U.S. patent application number 15/963529 was filed with the patent office on 2018-11-01 for salt of omecamtiv mecarbil and process for preparing salt.
The applicant listed for this patent is AMGEN INC., CYTOKINETICS, INC.. Invention is credited to Alan Martin Allgeier, Charles Bernard, Sheng Cui, Karl Bennett Hansen, Neil Fred Langille, Steven Mennen, Bradley Paul Morgan, Henry Morrison, Alex Muci, Karthik Nagapudi, Shawn Walker, Jacqueline Woo.
Application Number | 20180312469 15/963529 |
Document ID | / |
Family ID | 50549466 |
Filed Date | 2018-11-01 |
United States Patent
Application |
20180312469 |
Kind Code |
A1 |
Cui; Sheng ; et al. |
November 1, 2018 |
SALT OF OMECAMTIV MECARBIL AND PROCESS FOR PREPARING SALT
Abstract
Provided are omecamtiv mecarbil dihydrochloride salt forms,
compositions and pharmaceutical formulations thereof, and methods
for their preparation and use.
Inventors: |
Cui; Sheng; (Lexington,
MA) ; Morrison; Henry; (Moorpark, CA) ;
Nagapudi; Karthik; (Simi Valley, CA) ; Walker;
Shawn; (Woodland Hills, CA) ; Bernard; Charles;
(Moorpark, CA) ; Hansen; Karl Bennett; (Cohasset,
MA) ; Langille; Neil Fred; (Sudbury, MA) ;
Allgeier; Alan Martin; (Wilmington, DE) ; Mennen;
Steven; (Boston, MA) ; Woo; Jacqueline;
(Sherwood Park, CA) ; Morgan; Bradley Paul; (South
San Francisco, CA) ; Muci; Alex; (San Francisco,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC.
CYTOKINETICS, INC. |
Thousand Oaks
South San Francisco |
CA
CA |
US
US |
|
|
Family ID: |
50549466 |
Appl. No.: |
15/963529 |
Filed: |
April 26, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14773436 |
Sep 8, 2015 |
9988354 |
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PCT/US14/27146 |
Mar 14, 2014 |
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15963529 |
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61785763 |
Mar 14, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2018 20130101;
A61P 9/04 20180101; A61P 9/00 20180101; A61K 47/38 20130101; A61K
9/2013 20130101; C07D 213/75 20130101; A61K 31/496 20130101; A61K
9/2054 20130101 |
International
Class: |
C07D 213/75 20060101
C07D213/75; A61K 9/20 20060101 A61K009/20; A61K 31/496 20060101
A61K031/496; A61K 47/38 20060101 A61K047/38 |
Claims
1.-9. (canceled)
10. A method of preparing omecamtiv mecarbil dihydrochloride
hydrate comprising: (a) hydrogenating methyl
4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate in the presence
of a hydrogenation catalyst to form methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate; (b) admixing
methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate and phenyl
(6-methylpyridin-3-yl)carbamate in the presence of a trialkylamine
base to form omecamtiv mecarbil as a free base; and (c)
crystallizing the omecamtiv mecarbil free base in the presence of
aqueous hydrochloric acid and an alcohol solvent to form omecamtiv
mecarbil dihydrochloride hydrate salt.
11. The method of claim 10, further comprising formulating
omecamtiv mecarbil dihydrochloride hydrate salt.
12. The method of claim 10, wherein the hydrogenation catalyst
comprises palladium.
13. The method of claim 12, wherein the hydrogenation catalyst is
palladium on carbon.
14. The method of claim 10, wherein the trialkylamine base is
triethylamine, diisopropylethylamine, or a combination thereof.
15. The method of claim 10, wherein the trialkylamine base
comprises diisopropylethylamine.
16. The method of claim 10, wherein the alcohol solvent comprises
isopropyl alcohol.
17. The method of claim 10, wherein the omecamtiv mecarbil
dihydrochloride hydrate salt has an x-ray powder diffraction
pattern (XRPD) comprising peaks at about 6.6, 14.9, 20.1, 21.4, and
26.8.+-.0.2.degree. 2.theta. using Cu K.alpha. radiation.
18. The method of claim 17, wherein the XRPD pattern further
comprises peaks at about 8.4, 24.2, 26.0, and 33.3.+-.0.2.degree.
2.theta. using Cu K.alpha. radiation.
19. The method of claim 17, wherein the XRPD pattern further
comprises peaks at about 6.2, 9.7, 13.2, 14.3, 15.4, 16.3, 16.9,
18.9, 19.5, 20.7, 21.8, 22.8, 23.6, 25.1, 27.3, 27.7, 28.4, 29.4,
30.2, 31.2, 31.5, 31.9, 33.9, 34.5, 34.9, 36.1, 36.8, 37.7, 38.5,
and 39.7.+-.0.2.degree. 2.theta. using Cu K.alpha. radiation.
20. A method of preparing omecamtiv mecarbil comprising admixing
methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate and phenyl
(6-methylpyridin-3-yl)carbamate in the presence of a trialkylamine
base to form omecamtiv mecarbil.
21. The method of claim 20, wherein the trialkylamine base
comprises diisopropylethylamine.
22. The method of claim 20, further comprising crystallizing the
omecamtiv mecarbil in the presence of aqueous hydrochloric acid and
an alcohol solvent to form an omecamtiv mecarbil dihydrochloride
hydrate salt.
23. The method of claim 22, wherein the alcohol solvent comprises
isopropyl alcohol.
24. The method of claim 22, wherein the omecamtiv mecarbil
dihydrochloride hydrate salt has an x-ray powder diffraction
pattern (XRPD) comprising peaks at about 6.6, 14.9, 20.1, 21.4, and
26.8.+-.0.2o 2.theta. using Cu K.alpha. radiation.
25. The method of claim 24, wherein the XRPD pattern further
comprises peaks at about 8.4, 24.2, 26.0, and 33.3.+-.0.2o 2.theta.
using Cu K.alpha. radiation.
26. The method of claim 24, wherein the XRPD pattern further
comprises peaks at about 6.2, 9.7, 13.2, 14.3, 15.4, 16.3, 16.9,
18.9, 19.5, 20.7, 21.8, 22.8, 23.6, 25.1, 27.3, 27.7, 28.4, 29.4,
30.2, 31.2, 31.5, 31.9, 33.9, 34.5, 34.9, 36.1, 36.8, 37.7, 38.5,
and 39.7.+-.0.2o 2.theta. using Cu K.alpha. radiation.
27. A method of treating heart failure in a subject comprising
administering to the subject a pharmaceutical formulation
comprising omecamtiv mecarbil dihydrochloride hydrate salt and at
least one pharmaceutically acceptable excipient.
28. The method of claim 27, wherein the omecamtiv mecarbil
dihydrochloride hydrate salt has an x-ray powder diffraction
pattern (XRPD) comprising peaks at about 6.6, 14.9, 20.1, 21.4, and
26.8.+-.0.2o 2.theta. using Cu K.alpha. radiation.
29. The method of claim 28, wherein the XRPD pattern further
comprises peaks at about 8.4, 24.2, 26.0, and 33.3.+-.0.2o 2.theta.
using Cu K.alpha. radiation.
30. The method of claim 28, wherein the XRPD pattern further
comprises peaks at about 6.2, 9.7, 13.2, 14.3, 15.4, 16.3, 16.9,
18.9, 19.5, 20.7, 21.8, 22.8, 23.6, 25.1, 27.3, 27.7, 28.4, 29.4,
30.2, 31.2, 31.5, 31.9, 33.9, 34.5, 34.9, 36.1, 36.8, 37.7, 38.5,
and 39.7.+-.0.2o 2.theta. using Cu K.alpha. radiation.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The benefit of U.S. Provisional Application No. 61/785,763,
filed Mar. 14, 2014 is claimed, the disclosure of which is
incorporated by reference in its entirety.
FIELD
[0002] Provided are omecamtiv mecarbil dihydrochloride polymorph
forms, methods of making omecamtiv mecarbil, including omecamtiv
mecarbil dihydrochloride polymorph forms, compositions comprising
omecamtiv mecarbil dihydrochloride polymorph forms, and methods of
using omecamtiv mecarbil dihydrochloride salt polymorph forms.
BACKGROUND
[0003] The cardiac sarcomere is the basic unit of muscle
contraction in the heart. The cardiac sarcomere is a highly ordered
cytoskeletal structure composed of cardiac muscle myosin, actin and
a set of regulatory proteins. The discovery and development of
small molecule cardiac muscle myosin activators would lead to
promising treatments for acute and chronic heart failure. Cardiac
muscle myosin is the cytoskeletal motor protein in the cardiac
muscle cell. It is directly responsible for converting chemical
energy into the mechanical force, resulting in cardiac muscle
contraction.
[0004] Current positive inotropic agents, such as beta-adrenergic
receptor agonists or inhibitors of phosphodiesterase activity,
increase the concentration of intracellular calcium, thereby
increasing cardiac sarcomere contractility. However, the increase
in calcium levels increase the velocity of cardiac muscle
contraction and shortens systolic ejection time, which has been
linked to potentially life-threatening side effects. In contrast,
cardiac muscle myosin activators work by a mechanism that directly
stimulates the activity of the cardiac muscle myosin motor protein,
without increasing the intracellular calcium concentration. They
accelerate the rate-limiting step of the myosin enzymatic cycle and
shift it in favor of the force-producing state. Rather than
increasing the velocity of cardiac contraction, this mechanism
instead lengthens the systolic ejection time, which results in
increased cardiac muscle contractility and cardiac output in a
potentially more oxygen-efficient manner.
[0005] U.S. Pat. No. 7,507,735, herein incorporated by reference,
discloses a genus of compounds, including omecamtiv mecarbil (AMG
423, CK-1827452), having the structure:
##STR00001##
[0006] Omecamtiv mecarbil is a first in class direct activator of
cardiac myosin, the motor protein that causes cardiac contraction.
It is being evaluated as a potential treatment of heart failure in
both intravenous and oral formulations with the goal of
establishing a new continuum of care for patients in both the
in-hospital and outpatient settings.
[0007] Because drug compounds having, for example, improved
stability, solubility, shelf life, and in vivo pharmacology, are
consistently sought, there is an ongoing need for new or purer
salts, hydrates, solvates, and polymorphic crystalline forms of
existing drug molecules. The crystalline forms of omecamtiv
mecarbil described herein help meet this and other needs.
SUMMARY
[0008] Provided is a dihydrochloride form of omecamtiv
mecarbil.
[0009] Also provided is omecamtiv mecarbil dihydrochloride
hydrate.
[0010] Also provided is a crystalline form of a dihydrochloride
form of omecamtiv mecarbil.
[0011] Also provided is omecamtiv mecarbil dihydrochloride hydrate
Form A.
[0012] Also provided is anhydrous omecamtiv mecarbil
dihydrochloride.
[0013] Also provided is anhydrous omecamtiv mecarbil
dihydrochloride Form B.
[0014] Also provided is anhydrous omecamtiv mecarbil
dihydrochloride Form C.
[0015] Also provided are composition and pharmaceutical
compositions comprising a dihydrochloride form of omecamtiv
mecarbil.
[0016] Also provided is a method of preparing omecamtiv mecarbil
comprising admixing methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate and phenyl
(6-methylpyridin-3-yl)carbamate in the presence of a trialkylamine
base to form omecamtiv mecarbil.
[0017] Also provided is a method of preparing omecamtiv mecarbil
dihydrochloride hydrate comprising:
[0018] (a) hydrogenating methyl
4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate in the presence
of a hydrogenation catalyst to form methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate;
[0019] (b) admixing methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate and phenyl
(6-methylpyridin-3-yl)carbamate in the presence of a trialkylamine
base to form omecamtiv mecarbil as a free base; and
[0020] (c) crystallizing the omecamtiv mecarbil free base in the
presence of aqueous hydrochloric acid and an alcohol solvent to
form omecamtiv mecarbil dihydrochloride hydrate salt.
DESCRIPTION OF THE FIGURES
[0021] FIG. 1 shows the dynamic vapor sorption of a omecamtiv
mecarbil dihydrochloride hydrate form, Form A.
[0022] FIG. 2 shows an X-ray powder diffraction pattern (XRPD) for
Form A.
[0023] FIG. 3 shows an XRPD of a omecamtiv mecarbil dihydrochloride
hydrate salt form at varying relative humidity conditions.
[0024] FIG. 4 shows an XRPD of a omecamtiv mecarbil dihydrochloride
hydrate salt form at varying temperatures.
[0025] FIG. 5 shows the differential scanning calorimetry
thermograph and thermogravimetric analysis for Form A.
[0026] FIG. 6 shows an overlay of XRPD patterns for Forms A, B and
C of omecamtiv mecarbil dihydrochloride salt.
[0027] FIG. 7A shows drug release at two pHs (2 and 6.8) for a
formulation of omecamtiv mecarbil free base hemihydrate.
[0028] FIG. 7B shows drug release of two pHs (2 and 6.8) for a
omecamtiv mecarbil dihydrochloride hydrate salt form, Form A.
DETAILED DESCRIPTION
[0029] Unless otherwise specified, the following definitions apply
to terms found in the specification and claims:
[0030] "Treatment" or "treating" means any treatment of a disease
in a patient, including: a) preventing the disease, that is,
causing the clinical symptoms of the disease not to develop; b)
inhibiting the disease; c) slowing or arresting the development of
clinical symptoms; and/or d) relieving the disease, that is,
causing the regression of clinical symptoms. Treatment of diseases
and disorders herein is intended to also include the prophylactic
administration of a pharmaceutical formulation described herein to
a subject (i.e., an animal, preferably a mammal, most preferably a
human) believed to be in need of preventative treatment, such as,
for example, chronic heart failure.
[0031] The term "therapeutically effective amount" means an amount
effective, when administered to a human or non-human patient, to
treat a disease, e.g., a therapeutically effective amount may be an
amount sufficient to treat a disease or disorder responsive to
myosin activation. The therapeutically effective amount may be
ascertained experimentally, for example by assaying blood
concentration of the chemical entity, or theoretically, by
calculating bioavailability.
[0032] "Pharmaceutically acceptable salts" include, but are not
limited to salts with inorganic acids, such as hydrochlorate (i.e.,
hydrochloride), phosphate, diphosphate, hydrobromate, sulfate,
sulfinate, nitrate, and like salts; as well as salts with an
organic acid, such as malate, maleate, fumarate, tartrate,
succinate, citrate, acetate, lactate, methanesulfonate,
p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate,
stearate, and alkanoate such as acetate,
HOOC--(CH.sub.2).sub.n--COOH where n is 0-4, and like salts.
[0033] Similarly, pharmaceutically acceptable cations include, but
are not limited to sodium, potassium, calcium, aluminum, lithium,
and ammonium. Those skilled in the art will recognize various
synthetic methodologies that may be used to prepare non-toxic
pharmaceutically acceptable addition salts.
[0034] As used herein, the term "polymorphs" or "polymorphic forms"
refers to crystal forms of the same molecule. Different polymorphic
forms of a molecule have different physical properties as a result
of the arrangement or conformation of the molecules in the crystal
lattice. Some of the different physical properties include melting
temperature, heat of fusion, solubility, dissolution rate, and/or
or vibrational spectra. The physical form of a particular compound
is particularly important when the compound is used in a
pharmaceutical formulation because different solid forms of a
compound result in different properties of the drug product.
[0035] Polymorphs of a molecule can be obtained by a number of
methods, as shown in the art, such as, for example, melt
recrystallization, melt cooling, solvent recrystallization,
desolvation, rapid evaporation, rapid cooling, slow cooling, vapor
diffusion, and sublimation. Techniques for characterizing a
polymorph include X-ray powder diffraction (XRPD), single crystal
X-ray diffraction (XRD), differential scanning calorimetry (DSC),
vibrational spectroscopy (e.g., IR and Ram spectroscopy), solid
state nuclear magnetic resonance (ssNMR), hot stage optical
microscopy, scanning electron microscopy (SEM), electron
crystallography and quantitative analysis, particle size analysis
(PSA), surface area analysis, solubility studies, and dissolution
studies.
[0036] The term "hydrate" refers to the chemical entity formed by
the interaction of water and a compound.
[0037] As used herein, the term "monohydrate" refers a hydrate that
contains one molecule of water per one molecule of the
substrate.
[0038] As used herein, the term "crystalline" refers to a solid in
which the constituent atoms, molecules, or ions are arranged in a
regularly ordered, repeating pattern in three dimensions.
[0039] The specification and claims contain listing of species
using the language "selected from . . . and . . . " and "is . . .
or . . . " (sometimes referred to as Markush groups). When this
language is used in this application, unless otherwise stated it is
meant to include the group as a whole, or any single members
thereof, or any subgroups thereof. The use of this language is
merely for shorthand purposes and is not meant in any way to limit
the removal of individual elements or subgroups as needed.
[0040] Provided is a dihydrochloride hydrate form of omecamtiv
mecarbil. In various embodiments of this aspect, the
dihydrochloride hydrate form of omecamtiv mecarbil is crystalline
(Form A). Embodiments of the dihydrochloride hydrate form of
omecamtiv mecarbil can be characterized by one or more of the
parameters described in further detail below.
[0041] The dihydrochloride hydrate form of omecamtiv mecarbil has a
water solubility of greater than 40 mg/mL at a pH in a range of
about 3.5. Further, Form A is non-hygroscopic. For example, when
subjected to dynamic vapor sorption, Form A demonstrated a total
weight gain of about 0.55 wt. % between about 40% and about 95%
relative humidity (RH) and weight loss of about 2.7 wt % between
about 30% and about 5% RH. In some embodiments, the dihydrochloride
hydrate form of omecamtiv mecarbil has a dynamic vapor sorption
profile substantially as shown in FIG. 1 wherein by "substantially"
is meant that the reported DVS features can vary by about .+-.5%
RH.
[0042] The dynamic vapor sorption indicates that the salt
dehydrates when dried to 5% relative humidity, but almost fully
re-hydrates by 15% relative humidity. Above 15% relative humidity,
the sample is non-hygroscopic, showing only about a 1.0% weight
change upon reaching 95% relative humidity. No phase change
occurred after the vapor sorption experiment when examined by
XRPD.
[0043] Water solubility for Form A was determined to be greater
than 40 mg/mL (pH=3.5) with no phase change occurring during the 24
hour slurry experiment when examined by XRPD. Further still, Form A
is stable under accelerated stability testing conditions. For
example, Form A remains in substantially the same physical form
over 6 months at 40.degree. C. and 75% RH.
[0044] In various embodiments, Form A can be characterized by an
X-ray powder diffraction pattern, obtained as set forth in the
Examples, having peaks at about 6.6, 14.9, 20.1, 21.4, and
26.8.+-.0.2.degree. 20 using Cu K.alpha. radiation. Form A
optionally can be further characterized by an X-ray powder
diffraction pattern having additional peaks at about 8.4, 24.2,
26.0, 33.3.+-.0.2.degree. 20 using Cu K.alpha. radiation. Form A
optionally can be even further characterized by an X-ray powder
diffraction pattern having additional peaks at about 6.2, 9.7,
13.2, 14.3, 15.4, 16.3, 16.9, 18.9, 19.5, 20.7, 21.8, 22.8, 23.6,
25.1, 27.3, 27.7, 28.4, 29.4, 30.2, 31.2, 31.5, 31.9, 33.9, 34.5,
34.9, 36.1, 36.8, 37.7, 38.5, and 39.7.+-.0.2.degree. 20 using Cu
K.alpha. radiation. In various cases, Form A can be characterized
by an XRPD pattern having peaks at about 6.2, 6.6, 8.4, 9.7, 13.2,
14.3, 14.9, 15.4, 16.3, 16.9, 18.9, 19.5, 20.1, 20.7, 21.4, 21.8,
22.8, 23.6, 24.3, 25.1, 26.0, 26.8, 27.3, 27.7, 28.4, 29.4, 30.2,
31.2, 31.5, 31.9, 33.3, 33.9, 34.5, 34.9, 36.1, 36.8, 37.7, 38.5,
and 39.7.+-.0.2.degree. 20 using Cu K.alpha. radiation. In some
embodiments, Form A has an X-ray powder diffraction pattern
substantially as shown in FIG. 2, wherein by "substantially" is
meant that the reported peaks can vary by about .+-.0.2.degree.. It
is well known in the field of XRPD that while relative peak heights
in spectra are dependent on a number of factors, such as sample
preparation and instrument geometry, peak positions are relatively
insensitive to experimental details.
[0045] Form B and Form C polymorphs of omecamtiv mecarbil, are
metastable anhydrous dihydrochloride forms, and can be formed under
varied hydration conditions, as noted in FIGS. 3, 4, and 6.
Characteristic Form B 2-theta values include 6.8, 8.8, 14.7, 17.7,
and 22.3.+-.0.2.degree. 2.theta. using Cu K.alpha. radiation, and
can additionally include peaks at 9.6, 13.5, 19.2,
26.2.+-.0.2.degree. 2.theta. using Cu K.alpha. radiation. Form B
can be characterized with XRPD pattern peaks at 6.2, 6.8, 8.8, 9.6,
13.5, 14.4, 14.7, 15.4, 16.3, 17.0, 17.7, 18.3, 19.2, 19.9, 20.5,
20.8, 21.8, 22.3, 22.7, 23.0, 24.8, 25.1, 25.5, 26.2, 26.4, 26.8,
27.5, 28.5, 30.2, 30.6, 31.1, 31.5, 32.1, 32.7, 34.1, 34.4, 35.5,
35.9, 38.1, 38.9.+-.0.2.degree. 20 using Cu K.alpha. radiation.
Characteristic Form C 2-theta values include 6.7, 14.8, 17.4, 20.6,
and 26.2.+-.0.2.degree. 2.theta. using Cu K.alpha. radiation, and
can additionally include peaks at 8.7, 22.0, 27.1, and
27.7.+-.0.2.degree. 2.theta. using Cu K.alpha. radiation. Form C
can be characterized with XRPD pattern peaks at 6.2, 6.7, 8.7, 9.6,
13.5, 14.5, 14.8, 15.4, 16.4, 17.1, 17.4, 18.4, 19.3, 19.5, 19.9,
20.6, 20.8, 21.8, 22.0, 22.5, 22.8, 24.3, 24.7, 25.1, 25.6, 26.2,
26.5, 27.1, 27.3, 27.7, 28.5, 30.0, 30.5, 31.0, 31.5, 32.2, 32.8,
34.1, 35.2, 36.0, 36.9, and 38.8.+-.0.2.degree. 2.theta. using Cu
K.alpha. radiation. In some embodiments, Forms B and C have an
X-ray powder diffraction pattern substantially as shown in FIG. 6,
wherein by "substantially" is meant that the reported peaks can
vary by about .+-.0.2.degree..
[0046] In various embodiments, Form A can be characterized by a
single crystal x-ray diffraction (XRD) pattern, obtained as set
forth in the Examples section, wherein Form A comprises a triclinic
space group of P-1 and unit cell parameters of about a=5.9979(4)
.ANG., b=13.4375(9) .ANG., c=14.4250(9) .ANG.,
.alpha.=97.617(4.degree.); .beta.=93.285(4.degree.); and
.gamma.=94.585(5).degree.. Form A optionally can be further
characterized by the XRD parameters in the table, below.
TABLE-US-00001 Wavelength 1.54178 .ANG. Crystal system Triclinic
Space group P-1 Unit cell dimensions a = 5.9979(4) .ANG. .alpha. =
97.617(4).degree. b = 13.4375(9) .ANG. .beta. = 93.285(4).degree. c
= 14.4250(9) .ANG. .gamma. = 94.585(5).degree. Volume 1145.93(13)
.ANG..sup.3 Z 2 Density (calculated) 1.427 Mg/m.sup.3 Absorption
2.945 mm.sup.-1 coefficient
[0047] DSC thermographs were obtained for Form A. The DSC curve
indicates an endothermic transition that appears to be due to
melting/decomposition around 235.degree. C. Thus, in embodiments,
Form A can be characterized by a DSC thermograph having a
decomposition endotherm with an onset in a range of about
230.degree. C. to about 240.degree. C. when Form A in an open
aluminum pan. For example, in embodiments wherein Form A is heated
from about 25.degree. C. at a rate of about 10.degree. C./min, Form
A can be characterized by a DSC thermograph having a decomposition
endotherm with an onset of about 235.degree. C., as shown in FIG.
5.
[0048] Form A also can be characterized by thermogravimetric
analysis (TGA). Thus, Form A can be characterized by a weight loss
in a range of about 2% to about 5% with an onset temperature in a
range of about 100.degree. C. to about 150.degree. C. For example,
Form A can be characterized by a weight loss of about 3%, up to
150.degree. C. In some embodiments, Form A has a thermogravimetric
analysis substantially as depicted in FIG. 5, wherein by
"substantially" is meant that the reported TGA features can vary by
about .+-.5.degree. C. This weight loss was determined to be water
via Karl Fischer (KF) analysis. KF analysis shows that the water
content of Form A can be about 3.7, corresponding to a mono
hydrate.
[0049] Form A can be characterized via variable temperature XRPD
and variable relative humidity XRPD. The variable temperature XRPD
data are shown in FIG. 4. The data indicate that when Form A
hydrate is heated beyond the desolvation event shown in the TGA
curve (about 75.degree. C.), the material converts to a new
dehydrated phase, Form B. When the material is cooled back down to
ambient conditions, Form B resorbs water from the atmosphere and
converts back to the hydrate Form A. The variable relative humidity
XRPD data are shown in FIG. 3. The data indicate that when the
hydrate Form A is exposed to 5% relative humidity, the material
converts to a new dehydrated phase, Form C. When the material was
exposed to 15% relative humidity and higher, Form C resorbs water
from the environment and converts back to the hydrate Form A. These
data are consistent with the vapor sorption experiment. An overlay
of Form B and Form C are shown in FIG. 6. Arrows mark significant
reflections of the two powder patterns indicating that the two
phases are unique.
[0050] Also provided are compositions comprising a dihydrochloride
hydrate form of omecamtiv mecarbil. In some embodiments, the
compositions include at least about 50, about 60, about 70, about
80, about 90, about 95, about 96, about 97, about 98, or about 99%
by weight of the dihydrochloride hydrate form of omecamtiv
mecarbil. In some embodiments, the compositions include at least
about 50, about 60, about 70, about 80, about 90, about 95, about
96, about 97, about 98, or about 99% by weight of Form A of the
dihydrochloride hydrate form of omecamtiv mecarbil. In some
embodiments, the compositions contain a mixture of two or more of
Forms A, B, and C.
[0051] Also provided are pharmaceutical formulations comprising a
dihydrochloride hydrate form of omecamtiv mecarbil and at least one
pharmaceutically acceptable excipient. In some embodiments, the
formulations include at least about 50, about 60, about 70, about
80, about 90, about 95, about 96, about 97, about 98, or about 99%
by weight of the dihydrochloride hydrate form of omecamtiv
mecarbil. In some embodiments, the formulations include at least
about 50, about 60, about 70, about 80, about 90, about 95, about
96, about 97, about 98, or about 99% by weight of Form A of the
dihydrochloride hydrate form of omecamtiv mecarbil. In some
embodiments, the formulations contain a mixture of two or more of
Forms A, B, and C.
[0052] Also provided is a method for the use of such pharmaceutical
formulations for the treatment of heart failure, including but not
limited to: acute (or decompensated) congestive heart failure, and
chronic congestive heart failure; particularly diseases associated
with systolic heart dysfunction.
[0053] Also provided is a synthesis of omecamtiv mecarbil
comprising admixing methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate and phenyl
(6-methylpyridin-3-yl)carbamate in the presence of a trialkylamine
base to form omecamtiv mecarbil.
[0054] In some embodiments, the weight ratio of phenyl
(6-methylpyridin-3-yl)carbamate hydrochloride (i.e., SM-2 or phenyl
carbamate) to methyl
4-(3-amino-2-fluoro-benzyl)piperazine-1-carboxylate (i.e., SM-1 or
piperazine nitro) is between about 1.1 and 1.5. In some
embodiments, weight ratio of phenyl (6-methylpyridin-3-yl)carbamate
hydrochloride to methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate is about
1.2.
[0055] In some embodiments, the admixing is conducted in the
presence of an aprotic solvent. In some embodiments, the solvent is
THF.
[0056] In some embodiments, the trialkylamine base is
triethylamine, diisopropylethylamine, or a combination thereof. In
some embodiments, the trialkylamine base comprises
diisopropylethylamine.
[0057] In some embodiments, an excess of the trialkylamine base is
used. In some embodiments, between about 1.1 and 1.5 equivalents of
the trialkylamine base is used. In some embodiments, about 1.3
equivalents of the trialkylamine base is used.
[0058] In some embodiments, the admixing is conducted at 65.degree.
C.
[0059] In some embodiments, the method further comprises
crystallizing the omecamtiv mecarbil in the presence of aqueous
hydrochloric acid and an alcohol solvent to form omecamtiv mecarbil
dihydrochloride hydrate.
[0060] In some embodiments, the alcohol solvent comprises isopropyl
alcohol.
[0061] In some embodiments, the aqueous hydrochloric acid comprises
6N HCl.
[0062] In some embodiments, the method further comprises mixing the
omecamtiv mecarbil dihydrochloride hydrate with at least
pharmaceutically acceptable excipient to form a pharmaceutical
formulation.
[0063] In some embodiments, the pharmaceutical formulation
comprises omecamtiv mecarbil dihydrochloride hydrate; a sweller
layer; and a semi-permeable membrane coating having at least one
delivery port. The general properties of the drug layer and the
sweller layer can be found in U.S. Pat. Pub. 2011/0182947, herein
incorporated by reference.
[0064] In some embodiments, the pharmaceutical formulation is a
modified release matrix tablet comprising omecamtiv mecarbil
dihydrochloride hydrate; a control release agent; a pH modifying
agent; a filler; and a lubricant.
[0065] In some embodiments, the methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate is prepared by a
process comprising: hydrogenating methyl
4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate in the presence
of a hydrogenation catalyst to form methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate.
[0066] In some embodiments, the hydrogenation catalyst comprises
palladium. In some embodiments, the hydrogenation catalyst is
palladium on carbon.
[0067] Also provided is a method of preparing omecamtiv mecarbil
dihydrochloride hydrate comprising crystallizing omecamtiv mecarbil
in the presence of aqueous hydrochloric acid and an alcohol solvent
to form omecamtiv mecarbil dihydrochloride hydrate.
[0068] In some embodiments, the alcohol solvent comprises isopropyl
alcohol.
[0069] Also provided is a method of preparing omecamtiv mecarbil
dihydrochloride hydrate comprising:
[0070] (a) hydrogenating methyl
4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate in the presence
of a hydrogenation catalyst to form methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate;
[0071] (b) admixing methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate and phenyl
(6-methylpyridin-3-yl)carbamate in the presence of a trialkylamine
base to form omecamtiv mecarbil as a free base; and
[0072] (c) crystallizing the omecamtiv mecarbil free base in the
presence of aqueous hydrochloric acid and an alcohol solvent to
form omecamtiv mecarbil dihydrochloride hydrate salt.
[0073] This synthesis provides high overall yields (greater than
70%). In addition, the dihydrochloride salt that results from the
steps, can be formed as long rods when crystallized, having
improved bulk properties, filtration times of minutes (compared to
days for the free base form) and is highly soluble (greater than 40
mg/mL at pH 3.8). In various cases, the resulting salt is the
dihydrochloride hydrate Form A.
Examples
General Methods
[0074] Reagents and solvents were used as received from commercial
sources. 1H NMR spectra were recorded on a 400 MHz spectrometer.
Chemical shifts are reported in ppm from tetramethylsilane with the
solvent resonance as the internal standard (CDCl.sub.3,
DMSO-d.sub.6). Data are reported as follows: chemical shift,
multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=broad,
m=multiplet), coupling constants (Hz) and integration. .sup.13C NMR
spectra were recorded on a 100 MHz spectrometer with complete
proton decoupling. Chemical shifts are reported in ppm from
tetramethylsilane with the solvent as the internal reference
(CDCl.sub.3, DMSO-d.sub.6). All solvent charges are made with
respect to starting 2-Fluoro-3-nitrotoluene.
[0075] X-ray powder diffraction data was obtained using the
Phillips x-ray automated powder diffractometer (X'Pert) that was
equipped with a fixed slit. The radiation was CuK.alpha. (1.541837
.ANG.) and the voltage and current were 45 kV and 40 mA,
respectively. Data was collected at room temperature from 3.000 to
40.009 degree 2-theta; step size was 0.008 degrees; counting time
was 15.240 seconds. Samples ranging from 5-40 mg were prepared on
the sample holder and the stage was rotated at a revolution time of
2.000 seconds.
[0076] The thermal properties of omecamtiv mecarbil bis-HCl salt
were characterized using a DSC Q1000 or DSC Q 100 model, TA
Instruments, differential scanning calorimetry, and a Q 500, TA
Instruments, thermogravimetric analyzer. Data analysis was
performed utilizing Universal Analysis 2000, TA Instruments.
Heating rates of 10.degree. C./min were used over a variety of
temperature ranges for differential scanning calorimetry and
thermogravimetric analysis. Samples ranging from <1-5 mg were
prepared in crimped, hermetic or open aluminum pans for DSC
analysis.
[0077] Moisture balance data was collected using a VTI SGA 100
symmetrical vapor sorption analyzer. Relative humidity was varied
in increments of 5%, between 5% and 95% relative humidity during
the adsorption run, and from 95% to 5% relative humidity during the
desorption run. Equilibrium criteria was set at 0.01% weight change
in 1 minute with a max equilibrium time of 180 minutes.
Approximately 1-15 mg of sample was used.
[0078] A colorless blade of
C.sub.20H.sub.28C.sub.12FN.sub.5O.sub.4, approximate dimensions
0.03 mm.times.0.12 mm.times.0.50 mm, was used for the X-ray
crystallographic analysis. The X-ray intensity data were measured
at 100(2) K on a Bruker Kappa APEX II system equipped with a
graphite monochromator and a CuK.alpha. fine-focus sealed tube
(.lamda.=1.54178 .ANG.) operated at 1.2 kW power (40 kV, 30 mA).
The detector was placed at a distance of 5.0 cm. from the
crystal.
[0079] A total of 7824 frames were collected with a scan width of
0.5.degree. in .omega. and .phi. and an exposure time of 90
sec/frame. The total data collection time was 260 hours. The frames
were integrated with the Bruker SAINT software package using a
narrow-frame integration algorithm. The integration of the data
using a Triclinic cell yielded a total of 12349 reflections to a
maximum .theta. angle of 69.57.degree. (0.83 .ANG. resolution), of
which 4046 were independent (redundancy 3.06), completeness=93.6%,
R.sub.int=5.13%, R.sub.sig=5.18%) and 3351 (82.8%) were greater
than >2sigma(I) .sigma. (F.sup.2). The final cell constants of
a=5.9979(4).ANG., b=13.4375(9).ANG., c=14.4250(9).ANG.,
.alpha.=97.617(4).degree., .beta.=93.285(4).degree.,
.gamma.=94.585(5).degree., volume=1145.95(13).ANG..sup.3, are based
upon the refinement of the XYZ-centroids of 4790 reflections above
20 .sigma.(I) with 6.196.degree.<2.theta.<138.239.degree..
Analysis of the data showed negligible decay during data
collection. Data were corrected for absorption effects using the
multiscan technique (SADABS). The ratio of minimum to maximum
apparent transmission was 0.350. The calculated minimum and maximum
transmission coefficients (based on crystal size) are 0.3206 and
0.9168.
[0080] The structure was solved and refined using the Bruker
SHELXTL (Version 6.1) Software Package, using the space group P-1,
with Z=2 for the formula unit,
C.sub.20H.sub.28C.sub.12FN.sub.5O.sub.4. The final anisotropic
full-matrix least-squares refinement on F.sup.2 with 320 variables
converged at R1=6.43%, for the observed data and wR2=19.18% for all
data. The goodness-of-fit was 1.067. The largest peak on the final
difference electron density synthesis was 1.084 e.sup.-/.ANG..sup.3
and the largest hole was -0.527 e.sup.-/.ANG..sup.3 with an RMS
deviation of 0.101 e.sup.-/.ANG..sup.3 On the basis of the final
model, the calculated density was 1.427 g/cm.sup.3 and F(000), 516
e.sup.-.
[0081] Two positions for partial water occupancies were found and
refined in this structure. The occupancies of the waters were
refined independently to 53% and 41% for a total water content of
0.94 equivalents of water per omecamtiv mecarbil molecule. This is
consistent with other measures of water content in this form of
this compound. Hydrogen atoms on one of the solvating waters, the
one with an occupancy of 41%, were found in the electron density
difference map and refined with bond lengths fixed at 1.01 .ANG..
The hydrogen atoms on N3, C4 and N4 were found and allowed to
refine isotropically. All other hydrogen atoms were placed at
idealized positions and refined riding mode.
[0082] X-Ray powder diffraction data (XRPD) were obtained using a
PANalytical X'Pert PRO diffractometer (PANalytical, Almelo, The
Netherlands) fitted with a real time multiple strip (RTMS)
detector. The radiation used was CuK.alpha.(1.54 .ANG.) and the
voltage and current were set at 45 kV and 40 mA, respectively. Data
were collected at room temperature from 5 to 45 degrees 2-theta
with a step size of 0.0334 degrees. Samples were prepared on a low
background sample holder and placed on the sample stage which was
rotated with a 2 second revolution time.
[0083] Alternatively, XRPD data were obtained using a PANalytical
X'Pert PRO diffractometer (PANalytical, Almelo, The Netherlands)
fitted with a RTMS detector. The radiation used was CuK.alpha.(1.54
.ANG.) and the voltage and current were set at 45 kV and 40 mA,
respectively. Data were collected at room temperature from 5 to 40,
degrees 2-theta with a step size of either 0.0334 degrees. Samples
were prepared on a low background sample holder and placed on the
sample stage which was rotated with a 2 second revolution time.
[0084] Alternatively, XRPD data were obtained using a PANalytical
X'Pert PRO diffractometer (PANalytical, Almelo, The Netherlands)
fitted with a RTMS detector. The radiation used was CuK.alpha.(1.54
.ANG.) and the voltage and current were set at 45 kV and 40 mA,
respectively. Data were collected at room temperature from 5 to 40,
degrees 2-theta with a step size of either 0.0167 degrees. Samples
were prepared on a low background sample holder and placed on the
sample stage which was rotated with a 2 second revolution time.
[0085] Alternatively, XRPD data were obtained using a PANalytical
X'Pert Pro diffractometer (PANalytical, Almelo, The Netherlands)
fitted with a RTMS detector. The radiation used was CuK.alpha.
(1.54 .ANG.) and the voltage and current were set at 45 kV and 40
mA, respectively. Data were collected at room temperature from 3 to
40, degrees 2-theta with a step size of 0.008 degrees. Samples were
prepared on a low background sample holder and placed on the sample
stage with a 2 second revolution time.
[0086] Alternatively, XRPD data were obtained using a Bruker D8
Discover X-ray diffraction system (Bruker, Billerica, Mass.) fitted
with a motorized xyz sample stage and a GADDS area detector. The
radiation used was CuK.alpha. (1.54 .ANG.) and the voltage and
current were set at 45 kV and 40 mA, respectively. The solid
samples on a flat glass plate were mapped and for each sample an
area of 1 mm.sup.2 was scanned in an oscillating mode for 3 minutes
from 5 to 48 degrees 2-theta.
[0087] Differential Scanning Calorimetry (DSC) data was collected
using standard DSC mode (DSC Q200, TA Instruments, New Castle,
Del.). A heating rate of 10.degree. C./min was employed over a
temperature range from 40.degree. C. to 300.degree. C. Analysis was
run under nitrogen and samples were loaded in standard,
hermetically-sealed aluminum pans. Indium was used as a calibration
standard.
[0088] Alternatively, DSC data were collected using
temperature-modulated DSC mode (DSC Q200, TA Instruments, New
Castle, Del.). After sample equilibration at 20.degree. C. for five
minutes, the heating rate of 3.degree. C./min was employed with a
modulation of +/-0.75.degree. C./min over a temperature range from
20.degree. C. to 200.degree. C. Analysis was run under nitrogen and
samples were loaded in standard, uncrimped aluminum pans. Indium
was used as a calibration standard.
Manufacture of Omecamtiv Mecarbil Dihydrochloride Hydrate
Synthetic Route to Omecamtiv Mecarbil
##STR00002##
[0089] Synthesis of the API SM Piperazine Nitro-HCl
##STR00003##
[0091] In a 60 L reactor (containing no exposed Stainless steel,
Hastelloy.RTM., or other metal parts) equipped with a reflux/return
condenser and scrubber charged with a 5N NaOH solution, a
mechanically stirred mixture of FN-Toluene (2.0 kg, 12.89 mol, 1.0
equiv.), N-Bromosuccinimide (3.9 kg, 21.92 mol, 1.70 equiv.),
benzoyl peroxide (125.0 g, 0.03 equiv., 0.39 mol, containing 25 wt
% water), and acetic acid (7.0 L, 3.5 volumes) was heated to
85.degree. C. under an atmosphere of nitrogen for 7 hours. A
solution of H.sub.3PO.sub.3 (106.0 g, 1.29 mol, 0.1 equiv.) and
acetic acid (200 mL, 0.1 volume), prepared in separate vessel, was
added. The reaction mixture was agitated for 0.5 h and analysis of
an aliquot confirmed complete decomposition of benzoyl peroxide
(not detected, HPLC.sub.254 nm). The reaction mixture was cooled to
22.degree. C. DI Water (8.0 L, 4 volumes) and toluene (16.0 L, 8
volumes) were charged, the biphasic mixture was agitated (20 min),
and the layers were separated. Aqueous 1.6N NaOH (14.0 L, 7.0
volumes) was added to the organic layer at a rate allowing the
batch temperature to stay under 25.degree. C. and the pH of the
resultant aqueous phase was measured (.gtoreq.11). The biphasic
mixture was filtered through a 5 .mu.m Teflon.RTM. cartridge line
and the layers were separated. The filter line was washed with
another 2 L of toluene.
[0092] The assay yields were 2.5% of FN-Toluene, 62.3% of
FN-Bromide and 30.0% of Di-Bromide. The toluene solution contained
no benzoyl peroxide, succinimide, or .alpha.-bromoacetic acid and
water content by KF titration was 1030 ppm (This solution could be
held under nitrogen at room temperature for >12 h without any
change in the assay yield).
[0093] To this solution at room temperature was added
diisopropylethylamine (880.0 g, 6.63 mol, 0.53 equiv.) followed by
methanol (460 mL, 11.28 mol, 0.88 equiv.) and heated to 40.degree.
C. A solution of diethylphosphite (820.0 g, 5.63 mol, 0.46 equiv.)
in methanol (460 mL, 11.28 mol, 0.88 equiv.) was prepared and added
to the reaction mixture at 40.degree. C. through an addition funnel
over a period of 1 hour at such a rate that the batch temperature
was within 40.+-.5.degree. C. The contents were stirred for a
period of 3 h at 40.degree. C. from the start of addition and
cooled to room temperature and held under nitrogen atmosphere for
12 hours. The assay yield of the reaction mixture was 2.5%
FN-Toluene 92.0% FN-Bromide and 0.2% Di-Bromide. This solution is
used as such for the alkylation step.
[0094] Characterization for components of final product mixture
(collected for pure compounds).
2-Fluoro-3-Nitrotoluene (FN-Toluene)
[0095] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.37 (s,
1H), 7.13-7.20 (m, 1H), 7.45-7.51 (m, 1H), 7.79-7.85 (m, 1H).
.sup.13C NMR (100 MHz, CHLOROFORM-d) .delta. ppm 14.3 (d, J=5 Hz),
123.3 (d, J=3 Hz), 123.6 (d, J=5 Hz), 128.2 (d, J=16 Hz), 136.7 (d,
J=5 Hz), 137.5 (broad), 153.7 (d, J=261 Hz);
1-(bromomethyl)-2-fluoro-3-nitrobenzene (FN-Bromide)
[0096] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 4.56 (s,
1H), 7.28-7.34 (m, 1H), 7.69-7.76 (m, 1H), 7.98-8.05 (m, 1H).
.sup.13C NMR (100 MHz, CHLOROFORM-d) .delta. ppm 23.6 (d, J=5 Hz),
124.5 (d, J=5 Hz), 126.1 (d, J=3 Hz), 128.5 (d, J=14 Hz), 136.5 (d,
J=4 Hz), 137.7 (broad), 153.3 (d, J=265 Hz). DSC: single melt at
53.59.degree. C. Exact Mass [C.sub.7H.sub.5BrFNO.sub.2+H].sup.+:
calc.=233.9566, measured=233.9561;
1-(dibromomethyl)-2-fluoro-3-nitrobenzene (Dibromide)
[0097] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 6.97 (s,
1H), 7.39-7.45 (m, 1H), 8.03-8.10 (m, 1H), 8.16-8.21 (m, 1H).
.sup.13C NMR (100 MHz, CHLOROFORM-d) .delta. ppm 29.2 (d, J=7 Hz),
124.9 (d, J=5 Hz), 127.1 (d, J=2 Hz), 132.1 (d, J=11 Hz), 135.7 (d,
J=2 Hz), 137.2 (broad), 149.8 (d, J=266 Hz). DSC: single melt at
49.03.degree. C. Exact Mass
[C.sub.7H.sub.4Br.sub.2FNO.sub.2+H].sup.+: calc.=311.8671,
measured=311.8666.
Piperazine Nitro-HCl:
[0098] To a mechanically stirred toluene solution (9 volumes) of
FN-Bromide (prepared from previous step) in a 60 L reactor at
22.degree. C. under an atmosphere of nitrogen,
diisopropylethylamine was charged (1.90 kg, 14.69 mol, 1.14
equiv.). To this mixture a solution of piperazine carboxylate
methylester (Piperazine Carboxylate) (2.03 kg, 14.05 mol, 1.09
equiv.) in toluene (1.0 L, 0.5 volumes) was added at a rate
allowing the batch temperature to stay under 30.0.degree. C.
(Exothermic. During the addition, jacket temperature was adjusted
to 5.degree. C. in order to maintain batch temperature below
30.degree. C. The mixture was agitated at 22.degree. C. for 3 hours
and analysis of an aliquot confirmed completion of the alkylation
reaction (<1.0 LCAP FN-Bromide, HPLC.sub.254 nm). The reaction
mixture was treated with aqueous NH.sub.4Cl (20 wt %, 10.0 L, 5
volumes; prepared from 2.0 kg of NH.sub.4Cl and 10.0 L of DI
water), the biphasic mixture was agitated (30 min), and the layers
were separated. The organic layer was sequentially washed with
aqueous NaHCO.sub.3 (9 wt %, 10.0 L, 5 volumes; prepared from 0.90
kg of NaHCO.sub.3 and 10.0 L of DI water). The organic layer was
filtered through a 5 .mu.m Teflon.RTM. cartridge line and
transferred in a drum, washed the filter line with another 1.0 L
toluene and the combined toluene solution (10.0 volumes) weighed,
and assayed (HPLC) to quantify Piperazine Nitro free base. The
assay yield for the Piperazine Nitro-freebase is 89.0%, FN-Toluene
2.5% and FN-Bromide 0.2% with FN-Bromide undetected. The total loss
of product to the aqueous washes is <1.0%. This solution under
nitrogen atmosphere is stable for more than 12 h.
[0099] To a mechanically stirred toluene solution of Piperazine
Nitro free base, prepared as described above, at 22.degree. C. in a
60 L reactor under an atmosphere of nitrogen, IPA (19.4 L, 9.7
volumes) and DI water (1.0 L, 0.5 volume) were charged. The mixture
was heated to 55.degree. C. and 20% of the 1.4 equiv. of conc. HCl
(Titrated prior to use and charge based on titer value; 276.0 mL,
3.21 mol) was charged. The contents were agitated for 15 min and
Piperazine Nitro-HCl seed (130.0 g, 0.39 mol, 0.03 equiv.) was
charged as slurry in IPA (400 mL, 0.2 volume). The mixture was
agitated for 30 min and the remaining conc. HCl (80% of the charge,
1.10 L, 12.82 mol) was added over a period of 4 hours. The mixture
was stirred at 55.degree. C. for 1 h, cooled to 20.degree. C. in a
linear manner over 1.5 hours, and agitated at this temperature for
12 hours. The supernatant concentration of Piperazine Nitro-HCl was
measured (2.8 mg/g). The mixture was filtered through an aurora
filter equipped with a 5 .mu.m Teflon.RTM. cloth. The mother liquor
were transferred to a clean drum and assayed. The filter cake was
washed twice with IPA (11.2 L, 5.6 volumes) and dried to constant
weight (defined as .ltoreq.1.0% weight loss for 2 consecutive TGA
measurements over a period of 2 hours) on filter with vacuum and a
nitrogen sweep (14 h). The combined losses of Piperazine Nitro-HCl
in the mother liquors and the washes were 2.5%. Piperazine
Nitro-HCl was isolated 3.59 kg in 87.6% corrected yield with
>99.5 wt % and 99.0% LCAP purity.
[0100] Methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate
hydrochloride (Piperazine Nitro-HCl): 1H NMR (300 MHz, DMSO-d)
.delta. ppm 3.25 (br. s, 3H), 3.52-3.66 (m, 8H), 4.47 (s, 2H),
7.44-7.63 (t, 1H, J=8 Hz), 7.98-8.15 (m, 1H), 8.17-8.34 (m, 1H).
.sup.13C NMR (75 MHz, DMSO-d) .delta. ppm 50.3, 51.4, 52.8, 119.6
(d, J=14 Hz), 125.1 (d, J=5 Hz), 127.9, 137.4 (d, J=8 Hz), 139.8
(d, J=3 Hz), 152.2, 154.7, 155.7. DSC: melt onset at 248.4.degree.
C. Exact Mass [C.sub.13H.sub.16FN.sub.3O.sub.4+H].sup.+:
calculated=298.1203, measured=298.1198.
Alternative Processes for the Synthesis of Piperazine Nitro:
##STR00004##
[0102] A mixture of NaBH.sub.4 (1.7 g, 44 mmol) in THF (68 mL) was
treated 2-fluoro-3-nitrobenzoic acid (3.4 g, 18.4 mmol) and cooled
to 0-5.degree. C. A solution of iodine (4.7 g, 18.4 mmol) in THF
(12 mL) was then added drop wise at a rate to control off-gassing.
The progress of the reaction was assessed by HPLC. After 2 hours
HPLC assay indicated 4% AUC of 2-fluoro-3-nitrobenzoic acid
remained. The mixture was quenched into 1 M HCl (30 mL) and
extracted with MTBE (5 mL). The organics were then washed with 20%
aqueous KOH solution and 10% sodium thiosulfate. The organics were
dried with Na.sub.2SO.sub.4, filtered over Celite and concentrated
to afford (2-fluoro-3-nitrophenyl)methanol (2.8 g, 88%, 89% AUC by
HPLC).
[0103] A solution of (2-fluoro-3-nitrophenyl)methanol (2.8 g, 16
mmol) in 2-MeTHF (26 mL) was treated with triethylamine (4.5 mL, 32
mmol) and cooled to 0-5.degree. C. The solution was then treated
with methanesulfonyl chloride (1.6 mL, 21 mmol). The progress of
the reaction was assessed by HPLC. After 30 minutes at 0-5.degree.
C., the reaction was deemed complete. The mixture was quenched with
water (14 mL) and the phases were separated. The organics were
washed with brine, dried with Na.sub.2SO.sub.4, filtered over
Celite and concentrated to afford 2-fluoro-3-nitrobenzyl
methanesulfonate (3.3 g, 83.1%, 81% AUC by HPLC) as a yellow
oil.
[0104] A solution of 2-fluoro-3-nitrobenzyl methanesulfonate (3.3
g, 13 mmol, AMRI lot #46DAT067B) in toluene (33 mL), was treated
with diisopropylethylamine (2.7 mL, 15 mmol) in one portion. A
solution of methylpiperazine-1-carboxylate (2.1 g, 15 mmol) in
toluene (1.1 mL) was added slowly via syringe to maintain between
23-29.degree. C. The reaction was stirred for 16 hours following
the addition. An HPLC assay after this time showed that the
reaction was complete. 20% Aqueous NH.sub.4Cl (11 mL) was added at
20-25.degree. C. The biphasic mixture was stirred for 15 minutes,
and the phases were separated. This process was repeated using 9%
aqueous sodium bicarbonate (11 mL). The toluene layer was then
filtered over Celite at 20-25.degree. C. 2-propanol (50 mL) and
water (1.1 mL) were added to the toluene solution and the mixture
heated to 55-60.degree. C. The mixture was then treated with 37 wt
% HCl (1.6 mL, 18.7 mmol) over 20 minutes. A precipitate was noted
following the addition. When the addition was complete, the mixture
was allowed to cool gradually to 20-25.degree. C. and was stirred
for hours before filtering and washing with IPA (2 bed
volumes).
[0105] The cake was then dried at under vacuum to afford
4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate hydrochloride
(2.41 g, 54%, 90% AUC by HPLC, 88 wt % by HPLC).
Piperazine Nitro Freebase:
[0106] In a 60 L reactor equipped with a reflux/return condenser, a
mixture of Piperazine Nitro-HCl (2.0 kg, 5.99 mol, 1.0 equiv.) and
isopropyl acetate (6.0 L, 3.0 volumes) was mechanically agitated at
ambient temperature under an atmosphere of nitrogen. A solution of
sodium bicarbonate (629 g, 7.49 mol, 1.25 equiv.) and water (7.5 L,
3.75 volume), prepared in separate vessel, was added. The biphasic
mixture was agitated (15 min), and the layers were separated. The
upper organic layer (containing product) was transferred to a
separate vessel while the reactor was rinsed with water and
isopropanol. The organic layer was then transferred through an
inline 5 .mu.m Teflon.RTM. cartridge back into the clean 60 L
reactor. The filter line was washed with 4.0 L (2.0 volumes) of
isopropanol into the 60 L reactor. An additional 12.0 L (6.0
volumes) of isoproponal was added to the 60 L reactor and heated to
40.degree. C. Under reduced pressure (50 torr) the batch was
concentrated down to approximately 6 L (3.0 volumes). The solution
was cooled from 27.degree. C. to 20.degree. C. in a linear manner
over 10 minutes. Water (4.0 L, 2.0 volumes) was added at 20.degree.
C. over 30 minutes followed by Piperazine Nitro Freebase seed (18
g, 0.06 mol, 0.01 equiv). The mixture was aged for 5 minutes and
the remaining water (24.0 L, 12.0 volumes) was added over 90
minutes. After holding overnight at 20.degree. C., the supernatant
concentration of Piperazine Nitro Freebase was measured (<10
mg/mL). The mixture was filtered through an aurora filter equipped
with a 12 .mu.m Teflon.RTM. cloth. The filter cake was washed with
a mixture of water (3.3 L, 1.65 volumes) and isopropanol (700 mL,
0.35 volumes) and dried to constant weight (defined as .ltoreq.1.0%
weight loss for 2 consecutive TGA measurements over a period of 2
hours) on filter with vacuum and a nitrogen sweep (48 h). The
combined losses of Piperazine Nitro Freebase in the mother liquors
and the wash were aproximately 7.5%. Piperazine Nitro Freebase was
isolated 1.67 kg in 92.5% corrected yield with 100.0 wt % and 99.4%
LCAP purity.
Synthesis of the API SM Phenyl Carbamate-HCl
##STR00005##
[0108] A 60 L, glass-lined, jacketed reactor set at 20.degree. C.
under nitrogen atmosphere and vented through a scrubber (containing
5N NaOH) was charged with 2.5 kg of Amino Pyridine (1.0 equiv, 23.1
moles), followed by 25 L (19.6 kg, 10 vol) acetonitrile. After
initiating agitation and (the endothermic) dissolution of the Amino
Pyridine, the vessel was charged with 12.5 L of
N-methyl-2-pyrolidinone (12.8 kg, 5 vol). An addition funnel was
charged with 1.8 L (0.6 equiv, 13.9 moles) phenyl chloroformate
which was then added over 68 minutes to the solution of the Amino
Pyridine keeping the internal temperature .ltoreq.30.degree. C. The
reaction was agitated for >30 minutes at an internal temperature
of 20.+-.5.degree. C. The vessel was then charged with 61.+-.1 g of
seed as a slurry in 200 mL acetonitrile and aged for .gtoreq.30
min. The addition funnel was charged with 1.25 L (0.45 equiv, 9.7
moles) of phenyl chloroformate which was then added over 53 minutes
to the reaction suspension while again keeping the temperature
.ltoreq.30.degree. C. The contents of the reactor were aged
.gtoreq.30 hours at 20.+-.5.degree. C. After assaying the
supernatant (.ltoreq.15 mg/g for both product and starting
material), the solids were filtered using an Aurora filter equipped
with a 12 .mu.m Teflon cloth. The mother liquor was forwarded to a
2.sup.nd 60 L, glass-lined, jacketed reactor. The reactor and cake
were rinsed with 1.times.10 L of 5:10 NMP/ACN and 1.times.10 L ACN.
The washes were forwarded to the 2.sup.nd reactor as well. The cake
was dried under vacuum with a nitrogen bleed for .gtoreq.24 hours
to afford 5.65 kg (90.2% yield) of the product, Phenyl
Carbamate-HCl as an off-white solid in 98.8 wt % with 99.2% LCAP
purity.
[0109] Phenyl (6-methylpyridin-3-yl)carbamate hydrochloride (Phenyl
Carbamate-HCl) .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
11.24 (s, 1H), 8.81 (s, 1H), 8.41 (d, 1H, J=8.8 Hz), 7.85 (d, 1H,
J=8.8 Hz), 7.48-7.44 (m, 2H), 7.32-7.26 (m, 3H), 2.69 (s, 3H);
.sup.13C NMR (100 MHz, DMSO-d.sub.6) .delta. ppm 151.66, 150.01,
147.51, 136.14, 133.79, 129.99, 129.49, 127.75, 125.87, 121.70,
18.55: HR-MS: Calclulated for C.sub.13H.sub.12N.sub.2O.sub.2:
228.0899, M+H.sup.+=229.0972; Observed mass: 229.0961
Alternative Synthesis of Phenyl Carbamate HCl
[0110] 5-Amino-2-methylpyridine (53.2 kg, 1.0 equiv) and
acetonitrile (334 kg, 8.0 mL/g) were charged to a nitrogen flushed
glass-lined reactor. The contents of the reactor were stirred while
warming to 25-30.degree. C. The mixture was then recirculated
through a filter packed with activated carbon (11 kg, 20 wt %) for
3 h intervals while maintaining 25-30.degree. C. Following each 3 h
interval, a sample of the mixture was analyzed for color by
comparison to a color standard and UV Absorbance at 440 nm. Once a
satisfactory result was achieved, the filter was blown out into the
reactor and the filter was rinsed with acetonitrile (85 kg, 2.0
mL/g). The acetonitrile rinse was transferred into the reaction
mixture. 1-Methyl-2-pyrrolidinone (274 kg, 5.0 mL/g) was charged to
the reaction mixture in the glass-lined reactor. Phenyl
chloroformate (46.6 kg, 0.6 equiv) was slowly added to the mixture
while maintaining 15-30.degree. C. (typically 60-70 min). The
reaction mixture was stirred for approximately 60 minutes while
maintaining 20-25.degree. C. Phenyl(6-methylpyridin-3-yl)carbamate
hydrochloride (0.58 kg, 0.010 equiv) seed crystals were charged to
the stirring mixture. The slurry was then stirred for approximately
4 h at 20.+-.5.degree. C. Phenyl chloroformate (33.4 kg, 0.45
equiv) was slowly added to the slurry while maintaining
15-30.degree. C. The mixture was then allowed to age while stirring
for 8.+-.1 h whereupon concentration of 5-amino-2-methylpyridine
(target .ltoreq.15 mg/mL) and phenyl
(6-methylpyridin-3-yl)carbamate hydrochloride (target .ltoreq.15
mg/mL) were checked by HPLC. The batch was then filtered under
vacuum and washed with a mixture of acetonitrile (112 kg, 2.68
mL/g) and 1-methyl-2-pyrrolidinone (72 kg, 1.32 mL/g) followed by
washing thrise with acetonitrile (167 kg, 4.0 mL/g). The solids
were deliquored followed by transfering to a tray dryer maintained
between 20-40.degree. C. and 1.3-0.65 psia until an LOD of <1 wt
% was achieved, whereupon phenyl(6-methylpyridin-3-yl)carbamate
hydrochloride 106.3 kg (81.6% yield) was isolated from the
dryer.
Methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate
(Piperazine Aniline)
##STR00006##
[0112] To a 100-L jacketed glass-lined reactor were added methyl
4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate hydrochloride
(2.00 kg, 1.00 equiv) and isopropyl acetate (6.00 L, 3.00 Vol
with-respect to starting material). The resulting slurry was
agitated under a nitrogen sweep. To the mixture was added dropwise
over 45.+-.30 min: 7.7% w/w aqueous sodium bicarbonate solution
(629 g, 1.25 equiv of sodium bicarbonate dissolved in 7.50 L
water), maintaining an internal temperature of 20.+-.5.degree. C.
by jacket control (NOTE: addition is endothermic, and may evolve up
to 1 equiv of carbon dioxide gas). The mixture was stirred for
.gtoreq.15 min, resulting in a clear biphasic mixture. Agitation
was stopped and the layers were allowed to settle.
[0113] The bottom (aqueous) layer was drained and analyzed by pH
paper to ensure that the layer is pH >6. Quantititative HPLC
analysis of the upper (organic) layer revealed 97-100% assay yield
of the methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate
freebase (1.73-1.78 kg). The upper (organic) layer was transferred
through an in-line filter into a 20-L Hastelloy.RTM. hydrogenator,
and the 100-L reactor and lines were rinsed with an additional
aliquot of isopropyl acetate (2.00 L, 1.00 Vol). The hydrogenator
was purged with nitrogen and vented to atmospheric pressure. To the
reaction mixture was added a slurry of 5.0 wt % palladium on carbon
(20.0 g, Strem/BASF Escat.TM. 1421, approx 50% water) in isopropyl
acetate (400 mL), followed by a 400 mL rinse. The resulting
reaction mixture was diluted with an additional aliquot of
isopropyl acetate (1.2 L; total isopropyl acetate amount is 10.0 L,
5.00 Vol). The hydrogenator was purged three times with nitrogen
(pressurized to 60.+-.10 psig, then vented to atmospheric
pressure), then pressurized to 60.+-.5 psig with hydrogen. The
reaction mixture was stirred at <100 rpm at 30.+-.5.degree. C.
while maintaining 60.+-.5 psig hydrogen, for >2 hours until
reaction was deemed complete. This temperature and pressure
correspond to a measured kLa value of approx 0.40 in a 20-L
Hydrogenator. End of reaction is determined by dramatic decrease in
hydrogen consumption accompanied by a relief in the heat evolution
of the reaction. To control potential dimeric impurities, the
reaction is continued for at least 30 minutes after this change in
reaction profile, and HPLC analysis is performed to confirm that
>99.5% conversion of the hydroxyl-amine to the aniline is
achieved.
[0114] At the end of reaction, the hydrogenator was purged with
nitrogen twice (pressurized to 60.+-.10 psig, then vented to
atmospheric pressure). The crude reaction mixture was filtered
through a 5 .mu.m filter followed by a 0.45 .mu.m filter in series,
into a 40-L glass-lined reactor. The hydrogenator and lines were
washed with an additional aliquot of isopropyl acetate (2.00 L).
Quantitative HPLC analysis of the crude reaction mixture revealed
95-100% assay yield (1.52-1.60 kg aniline product). The reaction
mixture was distilled under reduced pressure (typically 250-300
mbar) at a batch temperature of 50.+-.5.degree. C. until the total
reaction volume was approximately 8.00 L (4.00 Vol). The batch was
subjected to a constant-volume distillation at 50.+-.5.degree. C.,
250-300 mbar, by adding heptane to control the total batch volume.
After approximately 8.00 L (4.00 Vol) of heptane were added, GC
analysis indicated that the solvent composition was approximately
50% isopropyl acetate, 50% heptane. Vacuum was broken, and the
internal batch temperature was maintained at 50.+-.5.degree. C. To
the reaction mixture was added a slurry of seed (20.0 grams of
product methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate,
in a solvent mixture of 80 mL heptane and 20 mL isopropyl acetate).
The resulting slurry was allowed to stir at 50.+-.5.degree. C. for
2.+-.1 hours, then cooled to 20.+-.5.degree. C. over 2.5.+-.1.0 h.
Additional heptane (24.0 L, 12.0 Vol) was added dropwise over 2
hours, and the batch was allowed to stir at 20.+-.5.degree. C. for
.gtoreq.1 hours (typically overnight). Quantitative HPLC analysis
of this filtered supernatant revealed <5 mg/mL product in
solution, and the product crystals were 50-400 .mu.m birefringent
rods. The reaction slurry was filtered at 20.degree. C. onto a
filter cloth, and the cake was displacement-washed with heptane
(6.00 L, 2.00 Vol). The cake was dried on the filter under nitrogen
sweep at ambient temperature for >4 hours, until sample dryness
was confirmed by LOD analysis (indicated <1.0 wt % loss). The
product methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate
(1.56 kg) was isolated as a pale-yellow powder in 86% yield at 99.8
wt % by HPLC with 100.0 LCAP.sub.210. [Analysis of the combined
filtrates and washes revealed 108 grams (7.0%) of product lost to
the mother liquors. The remaining mass balance is comprised of
product hold-up in the reactor (fouling).] .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta.: 6.81 (dd, J=7.53, 7.82 Hz, 1H),
6.67 (m, 1H), 6.49 (m, 1H), 5.04 (s, 2H), 3.58 (s, 3H), 3.45 (m,
2H), 3.34 (m, 4H), 2.33 (m, 4H). 19F NMR (d.sub.6-DMSO, 376 MHz)
.delta.: -140.2. .sup.13C NMR (d.sub.6-DMSO, 125 MHz) .delta.:
155.0, 150.5, 148.2, 136.2 (m), 123.7 (m), 117.6, 115.1, 73.7, 54.9
(m), 52.1 (m), 43.4. mp=89.2.degree. C.
Alternate Route to Piperazine Aniline
[0115] To a jacketed glass-lined reactor were added methyl
4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate hydrochloride
(46.00 kg, 1.00 equiv) and isopropyl acetate (200 kg, 5.0 mL/g).
The resulting slurry was agitated under a nitrogen sweep. To the
mixture was added 7.4% w/w aqueous sodium bicarbonate solution
(1.25 equiv) while maintaining an internal temperature of
25.+-.5.degree. C. The mixture was agitated for .gtoreq.30 min,
resulting in a clear biphasic mixture. Agitation was stopped and
the bottom (aqueous) layer was discharged. Analysis of aqueous
layer indicates pH .gtoreq.6. Water (92 kg, 2.0 mL/g) was charged
the organic layer and agitated for .gtoreq.15 min. Agitation was
then stopped and the bottom (water wash) layer was discharged.
Water (92 kg, 2.0 mL/g) was charged the organic layer and agitated
for .gtoreq.15 min. Agitation was then stopped and the bottom
(water wash) layer was discharged. The batch was distilled under
reduced pressure while maintaining the batch temperature between
40-50.degree. C. The batch volume was held constant throughout the
distillation by the continuous addition of isopropyl acetate. Once
the water content of the batch was <1,500 ppm, the solution was
passed through an inline filter into a Hastelloy reactor containing
5.0 wt % palladium on carbon (BASF Escat 1421, 0.69 kg, 1.5 wt %).
The jacketed glass-lined reactor was rinsed with isopropyl acetate
(100 kg, 2.5 mL/g) and added to the Hastelloy reactor though the
inline filter.
[0116] The batch was adjusted to approximately 25-35.degree. C.
(preferably 30.degree. C.) and hydrogen gas was added to maintain
about 4 barg with vigorous agitation. Hydrogenation was continued
for 1 h after hydrogen uptake has ceased, and .gtoreq.99.0%
conversion by HPLC were achieved. The palladium on carbon catalyst
was collected by filtration and the supernatant was collected in a
reactor. Isopropyl acetate (40 kg, 1.0 mL/g) was charged to the
Hastelloy reactor and transferred through the filter and collected
in the jacketed glass-lined reactor.
[0117] The batch was concentrated under reduced pressure while
maintaining the batch temperature between 35-55.degree. C. until
the final volume was approximately 4.0 mL/g. Heptane (219 kg, 7.0
mL/g) was added to the jacketed glass-lined reactor while
maintaining the batch between 50-60.degree. C., until 20-25%
isopropyl acetate in heptane was achieved as measured by GC. The
solution was cooled to between 40-50.degree. C. and seeded with
methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate (0.46 kg,
1.0 wt %) as a slurry in heptane (6.4 kg, 0.20 mL/g). The slurry
was aged for approximately 2 h, whereupon, the batch was distilled
under reduced pressure while maintaining the batch temperature
between 35-45.degree. C. The batch volume was held constant
throughout the distillation by the continuous addition of heptane
(219 kg, 7.0 mL/g). The batch was then cooled to between
15-25.degree. C. over approximately 3 h. Concentration of the
supernatant was measured to be .ltoreq.5 mg/mL methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate by HPLC.
[0118] The batch was filtered and the resulting solids were
successively washed with heptane (63 kg, 2.0 mL/g) then heptane (94
kg, 3.0 mL/g). The solids were dried on the filter with a stream of
dry nitrogen with vacuum until an LOD of .ltoreq.1 wt % was
achieved whereupon 33.88 kg (90.7% yield) was isolated from the
filter dryer.
Omecamtiv Mecarbil Dihydrochloride Hydrate Procedure
##STR00007##
[0120] To a 15 L glass lined reactor were charged methyl
4-(3-amino-2-fluoro-benzyl)piperazine-1-carboxylate (1,202 g, 4.50
mol), phenyl (6-methylpyridin-3-yl)carbamate hydrochloride (1,444
g, 5.40 mol), and tetrahydrofuran (4.81 L). The resulting slurry
was agitated under a nitrogen sweep and N,N-diisopropylethylamine
(1,019 L, 5.85 mol) was then charged to the slurry which resulted
in a brown solution. The temperature of the solution was increased
to 65.degree. C. and agitated for 22 h, until <1% AUC piperazine
aniline remained by HPLC analysis.
[0121] The batch was cooled to 50.degree. C. and distilled under
reduced pressure while maintaining the internal temperature of the
vessel below 50.degree. C. by adjusting vacuum pressure. 2-Propanol
was added with residual vacuum at a rate to maintain a constant
volume in the 15 L reactor. A total of 10.5 kg of 2-propanol was
required to achieve <5% THF by GC. Water (2.77 kg) was then
charged to the reactor followed by the addition of 6N HCl (1.98 kg)
at a rate to maintain the internal temperature below 60.degree. C.
The reactor was brought to ambient pressure under a nitrogen sweep.
The solution was then heated to 60.degree. C., and transferred to a
60 L glass lined reactor through an inline filter. The 15 L reactor
was then rinsed with 1:1 water/2-propanol (1.2 L) which was sent
through the inline filter to the 60 L reactor.
[0122] The 60 L reactor was adjusted to 45.degree. C. and a slurry
of seed (114 g, 0.23 mol) in 2-propanol (0.35 L) was added to the
reactor resulting in a slurry. The batch was aged at 45.degree. C.
for 1 h, followed by the addition of 2-propanol (3.97 kg) through
an inline filter over 2 h. The batch was heated to 55.degree. C.
over 1 h and held for 0.25 h, then cooled back to 45.degree. C.
over 1 h and held overnight at 45.degree. C. 2-propanol (11.71 kg)
was then added through an inline filter to the batch over 3 h. The
batch was aged for 1 h and then cooled to 20.degree. C. over 2 h
and held at 20.degree. C. for 0.5 h. The batch was then
recirculated though a wet mill affixed with 1-medium and 2-fine
rotor-stators operating at 56 Hz for 2.15 h, until no further
particle size reduction was observed by microscopy.
[0123] The batch was then filtered through a 20'' Hastelloy.RTM.
filter fitted with a 12 um filter cloth under 500 torr vacuum. A
wash solution of 95:5 2-propanol:water (1.82 L) was charged through
an inline filter to the 60 L reactor, then onto the filter. A
second wash of 2-propanol (2.85 L) was charged through an inline
filter to the 60 L reactor, then onto the filter. The batch was
then dried under 5 psi humidified nitrogen pressure until <5,000
ppm 2-propanol, and 2.5-5% water remained. The final solid was
discharged from the filter to afford 2.09 kg of methyl
4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxy-
late as an off-white crystalline solid in 89% yield at 99.88 wt %
by HPLC, 100.0% AUC. Total losses to liquors was 0.10 kg
(4.7%).
[0124] DSC: T.sub.onset=61.7.degree. C., T.sub.max=95.0.degree. C.;
TGA=2.2%, degradation onset=222.degree. C.; .sup.1H HMR (D.sub.2O,
500 MHz) .delta. 8.87 (s, 1H), 8.18 (d, J=8.9 Hz, 1H), 7.83 (t,
J=7.5 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.35-7.29 (m, 2H), 4.48 (s,
2H), 4.24 (br s, 2H), 3.73 (s, 3H), 3.31 (br s, 6H), 2.68 (s, 3H);
.sup.13C HMR (D.sub.2O, 150 MHz) .delta. 156.8, 154.2, 153.9 (J=249
Hz), 147.8, 136.3, 136.1, 130.1, 129.4, 128.0, 127.2, 125.5 (J=11.8
Hz), 125.1 (J=4.2 Hz), 116.1 (J=13.5 Hz), 53.54, 53.52, 53.49,
50.9, 40.5, 18.2.
Alternative Process for the Coupling (Aniline Phenyl Carbamate)
##STR00008##
[0126] A reaction vessel was charged methyl
4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate (2.5 g, 1.0
equiv), acetonitrile (25.0 mL, 10.0 mL/g) and
1-methyl-2-pyrrolidinone (12.5 mL, 5.0 mL/g). The batch was cooled
to 0.degree. C. whereupon phenyl chloroformate (1.20 mL, 1.02
equiv) was added over approximately 5 min. After 45 minutes the
resulting slurry resulted was allowed to warm to 20.degree. C. The
solids were collected by filtration and rinsed twice with
acetonitrile (10.0 mL, 4.0 mL/g). The solids were dried under a
stream of dry nitrogen to afford methyl
4-(2-fluoro-3-((phenoxycarbonyl)amino)benzyl)piperazine-1-carboxylate
hydrochloride 2.8 g (71% yield) as a white solid.
[0127]
4-(2-fluoro-3-((phenoxycarbonyl)amino)benzyl)piperazine-1-carboxyla-
te hydrochloride: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
3.08 (br. s., 2H), 3.24-3.52 (m, 4H), 3.62 (s, 3H), 4.03 (d,
J=11.25 Hz, 2H), 4.38 (br. s., 2H), 7.11-7.35 (m, 4H), 7.35-7.49
(m, 2H), 7.49-7.66 (m, 1H), 7.80 (s, 1H), 10.12 (br. s, 1H), 11.79
(br. s, 1H); HRMS=388.1676 found, 388.1667 calculated.
[0128] A reaction vessel was charged methyl
4-(2-fluoro-3-((phenoxycarbonyl)amino)benzyl)piperazine-1-carboxylate
hydrochloride (0.50 g, 1.0 equiv), 6-methylpyridin-3-amine (0.15 g,
1.2 equiv), tetrahydrofuran (2.0 mL, 4.0 mL/g) and
N,N-diisopropylethylamine (0.23 mL, 1.1 equiv). The batch was
heated to 65.degree. C. for 22 h, whereupon quantitative HPLC
analysis indicated 0.438 g (92% assay yield) of omecamtiv
mecarbil.
Alternative Omecamtiv Mecarbil Dihydrochloride Hydrate
Procedure
[0129] Omecamtiv Mecarbil, free base (3.0 kg, 1.0 equiv) was
charged to a nitrogen purged jacketed vessel followed by water (4.6
L, 1.5 mL/g) and 2-propanol (6.1 L, 2.60 mL/g). The slurry was
agitated and heated to approximately 40.degree. C., whereupon 6N
HCl (2.6 L, 2.10 equiv) was charged to the slurry resulting in a
colorless homogenous solution. The solution was heated to between
60-65.degree. C. and transferred through an inline filter to a 60 L
reactor pre-heated to 60.degree. C. The batch was cooled to
45.degree. C. whereupon Omecamtiv Mecarbil dihydrochloride hydrate
(150 g, 5.0 wt %) was charged to the vessel as a slurry in 95:5
(v/v) 2-Propanol/Water (600 mL, 0.20 mL/g). The resulting slurry
was maintained at 45.degree. C. for 0.5 h followed by cooling to
approximately 20.degree. C. then held for 3-16 h. 2-Propanol (33.0
L, 11.0 mL/g) was added over .gtoreq.2 h followed by a .gtoreq.1 h
isothermal hold at approximately 20.degree. C. (Supernatant pH
.ltoreq.7).
[0130] The batch was recirculated through a wet mill for 5-10 batch
turnovers until sufficient particle reduction was achieve as
compared to offline calibrated visual microscopy reference. The
slurry was filtered by vacuum and the resulting solids were washed
with two washes of 95:5 (v/v) 2-Propanol/Water (3.0 L, 1.0 mL/g)
and a final cake wash with 2-Propanol (6.0 L, 2.0 mL/g). The cake
was dried on the filter by pushing humidified nitrogen through the
cake until .ltoreq.5,000 ppm 2-propanol and 2.5-5% water were
measured by GC and KF analysis, respectively. Omecamtiv Mecarbil
dihydrochloride hydrate was isolated as a colorless crystalline
solid (3.40 kg, 93% yield).
pH Dependent Release Profiles
[0131] A formulation of omecamtiv mecarbil hemihydrate (free base)
and dihydrochloride hydrate (Form A) were prepared having the
following components, all components reported as a w/w %:
Free Base(75 mg matrix tablet) Active granulation: 15.37% free
base; 30% hypromellose, HPMC K100 MPrem CR; 10% citric acid
monohydrate; 11.88% microcrystalline cellulose, Avicel PH 101;
6.75% lactose monohydrate, FastFlo 316; 12.5% purified water; and
Citric Acid granulation: 20% citric acid monohydrate; 5%
microcrystalline cellulose, Avicel PH 101; and 1% magnesium
stearate, non-bovine. Form A (75 mg matrix tablet)
Intra-granulation: 18.37% Form A; 30% hypromellose, HPMC K100 MPrem
CR; 0.50% magnesium stearate; and Extra-granulation: 16.88%
microcrystalline cellulose, Avicel PH 101; 18.37% citric acid
anhydrous; and 0.5% magnesium stearate, non-bovine.
[0132] The formulations were tested at pH 2 and pH 6.8 and the
amount of drug released over time was measured. The results of this
drug release profile are shown in FIG. 6.
[0133] The foregoing is merely illustrative of the invention and is
not intended to limit the invention to the disclosed salts or
polymorphs. Variations and changes which are obvious to one skilled
in the art are intended to be within the scope and nature of the
invention which are defined in the appended claims.
* * * * *