eq.), PPh3 (0.87 g, 3.32 mmol, 1.3 mol %)
and Pd(OAc)2 (0.373 g, 1.66 mmol, 0.65 mol %). The ?ask
Was then degassed by three vacuum/nitrogen ?ll cycles and
stirred at about 10-20 C. for about 10-20 minutes. To the
chloropyrimidin-4-yl)phenyl)-2-(tert-butoxycarbony
50
the aqueous layer then extracted With EtOAc (400 g). The
combined organic layer Was treated With active carbon (50 g)
at 65~68 C. for 810 hours tWice. The resulting mixture Was
concentrated under vacuum to ~3 00 mL at 30~40 C. and then
for 2.5 hours. Additional EtOAc (3.3 vol) Was added to the
reactor and the contents Were charged to a separatory funnel
and the tWo phases separated. The aqueous phase (41 C.) Was
55
A %).
and the tWo phases Were separated. The aqueous phase (11.2
60
US 7,897,763 B2
29
30
ppm)
5.14. Optional Puri?cation of (S)-3-(4-(2-Amino-6
chloropyrimidin-4-yl)phenyl)-2-(tert-butoxycarbony
NHZ
20
B
O
OH
25
Cl
NHBoc
| \
rated. The organic layer Was Washed With H20 (100 ml, 5x)
and concentrated by rotary evaporating to around 160 ml of
overall volume. The solids Were collected by ?ltration and the
NYN
HN
NH;
30
| /N
\Y
C1
40
following methods.
toluene, 400 ml) and tert-butylamine (67 ml, 5.0 equiv) fol
loWed by i-PrOH (400 ml, 8x). The resulting mixture Was
45
50
rated. The organic layer Was Washed With H20 (100 ml, 5x)
and concentrated by rotary evaporating to around 160 ml of
60
US 7,897,763 B2
31
32
Weight to provide the ?nal product (208 mg, 68% yield, 92%
pure, 4.4% A, 1.4% B).
rimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)
(4-(2-Amino-6-chloropyrimidin-4-yl)phenyl)-2-(tert
OH
>
20
HO
NH2
\B
(60 ml) Was added. The mixture Was extracted tWice With
ethyl acetate (2x200 ml) and the aqueous layer Was acidi?ed
to pH ~3 using 1 N HCl. The mixture Was extracted With ethyl
acetate tWice (200 ml and 100 ml, respectively) and the com
bined organic layers Were concentrated and the residue Was
OH
1l
25
OH
>
HO\
NHBoc
B
(tert-butoxycarbonylamino)-3-(4-(4,4,5,5
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)
OH
35
12
O
40
OLi
>
0\
NHBOC
OH
/B
45
OH
Cl
| \
N
Cl
| \
NHBoc
NYN
50
NH2
NHBoc
/N
NH2
60
ride (60 mg, 0.5 mol %), and 100 ml ethanol. The resulting
US 7,897,763 B2
33
34
5.19. (S)-3-(4-(2-Amino-6-((R)-2,2,2-tri?uoro-1-(3'
(4-(2-Amino-6-chloropyrimidin-4-yl)phenyl)-2-(tert
methoxybiphenyl-4 -yl)ethoxy)pyrimidin-4-yl)phe
nyl)-2-(tert-butoxycarbonylamino)propanoic Acid
"WI/OH
+
OH
>
HO
NHZ
\B
OMe
OH
11
O
O
20
OH
OH
>
HO\
Cl
NHBoc
NHBoc
B
OH
NYN
25
12
NH2
8
O
OH 30
Cl
| \
N
c1:3
OH
NHBoc
O ""o I \
/N
35
NH;
NHBOC
NTN
NH2
OMe
9
40
45
diluted With Water (80 ml). TWo phases Were split and the
organic layer Was collected and diluted With ethyl acetate
(200 ml), Washed With a mixture of brine (50 ml) and 1 N HCl
(50 ml). The organic layer Was concentrated and the residue
Was puri?ed by column chromatography (gradient: 1:30 to
1:20 methanol/dichloromethane and 0.5% acetic acid) to
50
?ltrate Was Washed With ethyl acetate (200 ml) and diluted
With 3:1 THF/MTBE (120 ml). This mixture Was acidi?ed to
55
60
65
(DMSO-d6) 6 12.60 (br s, 1H), 8.00 (d, 1:80 HZ, 2H), 7.77
(d, 1:80 HZ, 2H), 7.67 (d, 1:80 HZ, 2H), 7.37 (m, 3H), 7.21
(m, 2H), 7.13 (d, 1:80 HZ, 1H), 6.96 (m, 1H), 6.84 (m, 2H),
6.75 (s, 2H, 4.15 (m, 1H), 3.82 (s, 3H), 3.10 (dd, 1:136, 4.4
HZ, 1H), 2.89 (dd, 1:136, 10.4 HZ, 1H), 1.32 (s, 9H). l3C
by HPLC analysis.
NMR(DMSO-d6)6173.4,168.4,166.1,162.9,159.7,155.4,
141.5,140.8,134.8,130.7,130.0,129.3,128.4,127.2,126.6,
US 7,897,763 B2
35
36
124.1 (q, 1:281 HZ), 119.1, 113.4, 112.3, 91.3, 78.0, 71.3 (q,
1:30 HZ), 55.1, 54.9, 36.2, 28.1. 19P NMR (DMSO-d6):
6-746 (d, J:7.2 HZ). Anal. Calcd. for C33H33F3N4O6: C,
62.06; hours, 5.21; N, 8.77. Found: C, 62.25; hours, 5.10; N,
-continued
equiv
entry
8.69.
time
% conversion
additive
(h)
(isolated yield)
i
i
24
20
0
98d
10 rnol %
17
98d
18
98d
18
88d
guanidine (5.0)
7
s
1.2
1.2
din-4-yl)phenyl)-2-(tert-butoxycarbonylamino)pro
10
K2CO3 (5.0)
Cs2CO3 (4.0)
nBu4NHSO4
1.2 Cs2CO3 (3.0)
10 rnol %
nBu4NHSO4
11
10 rnol %
nBu4NHSO4
All the reactions Were run in 10x dioxane except otherwise noted;
equiv
entry
time
% conversion
additive
(h)
(isolated yield)
1.2
Cs2CO3 (5.0)
17
97 (72)
2
3
4
5
6
1.2
1.2
1.2
1.2
1 .2
NaH (5.0)
NaOt-Bu (3.0)
NaOt-Arn (3.0)
DBU (5.0)
tetrarnethyl-
i
i
i
i
i
1
1
1
24
24
A
i
i
0
0
((R)-2,2,2-tri?uoro-1-(3'-methoxybiphenyl-4-yl)
ethoxy)pyrimidin-4 -yl)phenyl) -2-(tert-butoxycarbo
nylamino)propanoic Acid
MeO
OH
CF3
0\
/B
MeO
W
NHBOC
0
O
CF3
Cl
W
N
YN
NH2
c1:3
WOH
\
NY N
NHBoc
US 7,897,763 B2
37
38
A suspension of (R)-2,2,2-tri?uoro-1-(3'-methoxybiphe
-continued
on
(17.3 g, 0.053 mol) Was added and further stirred for 14 hours
at 100 C. Cooled to 50 C., Water (90 mL, 3x) Was added and
stirred for 30 minutes at room temperature. The organic layer
NH2
polish ?ltration. After diluted With toluene (300 mL, 10><) and
10
10
(20.00 g, 31.32 mmol) and THF (100 ml). The solid Was
dissolved upon stirring and 6 N hydrochloric acid (100 ml)
20
30
35
C13 WOH
"o
g6 N'
NHBOC
40
>
45
YNH2
amino-6-((R)-2,2,2-tri?uoro-1-(3'-methoxybiphenyl
OMe
4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic Acid
(10)
C113
""oH
OH
+ Cl
|
/N
OMe
NHBoc