U.S. patent application number 11/463703 was filed with the patent office on 2007-04-19 for process for the manufacturing of betamimetics.
Invention is credited to Adil Duran, Thomas KRUEGER, Zeno A. Leuter, Werner Rall, Uwe Ries, Juergen Schnaubelt, Rainer Soyka.
Application Number | 20070088160 11/463703 |
Document ID | / |
Family ID | 37198936 |
Filed Date | 2007-04-19 |
United States Patent
Application |
20070088160 |
Kind Code |
A1 |
KRUEGER; Thomas ; et
al. |
April 19, 2007 |
PROCESS FOR THE MANUFACTURING OF BETAMIMETICS
Abstract
The present invention relates to a process for preparing
betamimetics of formula 1, ##STR1## wherein n denotes 1 or 2;
R.sup.1 denotes hydrogen, halogen, C.sub.1-4-alkyl or
O--C.sub.1-4-alkyl; R.sup.2 denotes hydrogen, halogen,
C.sub.1-4-alkyl or O--C.sub.1-4-alkyl; R.sup.3 denotes hydrogen,
C.sub.1-4-alkyl, OH, halogen, O--C.sub.1-4-alkyl,
O--C.sub.1-4-alkylene-COOH,
O--C.sub.1-4-alkylene-COO--C.sub.1-4-alkyl.
Inventors: |
KRUEGER; Thomas; (Kisslegg,
DE) ; Ries; Uwe; (Biberach, DE) ; Schnaubelt;
Juergen; (Oberhoefen, DE) ; Rall; Werner;
(Mittelbiberach, DE) ; Leuter; Zeno A.;
(Weingarten, DE) ; Duran; Adil; (Rissegg, DE)
; Soyka; Rainer; (Biberach, DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Family ID: |
37198936 |
Appl. No.: |
11/463703 |
Filed: |
August 10, 2006 |
Current U.S.
Class: |
544/105 |
Current CPC
Class: |
C07C 49/84 20130101;
Y02P 20/55 20151101; C07D 265/36 20130101; C07C 233/18 20130101;
C07C 201/08 20130101; C07C 45/71 20130101; A61P 11/06 20180101;
A61P 43/00 20180101; C07C 221/00 20130101; C07C 233/13 20130101;
C07C 45/71 20130101; C07C 49/84 20130101; C07C 201/08 20130101;
C07C 205/45 20130101; C07C 221/00 20130101; C07C 225/22
20130101 |
Class at
Publication: |
544/105 |
International
Class: |
C07D 265/36 20060101
C07D265/36 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 15, 2005 |
EP |
05107470 |
Claims
1. A process for preparing a compound of formula 1, ##STR33##
wherein n denotes 1 or 2; R.sup.1 denotes hydrogen, halogen,
C.sub.1-4-alkyl or O--C.sub.1-4-alkyl; R.sup.2 denotes hydrogen,
halogen, C.sub.1-4-alkyl or O--C.sub.1-4-alkyl; R.sup.3 denotes
hydrogen, C.sub.1-4-alkyl, OH, halogen, O--C.sub.1-4-alkyl,
O--C.sub.1-4-alkylene-COOH,
O--C.sub.1-4-alkylene-COO--C.sub.1-4-alkyl; said process comprising
reacting a compound of formula 1a, ##STR34## wherein PG represents
a protective group, with a compound of formula 1b, ##STR35##
wherein R.sup.1, R.sup.2, R.sup.3 and n have the meanings given
above, in an organic solvent to obtain a compound of formula 1c,
##STR36## wherein R.sup.1, R.sup.2, R.sup.3, n and PG have the
meanings given above, and cleaving the protective group PG to
obtain the compound of formula 1.
2. A process for preparing a compound of formula 1 according to
claim 1, wherein n denotes 1 or 2; R.sup.1 denotes hydrogen,
halogen or C.sub.1-4-alkyl; R.sup.2 denotes hydrogen, halogen or
C.sub.1-4-alkyl; and R.sup.3 denotes hydrogen, C.sub.1-4-alkyl, OH,
halogen, O--C.sub.1-4-alkyl, O--C.sub.1-4-alkylene-COOH or
O--C.sub.1-4-alkylene-COO--C.sub.1-4-alkyl.
3. A process for preparing a compound of formula 1 according to
claim 1, wherein n denotes 1 or 2; R.sup.1 denotes hydrogen,
fluorine, chlorine, methyl or ethyl; R.sup.2 denotes hydrogen,
fluorine, chlorine, methyl or ethyl; and R.sup.3 denotes hydrogen,
C.sub.1-4-alkyl, OH, fluorine, chlorine, bromine,
O--C.sub.1-4-alkyl, O--C.sub.1-4-alkylene-COOH,
O--C.sub.1-4-alkylene-COO--C.sub.1-4-alkyl.
4. A process for preparing a compound of formula 1 according to
claim 1, wherein n denotes 1 or 2; R.sup.1 denotes hydrogen, methyl
or ethyl; R.sup.2 denotes hydrogen, methyl or ethyl; and R.sup.3
denotes hydrogen, methyl, ethyl, OH, methoxy, ethoxy,
O--CH.sub.2--COOH, O--CH.sub.2--COO-methyl or
O--CH.sub.2--COO-ethyl.
5. A process for preparing a compound of formula 1 according to
claim 1, wherein n denotes 1 or 2; R.sup.1 denotes hydrogen or
methyl; R.sup.2 denotes hydrogen or methyl; and R.sup.3 denotes
hydrogen, methyl, OH, methoxy, O--CH.sub.2--COOH or
O--CH.sub.2--COO-ethyl.
6. A process according to claim 1, wherein the compound of formula
1a is prepared by reacting a compound of formula 2a, ##STR37##
wherein PG is as defined in claim 1 and R.sup.4 denotes halogen
with DIP chloride in a suitable solvent.
7. A process according to claim 6 wherein the compound of formula
2a is prepared by reacting a compound of formula 3a, ##STR38##
wherein PG has the meaning given in claim 6, with a halogenating
reagent in a suitable solvent.
8. A process according to claim 7 wherein the compound of formula
3a is prepared by hydrogenating a compound of formula 4a in a
suitable solvent, ##STR39## wherein PG has the meaning given in
claim 7.
9. A process according to claim 8 wherein the compound of formula
4a is prepared by reacting a compound of formula 5a, ##STR40##
wherein PG has the meaning given in claim 8, with a nitrogenating
reagent in a suitable solvent.
10. A process according to claim 9 wherein the compound of formula
5a is prepared by reacting a compound of formula 6a in a suitable
solvent with a compound PG-A, wherein PG is a protective group and
A is a leaving group, ##STR41##
11. A process according to claim 1, wherein the compound of formula
1b is prepared by reacting a compound of formula 2b with a strong
base in a suitable solvent, ##STR42## wherein R.sup.1, R.sup.2,
R.sup.3 and n have are as defined in claim 1 and R.sup.5 denotes
Me.
12. A process according to claim 11 wherein the compound of formula
2b is prepared by reacting a compound of formula 3b with
acetonitrile in the presence of an acid in a suitable solvent,
##STR43## wherein R.sup.1, R.sup.2, R.sup.3 and n are as defined in
claim 11.
13. A process according to claim 12 wherein the compound of formula
3b is prepared by reacting in a suitable solvent a compound of
formula 4b with methylmagnesium bromide or methylmagnesium
chloride, ##STR44## wherein R.sup.1, R.sup.2, R.sup.3 and n are as
defined in claim 12.
14. A compound of formula 3a, ##STR45## wherein PG is as defined in
claim 1.
15. A compound of formula 4a, ##STR46## wherein PG is as defined in
claim 1.
16. A compound of formula 4a.sup.#, ##STR47## wherein PG is as
defined in claim 1.
17. A compound of formula 2b, ##STR48## wherein R.sup.1, R.sup.2,
R.sup.3 and n are as defined in claim 1, and R.sup.5 denotes
Me.
18. A process for preparing a compound of formula 2a, ##STR49##
wherein PG is as defined in claim 1 and R.sup.4 denotes halogen,
said process comprising reacting a compound of formula 3a,
##STR50## wherein PG is as defined in claim 1, with a halogenating
reagent selected from tetrabutylammonium tribromide,
benzyltrimethyl ammonium dichloriodide, N-bromo-succinimide,
N-chloro-succinimide, sulphuryl chloride and bromine/dioxane.
19. A process for preparing a compound of formula 3a, ##STR51##
wherein PG is as defined in claim 1, said process comprising
subjecting a compound of formula 4a to catalytic hydrogenation and
then reaction with chloroacetyl chloride, ##STR52## wherein PG is
as defined in claim 1.
20. A process according to claim 19, wherein a compound of formula
4a.sup.#, ##STR53## wherein PG is as defined in claim 19, is formed
as an intermediate product of the hydrogenation.
21. A process for preparing a compound of formula 4a, ##STR54##
wherein PG is as defined in claim 1, said process comprising
reacting a compound of formula 5a, ##STR55## wherein PG is as
defined in claim 1, with a nitrogenating reagent selected from 65%
nitric acid, potassium nitrate/sulphuric acid and nitronium
tetrafluoroborate.
22. A process for preparing a compound of formula 1b, ##STR56##
wherein R.sup.1, R.sup.2, R.sup.3 and n are as defined in claim 1,
said process comprising reacting a compound of formula 2b,
##STR57## wherein R.sup.1, R.sup.2, R.sup.3 and n are as defined in
claim 1 and R.sup.5 denotes Me, with a base selected from potassium
hydroxide, sodium hydroxide, lithium hydroxide and caesium
hydroxide.
23. A process for preparing a compound of formula 2b, ##STR58##
wherein R.sup.1, R.sup.2, R.sup.3 and n are as defined in claim 1
and R.sup.5 denotes Me, said process comprising reacting a compound
of formula 3b, ##STR59## wherein R.sup.1, R.sup.2, R.sup.3 and n
are as defined in claim 1, with a compound of formula ##STR60##
wherein R.sup.5 has the meaning given above, in the presence of a
hygroscopic reagent selected from sulphuric acid, formic acid,
p-toluenesulphonic acid, methanesulphonic acid, perchloric acid and
polyphosphoric acid and then with a base selected from aqueous
solutions of ammonia, sodium hydroxide, potassium hydroxide, sodium
carbonate and potassium carbonate.
Description
[0001] The present invention relates to a process for preparing
betamimetics of formula 1, ##STR2## wherein [0002] n denotes 1 or
2; [0003] R.sup.1 denotes hydrogen, halogen, C.sub.1-4-alkyl or
O--C.sub.1-4-alkyl; [0004] R.sup.2 denotes hydrogen, halogen,
C.sub.1-4-alkyl or O--C.sub.1-4-alkyl; [0005] R.sup.3 denotes
hydrogen, C.sub.1-4-alkyl, OH, halogen, O--C.sub.1-4-alkyl,
O--C.sub.1-4-alkylene-COOH,
O--C.sub.1-4-alkylene-COO--C.sub.1-4-alkyl.
BACKGROUND TO THE INVENTION
[0006] Betamimetics (.beta.-adrenergic substances) are known from
the prior art. For example reference may be made in this respect to
the disclosure of U.S. Pat. No. 4,460,581, which proposes
betamimetics for the treatment of a range of diseases.
[0007] For drug treatment of diseases it is often desirable to
prepare medicaments with a longer duration of activity. As a rule,
this ensures that the concentration of the active substance in the
body needed to achieve the therapeutic effect is guaranteed for a
longer period without the need to re-administer the drug at
frequent intervals. Moreover, giving an active substance at longer
time intervals contributes to the well-being of the patient to a
high degree. It is particularly desirable to prepare a
pharmaceutical composition which can be used therapeutically by
administration once a day (single dose). The use of a drug once a
day has the advantage that the patient can become accustomed
relatively quickly to regularly taking the drug at certain times of
the day.
[0008] The aim of the present invention is therefore to provide a
method of producing betamimetics which on the one hand confer a
therapeutic benefit in the treatment of COPD or asthma and are also
characterised by a longer duration of activity and can thus be used
to prepare pharmaceutical compositions with a longer duration of
activity. A particular aim of the invention is to prepare
betamimetics which, by virtue of their long-lasting effect, can be
used to prepare a drug for administration once a day for treating
COPD or asthma. A further objective of the invention, apart from
those mentioned above, is to prepare betamimetics which are not
only exceptionally potent but are also characterised by a high
degree of selectivity with respect to the
.beta..sub.2-adrenoceptor.
DETAILED DESCRIPTION OF THE INVENTION
[0009] The present invention relates to a process for preparing a
compound of formula 1, ##STR3## wherein [0010] n denotes 1 or 2;
[0011] R.sup.1 denotes hydrogen, halogen, C.sub.1-4-alkyl or
O--C.sub.1-4-alkyl; [0012] R.sup.2 denotes hydrogen, halogen,
C.sub.1-4-alkyl or O--C.sub.1-4-alkyl; [0013] R.sup.3 denotes
hydrogen, C.sub.1-4-alkyl, OH, halogen, O--C.sub.1-4-alkyl,
O--C.sub.1-4-alkylene-COOH,
O--C.sub.1-4-alkylene-COO--C.sub.1-4-alkyl, characterised in that a
compound of formula 1a, ##STR4## wherein PG represents a protective
group, is reacted with a compound of formula 1b, ##STR5## wherein
R.sup.1, R.sup.2, R.sup.3 and n have the meaning given above, in an
organic solvent to yield a compound of formula 1c, ##STR6## wherein
R.sup.1, R.sup.2, R.sup.3, n and PG have the meanings given above,
and the compound of formula 1 is obtained therefrom by cleaving the
protective group PG.
[0014] The above process is preferably used to prepare compounds of
formula 1, wherein [0015] n denotes 1 or 2; [0016] R.sup.1 denotes
hydrogen, halogen or C.sub.1-4-alkyl; [0017] R.sup.2 denotes
hydrogen, halogen or C.sub.1-4-alkyl; [0018] R.sup.3 denotes
hydrogen, C.sub.1-4-alkyl, OH, halogen, O--C.sub.1-4-alkyl,
O--C.sub.1-4-alkylene-COOH or
O--C.sub.1-4-alkylene-COO--C.sub.1-4-alkyl.
[0019] The above process is preferably used to prepare compounds of
formula 1, wherein [0020] n denotes 1 or 2; [0021] R.sup.1 denotes
hydrogen, fluorine, chlorine, methyl or ethyl; [0022] R.sup.2
denotes hydrogen, fluorine, chlorine, methyl or ethyl; R.sup.3
denotes hydrogen, C.sub.1-4-alkyl, OH, fluorine, chlorine, bromine,
O--C.sub.1-4-alkyl, O--C.sub.1-4-alkylene-COOH,
O--C.sub.1-4-alkylene-COO--C.sub.1-4-alkyl.
[0023] The above process is preferably used to prepare compounds of
formula 1, wherein [0024] n denotes 1 or 2; [0025] R.sup.1 denotes
hydrogen, methyl or ethyl; [0026] R.sup.2 denotes hydrogen, methyl
or ethyl; [0027] R.sup.3 denotes hydrogen, methyl, ethyl, OH,
methoxy, ethoxy, O--CH.sub.2--COOH, O--CH.sub.2--COO-methyl or
O--CH.sub.2--COO-ethyl.
[0028] The above process is preferably used to prepare compounds of
formula 1, wherein [0029] n denotes 1 or 2; [0030] R.sup.1 denotes
hydrogen or methyl; [0031] R.sup.2 denotes hydrogen or methyl;
[0032] R.sup.3 denotes hydrogen, methyl, OH, methoxy,
O--CH.sub.2--COOH or O--CH.sub.2--COO-ethyl.
[0033] In the process according to the invention a compound of
formula 1a is reacted with a compound of formula 1b in a suitable
solvent. Suitable solvents which may be used are organic solvents,
while particularly preferred solvents are selected from among
tetrahydrofuran, toluene, ethanol, n-propanol, n-butanol,
n-butylacetate, dimethylformamide, methoxyethanol, ethyleneglycol
and dioxane. According to the invention particularly preferred
solvents are n-propanol, tetrahydrofuran and dioxane, while dioxane
and n-propanol are of particular importance.
[0034] Based on the compound 1a used it is preferable according to
the invention to use at least stoichiometric amounts of compound
1b. Compound 1b may optionally also be used in excess, for example
in amounts of up to 3 equivalents, preferably up to 2.5
equivalents, particularly preferably about 1 to 2, optionally 1 to
1.5 equivalents based on the compound 1a used.
[0035] The reaction is preferably carried out at elevated
temperature, preferably at a temperature above 40.degree. C.,
particularly preferably at a temperature above 50.degree. C.
Particularly preferably, the reaction mixture is heated to the
boiling temperature of the solvent used.
[0036] At this temperature the reaction is then carried out over a
period of about 1 to 72 hours, preferably 10 to 60 hours,
particularly preferably 20 to 50 hours.
[0037] Once the reaction has ended the solvent is eliminated and
the residue remaining is taken up in an organic polar solvent,
preferably a C.sub.1-8-alcohol or C.sub.3-8-ester, particularly
preferably in ethanol or ethyl acetate, and filtered. The filtrate
is acidified, preferably with an inorganic acid, particularly
preferably with hydrochloric acid and after a period of about 10
minutes to 12 hours, preferably 20 minutes to 6 hours, particularly
preferably 30 minutes to 3 hours, the product is filtered off.
[0038] The protective group PG is preferably cleaved from compounds
of formula 1a by hydrogenation in a suitable solvent. Examples of
suitable solvents include organic solvents, preferably organic,
polar solvents, particularly preferred solvents are selected from
among tetrahydrofuran, various C.sub.3-8-esters and
C.sub.1-8-alcohols. Preferably, according to the invention, the
solvents used are tetrahydrofuran, ethanol and methanol, while
ethanol and methanol are of particular significance.
[0039] The hydrogenation in the process according to the invention
preferably uses catalysts in the presence of hydrogen. Preferred
catalysts are suitable transition metal catalysts, preferably
heterogeneous transition metal catalysts, particularly preferably
palladium-containing catalysts, particularly a palladium-charcoal
mixture.
[0040] The hydrogenation is preferably carried out in the presence
of an excess of hydrogen. The latter is provided according to the
invention by a hydrogen pressure of 1 bar to 10 bar, preferably
between 2 and 7 bar, particularly preferably between 2.5 and 4.5
bar.
[0041] Preferably the hydrogenation is carried out at elevated
temperature, preferably from 25 to 70.degree. C., particularly
preferably from 30 to 60.degree. C., particularly from 35 to
50.degree. C. After the reaction has ended the catalyst is removed,
preferably by filtration.
[0042] Then the solvent is eliminated and the product is
recrystallised from a suitable organic solvent, preferably a
C.sub.1-8-alcohol or a mixture of C.sub.1-8-alcohols, particularly
preferably from a mixture of methanol and an alcohol selected from
among i-propanol, n-propanol and ethanol.
[0043] In a preferred process according to the invention the
compound of formula 1a is prepared by reacting a compound of
formula 2a, ##STR7## wherein PG has the meaning given in claim 1
and R.sup.4 denotes halogen, preferably bromine or chlorine.
[0044] In the process according to the invention a compound of
formula 2a is reacted in a suitable solvent with DIP chloride
(diisopinocampheylchloroborane). Suitable solvents are preferably
organic solvents. Preferred solvents are selected from among
diethyl ether, tert-butyl-methylether 2-methyltetrahydrofuran,
tetrahydrofuran, toluene and dioxane. Particularly preferably
according to the invention the solvents used are
tert-butyl-methylether, tetrahydrofuran and dioxane, of which
dioxane and tetrahydrofuran are of particular importance.
[0045] The DIP chloride may be used in pure form or in the form of
a solution, preferably in an inert organic solvent, particularly
preferably an aliphatic solvent, particularly pentane, hexane,
heptane or octane.
[0046] The DIP chloride is added at reduced temperature in the
reaction medium, the temperature preferably being below 0.degree.
C., particularly preferably below -10.degree. C.; more particularly
the addition is carried out at -20 to -40.degree. C.
[0047] The DIP chloride is added over a period of 10 min to 6
hours, preferably 30 min to 4 hours, particularly preferably 1 to 3
hours. In particular, the addition takes place over a period of 70
to 110 min.
[0048] Based on the compound 2a used, according to the invention at
least stoichiometric amounts of DIP chloride are preferably used.
The DIP chloride may optionally also be used in excess, for example
in amounts of up to 3 equivalents, preferably 2.5 equivalents,
particularly preferably 1.5 to 2.5 equivalents based on the
compound 2a used.
[0049] After the DIP chloride has been added the reaction mixture
is stirred over a period of 10 min to 4 hours, preferably 30 min to
3 hours, particularly preferably 40 to 80 min; in particular, the
reaction mixture is stirred for another 50 to 70 min after the
addition has ended. During this time the reaction mixture is
adjusted to a temperature of -20 to 20.degree. C., particularly
preferably from -10 to 10.degree. C., particularly from -5 to
5.degree. C.
[0050] Once the desired temperature has been reached, an at least
stoichiometric amount of sodium hydroxide (NaOH), dissolved in
water, is added, based on the amount of DIP chloride used. If
desired the NaOH may also be used in excess, for example in amounts
of up to 3 equivalents, preferably in amounts of up to 2.5
equivalents, particularly preferably 1.5 to 2.5 equivalents, based
on the amount of DIP chloride used. Preferably a pH value of 12 to
14, particularly preferably 12.5 to 13.5, particularly 12.7 to 13.3
is measured in the reaction mixture after the addition of NaOH has
ended.
[0051] After the desired pH has been selected, the reaction mixture
is stirred over a period of 10 min to 4 hours, preferably 30 min to
3 hours, particularly preferably 40-80 min, and in particular the
reaction mixture is stirred for a further 50-70 min. During this
time the reaction mixture is adjusted to a temperature of 0 to
40.degree. C., particularly preferably from 10 to 30.degree. C.,
particularly from 15 to 25.degree. C. Then the reaction mixture is
adjusted to a pH of 7 to 10, particularly preferably 8 to 9,
particularly 8.2 to 8.8, with an acid, preferably an inorganic
acid, particularly preferably hydrochloric acid.
[0052] Finally, the product can be isolated from the reaction
mixture by extraction with an organic solvent and obtained as a
solid by precipitation with another suitable organic solvent.
[0053] In a preferred process according to the invention the
compound of formula 2a is prepared by reacting a compound of
formula 3a, ##STR8## wherein PG has the meaning given in claim
1.
[0054] In the process according to the invention a compound of
formula 3a is reacted with a halogenating reagent in a suitable
solvent. Examples of suitable solvents are organic solvents.
Preferred solvents are selected from among acetic acid, butyl
acetate, methylene chloride, tetrahydrofuran, toluene and dioxane.
Particularly preferred solvents according to the invention are
tetrahydrofuran and dioxane.
[0055] In a preferred embodiment of the invention the halogenating
reagent used is a brominating reagent, particularly preferably
bromine, N-bromosuccinimide, benzyltrimethylammonium tribromide and
tetrabutylammonium tribromide. Based on the compound 3a used,
preferably at least stoichiometric amounts of halogenating reagent
are used according to the invention. If required the halogenating
reagent may also be used in excess, for example in amounts of up to
3 equivalents, preferably in amounts of up to 2 equivalents,
particularly preferably 1 to 1.5 equivalents, based on the compound
3a used. The halogenating reagent may be added to the reaction
mixture in a solvent, preferably in an organic, polar solvent,
particularly preferably in methanol, ethanol and dioxane,
particularly in methanol and dioxane, or in a mixture thereof,
particularly in a mixture of methanol and dioxane.
[0056] The reaction is preferably carried out at a temperature of 0
to 40.degree. C., preferably at a temperature of 10 to 30.degree.
C., particularly preferably at a temperature of 15 to 25.degree.
C.
[0057] After the halogenating reagent has been added the reaction
mixture is stirred for a period of 10 min to 6 hours, preferably 30
min to 4 hours, particularly preferably 90 to 150 min.
[0058] To isolate the product water is added to the reaction
mixture, wherein the mixture is cooled to a temperature of
-10.degree. C. to 10.degree. C., preferably 0 to 10.degree. C.,
particularly preferably 0 to 5.degree. C. and stirred for a period
of 10 min to 4 hours, preferably 30 min to 2 hours, particularly
preferably 50 to 70 min, after the addition of the water. The
product may be obtained after filtration or centrifugation and
drying.
[0059] In a preferred process according to the invention the
compound of formula 3a is prepared by reacting a compound of
formula 4a, ##STR9## wherein PG has the meaning given in claim
1.
[0060] In the process according to the invention a compound of
formula 4a is hydrogenated in a suitable solvent. Examples of
suitable solvents are organic solvents, preferably organic, polar
solvents. Particularly preferred solvents are selected from among
dimethylformamide, N-methylpyrrolidinone, tetrahydrofuran,
2-methyltetrahydrofuran, toluene and dioxane. According to the
invention the following are particularly preferred as solvents:
dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran and
dioxane, wherein dimethylformamide and 2-methyltetrahydrofuran are
of particular importance.
[0061] The hydrogenation in the process according to the invention
preferably uses catalysts in the presence of hydrogen. Preferred
catalysts are suitable transition metal catalysts, preferably
heterogeneous transition metal catalysts, particularly preferably
nickel- or platinum-containing catalysts, particularly platinum
oxide.
[0062] The hydrogenation is preferably carried out in the presence
of an excess of hydrogen. The latter is provided according to the
invention by a hydrogen pressure of 1 bar to 10 bar, preferably
from 2 to 7 bar, particularly preferably from 2.5 to 4.5 bar.
[0063] Preferably the hydrogenation is carried out at a temperature
from 0 to 50.degree. C., particularly preferably from 10 to
40.degree. C., particularly from 20 to 30.degree. C. After the
reaction has ended the catalyst is removed from the liquid phase,
preferably by filtration.
[0064] The intermediate product 4a.sup.# in the solution, ##STR10##
wherein PG has the meaning given in claim 1, may be isolated or
further reacted directly to form a compound of formula 3a.
[0065] In accordance with the process of the invention a base,
preferably a weak base, particularly preferably a carbonate,
particularly potassium carbonate, is taken and the compound of
formula 4a.sup.# is added in pure form or in a solution,
particularly in the form of the solution filtered off from the
hydrogenation catalyst in the preceding step.
[0066] Based on the compound 4a used, preferably at least twice the
stoichiometric amount of the base is used according to the
invention. The base may optionally also be used in excess, for
example in amounts of up to 6 equivalents, preferably in amounts of
up to 4 equivalents, particularly preferably about 3 to 3.5
equivalents, based on the compound 4a used.
[0067] Then chloroacetyl chloride is added to the reaction mixture.
The chloroacetyl chloride is added over a period of 10 min to 2
hours, preferably 15 min to 1 hour, particularly preferably 25 to
35 min.
[0068] Based on the compound 4a used, preferably at least
stoichiometric amounts of the chloroacetyl chloride are used
according to the invention. If required, the chloroacetyl chloride
may also be used in excess, for example in amounts of up to 4
equivalents, preferably in amounts of up to 3 equivalents,
particularly preferably about 1.5 to 2 equivalents, based on the
compound 4a used.
[0069] After the chloroacetyl chloride has been added the reaction
mixture is stirred for a period of 10 min to 6 hours, preferably 1
to 4 hours, particularly preferably 140 to 160 min.
[0070] The reaction is preferably carried out at elevated
temperature, preferably at a temperature of above 40.degree. C.,
particularly preferably at a temperature of above 50.degree. C.,
particularly preferably from 60.degree. C. to 70.degree. C.
[0071] The reaction is ended by the addition of water. The compound
of formula 3a can be purified and isolated by extraction of the
reaction mixture with water and subsequent recrystallisation from a
suitable organic solvent. For the crystallisation it is preferable
to use an aliphatic hydrocarbon, particularly preferably an
aliphatic cyclic hydrocarbon, particularly cyclohexane and
methylcyclohexane.
[0072] In a preferred process according to the invention, the
compound of formula 4a is prepared by reacting a compound of
formula 5a, ##STR11## wherein PG has the meaning given in claim
1.
[0073] In the process according to the invention a compound of
formula 5a is reacted with a nitrogenating reagent in a suitable
solvent. Suitable solvents include organic solvents and acids,
preferably organic protic solvents and acids. Particularly
preferred solvents are acetic acid and sulphuric acid, particularly
acetic acid.
[0074] For the nitrogenation in the process according to the
invention it is preferable to use 6-65% nitric acid, as well as
nitronium tetrafluoroborate or acetyl nitrate. Nitric acid,
particularly 65% nitric acid, is particularly preferred.
[0075] Based on the compound 5a used, preferably at least
stoichiometric amounts of the nitrogenating reagent are used
according to the invention. If required the nitrogenating reagent
may also be used in excess, for example in amounts of up to 2
equivalents, preferably in amounts of up to 1.5 equivalents,
particularly preferably about 1 to 1.1 equivalents, based on the
compound 5a used.
[0076] After the nitrogenating reagent has been added the reaction
mixture is stirred over a period of 10 min to 4 hours, preferably
20 min to 3 hours, particularly preferably 40 to 80 minutes.
[0077] Then the reaction mixture is diluted with sufficient water
to precipitate the compound of formula 4a from the solution. To
complete the crystallisation stirring is continued for a further 20
min to 3 hours, preferably 30 min to 2 hours, particularly
preferably 40-80 min, at a temperature of 0.degree. C. to
20.degree. C., preferably at 5.degree. C. to 15.degree. C.,
particularly preferably at 8.degree. C. to 12.degree. C. The
compound of formula 4a may be obtained by separation from the
liquid phase, preferably by filtration or centrifugation.
[0078] In a preferred process according to the invention, the
compound of formula 5a is prepared by reacting a compound of
formula 6a, ##STR12##
[0079] In the process according to the invention a compound of
formula 6a is reacted in a suitable solvent with a protective group
PG-A, wherein A denotes a suitable leaving group such as for
example chlorine, bromine, iodine, methanesulphonyl,
trifluoromethanesulphonyl or p-toluenesulphonyl.
[0080] Preferably, a protective group is used which can be
eliminated as described with reference to the cleaving of the
protective group PG from compounds of formula 1a. Particularly
preferably, an optionally substituted benzyl protective group is
used.
[0081] In a preferred process according to the invention, the
compound of formula 1b is prepared by reacting a compound of
formula 2b, ##STR13## wherein R.sup.1, R.sup.2, R.sup.3 and n have
the meanings given in claims 1 to 5 and [0082] R.sup.5 denotes
Me.
[0083] In the process according to the invention a compound of
formula 2b is reacted with a strong base in a suitable solvent.
Examples of suitable solvents include organic solvents;
particularly preferred solvents are selected from among ethanol,
2-ethoxyethanol and ethyleneglycol or mixtures thereof.
Particularly preferably, 2-ethoxyethanol or ethyleneglycol or a
mixture thereof is used as the solvent according to the invention.
Preferably, the mixture consists of equal parts by volume of
2-ethoxyethanol and ethyleneglycol, although a slight excess of one
or other solvent is also possible.
[0084] The strong base used is particularly an inorganic hydroxide,
preferably an alkaline earth or alkali metal hydroxide,
particularly sodium hydroxide or potassium hydroxide. According to
the invention potassium hydroxide is of particular importance.
[0085] Based on the compound 2b used, preferably at least
stoichiometric amounts of the strong base are used according to the
invention. If required the strong base may also be used in excess,
for example in amounts of up to 8 equivalents, preferably in
amounts of up to 6 equivalents, preferably about 2 to 4,
particularly preferably 3.5 to 4.5 equivalents, based on the
compound 2b used.
[0086] The reaction is preferably carried out at elevated
temperature, preferably at a temperature of above 100.degree. C.,
particularly preferably at a temperature of above 120.degree. C.
Particularly preferably the reaction mixture is heated to
140-160.degree. C., particularly to 145-155.degree. C.
[0087] Then for extraction the reaction mixture is diluted with a
solvent and water. Solvents of particular interest are toluene,
xylene, heptane, methylcyclohexane or tert-butyl-methylether,
preferably toluene or xylene. The aqueous phase is eliminated, the
organic phase is extracted with water in additional purification
steps. The water may be acidic, neutral or alkaline, by the use of
common additives. Preferably the organic phase is extracted once
with acidified water and then with basic water. The product may be
obtained from the organic phase by elimination of the solvent.
[0088] In a preferred process according to the invention, the
compound of formula 2b is prepared by reacting a compound of
formula 3b, ##STR14## wherein R.sup.1, R.sup.2, R.sup.3 and n have
the meanings given in claims 1 to 5.
[0089] In the process according to the invention a compound of
formula 3b is reacted in a suitable solvent with acetonitrile in
the presence of an acid. Examples of suitable solvents are acids,
preferably organic acids, while the particularly preferred solvent
is acetic acid.
[0090] Based on the compound 3b used, preferably at least
stoichiometric amounts of acetonitrile are used according to the
invention. Preferably the acetonitrile is used in excess, for
example in amounts of up to 6 equivalents, preferably in amounts of
up to 5 equivalents, particularly preferably about 2 to 4
equivalents, particularly 2.5 to 3.5 equivalents, based on the
compound 3b used.
[0091] The acid in whose presence the reaction is carried out is
preferably sulphuric acid, formic acid, p-toluenesulphonic acid,
methanesulphonic acid, perchloric acid or polyphosphoric acid,
particularly preferably sulphuric acid.
[0092] Based on the compound 3b used, preferably at least
stoichiometric amounts of the acid are used according to the
invention. If required the acid may also be used in excess, for
example in amounts of up to 2 equivalents, preferably in amounts of
up to 1.5 equivalents, particularly preferably about 1 to 1.1
equivalents, based on the compound 5a used. After the acid has been
added the reaction mixture is stirred for a period of 1 to 5 hours,
preferably 2 to 4 hours, particularly preferably 170 to 190
min.
[0093] The reaction is preferably carried out at elevated
temperature, preferably at a temperature of above 30.degree. C.,
particularly preferably at a temperature of above 40.degree. C.,
particularly preferably from 45.degree. C. to 60.degree. C.
Surprisingly, it has been found that in this process no undesirable
cleaving of the methyl ether function takes place as might have
been expected from the literature (Can. J. Chem. 56 (1978),
3054-3058).
[0094] Then the reaction mixture is transferred into a second
reactor which contains a cooled mixture of solvents. Examples of
suitable solvents include mixtures of polar and non-polar solvents,
preferably aqueous, organic, polar and non-polar solvents.
Particularly preferred solvents as components of the mixture are
selected from among water, tert-butyl-methylether, tetrahydrofuran,
toluene, dioxane, hexane, cyclohexane and methylcyclohexane.
According to the invention it is particularly preferable to use, as
ingredients of the mixture, water, tert-butylmethylether,
tetrahydrofuran, toluene, cyclohexane and methylcyclohexane, while
a mixture of water, tert-butylmethylether and methylcyclohexane is
of particular importance.
[0095] Preferably the mixture of solvents is kept at a reduced
temperature, preferably at a temperature of below 20.degree. C.,
particularly preferably at a temperature below 15.degree. C.,
particularly preferably 0.degree. C. to 15.degree. C.
[0096] In order to precipitate the product out of the solvent, the
pH of the reaction mixture is raised, preferably into the basic
range, particularly preferably from pH 8 to 12, particularly from
pH 9 to 10. Preferably an ammonia solution is used to raise the pH
value.
[0097] After the addition has ended and the pH has been adjusted
the reaction mixture is stirred for a period of 10 min to 3 hours,
preferably 20 min to 2 hours, particularly preferably 50 to 70
min.
[0098] Then the product is removed by centrifuging and washed with
the above-mentioned solvents used for the reaction. A product of
greater purity can be obtained by further recrystallisation, or
precipitation, e.g. with C.sub.1-8-alcohols and water.
[0099] In a preferred process according to the invention, the
compound of formula 3b is prepared by reacting a compound of
formula 4b, ##STR15## wherein R.sup.1, R.sup.2, R.sup.3 and n have
the meanings given in claims 1 to 5.
[0100] In the process according to the invention a compound of
formula 4b is subjected to a Grignard reaction in a suitable
solvent with methylmagnesium bromide. Organic solvents are suitable
for use as the solvent. Preferred solvents are selected from among
diethyl ether, tert-butyl-methylether, tetrahydrofuran, toluene and
dioxane. According to the invention it is particularly preferable
to use tert-butyl-methylether, tetrahydrofuran and toluene as
solvent.
[0101] The reaction is preferably carried out at ambient
temperature, preferably at a temperature of 10 to 20.degree. C.,
particularly preferably at a temperature of 15 to 25.degree. C.
[0102] After the educts have been combined the reaction mixture is
stirred for a period of 10 min to 3 hours, preferably 20 min to 2
hours, particularly preferably 50 to 70 min.
[0103] To stop the reaction, water and an acid, preferably
sulphuric acid, are added to the reaction mixture. After extraction
of the organic phase using standard methods the product may be
isolated by elimination of the solvent. The purity of the product
can be increased by recrystallisation from an organic non-polar
solvent, preferably n-heptane.
[0104] The invention further relates to the new intermediate
products of formula 3a, ##STR16## wherein PG has the meaning given
in claim 1.
[0105] The invention further relates to the new intermediate
products of formula 4a, ##STR17## wherein PG has the meaning given
in claim 1.
[0106] The invention further relates to the new intermediate
products of formula 4a.sup.#, ##STR18## wherein PG has the meaning
given in claim 1.
[0107] The invention further relates to the new intermediate
products of formula 2b, ##STR19## wherein R.sup.1, R.sup.2, R.sup.3
and n have the meanings given in claims 1 to 5 and [0108] R.sup.5
denotes Me.
[0109] The subject matter of the invention also includes a process
for preparing compounds of formula 2a, ##STR20## wherein PG has the
meaning given in claim 1 and R.sup.4 denotes halogen, preferably
bromine or chlorine, characterised in that a compound of formula
3a, ##STR21## wherein PG has the meaning given in claim 1, is
reacted with the halogenating reagent selected from among
tetrabutylammonium tribromide, benzyltrimethylammonium
dichloriodide, N-bromo-succinimide, N-chloro-succinimide, sulphuryl
chloride and bromine/dioxane, preferably tetrabutylammonium
tribromide or N-bromo-succinimide.
[0110] The subject matter of the invention also includes a process
for preparing compounds of formula 3a, ##STR22## wherein PG has the
meaning given in claim 1, characterised in that a compound of
formula 4a, ##STR23## wherein PG has the meaning given in claim 1,
is subjected to catalytic hydrogenation and then reacted with
chloroacetyl chloride.
[0111] The subject matter of the invention also includes a process
according to claim 16, wherein a compound of formula 4a.sup.#,
##STR24## wherein PG has the meaning given in claim 1, is formed as
the intermediate product of the hydrogenation.
[0112] The subject matter of the invention also includes a process
for preparing compounds of formula 4a, ##STR25## wherein PG has the
meaning given in claim 1 and is characterised in that a compound of
formula 5a, ##STR26## wherein PG has the meaning given in claim 1,
is reacted with a nitrogenating reagent selected from among 65%
nitric acid, potassium nitrate/sulphuric acid or nitronium
tetrafluoroborate, preferably 65% nitric acid.
[0113] The subject matter of the invention also includes a process
for preparing compounds of formula 1b, ##STR27## wherein R.sup.1,
R.sup.2, R.sup.3 and n have the meanings given in claims 1 to 5,
characterised in that a compound of formula 2b, ##STR28## wherein
R.sup.1, R.sup.2, R.sup.3 and n have the meanings given in claims 1
to 5 and R.sup.5 denotes Me, is reacted with a base selected from
among potassium hydroxide, sodium hydroxide, lithium hydroxide and
caesium hydroxide, preferably potassium hydroxide or sodium
hydroxide.
[0114] The subject matter of the invention also includes a process
for preparing compounds of formula 2b, ##STR29## wherein R.sup.1,
R.sup.2, R.sup.3 and n have the meanings given in claims 1 to 5 and
[0115] R.sup.5 denotes Me, [0116] characterised in that a compound
of formula 3b, ##STR30## wherein R.sup.1, R.sup.2, R.sup.3 and n
have the meanings given in claims 1 to 5, is reacted with a
compound of formula ##STR31## wherein R.sup.5 has the meaning given
above, in the presence of a hygroscopic reagent selected from among
sulphuric acid, formic acid, p-toluenesulphonic acid,
methanesulphonic acid, perchloric acid and polyphosphoric acid,
preferably sulphuric acid, and is then reacted with a base selected
from among aqueous solutions of ammonia, sodium hydroxide,
potassium hydroxide, sodium carbonate and potassium carbonate.
Terms and Definitions Used
[0117] By an "organic solvent" is meant, within the scope of the
invention, an organic, low-molecular substance which can dissolve
other organic substances by a physical method. To be suitable the
prerequisite for the solvent is that neither the dissolving
substance nor the dissolved substance should be chemically altered
during the dissolving process, i.e. the components of the solution
should be recoverable in their original form by physical separation
processes such as distillation, crystallisation, sublimation,
evaporation or adsorption. For various reasons, not only the pure
solvents but also mixtures that combine the dissolving properties
may be used. Examples include: [0118] alcohols, preferably
methanol, ethanol, propanol, butanol, octanol, cyclohexanol; [0119]
glycols, preferably ethyleneglycol, diethyleneglycol; [0120]
ethers/glycolethers, preferably diethyl ether,
tert-butyl-methylether, dibutylether, anisol, dioxane,
tetrahydrofuran, mono-, di-, tri-, polyethyleneglycol ethers;
[0121] ketones, preferably acetone, butanone, cyclohexanone; [0122]
esters, preferably acetic acid esters, glycolesters; [0123] amides
and other nitrogen compounds, preferably dimethylformamide,
pyridine, N-methylpyrrolidone, acetonitrile; [0124] sulphur
compounds, preferably carbon disulphide, dimethylsulphoxide,
sulpholane; [0125] nitro compounds, preferably nitrobenzene; [0126]
halogenated hydrocarbons, preferably dichloromethane, chloroform,
tetrachlormethane, tri- and tetrachloroethene, 1,2-dichloroethane,
chlorofluorocarbons; [0127] aliphatic or alicyclic hydrocarbons,
preferably benzines, petroleum ether, cyclohexane,
methylcyclohexane, decaline, terpene-L; or [0128] aromatic
hydrocarbons, preferably benzene, toluene, o-xylene, m-xylene,
p-xylene; or corresponding mixtures thereof.
[0129] By the term "C.sub.1-4-alkyl" (including those which are
part of other groups) are meant branched and unbranched alkyl
groups with 1 to 4 carbon atoms. Examples include: methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl.
In some cases the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu,
t-Bu, etc. are also used for the above-mentioned groups. Unless
stated otherwise, the definitions propyl and butyl include all the
possible isomeric forms of the groups in question. Thus, for
example, propyl includes n-propyl and iso-propyl, butyl includes
iso-butyl, sec-butyl and tert-butyl etc.
[0130] By the term "C.sub.1-4-alkylene" (including those which are
part of other groups) are meant branched and unbranched alkylene
groups with 1 to 4 carbon atoms. Examples include: methylene,
ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene,
1,1-dimethylethylene or 1,2-dimethylethylene. Unless stated
otherwise, the definitions propylene and butylene include all the
possible isomeric forms of the groups in question with the same
number of carbons. Thus, for example, propyl also includes
1-methylethylene and butylene includes 1-methylpropylene,
1,1-dimethylethylene, 1,2-dimethylethylene.
[0131] By the term "C.sub.1-8-alcohol" are meant branched and
unbranched alcohols with 1 to 8 carbon atoms and one or two hydroxy
groups. Alcohols with 1 to 4 carbon atoms are preferred. Examples
include: methanol, ethanol, n-propanol, iso-propanol, n-butanol,
iso-butanol, sec-butanol or tert-butanol. In some cases the
abbreviations MeOH, EtOH, n-PrOH, i-PrOH, n-BuOH, i-BuOH, t-BuOH,
etc. are optionally also used for the above-mentioned molecules.
Unless stated otherwise, the definitions propanol, butanol,
pentanol and hexanol include all the possible isomeric forms of the
groups in question. Thus for example propanol includes n-propanol
and iso-propanol, butanol includes iso-butanol, sec-butanol and
tert-butanol etc.
[0132] By the term "C.sub.3-8-esters" are meant branched and
unbranched esters with a total of 3 to 8 carbon atoms. Esters of
acetic acid with 3 to 6 carbon atoms are preferred. Examples
include: methyl acetate, ethyl acetate, n-propyl acetate, i-propyl
acetate or n-butyl acetate, of which ethyl acetate is
preferred.
[0133] "Halogen" within the scope of the present invention denotes
fluorine, chlorine, bromine or iodine. Unless stated to the
contrary, fluorine, chlorine and bromine are regarded as preferred
halogens.
[0134] "Protective groups" for the purposes of the present
invention is a collective term for organic groups with which
certain functional groups of a molecule containing a number of
active centres can temporarily be protected from attack by reagents
so that reactions take place only at the desired (unprotected)
sites. The protective groups should be introduced selectively under
mild conditions. They must be stable for the duration of the
protection under all the conditions of the reactions and purifying
procedures which are to be carried out; racemisations and
epimerisations must be suppressed. Protective groups should be
capable of being cleaved again under mild conditions selectively
and ideally in high yields. The choice of a suitable protective
group, the reaction conditions (solvent, temperature, duration,
etc.), and also the options for removing a protective group are
known in the art (e.g. Philip Kocienski, Protecting Groups, 3rd ed.
2004, THIEME, Stuttgart, ISBN: 3131370033). Preferred protective
groups are optionally substituted benzyl, diphenylmethyl, trityl,
tosyl, mesyl or triflate, of which optionally substituted benzyl is
particularly preferred.
EXPERIMENTAL SECTION
[0135] ##STR32## wherein Bn denotes benzyl and [0136] n may denote
1 or 2; [0137] R.sup.1 may denote hydrogen, halogen,
C.sub.1-4-alkyl or O--C.sub.1-4-alkyl; [0138] R.sup.2 may denote
hydrogen, halogen, C.sub.1-4-alkyl or O--C.sub.1-4-alkyl; [0139]
R.sup.3 may denote hydrogen, C.sub.1-4-alkyl, OH, halogen,
O--C.sub.1-4-alkyl, O--C.sub.1-4-alkylene-COOH,
O--C.sub.1-4-alkylene-COO--C.sub.1-4-alkyl.
[0140]
8-[(1R)-1-hydroxy-2-[[2-aryl-1,1-dimethyl-ethyl]-amino]ethyl]-6-(p-
henylmethoxy)-2H-1,4-benzoxazin-3(4H)-one-hydrochloride of formula
1c: 7.00 kg (23.54 mol)
8-(2R)-oxiranyl-6-(phenylmethoxy)-2H-1,4-benzoxazin-3 (4H)-one 1a
and 34.70 mol aryl-1,1-dimethyl-ethylamine of formula 1b are placed
in 70 l 1,4-dioxane. The reactor contents are heated to 97.degree.
C. and stirred for 48 hours at this temperature. Then the mixture
is cooled to 40.degree. C. and 56 l of 1,4-dioxane are distilled
off in vacuo. 70 l ethanol are added to the residue, it is cooled
to 25.degree. C., and 4.15 kg (34.14 mol) hydrochloric acid (30%)
are added at 25.degree. C. within 15 minutes. Then the mixture is
inoculated and stirred until crystallisation occurs. The resulting
suspension is cooled to 20.degree. C. and stirred for a further 2
hours. The product is centrifuged, washed with 21 l of ethanol and
dried in vacuo at 50.degree. C.
[0141] Yield (1c): 84-90%, enantiomer purity according to HPLC:
89.5-99.5%.
[0142]
6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-aryl-1,1-dimethyl-ethyl]-amino]e-
thyl]-2H-1,4-benzoxazin-3(4H)-one-hydrochloride of formula 1: 19.49
mol of
8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethyl-ethyl]-amino]ethyl-
]-6-(phenylmethoxy)-2H-1,4-benzoxazin-3(4H)-one-hydrochloride of
formula 1c are placed in the hydrogenation reactor and suspended
with 40 l methanol. 500 g palladium on charcoal 10% (50% water) are
suspended in 17 l methanol and added to the hydrogenation reactor.
The mixture is hydrogenated at 40.degree. C. internal temperature
and at 3 bar hydrogen pressure until no further uptake of hydrogen
is discernible. The catalyst is filtered off and rinsed with 13.3 l
methanol. 60 l of methanol are distilled off under a weak vacuum.
If there is no crystal formation, the distillation residue is
inoculated. Then at 50.degree. C. 30 l of propanol are metered in
and within 1 hour the mixture is cooled to 0.degree. C. At
0.degree. C. it is stirred for 1 hour, suction filtered and washed
with 15 l cold i-propanol. The moist product is dissolved in 50
litres of methanol. The resulting solution is filtered clear and
the pressure filter is rinsed with 10 litres of methanol. Then 52 l
methanol are distilled off under a weak vacuum (about 500 mbar). If
there is no crystal formation, the distillation residue is
inoculated.
[0143] Then 22.6 l i-propanol are metered in. The mixture is cooled
to 0.degree. C., and the suspension is stirred for 1 hour at
0.degree. C. The suspension is suction filtered, washed with 15
litres of cold i-propanol and dried in vacuo at 50.degree. C. Yield
(1): 63-70%.
[0144] 1-[2-hydroxy-5-(phenylmethoxy)-phenyl]-ethanone: 20 kg
(131.4 mol) 2-acetyl-hydroquinone 6a are dissolved in 150 l
methylisobutylketone and combined with 19.98 kg (144.6 mol)
potassium carbonate. At 60.degree. C., 22.48 kg (131.5 mol) benzyl
bromide are added. The reaction mixture is stirred for 20 hours at
60.degree. C. The reaction mixture is cooled to 25.degree. C. and
the solid is filtered off. The filtrate is washed twice with a
solution of 0.96 kg (11.8 mol) sodium hydroxide solution (50%) and
60 l water at 25.degree. C. The methylisobutylketone is largely
distilled off in vacuo, and the residue is dissolved in 80 l
methanol at 60.degree. C. The solution is cooled to 0.degree. C.
and stirred for 1 hour at this temperature to complete the
crystallisation.
[0145] Yield (5a): 24.07 kg (75.6%), chemical purity according to
HPLC: 99.2%.
[0146] 1-[2-hydroxy-3-nitro-5-(phenylmethoxy)-phenyl]-ethanone:
10.00 kg (41.27 mol)
1-[2-hydroxy-5-(phenylmethoxy)-phenyl]-ethanone 5a are dissolved in
50 l acetic acid. 4.40 kg (45.40 mol) nitric acid 65% are metered
into this solution at 15 to 20.degree. C. The feed vessel is rinsed
with 4 l acetic acid. The reaction mixture is stirred for 1 hour.
After inoculation 50 l water are added. The suspension obtained is
stirred for 1 hour at 10.degree. C. to complete the
crystallisation. The product is centrifuged and dried at 50.degree.
C.
[0147] Yield (4a): 10.34 kg (87.2%), chemical purity according to
HPLC: 99.0%.
[0148] 8-acetyl-6-(phenylmethoxy)-2H-1,4-benzoxazin-3(4H)-one:
15.00 kg (52.22 mol)
1-[2-hydroxy-3-nitro-5-(phenylmethoxy)-phenyl]-ethanone 4a, 0.165
kg platinum(IV)oxide and 45 l 2-methyltetrahydrofuran are
hydrogenated at 3 bar hydrogen pressure and an internal temperature
of 25.degree. C. until no further hydrogen uptake is discernible.
The catalyst is filtered off and washed with 20 l of
2-methyltetrahydrofuran. 23.09 kg (167.09 mol) potassium carbonate
are placed in another reactor, and the reaction mixture from the
first reactor is added. It is rinsed with 22 l of
2-methyltetrahydrofuran. Then within 30 minutes 9.44 kg (83.55 mol)
chloroacetyl chloride are metered into the suspension. After 2.5
hours reaction time at 65.degree. C., 101 l water are added. The
aqueous phase is separated off at 55.degree. C. Then 34 l
2-methyltetrahydrofuran are distilled off from the organic phase in
vacuo. After heating to reflux temperature, 180 l methylcyclohexane
are metered in within 30 minutes at reflux temperature. The
suspension obtained is cooled to 20.degree. C. and stirred for
another 1 hour at this temperature to complete the crystallisation.
Then the precipitate is removed by centrifuging, washed with 113 l
methylcyclohexane and dried at 50.degree. C.
[0149] Yield (3a): 12.70 kg (81.8%), chemical purity according to
HPLC: 98.4%.
[0150]
8-(bromoacetyl)-6-(phenylmethoxy)-2H-1,4-benzoxazin-3(4H)-one:
12.00 kg (40.36 mol)
8-acetyl-6-(phenylmethoxy)-2H-1,4-benzoxazin-3(4H)-one 3a are
dissolved in 108 l 1,4-dioxane. Then a solution of 24.33 kg (50.45
mol) tetrabutylammonium tribromide in 48 l of 1,4-dioxane and 12 l
methanol is metered into the suspension at 20.degree. C. The
reactor contents are stirred for 2 hours at 20.degree. C. Then 72 l
water are added at 20.degree. C. within 15 minutes. After cooling
to 3.degree. C. the mixture is stirred for 1 hour, centrifuged and
washed with a mixture of 9 l of 1,4-dioxane and 4.5 l water. Then
it is washed with 60 l water and dried in vacuo at 50.degree.
C.
[0151] Yield (2a): 11.29 kg (74.4%), chemical purity according to
HPLC: 98.0%.
[0152]
8-(2R)-Oxiranyl-6-(phenylmethoxy)-2H-1,4-benzoxazin-3(4H)-one:
12.00 kg (31.90 mol)
8-(bromoacetyl)-6-(phenylmethoxy)-2H-1,4-benzoxazin-3(4H)-one 2a
are dissolved in 180 l tetrahydrofuran and cooled to -30.degree. C.
63 kg (70.18 mol) (-)-DIP chloride in hexane 65% are metered in
within 1.5 hours. The reaction mixture is stirred for 1 hour and
heated to 0.degree. C. At this temperature 11.48 kg (143.54 mol)
sodium hydroxide solution (50%), mixed with 36 l water, are metered
in. Then the feed vessel is rinsed with 9 l water. The pH value at
the end of the addition should be 13. The mixture is heated to
20.degree. C. and stirred for 1 hour. A mixture of 4.5 l (42.11
mol) industrial grade hydrochloric acid (30%) and 18.6 l water is
metered in until a pH of 8.5 is achieved. After the addition of 84
l of ethyl acetate the mixture is heated to 30.degree. C. After
phase separation half the solvent is distilled off from the organic
phase, the residue is combined with 120 l tert-butyl-methylether,
cooled to 0.degree. C. and stirred for 1 hour. The product is
isolated, washed with tert-butylmethylether and dried in vacuo at
50.degree. C.
[0153] Yield (1a): 8.06 kg (85.0%), purity of enantiomers according
to HPLC: 98.3%.
[0154] Compounds of formula 3b: 24.68 kg (72.6 mol) methylmagnesium
chloride (22% solution in THF) are dissolved in 35 l toluene and
cooled to 16.degree. C. At 16-22.degree. C. a solution of 60.9 mol
arylacetone of formula 4b and 10 l toluene is metered in and the
mixture is stirred at 22.degree. C. for 1 hour. The reaction
solution is metered into a mixture of 45 l water and 5.22 kg (51.1
mol) sulphuric acid at a temperature of 2-17.degree. C. The
two-phase mixture is stirred, and the aqueous phase is separated
off. The organic phase is washed with a solution of 1.00 kg (11.9
mol) sodium hydrogen carbonate and 11 l water. The solvent is
dissolved off completely in vacuo. The residue is dissolved in 65.5
l of n-heptane. After cooling to 2.degree. C. the reaction mixture
is stirred for 3 hours at this temperature. Then the product is
isolated, washed with 17.5 l of n-heptane and dried in vacuo at
25.degree. C.
[0155] Yield (3b): 75-80%, chemical purity according to HPLC:
98.9-99.9%.
[0156] Compounds of formula 2b: 55.48 mol of
1-aryl-2-methyl-propan-2-ol of formula 3b are placed in 6.83 kg
(166.44 mol) acetonitrile and 13 l acetic acid and heated to
40.degree. C. 5.66 kg (55.48 mol) sulphuric acid are metered in at
50-55.degree. C. Then the mixture is stirred for 3 hours at
50.degree. C. In a second reactor 160 l water, 20 l
tert-butylmethylether and 21 l methylcyclohexane are cooled to
10.degree. C. The contents of the first reactor are transferred
into the second reactor. The pH of the reactor contents is adjusted
to 9.5 with about 40 l of ammonia solution (25%). The suspension is
cooled to 5.degree. C. and stirred for 1 hour at this temperature.
The product is separated by centrifuging and washed with 30 l water
as well as with a mixture of 7.5 l tert-butylmethylether and 7.5 l
methylcyclohexane. The damp product is heated to 75.degree. C. in
25 l ethanol (96%) and at this temperature combined with 30 l
water. The solution is stirred for 15 minutes at 85.degree. C.,
then cooled to 2.degree. C. and stirred for 1 hour at this
temperature. The product is isolated, washed with a mixture of 5 l
water and 5 l ethanol (96%) and dried.
[0157] Yield (2b): 65-71%, chemical purity according to HPLC:
98.6-99.8%.
[0158] Compounds of formula 1b: A mixture of 45.2 mol
N-[2-aryl-1,1-dimethyl-ethyl]-acetamide of formula 2b, 12.07 kg KOH
(180.8 mol), 15 l ethoxyethanol and 15 l ethyleneglycol is heated
to 150.degree. C. for 12 hours. After cooling to ambient
temperature the mixture is diluted with 61 l water and 31 l
toluene. The phases are separated and the organic phase is washed
once more with 30 l water. The organic phase is combined with 52 l
water. It is acidified with 8.91 kg hydrochloric acid (90.4 mol).
After phase separation the aqueous product phase is combined with
30 l toluene and made alkaline with 9.04 kg 50% NaOH (113.0 mol).
After phase separation the organic product phase is evaporated down
in vacuo to leave an oily residue.
[0159] Yield (1b): 69-75%, chemical purity according to HPLC:
94-96%.
[0160] In the methods described above for synthesising the
compounds of formulae 3b, 2b and 1b the groups R.sup.1, R.sup.2 and
R.sup.3 may have the following meanings, for example:
TABLE-US-00001 R.sup.1 R.sup.2 R.sup.3 Example 1 H H OMe Example 2
2-F H F Example 3 3-F 5-F H Example 4 H H OEt Example 5 H H F
[0161] Analogously to the preparation methods described
hereinbefore it is thus possible to obtain the R-forms of the
following compounds of formula 1: [0162]
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one; [0163]
8-{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one; [0164]
8-{2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one; [0165]
8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one; [0166]
8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one.
* * * * *