U.S. patent application number 14/507114 was filed with the patent office on 2015-05-21 for process for the preparation of adapalene and related compounds.
The applicant listed for this patent is MEDICHEM, S.A.. Invention is credited to Jordi PUIG SERRANO.
Application Number | 20150141696 14/507114 |
Document ID | / |
Family ID | 38189034 |
Filed Date | 2015-05-21 |
United States Patent
Application |
20150141696 |
Kind Code |
A1 |
PUIG SERRANO; Jordi |
May 21, 2015 |
PROCESS FOR THE PREPARATION OF ADAPALENE AND RELATED COMPOUNDS
Abstract
The invention provides an improved process for the preparation
of a benzonaphthalene derivative including, in particular, the
manufacture of high purity adapalene. The invention further
includes a method for assessing the color of adapalene by means of
a quantitative colorimetric measurement of the produced
adapalene.
Inventors: |
PUIG SERRANO; Jordi; (Canet
d'adri, ES) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MEDICHEM, S.A. |
Barcelona |
|
ES |
|
|
Family ID: |
38189034 |
Appl. No.: |
14/507114 |
Filed: |
October 6, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13359793 |
Jan 27, 2012 |
8871972 |
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14507114 |
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11922353 |
May 1, 2008 |
8119834 |
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PCT/IB2006/003987 |
Jun 16, 2006 |
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13359793 |
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60691259 |
Jun 17, 2005 |
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Current U.S.
Class: |
562/467 |
Current CPC
Class: |
C07C 51/09 20130101;
C07C 65/26 20130101; C07C 67/343 20130101; C07C 51/02 20130101;
C07C 51/43 20130101; C07C 51/47 20130101; C07C 51/09 20130101; C07C
51/412 20130101; C07C 51/47 20130101; C07C 51/50 20130101; C07C
51/02 20130101; C07C 67/343 20130101; C07C 51/412 20130101; C07C
65/26 20130101; C07C 2603/74 20170501; C07C 65/26 20130101; C07C
65/26 20130101; C07C 65/26 20130101; C07C 69/94 20130101 |
Class at
Publication: |
562/467 |
International
Class: |
C07C 65/26 20060101
C07C065/26; C07C 51/50 20060101 C07C051/50; C07C 51/43 20060101
C07C051/43 |
Claims
1.-27. (canceled)
28. Adapalene, or a salt thereof, suitable for pharmaceutical use,
obtained according to a process comprising the steps of: (a)
providing adapalene, or a salt thereof; (b) assessing the purity of
said adapalene, or a salt thereof, by using
3,3'-diadamantyl-4,4'-dimethoxybiphenyl as a reference marker to
determine the level of 3,3'-diadamantyl-4,4'-dimethoxybiphenyl
impurity; and (c) subjecting the adapalene, or a salt thereof, to
one or more purification steps until the content of
3,3'-diadamantyl-4,4'-dimethoxybiphenyl in said adapalene is not
more than 0.2% with respect to adapalene.
29. Adapalene, or a salt thereof, suitable for pharmaceutical use,
obtained according to a process as defined in claim 28, wherein
step (c) is carried out until the amount of
3,3'-diadamantyl-4,4'-dimethoxybiphenyl is not more than 0.1% with
respect to adapalene.
30. Adapalene, or a salt thereof, suitable for pharmaceutical use,
obtained according to a process as defined in claim 28, wherein
step (c) is carried out until the
3,3'-diadamantyl-4,4'-dimethoxybiphenyl is not detected.
31. Adapalene, or a salt thereof, suitable for pharmaceutical use,
obtained according to a process as defined in claim 28, wherein
step (c) is carried out until the adapalene is more than 99.8%
pure.
32. Adapalene, or a salt thereof, suitable for pharmaceutical use,
obtained according to a process as defined in claim 28, wherein
step (c) is carried out until the adapalene is more than 99.9%
pure.
33. Adapalene, or a salt thereof, suitable for pharmaceutical use,
obtained according to a process as defined in claim 28, wherein the
purification step of step (c) comprises at least one of the steps
of (i) suspending or recrystallizing solid adapalene, or salt
thereof, in an organic solvent; and (ii) dissolving the
3,3'-diadamantyl-4,4'-dimethoxybiphenyl impurity in an aromatic
apolar solvent.
34. Adapalene, or a salt thereof, suitable for pharmaceutical use,
obtained according to a process as defined in claim 33, wherein the
aromatic apolar solvent is toluene.
35. Adapalene, or a salt thereof, suitable for pharmaceutical use,
obtained according to a process as defined in claim 33, wherein the
organic solvent is at least one of an aromatic hydrocarbon solvent,
a ketone solvent, an ether solvent, an alcohol solvent, an ester
solvent, water, and mixtures thereof.
36. Adapalene, or a salt thereof, suitable for pharmaceutical use,
obtained according to a process as defined in claim 28, wherein the
adapalene salt is the sodium salt, potassium salt, lithium salt, or
cesium salt.
37. Adapalene, or a salt thereof, suitable for pharmaceutical use,
obtained according to a process as defined in claim 28, wherein the
use of 3,3'-diadamantyl-4,4'-dimethoxybiphenyl as a reference
marker comprises providing a standard solution of
3,3'-diadamantyl-4,4'-dimethoxybiphenyl and using the solution as a
reference marker to determine the level of
3,3'-diadamantyl-4,4'-dimethoxybiphenyl impurity.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention provides an improved process for the
preparation of a benzonaphthalene derivative. More particularly,
the invention provides an improved process for the manufacture of
high purity adapalene. The invention further includes a method for
assessing the color of adapalene by means of a quantitative
colorimetric measurement of the solid adapalene.
[0003] 2. Relevant Background
[0004] The chemical name for adapalene is
6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, which is
represented by Compound I (below):
##STR00001##
[0005] Adapalene has been approved by the FDA as a cream, a gel, a
solution and pledgets for the topical treatment of acne vulgaris
and is marketed under the tradename of DIFFERIN.RTM..
[0006] U.S. Pat. No. 4,717,720 ("the '720 patent") discloses
benzonaphthalene derivatives, including adapalene. The '720 patent
describes a process for preparing adapalene (i.e., according to
example 9c followed by example 10) that involves two reaction
steps.
[0007] The first step for preparing adapalene according to the '720
patent involves the preparation of the methyl ester of
6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid. According to
example 9c of the '720 patent, 2-(1-adamantyl)-4-bromoanisole (also
known as 1-(5-bromo-2-methoxyphenyl)adamantane) is converted to its
organomagnesium derivative and then into its organozinc derivative.
The organozinc derivative is next coupled to methyl
6-bromo-2-naphthoate by adding a catalytic amount of
NiCl.sub.2/DPPE complex (also known as [bis(diphenylphosphino)
ethane]dichloronickel(II)). Upon completion of the reaction, the
mixture is poured into water, extracted with dichloromethane, and
then dried. The product is next isolated by column chromatography
by eluting with a mixture of heptane (70%) and dichloromethane
(30%). The resulting product is then recrystallized in ethyl
acetate (yield: 78%).
[0008] The second step for preparing adapalene according to the
'720 patent involves hydrolyzing the product of step 1 (above).
According to example 10 of the '720 patent, the ester obtained in
Example 9c can be treated with a solution of soda in methanol
followed by heating at reflux for 48 hours. The solvents are then
evaporated and the resulting residue is taken up in water and
acidified with concentrated HCl to neutralize the resulting
adapalene sodium salt. The resulting solid is next filtered and
dried under vacuum over phosphoric anhydride and then
recrystallized in a mixture of tetrahydrofuran and ethyl acetate to
yield adapalene (yield: 81%).
[0009] The process of preparing adapalene according to the '720
patent is both difficult and uneconomical to conduct on an
industrial scale. Regarding step 1, the use of dichloromethane is
both toxic and hazardous for the environment. Additionally,
purification of the intermediate product by column chromatography,
followed by recrystallization, in order to obtain a crystalline
product of acceptable purity is both expensive and laborious.
Moreover, the step 1 process produces as a biaryllic C--C bond, and
the catalytic coupling is noticeably exothermic. Regarding step 2,
the synthesis of adapalene and/or its sodium salt requires a long
reaction time (i.e., 48 hours) at methanol reflux and further
requires a high ratio of solvent (volume) to product (mass).
[0010] Additionally, according to the prior art, the manufacture of
adapalene is not satisfactory for industrial implementation because
the presence of high amounts of undesired by-products makes it
necessary to use uneconomical purification procedures to isolate
the product according to quality specifications. One significant
undesired by-product produced during the Grignard reaction of step
1 in the synthesis of adapalene is
3,3'-diadamantyl-4,4'-dimethoxybiphenyl, which has not been
previously described in the literature and which is represented by
Compound VI (below):
##STR00002##
[0011] The level of the by-product in a sample of adapalene,
adapalene methyl ester and/or an adapalene salt can be determined
using standard analytical techniques known to those of ordinary
skill in the art. For example, the level can be determined by HPLC.
A specific method for determining the level of this impurity is
provided herein.
[0012] Since the solubility of the dimeric by-product is very low
in most solvents, the design of an economical industrial process
that yields pure adapalene without the use of expensive
chromatographic methods requires the selection of the proper
solvents and conditions to inhibit formation of the by-product
during the manufacturing process.
[0013] Additionally, adapalene has been described as being white
(see, e.g, Merck Index, 13.sup.th ed., p. 29). It has been observed
that adapalene has a tendency to yellow under certain synthetic
conditions or due to the quality of the starting materials used in
its preparation. In this regard, color must be attributed to the
presence of some specific impurities that may or may not be
detectable by conventional methods such as HPLC.
SUMMARY OF THE INVENTION
[0014] The invention provides an improved process for the
preparation of a benzonaphthalene derivative. More particularly,
the invention provides an improved process for the manufacture of
high purity adapalene. The invention further includes a method for
assessing the color of adapalene by means of a quantitative
colorimetric measurement of the solid adapalene.
[0015] Another aspect of the invention includes a method for
assessing the purity of adapalene by means of a quantitative
colorimetric measurement of the solid adapalene. This method
consists in using a colorimeter or spectrophotometer apparatus to
measure the L*, a* and b* coordinates of the solid sample of
adapalene. Thus, the color of the solid sample is located in the
CIE 1976 L*, a*, b* Color Space (CIELAB; CIE stands for Commission
Internationale de 1'Eclairage or International Commission on
Illumination). The three parameters in the model represent the
lightness of the color (i.e., L*, an L*=0 indicates black and an
L*=100 indicates white), its position between magenta and green
(i.e., a*, negative values indicate green while positive values
indicate magenta) and its position between yellow and blue (i.e.,
b*, negative values indicate blue and positive values indicate
yellow).
[0016] Thus, the process of preparing adapalene according to the
invention provides adapalene that is white by visual inspection and
this fact is corroborated by the colorimetric measurements that
yield values in the CIELAB color space that are very close to the
values of absolute white that are L*=100; a*=0; b*=0. See, e.g., US
Pharmacopoeia 29.sup.th ed., General Chapter 1061, p. 2896.
BRIEF DESCRIPTION OF THE DRAWING
[0017] The accompanying drawings, which are included to provide a
further understanding of the invention and are incorporated in and
constitute a part of this specification, illustrate embodiments of
the invention and together with the description serve to explain
the principles of the invention. In the drawings:
[0018] FIG. 1 illustrates the X-ray diffractogram of adapalene made
in by the process of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0019] Reference will now be made in detail to the preferred
embodiments of the invention. This invention may, however, be
embodied in many different forms and should not be construed as
limited to the embodiments set forth herein. In addition and as
will be appreciated by one of skill in the art, the invention may
be embodied as a method, system or process.
[0020] The invention provides an improved process for preparing
adapalene. In particular, the invention provides an improved
process for preparing adapalene that includes isolating adapalene
potassium salt. As illustrated in Scheme 1 (below), the process of
the invention includes three reaction steps.
[0021] The first step ("step 1") of the process of the invention
involves the preparation of the adapalene methyl ester as described
in detail below in Example/Step 1. According to the process of the
invention, step 1 includes charging the catalyst (NiCl.sub.2/DPPE
complex) prior to the addition of methyl 6-bromo-2-naphthoate.
Doing so provides better control of the reaction and thus helps
minimize the generation of heat. In particular, addition of the
methyl 6-bromo-2-naphthoate over a suspension of the organozinc
derivative and the catalyst minimizes the exothermic reaction and
associated risks at the industrial scale.
[0022] Additionally, step 1 of the process of the invention is
considerably less laborious that known procedures. In particular,
the product is isolated by filtration as a solid from the reaction
mixture, thus avoiding the use of dichloromethane (which also
results in extraction of impurities). Once isolated, the solid
product can be purified by suspending/recrystallizing it in an
organic solvent (e.g., an aromatic hydrocarbon solvent, a ketone
solvent, an ether solvent, an alcohol solvent, an ester solvent,
water and/or mixtures thereof) therefore avoiding the need to
purify the product by column chromatography. Preferable solvents
include methyl ethyl ketone and/or mixtures of tetrahydrofuran and
water.
[0023] The second step ("step 2") of the process of the invention
involves the hydrolysis of the adapalene methyl ester to yield
adapalene potassium salt. According to the process of the
invention, step 2 includes performing the hydrolysis in the
presence of a phase transfer catalyst in an aromatic apolar solvent
(e.g., toluene). Performing the hydrolysis under these conditions
reduces the reaction time from 48 hours to approximately 2 to 3
hours. Additionally, the adapalene potassium salt prepared in step
2 can be recovered from the reaction mixture by filtration.
Importantly, the homocoupling product (i.e.,
3,3'-diadamantyl-4,4'-dimethoxy biphenyl, Compound VI) is more
soluble in aromatic apolar solvents (e.g., toluene) than the
corresponding potassium salt. Thus, elimination of most, if not
all, of the by-product is achieved via filtration. The adapalene
potassium salt can optionally be purified by
suspending/recrystallizing it in an organic solvent (e.g., an
aromatic solvent, an ether solvent, a mixture of an alcohol and
water and/or mixtures thereof).
[0024] It is believed that step 2 of the process of the invention
can be performed using other adapalene salts other than the
potassium salt. Such additional adapalene salts include, for
example, the sodium salt, the lithium salt, the cesium salt and/or
other salts arising from other bases that could alternatively be
used for hydrolyzing the adapalene methyl ester.
[0025] The third step ("step 3") of the process of the invention
involves the neutralization of the adapalene potassium salt to
yield adapalene. According to the process of the invention, step 3
includes performing the neutralization in an alcoholic solvent,
which facilitates the neutralization and avoids solid-solid
occlusions. Additionally, the neutralization is performed at a
temperature not exceeding than 40.degree. C. in order to prevent
the unwanted esterification of the adapalene product.
[0026] In step 3 of the process of the invention, insolubles can
optionally be removed by filtration and decolorizing agents can
optionally be employed to improve the color of the crude adapalene.
Such steps can be performed in, for example, tetrahydrofuran and/or
mixtures of tetrahydrofuran and water. Suitable decolorizing agents
can be any conventional decolorizing agent, including, for example,
alumina, activated alumina, silica, a metabisulphite salt and
charcoal. The preferred decolorizing agent is a sulfur based
reducing agent including, for example, metabisulphite or dithionite
salts. Partial distillation of the tetrahydrofuran and, optionally,
addition of a protic solvent (e.g., methanol or water) yields the
desired crystalline product.
[0027] Scheme 1 illustrates the preparation of adapalene prepared
according to one aspect of the invention.
##STR00003##
Scheme 1 Legend:
TABLE-US-00001 [0028] Compound Name I Adapalene II
1-(5-Bromo-2-Methoxyphenyl)Adamantane III 6-Bromo-2-Naphthoate IV
Methyl 6-[3-(1-adamantyl)-4-Methoxyphenyl]-2-Naphthoate V
6-[3-(1-Adamantyl)-4-Methoxyphenyl]-2-Naphthoic Acid Potassium
Salt
[0029] One aspect of the invention includes a process for preparing
adapalene from a corresponding salt.
[0030] Another aspect of the invention includes a process for
preparing adapalene methyl ester.
[0031] Another aspect of the invention includes adapalene salts and
a process for preparing them.
[0032] Another aspect of the invention includes
purifying/crystallizing adapalene salts.
[0033] Another aspect of the invention includes a process for
preparing adapalene from its corresponding potassium salt.
[0034] Another aspect of the invention includes the
3,3'-diadamantyl-4,4'-dimethoxybiphenyl by-product (Compound VI,
above) and its use as a reference marker for the assessment of the
quality of adapalene and/or pharmaceutical compositions containing
adapalene.
[0035] Another aspect of the invention includes the use of
3,3'-diadamantyl-4,4'-dimethoxybiphenyl by-product (Compound VI,
above) as a reference marker for evaluating the quality of an
adapalene methyl ester intermediate.
[0036] Another aspect of the invention includes the use of
3,3'-diadamantyl-4,4'-dimethoxybiphenyl by-product (Compound VI,
above) as a reference marker for measuring the quality of an
adapalene salt intermediate.
[0037] Another aspect of the invention includes charging the
NiCl.sub.2/DPPE complex before the addition of methyl
6-bromo-2-naphthoate in the catalytic coupling step.
[0038] Another aspect of the invention includes washing adapalene
methyl ester with a solvent that includes an aromatic hydrocarbon
solvent, a ketone solvent, an ether solvent, an alcohol solvent, an
ester solvent, water and/or mixtures thereof, thus avoiding the
need to purify the product by column chromatography. Preferable
solvents include methyl ethyl ketone and/or mixtures of
tetrahydrofuran and water.
[0039] Another aspect of the invention includes using a phase
transfer catalyst and a base to hydrolyze adapalene methyl
ester.
[0040] Another aspect of the invention includes using a phase
transfer catalyst and an inorganic base to hydrolyze adapalene
methyl ester.
[0041] Another aspect of the invention includes using a phase
transfer catalyst and an inorganic base, preferably an alkali
hydroxide, to hydrolyze adapalene methyl ester.
[0042] Another aspect of the invention includes using a phase
transfer catalyst and an inorganic base, preferably an alkali
hydroxide, and most preferably potassium hydroxide, to hydrolyze
adapalene methyl ester.
[0043] Another aspect of the invention includes using a phase
transfer catalyst to hydrolyze adapalene methyl ester, where the
phase transfer catalyst is a quaternary ammonium salt.
[0044] Another aspect of the invention includes using a phase
transfer catalyst to hydrolyze adapalene methyl ester, where the
phase transfer catalyst is a quaternary ammonium salt, preferably a
tetraalkylammonium halide and, most preferably, tetrabutylammonium
bromide.
[0045] Another aspect of the invention includes using an apolar
solvent, preferably an aromatic apolar solvent, and most preferably
toluene to hydrolyze adapalene methyl ester.
[0046] Another aspect of the invention includes using a reaction
time of less than approximately 3 hours to hydrolyze adapalene
methyl ester.
[0047] Another aspect of the invention includes washing an
adapalene salt with a solvent, including, for example, an aromatic
hydrocarbon, esters, ethers, ketones, alcohols and water or a
mixture thereof, and, preferably, mixtures of tetrahydrofuran and
toluene and/or mixtures of methanol and water.
[0048] Another aspect of the invention includes using adapalene
methyl ester that contains variable amounts of dimeric compound of
Compound VI when hydrolyzing adapalene methyl ester.
[0049] Another aspect of the invention includes purifying adapalene
by decolorizing and/or filtering a dissolution of adapalene.
[0050] Another aspect of the invention includes using methanol when
neutralizing an adapalene salt.
[0051] Another aspect of the invention includes removing by
filtration any insoluble particles of a solution of adapalene in
tetrahydrofuran.
[0052] Another aspect of the invention includes decolorizing
adapalene in tetrahydrofuran and, preferably, using a decolorizing
agent that is a salt of metabisulphite and, more preferably, sodium
metabisulphite.
[0053] Another aspect of the invention includes a partial
distillation of tetrahydrofuran and filtration of the precipitated
adapalene.
[0054] Another aspect of the invention includes a partial
distillation of tetrahydrofuran and precipitation of adapalene that
includes adding a protic solvent, preferably methanol or water.
[0055] Another aspect of the invention includes a process for
preparing adapalene of high purity.
[0056] Another aspect of the invention includes a process for
preparing adapalene of high purity and, preferably, where the
adapalene is more than 99.8% pure when analyzed according to
reverse phase high performance liquid chromatography and, more
preferably, more than 99.9% pure when analyzed by reverse phase
high performance liquid chromatography.
[0057] Another aspect of the invention includes a process for
preparing adapalene of high purity where the adapalene is 100.0%
pure when analyzed according to reverse phase high performance
liquid chromatography.
[0058] Another aspect of the invention includes a process for
preparing adapalene having a residue on ignition of less than 0.1%
and, more preferably, less than 0.05%.
[0059] Another aspect of the invention includes using adapalene of
high purity in the manufacture of pharmaceutical compositions.
[0060] Another aspect of the invention includes adapalene that is
substantially white by visual inspection.
[0061] Another aspect of the invention includes substantially white
adapalene having the following measurements in the CIE (1976) L*,
a*, b* Color Space (CIELAB) when using a colorimeter or
spectrophotometer, illuminant D65 (daylight) and a 2.degree. angle
of observation:
TABLE-US-00002 L* 98.5 to 100 a* -0.38 to -0.60 b* +0.31 to
+0.93
[0062] Another aspect of the invention includes substantially white
adapalene having the following measurements in the CIE (1976) L*,
a*, b* Color Space (CIELAB) when using a colorimeter or
spectrophotometer, illuminant C and a 2.degree. angle of
observation:
TABLE-US-00003 L* 97.30 to 98.47 a* +0.20 to +0.45 b* 0.00 to
-0.75
[0063] Another aspect of the invention includes a method for
assessing the purity of adapalene by means of a quantitative
colorimetric measurement of the solid adapalene. In this method,
the L*, a* and b* coordinates of a solid sample of adapalene are
measured using a colorimeter or spectrophotometer apparatus.
[0064] It will be apparent to those skilled in the art that various
modifications and variations can be made in the present invention
and specific examples provided herein without departing from the
spirit or scope of the invention. Thus, it is intended that the
present invention covers the modifications and variations of this
invention that come within the scope of any claims and their
equivalents.
Specific Examples
[0065] The following examples are for illustrative purposes only
and are not intended, nor should they be interpreted to, limit the
scope of the invention.
Example/Step 1
Preparation of Methyl 6-[3-(1-adamantyl)-4-methoxy
phenyl]-2-naphthoate (i.e., Adapalene Methyl Ester)
[0066] To a 2 L, five-necked cylindrical reaction vessel equipped
with a reflux condenser, heat-transfer jacket, compensated-pressure
addition funnel, anchor impeller and purged with nitrogen, were
added 1.13 g of 1-(5-bromo-2-methoxyphenyl) adamantane
(3.52.times.10.sup.-3 mol), 3.75 g of magnesium granules
(1.54.times.10.sup.-1 mol) and 90 mL of tetrahydrofuran. Into the
compensated-pressure addition funnel was added a previously
prepared solution of 36.37 g of
1-(5-bromo-2-methoxyphenyl)adamantane (1.13.times.10.sup.-1 mol)
and 270 mL of tetrahydrofuran. The reaction mixture was then heated
to approximately 45.degree. C., at which point 2.50 g of
1,2-dibromoethane (1.33.times.10.sup.-2 mol) was charged to the
mixture. During the addition, the internal temperature increased
and bubbling was observed, indicating initiation of the
reaction.
[0067] At approximately 50.degree. C., addition of the solution in
the compensated-pressure addition funnel was initiated and
continued over approximately 45 minutes during which time the
internal temperature of the solution was maintained between
approximately 50 and 55.degree. C. Following the addition, the
reaction mixture was stirred for approximately 45 minutes at
approximately 50.degree. C. and then cooled to approximately
20-25.degree. C. To the cooled suspension was added 18.18 g of
anhydrous zinc chloride (1.33.times.10.sup.-1 mol) and an increase
in temperature was observed within a few seconds. The mixture was
permitted to cool and was stirred for approximately 1 hour at
approximately 20-25.degree. C. Thereafter, 1.05 g of
1,2-[bis(diphenylphosphino)ethane]dichloronickel(II)
(2.20.times.10.sup.-3 mol) was charged to the reaction mixture
followed by the addition of 24.00 g of methyl 6-bromo-2-naphthoate
(9.05.times.10.sup.-2 mol). The mixture was permitted cool and was
stirred for approximately two hours at room temperature.
[0068] Next, 50 mL of water was slowly added and the mixture was
stirred for approximately minutes, at which point 200 mL of 1N HCl
was slowly added. The mixture was then stirred overnight at room
temperature or until the excess of magnesium pellets were
dissolved. The mixture was then filtered, and the cake was washed
with methyl ethyl ketone ("MEK"). The resulting solid was next
suspended in 500 mL of 1N HCl and 125 mL of MEK. The resulting
suspension was then stirred at room temperature for approximately 1
hour. The mixture was then filtered, and the cake was washed with
MEK. The resulting solid was next suspended in 270 mL of MEK and
the mixture was heated to reflux for approximately 30 minutes,
cooled and filtered. The resulting cake was then washed with
MEK.
[0069] The wet solid obtained was suspended in 184 mL of
tetrahydrofuran and was heated to approximately 50-60.degree. C.
for approximately 30 minutes, cooled and precipitated by addition
of 300 mL of methanol. The precipitate was then filtered and dried
at approximately 60.degree. C. in a vacuum oven to yield 34.31 g of
adapalene methyl ester (8.044.times.10.sup.-2 mol; yield: 88.83%)
as an off-white powder. Analytical data: HPLC Purity (HPLC at 272
nm): 97.32%; Impurity (i.e.,
3,3'-diadamantyl-4,4'-dimethoxybiphenyl) area percent (HPLC at 272
nm): 2.05%.
[0070] The product may also contain a small amount of an
unidentified impurity, which is more polar than the final product.
This unidentified impurity, when observed, as well as the
3,3'-diadamantyl-4,4'-dimethoxybiphenyl impurity, are eliminated
from the synthetic pathway during the work-up described in the
Example/Step 2 (below).
Example/Step 2
Preparation of 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic
acid-potassium salt (i.e., Adapalene Potassium Salt)
[0071] In a 2 L, five necked cylindrical reaction vessel equipped
with reflux condenser, distillation kit, heat-transfer jacket,
anchor impeller and purged with nitrogen, were added 48.38 g (dry
equivalent amount) of methyl
6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate
(1.134.times.10.sup.-1 mol), wet with methanol, 2.73 g of
tetrabutylammonium bromide (8.47.times.10.sup.-3 mol), 18.39 g of
potassium hydroxide (85% alkali content, freshly titrated.
2.79.times.10.sup.-1 mol) and 581 mL of toluene. The mixture was
heated to reflux temperature, and the methanol/water was removed by
distillation. The distilled mixture was replaced by pure toluene
and the mixture was stirred at reflux for approximately three hours
(including the time required for the distillation). The solution
was then cooled to approximately 20-25.degree. C., filtered and the
resulting solid was washed with toluene.
[0072] The solid was next suspended in 187 mL of tetrahydrofuran
and stirred for approximately 30 minutes. Then, 375 mL of toluene
was added, and the mixture was heated to reflux and maintained at
that temperature for approximately 1 hour. The solution was then
cooled to approximately 20-25.degree. C., filtered, and the
resulting solid washed with toluene. The toluene-wet product was
then suspended in 256 mL of methanol, heated to reflux for
approximately 30 minutes and cooled to 50-60.degree. C. After
cooling, 409 mL of water was added dropwise. The mixture was then
again heated to reflux for approximately 15 additional minutes,
cooled to room temperature and filtered. The resulting solid was
washed with water to yield 50.69 g (wet) of adapalene potassium
salt (1.12.times.10.sup.-1 mol, dry equivalent amount calculated
from loss on drying; yield: 99.18%). Analytical data: HPLC Purity
(HPLC at 272 nm): 99.86%; Impurity (i.e.,
3,3'-diadamantyl-4,4'-dimethoxybiphenyl) area percent (HPLC at 272
nm): not detected; .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 1.83
(broad s, 6H), 2.08 (broad s, 3H), 2.21 (broad s, 6H), 3.88 (s,
3H), 7.04 (d, 1H, J=8.4 Hz), 7.56 (overlapped, 1H, J=2.4, 9.6 Hz),
7.57 (overlapped s, 1H), 7.74 (dd, 1H, J=8.7, 1.8 Hz), 7.87 (d, 1H,
J=9.0 Hz), 7.97 (d, 1H, J=8.7 Hz), 8.00 (broad d, 1H, J=0.9 Hz),
8.06 (dd, 1H, 8.4, J=1.8 Hz), 8.47 (broad d, 1H, J=0.9 Hz);
.sup.13C-NMR (75.4 MHz, CD.sub.3OD): .delta. 30.6, 38.3, 41.8,
55.5, 113.3, 125.3, 126.4, 126.6, 127.8, 128.3, 130.0, 130.4,
133.0, 134.2, 136.1, 136.3, 139.7, 141.1, 159.9, 175.4.
Example/Step 3
Preparation of 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic
acid (i.e., Adapalene)
[0073] In 500 mL of methanol was added 49.59 g
(1.10.times.10.sup.-1 mol, dry equivalent amount) of the wet solid
obtained in Example/Step 2, and the mixture was heated to reflux
for 30 minutes and cooled to approximately 40.degree. C. Next,
33.17 g of concentrated HCl was slowly added over approximately 1
hour with gentle stirring in order to ensure homogeneity, followed
by the slow addition of 248 mL of water. The resulting mixture was
stirred for approximately 30 additional minutes at approximately
40.degree. C. and then cooled to room temperature, filtered and
washed with methanol. The wet solid was then suspended with 1020 mL
of tetrahydrofuran and heated to reflux for approximately 10
minutes or until complete dissolution. The solution was then cooled
to approximately 35.degree. C., the solid particles were removed by
filtration, and the filter was washed with tetrahydrofuran.
[0074] The collected mother liquors were heated to reflux, and 654
g of tetrahydrofuran was removed by distillation. The mixture was
then cooled to approximately 55-60.degree. C. Thereafter, 650 mL of
methanol was added over approximately 10 minutes, and the mixture
heated to reflux for approximately 30 minutes, cooled, and
filtered. The resulting solid was filtered with methanol and dried
at 80.degree. C. in a vacuum oven to yield 40.54 g of adapalene
(9.83.times.10.sup.-2 mol; yield: 89.29% (from adapalene potassium
salt); 88.56% (from adapalene methyl ester); and 78.67% (from
methyl 6-bromo-2-naphthoate)). Analytical data: HPLC Purity (HPLC
at 272 nm): 100.00%; Assay: 99.99%; Residue on Ignition: 0.02%; IR:
matches reference.
[0075] Table 1 (below) lists the peak assignments of the X-ray
powder diffractogram of the adapalene obtained and are illustrated
in FIG. 1.
TABLE-US-00004 TABLE 1 peak peak_position peak_intensity background
1 9.94547 175.32198 42.94638 2 13.18338 239.32156 48.88440 3
14.87487 234.32591 47.91444 4 15.28319 573.40082 53.73505 5
16.37472 1207.21631 69.64595 6 16.54000 882.00000 68.42529 7
17.39657 110.88804 58.39248 8 17.93203 114.02068 55.36037 9
19.44575 285.34473 113.52401 10 19.94692 569.60516 153.63921 11
22.43198 2846.14307 110.81189 12 24.02238 140.20882 85.37505 13
25.04586 925.64282 121.97974 14 25.41035 240.42351 102.81077 15
26.68556 362.45480 68.05973 16 27.71646 141.77916 72.53469 17
40.51307 133.00453 43.44914 18 46.52728 130.31587 50.16773
Example/Step 4
Preparation of 3,3'-diadamantyl-4,4'-dimethoxybiphenyl
[0076] To a 100 mL rounded bottom reaction vessel equipped with a
magnetic stirrer, thermometer, reflux condenser, pressure
compensated addition funnel, were added 0.15 g of
1-(5-bromo-2-methoxyphenyl)adamantane, 0.47 g of magnesium turnings
and 7 mL of tetrahydrofuran. The mixture was heated to
approximately 35.degree. C., and 0.13 mL of 1,2-dibromoethane were
added to the mixture. Reaction exothermy self-heated the mixture.
Next, a solution of 4.85 g of 1-(5-bromo-2-methoxyphenyl)adamantane
and 28 mL of tetrahydrofuran was added to the mixture dropwise.
During this addition, the temperature of the mixture dropped from
reflux temperature to approximately 45.degree. C. The reaction was
then stirred for approximately 45 additional minutes at
approximately 45.degree. C. and was permitted to cool to
approximately 22.degree. C. Next, 2.3 g of ZnCl.sub.2 was added to
the mixture, resulting in an exothermic reaction that raised the
temperature of the mixture to approximately 38.degree. C. The
mixture was then permitted to cool to approximately 22.degree. C.
and was stirred for approximately 1 hour at this temperature.
[0077] Next, 0.03 g of Pd(OAc).sub.2 and 3.5 g of
1-(5-bromo-2-methoxyphenyl) adamantane were added to the mixture,
followed by 25 mL of tetrahydrofuran in order to improve agitation,
and the mixture was heated at reflux for approximately 24 hours.
The resulting mixture was then evaporated to dryness and poured
into 103 mL of 0.015 N HCl. Next, 150 mL of dichloromethane and 100
mL of water were added to yield a mixture consisting of a solid, an
aqueous layer and an organic layer. The mixture was then filtered
to separate the solid, the aqueous layer was discarded, and the
organic layer was washed with 200 mL of water and decanted again.
This process was repeated twice on the filtered solid. The three
collected organic layers were evaporated to dryness, washed in
methanol, and dried to yield 2.1 g of
3,3'-diadamantyl-4,4'-dimethoxybiphenyl (yield: 39.9%). Analytical
data: Melting point: 288.1-289.1.degree. C.; Elemental analysis: C
83.63%, H 8.73%; .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 1.78
(broad s, 12H), 2.08 (broad s, 6H), 2.15 (broad s, 12H), 3.86 (s,
6H), 6.92 (dm, 2H, J=8.1 Hz), 7.34 (dd, 2H, J=2.4, 8.1 Hz), 7.39
(d, 2H, J=2.4 Hz); .sup.13C-NMR (75.4 MHz, CDCl.sub.3): .delta.
29.2, 37.1, 37.2, 40.6, 55.1, 111.9, 125.0, 125.5, 134.0, 138.5,
157.8; MS (EI, 70 eV): m/z=484 (6), 483 (36), 412 (M.sup.+, 100),
410 (5), 347 (8), 135 (22), 107 (7), 93 (14), 79 (17), 67 (9), 55
(6); IR (Selected absorption bands): 2992, 2964, 2898, 2850, 1603
cm.sup.-1.
Example 5
Colorimetric Measurement
[0078] Adapalene was prepared according to the procedure described
above, with the exception that the crude product was stirred twice
in a mixture of THF/methanol at 20.degree. C. instead of being
refluxed in methanol (as indicated above). This change, however, is
not relevant to the final product color. The results of the
colorimetric measurement (according to the CIE 1976 L*, a*, b*
color space) are illustrated in Tables 2 and 3.
TABLE-US-00005 TABLE 2 L* a* 13* Value 99.11 -0.52 0.86 Standard
Deviation 0.10 0.02 0.06 Number of Replicates: 7 Illuminant:
D.sub.65 Measurement geometry: 2.degree. White Index (WI E313):
93.85
[0079] The whiteness of the adapalene sample was then obtained by
depositing, leveling and measuring the sample without any special
compacting treatment. The results of the whiteness measurement are
illustrated in Table 3. It should be noted that the lab coordinates
are necessarily different for the same sample since the illuminant
used is different.
TABLE-US-00006 TABLE 3 L* a* b* Value 97.97 0.24 -0.02 Standard
Deviation 0.07 0.03 0.01 Number of Replicates: 3 Illuminant: C
Measurement geometry: 2.degree. White Index (WI E313): 94.35
[0080] The White Index (WI) was calculated according to ASTM
E313-05 "Standard Practice for Calculating Yellowness and Whiteness
Indices from Instrumentally Measured Color Coordinates" using the
following formula:
WI=Y+(WI,x)(x.sub.n-x)+(WI,y)(y.sub.n-y)
Where: x.sub.n and y.sub.n are the chromaticity coordinates for the
CIE Standard illuminant and source used, WI,x and WI,y are
numerical coefficients, and Y, x, and y are the luminance factor
and the chromaticity coordinates of the specimen (which can be
derived from the L, a, b coordinates for a given illuminant and
measurement geometry).
[0081] Values for all these variable (except those measured for the
specimen) are provided in Table 4.
TABLE-US-00007 TABLE 4 Illuminant/Measurement Geometry
D.sub.65/2.degree. C/2.degree. x.sub.n 0.3127 0.3101 y.sub.n 0.3290
0.3161 WI, x 800 800 WI, y 1700 1700
General Experimental Conditions:
[0082] A. Raw Materials
[0083] The 6-bromo-2-naphthoate and
1-(5-bromo-2-methoxyphenyl)adamantane test solution were prepared
by adding 20 mg, accurately weighed, of the substance to be
examined into a 100 mL volumetric flask. To the flask was added 5
mL of tetrahydrofuran and the solution was sonicated until the
sample dissolved. Next, 60 mL of mobile phase was added, the sample
was sonicated again, and the flask was filled to 100 mL with mobile
phase.
[0084] B. Intermediates and Final Product Test
[0085] The methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate
test solution (i.e., adapalene methyl ester) was prepared by adding
20 mg, accurately weighed, of the substance to be examined into a
100 mL volumetric flask. To the flask was added 5 mL of
tetrahydrofuran and the solution was sonicated until the sample
dissolved. Next, 60 mL of mobile phase was added, the sample was
sonicated again, and the flask was filled to 100 mL with mobile
phase.
[0086] The 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid
(i.e., adapalene) or its potassium salt test solution was prepared
by adding 20 mg, accurately weighed, of the substance to be
examined into a 100 mL volumetric flask. To the flask was added 5
mL of tetrahydrofuran and the solution was sonicated until the
sample dissolved. Next, 60 mL of mobile phase was added, the sample
was sonicated again, and the flask was filled to 100 mL with mobile
phase.
[0087] C. Impurities Standard Solutions
[0088] The impurity 3,3'-diadamantyl-4,4'-dimethoxybiphenyl
standard solution was prepared by dissolving 20 mg, accurately
weighed, of 3,3'-diadamantyl-4,4'-dimethoxybiphenyl working
standard in 100 mL of tetrahydrofuran in a volumetric flask which
was diluted 1 mL to 100 mL with mobile phase.
[0089] D. Colorimetric Measurement
[0090] Colorimetric measurements were obtained using two different
sets of equipment. Measurements using illuminant D65 were obtained
using a Chroma meter CR-300 (Minolta brand) and a measurement
geometry of 2.degree.. Measurements using illuminant C were
obtained using a Technibrite ERIC-950 (Technidyne Corporation)
Spectrophotometer and a measurement geometry of 2.degree..
[0091] E. Chromatographic Separation
[0092] In each of the foregoing examples/steps, the chromatographic
separation (i.e., HPLC analysis) was performed by reversed-phase
chromatography in a Symmetry C18 column of 5 .mu.m and
250.times.4.6 mm, using an isocratic system comprising a mobile
phase prepared by mixing acetonitrile, tetrahydrofuran, water,
trifluoroacetic acid (43:30:27:0.02 v/v/v/v). This mobile phase was
mixed and filtered through a 0.22 .mu.M filter under vacuum. The
chromatograph was equipped with a 235/272 nm dual wavelength
detector, and the flow rate was 1.0 mL per minute at room
temperature.
[0093] Although the invention has been described and illustrated
with a certain degree of particularity, it is understood that the
present disclosure has been made only by way of example, and that
numerous changes in the conditions and order of steps can be
resorted to by those skilled in the art without departing from the
spirit and scope of the invention.
* * * * *