U.S. patent application number 11/749207 was filed with the patent office on 2007-09-13 for process for the manufacture of fused piperazin-2-one derivatives.
Invention is credited to Adil DURAN, Guenter Linz.
Application Number | 20070213534 11/749207 |
Document ID | / |
Family ID | 35923724 |
Filed Date | 2007-09-13 |
United States Patent
Application |
20070213534 |
Kind Code |
A1 |
DURAN; Adil ; et
al. |
September 13, 2007 |
Process for the Manufacture of fused piperazin-2-one
derivatives
Abstract
Disclosed are processes for the preparation of fused
piperazin-2-one derivatives of general formula (I) ##STR1## wherein
the groups R.sup.1 to R.sup.5, A.sub.1 and A.sub.2 have the
meanings given in the claims and in the description, particularly
the preparation of 7,8-dihydro-5H-pteridin-6-one derivatives and
intermediates thereof.
Inventors: |
DURAN; Adil; (Biberach,
DE) ; Linz; Guenter; (Mittelbiberach, DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Family ID: |
35923724 |
Appl. No.: |
11/749207 |
Filed: |
May 16, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11284836 |
Nov 22, 2005 |
7238807 |
|
|
11749207 |
May 16, 2007 |
|
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Current U.S.
Class: |
544/354 |
Current CPC
Class: |
C07D 475/00 20130101;
A61P 35/00 20180101; A61P 35/04 20180101 |
Class at
Publication: |
544/354 |
International
Class: |
C07D 241/36 20060101
C07D241/36 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 2, 2004 |
DE |
10 2004 058 337 |
Claims
1. A process for preparing compounds of the formula I ##STR12##
wherein R.sup.1 denotes a group selected from the group consisting
of chlorine, fluorine, bromine, methanesulphonyl, ethanesulphonyl,
trifluoromethanesulphonyl, para-toluenesulphonyl,
CH.sub.3S(.dbd.O)-- and phenylS(.dbd.O)--, R.sup.2 denotes hydrogen
or C.sub.1-C.sub.3-alkyl, R.sup.4, R.sup.5 which may be identical
or different denote hydrogen or optionally substituted
C.sub.1-C.sub.6-alkyl, or R.sup.4 and R.sup.5 together denote a 2-
to 5-membered alkyl bridge, which may contain 1 to 2 heteroatoms,
and R.sup.4 and R.sup.3 or --R.sup.5 and R.sup.3 together denote a
saturated or unsaturated C.sub.3-C.sub.4-alkyl bridge, which may
optionally contain 1 heteroatom, and A.sub.1 and A.sub.2 denote
--CH.dbd., comprising a) hydrogenating with hydrogen in the
presence of a hydrogenation catalyst and a compound of formula II
##STR13## wherein R.sup.1 to R.sup.5, A.sub.1 and A.sub.2 have the
meanings given above and R.sup.6 denotes C.sub.1-C.sub.4-alkyl, and
b) adding a copper, iron or vanadium compound, wherein in which
steps a) and b) may take place simultaneously or successively.
2. The process according to claim 1, wherein in step b) a copper
compound is added.
3. The process according to claim 1, wherein in step b) an iron
compound is added.
4. The process according to claim 1, wherein in step b) a vanadium
compound is added.
5. The process according to claim 1 wherein steps a) and b) are
carried out successively.
6. The process according to claim 5, wherein that after the first
step a) the intermediate product of formula III is first obtained,
which may optionally be isolated, ##STR14## and after the
subsequent step b) a compound of formula I is obtained.
7. The process according to claim 1, wherein steps a) and b) are
carried out simultaneously.
8. The process according to claim 1, wherein the hydrogenation
catalyst is selected from the group consisting of rhodium,
ruthenium, iridium, platinum, palladium and nickel.
9. The process according to claim 1, wherein the amount of
hydrogenation catalyst added is between 0.1 and 10 wt.-%, based on
the compound of formula (II) used.
10. The process according to claim 1, wherein the amount of copper,
iron or vanadium compound added is between 0.01 and 10 wt.-%, based
on the compound of formula (II) used.
11. The process according to claim 1, wherein the reaction is
carried out in a solvent or mixture of solvents selected from the
group consisting of dipolar, aprotic solvents, alcohols, ethers,
esters, carboxylic acids, apolar solvents, acetonitrile, methylene
chloride and water.
12. The process according to claim 1, wherein the reaction
temperature is between 0.degree. C. and 150.degree. C.
13. The process according to claim 1, wherein the hydrogen pressure
is from 1 bar to 100 bar.
14. A process for preparing compounds of the formula I ##STR15##
wherein R.sup.1 denotes a group selected from the group consisting
of chlorine, fluorine, bromine, methanesulphonyl, ethanesulphonyl,
trifluoromethanesulphonyl, para-toluenesulphonyl,
CH.sub.3S(.dbd.O)-- and phenylS(.dbd.O)--, R.sup.2 denotes hydrogen
or C.sub.1-C.sub.3-alkyl, R.sup.4, R.sup.5 which may be identical
or different denote hydrogen or optionally substituted
C.sub.1-C.sub.6-alkyl, or R.sup.4 and R.sup.5 together denote a 2-
to 5-membered alkyl bridge, which may contain 1 to 2 heteroatoms,
and R.sup.4 and R.sup.3 or --R.sup.5 and R.sup.3 together denote a
saturated or unsaturated C.sub.3-C.sub.4-alkyl bridge, which may
optionally contain 1 heteroatom, and A.sub.1 and A.sub.2 denote
--CH.dbd., comprising hydrogenating a compound of formula III with
hydrogen in the presence of a hydrogenation catalyst and a copper,
iron or vanadium compound ##STR16## wherein R.sup.1 to R.sup.5 and
A.sub.1, A.sub.2 have the meanings given above in this claim.
Description
APPLICATION DATA
[0001] This application is a divisional application of U.S.
application Ser. No. 11/284,836 filed Nov. 22, 2005 which claims
priority to German application DE 10 2004 058 337 filed Dec. 2,
2004, both of which are incorporated herein in their entirety by
reference.
[0002] The invention relates to a process for preparing fused
piperazin-2-one derivatives of general formula (I) ##STR2## wherein
the groups R.sup.1 to R.sup.5 have the meanings given in the claims
and specification, particularly a process for preparing
7,8-dihydro-5H-pteridin-6-one derivatives.
BACKGROUND TO THE INVENTION
[0003] Pteridinone derivatives are known from the prior art as
active substances with an antiproliferative activity. WO 03/020722
describes the use of dihydropteridinone derivatives for the
treatment of tumoral diseases and processes for preparing them.
[0004] 7,8-Dihydro-5H-pteridin-6-one derivatives of formula (I) are
important intermediate products in the synthesis of these active
substances. Up till now they have been prepared using methods
involving reduction of nitro compounds of formula (II) below, which
led to strongly coloured product mixtures and required laborious
working up and purification processes.
[0005] WO 96/36597 describes the catalytic hydrogenation of nitro
compounds using noble metal catalysts with the addition of a
vanadium compound, while disclosing as end products free amines,
but no lactams.
[0006] The aim of the present invention is to provide an improved
process for preparing compounds of formula (I), particularly
7,8-dihydro-5H-pteridin-6-one derivatives.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The present invention solves the problem outlined above by
the method of synthesising compounds of formula (I) described
hereinafter.
[0008] The invention thus relates to a process for preparing
compounds of general formula I ##STR3## wherein [0009] R.sup.1
denotes a group selected from the group consisting of chlorine,
fluorine, bromine, methanesulphonyl, ethanesulphonyl,
trifluoromethanesulphonyl, para-toluenesulphonyl,
CH.sub.3S(.dbd.O)-- and phenylS(.dbd.O)-- [0010] R.sup.2 denotes
hydrogen or C.sub.1-C.sub.3-alkyl, [0011] R.sup.3 denotes hydrogen
or a group selected from the group consisting of optionally
substituted C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkynyl and C.sub.6-C.sub.14-aryl, or a group
selected from the group consisting of optionally substituted and/or
bridged C.sub.3-C.sub.12-cycloalkyl, C.sub.3-C.sub.12-cycloalkenyl,
C.sub.7-C.sub.12-polycycloalkyl, C.sub.7-C.sub.12-polycycloalkenyl,
C.sub.5-C.sub.12-spirocycloalkyl and saturated or unsaturated
C.sub.3-C.sub.12-heterocycloalkyl, which contains 1 to 2
heteroatoms, [0012] R.sup.4, R.sup.5 which may be identical or
different denote hydrogen or optionally substituted
C.sub.1-C.sub.6-alkyl, or [0013] R.sup.4 and R.sup.5 together
denote a 2- to 5-membered alkyl bridge which may contain 1 to 2
heteroatoms, or [0014] R.sup.4 and R.sup.3 or R.sup.5 and R.sup.3
together denote a saturated or unsaturated C.sub.3-C.sub.4-alkyl
bridge, which may optionally contain 1 heteroatom, and [0015]
A.sub.1 and A.sub.2 which may be identical or different represent
--CH.dbd. or --N.dbd., preferably --N.dbd., in which a compound of
formula II ##STR4## wherein [0016] R.sup.1-R.sup.5 and A.sub.1,
A.sub.2 have the stated meaning and [0017] R.sup.6 denotes
C.sub.1-C.sub.4-alkyl, [0018] a) is hydrogenated with hydrogen in
the presence of a hydrogenation catalyst and [0019] b) a copper,
iron or vanadium compound is added, in which steps a) and b) may
take place simultaneously or successively.
[0020] In a preferred process, the hydrogenation of the compound of
formula II is carried out directly in the presence of the
hydrogenation catalyst and the copper, iron or vanadium compound to
form the compound of formula I.
[0021] In a particularly preferred process, after the first
hydrogenation step a), first of all the intermediate product of
formula III is obtained, which may optionally be isolated, ##STR5##
and is then further reduced in the presence of a hydrogenation
catalyst and a copper, iron or vanadium compound to form a compound
of formula I ##STR6##
[0022] Also preferred is a process in which the hydrogenation
catalyst is selected from the group consisting of rhodium,
ruthenium, iridium, platinum, palladium and nickel, preferably
platinum, palladium and Raney nickel. Platinum is particularly
preferred. Platinum may be used in metallic form or oxidised form
as platinum oxide on carriers such as e.g. activated charcoal,
silicon dioxide, aluminium oxide, calcium carbonate, calcium
phosphate, calcium sulphate, barium sulphate, titanium dioxide,
magnesium oxide, iron oxide, lead oxide, lead sulphate or lead
carbonate and optionally additionally doped with sulphur or lead.
The preferred carrier material is activated charcoal, silicon
dioxide or aluminium oxide.
[0023] Preferred copper compounds are compounds in which copper
assumes oxidation states I or II, for example the halides of copper
such as e.g. CuCl, CuCl.sub.2, CuBr, CuBr.sub.2, CuI or CuSO.sub.4.
Preferred iron compounds are compounds wherein iron assumes
oxidation states II or III, for example the halides of iron such as
e.g. FeCl.sub.2, FeCl.sub.3, FeBr.sub.2, FeBr.sub.3, FeF.sub.2 or
other iron compounds such as e.g. FeSO.sub.4, FePO.sub.4 or
Fe(acac).sub.2.
[0024] Preferred vanadium compounds are compounds wherein vanadium
assumes the oxidation states 0, II, III, IV or V, for example
inorganic or organic compounds or complexes such as e.g.
V.sub.2O.sub.3, V.sub.2O.sub.5, V.sub.2O.sub.4, Na.sub.4VO.sub.4,
NaVO.sub.3, NH.sub.4VO.sub.3, VOCl.sub.2, VOCl.sub.3, VOSO.sub.4,
VCl.sub.2, VCl.sub.3, vanadium oxobis(1-phenyl-1,3-butanedionate),
vanadium oxotriisopropoxide, vanadium(III) acetylacetonate
[V(acac).sub.3] or vanadium(IV) oxyacetylacetonate
[VO(acac).sub.2]. Vanadium(IV) oxyacetylacetonate [VO(acac).sub.2]
is particularly preferred
[0025] The copper, iron or vanadium compound may be used either
directly at the start of the hydrogenation or after the formation
of the intermediate of formula (III), as preferred.
[0026] Also preferred is a process wherein the amount of added
hydrogenation catalyst is between 0.1 and 10 wt.-% based on the
compound of formula (II) used.
[0027] Also preferred is a process wherein the amount of copper,
iron or vanadium compound used is between 0.01 and 10 wt.-% based
on the compound of formula (II) used.
[0028] Also preferred is a process wherein the reaction is carried
out in a solvent selected from the group consisting of dipolar,
aprotic solvents, for example dimethylformamide, dimethylacetamide,
N-methylpyrrolidinone, dimethylsulphoxide or sulpholane; alcohols,
for example methanol, ethanol, 1-propanol, 2-propanol, the various
isomeric alcohols of butane and pentane; ethers, for example
diethyl ether, methyl-tert.-butylether, tetrahydrofuran,
2-methyltetrahydrofuran, dioxane or dimethoxyethane; esters, for
example ethyl acetate, 2-propylacetate or 1-butylacetate; ketones,
for example acetone, methylethylketone or methylisobutylketone;
carboxylic acids, for example acetic acid; apolar solvents, for
example toluene, xylene, cyclohexane or methylcyclohexane, as well
as acetonitrile, methylene chloride and water. The solvents may
also be used as mixtures.
[0029] Also preferred is a process wherein the reaction temperature
is between 0.degree. C. and 150.degree. C., preferably between
20.degree. C. and 100.degree. C.
[0030] Also preferred is a process wherein the hydrogen pressure is
1 bar to 100 bar.
[0031] The invention further relates to a compound of formula (III)
##STR7## wherein R.sup.1 to R.sup.5 may have the stated
meaning.
[0032] Preferred compounds of formula (III) are those wherein
A.sub.1 and A.sub.2 are identical and denote --N.dbd..
[0033] The reactions are worked up by conventional methods e.g. by
extractive purification steps or precipitation and crystallisation
methods.
[0034] The compounds according to the invention may be present in
the form of the individual optical isomers, mixtures of the
individual enantiomers, diastereomers or racemates, in the form of
the tautomers as well as in the form of the free bases or the
corresponding acid addition salts with acids--such as for example
acid addition salts with hydrohalic acids, for example hydrochloric
or hydrobromic acid, or organic acids, such as for example oxalic,
fumaric, diglycolic or methanesulphonic acid.
[0035] Examples of alkyl groups, including those which are part of
other groups, are branched and unbranched alkyl groups with 1 to 12
carbon atoms, preferably 1-6, particularly preferably 1-4 carbon
atoms, such as for example: methyl, ethyl, propyl, butyl, pentyl,
hexyl, heptyl, octyl, nonyl, decyl and dodecyl. Unless otherwise
stated, the above-mentioned designations propyl, butyl, pentyl,
hexyl, heptyl, octyl, nonyl, decyl and dodecyl include all the
possible isomeric forms. For example the term propyl includes the
two isomeric groups n-propyl and iso-propyl, the term butyl
includes n-butyl, iso-butyl, sec. butyl and tert.-butyl, the term
pentyl includes isopentyl, neopentyl etc.
[0036] In the above-mentioned alkyl groups one or more hydrogen
atoms may optionally be replaced by other groups. For example these
alkyl groups may be substituted by fluorine. It is also possible
for all the hydrogen atoms of the alkyl group to be replaced.
[0037] Examples of alkyl bridges, unless otherwise stated, are
branched and unbranched alkyl groups with 2 to 5 carbon atoms, for
example ethylene, propylene, isopropylene, n-butylene, iso-butyl,
sec. butyl and tert.-butyl etc. bridges. Particularly preferred are
ethylene, propylene and butylene bridges. In the above-mentioned
alkyl bridges 1 to 2 C atoms may optionally be replaced by one or
more heteroatoms selected from among oxygen, nitrogen or
sulphur.
[0038] Examples of alkenyl groups (including those which are part
of other groups) are branched and unbranched alkylene groups with 2
to 12 carbon atoms, preferably 2-6 carbon atoms, particularly
preferably 2-3 carbon atoms, provided that they have at least one
double bond. The following are mentioned by way of example:
ethenyl, propenyl, butenyl, pentenyl etc. Unless otherwise stated,
the above-mentioned designations propenyl, butenyl etc. include all
the possible isomeric forms. For example the term butenyl includes
1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,
1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl and
1-ethyl-1-ethenyl.
[0039] In the above-mentioned alkenyl groups, unless otherwise
described, one or more hydrogen atoms may optionally be replaced by
other groups. For example these alkyl groups may be substituted by
the halogen atom fluorine. It is also possible for all the hydrogen
atoms of the alkenyl group to be replaced.
[0040] Examples of alkynyl groups (including those which are part
of other groups) are branched and unbranched alkynyl groups with 2
to 12 carbon atoms, provided that they have at least one triple
bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl
etc., preferably ethynyl or propynyl.
[0041] In the above-mentioned alkynyl groups, unless otherwise
described, one or more hydrogen atoms may optionally be replaced by
other groups. For example these alkyl groups may be
fluorosubstituted. It is also possible for all the hydrogen atoms
of the alkynyl group to be replaced.
[0042] The term aryl denotes an aromatic ring system with 6 to 14
carbon atoms, preferably 6 or 10 carbon atoms, preferably phenyl,
which, unless otherwise described, may for example carry one or
more of the following substituents: OH, NO.sub.2, CN, OMe,
--OCHF.sub.2, --OCF.sub.3, halogen, preferably fluorine or
chlorine, C.sub.1-C.sub.10-alkyl, preferably C.sub.1-C.sub.5-alkyl,
preferably C.sub.1-C.sub.3-alkyl, particularly preferably methyl or
ethyl, --O--C.sub.1-C.sub.3-alkyl, preferably --O-methyl or
--O-ethyl, --COOH, --COO--C.sub.1-C.sub.4-alkyl, preferably
--O-methyl or --O-ethyl, --CONH.sub.2.
[0043] Examples of cycloalkyl groups are cycloalkyl groups with
3-12 carbon atoms, for example cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably
cyclopropyl, cyclopentyl or cyclohexyl, while each of the
above-mentioned cycloalkyl groups may optionally also carry one or
more substituents, for example: OH, NO.sub.2, CN, OMe,
--OCHF.sub.2, --OCF.sub.3 or halogen, preferably fluorine or
chlorine, C.sub.1-C.sub.10-alkyl, preferably C.sub.1-C.sub.5-alkyl,
preferably C.sub.1-C.sub.3-alkyl, particularly preferably methyl or
ethyl, --O--C.sub.1-C.sub.3-alkyl, preferably --O-methyl or
--O-ethyl, --COOH, --COO--C.sub.1-C.sub.4-alkyl, preferably
--COO-methyl or --COO-ethyl or --CONH.sub.2. Particularly preferred
substituents of the cycloalkyl groups are .dbd.O, OH, methyl or
F.
[0044] Examples of cycloalkenyl groups are cycloalkyl groups with
3-12 carbon atoms, which have at least one double bond, for example
cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or
cycloheptenyl, preferably cyclopropenyl, cyclopentenyl or
cyclohexenyl, while each of the above-mentioned cycloalkenyl groups
may optionally also carry one or more substituents.
[0045] ".dbd.O" denotes an oxygen atom linked by a double bond.
[0046] Examples of heterocycloalkyl groups are, unless otherwise
described in the definitions, 3- to 12-membered, preferably 5-, 6-
or 7-membered, saturated or unsaturated heterocycles, which may
contain nitrogen, oxygen or sulphur as heteroatoms, for example
tetrahydrofuran, tetrahydrofuranone, .gamma.-butyrolactone,
.alpha.-pyran, .gamma.-pyran, dioxolane, tetrahydropyran, dioxane,
dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine,
pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole,
piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine,
tetrazine, morpholine, thiomorpholine, diazepan, oxazine,
tetrahydro-oxazinyl, isothiazole and pyrazolidine, preferably
morpholine, pyrrolidine, piperidine or piperazine, while the
heterocycle may optionally carry substituents, for example
C.sub.1-C.sub.4-alkyl, preferably methyl, ethyl or propyl.
[0047] Examples of polycycloalkyl groups are optionally
substituted, bi-, tri-, tetra- or pentacyclic cycloalkyl groups,
for example pinane, 2,2,2-octane, 2,2,1-heptane or adamantane.
Examples of polycycloalkenyl groups are optionally bridged and/or
substituted, 8-membered bi-, tri-, tetra- or pentacyclic
cycloalkenyl groups, preferably bicycloalkenyl or tricycloalkenyl
groups, if they contain at least one double bond, for example
norbornene.
[0048] Examples of spiroalkyl groups are optionally substituted
spirocyclic C.sub.5-C.sub.12 alkyl groups.
[0049] Halogen generally denotes fluorine, chlorine, bromine or
iodine, preferably fluorine, chlorine or bromine, particularly
preferably chlorine.
[0050] The substituent R.sup.1 may represent a group selected from
the group consisting of chlorine, fluorine, bromine,
methanesulphonyl, ethanesulphonyl, trifluoromethanesulphonyl and
para-toluenesulphonyl, preferably chlorine.
[0051] The substituent R.sup.2 may represent hydrogen or
C.sub.1-C.sub.3-alkyl, preferably hydrogen.
[0052] The substituent R.sup.3 may represent hydrogen, [0053] or a
group selected from the group consisting of optionally substituted
C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkynyl, and C.sub.6-C.sub.14-aryl, preferably
phenyl, or a group selected from the group consisting of optionally
substituted and/or bridged C.sub.3-C.sub.12-cycloalkyl, preferably
cyclopentyl, C.sub.3-C.sub.12-cycloalkenyl,
C.sub.7-C.sub.12-polycycloalkyl, C.sub.7-C.sub.12-polycycloalkenyl,
C.sub.5-C.sub.12-spirocycloalkyl and saturated or unsaturated
C.sub.3-C.sub.12-heterocycloalkyl, which contains 1 to 2
heteroatoms.
[0054] The substituents R.sup.4, R.sup.5 may be identical or
different and may represent hydrogen, [0055] or optionally
substituted C.sub.1-C.sub.6-alkyl, [0056] or R.sup.4 and R.sup.5
together represent a 2- to 5-membered alkyl bridge which may
contain 1 to 2 heteroatoms, [0057] or R.sup.4 and R.sup.3 or
R.sup.5 and R.sup.3 together represent a saturated or unsaturated
C.sub.3-C.sub.4-alkyl bridge, which may optionally contain 1
heteroatom.
[0058] A.sub.1 and A.sub.2 which may be identical or different
represent --CH.dbd. or --N.dbd., preferably --N.dbd..
[0059] R.sup.6 may represent a C.sub.1-C.sub.4-alkyl, preferably
methyl or ethyl.
[0060] The compound of formula (II) may be prepared according to
methods known from the literature, for example analogously to the
syntheses described in WO 03/020722.
[0061] The compounds of general formula (I) may be prepared inter
alia analogously to the following examples of synthesis. These
Examples are, however, intended only as examples of procedures to
illustrate the invention, without restricting it to their content.
The general synthesis is shown in Scheme (1). ##STR8##
Synthesis of
(7R)-2-chloro-8-cyclopentyl-7-ethyl-5-hydroxy-7,8-dihydro-5H-pteridin-6-o-
ne
[0062] ##STR9##
[0063] 30 g (84.2 mmol) of 1 are dissolved in 300 ml of
tetrahydrofuran and 3 g Pt/C (5%) are added. The reaction mixture
is hydrogenated for 5 h at 35.degree. C. and a hydrogen pressure of
4 bar. The catalyst is filtered off and washed with approx. 30 ml
of tetrahydrofuran. The filtrate is concentrated by evaporation
under reduced pressure. 25.6 g of product 2 are obtained as a
yellow solid.
[0064] .sup.1H-NMR (400 MHZ) (DMSO.sub.d6): .delta. 11.05 (bs 1H);
7.85 (s 1H); 4.47-4.45 (dd 1H); 4.16-4.08 (t 1H); 1.95-1.67 (m
10H); 0.80-0.73 (t 3H)
Synthesis of
(7R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one
[0065] ##STR10##
[0066] 5.22 g (17.6 mmol) of 2 are dissolved in 55 ml of
tetrahydrofuran. 520 mg Pt-C (5%) and 250 mg vanadium(IV)
oxyacetylacetonate are added. The reaction mixture is hydrogenated
for 6 hours at 20.degree. C. and a hydrogen pressure of 4 bar. The
catalyst is filtered off and washed with approx. 15 ml of
tetrahydrofuran. The filtrate is concentrated by evaporation under
reduced pressure.
[0067] 5.0 g of product 3 are obtained as a yellow powder.
[0068] .sup.1H-NMR (400 MHz) (DMSO.sub.d6): .delta. 11.82 (bs 1H);
7.57 (s 1H); 4.24-4.21 (dd 1H); 4.17-4.08 (m 1H); 1.97-1.48 (m
10H); 0.80-0.77 (t 3H).
Synthesis of:
(7R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one
[0069] 70 g Pt/C (5%) are added to a solution of 700 g (1.96 mol)
of 1 in 700 ml of tetrahydrofuran. The reaction mixture is
hydrogenated for 2.5 hours at 35.degree. C. and a hydrogen pressure
of 4 bar until the hydrogen uptake has stopped. The autoclave is
opened and 35 g vanadium(IV) oxyacetylacetonate are added. The
mixture is hydrogenated for a further 2.5 hours at 35.degree. C.
and a hydrogen pressure of 4 bar. It is filtered and the residue is
washed with tetrahydrofuran. The filtrate is concentrated by
evaporation under reduced pressure. The residue is dissolved in
2.75 L acetone and precipitated by the addition of an equal amount
of demineralised water. The solid is suction filtered and washed
with an acetone/water mixture (1:1), then with
tert.-butylmethylether. After drying 551 g of product 3 are
obtained.
Synthesis of:
(7R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one
[0070] 30 g (84 mmol) of 1 are dissolved in 300 ml of
tetrahydrofuran. 3 g Pt/C (5%) and 1.5 g vanadium(IV)
oxyacetylacetonate are added. The reaction mixture is hydrogenated
for 24 hours at 35.degree. C. and a hydrogen pressure of 4 bar
until the reaction is complete. It is filtered, the residue is
washed with tetrahydrofuran and the filtrate is concentrated by
evaporation under reduced pressure. The residue is dissolved in 118
ml acetone and precipitated by the addition of an equal amount of
demineralised water. The solid is suction filtered and washed with
an acetone/water mixture (1:1) and then with
tert.-butylmethylether. After drying 18 g of product 3 are
obtained.
Synthesis of:
(7R)-2-chloro-7-ethyl-8-isopropyl-7,8-dihydro-5H-pteridin-6-one
[0071] ##STR11##
[0072] 10 g (316 mmol) of 4 are dissolved in 800 ml of
tetrahydrofuran and 200 ml isopropanol. 10 g Pt/C (5%) and 5 g
vanadium(IV) oxyacetylacetonate are added. The reaction mixture is
hydrogenated for 24 hours at 35.degree. C. and a hydrogen pressure
of 4 bar until the reaction is complete. It is filtered and the
filtrate is evaporated down until crystallisation sets in. 150 ml
isopropanol are added and the suspension is heated to 70-80.degree.
C. until fully dissolved. After the addition of 600 ml
demineralised water the product is brought to crystallisation. It
is suction filtered and washed with demineralised water. After
drying 68 g of product 5 are obtained.
[0073] .sup.1H-NMR (400 MHz) (DMSO.sub.d6): .delta. 10.81 (bs 1H);
7.56 (s 1H); 4.37-4.24 (m 2H); 1.89-1.65 (m 2H); 1.34-1.31 (m 6H);
0.80-0.73 (t 3H)
* * * * *