NZ605270B - Process for the preparation of the l-arginine salt of perindopril - Google Patents
Process for the preparation of the l-arginine salt of perindopril Download PDFInfo
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- NZ605270B NZ605270B NZ605270A NZ60527012A NZ605270B NZ 605270 B NZ605270 B NZ 605270B NZ 605270 A NZ605270 A NZ 605270A NZ 60527012 A NZ60527012 A NZ 60527012A NZ 605270 B NZ605270 B NZ 605270B
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- New Zealand
- Prior art keywords
- perindopril
- arginine
- formula
- arginine salt
- temperature
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- IPVQLZZIHOAWMC-QXKUPLGCSA-N Perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 title claims abstract description 60
- 229960002582 Perindopril Drugs 0.000 title claims abstract description 59
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical class OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 46
- 239000000203 mixture Substances 0.000 claims abstract description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 30
- RYCSJJXKEWBUTI-YDYAIEMNSA-N perindopril arginine Chemical compound OC(=O)[C@@H](N)CCCNC(N)=N.C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 RYCSJJXKEWBUTI-YDYAIEMNSA-N 0.000 claims abstract description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 27
- 150000008535 L-arginines Chemical class 0.000 claims abstract description 24
- 238000001914 filtration Methods 0.000 claims abstract description 23
- PFKFTWBEEFSNDU-UHFFFAOYSA-N Carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims abstract description 22
- 235000014852 L-arginine Nutrition 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- AUVAVXHAOCLQBF-UHFFFAOYSA-N 2-[(1-ethoxy-1-oxopentan-2-yl)azaniumyl]propanoate Chemical compound OC(=O)C(C)NC(CCC)C(=O)OCC AUVAVXHAOCLQBF-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 12
- 230000004913 activation Effects 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- IYNMDWMQHSMDDE-MHXJNQAMSA-N perindopril erbumine Chemical compound CC(C)(C)N.C1CCC[C@@H]2N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H](C(O)=O)C[C@@H]21 IYNMDWMQHSMDDE-MHXJNQAMSA-N 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- UCPYLLCMEDAXFR-UHFFFAOYSA-N Triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 6
- PFCUZDIEKKTHCH-UHFFFAOYSA-N acetonitrile oxide Chemical compound CC#N=O PFCUZDIEKKTHCH-UHFFFAOYSA-N 0.000 claims abstract description 5
- YHNUDLCUIKMNSN-UHFFFAOYSA-N bis(1,2,4-triazol-1-yl)methanone Chemical compound C1=NC=NN1C(=O)N1C=NC=N1 YHNUDLCUIKMNSN-UHFFFAOYSA-N 0.000 claims abstract description 5
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000002955 isolation Methods 0.000 claims abstract description 5
- YGYAWVDWMABLBF-UHFFFAOYSA-N phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- CQYBNXGHMBNGCG-FXQIFTODSA-N (2S,3aS,7aS)-2,3,3a,4,5,6,7,7a-octahydro-1H-indol-1-ium-2-carboxylate Chemical compound C1CCC[C@@H]2[NH2+][C@H](C(=O)[O-])C[C@@H]21 CQYBNXGHMBNGCG-FXQIFTODSA-N 0.000 abstract 2
- 150000003462 sulfoxides Chemical class 0.000 abstract 1
- 239000000047 product Substances 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 238000010899 nucleation Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 5
- 229960003076 Perindopril arginine Drugs 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N Tert-Butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- AUVAVXHAOCLQBF-YUMQZZPRSA-N (2S)-2-[[(2S)-1-ethoxy-1-oxopentan-2-yl]azaniumyl]propanoate Chemical group OC(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC AUVAVXHAOCLQBF-YUMQZZPRSA-N 0.000 description 2
- FMVLIEVJRBLHDX-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydroindole-1-carboxylic acid Chemical compound C1CCCC2N(C(=O)O)CCC21 FMVLIEVJRBLHDX-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-Methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000011068 load Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N 2-methylpropanenitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N Angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 229950006323 Angiotensin ii Drugs 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 108060001001 BRK1 Proteins 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N Bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 206010007554 Cardiac failure Diseases 0.000 description 1
- 208000008787 Cardiovascular Disease Diseases 0.000 description 1
- 208000004981 Coronary Disease Diseases 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N DMSO dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failure Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II dizwitterion Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 102100011311 KNG1 Human genes 0.000 description 1
- 229960003929 Perindopril Erbumine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 201000008739 coronary artery disease Diseases 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000004059 degradation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000004301 light adaptation Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- XGZVLEAZGCUUPH-UHFFFAOYSA-N methylamino(methylimino)methanesulfonic acid Chemical compound CNC(=NC)S(O)(=O)=O XGZVLEAZGCUUPH-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- -1 succinimidyl Chemical group 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 230000000261 vasodilator Effects 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Abstract
605270 Disclosed herein is a process for the preparation of perindopril L-arginine salt of formula (I) comprising the reaction between perindopril and L-arginine in a solvent system selected from: A binary mixture of acetonitrile and dimethyl sulfoxide A binary mixture of ethyl acetate and dimethyl sulfoxide A ternary mixture of acetonitrile, dimethyl sulfoxide and toluene at a temperature from 10 to 100C, followed by isolation by means of filtration of the L-arginine salt thereby obtained. Additionally disclosed is the process wherein the perindopril is obtain by reaction N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine of formula (II) with an activation agent of formula X2C=O wherein X represents a leaving group, in an organic solvent or a system of organic solvents, at a temperature from —20 to 80°C, followed by reaction of the intermediate compound of formula (III) thereby obtained with (2S, 3aS, 7aS)-2-carboxyperhydroindole, at a temperature from 0 to 80°C. More particularly wherein the activation agent is N,N'-carbonyldiimidazole, phosgene, triphosgene, (1,1'- carbonyldi(1,2,4-triazole) or di(N-succinimidyl) carbonate in an amount between 0.8 and 1.2 moles, inclusive, per mole of N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine. Additionally disclosed is the process wherein the perindopril is obtained by desaltification of perindopril tert-butylamine with an acid. yl sulfoxide A ternary mixture of acetonitrile, dimethyl sulfoxide and toluene at a temperature from 10 to 100C, followed by isolation by means of filtration of the L-arginine salt thereby obtained. Additionally disclosed is the process wherein the perindopril is obtain by reaction N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine of formula (II) with an activation agent of formula X2C=O wherein X represents a leaving group, in an organic solvent or a system of organic solvents, at a temperature from —20 to 80°C, followed by reaction of the intermediate compound of formula (III) thereby obtained with (2S, 3aS, 7aS)-2-carboxyperhydroindole, at a temperature from 0 to 80°C. More particularly wherein the activation agent is N,N'-carbonyldiimidazole, phosgene, triphosgene, (1,1'- carbonyldi(1,2,4-triazole) or di(N-succinimidyl) carbonate in an amount between 0.8 and 1.2 moles, inclusive, per mole of N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine. Additionally disclosed is the process wherein the perindopril is obtained by desaltification of perindopril tert-butylamine with an acid.
Description
NEW ZEALAND
PATENTS ACT, 1953
COMPLETE SPECIFICATION
PROCESS FOR THE PREPARATION OF THE L-ARGININE SALT OF PERINDOPRIL
We, LES LABORATOIRES SERVIER, a French body corporate of 35, rue de Verdun, F-
92284 Suresnes Cedex, France, do hereby declare the invention for which we pray that a
patent may be granted to us, and the method by which it is to be performed, to be particularly
described in and by the following statement
The present invention relates to a process for the preparation of perindopril L-arginine salt of
formula (I):
OH NH
N CO H
O N NH
CO Et
Perindopril and its pharmaceutically acceptable salts, and more especially its L-arginine salt,
have valuable pharmacological properties.
Their principal property is that of inhibiting angiotensin I converting enzyme (or kininase II),
which makes it possible to prevent, on the one hand, conversion of the decapeptide
angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and, on the other hand,
degradation of bradykinin (a vasodilator) to an inactive peptide.
Those two actions contribute to the beneficial effects of perindopril in cardiovascular
diseases, more especially in arterial hypertension, heart failure and stable coronary disease.
Perindopril, its preparation and its use in therapeutics have been described in European Patent
specification EP 0 049 658.
The L-arginine salt of perindopril was first described in European Patent specification
EP 1 354 873.
The alpha and beta crystalline forms of the L-arginine salt of perindopril have been described
in European Patent specifications EP 1 989 182 and EP 2 016 051.
The gamma crystalline form of the L-arginine salt of perindopril has been described in Patent
Application .
In view of the pharmaceutical value of perindopril L-arginine, it was of great importance to
obtain it in a good yield and with excellent purity.
More especially, the problem consisted both of finding conditions under which conversion of
perindopril into a salt with L-arginine takes place correctly and of readily isolating the L-
arginine salt of perindopril from the reaction mixture.
Indeed, most of the tests carried out by the Applicant in order to obtain the L-arginine salt of
perindopril starting from perindopril and L-arginine resulted in a product of gelatinous
appearance which was very difficult to process subsequently.
Patent specification EP 1 279 665 describes a method of obtaining perindopril salts, more
specifically the tert-butylamine salt. The method described allows coupling of the N-[1-(S)-
ethoxycarbonyl-butyl]-(S)-alanine moiety to the (2S, 3aS, 7aS)carboxyperhydroindole
moiety whilst avoiding the cyclisation impurities that customarily result from peptide
coupling. The tert-butylamine salt of perindopril is accordingly obtained in Example 3 of
EP 1 279 665 in a good yield (80 %) and with excellent purity (99 %).
The Applicant applied the process described in Example 3 of EP 1 279 665 to preparation of
the L-arginine salt of perindopril. However, replacing the tert-butylamine with (L)-arginine
and otherwise following the procedure of EP 1 279 665 did not make it possible to obtain the
L-arginine salt of perindopril in a good yield (see Comparison Example A).
Surprisingly, when conversion into a salt is instead carried out in a solvent system selected
from acetonitrile/dimethyl sulphoxide, ethyl acetate/dimethyl sulphoxide and
acetonitrile/dimethyl sulphoxide/toluene, the L-arginine salt of perindopril is then obtained in
a good yield and with excellent purity, and isolation is greatly facilitated.
More specifically, the present invention relates to a process for the preparation of the L-
arginine salt of perindopril by means of reaction between perindopril and L-arginine in a
solvent system selected from:
a binary mixture of acetonitrile and dimethyl sulphoxide,
a binary mixture of ethyl acetate and dimethyl sulphoxide,
a ternary mixture of acetonitrile, dimethyl sulphoxide and toluene,
at a temperature from 10 to 100°C, preferably from 40 to 80°C,
followed by isolation by means of filtration of the L-arginine salt thereby obtained.
In accordance with an embodiment of the present invention, the perindopril (free acid) used
in the reaction is obtained by reaction of N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine of
formula (II):
(II)
(S) (S)
EtO C NH CO H
with an activation agent, preferably N,N'-carbonyldiimidazole, phosgene, triphosgene, (1,1'-
carbonyldi(1,2,4-triazole) or di(N-succinimidyl) carbonate,
in an organic solvent or a system of organic solvents, preferably acetonitrile, ethyl acetate or
dichloromethane,
at a temperature from -20°C to 80°C, preferably from -10 to 40°C,
followed by reaction of the intermediate compound of formula (III) thereby obtained:
(III)
EtO C N
with (2S, 3aS, 7aS)carboxyperhydroindole,
at a temperature from 0°C to 80°C, preferably from 5 to 40°C.
An "activation agent" is understood to mean a compound of formula X C=O wherein X
represents a leaving group such as, for example, a halogen atom or a tosylate, mesylate,
imidazolyl, 1,2,4-triazolyl, succinimidyl or optionally substituted alkoxy group.
When the activation agent is N,N'-carbonyldiimidazole, the amount of N,N'-carbonyl-
diimidazole is preferably between 0.8 and 1.2 moles, inclusive, per mole of N-[1-(S)-
ethoxycarbonyl-butyl]-(S)-alanine.
The amount of (2S, 3aS, 7aS)carboxyperhydroindole is preferably between 0.8 and
1.2 moles, inclusive, per mole of N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine.
In accordance with another embodiment of the present invention, the perindopril (free acid)
used in the reaction is obtained by desaltification of perindopril tert-butylamine by the action
of an acid.
"Desaltification of perindopril tert-butylamine" is understood to mean returning it to
perindopril in the form of the free acid.
The following Example illustrate the invention.
These Examples do not all result in the pure delta crystalline form.
Abbreviations:
CDT (1,1'-CarbonylDi(1,2,4-Triazole))
DMSO Dimethyl sulphoxide
DSC (Di(N-Succinimidyl) Carbonate)
HPLC High Performance Liquid Chromatography
The filtrations are expressed in standard manner: in terms of kg of liquor filtered per hour and
per m of filtration area.
EXAMPLE 1: L-arginine salt of perindopril – starting from perindopril (free acid), in a
binary mixture of acetonitrile/DMSO 25/75 without seeding
Perindopril (12.5 g, 1 eq.) and L-arginine (5.32 g – 0.9 eq) are suspended in a mixture of
acetonitrile (20 g, d = 0.787) and DMSO (61 g, d = 1.100). The reaction mixture is heated at
50°C overnight. The product is then isolated by filtration over a frit. The filter cake is washed
and dried.
Perindopril arginine (14.5 g) is obtained in a yield of 79 % relative to the perindopril. The
crystalline phase isolated is the delta phase. The HPLC quality of the isolated product is
greater than 99.0 %.
The filtration rate of the mother liquors is of the order of 6000 kg/h/m .
The L-arginine salt of perindopril thereby obtained is in the delta crystalline form. This form
has the following X-ray powder diffraction diagram, measured using a diffractometer with a
copper anticathode and expressed in terms of interplanar spacing d, Bragg's angle 2 theta, and
relative intensity expressed as a percentage in relation to the most intense line:
Interplanar spacing d Relative intensity
Angle 2 theta (°)
[Å] [%]
4.34 20.37 66.2
.57 15.86 5.2
11.04 8.02 57.5
11.15 7.94 47.5
11.87 7.454 35.0
12.47 7.09 17.9
13.21 6.70 33.6
14.06 6.30 6.6
14.64 6.05 31.8
16.03 5.53 17.5
17.11 5.18 5.6
18.27 4.85 4.1
19.23 4.61 100
19.44 4.57 17.8
.04 4.43 13.6
21.11 4.21 3.7
21.93 4.05 23.0
22.20 4.00 16.9
22.61 3.93 21.2
23.21 3.83 4.5
24.30 3.66 2.3
.09 3.55 9.4
.95 3.43 1.7
29.54 3.02 4.2
Each line is considered to have an accuracy of ± 0.2° in 2-theta.
Figure 1: Diffractogram of the delta form of perindopril L-arginine.
EXAMPLE 2: L-arginine salt of perindopril – starting from perindopril (free acid), in a
binary mixture of acetonitrile/DMSO 25/75 with seeding
Perindopril (100 g, 1 eq.) and L-arginine (42.6 g, 0.9 eq.) are suspended in a mixture of
acetonitrile (220 g, d = 0.787) and dimethyl sulphoxide (630 g, d = 1.100). The reaction
mixture is heated at 70°C for 3 hours and seeded with 2 % of the delta phase, and it is then
cooled to 40°C over 1 hour. The mixture is held at 40°C for 18 hours with stirring and is then
cooled to 20°C over 1 hour. The product is then isolated by filtration. The filter cake is washed
and dried.
Perindopril (L)-arginine (119 g) is obtained in a yield of 79 % relative to the perindopril. The
HPLC quality of the isolated product is greater than 99.0 %.
The filtration rate of the mother liquors is about 6000 kg/h/m .
EXAMPLE 3: General procedure for production of perindopril (free acid) starting
from (2S, 3aS, 7aS)carboxy-perhydroindole and N-[1-(S)-ethoxy-
carbonyl-butyl]-(S)-alanine by activation with N,N'-carbonyl-
diimidazole.
N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine (65 g, 1 eq.) and N,N'-carbonyldiimidazole (48 g,
1 eq.) are introduced and then acetonitrile (500 g) is added. The reaction mixture is then stirred
at a temperature less than +10°C for 3 hours.
The reaction mixture is poured into (2S, 3aS, 7aS)carboxyperhydroindole (50 g, 1 eq.); an
amount of fresh acetonitrile (80 g) is used to rinse the apparatus.
The reaction mixture is then stirred for 5 hours at a temperature less than +10°C and is then
clarified over a filter to obtain a clear solution.
EXAMPLE 4: L-arginine salt of perindopril – starting from (2S, 3aS, 7aS)carboxy-
perhydroindole, in a binary mixture of acetonitrile/DMSO 50/50 with
seeding
Perindopril L-arginine (110 g) is obtained by pouring the solution, in acetonitrile, of
perindopril (100 g of product) synthesised according to the general procedure of Example 3
into a suspension of L-arginine (44.3 g, 0.85 eq.) in DMSO (540 g, d = 1.100) at 50°C; the
reaction mixture is seeded with 2 % of the delta crystalline form (compound of Example 1).
The mixture is maintained at 50°C for 15 hours, with stirring, and is then cooled to 20°C at a
rate of 0.5°C/min. The suspension is filtered using a filtration cell. The yield is 75 % relative
to the perindopril used. The quality of the isolated product is greater than 99.0 % according to
HPLC.
The filtration rate of the mother liquors is about 5000 kg/h/m .
EXAMPLE 5: L-arginine salt of perindopril – starting from (2S, 3aS, 7aS)carboxy-
perhydroindole, in a binary mixture of acetonitrile/DMSO 75/25 with
seeding
Perindopril L-arginine (42 g) is obtained by pouring the solution, in acetonitrile, of perindopril
(38 g of product) synthesised according to the general procedure of Example 3 by adding
L-arginine (17 g, 0.85 eq.) suspended in dimethyl sulphoxide (78 g) at a temperature of 40°C
and after seeding with 4 % by weight of perindopril L-arginine in delta form (compound of
Example 1). Filtration is carried out at 40°C using a filtration cell.
The yield is 73 % relative to the perindopril used. The quality of the isolated product is greater
than 99.0 % according to HPLC.
The filtration rate of the mother liquors is about 5700 kg/h/m .
EXAMPLE 6: L-arginine salt of perindopril - starting from (2S, 3aS, 7aS)carboxy-
perhydroindole and triphosgene
N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine (20 g, 1 eq.) and Na HPO .12 H O (43 g, 1.3 eq.)
2 4 2
are suspended in dichloromethane (212 g). The reaction mixture is heated to reflux and then a
solution of triphosgene (9.55 g, 0.35 eq.) in dichloromethane (64 g) is poured in. After
liquid/liquid washings of the organic phase with water, the dichloromethane is evaporated off
to yield activated N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine of formula (III) (22 g). The latter
is then dissolved in acetonitrile (180 g). The solution is poured into (2S, 3aS, 7aS)
carboxyperhydroindole (15 g, 1 eq.) and the reaction mixture is stirred for about 5 hours in the
presence of triethylamine (9.15 g, 1 eq.) at a temperature less than 10°C, and it is then clarified
through a filter in order to obtain a clear solution. The L-arginine salt of perindopril is obtained
by adding L-arginine (14.5 g, 0.90 eq.) suspended in DMSO (180 g) at a temperature of 50°C.
After a contact time of about 5 hours, the mixture is seeded with 2 % of the delta form and is
then stirred overnight at 50°C and filtered using a filtration cell.
Perindopril L-arginine (43 g) is obtained in a yield of 89 % relative to the (2S, 3aS, 7aS)
carboxyperhydroindole (seed subtracted). The HPLC quality of the isolated product is greater
than 99 %.
The filtration rate of the mother liquors is about 2000 kg/h/m .
EXAMPLE 7: L-arginine salt of perindopril – starting from perindopril tert-
butylamine, in a ternary mixture of acetonitrile/dimethyl
sulphoxide/toluene 30/40/30, with seeding
Suspend perindopril tert-butylamine (103 g, 1.00 eq.) and sodium chloride (5.84 g) in toluene
(268 g, d = 0.867). Stir at ambient temperature.
Add a solution of hydrochloric acid (57.8 mL, # 4 N, 1 eq.). Stir for 40 minutes at ambient
temperature. Separate the toluene phase from the aqueous phase.
Wash the aqueous phase with toluene (2 x 90 g, d = 0.867).
At this stage, the perindopril is in solution in the toluene at a concentration of 16% w/w.
L-arginine (36.6 g, 0.90 eq.) and dimethyl sulphoxide (566 g, d = 1.100) are added and the
reaction mixture is heated at 50°C for 5 hours. Acetonitrile (405 g, d = 0.787) is added and the
reaction mixture is seeded with 2 % by weight of perindopril L-arginine in the delta form
(compound of Example 1).
The suspension is stirred for 17 hours; the temperature is then brought to 30°C over 30 minutes.
After stirring for 2 hours, the product is isolated by filtration. The filter cake is washed and
dried.
Perindopril L-arginine (95 g) is obtained in a yield of 75 % relative to the perindopril tert-
butylamine. The HPLC quality of the isolated product is greater than 99.8 %.
The filtration rate of the mother liquors is about 4000 kg/h/m .
EXAMPLE 8: L-arginine salt of perindopril – starting from perindopril (free acid), in a
ternary mixture of acetonitrile/DMSO/toluene 30/40/30, with seeding
Lyophilised perindopril (8.3 g, 1 eq.) is dissolved in a mixture of toluene (43 g) and DMSO
(55 g). L-arginine (3.9 g, 1 eq.) is introduced in the form of a suspension in acetonitrile (40 g),
and the entire batch is heated at 50°C.
The reaction mixture is seeded with 3 % of perindopril arginine in the delta form and the
suspension is stirred at 50°C for 22 hours.
The product is isolated by filtration.
Perindopril L-arginine (9 g) is obtained in a yield of 73 % relative to the perindopril. The
HPLC quality of the isolated product is greater than 99 %.
EXAMPLE 9: L-arginine salt of perindopril – starting from perindopril tert-
butylamine, in a binary mixture of ethyl acetate/DMSO 55/45, with
seeding
Load perindopril erbumine (200 g, 1 eq.), methyltetrahydrofuran (700 g) and methanesulphonic
acid (43.5 g, 1 eq.) into a reactor.
Filter off the insoluble material and add L-arginine (78.8 g, 1 eq.) and DMSO (500 g) to the
solution.
Distil off the methyltetrahydrofuran and heat at 70°C for 1 hour.
Add ethyl acetate (600 g) and seed with 2 % of perindopril arginine in the delta crystalline
form.
Cool to 25°C over 4 hours, filter and wash the product with a mixture of ethyl acetate/DMSO.
Perindopril L-arginine (217 g, seed subtracted) is obtained in a yield of 88 % relative to the
perindopril. The HPLC quality of the product isolated is greater than 99 %.
The filtration rate of the mother liquors is more than 1500 kg/h/m .
EXAMPLE 10: L-arginine salt of perindopril – starting from perindopril (free acid), in a
ternary mixture of acetonitrile/DMSO/toluene 45/50/5, with seeding
Load lyophilised perindopril (30 g, 1 eq.), DMSO (100 g) and L-arginine (13.8 g, 1 eq.) into a
reactor. The mixture is heated at 70°C for 2 hours.
Add a mixture of acetonitrile (90 g) and toluene (10 g) and seed with 2 % of perindopril
arginine in the delta crystalline form. The suspension is stirred at 70°C for 2 hours.
Cool to 25°C over 4 hours, filter and wash the product with acetonitrile and DMSO.
Perindopril L-arginine (41 g, seed subtracted) is obtained in a yield of 92 % relative to the
perindopril. The HPLC quality of the isolated product is greater than 99%.
The filtration rate of the mother liquors is more than 1500 kg/h/m .
Comparison EXAMPLE A: Adaptation of the procedure of Example 3 of EP 1 279 665 to
obtaining the L-arginine salt of perindopril
The reactor is cooled to 0°C beforehand. N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine (80 g –
1 eq.) and dichloromethane (1325 g, d = 1.325) are introduced. N,N'-carbonyldiimidazole
(71.5 g – 1.2 eq.) and 0.336 L of dichloromethane are added to the mixture. The temperature of
the mixture is brought to –5°C prior to adding (2S, 3aS, 7aS)carboxyperhydroindole (81 g –
1.3 eq.). After a contact time of 2 hours 30 minutes, the mixture is dried and then taken up in
water (1200 g, d = 1.00). After acidification of the aqueous phase (with 185 ml of 4N HCl
solution), the solution is extracted with dichloromethane (2517.5 g, d = 1.325) and the aqueous
phase is saturated with NaCl. The organic phase is dried and the residue from drying is taken
up in ethyl acetate (1176.6 g, d = 0.902). L-arginine is then added (68 g- 1.06 eq.) and the
mixture is held at 50°C overnight, with stirring.
Filtration of the mixture is found to be impossible because the solid has a sticky consistency.
The solid is removed from the reactor by dismantling of the tank.
Yield (determined by titration) : 1.6 %.
Comparison EXAMPLE B: according to Example 6 of Patent Application
Perindopril (30 g) and L-arginine (13.8 g) are suspended in toluene (130 g, d = 0.867) at
ambient temperature. The mixture is refluxed for one hour. Then acetonitrile (1180.5 g,
d = 0.787) is added at 80°C. After maintaining stirring for one hour at that temperature, the
suspension is filtered using a cell under 0.3 bar of nitrogen.
The average filtration rate of the mother liquors was measured at 100 kg/h/m . The product
isolated has a sticky consistency and is pale pink in colour. The yield by weight is 46.5 %. The
HPLC quality of the product isolated is of the order of 83 %.
Claims (9)
1. Process for the preparation of perindopril L-arginine salt of formula (I): N CO H N NH CO Et by means of reaction between perindopril and L-arginine in a solvent system selected 5 from: a binary mixture of acetonitrile and dimethyl sulphoxide, a binary mixture of ethyl acetate and dimethyl sulphoxide, a ternary mixture of acetonitrile, dimethyl sulphoxide and toluene, at a temperature from 10 to 100°C, 10 followed by isolation by means of filtration of the L-arginine salt thereby obtained.
2. Process for the preparation of perindopril L-arginine salt according to claim 1, wherein the perindopril is obtained by reaction of N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine of formula (II): (II) (S) (S) EtO C NH CO H 15 with an activation agent of formula X C=O wherein X represents a leaving group, in an organic solvent or a system of organic solvents, at a temperature from –20 to 80°C, followed by reaction of the intermediate compound of formula (III) thereby obtained: (III) EtO C with (2S, 3aS, 7aS)carboxyperhydroindole, at a temperature from 0 to 80°C, and then the perindopril thereby obtained is reacted with L-arginine in accordance with 5 the process of claim 1.
3. Process for the preparation of perindopril L-arginine salt according to claim 2, wherein the activation agent is N,N'-carbonyldiimidazole, phosgene, triphosgene, (1,1'- carbonyldi(1,2,4-triazole) or di(N-succinimidyl) carbonate.
4. Process for the preparation of perindopril L-arginine salt according to claim 3, wherein 10 the activation agent is N,N'-carbonyldiimidazole and the amount of N,N'- carbonyldiimidazole is between 0.8 and 1.2 moles, inclusive, per mole of N-[1-(S)- ethoxycarbonyl-butyl]-(S)-alanine.
5. Process for the preparation of perindopril L-arginine salt according to any one of claims 2 to 4, wherein the amount of (2S, 3aS, 7aS)carboxyperhydroindole is 15 between 0.8 and 1.2 moles, inclusive, per mole of N-[1-(S)-ethoxycarbonyl-butyl]-(S)- alanine.
6. Process for the preparation of perindopril L-arginine salt according to claim 1, wherein the perindopril is obtained by desaltification of perindopril tert-butylamine by the action of an acid, and then the perindopril thereby obtained is reacted with L-arginine 20 in accordance with the process of claim 1.
7. Perindopril L-arginine salt of formula (I) obtained by a process of any one of claims 1 to 6, substantially as herein described with reference to any example thereof.
8. A process of claim 1, substantially as herein described with reference to any example thereof.
9. A product of claim 7, substantially as herein described with reference to any example 5 thereof.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR12/00034 | 2012-01-05 |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ605270A NZ605270A (en) | 2013-10-25 |
NZ605270B true NZ605270B (en) | 2014-01-28 |
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