U.S. patent application number 13/956604 was filed with the patent office on 2014-02-06 for process for preparing spiro[2.5]octane-5,7-dione.
This patent application is currently assigned to Boehringer Ingelheim International GmbH. The applicant listed for this patent is Sven ANKLAM, Torsten BUSCH, Joerg JUNG, Markus OSTERMEIER. Invention is credited to Sven ANKLAM, Torsten BUSCH, Joerg JUNG, Markus OSTERMEIER.
Application Number | 20140039203 13/956604 |
Document ID | / |
Family ID | 48875692 |
Filed Date | 2014-02-06 |
United States Patent
Application |
20140039203 |
Kind Code |
A1 |
BUSCH; Torsten ; et
al. |
February 6, 2014 |
Process for preparing spiro[2.5]octane-5,7-dione
Abstract
Disclosed is a method for the synthesis of
spiro[2.5]octane-5,7-dione useful as intermediate in the
manufacture of pharmaceutically active ingredients. Also disclosed
are novel intermediates used in the synthesis of this compound.
Inventors: |
BUSCH; Torsten; (Frankfurt
am Main, DE) ; ANKLAM; Sven; (Kelkheim, DE) ;
JUNG; Joerg; (Floersheim, DE) ; OSTERMEIER;
Markus; (Biberach an der Riss, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BUSCH; Torsten
ANKLAM; Sven
JUNG; Joerg
OSTERMEIER; Markus |
Frankfurt am Main
Kelkheim
Floersheim
Biberach an der Riss |
|
DE
DE
DE
DE |
|
|
Assignee: |
Boehringer Ingelheim International
GmbH
Ingelheim am Rhein
DE
|
Family ID: |
48875692 |
Appl. No.: |
13/956604 |
Filed: |
August 1, 2013 |
Current U.S.
Class: |
549/331 ;
560/124; 562/506; 568/346 |
Current CPC
Class: |
C07C 67/30 20130101;
C07C 45/455 20130101; C07C 51/083 20130101; C07C 51/08 20130101;
C07C 67/343 20130101; C07C 45/65 20130101; C07C 67/343 20130101;
C07C 2601/02 20170501; C07C 67/08 20130101; C07C 51/083 20130101;
C07C 67/08 20130101; C07C 259/06 20130101; C07C 69/608 20130101;
C07D 311/96 20130101; C07C 59/205 20130101; C07C 51/08 20130101;
C07C 45/455 20130101; C07C 69/716 20130101; C07C 2602/50 20170501;
C07C 69/635 20130101; C07C 49/443 20130101; C07C 59/205 20130101;
C07C 55/28 20130101; C07C 49/443 20130101; C07C 69/716 20130101;
C07C 69/716 20130101; C07C 69/608 20130101; C07C 69/608 20130101;
C07C 67/08 20130101; C07C 67/30 20130101 |
Class at
Publication: |
549/331 ;
560/124; 562/506; 568/346 |
International
Class: |
C07D 311/96 20060101
C07D311/96; C07C 45/65 20060101 C07C045/65 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 3, 2012 |
EP |
12005681.7 |
Oct 2, 2012 |
EP |
12186998.6 |
Claims
1. A method of preparing spiro[2.5]octane-5,7-dione having the
formula ##STR00042## said method comprising cyclizing a
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid ester, having the
formula ##STR00043## wherein R is preferably C.sub.1-C.sub.6 alkyl,
preferably C.sub.1-C.sub.4 alkyl, more preferably C.sub.1-C.sub.3
alkyl or even more preferably C.sub.1-C.sub.2 alkyl, particularly
methyl, to form spiro[2.5]octane-5,7-dione.
2. A process for the manufacture of spiro[2.5]octane-5,7-dione
having the formula ##STR00044## said process comprising the
following reaction steps (wherein R is preferably C.sub.1-C.sub.6
alkyl, preferably C.sub.1-C.sub.4 alkyl, more preferably
C.sub.1-C.sub.3 alkyl or even more preferably C.sub.1-C.sub.2
alkyl, particularly methyl): ##STR00045##
3. A process for the manufacture of spiro[2.5]octane-5,7-dione
having the formula ##STR00046## said process comprising the
following reaction steps, via route I or via route II, wherein R is
preferably C.sub.1-C.sub.6 alkyl, preferably C.sub.1-C.sub.4 alkyl,
more preferably C.sub.1-C.sub.3 alkyl or even more preferably
C.sub.1-C.sub.2 alkyl, particularly methyl: ##STR00047##
4. A compound useful as intermediate selected from a group
consisting of: (1-Carboxymethyl-cyclopropyl)-acetic acid,
6-Oxa-spiro[2.5]octane-5,7-dione,
(1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid,
(1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl ester,
[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester,
[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid, and
{1-[(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid, or
a tautomer or salt thereof.
5. 6-Oxa-spiro[2.5]octane-5,7-dione having the formula:
##STR00048##
6. (1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid having the
formula: ##STR00049##
7. (1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl ester
having the formula: ##STR00050##
8. [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester having
the formula: ##STR00051##
9. [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid having the formula:
##STR00052##
10. {1-[(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid
having the formula: ##STR00053##
11. A compound of the following general formula ##STR00054##
wherein R is C.sub.1-C.sub.6 alkyl, preferably C.sub.1-C.sub.4
alkyl.
12. A compound according to claim 4 in a salt form.
13. A compound according to claim 4, either in isolated form or in
solution.
14. One or more of the reaction steps of claim 2, or any
combination of two or more successive steps.
15. One or more of the reaction steps of claim 3, or any
combination of two or more successive steps.
16. The method according to claim 1 wherein the
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid ester, particularly
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester, is
subjected to condensation conditions using a suitable base such as
e.g. the respective sodium alcoholate, particularly sodium
methanolate in a suitable solvent such as e.g. comprising
tetrahydrofuran at a suitable reaction temperature for cyclization
to form spiro[2.5]octane-5,7-dione.
17. Use of a [1-(2-oxo-propyl)-cyclopropyl]-acetic acid ester to
prepare spiro[2.5]octane-5,7-dione.
Description
TECHNICAL FIELD
[0001] This invention relates to a novel process or method for the
synthesis of spiro[2.5]octane-5,7-dione useful as intermediate in
the manufacture of pharmaceutically active ingredients.
BACKGROUND
[0002] Spiro[2.5]octane-5,7-dione is an important intermediate for
the production of pharmaceutically active ingredients. The
synthesis of this intermediate has been described in WO 2006/72362
and is quite complex, costly and unattractive for larger
quantities. Therefore there is a need for a new synthesis route to
manufacture spiro[2.5]octane-5,7-dione efficiently and in the high
quality needed for pharmaceutical intermediates.
DESCRIPTION OF THE INVENTION
[0003] The present invention provides an efficient process for the
manufacture of spiro[2.5]octane-5,7-dione having the formula
##STR00001##
in the steps as described herein below.
[0004] A general process for preparing spiro[2.5]octane-5,7-dione
is outlined in Scheme 1. In one embodiment, the present invention
is directed to the general multi-step synthetic method for
preparing spiro[2.5]octane-5,7-dione as set forth in Scheme 1
below. In other embodiments, the invention is directed to each of
the individual steps of Scheme 1 and any combination of two or more
successive steps of Scheme 1. The invention may also be directed to
the intermediate compounds, e.g. as set forth in Scheme 1.
##STR00002##
[0005] An alternative general process for preparing
spiro[2.5]octane-5,7-dione is outlined in Scheme 2. In one
embodiment, the present invention is directed to the general
multi-step synthetic method for preparing
spiro[2.5]octane-5,7-dione as set forth in Scheme 2 below. In other
embodiments, the invention is directed to each of the individual
steps of Scheme 2 and any combination of two or more successive
steps of Scheme 2. The invention may also be directed to the
intermediate compounds, e.g. as set forth in Scheme 2.
##STR00003##
[0006] Thus, in one aspect, the present invention relates to a
process for the manufacture of spiro[2.5]octane-5,7-dione having
the formula
##STR00004##
said process comprising the following steps (Scheme 1):
##STR00005##
[0007] Accordingly, the present invention further relates to one or
more of the above steps of Scheme 1.
[0008] With reference to the steps shown in Scheme 1 of the
invention, a process or method according to the present invention
comprises one or more of the following: [0009] hydrolizing
(1-cyanomethyl-cyclopropyl)-acetonitrile to form
(1-carboxymethyl-cyclopropyl)-acetic acid (such as e.g. in the
presence of a suitable base, such as aqueous potassium hydroxide),
[0010] cyclizing (1-carboxymethyl-cyclopropyl)-acetic acid to form
6-oxa-spiro[2.5]octane-5,7-dione (such as e.g. in the presence of a
suitable carboxylic acid anhydride forming agent, such as
acetanhydride, preferably in mesitylene as reaction solvent, at
elevated temperature), [0011] reacting
6-oxa-spiro[2.5]octane-5,7-dione with an alcohol (e.g.
C.sub.1-C.sub.6 alkanol, preferably C.sub.1-C.sub.4 alkanol, more
preferably C.sub.1-C.sub.3 alkanol or even more preferably
C.sub.1-C.sub.2 alkanol, particularly methanol) to form
(1-alkoxycarbonylmethyl-cyclopropyl)-acetic acid (such as e.g. in
the presence of 4-dimethylaminopyridine as promotor, preferably in
a reaction medium comprising an excess of the alcohol and/or
toluene, at elevated temperature), [0012] converting
(1-alkoxycarbonylmethyl-cyclopropyl)-acetic acid into the
corresponding (1-alkoxycarbonylmethyl-cyclopropyl)-acetic acid
chloride (such as e.g. in the presence of a suitable carboxylic
acid chloride forming agent, such as thionyl chloride, preferably
in the presence of N,N-dimethylformamide as promotor, preferably in
toluene as reaction medium), [0013] methylation of
(1-alkoxycarbonylmethyl-cyclopropyl)-acetic acid chloride to form
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid alkyl ester (such as
e.g. in the presence of a suitable nucleophilic methylating agent,
such as e.g. a methyl magnesium (Grignard) in the presence of an
iron containing catalyst, or a methyl copper reagent, preferably in
a reaction solvent comprising toluene and/or tetrahydrofurane),
[0014] cyclizing [1-(2-oxo-propyl)-cyclopropyl]-acetic acid alkyl
ester to form spiro[2.5]octane-5,7-dione (such as e.g. in the
presence of a suitable base, such as a respective metal alcoholate
(e.g. sodium methanolate, sodium ethanolate, or the like),
preferably in a reaction solvent comprising tetrahydrofurane and/or
the respective alcohol).
[0015] Further thus, in another aspect, the present invention
relates to a process for the manufacture of
spiro[2.5]octane-5,7-dione having the formula
##STR00006##
said process comprising the following steps (Scheme 2), either via
variant I or via variant II:
##STR00007##
[0016] Accordingly, the present invention further relates to one or
more of the above steps of Scheme 2.
[0017] With reference to the steps shown in variant I of Scheme 2
of the invention, a process or method according to the present
invention comprises one or more of the following: [0018] ring
opening methylation of 6-oxa-spiro[2.5]octane-5,7-dione to form
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid (such as e.g. in the
presence of a suitable nucleophilic methylating agent, such as e.g.
a methyl copper reagent, or a methyl magnesium (Grignard) reagent
in the presence of a metal (e.g. Fe or Cu) containing catalyst,
preferably in a reaction solvent comprising tetrahydrofurane),
[0019] esterification of [1-(2-oxo-propyl)-cyclopropyl]-acetic acid
with an alcohol (e.g. C.sub.1-C.sub.6 alkanol, preferably
C.sub.1-C.sub.4 alkanol, more preferably C.sub.1-C.sub.3 alkanol or
even more preferably C.sub.1-C.sub.2 alkanol, particularly
methanol) to form [1-(2-oxo-propyl)-cyclopropyl]-acetic acid alkyl
ester (such as e.g. in the presence of a suitable acid (e.g.
hydrochloric acid), preferably in a suitable reaction solvent
comprising an excess of the alcohol and/or mesitylene, at elevated
temperature), [0020] cyclizing
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid alkyl ester to form
spiro[2.5]octane-5,7-dione (such as e.g. in the presence of a
suitable base, such as a respective metal alcoholate (e.g. sodium
methanolate, sodium ethanolate, or the like), preferably in a
reaction solvent comprising tetrahydrofurane and/or the respective
alcohol).
[0021] With reference to the steps shown in variant II of Scheme 2
of the invention, a process or method according to the present
invention comprises one or more of the following: [0022] reacting
6-oxa-spiro[2.5]octane-5,7-dione with N,O-dimethylhydroxylamine to
form {1-[(methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic
acid (such as e.g. in the presence of a suitable base (e.g.
pyridine)), [0023] methylation of
{1-[(methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid to
form [1-(2-oxo-propyl)-cyclopropyl]-acetic acid (such as e.g. in
the presence of a suitable nucleophilic methylating agent, such as
methyl lithium, methyl copper or methyl magnesium (Grignard)
reagent, optionally in the presence of a metal (e.g. Fe or Cu)
containing catalyst, preferably in a reaction solvent comprising
tetrahydrofurane), [0024] esterification of
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid with an alcohol (e.g.
C.sub.1-C.sub.6 alkanol, preferably C.sub.1-C.sub.4 alkanol, more
preferably C.sub.1-C.sub.3 alkanol or even more preferably
C.sub.1-C.sub.2 alkanol, particularly methanol) to form
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid alkyl ester (such as
e.g. according to above-described conditions), [0025] cyclizing
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid alkyl ester to form
spiro[2.5]octane-5,7-dione (such as e.g. according to
above-described conditions).
[0026] In certain more detailed embodiments of the invention, the
present invention relates to the process and/or the individual
process steps substantially as described by way of example in the
following examples.
[0027] Further, the invention relates to a compound useful as
intermediate selected from:
[0028] (1-Carboxymethyl-cyclopropyl)-acetic acid,
[0029] 6-Oxa-spiro[2.5]octane-5,7-dione,
[0030] (1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid,
[0031] (1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl
ester,
[0032] [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester,
[0033] [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid, and
[0034] {1- [(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic
acid,
[0035] or a tautomer or salt thereof.
[0036] In a further embodiment, the present invention is not
limited to the use of a methyl ester of formula
##STR00008##
within the processes or methods according to the present invention,
in addition to the respective methyl esters, a broader genus of
esters of formula
##STR00009##
in each of which R may be C.sub.1-C.sub.6 alkyl, preferably
C.sub.1-C.sub.4 alkyl (such as e.g. methyl, ethyl, propyl,
isopropyl, or the like), more preferably C.sub.1-C.sub.3 alkyl or
even more preferably C.sub.1-C.sub.2 alkyl, particularly methyl,
may be considered.
[0037] Accordingly, in alternative embodiments, the present
invention refers to processes or methods as disclosed hereinabove
or hereinbelow (e.g. Scheme 1 or Scheme 2) wherein a compound of
formula
##STR00010##
in each of which R is C.sub.1-C.sub.6 alkyl, preferably
C.sub.1-C.sub.4 alkyl (such as e.g. methyl, ethyl, propyl,
isopropyl, or the like), more preferably C.sub.1-C.sub.3 alkyl or
even more preferably C.sub.1-C.sub.2 alkyl, particularly methyl, is
used or involved instead of a compound of formula
##STR00011##
respectively.
[0038] In a particular embodiment, the present invention provides
and relates to the following compound or a salt thereof as well as
its preparation:
[0039] 6-Oxa-spiro[2.5]octane-5,7-dione having the formula:
##STR00012##
[0040] In a particular embodiment, the present invention provides
and relates to the following compound or a salt thereof, as well as
its preparation:
[0041] (1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid having the
formula:
##STR00013##
[0042] In a particular embodiment, the present invention provides
and relates to the following compound or a salt thereof, as well as
its preparation:
[0043] (1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl
ester having the formula:
##STR00014##
[0044] In a particular embodiment, the present invention provides
and relates to the following compound or a salt thereof, as well as
its preparation:
[0045] [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester
having the formula:
##STR00015##
[0046] In another embodiment, the present invention provides and
relates to the following compound or a salt thereof, as well as its
preparation:
[0047] [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid having the
formula:
##STR00016##
[0048] In another embodiment, the present invention provides and
relates to the following compound or a salt thereof, as well as its
preparation:
[0049] {1-[(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic
acid having the formula:
##STR00017##
[0050] In a further embodiment, the present invention provides and
relates to the following compound or a salt thereof, as well as its
preparation:
##STR00018##
[0051] wherein R is C.sub.1-C.sub.6 alkyl, preferably
C.sub.1-C.sub.4 alkyl (such as e.g. methyl, ethyl, propyl,
isopropyl, or the like), which may be prepared analogously to the
methyl ester as described herein and may be also useful as
intermediates within the present invention.
[0052] In a further embodiment, the present invention provides and
relates to the following compound or a salt thereof, as well as its
preparation:
##STR00019##
[0053] wherein R is preferably C.sub.1-C.sub.6 alkyl, preferably
C.sub.1-C.sub.4 alkyl (such as e.g. methyl, ethyl, propyl,
isopropyl, or the like), which may be prepared analogously to the
methyl ester as described herein and may be also useful as
intermediates within the present invention.
[0054] In a further embodiment, the present invention provides and
relates to the following compound or a salt thereof, as well as its
preparation:
##STR00020##
[0055] wherein R is C.sub.i-C.sub.6 alkyl, preferably
C.sub.1-C.sub.4 alkyl (such as e.g. methyl, ethyl, propyl,
isopropyl, or the like), which may be prepared analogously to the
methyl ester as described herein and may be also useful as
intermediates within the present invention.
[0056] In certain embodiments, the present invention relates to an
indicated intermediate in isolated form, such as e.g. in solid or
crystalline form.
[0057] In certain embodiments, the present invention relates to an
indicated intermediate in solution form.
[0058] Further, the present invention relates to
spiro[2.5]octane-5,7-dione obtainable or obtained by a process or
method according to the present invention.
[0059] Further, the present invention relates in particular to
spiro[2.5]octane-5,7-dione having the formula
##STR00021##
obtainable or obtained by cyclization of
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester having the
formula
##STR00022##
such as e.g. substantially as described herein.
[0060] Further, the present invention relates in particular to a
method of preparing spiro[2.5]octane-5,7-dione having the
formula
##STR00023##
said method comprising cyclizing
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester having the
formula
##STR00024##
to form spiro[2.5]octane-5,7-dione, such as e.g. under conditions
substantially as described herein by way of example in the
following example, e.g. under Claisen condensation conditions in
the presence of a suitable base (such as e.g. sodium methanolate)
for enolisation, in a suitable solvent (such as e.g.
tetrahydrofuran) at a suitable reaction temperature.
[0061] Further on, the present invention relates to
spiro[2.5]octane-5,7-dione having the formula
##STR00025##
obtainable or obtained by cyclization of a
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid ester such as having the
formula
##STR00026##
wherein R is C.sub.1-C.sub.6 alkyl, preferably C.sub.1-C.sub.4
alkyl (such as e.g. methyl, ethyl, propyl, isopropyl, or the like),
more preferably C.sub.1-C.sub.3 alkyl or even more preferably
C.sub.1-C.sub.2 alkyl, particularly methyl, such as e.g.
substantially as described herein or analogously thereto.
[0062] Further on, the present invention relates to a method of
preparing spiro[2.5]octane-5,7-dione having the formula
##STR00027##
said method comprising cyclizing
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid ester having the
formula
##STR00028##
wherein R is C.sub.1-C.sub.6 alkyl, preferably C.sub.1-C.sub.4
alkyl (such as e.g. methyl, ethyl, propyl, isopropyl, or the like),
more preferably C.sub.1-C.sub.3 alkyl or even more preferably
C.sub.1-C.sub.2 alkyl, particularly methyl, to form
spiro[2.5]octane-5,7-dione, such as e.g. under conditions
substantially as described herein by way of example in the
following example or analogously or similarly thereto, e.g. under
Claisen condensation conditions in the presence of a suitable base
(such as e.g. the respective metal alcoholate, particularly sodium
methanolate) for enolisation, in a suitable solvent (such as e.g.
tetrahydrofuran) at a suitable reaction temperature.
[0063] The intermediates and final compound of the invention may be
obtained using methods of synthesis known in principle. Preferably,
the intermediates involved and the final compound may be obtained
by the following methods according to the invention which are
described in more detailed example hereinafter.
[0064] The process steps may be performed substantially as
described herein by way of example. A process or method of this
invention may comprise one or more steps of converting and/or
reacting the mentioned intermediates with the appropriate reaction
partners, suitably under conditions as disclosed herein (e.g. by
using the indicated reagents and/or solvents and/or temperatures,
etc.).
[0065] Optimum reaction conditions and reaction times may vary
depending on the particular reactants used. Unless otherwise
specified, solvents, temperatures, pressures, and other reaction
conditions may be readily selected by one of ordinary skill in the
art. Specific procedures are provided in the Synthetic Examples
section. Typically, reaction progress may be monitored by gas
chromatography (GC), High Pressure Liquid Chromatography (HPLC) or
Thin Layer Chromatography, if desired.
EXAMPLES
[0066] In order that this invention be more fully understood, the
following examples are set forth. These examples are for the
purpose of illustrating preferred embodiments of this invention,
and are not to be construed as limiting the scope of the invention
in any way.
(1-Carboxymethyl-cyclopropyl)-acetic acid
##STR00029##
[0068] 300 g of (1-cyanomethyl-cyclopropyl)-acetonitrile (2.5 mole)
are combined with 3495 g of a 20% aqueous potassium hydroxide
solution (12.5 mole, 5 eq) and the mixture is slowly heated to
reflux. After 7.5 hours at reflux the mixture is cooled to room
temperature and washed with 600 ml methyl tert-butyl ether. The
aqueous phase is acidified to pH 2.5, and extracted two times with
a total volume of 1500 ml of 2-methyltetrahydrofuran. The combined
organic phases are washed with brine (110 ml), filtered and
evaporated to dryness to yield a colorless solid.
[0069] Yield: 354.4 g (90% of theory; 83% assay-corrected)
[0070] Purity (HPLC a/a): 92%
[0071] 1H NMR (400 MHz, D2O): .delta.H=2.29 (s, 4H), 0.43 (s, 4H)
ppm.
6-Oxa-spiro[2.5]octane-5,7-dione
##STR00030##
[0073] 350 g crude (1-carboxymethyl-cyclopropyl)-acetic acid (2.2
mole, 92% purity, from step 1) are suspended in a mixture of 350 ml
of mesitylene and 678 g of acetic anhydride (6.6 mole, 3 eq) and
heated to 100.degree. C. Upon reaching that temperature, the
pressure is reduced to approximately 200 mbar and 45% of the
solvent mixture are distilled off (distillation takes approx. 1 h).
Then the mixture is slowly cooled to 0-5.degree. C. and the
precipitate is collected by filtration. The filter cake is washed
with 87 ml of cold mesitylene and then dried in vaccuo at
40.degree. C.
[0074] Yield: 252.1 g (81% of theory)
[0075] Purity (GC a/a): 99%
[0076] Mass spectrometry (EI+): m/z=140 [M]+
[0077] 1H NMR (400 MHz, CDCl3): .delta.H=2.61 (s, 4H), 0.63 (s, 4H)
ppm.
[0078] Additional material can be obtained by concentrating the
mother liquor to dryness and recrystallizing the residue from 3.5
vol of mesitylene (increasing the yield to 87%).
(1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid
##STR00031##
[0080] To a suspension of 150 g 6-oxa-spiro[2.5]octane-5,7-dione
(1.07 mole) in 150 ml toluene are added 69 g methanol (2.1 mole, 2
eq) and 75 mg 4-dimethylaminopyridine (0.06 mole-%). The mixture is
heated under reflux (approx. 85.degree. C.). After one hour the
mixture is cooled to 40-50.degree. C. and 150 ml of toluene are
added. Then vacuum is applied and 180 g of distillate are removed
from the reaction mixture. The remaining solution is directly used
in the next step. Purity (GC a/a, derivatization with
N-methy-N-(trimethylsilyl)trifluoroacetamide): 98% 1H NMR (400 MHz,
CDCl3): .delta.H=11.44 (br s, 1H), 3.63 (s, 3H), 2.41 (s, 2H), 2.38
(s, 2H), 0.52 (s, 4H) ppm.
[0081] By the use of the appropriate alcohols other than methanol
(such as e.g. ethanol), the corresponding non-methyl esters (e.g.
the ethyl ester) may be obtained analogously or similarly to the
procedure as described for the methyl ester.
(1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl ester
##STR00032##
[0083] The crude (1-methoxycarbonylmethyl-cyclopropyl)-acetic acid
solution from the previous step (containing approx. 184 g (1.07
mole) (1-methoxycarbonylmethyl-cyclopropyl)-acetic acid in 180 ml
of toluene) is diluted with 120 ml of toluene. Ten drops of
dimethylformamide are added, the mixture is heated to 40.degree. C.
and a solution of 159 g of thionyl chloride (1.34 mole, 1.25 eq) in
75 ml of toluene is added dropwise. Then the mixture is slowly
heated to 70.degree. C. and stirred over night. Then the solvent is
removed by vacuum distillation and the residue is co-evaporated
three times with 185 ml of toluene each, yielding a dark oil.
[0084] Yield: 207.2 g (crude product, 102% (over two steps) of
theory)
[0085] Purity (GC a/a, derivatization with isopropanol): 97%
[0086] 1H NMR (400 MHz, CDCl3): .delta.H=3.64 (s, 3H), 3.01 (s,
2H), 2.34 (s, 2H), 0.56 (s, 4H) ppm.
[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester
##STR00033##
[0088] 207.2 g crude (1-chlorocarbonylmethyl-cyclopropyl)-acetic
acid methyl ester (approx. 1.07 mole, 97% purity, from step 4) are
dissolved in 1428 ml of a 3:1 mixture of tetrahydrofuran and
toluene. The mixture is cooled to -50.degree. C. and 6.3 g of
iron(III)bromide (0.02 mole, 0.02 eq) are added. Then 357 ml of
methylmagnesium chloride in tetrahydrofuran (3 M solution in
tetrahydrofuran, 1.07 mole, 1.0 eq) are added dropwise over two
hours. After in-process control another 55 ml of methylmagnesium
chloride in tetrahydrofuran (3 M solution in tetrahydrofuran, 0.17
mole, 0.15 eq) are added dropwise. Stirring is continued for 40
min, then the mixture is warmed to approx. 0.degree. C., and
diluted with 750 ml of methyl tert-butyl ether. Then the mixture is
transferred onto a mixture of 27 ml of 37% hydrochloric acid and
480 ml of water. The phases are separated and the aqueous phase is
extracted with 480 ml of methyl tert-butyl ether. The combined
organic phases are washed twice with 480 ml of water (each) and
then with 210 ml of brine, then dried over magnesium sulfate and
evaporated to dryness to yield a dark red/brown oil.
[0089] Yield: 167.7 g (88% assay, 81% (over three steps) of
theory)
[0090] Purity (GC): 92%
[0091] Mass spectrometry (EI+): m/z=170 [M]+, 155 [M-CH3]+
[0092] 1H NMR (400 MHz, CDCl3): .delta.H=3.66 (s, 3H), 2.53 (s,
2H), 2.36 (s, 2H), 2.13 (s, 3H), 0.57-0.54 (m, 2H), 0.48-0.45 (m,
2H) ppm.
Spiro[2.5]octane-5,7-dione
##STR00034##
[0094] 23.3 g of crude [1-(2-oxo-propyl)-cyclopropyl]-acetic acid
methyl ester (60% purity, from step 5) are dissolved in 135 ml of
tetrahydrofuran and 17.1 g of a sodium methanolate solution in
methanol (30% in methanol) are added at room temperature and the
mixture is stirred for six hours. Then the solution is diluted with
135 ml of methyl tert-butyl ether and quenched with 135 ml of
water. Stirring is continued for five minutes, then the phases are
separated. The aqueous phase is extracted with 67.5 ml of methyl
tert-butyl ether, then acidified to pH 2-3 with 37% HCl and washed
twice with 67.5 ml of methyl tert-butyl ether each. The combined
organic phases are washed with 18 ml of water and concentrated to
dryness. The crude product is stirred with 18 ml of cold methyl
tert-butyl ether and then the precipitate is isolated by
filtration. The filter cake is washed with 18 ml of cold methyl
tert-butyl ether to yield the product as an off-white solid.
[0095] Yield: 6.6 g (60% of theory)
[0096] Purity (HPLC a/a): 99.8%
[0097] Mass spectrometry (EI+): m/z=138 [M]+
[0098] 1H NMR (400 MHz, CDCl3): .delta.H=3.45 (s, 2H), 2.43 (s,
4H), 0.54 (s, 4H) (keto form); 10.14 (br s, 1H), 5.54 (s, 1H), 2.25
(s, 4H), 0.47 (s, 4H) (enol form) ppm.
[0099] Alternative:
##STR00035##
[0100] Alternative Route I:
[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid
##STR00036##
[0102] To a solution of 4.4 g 6-oxa-spiro[2.5]octane-5,7-dione (31
mmole) in 66 ml tetrahydrofuran are added 600 mg copper(I)chloride
(6 mmole, 0.2 eq). The mixture is cooled to -20.degree. C. and 9.8
ml of methylmagnesium bromide in 2-methyl tetrahydrofuran (3.2 M
solution in 2-methyl tetrahydrofuran, 31 mmole, 1.0 eq) are added
dropwise over 0.5 hours. The mixture is warmed to room temperature
and stirred for 2 hours. 66 ml of water are added and the mixture
is acidified to pH 3.0 by addition of 20.4 g of 2 M hydrochloric
acid. 50 ml of methyl tert-butyl ether are added and the phases are
separated. The aqueous phase is extracted again with 50 ml of
methyl tert-butyl ether and the combined organic phases are washed
with 20 ml of brine and concentrated to dryness. The resulting
crude product is directly used in the next step (esterification to
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester).
[0103] Yield: 4.9 g (crude)
[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester
##STR00037##
[0105] To a solution of 4.9 g crude
[1-(2-oxo-propyl)-cyclopropyl]-acetic acid (31 mmole) in 73.5 ml
methanol are added 1 ml of mesitylene (GC standard) and 2.5 ml of
conc. hydrochloric acid. The mixture is heated to reflux for 1 hour
and then concentrated to dryness. 40 ml of water are added to the
residue and the resulting mixture is extracted with 100 ml of
methyl tert-butyl ether in two portions. The combined organic
phases are concentrated to dryness. The resulting crude product is
directly used in the next step (spiro[2.5]octane-5,7-dione).
[0106] Yield: 5.3 g (crude)
[0107] Purity (GC a/a): 20.0%
[0108] By the use of the appropriate alcohols other than methanol
(such as e.g. ethanol), the corresponding non-methyl esters (e.g.
the ethyl ester) may be obtained analogously or similarly to the
procedure as described for the methyl ester.
Spiro[2.5]octane-5,7-dione
##STR00038##
[0110] Experimental details: See above
[0111] Yield: 0.33 g (8% over three steps)
[0112] Purity (GC a/a): 99.7%
[0113] Alternative Route II:
{1-[(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid
##STR00039##
[0115] To a mixture of 5 g 6-oxa-spiro[2.5]octane-5,7-dione (36
mmole), 3.8 g of N,O-dimethylhydroxylamine hydrochloride (39 mmole,
1.1 eq) and 75 ml of dichloromethane are added 7 ml of pyridine (78
mmole, 2.2 eq) at 0-5.degree. C. The solution is warmed to room
temperature, stirred over night and washed with 50 ml of brine. The
aqueous phase is extracted with 3.times.30 ml of dichloromethane
and the combined organic phases are dried over magnesium sulfate
and evaporated to dryness. The resulting crude product is directly
used in the next step ([1-(2-oxo-propyl)-cyclopropyl]-acetic
acid).
[0116] Yield: 7.9 g (crude, 110% of theory)
[0117] Purity (HPLC a/a): >99.9%
[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid
##STR00040##
[0119] To a solution of 3.6 g crude
{1-[(methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid (18
mmole) in 54 ml of THF are added 24.5 ml of methyllithium (1.6 M
solution in diethyl ether, 39.2 mmole, 2.2 eq) at <-75.degree.
C. Stirring is continued for 2 hours, then the mixture is quenched
by addition of 2 ml of methanol and warmed to room temperature. 54
ml of water are added and the phases are separated. The aqueous
product phase is washed with 27 ml of methyl tert-butyl ether,
acidified to pH 2.5 by addition of conc. HCl and extracted three
times with 27 ml ethyl acetate each. The combined organic phases
are concentrated to dryness and the residue is directly used in the
next step (esterification to [1-(2-oxo-propyl)-cyclopropyl]-acetic
acid methyl ester).
[1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester
##STR00041##
[0121] Experimental details: See above
[0122] Yield: 2.4 g (84% assay, 66% over three steps
(assay-corrected))
[0123] Purity (GC a/a): 86.3%
* * * * *