Millennium Pharmaceuticals, Inc. INNOVATOR
Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Limited,
MLN4924, MLN 4924-003, TAK-924
905579-51-3 BASE
1160295-21-5 HcL
A
potent and selective inhibitor of NAE. An inhibitor of NEDD8-activating
enzyme as a new approach to treat cancer. The ubiquitin-proteasome
pathway mediates the destruction of unwanted proteins.
(((1
S,2
S,4
R)-4-{4-[(
S)-2,3-Dihydro-1
H-inden-1-ylamino]-7
H-pyrrolo[2,3-
d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl
sulfamate hydrochloride) (pevonedistat), a novel NEDD8-activating
enzyme (NAE) inhibitor, has demonstrated in vitro cytotoxic activity
against a variety of human malignancies and is currently being developed
by Takeda Pharmaceuticals Company Limited as a clinical candidate for
the treatment of cancer
In 2011, orphan drug designation was
assigned to MLN-4924 for the treatment of MDS and for the treatment of
acute myelogenous leukemia.
PHASE 1.......CANCER SOLID TUMOR
......................
PATENT
http://www.google.com/patents/US20120330013
preparing a compound represented by the following formula 1 by reacting the compound of formula 11 with TFA (step 9):
The retrosynthetic analysis of MLN4924 (1), as the final desired nucleoside, is shown in the following.
MLN
4924 (1) can be synthesized by condensing cyclic sulfate 3 as the
glycosyl donor with a purine base. The glycosyl donor 3 can be produced
from diol 4, which in turn can be obtained from cyclopentanone 5 via a
stereoselective reduction and a regioselective cleavage of the
isopropylidene moiety. The cyclopentanone 5 can be synthesized from
cyclopentenone 6 by stereoselective reduction. The intermediate
cyclopentenone 6 can be easily derived from D-ribose according to our
previously published procedure (Jeong, L. S. et al., J. Org. Chem. 2004,
69, 2634-2636).
The synthetic route for the glycosyl donor 3 is shown in the following scheme 1.
Example
1 Preparation of MLN4924 Step 1: Preparation of
6-(tert-butyl-diphenyl-silanyloxymethyl)-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-one
(Compound 5)
To
a suspension of the compound 6 (20.0 g, 47.1 mmol) in methanol (400 ml)
was added 10% palladium on activated carbon (1.0 g), and the mixture
was stirred at room temperature overnight under H2 atmosphere.
After filtration of the reaction mixture, the solvent was removed and
the residue was dissolved in methylene chloride and then filtered
through short pad silica gel. Then, the solvent was evaporated to give
the compound 5 (20.1 g, 100%) as a colorless syrup.
[α]20 D −28.32 (c 1.49, MeOH); HR-MS (ESI): m/z calcd for C25H32NaO4Si [M+Na]+ 447.1968, Found 447.1956; 1H NMR (400 MHz, CDCl3)
δ 7.69 (m, 4H), 7.40 (m, 6H), 4.84 (t, J=4.4 Hz, 1H), 4.22 (dd, J=1.2,
4.8 Hz, 1H), 3.96 (dd, J=8.0, 10.0 Hz, 1H), 3.82 (dd, J=6.8, 10.0 Hz,
1H), 2.37 (m, 1H), 2.30 (ddd, J=1.2, 8.4, and 18.4 Hz, 1H), 2.20 (ddd,
J=1.2, 12.0, and 18.4 Hz, 1H), 1.37 (s, 3H), 1.35 (s, 3H), 1.06 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 112.6, 80.5, 77.6, 77.2, 76.9, 63.6, 38.1, 36.9, 27.1, 27.02, 27.01, 25.3, 19.5; Anal. Calcd for C25H32O4Si: C, 70.72; H, 7.60. Found: C, 70.79; H, 7.75.
Step 2: Preparation of 6-(tert-butyl-diphenyl-silanyloxymethyl)-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-ol (Compound 7)
To
a suspension of the compound 5 (20.1 g, 47.1 mmol) in methanol (500 ml)
were added sodium borohydride (2.17 g, 57.4 mmol) and cerium (III)
chloride heptahydrate (21.3 g, 57.2 mmol) at 0° C., and the mixture was
stirred at room temperature for 30 min. After the solvent was removed,
the residue was partitioned between ethyl acetate and water. The organic
layer was then washed with brine, dried with anhydrous MgSO4,
filtered, and evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=5/1) to give the compound 7 (20.86
g, 98%) as a colorless syrup.
[α]20 D +34.55 (c 0.55, MeOH); HR-MS (ESI): m/z calcd for C25H34NaO4Si [M+Na]+: 449.2124; Found: 449.2110; 1H NMR (400 MHz, CDCl3)
δ 7.69 (m, 4H), 7.39 (m, 6H), 4.62 (t, J=5.6 Hz, 1H), 4.44 (t, J=5.6
Hz, 1H), 3.89 (dd, J=6.0, 7.6 Hz, 1H), 3.84 (m, 1H), 3.68 (dd, J=6.4,
10.0 Hz, 1H), 1.91 (m, 2H), 1.26 (m, 1H), 1.42 (s, 3H), 1.33 (s, 3H),
1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 135.9,
135.8, 134.2, 134.1, 129.8, 129.7, 127.8, 127.7, 110.6, 79.4, 78.9,
77.6, 77.2, 76.9, 72.5, 62.9, 41.6, 33.4, 27.0, 25.9, 27.0, 25.9, 24.4,
19.5; Anal. Calcd for C25H34O4Si: C, 70.38; H, 8.03. Found: C, 70.41; H, 8.08.
Step 3: Preparation of 3-tert-butoxy-4-(tert-butyl-diphenyl-silanyloxymethyl)-cyclopentane-1,2-diol (Compound 4)
To
a solution of the compound 7 (20.86 g, 47.12 mmol) in methylene
chloride was added trimethylaluminum (2.0 M in toluene, 132.1 ml) at 0°
C., and the mixture was stirred at room temperature for 2 days. The
mixture was cooled to 0° C., slowly quenched with an aqueous saturated
ammonium chloride solution, filtered, and evaporated. The residue was
partitioned between ethyl acetate and water. The organic layer was
washed with brine, dried with anhydrous MgSO4, filtered, and
evaporated. The residue was purified by silica gel column chromatography
(hexane/ethyl acetate=2/1) to give the compound 4 (13.42 g, 62%) as a
colorless syrup.
[α]20 D +3.30 (c 0.55, MeOH); HR-MS (ESI): m/z calcd for C26H38NaO4Si [M+Na]+: 465.2437; Found: 465.2423; 1H NMR (400 MHz, CDCl3)
δ 7.70 (m, 4H), 7.41 (m, 6H), 4.05 (dd, J=4.4, 7.2 Hz, 1H), 3.93 (m,
1H), 3.72 (m, 2H), 3.59 (dd, J=3.6, 12.0 Hz, 2H), 2.70 (d, J=20.8 Hz,
1H), 2.10 (m, 2H), 1.60 (m, 1H), 1.20 (s, 9H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 135.9, 133.5, 130.0, 129.9, 127.9, 127.9, 77.6, 77.2, 76.9, 74.9,
73.8, 72.7, 72.1, 63.3, 42.1, 34.0, 28.5, 27.0, 19.4; Anal. Calcd for C26H38O4Si: C, 70.55; H, 8.65. Found: C, 70.61; H, 8.70.
Step
4: Preparation of
(4-tert-butoxy-2,2-dioxo-tetrahydro-2-yl-6-cyclopenta[1,3,2]-dioxathiol-5-ylmethoxy)-tert-butyl-diphenyl-silane
(Compound 3)
To
a solution of the compound 4 (13.42 g, 30.3 mmol) in methylene chloride
were added triethyl amine (14.5 ml, 101.0 mmol) and thionyl chloride
(3.7 ml, 47.4 mmol) at 0° C., and the reaction mixture was stirred at 0°
C. for 10 minutes. The reaction mixture was partitioned between
methylene chloride and water. The organic layer was washed with brine,
dried with anhydrous MgSO4, filtered, and evaporated. The
residue was purified by silica gel column chromatography (hexane/ethyl
acetate=6/1) to give the cyclic sulfite (14.37 g, 97%) as a white foam.
[α]20 D +20.00 (c 0.05, MeOH); HR-MS (ESI): m/z calcd for C26H36NaO5SSi [M+Na]+: 511.1950; Found: 511.1929; 1H NMR (400 MHz, CDCl3)
δ 7.64 (m, 4H), 7.40 (m, 6H), 5.23 (m, 1H), 5.04 (dd, J=4.4, 6.0 Hz,
1H), 4.01 (t, J=4.8 Hz, 1H), 3.68 (dd, J=3.6, 10.4 Hz, 1H), 3.56 (dd,
J=8.0, 10.4 Hz, 1H), 2.07 (m, 2H), 1.96 (m, 1H), 1.14 (s, 9H), 1.05 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 135.8, 135.7,
133.9, 133.8, 129.9, 129.9, 127.9, 127.8, 85.7, 83.2, 77.6, 77.2, 76.9,
75.0, 71.1, 62.7, 44.7, 31.4, 28.5, 27.1, 19.4; Anal. Calcd for C26H36O5SSi: C, 63.90; H, 7.42; S, 6.56. Found: C, 63.94; H, 7.45; S, 6.61.
To
a solution of the cyclic sulfite obtained above (14.37 g, 29.4 mmol) in
the mixture of carbon tetrachloride, acetonitrile and water (1:1:1.5,
210 ml) were added sodium metaperiodate (18.56 g, 56.4 mmol) and
ruthenium chloride (1.72 g, 8.25 mmol), and the reaction mixture was
stirred at room temperature for 10 minutes. The reaction mixture was
partitioned between methylene chloride and water. The organic layer was
washed with brine, dried with anhydrous MgSO4, filtered, and
evaporated. The residue was purified by silica gel column chromatography
(hexane/ethyl acetate=4/1) to give the compound 3 (13.36 g, 90%) as a
white solid.
mp 101-104° C.; [α]20 D −80.00 (c 0.05, MeOH); HR-MS (ESI): m/z calcd for C26H36NaO6SSi [M+Na]+: 527.1900; Found: 527.1881; 1H NMR (400 MHz, CDCl3)
δ 7.64 (m, 4H), 7.41 (m, 6H), 5.13 (m, 1H), 4.83 (dd, J=4.4, 6.8 Hz,
1H), 4.13 (t, J=4.0 Hz, 1H), 3.92 (dd, J=6.4, 10.4 Hz, 1H), 3.69 (dd,
J=5.2, 10.4 Hz, 1H), 2.11 (m, 2H), 2.02 (m, 1H), 1.15 (s, 9H), 1.05 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 135.7, 135.0,
133.8, 133.7, 130.0, 128.0, 127.9, 83.5, 82.2, 77.6, 77.2, 76.9, 75.4,
70.4, 70.4, 62.2, 43.9, 31.3, 28.2, 27.1, 26.8, 19.4; Anal. Calcd for C26H36O6SSi: C, 61.87; H, 7.19; S, 6.35. Found: C, 61.91; H, 7.14; S, 6.30.
Step
5: Preparation of
2-tert-butoxy-3-(tert-butyl-diphenyl-silanyloxymethyl)-5-[4-(indan-1-ylamino)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentanol
(Compound 8)
A suspension of N6-indanyl-7-deazaadenine
(8.80 g, 35.2 mmol), sodium hydride (1.38 g, 45.7 mmol) and 18-crown-6
(9.11 g, 45.7 mmol) in THF (200 ml) was stirred at 80° C. To the
reaction mixture was added a solution for the compound 3 (13.36 g, 26.5
mmol) in THF (150 ml), and the stirring was continued at 80° C.
overnight. The reaction mixture was cooled down to 0° C., and conc. HCl
was added slowly until pH reaches 1-2. Then the reaction mixture was
further stirred at 80° C. for 2 hours. After neutralized with saturated
aqueous NaHCO3 solution, the reaction mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
brine, dried with anhydrous MgSO4, filtered, and evaporated.
The residue was purified by silica gel column chromatography
(hexane/ethyl acetate=2/1) to give the compound 8 (11.62 g, 65%) as a
white foam.
UV (CH2Cl2) λmax 272.5 nm; [α]20 D −8.89 (c 0.45, MeOH); HR-MS (ESI): m/z calcd for C41H51N4O3Si [M+H]+: 675.3730; Found: 675.3717; 1H NMR (400 MHz, CDCl3)
δ 8.38 (s, 1H), 7.70 (m, 4H), 7.41 (m, 6H), 6.92 (d, J=3.6 Hz, 1H),
6.29 (d, J=3.2 Hz, 1H), 5.91 (dd, J=7.6, 14.8 Hz, 1H), 5.14 (br d, J=6.8
Hz, 1H), 4.77 (m, 1H), 4.36 (t, J=6.0 Hz, 1H), 4.22 (dd, J=5.2, 10.8
Hz, 1H), 3.84 (dd, J=5.6, 10.4 Hz, 1H), 3.73 (dd, J=8.4, 10.4 Hz, 1H),
3.37 (d, J=5.6 Hz, 1H), 3.06 (m, 1H), 2.95 (m, 1H), 2.75 (m, 1H), 2.75
(m, 1H), 2.58 (m, 1H), 2.38 (m, 1H), 2.15 (m, 1H), 1.98 (m, 1H), 1.65
(s, 1H), 1.55 (s, 1H), 1.16 (s, 9H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 156.4, 151.8, 150.3, 144.1, 143.8, 135.9, 134.0, 129.9, 128.2, 127.9,
127.9, 127.0, 125.1, 124.4, 123.3, 103.8, 97.4, 77.8, 77.6, 77.2, 76.9,
74.9, 72.4, 63.5, 62.1, 56.3, 43.9, 34.9, 30.5, 30.5, 28.5, 27.2, 19.5;
Anal. Calcd for C41H50N4O3Si: C, 72.96; H, 7.47; N, 8.30. Found: C, 73.01; H, 7.45; N, 8.36.
Step
6: Preparation of
{7-[3-tert-butoxy-4-(tert-butyl-diphenyl-silanyloxymethyl)-cyclopentyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-indan-1-yl-amine
(Compound 9)
To
a solution of the compound 8 (11.62 g, 17.2 mmol) in methylene chloride
(300 ml) were added N,N-dimethylaminopyridine (5.64 g, 51.6 mmol) and
phenyl chlorothionocarbonate (4.3 ml, 34.4 mmol), and the reaction
mixture was stirred at room temperature overnight. After the solvent was
removed, the residue was purified by silica gel column chromatography
(hexane/ethyl acetate=6/1) to give the thiocarbonate (13.82 g, 99%) as a
white foam.
UV (MeOH) λmax 271.50 nm; [α]20 D +10.00 (c 0.15, MeOH); HR-MS (ESI): m/z calcd for C48H55N4O4SSi [M+H]+: 811.3713; Found: 811.3687; 1H NMR (400 MHz, CDCl3)
δ 8.36 (s, 1H), 7.61 (dd, J=1.6, 7.6 Hz, 4H), 7.34 (m, 5H), 7.26 (m,
4H), 7.18 (m, 6H), 6.86 (s, 1H), 6.25 (d, J=3.2 Hz, 1H), 6.00 (dd,
J=3.2, 8.4 Hz, 1H), 5.83 (d, J=6.8 Hz, 1H), 5.19 (m, 1H), 5.07 (br s,
1H), 4.48 (t, J=3.6 Hz, 1H), 3.82 (dd, J=7.2, 10.4 Hz, 1H), 3.52 (dd,
J=7.2, 10.0 Hz, 1H), 2.99 (m, 1H), 2.88 (m, 2H), 2.69 (m, 2H), 2.18 (dd,
J=11.2, 13.6 Hz, 1H), 1.94 (m, 2H), 1.12 (s, 9H), 0.98 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 194.9, 153.5, 152.1, 143.9, 135.9, 135.8, 134.1, 129.9, 129.6, 128.3,
127.9, 127.0, 126.7, 125.1, 124.6, 123.2, 122.0, 87.9, 77.6, 77.2,
76.9, 74.6, 70.4, 63.5, 57.3, 42.8, 35.0, 30.7, 30.5, 29.9, 28.7, 27.1,
19.4; Anal. Calcd for C48H54N4O4SSi: C, 71.08; H, 6.71; N, 6.91; S, 3.95. Found: C, 71.14; H, 6.75; N, 6.95; S, 4.01.
To
a solution of the thiocarbonate obtained above (13.82 g, 17.0 mmol) in
toluene (200 ml) were added tri-n-butyltinhydride (9.4 ml, 34.1 mmol)
and 2,2′-azo-bis-isobutyronitrile (4.32 g, 26.3 mmol), and the reaction
mixture was stirred at 110° C. for 1 hour. After the mixture was cooled
down, the solvent was removed. The resulting residue was purified by
silica gel column chromatography (hexane/ethyl acetate=3/1) to give the
compound 9 (9.21 g, 82%) as a white foam.
UV (MeOH) λmax 272.50 nm; [α]20 D −10.00 (c 0.20, MeOH); HR-MS (ESI): m/z calcd for C41H51N4O2Si [M+H]+: 659.3781; Found: 659.3757; 1H NMR (400 MHz, CDCl3)
δ 8.41 (s, 1H), 7.69 (m, 4H), 7.41 (m, 6H), 7.29 (m, 2H), 7.23 (m, 2H),
6.92 (d, J=3.6 Hz, 1H), 6.31 (d, J=3.6 Hz, 1H), 5.90 (dd, J=7.2, 14.8
Hz, 1H), 5.38 (m, 1H), 5.15 (br s, 1H), 4.33 (dd, J=5.2, 8.4 Hz, 1H),
3.88 (dd, J=6.4, 10.0 Hz, 1H), 3.68 (dd, J=7.2, 10.4 Hz, 1H), 3.05 (m,
1H), 2.96 (dd, J=7.6, 15.6 Hz, 1H), 2.76 (m, 1H), 2.45 (d, J=5.2 Hz,
1H), 2.29 (m, 2H), 2.06 (m, 1H), 1.95 (m, 2H), 1.55 (s, 1H), 1.13 (s,
9H), 1.06 (s, 9H);13C NMR (100 MHz, CDCl3) δ
156.3, 151.9, 144.1, 143.9, 135.9, 135.8, 134.3, 129.8, 128.2, 127.8,
127.0, 125.1, 124.6, 121.8, 77.6, 77.2, 76.7, 73.5, 72.2, 63.6, 56.4,
52.8, 46.8, 42.8, 34.9, 34.5, 30.5, 28.6, 27.2, 28.7, 19.4; Anal. Calcd
for C41H50N4O2Si: C, 74.73; H, 7.65; N, 8.30. Found: C, 74.79; H, 7.61; N, 8.25.
Step 7: Preparation of 2-tert-butoxy-4-[4-(indan-1-ylamino)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentanol (Compound 10)
To
a solution of the compound 9 (9.21 g, 13.97 mmol) in the mixture of THF
and pyridine (1:1, 160 ml) was added dropwise pyridine hydrofluoride
(18.42 ml, 190.0 mmol) at 0° C., and the reaction mixture was stirred at
room temperature for 1 hour. The mixture was neutralized with saturated
aqueous NaHCO3 solution and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with anhydrous MgSO4,
filtered, and evaporated. Then, the residue was purified by silica gel
column chromatography (hexane/ethyl acetate=1/3) to give the compound 10
(5.63 g, 99%) as a white foam.
UV (MeOH) λmax 273.00 nm; [α]20 D −6.36 (c 1.10, MeOH); HR-MS (ESI): m/z calcd for C25H33N4O2 [M+H]+: 421.2604; Found: 421.2599; 1H NMR (400 MHz, CDCl3)
δ 8.34 (s, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.22 (d, J=7.2 Hz, 2H), 7.15
(t, J=6.8 Hz, 1H), 6.88 (d, J=3.2 Hz, 1H), 6.23 (d, J=3.6 Hz, 1H), 5.83
(dd, J=7.2, 15.2 Hz, 1H), 5.28 (m, 1H), 5.06 (m, 1H), 4.47 (dd, J=5.6,
10.4 Hz, 1H), 3.78 (m, 1H), 3.70 (m, 1H), 3.24 (t, J=5.2 Hz, 1H), 2.98
(m, 1H), 2.87 (m, 1H), 2.68 (m, 1H), 2.46 (m, 1H), 2.37 (m, 2H), 1.93
(m, 2H), 1.18 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
156.2, 151.8, 147.9, 143.9, 143.9, 128.3, 126.9, 125.1, 124.5, 121.9,
97.7, 77.6, 77.2, 76.9, 75.5, 74.9, 63.4, 56.4, 53.8, 44.2, 42.2, 34.9,
33.2, 30.5, 28.6; Anal. Calcd for C25H32N4O2: C, 71.40; H, 7.67; N, 13.32. Found: C, 71.46; H, 7.60; N, 13.35.
Step
8: Preparation of sulfamic acid
2-tert-butoxy-4-[4-(indan-1-ylamino)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentylmethyl
ester (Compound 11)
Preparation
of 2.0 M solution of chlorosulfonamide in acetonitrile: Formic acid
(14.15 ml, 166.0 mmol) was added dropwise to chlorosulfonyl isocyanate
(32.0 ml, 162.5 mmol) under nitrogen atmosphere at 0° C. When the
addition was completed, the mixture was solidified. To the mixture was
added acetonitrile (61.3 ml), and the resulting solution was left to
stand under nitrogen source at room temperature overnight.
To
a solution of the compound 10 (5.63 g, 13.83 mmol) and triethyl amine
(9.7 ml, 0.74 mmol) in acetonitrile (278 ml) was added 2.0 M solution of
chlorosulfonamide in acetonitrile (13.83 ml, 27.76 mmol) at 0° C., and
the reaction mixture was stirred at room temperature for 45 minutes.
Additional 2.0 M chlorosulfonamide solution in acetonitrile (13.83 ml,
27.76 mmol) was added and the mixture was stirred at room temperature
for 15 minutes. The reaction was quenched with methanol, and the solvent
was removed. The residue was purified by silica gel column
chromatography (methylene chloride/methanol=20/1) to give the compound
11 (6.37 g, 92%) as a white foam.
UV (MeOH) λmax 273.00 nm; [α]20 D −18.00 (c 0.50, MeOH); HR-MS (ESI): m/z calcd for C25H34N5O4S [M+H]+: 500.2332; Found: 500.2331; 1H NMR (400 MHz, CDCl3)
δ 8.38 (s, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.22
(m, 2H), 6.95 (d, J=3.6 Hz, 1H), 6.31 (d, J=3.2 Hz, 1H), 5.89 (d, J=6.4
Hz, 1H), 5.10 (s, 2H), 4.41 (m, 2H), 4.26 (m, 1H), 3.05 (m, 1H), 2.94
(m, 1H), 2.76 (m, 2H), 2.27 (m, 3H), 2.06 (m, 1H), 1.97 (m, 1H), 1.76
(br s, 1H); 13C NMR (100 MHz, CDCl3) δ 156.4,
151.9, 149.9, 143.9, 143.8, 128.3, 126.9, 125.1, 124.5, 121.9, 121.9,
103.5, 97.9, 77.4, 77.2, 76.9, 74.3, 71.9, 71.3, 56.4, 53.1, 49.0, 42.3,
34.9, 34.3, 30.5, 28.6; Anal. Calcd for C25H33N5O4S: C, 60.10; H, 6.66; N, 14.02; S, 6.42. Found: C, 60.15; H, 6.71; N, 13.98; S, 6.39.
Step
9: Preparation of sulfamic acid
2-hydroxy-4-[4-(indan-1-ylamino)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclopentylmethyl
ester (Compound 1)
A
solution of the compound 11 (6.37 g, 12.72 mmol) in 70% trifluoroacetic
acid (149.24 ml) was stirred at room temperature for 2 hours. The
solvent was removed and the residue was purified by silica gel column
chromatography (hexane/ethylene acetate=1/2) to give the compound 1
(5.08 g, 90%) as a white foam. BASE
UV (MeOH) λmax 279.50 nm; [α]20 D −6.41 (c 2.34, MeOH);
HR-MS (ESI): m/z calcd for C21H26N5O4S [M+H]+: 444.1705; Found: 444.1706;
1H NMR (400 MHz, CD3OD)
δ 8.17 (d, J=1.6 Hz, 1H), 7.25 (m, 2H), 7.18 (m, 2H), 6.64 (d, J=3.6
Hz, 1H), 5.86 (t, J=7.6 Hz, 1H), 5.46 (m, 1H), 4.49 (d, J=2.8 Hz, 1H),
3.07 (m, 1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.64 (m, 1H), 2.35 (m, 1H),
2.25 (m, 2H), 2.03 (m, 2H);
13C NMR (100 MHz, CD3OD) δ 152.1, 145.3, 144.6, 128.8, 127.6, 125.7, 125.2, 122.6, 100.5, 73.1, 70.9, 56.9, 54.0, 44.8, 43.6, 34.9, 34.6, 31.1;
Anal. Calcd for C21H25N5O4S: C, 56.87; H, 5.68; N, 15.79; S, 7.23. Found: C, 56.91; H, 5.73; N, 15.82; S, 7.26.
.........................
http://www.google.com/patents/WO2010132110A1?cl=en
((lS,2S,4R)-4-{4-[(lS)-2,3-dihydro-lH-inden-l-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl
}-2-hydroxycyclopentyl)methyl sulfamate (//) is described in Intl. App.
Pub. No. WO 07/092213, U.S. App. Pub. No. 2007/0191293, and U.S. App.
Pub. No. 2009/0036678. The potassium salt of ((lS,2S,4R)-4-{4-[( 1
S)-2,3-dihydro- 1 H-inden- 1 -ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl }
-2-hydroxycyclopentyl)methyl sulfamate is disclosed in Intl. App. Pub.
No. WO 07/092213 and U.S. App. Pub. No. 2007/0191293.
(H)
((lS,2S,4R)-4-{4-[(lS)-2,3-dihydro-lH-
inden-l-ylamino]-7H-pyπOlo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl
sulfamate (/):
Step
3: Synthesis of
((lS,2S.4R)-4-(4-r(lS)-2,3-dihydro-lH-inden-l-ylaminol-7H-pyrrolor2.3-dlpyrimidin-7-yl}-2-hvdroxycvclopentyl)methyl
sulfamate hydrochloride Form 1
[0158] A reactor was charged with
((lS,2S,4R)-4-{4-[(lS)-2,3-dihydro-lH-inden-l-ylarnino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl
}-2-hydroxycyclopentyl)methyl sulfamate (13.4 Kg, 30.2 mol) and
200-proof ethanol (106.2 Kg). The mixture was heated to reflux to afford
a clear solution. The mixture was cooled to 50 ± 5 0C and
passed through a cartridge filter. 200 proof ethanol (8.9 Kg) was used
to rinse the filter. 1.27M hydrogen chloride in ethanol (10.2 Kg) was
added via a cartridge filter at a rate to maintain a temperature of 50 ±
5 0C. The mixture was then seeded with Form 1 (67 g).
Further 1.27M HCl (10.2 Kg) was added via a cartridge filter at a rate
to maintain a temperature of 50 ± 5 0C. The mixture was then stirred at 50 ± 5 0C for about 3 hours. The mixture was then cooled to 20 ± 5 0C
over about 3 hours and then stirred for about 2.5 hours. The solid
product was then isolated by filtration and washed with 200-proof
ethanol (I x 20.4 Kg and 1 x 21.2 Kg). The solids were dried by
aspiration on the filter until no supernatant was seen to be collected,
and then further dried under reduced pressure at <30 0C to
afford the title compound (12.2 Kg) as a white solid determined to be
Form 1 by XRPD. IH NMR (300MHz, DMSO, δ): 9.83 (s, IH), 8.34 (s, IH),
7.62 (s, IH), 7.44 (s, 2H), 7.30 (m, 3H), 7.22 (t, IH), 7.07 (s, IH),
5.86 (dd, IH), 5.42 (m, IH), 4.32 (m, IH), 4.21 (dd, IH), 4.02 (dd, IH),
3.04 (m, IH), 2.88 (m, IH), 2.67 (m, 2H), 2.15 (m, 2H), 2.08 (m, 2H),
1.94 (m, IH). XRPD data for Form 1 is shown in FIGURE 1 and Table 1; DSC
data is shown in FIGURE 2, and TGA data for Form 1 is shown in FIGURE
3.
..............
http://www.google.com/patents/WO2007092213A2?cl=en
Example 70: Diastereoisomeric mixture of (lS
/2R
/4R)-4-{4-[(lS)-2
/3-dihydro-lH-inden-l- ylaimnol-ZH-pyrrolop^-dlpyxirnidin-Z-ylJ^-hydroxycyclopentyl s ulf amate and (lR
f2S
/4S)-4-{4-[(lS)-2,3-dihydro-lH-inden-l-ylaminol-7H-pyrrolo[2,3d]-
pyrimidin-7-yl}-2-hydroxycyclopentyl sulfamate (Compounds 1-77 and
1-78)
Step a: Cyclopent-3-en-l-yl methanesulfonate
[0335] 3-Cydopentene-l-ol (0.500 g, 5.94 mmol) was stirred in DCM (95 mL).
Pyridine
(2.40 mL), N,N-dimethylaminopyridine (0.10 g, 1.00 mmol) and
methanesulfonyl chloride (0.690 mL, 8.92 mmol) were added, and the
reaction mixture was stirred at 35
0C for 4 h.
N,N-Dimethylarrιinopyridirιe (0.14 g, 1.2 mmol) and methanesulfonyl
chloride (0.69 mL, 8.92 mmol) were added, and the reaction was stirred
overnight. TLC indicated complete conversion. The reaction mixture was
cooled and concentrated. The residue was purified by silica gel
chromatography, eluting with DCM, to afford the title compound as a
clear oil (0.660 g, 68%).
Step b: 7-Cyclopent-3-en-l-yl-N-r(lSV2,3-dihydro-lH-inden-l-yn-7H-pyrrolor2,3-rfl- pyrmτidin-4-arnine
[0336] N-[(lS)-2,3-DihydrcHlH-mden-l-yl]-7H-pyrrolo[2
/3-d]p3αimidin-4-amine
(1.32 g, 5.29 mmol) was azeotroped with toluene and placed under high
vacuum for 30 min. N,N-Dimethylformamide (17.7 mL) was added, followed
by cesium carbonate (1.99 g, 6.10 mmol). The mixture was stirred at 70
0C
for 10 min. Cyclopent-3-en-l-yl methanesulfonate (0.660 g, 4.07 mmol)
in N,N-dimethylformarnide (12.6 mL) was added dropwise. The reaction
mixture was heated to 110
0C for 1 h. The reaction mixture was cooled, quenched with brine and diluted with H
2O. The aqueous layer was extracted with EtOAc (3x), washed with H
2O and brine, dried (Na
2SO
4),
filtered, and concentrated. The residue -was purified by via silica gel
chromatography, eluting with a gradient of 0 to 5% MeOH in DCM followed
by 25 to 50% EtOAc in hexanes, to afford the title compound as a pale
brown solid (0.684 g, 53%). LC/MS: R
1 = 1.38 min, ES
+
317 (FA standard). Step c:
(lR,2S,45)-4-{4-r(lS)-2,3-dihydro-lH-inden-l-ylaininol-7H-pyrrolof2.3-
rf1pyrimidin-7-yl}cyclopentane-l,2-diol
[0337]
7-Cyclopent-3-en-l-yl-N-[(lS)-2^-dihyrdo-lH-inden-l-yl]-7H-pyrrolo[2,3-
d]pyτimidin-4-amine (0.312 g, 0.986 mmol) was stirred in tert-butyl
alcohol (4.9 mL) and H
2O (4.9 mL). AD-mix-α (Sigma- Aldrich,
1.4 g) was added, and the suspension was stirred at rt overnight. TLC
indicated complete conversion. The reaction was quenched with sodium
sulfite (1.48 g, 11.7 mmol), and the mixture was stirred for 5 h. The
reaction mixture was diluted with EtOAc and H
2O, and the aqueous layer was extracted with EtOAc (2x). The organic layer was dried (Na
2SO
4),
filtered, and concentrated. The residue was purified via silica gel
chromatography, eluting with EtOAc, to afford the title compound as a
white solid (0.190 g, 55%).
Step d: Diastereoisomeric mixture of
(lS,2R,4R)-4-{4-r(15)-23-dihydro-lH-inden-l-
ylarninoi^jH-pyrrolofΣ^dlpyrirnidin-y-yll-l-hydroxycyclopentyl sulfamate
and
(lR,2S,4S)-4-{4-iαSV2,3-dihydro-lH-inden-l-ylarninol-7H-pyrrolor2,3-
rf1pyrimidm-7-yl)-2-hydroxycyclopenryl sulfamate (Compounds 1-77 and
1-78)
[0338] (lR,2S,4S)-4-{4-[(lS)-2,3-Dihydro-lH-inden-l-ylarnino]-7H-pyrrolo[2
/3-
d]pyrimidin-7-ylJcyclopentane-l,2-diol (0.080 g, 0.23 mmol) was
azeotroped with toluene and then was dissolved in anhydrous acetonitrile
(2.3 mL). Pyridine (0.0369 mL, 0.458 mmol) was added. The reaction
mixture was cooled to 0
0C, and a 2N solution of
chlorosulfonamide in acetonitrile (0.144 mL) was added dropwise. The
reaction was stirred for 1 h, and then additional 2N chlorosulfonamide
in acetonitrile (0.028 mL) was added. After 30 min, additional 2N
chlorosulfonamide in acetonitrile (0.0342 mL) was added, and the
reaction mixture was stirred for 2 h. The reaction was quenched with
methanol, and the mixture was concentrated in vacuo. The residue was
purified by preparative thin layer chromatography using DCM:AcCN:MeOH
(50:45:5). The relevant band was cut, washed with acetone, filtered, and
concentrated to give a mixture of diastereomers as a white solid. (11
mg, 11%).
1H NMR (CDCl
3, 400 NMR, δ): 8.36-8.27
(m, IH); 7.38-7.09 (m, 5H); 6.90-6.80 (m, IH); 6.36- 6.20 (m, IH);
5.95-5.76 (m, IH); 5.51-5.22 (m, 2H); 4.83-4.68 (m, IH); 3.87-3.72 (m,
IH); 3.12- 2.83 (m, 2H); 2.75-2.53 (m, IH); 2.50-2.14 (m, 2H); 2.08-1.79
(m, 2H) ppm. LC/MS: R, = 1.16 min, ES
+ 430 (FA standard).
............
WO 2012061551
http://www.google.im/patents/WO2012061551A1?cl=en
The
compound
((lS,2S,4R)-4-(4-((lS)-2,3-dihydro-lH-inden-l-ylamino)-7H-pyrrolo[2,3-d]-
pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate:
also
known as MLN4924, is an inhibitor of NEDD8-activating enzyme (NAE).
Inhibition of NAE has been shown to induce cancer cell death and inhibit
the growth of tumors in xenograft models. See, e.g., T.A. Soucy et al.,
Nature, 2009, 458, 732-737; T.A. Soucy ei al., Clin. Cancer Res., 2009,
15 (12), 3912-3916; and J.E. Brownell et al., Mol. Cell., 2010, 37 (1),
102-111, each of which is hereby incorporated by reference herein in
its entirety. MLN4924, pharmaceutical compositions of MLN4924, processes
for its synthesis, and polymorphic forms have been described
previously. See, e.g., US Patent Appl. Nos. 11/700,614 (Publ. No.
2007/0191293), 12/221,399 (Publ. No. 2009/0036678) and 12/779,331 (Publ.
No. 2011/0021544),
...............
Org. Process Res. Dev., Article ASAP
A
practical synthesis of a novel NEDD8-activating enzyme (NAE) inhibitor
pevonedistat (MLN4924) is described. Key steps include an
enantioselective synthesis of an amino-diol cyclopentane intermediate
containing three chiral centers and a novel, regioselective
sulfamoylation using N-(tert-butoxycarbonyl)-N-[(triethylenediammonium)sulfonyl]azanide.
The linear process, involving six solid isolations, has been carried
out in multiple cGMP productions on 15–30 kg scale to produce
pevonedistat in 98% (a/a) chemical purity and 25% overall yield.
((1S,2S,4R)-4-(4-(((S)-2,3-Dihydro-1H-inden-1-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl Sulfamate (1)
The reaction yielded 1 (0.285 kg, 58.5%, 93.0% a/a) as an off-white solid.
HPLC retention time of 1 BASE(Method C): 22.6 min;
1H NMR (400 MHz, DMSO) δ 8.19 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.45 (s, 2H), 7.31–7.26 (m, 2H), 7.22 (t, J = 6.6 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 3.5 Hz, 1H), 5.92 (q, J = 8.0 Hz, 1H), 5.39 (qd, J = 8.8, 5.7 Hz, 1H), 4.95 (d, J = 3.9 Hz, 1H), 4.42–4.31 (m, 1H), 4.25 (dd, J = 9.7, 7.0 Hz, 1H), 4.07 (dd, J = 9.6, 8.0 Hz, 1H), 3.01 (ddd, J = 15.7, 8.7, 3.0 Hz, 1H), 2.95–2.81 (m, 1H), 2.81–2.65 (m, 1H), 2.58–2.49 (m, 1H), 2.31–1.86 (m, 5H);
13C
NMR (100 MHz, DMSO) δ 155.91, 151.18, 149.02, 144.66, 142.98, 127.30,
126.28, 124.49, 124.11, 121.68, 102.83, 98.86, 70.82, 69.37, 54.48,
52.15, 42.58, 42.25, 33.50, 33.26, 29.72;
m/z: 444.4 (M + H)+;
mp: 164–166 °C.
((1S,2S,4R)-4-(4-(((S)-2,3-Dihydro-1H-inden-1-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl Sulfamate·Hydrochloride (Pevonedistat)
Pevonedistat (14.0 g, 92.5%, 99.0% a/a) as a white solid.
HPLC retention time of pevonedistat (Method C): 22.6 min;
1H
NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 8.39 (s, 1H), 7.63 (s, 1H), 7.45
(s, 2H), 7.41–7.20 (m, 4H), 7.04 (s, 1H), 5.78 (s, 1H), 5.44 (s, 1H),
4.42–4.28 (m, 1H), 4.24 (dd, J = 9.7, 6.9 Hz, 1H), 4.05 (dd, J = 9.6, 8.0 Hz, 1H), 3.18–2.99 (m, 1H), 2.91 (dt, J = 15.6, 7.7 Hz, 1H), 2.81–2.57 (m, 2H), 2.24–1.86 (m, 6H).
13C
NMR (100 MHz, DMSO) δ 149.12, 145.71, 143.23, 142.11, 141.30, 128.28,
126.64, 124.97, 124.82, 124.49, 102.57, 101.74, 70.67, 69.22, 57.38,
53.14, 42.52, 42.40, 33.57, 32.56, 29.80;
m/z: 444.4 (M + H)+;
mp: 155–157 °C.
.................
J. Org. Chem., 2011, 76 (9), pp 3557–3561
DOI: 10.1021/jo2001897
MLN4924 (1), which is in clinical trials as an anticancer agent, was stereoselectively synthesized from d-ribose
via a route involving stereoselective reduction, regioselective
cleavage of an isopropylidene moiety, and selective displacement of a
cyclic sulfate moiety as key steps.
Sulfamic Acid 2-Hydroxy-4-[4-(indan-1-ylamino)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentylmethyl Ester (1) BASE
purified by silica gel column chromatography (hexane/ethyl acetate = 1/2) to give 1 (5.08 g, 90%) as a white foam:
UV (MeOH) λmax 279.50 nm;
[α]20D −6.41 (c 2.34, MeOH);
HR-MS (ESI) m/z calcd for C21H26N5O4S [M + H]+ 444.1705, found 444.1706;
1H NMR (400 MHz, CD3OD) δ 8.17 (d, J = 1.6 Hz, 1H), 7.25 (m, 2H), 7.18 (m, 2H), 6.64 (d, J = 3.6 Hz, 1H), 5.86 (t, J = 7.6 Hz, 1H), 5.46 (m, 1H), 4.49 (d, J = 2.8 Hz, 1H), 3.07 (m, 1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.64 (m, 1H), 2.35 (m, 1H), 2.25 (m, 2H), 2.03 (m, 2H);
13C NMR (100 MHz, CD3OD)
δ 152.1, 145.3, 144.6, 128.8, 127.6, 125.7, 125.2, 122.6, 100.5, 73.1,
70.9, 56.9, 54.0, 44.8, 43.6, 34.9, 34.6, 31.1. Anal. Calcd for C21H25N5O4S: C, 56.87; H, 5.68; N, 15.79; S, 7.23. Found: C, 56.91; H, 5.73; N, 15.82; S, 7.26.
| WO2012061551A1 * | Nov 3, 2011 | May 10, 2012 | Millennium Pharmaceuticals, Inc. | Administration of nedd8-activating enzyme inhibitor |
| WO2013028832A2 * | Aug 23, 2012 | Feb 28, 2013 | Millennium Pharmaceuticals, Inc. | Inhibitors of nedd8-activating enzyme |
| WO2013028832A3 * | Aug 23, 2012 | May 2, 2013 | Millennium Pharmaceuticals, Inc. | Inhibitors of nedd8-activating enzyme |
| US8809356 | Aug 23, 2012 | Aug 19, 2014 | Millennium Pharmaceuticals, Inc. | Inhibitors of NEDD8-activating enzyme |
| Reference |
|---|
| 1 | * | Lee, et. al., Journal of Organic Chemistry (2011), 76(9), 3557-3561. |
- (1) Lee, Hyuk Woo; Journal of Organic Chemistry 2011, 76(9), P3557-3561
- (2) Soucy, Teresa A.; Nature (London, United Kingdom) 2009, 458(7239), P732-736
1H NMR PREDICT
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13 C NMR
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//////////Pevonedistat, MLN4924, Millennium Pharmaceuticals, TAKEDA, TAK-924 , PHASE 1, orphan drug designation
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