U.S. patent application number 13/399337 was filed with the patent office on 2012-08-23 for method for preparing enantiomerically enriched n-carboxyanhydride.
This patent application is currently assigned to SANOFI. Invention is credited to Antony BIGOT, Maxime LAMPILAS.
Application Number | 20120215007 13/399337 |
Document ID | / |
Family ID | 38863061 |
Filed Date | 2012-08-23 |
United States Patent
Application |
20120215007 |
Kind Code |
A1 |
BIGOT; Antony ; et
al. |
August 23, 2012 |
METHOD FOR PREPARING ENANTIOMERICALLY ENRICHED
N-CARBOXYANHYDRIDE
Abstract
This disclosure relates to methods for preparing an
enantiomerically enriched N-carboxyanhydride of an amino alpha acid
of the formula (IIIa) or (IIIb): ##STR00001## from a compound of
the formula (IIa) or (IIb), respectively: ##STR00002## wherein R1,
R2, and R3 are as defined in the disclosure.
Inventors: |
BIGOT; Antony; (Massy,
FR) ; LAMPILAS; Maxime; (Paris, FR) |
Assignee: |
SANOFI
Paris
FR
|
Family ID: |
38863061 |
Appl. No.: |
13/399337 |
Filed: |
February 17, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12617398 |
Nov 12, 2009 |
8119813 |
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13399337 |
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PCT/FR2008/000703 |
May 22, 2008 |
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12617398 |
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Current U.S.
Class: |
548/227 ;
560/157 |
Current CPC
Class: |
C07D 263/44
20130101 |
Class at
Publication: |
548/227 ;
560/157 |
International
Class: |
C07D 263/04 20060101
C07D263/04; C07C 271/22 20060101 C07C271/22 |
Foreign Application Data
Date |
Code |
Application Number |
May 25, 2007 |
FR |
0703702 |
Claims
1. A method for preparing an enantiomerically enriched
.alpha.-amino acid N-carboxyanhydride of formula (IIIa) or (IIIb):
##STR00012## from the compound of formula (IIa) or (IIb)
respectively: ##STR00013## wherein in the formulae: R1 and R2
denote, independently of one another, an alkyl, alkenyl,
cycloalkyl, alkylcycloalkyl, alkylaryl or aryl group; and R3
denotes an alkyl or alkylaryl group; comprising the following
steps: (i) bringing the compound of formula (IIa) or (IIb)
respectively into contact with SOCl.sub.2 in a solvent; (ii)
precipitating the N-carboxyanhydride formed in step (i) using a
non-solvent; and (iii) recovering the N-carboxyanhydride, and not
comprising any recrystallization step, nor a sublimation step of
the N-carboxyanhydride.
2. The method according to claim 1, wherein R3 denotes a methyl or
ethyl group.
3. The method according to claim 1, wherein R1 and R2 denote,
independently of one another, a methyl or ethyl group.
4. The method according to claim 2, wherein R1 and R2 denote,
independently of one another, a methyl or ethyl group.
5. The method according to claim 1, wherein R1, R2 and R3 denote a
methyl group.
6. The method according to claim 1, wherein the compound of formula
(IIa) is prepared according to the following reaction: ##STR00014##
in the presence of a base.
7. The method according to claim 1, wherein the compound of formula
or (IIb) is prepared according to the following reaction:
##STR00015## in the presence of a base.
8. The method according to claim 6, in which the reaction
constitutes a step preceding step (i).
9. The method according to claim 7, in which the reaction
constitutes a step preceding step (i).
10. A method of preparing enantiomerically enriched
N-carboxyanhydride of formula (A) or (B): ##STR00016## comprising
the following steps: (i) bringing the compound of formula
##STR00017## or respectively ##STR00018## into contact with
SOCl.sub.2 in a solvent; (ii) precipitating the N-carboxyanhydride
formed in step (i) using a non-solvent; and (iii) recovering the
N-carboxyanhydride; and not comprising any recrystallization step,
nor a sublimation step of the N-carboxyanhydride.
11. The method according to claim 1, wherein the reaction from step
(i) is carried out at a temperature between -10 and 50.degree.
C.
12. The method according to claim 10, wherein the reaction from
step (i) is carried out at a temperature between -10 and 50.degree.
C.
13. The method according to claim 1, wherein the reaction from step
(i) is carried out with 1 to 3 equivalent(s) of SOCl.sub.2 relative
to the compound (IIa) or (IIb) respectively.
14. The method according to claim 10, wherein the reaction from
step (i) is carried out with 1 to 3 equivalent(s) of SOCl.sub.2
relative to the compound (C) or (D) respectively.
15. The method according to claim 1, wherein the reaction from step
(i) is carried out with 1 to 3 equivalent(s) of SOCl.sub.2 relative
to the compound (IIa) or (IIb) respectively.
16. The method according to claim 10, wherein the reaction from
step (i) is carried out with 1 to 3 equivalent(s) of SOCl.sub.2
relative to the compound (C) or (D) respectively.
17. The method according to claim 1, wherein the non-solvent from
step (ii) is a liquid alkane or an oil cut.
18. The method according to claim 10, wherein the non-solvent from
step (ii) is a liquid alkane or an oil cut.
19. The method according to claim 1, wherein the solvent is a
chlorinated solvent and the non-solvent is a liquid alkane or oil
cut.
20. The method according to claim 1, wherein the solvent is
dichloromethane and the non-solvent is n-heptane.
21. The method according to claim 10, wherein the solvent is
dichloromethane and the non-solvent is n-heptane.
22. The method according to claim 1, wherein the recovery of the
N-carboxy-anhydride from step (iii) is a filtration/drying
operation.
23. The method according to claim 10, wherein the recovery of the
N-carboxy-anhydride from step (iii) is a filtration/drying
operation.
24. A compound of formula: ##STR00019##
Description
[0001] This application is a continuation of International
Application No. PCT/FR2008/000703, filed May 22, 2008, which is
incorporated herein by reference in its entirety; which claims the
benefit of priority of French Patent Application No. 0703702, filed
May 25, 2007.
[0002] The present application relates to a method for preparing an
enantiomerically enriched .alpha.-amino acid N-carboxyanhydride,
more particularly (L)- or (D)-N-methylalanine carboxyanhydride. The
application also relates to a chemical intermediate which is used
in the preparation of (L)- or (D)-N-methylalanine
carboxyanhydride.
TECHNICAL FIELD AND TECHNICAL PROBLEM
[0003] Amino acid N-carboxyanhydrides are acylating agents that
have the advantage of not forming troublesome by-products in the
acylation reactions. When they are enantiomerically enriched, they
furthermore make it possible to introduce a chiral carbon. These
are therefore chemical compounds that are useful in organic
syntheses, in particular in the case of syntheses of pharmaceutical
compounds which are often syntheses having several reaction steps.
However, it is necessary that these compounds have sufficient
purity, in particular enantiomeric purity. The industrial
preparation method must additionally be simple and have a good
overall yield.
[0004] The Applicant has developed a simple method of preparing
.alpha.-amino acid N-carboxy-anhydride having a good overall yield
and that makes it possible to attain a pure and enantiomerically
enriched product. This method applies more particularly to (L)- or
(D)-N-methylalanine carboxyanhydride.
[0005] In Tetrahedron 1994, 50, No. 18, 5309-5322, the preparation
of N-carboxyanhydrides protected on the nitrogen atom by
RO--C(.dbd.O)-- from N,N-bis(alkoxycarbonyl)amino acids and the
Vilsmeier-Haack reagent SOCl.sub.2/DMF is described.
[0006] In the article "Untersuchungen uber
Alpha-amino-N-carbonsaureanhydride. I" from Zeitschrift fur
Physiologische Chemie", Walter de Bruyter, Berlin 1925, 46, 72-90,
the preparation of N-carboxyanhydrides is described, but without
any purification step.
[0007] In Angew. Chem. Int. Ed. 2003, 42, 5348-5351, the
preparation of N-carboxyanhydrides protected on the nitrogen atom
by RO--C(.dbd.O)-- is described in Scheme 3 referring to
Tetrahedron Letters 1996, 37, 8439, but no purification step is
described.
[0008] In J. Org. Chem. 1994, 59, 2437-2446, the preparation of
N-carboxyanhydrides is described but using another chemical
reaction.
[0009] In Tetrahedron 1994, 50, 30, 9051-9060, the preparation of
N-carboxyanhydrides from amino acids protected by tBuO-C(.dbd.O)--
(BOC) and PCl.sub.3 is described. The use of PCl.sub.3 leads to the
formation of phosphorus-containing by-products which remain
combined with the N-carboxyanhydride and which it is necessary to
remove by a step of washing with an industrially unacceptable
perchlorinated solvent (CCl.sub.4).
[0010] In Journal of Chemical Society 1950, 3009-3013, the
preparation of N-carboxyanhydrides is carried out starting from a
mixture of the two amino acids (D and L) protected by
MeO--C(.dbd.O)-- and SOCl.sub.2 and not starting from the D or else
L amino acid. Furthermore, the final product is obtained after a
precipitation step, a recrystallization step and a sublimation
step. The calculated yield, by weight, is only 39%.
[0011] In J. Mar. Chim. Heterocycl. 2002, 1, 44-47, the preparation
of N-carboxyanhydrides is carried out starting from a protected
amino acid and POCl.sub.3.
[0012] None of these documents describes or suggests the method of
the invention.
DESCRIPTION OF THE INVENTION
Definitions Used
[0013] alkyl group: a linear or branched, saturated aliphatic
hydrocarbon-based group. As examples, mention may be made of
methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl
groups. It is preferably a (C.sub.1-C.sub.4) group; [0014] alkenyl
group: an alkyl group comprising a C.dbd.C double bond; [0015]
cycloalkyl group: a cyclic alkyl group comprising between 3 and 8
carbon atoms, all the carbon atoms being incorporated in the cyclic
structure. As examples, mention may be made of cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl groups; and [0016] aryl
group: an aromatic group comprising from 6 to 10 ring members, for
example a phenyl group.
[0017] The present invention relates to a method for preparing an
enantiomerically enriched .alpha.-amino acid N-carboxyanhydride of
formula (IIIa):
##STR00003##
from the compound of formula (IIa):
##STR00004##
in which formulae: [0018] R1 and R2 denote, independently of one
another, an alkyl (e.g. methyl, ethyl, isopropyl), alkenyl (e.g.
allyl), cycloalkyl, alkylcycloalkyl (e.g. --CH.sub.2-cyclohexyl),
alkylaryl (e.g. benzyl) or aryl group; [0019] R3 denotes an alkyl
(e.g. methyl, ethyl, tert-butyl) or alkylaryl (e.g. benzyl) group;
comprising the following steps: [0020] (i) bringing the compound of
formula (IIa) (or (IIb) respectively) into contact with SOCl.sub.2
in a solvent; [0021] (ii) precipitating the N-carboxyanhydride
formed in step (i) using a non-solvent; and [0022] (iii) recovering
the N-carboxyanhydride.
[0023] This method does not comprise any recrystallization step nor
sublimation step of the N-carboxyanhydride.
[0024] This method applies in a similar manner to the compound
(IIIb) from the compound (IIb):
##STR00005##
[0025] Preferably, R3 denotes a methyl or ethyl group, more
preferably still a methyl group, since, at the end of step (i), a
light compound (R3Cl) is then formed which may be easily
removed.
[0026] Preferably, R1 and R2 denote, independently of one another,
a methyl or ethyl group. More preferably, R1 and R2 both denote a
methyl group and the N-carboxyanhydride of formula (A) (or (B))
below is obtained:
##STR00006##
(A) is (L)-N-methylalanine N-carboxyanhydride. Preferably, use is
made of the compound (IIa) of formula:
##STR00007##
which is the methyl carbamate of (L)-N-methylalanine. (B) is
(D)-N-methylalanine N-carboxyanhydride. Preferably, use is made of
the compound (IIb) which is the carbamate of
(D)-N-methylalanine:
##STR00008##
Step (i)
[0027] The solvent from step (i) may be a chlorinated solvent such
as dichloromethane, an alkyl or aryl ether such as, for example,
tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, an
aromatic solvent such as, for example, toluene, a xylene or
trifluoromethylbenzene, a ketone such as, for example, acetone,
methyl isobutyl ketone or methyl ethyl ketone. It is also possible
to use a mixture of two or more of these solvents.
[0028] Use is generally made of between 1 and 3 equivalent(s) of
SOCl.sub.2 relative to the compound (IIa) (or (IIb)).
[0029] The reaction is carried out at a temperature between -10 and
50.degree. C., preferably between 0 and 30.degree. C., more
preferably still between 20 and 30.degree. C. The reaction time is
generally between 30 and 60 min.
Step (ii)
[0030] The precipitation of the N-carboxyanhydride formed in step
(i) is carried out using a non-solvent. Use is advantageously made
of a liquid alkane (e.g. n-heptane or octane) or else an oil cut
(e.g. petroleum ether). The N-carboxyanhydride may first be
concentrated by eliminating some of the solvent from the reaction
from step (i).
[0031] It is possible to use, as a solvent/non-solvent pair, a
chlorinated solvent and a liquid alkane or oil cut, especially the
dichloromethane/n-heptane pair described in Example 2.
Step (iii)
[0032] The N-carboxyanhydride may be recovered simply by
filtration/drying. This is one of the advantages of the method of
the invention, namely not requiring a recrystallization or
sublimation step to obtain sufficient purity and a good yield. The
advantage of using a liquid alkane in step (ii) is in being able to
easily dry the N-carboxyanhydride.
Preparation of the Compound of Formula (IIa) or (IIb)
[0033] The compound of formula (IIa) (or (IIb)) may be prepared
according to the following reaction (optionally in the course of a
step preceding step (i)):
##STR00009##
(or else respectively according to:
##STR00010##
in the presence of a base. The base may be, for example, a
carbonate, a bicarbonate or a hydroxide of an alkali metal. A
preferred base is NaOH.
[0034] This reaction may be carried out in a solvent which may be,
for example, water or one of the solvents cited previously. The
reaction is carried out at a temperature between 0 and 5.degree. C.
The reaction time is generally between 5 and 6 hours. Preferably, a
ClCO.sub.2R3/(IIa) (or (IIb)) molar ratio >1.9 is used. Also
preferably, a base/(IIa) (or (IIb)) molar ratio >2 is used.
[0035] The method of the present invention makes it possible to
obtain (whether or not the method includes the reaction preceding
step (i)) an N-carboxyanhydride in a simple manner, with a good
yield (>the yield disclosed in Journal of the Chemical Society,
1950) and high purity. In particular, it does not require any
recrystallization nor sublimation step. The cyclization in step (i)
preserves the integrity of the asymmetric centre and makes it
possible to obtain an enantiomerically enriched product (no
epimerization).
EXAMPLES
[0036] A person skilled in the art could advantageously take
inspiration from the conditions disclosed in the following two
examples.
Ex. 1
Preparation of (S)-2-(methoxycarbonylmethylamino)propionic Acid
##STR00011##
[0038] A 250 ml two-necked flask, under a nitrogen atmosphere, was
successively charged with: 10 g (97 mmol) of (L)-N-methylalanine,
then 200 ml of a 1 M aqueous solution of NaOH (200 mmol, 2.06 eq.).
The white suspension thus obtained was stirred until it had
completely dissolved (around 30 minutes). This solution was cooled
to around 3.degree. C. using a water/ice bath and, with vigorous
stirring (around 750 rpm), 15 ml of methyl chloroformate (192 mmol,
1.98 eq.) were added over around 30 minutes using a 50 ml dropping
funnel. The two-phase medium thus obtained was stirred at 3.degree.
C.
[0039] After 6 hours, the temperature of the reaction medium was
raised to around 20.degree. C. by removing the ice/water bath, and
the pH of the reaction medium was brought to around 1 (measured
with pH paper) using 37% aqueous HCl. This aqueous phase was then
extracted with 3 times 50 ml of AcOEt. The organic phases were
combined, washed with 50 ml of demineralized water, then dried over
around 10 g of anhydrous MgSO.sub.4. The medium was filtered
through sintered glass, then the filtrate was concentrated to
dryness under vacuum (temperature of the bath at around 35.degree.
C., vacuum of around 40 mbar). Thus, 13.4 g (86%) of product were
obtained in the form of a colourless viscous oil.
[0040] Structural analyses: LC-MS-DAD-ELSD: 160(-)=(M-H)(-),
162(+)=(M+H)(+); .sup.1H NMR (DMSO-d.sub.6 at 400 MHz): for this
batch, a 60-40% mixture of conformational isomers was observed,
with: 1.31 (d, J=7.5 Hz, 3H); 2.78 (s, 3H); 3.58 (s, 1.2H); 3.60
(s, 1.8H); 4.50 (q, J=7.5 Hz, 0.4H); 4.58 (q, J=7.5 Hz, 0.6H); 10.7
(broad m, 1H).
[0041] Analysis by gas chromatography on a chiral column made it
possible to show that the enantiomeric excess of the
N-methylalanine methyl carbamate was >99%. The conditions for
the chromatographic analysis are given below: RT-Gammadex column
(30 m/0.25 mm/0.25 .mu.m); isotherm at 120.degree. C. (3 min), then
5.degree. C./min to 180.degree. C., isotherm at 180.degree. C. (3
min); injection split 1:25; helium carrier gas at 1.8 ml/min; FID
detection; solution at a concentration of 2 mg/ml in
CH.sub.2Cl.sub.2, esterification with 0.2 M TMSH. Under these
conditions, the (L)-N-methylalanine methyl carbamate had a
retention time rt=8.8 min. The other enantiomer,
(D)-N-methylalanine methyl carbamate, had a retention time rt=8.5
min.
Ex. 2
Preparation of (S)-3,4-dimethyl-1,3-oxazolidine-2,5-dione
[0042] 1 g (6.2 mmol) of the product obtained previously was
dissolved in 3 ml of CH.sub.2Cl.sub.2, stirred for 5 minutes at
around 20.degree. C., then treated with SOCl.sub.2 (500 .mu.l, 1.1
eq.). The reaction medium was then heated at around 30.degree. C.,
and the heating was maintained for around 30 min. The reaction
medium was then concentrated to around 1.5 volumes, and, still with
stirring, 10 ml of n-heptane were added. The white mass thus
obtained was then cooled to around -20.degree. C., and stirred for
1 hour at this temperature. The suspension was then filtered
through sintered glass, the solid was washed with 3 times 3 ml of
n-heptane. After drying in air for 2 hours, the product (700 mg,
87.4%) was obtained in the form of white needles.
[0043] Structural analyses: .sup.1H NMR (DMSO-d.sub.6 at 400 MHz):
1.39 (d, J=7.5 Hz, 3H); 2.83 (s, 3H); 4.40 (q, J=7.5 Hz, 1H).
[0044] Analysis by gas chromatography on a chiral column made it
possible to show that the enantiomeric excess of
(S)-3,4-dimethyl-1,3-oxazolidine-2,5-dione) was >99%, and that
no epimerization took place under the cyclization conditions. Gas
chromatography conditions: RT-Gammadex column (30 m/0.25 mm/0.25
.mu.m); initial temperature 180.degree. C., then 5.degree. C./min
to 220.degree. C., isotherm at 180.degree. C. for 5 min; injection
split 1:25; helium carrier gas at 1.8 ml/min; FID detection;
solution at a concentration of 2 mg/ml in CH.sub.2Cl.sub.2. Under
these conditions, the (S)-3,4-dimethyl-1,3-oxazolidine-2,5-dione
had a retention time rt=8.4 min. The other enantiomer,
(R)-3,4-dimethyl-1,3-oxazolidine-2,5-dione, had a retention time
rt=8.7 min.
[0045] The overall yield calculated from the initial
(L)-N-methylalanine is therefore 86%.times.87.4%, i.e. 75%. This
yield is greater than that obtained in the Journal of the Chemical
Society, 1950.
* * * * *