U.S. patent application number 15/927264 was filed with the patent office on 2019-06-27 for process for the preparation of crisaborole.
The applicant listed for this patent is OLON S.p.A.. Invention is credited to Giorgio BERTOLINI, Lazzaro FELICIANI, Federico GASSA, Alberto MAZZA, Marco QUARONI, Mara SADA.
Application Number | 20190194230 15/927264 |
Document ID | / |
Family ID | 61802301 |
Filed Date | 2019-06-27 |
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United States Patent
Application |
20190194230 |
Kind Code |
A1 |
GASSA; Federico ; et
al. |
June 27, 2019 |
PROCESS FOR THE PREPARATION OF CRISABOROLE
Abstract
The present invention relates to a process for the preparation
of crisaborole of formula (I): ##STR00001## by preparing
intermediates of formulas (II) and (III): ##STR00002##
Inventors: |
GASSA; Federico; (Lodigiano,
IT) ; FELICIANI; Lazzaro; (Lodigiano, IT) ;
MAZZA; Alberto; (Lodigiano, IT) ; QUARONI; Marco;
(Lodigiano, IT) ; SADA; Mara; (Lodigiano, IT)
; BERTOLINI; Giorgio; (Lodigiano, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OLON S.p.A. |
Rodano |
|
IT |
|
|
Family ID: |
61802301 |
Appl. No.: |
15/927264 |
Filed: |
March 21, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07F 5/025 20130101;
B01J 27/053 20130101; C07C 39/205 20130101; B01J 23/42 20130101;
C07C 255/54 20130101; C07F 5/027 20130101; B01J 27/232 20130101;
C07B 47/00 20130101; C07C 37/02 20130101; B01J 23/44 20130101; C07C
253/30 20130101; C07C 39/15 20130101; C07C 253/30 20130101; C07C
255/54 20130101 |
International
Class: |
C07F 5/02 20060101
C07F005/02; C07C 37/02 20060101 C07C037/02; C07C 39/15 20060101
C07C039/15; C07C 39/205 20060101 C07C039/205; B01J 23/42 20060101
B01J023/42; B01J 23/44 20060101 B01J023/44; B01J 27/053 20060101
B01J027/053; B01J 27/232 20060101 B01J027/232 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 21, 2017 |
IT |
102017000148330 |
Claims
1-14. (canceled)
15. A process for the preparation of Crisaborole of formula (I):
##STR00021## wherein said process comprises the following steps: a)
converting compound of formula (II): ##STR00022## into compound of
formula (III): ##STR00023## in the presence of a tri
(C.sub.1-C.sub.4) alkyl borate and a (C.sub.4-C.sub.6) alkyl
lithium or aryl lithium and subsequent acidification of the
reaction medium; and b) converting the resulting compound of
formula (III) into Crisaborole of formula (I) by catalytic
hydrogenation.
16. The process according to claim 15, wherein the
(C.sub.4-C.sub.6) alkyl lithium used in process step a) is selected
from butyl lithium and hexyl lithium.
17. The process according to claim 15, wherein the tri
(C.sub.1-C.sub.4) alkyl borate used in step a) is selected from
trimethyl borate and triisopropyl borate.
18. The process according to claim 15, wherein step a) is carried
out in a solvent selected from cyclic or linear ethers or mixtures
thereof.
19. The process according to claim 15, wherein the catalytic
hydrogenation of step b) is carried out with palladium or platinum
catalysts supported on carbon, barium sulphate or barium
carbonate.
20. The process according to claim 15, wherein compound of formula
(II) is obtained by the following steps: i) reacting compound of
formula (IV): ##STR00024## wherein X is --COH or --CH.sub.2OH, with
compound of formula (V): ##STR00025## in the presence of an
inorganic base, to give compound of formula (I) when X is
--CH.sub.2OH, or compound of formula (VI) when X is --COH:
##STR00026## and ii) reducing compound of formula (VI) to give
compound formula II).
21. The process according to claim 20, wherein the reaction of step
i) is carried out in an aprotic polar solvent selected from
toluene, dimethylformamide dimethylacetamide, methylisobutylketone
or mixtures thereof.
22. The process according to claim 20, wherein the inorganic base
is an alkali metal or alkaline earth metal carbonate.
23. The process according to claim 20, wherein the reduction
reaction of step ii) is carried out with reducing compounds
selected from potassium borohydride, sodium borohydride and lithium
borohydride.
24. The process according to claim 23, wherein the reduction is
carried out in aprotic polar solvents or mixtures thereof.
25. The process according to claim 20, wherein compound of formula
(IV) wherein X is --COH is reacted with compound of formula (V),
and steps i) and ii) are carried out without isolating compound of
formula (VI).
26. The process according to claim 25, wherein reactions i) and ii)
are carried out in an aprotic polar solvent selected from DMF, DMA
and toluene or mixtures thereof, optionally in the presence of a
phase transfer catalyst selected from tetrabutylammonium bromide,
benzyl triethylammonium chloride, hexadecyl trimethylammonium
bromide, tetrabutylammonium hydrogen sulphate and
tetramethylammonium chloride.
27. Compound of formula (II): ##STR00027##
28. Compound of formula (III): ##STR00028##
Description
[0001] The present invention relates to a process for the
preparation of Crisaborole, a non-steroidal medicament used for the
treatment of atopic dermatitis. The invention also relates to novel
synthesis intermediates.
TECHNICAL CONTEXT
[0002] Crisaborole is the international non-proprietary name of the
compound 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
having formula (I):
##STR00003##
[0003] Crisaborole is the active ingredient of Eucrisa, a topical
non-steroidal medicament approved by the FDA in the USA for the
treatment of atopic dermatitis in patients from two years old. The
molecule is currently undergoing clinical trials (phase II) for the
treatment of (inter alia) psoriasis.
[0004] Crisaborole and its synthesis route were described and
claimed for the first time in patent application WO2006/089067 by
Anacor Pharmaceutical Inc. No alternative synthesis routes to the
one described in the originator's patent and publications exist to
date.
[0005] The synthesis route used in WO2006/089067 (scheme) involves
numerous steps, and the total yield is not very high, which makes
the process expensive.
##STR00004## ##STR00005##
[0006] It has surprisingly been found that by using a dichloroaryl
intermediate of formula (V), as defined below, activated in the
ortho position to the nitrile group by two electron-attracting
groups, in particular two halogens, the reactions indicated in the
2-bromo-hydroxybenzaldehyde protection step (step 1) and the
nucleophilic substitution reaction between the protected aldehyde
and the fluorinated intermediate and subsequent reduction of the
resulting product (step 2) can be replaced by a one-pot reaction,
thus eliminating several steps.
[0007] The process according to the invention produces Crisaborole
with a high degree of purity and excellent yields, and can be
effected on an industrial scale.
DESCRIPTION OF THE INVENTION
[0008] The object of the present invention is a process for the
preparation of Crisaborole of formula (I):
##STR00006##
[0009] wherein said process comprises the following steps:
[0010] a) converting compound of formula (II):
##STR00007##
[0011] to compound of formula (III):
##STR00008##
[0012] in the presence of a tri (C.sub.1-C.sub.4) alkyl borate and
a (C.sub.4-C.sub.6) alkyl lithium or aryl lithium, and subsequent
acidification of the reaction medium; and
[0013] b) converting the resulting compound of formula (III) to
Crisaborole of formula (I) by catalytic hydrogenation.
[0014] The term (C.sub.4-C.sub.6) alkyl, as used herein, means a
straight or branched alkyl chain having 4 to 6 carbon atoms such as
n-hexyl, n-pentyl, n-butyl, isobutyl, isopentyl or tert-butyl.
[0015] The term (C.sub.1-C.sub.4) alkyl, as used herein, means a
straight or branched alkyl chain having 1 to 4 carbon atoms such as
methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
[0016] The (C.sub.4-C.sub.6) alkyl lithium used in step a) of the
process described above is preferably selected from butyl lithium
and hexyl lithium.
[0017] The tri (C.sub.1-C.sub.4) alkyl borate used in step a) is
preferably selected from trimethyl borate and triisopropyl
borate.
[0018] Step a) is effected in a polar aprotic solvent such as
cyclic or linear ethers or mixtures thereof, preferably
tetrahydrofuran or methyl tetrahydrofuran, at a temperature ranging
between -30.degree. and -80.degree. C.
[0019] The reaction medium is preferably acidified with acids such
as hydrochloric acid, sulphuric acid, acetic acid and formic acid,
in particular hydrochloric acid or acetic acid.
[0020] The catalytic hydrogenation of step b) is effected with
palladium or platinum catalysts supported on carbon, barium
sulphate or barium carbonate, such as 5% palladium on carbon, in a
solvent such as ether, alcohol or water or in mixtures, at a
temperature ranging between 0.degree. and 50.degree. C.
[0021] A further object of the invention is the process for the
preparation of Crisaborole of formula (I) as described above,
wherein compound of formula (II) is obtained by the following
steps:
[0022] i) reacting compound of formula (IV):
##STR00009##
wherein X is --COH or --CH.sub.2OH, with compound of formula
(V):
##STR00010##
[0023] in the presence of an inorganic base, to give compound of
formula (II) when X is --CH.sub.2OH or compound of formula (VI)
when X is --COH:
##STR00011##
[0024] and
[0025] ii) reducing compound of formula (VI) to give compound of
formula (II).
[0026] The nucleophilic substitution reaction of step i) is
effected in polar aprotic solvents such as toluene, dimethyl
formamide, dimethylacetamide and methyl isobutyl ketone or mixtures
thereof, preferably dimethyl formamide or dimethylacetamide, in the
presence of inorganic bases such as alkali metal or alkaline-earth
metal carbonates, in particular potassium carbonate.
[0027] The reaction is effected at a temperature ranging between
0.degree. and 80.degree. C.
[0028] The reduction reaction of step ii) is effected with reducing
compounds such as KBH.sub.4, NaBH.sub.4 and LiBH.sub.4 (potassium
borohydride, sodium borohydride and lithium borohydride),
preferably NaBH.sub.4, in polar aprotic solvents such as THF,
MeTHF, DMF and DMA (tetrahydrofuran, methyltetrahydrofuran,
dimethylformamide, dimethylacetamide) or mixtures thereof,
preferably tetrahydrofuran or methyltetrahydrofuran, at a
temperature ranging between 0.degree. and 50.degree. C.
[0029] Another object of the invention is the process described
above wherein compound of formula (IV), wherein X is --COH, is
reacted with compound of formula (V), and steps i) and ii) are
effected without isolating compound of formula (VI) (one-pot
reaction).
[0030] Nucleophilic substitution reaction i) and reduction reaction
ii), effected without isolating intermediate (VI), can be carried
out by operating in solvents such as DMF, DMA and toluene or
mixtures thereof, where necessary adding a phase-transfer catalyst
such as tetrabutylammonium bromide, benzyl triethylammonium
chloride, hexadecyl trimethylammonium bromide, tetrabutylammonium
hydrogen sulphate and tetramethylammonium chloride (preferably
tetrabutylammonium bromide).
[0031] Both reactions are effected at a temperature ranging between
0.degree. and 120.degree. C.
[0032] Compound of formula (IV) wherein X is --CH.sub.2OH can be
obtained by reducing compound of formula (IV) wherein X is --COH.
Compound of formula (IV) wherein X is --COH is a commercial
product.
[0033] The reduction of compound of formula (IV) wherein X is --COH
can be effected in the presence of a reducing reagent such as
potassium borohydride, sodium borohydride or lithium borohydride,
preferably sodium borohydride, in polar aprotic solvents selected
from tetrahydrofuran, dioxane, methyltetrahydrofuran, dimethyl
formamide, dimethyl acetamide and toluene or mixtures thereof,
preferably tetrahydrofuran or methyltetrahydrofuran.
[0034] The reaction is effected at a temperature ranging between 0
and 30.degree. C.
[0035] Compound of formula V is a commercial product or obtainable
by known processes from commercial products.
[0036] A further object of the invention is the reaction
intermediates of formulae (II) and (III).
[0037] The process for the preparation of Crisaborole disclosed in
WO2006/089067, and in Bioorg. Med. Chem. Lett: 19 (2009) 2129-2132
by the same authors, involves five chemical steps and a total yield
of 32% (mean values of the methods described), and also involves
lengthy reactions, with hot treatments (100.degree. C.). The
processing of the intermediates involves distillations of large
amounts of solvent, which are expensive and not very safe. No less
than four chemical steps (aldehyde protection and alkylation,
followed by deprotection and reduction) are required to obtain the
key intermediate, and although they produce fairly good yields,
they are lengthy and expensive.
[0038] In a preferred embodiment thereof, the process of the
invention, starting with 2-bromo-5-hydroxybenzaldehyde or the
corresponding alcohol (2-bromo-5-hydroxy phenylmethanol), enables
the key intermediate
(4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile) to
be prepared without isolating intermediates, operating at room
temperature. The product is isolated by simple filtration after
adding water as antisolvent to the reaction mixture. This is
possible due to the addition of two chlorine atoms to the 4-fluoro
benzonitrile, which activate the aromatic nucleophilic substitution
reaction. The two chlorine atoms are then removed to obtain
Crisaborole by reduction. Despite the addition of this step, the
process of the invention only consists of three steps, as against
five. The total yield is higher (74% vs. 32%), the operating
conditions are milder, and the processes are simpler and safer.
EXAMPLES
Example 1
Synthesis of 4-bromo-3-(hydroxymethyl)phenol (Compound of Formula
(IV) wherein X is --CH.sub.2OH)
##STR00012##
[0040] 2-Bromo-5-hydroxy benzaldehyde (compound of formula IV
wherein X is --COH) (20.1 g, 100 mmol) was dissolved in THF (80
mL), and the solution was cooled to 0-5.degree. C. A solution of
NaBH.sub.4 (1.9 g, 50 mmol) in water (10 mL, stabilised with NaOH)
was added in 30 min. The solution was stirred for a further 30 min.
Acetone (25 mL) was added dropwise to the solution in 30 min. Water
(50 mL) was then added, and THF was distilled off. The residual oil
was extracted with AcOEt (200 mL). The organic phase was washed
with saline solution (50 mL), then AcOEt was distilled off. The
resulting solid was treated at 50.degree. C. with 50 mL of toluene,
and the suspension cooled to 20.degree. C. The solid was filtered
and dried at 65.degree. C. to obtain the title compound as a white
solid (18.6 g, 91%).
[0041] .sup.1H-NMR; 300 MHz, DMSO-d.sub.6. 9.64 (brs, 1H), 7.27 (d,
1H), 7.01 (d, 1H), 6.60 (dd, 1H), 5.37 (brs, 1H), 4.41 (s, 2H)
[0042] .sup.13C-NMR; 300 MHz, DMSO-d.sub.6. .delta. 157.5, 142.4,
132.9, 115.9, 115.6, 109.4, 63.0.
Example 2
Synthesis of
4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile of
Formula (II)
##STR00013##
[0044] 4-Bromo-3-(hydroxymethyl)phenol (5.0 g, 25 mmols) (compound
of formula (IV) wherein X is --CH.sub.2OH) was dissolved in DMF (30
mL). 2,6 Dichloro-4 fluorobenzonitrile (4.9 g, 26 mmol) (compound
of formula (V)) and K.sub.2CO.sub.3 (3.9 g, 28 mmols) were added,
and the suspension was stirred for 5 hours. Water (100 mL) was
added, and compound of formula (II) was collected as a white solid
by filtration (7.3 g, 19.6 mmols, 80%).
[0045] .sup.1H-NMR; 300 MHz, DMSO-d.sub.6. .delta. 7.65 (d, 1H),
7.30 (d, 1H), 7.06 (dd, 1H), 5.55 (t, 1H), 4.49, (d, 2H).
[0046] .sup.13C-NMR; 300 MHz, DMSO-d.sub.6. .delta. 161.8, 153.6,
144.4, 139.1, 134.4, 120.9, 102.1, 118.0, 117.4, 114.0, 107.5,
62.8.
Example 3
Synthesis of
2,6-dichloro-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benz-
onitrile of Formula (III)
##STR00014##
[0048]
4-(4-Bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile of
formula (II) (50.0 g, 164 mmols), 3,4-dihydropyran (34.9 g, 415
mmols) and pyridinium p-toluenesulphonate (2.0 g, 8 mmols) were
stirred in THF for 24 hours. TiPrOB (49.2, 262 mmols) was added,
and the solution was cooled to -78.degree. C. A hexyllithium 2.3
molar solution in hexane was added dropwise in 40 min., and the
final mixture was stirred at said temperature for 90 min. The
solution was heated to room temperature and kept under stirring at
said temperature for a total of 2 hours. THF was then distilled off
100 mL of 6N HCl was added slowly, and the suspension was stirred
for 16 hours. EtOH (400 mL) was added, and compound of formula
(III) was obtained by filtration (36.0 g, 112 mmols, 84%).
[0049] .sup.1H-NMR; 300 MHz, DMSO-d.sub.6. .delta. 9.25 (s, 1H),
7.82 (d, 1H), 7.33 (s, 2H), 7.23 (d, 1H), 7.15 (dd, 1H), 4.98 (s,
2H)
[0050] .sup.13C-NMR; 300 MHz, DMSO-d.sub.6. .delta. 161.8, 157.2,
156.4, 139.1, 133.2, 119.6, 118.4, 114.1, 113.7, 107.5, 70.1
Example 4
Synthesis of Crisaborole of Formula (I)
##STR00015##
[0052]
2,6-Dichloro-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)ox-
y)-benzonitrile (10.0 g, 31 mmols) and KOH (5.0 g, 84 mmols) were
suspended in a mixture of ethanol (100 mL) and water (100 mL). 5%
Pd on carbon (1.0 g) was then added, and the mixture was placed
under hydrogen atmosphere at 1-5 ATM. The reaction was completed
after 1 h, and the catalyst was filtered off 37% Hydrochloric acid
was added to the filtered solution to obtain a pH of less than 2.
The solution was concentrated under vacuum at 50 mL, and a white
solid precipitated. The suspension was cooled to room temperature
and stirred for 1 hour. Crisaborole was then isolated by filtration
(7.0 g, 28 mmol, 90%).
Example 5
Synthesis of
4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile
(One-Pot Reaction in DMA) of Formula (II)
##STR00016##
[0054] 2-Bromo-5-hydroxybenzaldehyde (30.0 g, 149 mmols) and
2,6-dichloro-4-fluorobenzonitrile (30.0 g, 158 mmols) were
dissolved in DMA (130 mL), and K.sub.2CO.sub.3 (27.0 g, 195 mmols)
was added to the solution. The reaction was maintained at
20-30.degree. C. for 3-6 hours, after which a solution of
NaBH.sub.4 (2.0 g, 53 mmols) in water (20 mL, stabilised with 5%
NaOH) was added in 20 min. The solution was kept under stirring for
a further 30 min., then water (500 mL) was added. The solution was
kept under stirring for 1 hour, and the title product was isolated
as a white solid by filtration (54.6 g, 146 mmols, 98%).
Example 6
Synthesis of 4-(4-bromo-3-(formylphenoxy)-2,6-dichlorobenzonitrile
of formula (VI)
##STR00017##
[0056] 2-Bromo-5-hydroxy benzaldehyde (30.0 g, 149 mmols) was
dissolved in DMF (120 mL), 2,6-dichloro-4-fluorobenzonitrile (30.0
g. 158 mmols) and K.sub.2CO.sub.3 (27.0 g, 195 mmols) were added to
the solution, and the suspension was stirred for 1-4 h, maintaining
the temperature under 30.degree. C. Water (300 mL) was added, and a
white solid was collected by filtration and washing with water (100
mL). (54.2 g, 146 mmol, 97%).
[0057] .sup.1H-NMR; 300 MHz, CDCl.sub.3. .delta. 10.33 (s, 1H),
7.76 (d, 1H), 7.60 (d, 1H), 7.22 (dd, 1H), 6.98 (s, 2H)
[0058] .sup.13C-NMR; 300 MHz, CDCl.sub.3. .delta. 190.5, 160.6,
153.7, 139.9, 136.1, 135.2, 127.3, 123.2, 117.3, 113.2, 109.1.
Example 7
Synthesis of
4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile of
Formula (II)
##STR00018##
[0060] 4-(4-Bromo-3-formylphenoxy)-2,6-dichlorobenzonitrile (77.8
g, 210 mmols) was dissolved in THF (365 mL), and the solution was
cooled to 0-5.degree. C. A solution of NaBH.sub.4 (2.7 g, 71 mmols)
in water (25 mL, stabilised by NaOH) was added in 1 hour. The
solution was kept under stirring for a further 30 min. Acetone (25
mL) was added dropwise in 30 min., then water (150 mL) was added.
THF was distilled off, and a solid precipitate was obtained. The
suspension was cooled to room temperature, and the product was
isolated as a white solid by filtration (77.6 g, 208 mmols, 98%).
The crude product was suspended in toluene (320 mL) and placed
under reflux for 30 minutes. The solution was slowly cooled to room
temperature, and the pure white solid was recovered by filtration
(75.3 g, 95%).
Example 8
Synthesis of
4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile of
Formula (II) (Phase-Transfer Conditions)
##STR00019##
[0062] 4-(4-Bromo-3-formylphenoxy)-2,6-dichlorobenzonitrile (15.0
g, 40 mmols) and TBAB (0.15 g, 0.5 mmols) were suspended in toluene
(140 mL), and the solution was heated to 45-50.degree. C. A
solution of NaBH.sub.4 (0.6 g, 16 mmol) in water (6 mL, stabilised
with NaOH) was added in 10 min. The solution was kept under
stirring for a further 60 min. Acetic acid (3.6 g) was added
dropwise in 30 min., and the mixture was then kept under stirring
for 30 min. The suspension was heated to 80.degree. C., and the
aqueous phase was separated. 70 mL of toluene was distilled off,
and the solution was cooled to room temperature. The product was
isolated as a white solid by filtration (13.0 g, 35 mmols,
88%).
Example 9
Synthesis of
4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile of
Formula (II) (Reaction in Phase-Transfer Conditions)
##STR00020##
[0064] 2-Bromo-5-hydroxy-benzaldehyde (10.0 g, 50 mmols),
2,6-dichloro-4-fluoro benzonitrile (9.9 g, 52 mmols),
K.sub.2CO.sub.3 (8.9 g, 64 mmols) and TBAB (1 g, 0.3 mmols) were
suspended in toluene (100 mL), and the solution was heated to
70.degree. C. for 24 hours. The solution was cooled to room
temperature and washed twice with water (50 ml). A solution of
NaBH.sub.4 (0.65 g, 170 mmols) in water (15 mL) was added dropwise,
and the solution was kept under stirring for a further 30 min. The
solution was washed twice with water (50 mL) and concentrated to 40
mL. The solution was then cooled to room temperature, and the
product was isolated as a white solid by filtration (16.6 g, 44
mmols, 88%).
* * * * *