trelagliptin succinate
Compound I, A, TRELAGLIPTIN which has the formula:
is a DPP-IV inhibitor that is described in U.S. patent application
Ser. No. 11/080,992 filed Mar. 15, 2005 (see Compound 34). Its dosing,
administration and biological activities are described in U.S. patent
application Ser. No. 11/531,671 filed Sep. 13, 2006. U.S. patent
application Ser. No. 11/080,992 and Ser. No. 11/531,671 are incorporated
herein by reference in their entirety.
Dipeptidyl peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5)
(referred herein as “DPP-IV”) is a type II membrane protein and a
non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides
from the amino terminus (N-terminus) of polypeptides and proteins.
DPP-IV is constitutively expressed on epithelial and endothelial cells
of a variety of different tissues (e.g., intestine, liver, lung, kidney
and placenta), and is also found in body fluids. DPP-IV is also
expressed on circulating T-lymphocytes and has been shown to be
synonymous with the cell-surface antigen, CD-26. DPP-IV has been
implicated in a number of human disease states, including, but are not
limit to, diabetes, particularly type II diabetes mellitus, diabetic
dislipidemia, conditions of impaired glucose tolerance (IGT), conditions
of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis,
appetite regulation and obesity; autoimmune diseases such as
inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis;
AIDS; and cancers.
DPP-IV inhibitors are believed to be useful agents for the
prevention, delay of progression, and/or treatment of conditions
mediated by DPP-IV.
Compound (A) or a salt thereof has been reported as an inhibitor of
dipeptidyl peptidase (DPP-IV) , which is an enzyme that decomposes
glucagon-like peptide-1 (GLP-1) , a hormone increasing insulin secretion
(patent document 1) .
In addition, a method including administering 1 – 250 mg of compound
(A) or a salt thereof to a patient once per week (patent documents 2,
3), crystal polymorphs of compound (A) (patent documents 4, 5) , and a
preparation of compound (A)
(patent documents 6, 7) have also been reported. Compound (A) and a
salt thereof are recommended for oral administration in view of the
easiness of self-administration, and a tablet, particularly a tablet in
the dosage form for administration once per week, is desired. [0006]
The dosage form of once per week is expected to improve drug
compliance of patients, whereas it requires supply of compound (A) or a
salt thereof to patients in a high dose as compared to, for example, the
dosage form of once per day. Since a solid preparation containing
compound (A) or a salt thereof in a high dose increases its size, it may
conversely degrade the drug compliance for patients, particularly
infants and elderly patients having difficulty in swallowing
……………………..
SYNTHESIS
Compound 34 IS TRELAGLIPTIN
4-Fluoro-2-methylbenzonitrile (31).
A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2
g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was
diluted with water and extracted with hexane. The organics were dried
over MgSO4 and the solvent removed to give product 31 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
2-Bromomethyl-4-fluorobenzonitrile (32).
A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was
refluxed under nitrogen for 2 hours. The reaction was cooled to room
temperature. The solid was removed by filtration. The organic solution
was concentrated to give crude product as an oil, which was used in the
next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).
Alternatively, 32 was made as follows.
4-Fluoro-2-methylbenzonitrile (1 kg) in DCE (2 L) was treated with
AIBN (122 g) and heated to 75° C. A suspension of DBH (353 g) in DCE
(500 mL) was added at 75° C. portionwise over 20 minutes. This operation
was repeated 5 more times over 2.5 hours. The mixture was then stirred
for one additional hour and optionally monitored for completion by, for
example, measuring the amount of residual benzonitrile using HPLC.
Additional AIBN (e.g., 12.5 g) was optionally added to move the reaction
toward completion. Heating was stopped and the mixture was allowed to
cool overnight. N,N-diisopropylethylamine (1.3 L) was added (at <10°
C. over 1.5 hours) and then diethyl phosphite (1.9 L) was added (at
<20° C. over 30 min). The mixture was then stirred for 30 minutes or
until completion. The mixture was then washed with 1% sodium
metabisulfite solution (5 L) and purified with water (5 L). The organic
phase was concentrated under vacuum to afford 32 as a dark brown oil
(3328 g), which was used without further purification (purity was 97%
(AUC)).
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (33).
A mixture of crude 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5
g, 4 mmol) in DMSO (10 mL) was stirred at 60° C. for 2 hours. The
reaction was diluted with water and extracted with EtOAc. The organics
were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3):
δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m,
1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES)
[m+H] calc’d for C13H9ClFN3O2, 293.68; found 293.68.
Alternatively, 33 was made as follows.
To a solution of 6-chloro-3-methyluracil (750 g) and
N,N-diisopropylethylamine (998 mL) in NMP (3 L) was added (at <30° C.
over 25 min) a solution of 32 (2963 g crude material containing 1300 g
of 32 in 3 L of toluene). The mixture was then heated at 60° C. for 2
hours or until completion (as determined, for example, by HPLC). Heating
was then stopped and the mixture was allowed to cool overnight.
Purified water (3.8 L) was added, and the resultant slurry was stirred
at ambient temperature for 1 hour and at <5° C. for one hour. The
mixture was then filtered under vacuum and the wet cake was washed with
IPA (2×2.25 L). The material was then dried in a vacuum oven at 40±5° C.
for 16 or more hours to afford 33 as a tan solid (>85% yield; purity
was >99% (AUC)).
TFAsalt OF TRELAGLIPTIN
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (34).
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile
(300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5
mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a
sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was
obtained as TFA salt after HPLC purification. 1H-NMR (400 MHz, CD3OD):
δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq,
2H, J 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m,
1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79
(m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.
FREE BASE OF TRELAGLIPTIN
Alternatively, the free base of 34 was prepared as follows. A mixture
of 33 (1212 g), IPA (10.8 L), (R)-3-amino-piperidine dihydrochloride
(785 g), purified water (78 mL) and potassium carbonate (2.5 kg, powder,
325 mesh) was heated at 60° C. until completion (e.g., for >20
hours) as determined, for example, by HPLC. Acetonitrile (3.6 L) was
then added at 60° C. and the mixture was allowed to cool to <25° C.
The resultant slurry was filtered under vacuum and the filter cake was
washed with acetonitrile (2×3.6 L). The filtrate was concentrated at 45°
C. under vacuum (for >3 hours) to afford 2.6 kg of the free base of
34.
HCL salt OF TRELAGLIPTIN
The HCl salt of 34 was prepared from the TFA salt as follows. The TFA
salt (34) was suspended in DCM, and then washed with saturated Na2CO3.
The organic layer was dried and removed in vacuo. The residue was
dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0°
C. The HCl salt was obtained after removing the solvent. 1H-NMR (400 MHz, CD3OD):
δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq,
2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H),
2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m,
2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.
Alternatively, the HCl salt was prepared from the free base as follows. To a solution of free base in CH2Cl2 (12
L) was added (at <35° C. over 18 minutes) 2 M hydrochloric acid (3.1
L). The slurry was stirred for 1 hour and then filtered. The wet cake
was washed with CH2Cl2 (3.6 L) and then THF (4.8
L). The wet cake was then slurried in THF (4.8 L) for one hour and then
filtered. The filter cake was again washed with THF (4.8 L). The
material was then dried in a vacuum oven at 50° C. (with a nitrogen
bleed) until a constant weight (e.g., >26 hours) to afford 34 as the
HCl salt as a white solid (1423 g, >85% yield).
Succinate salt OF TRELAGLIPTIN
The succinate salt of 34 was prepared from the HCl salt as follows. To a mixture of the HCl salt of 34 (1414 g), CH2Cl2 (7
L) and purified water (14 L) was added 50% NaOH solution (212 mL) until
the pH of the mixture was >12. The biphasic mixture was stirred for
30 min and the organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (5.7 L) and the combined
organic layers were washed with purified water (6 L). The organic layer
was then passed through an in-line filter and concentrated under vacuum
at 30° C. over three hours to afford the free base as an off-white
solid. The free base was slurried in prefiltered THF (15 L) and
prefiltered IPA (5.5 L). The mixture was then heated at 60° C. until
complete dissolution of the free base was observed. A prefiltered
solution of succinic acid (446 g) in THF (7 L) was added (over 23 min)
while maintaining the mixture temperature at >57° C. After stirring
at 60° C. for 15 min, the heat was turned off, the material was allowed
to cool, and the slurry was stirred for 12 hours at 25±5° C. The
material was filtered under vacuum and the wet cake was washed with
prefiltered IPA (2×4.2 L). The material was then dried in a vacuum oven
at 70±5° C. (with a nitrogen bleed) for >80 hours to afford the
succinate salt of 34 as a white solid (1546 g, >90% yield).
The product was also converted to a variety of corresponding acid
addition salts. Specifically, the benzonitrile product (approximately 10
mg) in a solution of MeOH (1 mL) was treated with various acids (1.05
equivalents). The solutions were allowed to stand for three days open to
the air. If a precipitate formed, the mixture was filtered and the salt
dried. If no solid formed, the mixture was concentrated in vacuo and
the residue isolated. In this way, salts of 34 were prepared from the
following acids: benzoic, p-toluenesulfonic, succinic, R-(−)-Mandelic
and benzenesulfonic. The succinate was found to be crystalline as determined by x-ray powder diffraction analysis.
Methanesulfonate salt
In addition, the methanesulfonate salt was prepared as follows. A
10.5 g aliquot of the benzonitrile product was mixed with 400 mL of
isopropylacetate. The slurry was heated to 75° C. and filtered through
#3 Whatman filter paper. The solution was heated back to 75° C. and a 1M
solution of methanesulfonic acid (30.84 mL) was added slowly over 10
minutes while stirring. The suspension was cooled to room temperature at
a rate of about 20° C./hr. After 1 hr at room temperature, the solid
was filtered and dried in an oven overnight to obtain the
methanesulfonate salt.
…………………………
FORMULATION
COMPD A IS TRELAGLIPTIN
Examples (Comparative Example IA)
Succinate of compound (A) (26.6 mg) was weighed in a glass bottle and used as Comparative Example IA. (Comparative Example 2A)
The succinate of compound (A) and microcrystalline cellulose were
uniformly mixed in a mortar at a ratio of 1:10, and the mixture (226.6
mg) was weighed in a glass bottle and used as Comparative Example 2A.
(Comparative Example 3A)
The succinate of compound (A) and corn starch were uniformly mixed in
a mortar at a ratio of 1:5, and the mixture (126.6 mg) was weighed in a
glass bottle and used as Comparative Example 3A. (Example IA) Succinate
of compound (A) , mannitol and corn starch according to the formulation
of Table IA were uniformly mixed in a fluid bed granulator (LAB-I,
POWREX CORPORATION) , and the mixture was granulated by spraying an
aqueous solution of dissolved hypromellose 2910, and dried therein. The
obtained granules were passed through a sieve -(16M) to give milled
granules. To the milled granules were added croscarmellose sodium,
microcrystalline cellulose and magnesium stearate, and they were mixed
in a bag to give granules for tableting. The granules were punched by a
rotary tableting machine (Correct 19K, Kikusui Seisakusho, Ltd.) with a
6.5 mmφ punch to give a plain tablet weighting 121 mg. On the other
hand, titanium oxide, yellow ferric oxide and talc were dispersed in a
hypromellose 2910 aqueous solution to prepare a film coating liquid. The
aforementioned coating liquid was sprayed onto the above-mentioned
plain tablet in a film coating machine (Hicoater HCP-75, Freund
Corporation), to give 2500 film- coated tablets containing 3.125 mg of
compound (A) (free form) per tablet. Table IA
………………………..
POLYMORPHS AND SYNTHESIS
FORM A
Form A may be prepared by crystallization from the various solvents
and under the various crystallization conditions used during the
polymorph screen (e.g., fast and slow evaporation, cooling of saturated
solutions, slurries, and solvent/antisolvent additions). Tables B and C
of Example 3 summarize the procedures by which Form A was prepared. For
example, Form A was obtained by room temperature slurry of an excess
amount of Compound I in acetone, acetonitrile, dichloromethane,
1,4-dioxane, diethyl ether, hexane, methanol, isopropanol, water,
ethylacetate, tetrahydrofuran, toluene, or other like solvents on a
rotating wheel for approximately 5 or 7 days. The solids were collected
by vacuum filtration, and air dried in the hood. Also, Form A was
precipitated from a methanol solution of Compound I by slow evaporation
(SE).
[0091] Form A was characterized by XRPD, TGA, hot stage microscopy, IR, Raman spectroscopy, solution 1H-NMR, and solid state 13C-NMR.
[0092] Figure 1 shows a characteristic XRPD spectrum (CuKa,
λ=1.5418A) of Form A. The XRPD pattern confirmed that Form A was
crystalline. Major X-Ray diffraction lines expressed in °2Θ and their
relative intensities are summarized in Table 1.
Table 1. Characteristic XRPD Peaks (CuKa) of Form A
Characterization Data of Form A of Compound I
8. Amorphous Form
[0137] The Amorphous Form of Compound I was prepared by
lyophilization of an aqueous solution of Compound I (Example 10). The
residue material was characterized by XRPD and the resulting XRPD
spectrum displayed in Figure 26. The XRPD spectrum shows a broad halo
with no specific peaks present, which confirms that the material is
amorphous. The material was further characterized by TGA, DSC, hot stage
microscopy, and moisture sorption analysis.
Table A. Approximate Solubilities of Compound I
Compound I having the formula
POLYMORPH SCREEN
Crystallization Experiments of Compound I from Solvents
a) FE = fast evaporation; SE = slow evaporation; RT = room
temperature; SC = slow cool;CC = crash cool, MB = moisture
sorption/desorption analysis b) qty = quantity; PO = preferred
orientation
…………………………
SYNTHESIS
EXAMPLES
1. Preparation of
2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-
2H-pyrimidin-l-ylmethyl]-4-fluoro-benzonitrile and pharmaceutically
acceptable salts
4-Fluoro-2-methylbenzonitrile (3)
[0166] A mixture of 2-bromo-5fluorotoluene ( 2) (3.5 g, 18.5 mmol)
and CuCN (2 g, 22 mmol) in DMF (100 mL) was re fluxed for 24 hours. The
reaction was diluted with water and extracted with hexane. The organics
were dried over MgSO4 and the solvent removed to give product 3 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, IH), 6.93-7.06 (m, 2H), 2.55 (s, 3H). 2-Bromomethyl-4-fluorobenzonitrile (4)
[0167] A mixture of 4-fluoro-2-methylbenzonitrile (3) (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4
was refluxed under nitrogen for 2 hours. The reaction was cooled to
room temperature. The solid was removed by filtration. The organic
solution was concentrated to give crude product as an oil, which was
used in the next step without further purification.1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J= 5.2, 8.4 Hz, IH), 7.28 (dd, J= 2.4, 8.8 Hz, IH), 7.12 (m, IH), 4.6 (s, 2H).
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro- benzonitrile (6)
[0168] A mixture of crude 3-methyl-6-chlorouracil (5) (0.6 g, 3.8
mmol), 2- Bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO
(10 mL) was stirred at 60 C for 2 hours. The reaction was diluted
with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3):
δ 7.73 (dd, 1=12, 8.4Hz, IH), 7.26 (d, J- 4.0Hz, IH), 7.11-7.17 (m,
IH), 6.94 (dd, J=2.0, 9.0 Hz, IH), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES)
[m+H] calc’d for Ci3H9ClFN3O2, 293.68; found 293.68.
2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-
ylmethyl]-4-fluoro-benzonitrile, TFA salt (1) (TFA salt of Compound I)
[0169]
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-
fluoro-benzonitrile (5) (300 mg, 1.0 mmol), (i?)-3-amino-piperidine
dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4
mmol) were stirred in a sealed tube in EtOH (3 mL) at 100 0C for 2 hrs. The final compound was obtained as a TFA salt after HPLC purification. 1H-NMR (400 MHz, CD3OD):
δ. 7.77-7.84 (m, IH), 7.16-7.27 (m, 2H), 5.46 (s, IH), 5.17-5.34 (ABq,
2H, J = 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m,
IH), 2.67-2.92 (m, 2H), 2.07-2.17 (m, IH), 1.82-1.92 (m, IH), 1.51-1.79
(m, 2H). MS (ES) [m+H] calc’d for Ci8H20FN5O2, 357.38; found, 357.38.
2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l- ylmethyl]-4-fluoro-benzonitrile, HCl salt
[0170] The TFA salt of Compound I was suspended in DCM, and then washed with saturated Na2CO3.
The organic layer was dried and removed in vacuo. The residue was
dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0 C.
The HCl salt was obtained after removing the solvent. 1H-NMR (400 MHz, CD3OD):
δ. 7.77-7.84 (m, IH), 7.12-7.26 (m, 2H), 5.47 (s, IH), 5.21-5.32 (ABq,
2H, J = 32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m,
IH), 2.69-2.93 (m, 2H), 2.07-2.17 (m, IH), 1.83-1.93 (m, IH), 1.55-1.80
(m, 2H). MS (ES) [m+H] calc’d for Ci8H20FN5O2, 357.38; found, 357.38.
General procedure for the preparation of salts of Compound I.
[0171] The benzonitrile product may be isolated as the free base if
desired, but preferably, the product may be further converted to a
corresponding acid addition salt. Specifically, the benzonitrile product
(approximately 10 mg) in a solution of MeOH (1 mL) was treated with
various acids (1.05 equivalents). The solutions were allowed to stand
for three days open to the air. If a precipitate formed, the mixture was
filtered and the salt dried. If no solid formed, the mixture was
concentrated in vacuo and the residue isolated. In this way, salts of
Compound I were prepared from the following acids: benzoic,
p-toluenesulfonic, succinic, R-(-)-Mandelic and benzenesulfonic. [0172]
The isolation and/or purification steps of the intermediate compounds in
the above described process may optionally be avoided if the
intermediates from the reaction mixture are obtained as relatively pure
compounds and the by-products or impurities of the reaction mixture do
not interfere with the subsequent reaction steps. Where feasible, one or
more isolation steps may be eliminated to provide shorter processing
times, and the elimination of further processing may also afford higher
overall reaction yields.
…………………..
TABLET
2. Exemplary formulations comprising succinate salt of
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile
Provided are examples of tablet formulations that may be used to
administer succinate salt of
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile
(Succinate salt of Compound I) according to the present invention. It
is noted that the formulations provided herein may be varied as is known
in the art.
The exemplary tablet formulations are as follows:
|
|
| 12.5 mg of Compound I (weight of free base form) per tablet |
|
| Core Tablet Formulation |
|
(1) |
2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4- |
17.0 |
mg |
|
|
dioxo-3,4-dihydro-2H-pyrimidin-1- |
|
|
ylmethyl]-4-fluoro-benzonitrile (succinate salt) |
|
(2) |
Lactose Monohydrate, NF, Ph, Eur |
224.6 |
mg |
|
|
(FOREMOST 316 FAST FLO) |
|
(3) |
Microcrystalline Cellulose, NF, Ph, Eur |
120.1 |
mg |
|
|
(AVICEL PH 102) |
|
(4) |
Croscarmellose Sodium, NF, Ph, Eur |
32.0 |
mg |
|
|
(AC-DO-SOL) |
|
(5) |
Colloidal Silicon Dioxide, NF, Ph, Eur |
3.2 |
mg |
|
|
(CAB-O-SIL M-5P) |
|
(6) |
Magnesium Stearate, NF, Ph, Eur |
3.2 |
mg |
|
|
(MALLINCKRODT, Non-bovine Hyqual) |
|
|
TOTAL |
400.0 |
mg |
|
(per tablet) |
|
…………..
POLYMORPHS AND SYNTHESIS
EXAMPLES Example 1 Preparation of
2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile
succinate (Compound I)
Compound I may be prepared by the follow synthetic route (Scheme 1)
A. Preparation of 4-fluoro-2-methylbenzonitrile (Compound B)
Compound B was prepared by refluxing a mixture of
2-bromo-5-fluoro-toluene (Compound A) (3.5 g, 18.5 mmol) and CuCN (2 g,
22 mmol) in DMF (100 mL) for 24 hours. The reaction was diluted with
water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product B (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
B. Preparation of 2-bromomethyl-4-fluorobenzonitrile (Compound C)
Compound C was prepared by refluxing a mixture of
4-fluoro-2-methylbenzonitrile (Compound B) (2 g, 14.8 mmol),
N-bromosuccinimide (NBS) (2.64 g, 15 mmol) and azo-bis-isobutyronitrile
(AIBN) (100 mg) in CCl4 under nitrogen for 2 hours. The
reaction was cooled to room temperature. The solid was removed by
filtration. The organic solution was concentrated to give the crude
product the form of an oil, which was used in the next step without
further purification. 1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).
C. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound D)
Compound E was prepared by stirring a mixture of crude
3-methyl-6-chlorouracil D (0.6 g, 3.8 mmol),
2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5
g, 4 mmol) in DMSO (10 mL) at 60° C. for 2 hours. The reaction was
diluted with water and extracted with EtOAc. The organics were dried
over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3):
δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m,
1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES)
[m+H] calc’d for C13H9ClFN3O2, 293.68; found 293.68.
D. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound F)
Compound F was prepared by mixing and stirring
2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile
(Compound E) (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride
(266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) in a
sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was
obtained as trifluoroacetate (TFA) salt after HPLC purification. 1H-NMR (400 MHz, CD3OD):
δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq,
2H, J=35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m,
1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79
(m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.
E. Preparation of Compound I: the succinic acid salt of
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile
The TFA salt prepared in the above step (Example 1, Step D) was suspended in DCM, and then washed with saturated Na2CO3.
The organic layer was dried and removed in vacuo. The benzonitrile
product (approximately 10 mg) was dissolved in MeOH (1 mL) and to which
succinic acid in THF (1.05 equivalents) was added. The solutions were
allowed to stand for three days open to the air. If a precipitate
formed, the solid was collected by filtration. If no solid formed, the
mixture was concentrated in vacuo, and the succinate salt was obtained
after removing the solvent.
SUCCINATE SALT OF TRELAGLIPTIN
1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H),
7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz),
3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H),
2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H]
calc’d for C18H20FN5O2, 357.38; found, 357.38.
Compound I such prepared was found to be crystalline as determined by
x-ray powder diffraction analysis (FIG. 1). The crystal material was
designated Form A.
……………
patents
1. US 2013172377
2. WO 2011013639
3. WO 2009099172
4.WO 2009099171
5. WO 2008114807
6.WO 2008114800
7. WO 2008033851
8. WO 2007074884
9WO 2007035629
patent document 1: US2005/0261271
patent document 2: US2007/0060530
patent document 3: US2008/0287476
patent document 4: US2008/0227798
patent document 5: US2008/0280931
patent document 6: WO2008/114800
patent document 7: WO2011/013639
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