NZ621358B2 - Pures-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1h,-5h-benzo[i,j]quinolizine-2- carboxylic acid l-arginine salt tetrahydrate and a process for its preparation - Google Patents
Pures-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1h,-5h-benzo[i,j]quinolizine-2- carboxylic acid l-arginine salt tetrahydrate and a process for its preparation Download PDFInfo
- Publication number
- NZ621358B2 NZ621358B2 NZ621358A NZ62135812A NZ621358B2 NZ 621358 B2 NZ621358 B2 NZ 621358B2 NZ 621358 A NZ621358 A NZ 621358A NZ 62135812 A NZ62135812 A NZ 62135812A NZ 621358 B2 NZ621358 B2 NZ 621358B2
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- New Zealand
- Prior art keywords
- benzo
- fluoro
- acid
- dihydro
- quinolizinecarboxylic
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 7
- PLHMMMBDEVOCJW-NDNWHDOQSA-N O.O.O.O.OC(=O)[C@@H](N)CCCNC(N)=N Chemical compound O.O.O.O.OC(=O)[C@@H](N)CCCNC(N)=N PLHMMMBDEVOCJW-NDNWHDOQSA-N 0.000 claims abstract description 43
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 32
- -1 arginine salt tetrahydrate Chemical class 0.000 claims abstract description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 12
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000010992 reflux Methods 0.000 claims abstract description 6
- 235000014852 L-arginine Nutrition 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 238000007865 diluting Methods 0.000 claims abstract description 5
- 239000007787 solid Substances 0.000 claims abstract description 5
- 238000010792 warming Methods 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims description 65
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 46
- 239000012523 bacterial endotoxin Substances 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 150000008535 L-arginines Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000002471 4H-quinolizinyl group Chemical class C=1(C=CCN2C=CC=CC12)* 0.000 claims 2
- 238000001291 vacuum drying Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 16
- KQFZOWUXULRDDS-UHFFFAOYSA-N 4H-quinolizine-1-carboxylic acid Chemical compound C1=CC=CN2CC=CC(C(=O)O)=C21 KQFZOWUXULRDDS-UHFFFAOYSA-N 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 239000002158 endotoxin Substances 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 150000003250 quinolizines Chemical class 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000006011 modification reaction Methods 0.000 description 4
- 239000005695 Ammonium acetate Substances 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 206010060945 Bacterial infection Diseases 0.000 description 1
- 102100018344 PRPF3 Human genes 0.000 description 1
- 101700055558 PRPF3 Proteins 0.000 description 1
- 101710005260 RPL6A Proteins 0.000 description 1
- 101710005264 RPL6B Proteins 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- IXGNPUSUVRTQGW-UHFFFAOYSA-M sodium;perchlorate;hydrate Chemical compound O.[Na+].[O-]Cl(=O)(=O)=O IXGNPUSUVRTQGW-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
Abstract
Pure S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,-5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate and a process for its preparation is disclosed. The preparative process comprises (a) dissolving L-arginine in a mixture of acetone and water; (b) adding the compound of formula (I); (c) warming the solution obtained in step (b) to get a clear solution; (d) optionally treating the warm solution obtained in step (c) with activated carbon and filtering the treated solution; (e) diluting the warm solution obtained in step (d) with acetone and refluxing the diluted solution; (f) cooling the solution obtained in step (e) to obtain the solid arginine salt tetrahydrate; and (g) collecting the L-arginine salt tetrahydrate obtained in step (f) by filtration, and optionally washing it with acetone. ding the compound of formula (I); (c) warming the solution obtained in step (b) to get a clear solution; (d) optionally treating the warm solution obtained in step (c) with activated carbon and filtering the treated solution; (e) diluting the warm solution obtained in step (d) with acetone and refluxing the diluted solution; (f) cooling the solution obtained in step (e) to obtain the solid arginine salt tetrahydrate; and (g) collecting the L-arginine salt tetrahydrate obtained in step (f) by filtration, and optionally washing it with acetone.
Description
FIELD OF THE INVENTION
The invention relates to substantially pure S-(-)fluoro-6,7-dihydro(4-
hydroxypiperidinyl)methyl- 1-oxo-1H,-5H-benzo[i,j]quinolizine-Z-carboxylic acid
L-arginine salt ydrate and a process for its preparation.
OUND OF THE INVENTION
The compound of Formula (I), chemically known as S-(-)fluoro(4-hydroxy
piperidinyl)methyl-6, 7-dihydrooxo- 1 H, 5H-benzo [i, j] quinolizinecarboxylic
acid, belongs to a class of antibacterial agents generally known as flouroquinolones and is
useful in treating a broad range of bacterial infections.
N N
Formula (I)
US Patent No. 7,164,023 discloses a crystalline 9-fluoro-6,7-dihydro(4-
hydroxypiperidinyl)methyloxo-1H,- 5H-benzo[i,j ]quinolizine-Z-carboxylic acid
L-arginine salt tetrahydrate and its preparation.
The present ion is directed to a substantially pure S-(-)fluoro-6,7-
dihydro(4-hydroxypiperidinyl)methyloxo-1H,- 5H-benzo [i,j ]quinolizine
ylic acid L-arginine salt tetrahydrate and a process for its preparation.
SUMMARY OF THE INVENTION
Accordingly, there is provided a substantially pure S-(-)fluoro-6,7-dihydro-
8-(4-hydroxypiperidinyl)methyloxo-1H,- 5H-benzo[i,j]quinolizine
ylic acid L-arginine salt tetrahydrate and a process for it’s preparation.
In one general aspect, there is provided a pharmaceutical composition
comprising S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-
1H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate having a
purity of at least 99% w/w as determined by HPLC, said S-(-)fluoro-6,7-dihydro
(4-hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic
acid L-arginine salt tetrahydrate further comprising less than 0.15% w/w of 9-fluoro-
8-hydroxymethyl-6,7-dihydrooxo-1H,5H-benzo [i,j]quinolizine carboxylic
acid as determined by HPLC.
In another general aspect, there is provided a pharmaceutical ition
sing S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-
1H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate having a
purity of at least 99% w/w as determined by HPLC, said S-(-)fluoro-6,7-dihydro
(4-hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic
acid L-arginine salt tetrahydrate further sing less than 0.15% w/w of 8-fluoro-
9-(4-hydroxy-piperidinyl)methyl-6,7-dihydrooxo-1H,5H-
benzo[i,j]quinolizinecarboxylic acid as determined by HPLC.
In another general aspect, there is provided a pharmaceutical ition
comprising S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-
1H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate having a
purity of at least 99% w/w as determined by HPLC, said 9-fluoro-6,7-dihydro
(4-hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic
acid L-arginine salt tetrahydrate further comprising less than 0.15% w/w of 8-(4-
hydroxypiperidinyl)methyl-6,7-dihydrooxo-1H, 5H-benzo[i,j]quinolizine
carboxylic acid as determined by HPLC.
In another general aspect, there is provided a pharmaceutical composition
comprising S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-
-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate having a
purity of at least 99% w/w as determined by HPLC, said S-(-)fluoro-6,7-dihydro
(4-hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic
acid L-arginine salt tetrahydrate further comprising less than 0.15% w/w of 8,9-
romethyl-6,7-dihydrooxo-1H,5H-benzo[i,j] quinolizinecarboxylic acid
as ined by HPLC.
In another general aspect, there is provided a pharmaceutical composition
comprising S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-
1H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate having a
purity of at least 99% w/w as determined by HPLC, said S-(-)fluoro-6,7-dihydro
(4-hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic
acid L-arginine salt tetrahydrate further sing less than 0.5% w/w of R-(+)
fluoro(4-hydroxy-piperidinyl)methyl-6,7-dihydrooxo-1H,5H-
i,j]quinolizinecarboxylic acid as determined by HPLC.
In r general aspect there is provided a pharmaceutical composition
sing S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-
1H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate having a
purity of at least 99% w/w as determined by HPLC, said S-(-)fluoro-6,7-dihydro
(4-hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic
acid L-arginine salt tetrahydrate further comprising bacterial endotoxins in an amount
less than 0.35 USP Endotoxin Units per mg.
In yet another general aspect there is provided a pharmaceutical ition
comprising S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-
1H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate having a
purity of at least 99% w/w as determined by HPLC, said S-(-)fluoro-6,7-dihydro
(4-hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic
acid L-arginine salt tetrahydrate further comprising one or more of the following:
(i) less than 0.15% w/w of 9-fluorohydroxymethyl-6,7-dihydrooxo-
1H,5H-benzo [i,j]quinolizine carboxylic acid as determined by HPLC;
(ii) less than 0.15% w/w of 8-fluoro(4-hydroxy-piperidinyl)methyl-
6,7-dihydrooxo-1H,5H-benzo[i,j]quinolizinecarboxylic acid as determined by
HPLC;
(iii) less than 0.15% w/w of 8-(4-hydroxypiperidinyl)methyl-6,7-
dihydrooxo-1H, zo[i,j]quinolizinecarboxylic acid as determined by
HPLC;
(iv) less than 0.15% w/w of 8,9-difluoromethyl-6,7-dihydrooxo-1H,5H-
benzo[i,j] quinolizinecarboxylic acid as determined by HPLC;
(v) less than 0.5% w/w of R-(+)fluoro(4-hydroxy-piperidinyl)
methyl-6,7-dihydrooxo-1H,5H-benzo[i,j]quinolizinecarboxylic acid as
determined by HPLC; or
(vi) bacterial endotoxins in an amount less than 0.35 USP Endotoxin Units per
In another l aspect, there is provided a process for preparing S-(-)
fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-1H,-5H-
benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate having a purity of
at least 99% w/w as determined by HPLC, said process comprising:
(a) dissolving L-arginine in a mixture of acetone and water;
(b) adding S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyl
,-5H-benzo[i,j]quinolizinecarboxylic acid to the on obtained in step
(a);
(c) warming the on obtained in step (b) to get a clear solution;
(d) optionally treating the warm solution obtained in step (c) with activated
carbon and filtering the treated solution;
(e) diluting the warm solution obtained in step (d) with acetone and refluxing
the diluted solution;
(f) g the solution obtained in step (e) to obtain solid S-(-)fluoro-6,7-
dihydro(4-hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizine
ylic acid L-arginine salt tetrahydrate; and
(g) collecting S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)
oxo-1H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt
tetrahydrate obtained in step (f) by filtration, and optionally washing it with e.
The details of one or more embodiments of the inventions are set forth in the
description below. Other features, aspects and advantages of the inventions will be
apparent from the following description including claims
DETAILED DESCRIPTION OF THE INVENTION
Reference will now be made to the ary ments, and specific
language will be used herein to describe the same. It should nevertheless be
understood that no limitation of the scope of the invention is thereby intended.
Alterations and further modifications of the inventive features rated herein, and
additional applications of the principles of the inventions as rated herein, which
would occur to one skilled in the relevant art and having possession of this disclosure,
are to be considered within the scope of the invention. It must be noted that, as used in
this specification and the appended claims, the singular forms "a," "an," and "the"
include plural referents unless the content clearly dictates otherwise. All references
including patents, patent applications, and literature cited in the specification are
expressly incorporated herein by reference in their ty.
Where the terms “comprise”, “comprises”, “comprised” or “comprising” are
used in this specification, they are to be interpreted as specifying the ce of the
stated features, integers, steps or components referred to, but not to preclude the
presence or addition of one or more other feature, integer, step, component or group
thereof.
WO 46061
The ion provides substantially pure S-(-)fluoro-6,7-dihydro(4-
hydroxypiperidin- l -yl)methyl- l -oxo- l H,-5H-benzo[i,j ]quinolizinecarboxylic acid
L-arginine salt tetrahydrate and a process for its preparation.
The term “substantially pure S-(-)fluoro-6,7-dihydro(4-hydroxypiperidin-l-
yl)methyl- l -oxo- l H,-5H-benzo[i,j] quinolizinecarboxylic acid L-arginine salt
tetrahydrate” as used herein refers to 9-fluoro-6,7-dihydro(4-hydroxypiperidin-lyl
)methyl- l -oxo- l H,-5H-benzo[i,j] quinolizinecarboxylic acid L-arginine salt
ydrate having one or more of the following specifications:
(i) S-(-)fluoro-6,7-dihydro(4-hydroxypiperidin-l -yl)methyl-l-oxo-1H,-
5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate having a purity of
at least 99% W/W as determined by HPLC;
(ii) S-(-)fluoro-6,7-dihydro(4-hydroxypiperidin- l -yl)methyl- l -oxo- 1H,-
5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate having a purity of
at least 99% W/W, further containing less than 0.15% W/W of 9-fluorohydroxy
methyl-6,7-dihydro-l-oxo-lH,5H-benzo [i,j] quinolizine carboxylic acid, as
determined by HPLC;
(iii) S-(-)fluoro-6,7-dihydro(4-hydroxypiperidin- l-yl)methyl-l -oxo-1H,-
5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt ydrate having a purity of
at least 99% W/W, further containing less than 0.15% W/W of 8-fluoro(4-hydroxy-
piperidin- l -yl)methyl-6,7-dihydro- l -oxo- l H,5H-benzo [i,j]quinolizinecarboxylic
acid, as determined by HPLC;
(iv) S-(-)fluoro-6,7-dihydro(4-hydroxypiperidin-l-yl)methyl-l -oxo-1H,-
5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate having a purity of
at least 99% W/W, r containing less than 0.15% w/W of 8-(4-hydroxy-l-piperidinyl)-
-methyl-6,7-dihydro-l-oxo-1H, 5H-benzo[i,j ]quinolizinecarboxylic acid, as
determined by HPLC;
(V) S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-1H,—
5H-benzo[i,j]quinolizine-Z-carboxylic acid L-arginine salt tetrahydrate having a purity of
at least 99% W/W, further containing less than 0.15% W/W of 8,9-difluoromethyl-6,7-
dihydro-l-oxo-lH,5H-benzo[i,j] quinolizinecarboxylic acid, ined by HPLC;
(vi) S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-1H,—
5H-benzo[i,j]quinolizine-Z-carboxylic acid L-arginine salt tetrahydrate having a purity of
at least 99% W/W, further containing less than 0.5% W/W of R-(+)fluoro(4-hydroxy-
piperidin- l -yl)methyl-6,7-dihydro0X0- 1 H,5H-benzo [i,j]quinolizinecarboxylic
acid, as determined by HPLC; or
(vii) S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-1H,-
5H-benzo[i,j]quinolizine-Z-carboxylic acid L-arginine salt ydrate having a purity of
at least 99% W/W, further containing bacterial endotoxins in an amount less than 0.35
USP Endotoxin Unit per mg.
In some embodiments, there is provided 9-fluoro-6,7-dihydro(4-
hydroxypiperidin- l -yl)methyl0X0- 1 H,-5H-benzo[i,j ]quinolizinecarboxylic acid
L-arginine salt tetrahydrate having a purity of at least 99% W/W as determined by HPLC.
In some other embodiments, there is provided S-(-)fluoro-6,7-dihydro(4-
hydroxypiperidin- l -yl)methyl0X0- 1 H,-5H-benzo[i,j ]quinolizinecarboxylic acid
L-arginine salt tetrahydrate having a purity of at least 99% W/W, further containing less
than 0.15% W/W of 9-fluorohydroxymethyl-6,7-dihydrooxo-1H,5H-benzo [i,j]
izine carboxylic acid, as determined by HPLC.
In some other embodiments, there is provided S-(-)fluoro-6,7-dihydro(4-
ypiperidin- l -yl)methyl0X0- 1 H,-5H-benzo[i,j ]quinolizinecarboxylic acid
L-arginine salt tetrahydrate having a purity of at least 99% W/W, further containing less
than 0.15% W/W of 8-fluoro(4-hydroxy-piperidinyl)methyl-6,7-dihydrooxo-
1H,5H-benzo[i,j]quinolizinecarboxylic acid, as determined by HPLC.
In some other embodiments, there is provided S-(-)fluoro-6,7-dihydro(4-
hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic acid
L-arginine salt tetrahydrate having a purity of at least 99% W/W, further containing less
than 0.15% W/W of 8-(4-hydroxypiperidinyl)methyl-6,7-dihydrooxo-1H, 5H-
benzo[i,j]quinolizinecarboxylic acid, as determined by HPLC.
In some embodiments, there is provided S-(-)fluoro-6,7-dihydro(4-
hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic acid
L-arginine salt tetrahydrate having a purity of at least 99% W/W, further containing less
than 0.15% W/W of 8,9-difluoromethyl-6,7-dihydrooxo-1H,5H-benzo[i,j]
quinolizinecarboxylic acid, determined by HPLC.
In some embodiments, there is provided S-(-)fluoro-6,7-dihydro(4-
ypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic acid
L-arginine salt tetrahydrate haVing a purity of at least 99% W/W, further containing less
than 0.5% W/W of R—(+)fluoro(4-hydroxy-piperidinyl)methyl-6,7-dihydro
,5H-benzo[i,j]quinolizinecarboxylic acid, as determined by HPLC.
In another general aspect, there is provided a process for preparing S-(-)fluoro-
6,7-dihydro(4-hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizine-
2-carboxylic acid L-arginine salt ydrate haVing a purity of at least 99% W/W as
determined by HPLC, said s sing:
(a) dissolVing nine in a mixture of acetone and water;
(b) adding S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyl- 1-
oxo-1H,-5H-benzo[i,j]quinolizinecarboxylic acid to the solution obtained in step (a);
(c) warming the solution obtained in step (b) to get a clear solution;
(d) optionally treating the warm solution obtained in step (c) with activated
carbon and filtering the treated solution;
(e) diluting the warm on ed in step (d) with acetone and refluxing the
diluted solution;
(f) cooling the on obtained in step (e) to obtain solid S-(-)fluoro-6,7-
dihydro(4-hydroxypiperidin- l -yl)methyl0X0- -benzo[i,j ]quinolizine
carboxylic acid L-arginine salt tetrahydrate; and
(g) collecting S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyl
oxo-lH,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate obtained
in step (I) by filtration, and optionally washing it with acetone.
In some ments there is provided S-(-)fluoro-6,7-dihydro(4-
hydroxypiperidin- l -methyl0X0- 1 H,-5H-benzo[i,j ]quinolizinecarboxylic acid
L-arginine salt tetrahydrate haVing a purity of at least 99% W/W, further containing
bacterial endotoxins in an amount less than 0.35 USP Endotoxin Unit per mg.
In some embodiments, there is provided a pharmaceutical composition
comprising substantially pure S-(-)fluoro-6,7-dihydro(4-hydroxypiperidin-l-yl)
methyl0X0- 1 H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate
according to the invention.
In some other embodiments, the pharmaceutical compositions according to the
invention may further se one or more pharmaceutically acceptable excipients.
It will be readily apparent to one skilled in the art that varying tutions
and modifications may be made to the invention disclosed herein t departing
from the scope and spirit of the invention. For example, those skilled in the art will
recognize that the invention may be practiced using a variety of different compounds
within the described generic descriptions.
EXAMPLES
The following examples illustrate the embodiments of the invention that are
presently best known. However, it is to be tood that the following are only
exemplary or rative of the application of the ples of the present ion.
Numerous modifications and alternative compositions, methods, and systems may be
devised by those skilled in the art without departing from the spirit and scope of the
present invention. The appended claims are intended to cover such modifications and
arrangements. Thus, while the present ion has been described above with
particularity, the following examples provide further detail in tion with what
are presently deemed to be the most practical and preferred embodiments of the
invention.
Example 1. Synthesis of substantially Pure S-(-)fluoro-6,7-dihydro(4-
hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic
acid nine salt ydrate.
In a typical experiment, 0.45Kg of L-arginine was dissolved in 7.5 Ltr of
mixture of acetone and water (4:3.5). 1 Kg of S-(-)fluoro-6,7-dihydro(4-
hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic
acid was charged to this solution and warmed to 55°C to obtain a clear solution. The
clear solution was treated with activated carbon at 50°C for 0.5 hours and hot filtered
through a 5μ filter and finally through a 0.2μ filter. The te thus obtained was
diluted slowly with 9.8 Ltr of acetone (0.2μ filtered) at 50 - 55°C. The reaction mass
thus obtained was refluxed for 0.5 hours and slowly cooled to about 10-15°C. The
solid product thus obtained was collected by filtration and washed with acetone. The
wet material was vacuum dried at 30-40°C to get
about 1.4 Kg of S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-
1H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate which was
analyzed for content of various components using HPLC and the results are described in
Table 1.
The amount of R-(+)fluoro(4-hydroxy-piperidinyl)methyl-6,7-dihydro
oxo-1H,5H-benzo[i,j]quinolizinecarboxylic acid (or R-(+)-isomer content) was
determined using HPLC s 2695 separation module or equivalent). The HPLC
column having 250 mm length and 4.6 mm ID packed with 1011 particles of (8,8) Whelk-
01 10/100 was used. Mobile phase used was a mixture of ammonium acetate solution
(1.52 gm in 1000 ml of HPLC grade water) and ethanol in ratio of 45:55, v/v. Flow rate
of mobile phase was maintained at 1.2 ml/min. Column temperature was maintained at
40°C. Detection was carried out using UV detector at wavelength 295 nm. Standard
solution and test solution were prepared in ol.
The t of other substances (Table 1, Sr. No. 1 to 5) in the product was
determined using HPLC s 2695 separation module or equivalent). The HPLC
column having 150mm length and 4.6mm ID packed with 3.5 u les of X-Terra RP18
was used. Mobile phase A used was a mixture of ammonium acetate (3.0 gm) and sodium
perchlorate monohydrate (8.4 gm) in 1000 ml of HPLC grade water with final pH
adjusted to 2.2 with orthophosphoric acid. Mobile phase B was mixture of methanol and
acetonitrile in ratio of 60:40, v/v. Mobile phase was run in gradient mode. Initially
mobile phase A and B was run at 75:25 for 15 minutes, slowly ratio of mobile phase B
was raised to 50% in 20 min, held for 10 s at this concentration and brought back
to initial condition in next 3 minutes and held for 7 minutes before next run. Flow rate of
mobile phase was ined at 1.2 ml/min. Column temperature was maintained at
40°C. Detection was d out using UV detector at wavelength 237 nm. Standard
solution and test solution were prepared in mixture of water and mobile phase B in ratio
of 50:50, v/v with pH adjusted to 8.5 with dilute ammonia.
Table 1. Results of HPLC analysis of S-(-)fluoro-6,7-dihydro(4-hydroxypiperidin
yl)methyloxo-1H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt
tetrahydrate according to the invention
Sr Component t (as
determined by
HPLC)
S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyl- At least 99%
1-oxo-1H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine W/W
salt tetrahydrate.
9-fluorohydroxymethyl-6,7-dihydrooxo-1H,5H-benzo Less than 0.15%
[i,j]quinolizine carboxylic acid W/W
8-fluoro(4-hydroxy-piperidinyl)methyl-6,7-dihydro-1 - Less than 0.15%
oxo-1H,5H-benzo[i,j]quinolizinecarboxylic acid W/W
ydroxypiperidinyl)methyl-6,7-dihydrooxo-1H, 5H- Less than 0.15%
benzo[i,j]quinolizinecarboxylic acid W/W
8,9-difluoromethyl-6,7-dihydrooxo-1H,5H-benzo[i,j] Less than 0.15%
quinolizinecarboxylic acid W/W
9-fluoro(4-hydroxy-piperidinyl)methyl-6 ,7- Less than 0.5%
dihydrooxo-1H,5H-benzo[i,j]quinolizinecarboxylic acid W/W
Bacterial endotoxins Less than 0.35
USP Endotoxin
Units per mg
Claims (9)
1. A process for ing substantially pure S-(-)fluoro-6,7-dihydro(4- ypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizine carboxylic acid L-arginine salt tetrahydrate, said s comprising: (a) dissolving L-arginine in a mixture of acetone and water; (b) adding S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyl oxo-1H,-5H-benzo[i,j]quinolizinecarboxylic acid to the solution obtained in step (a); (c) warming the solution obtained in step (b) to get a clear solution; (d) optionally treating the warm solution obtained in step (c) with activated carbon and filtering the d solution; (e) diluting the warm solution obtained in step (d) with acetone and refluxing the diluted solution; (f) cooling the solution ed in step (e) to obtain solid S-(-)fluoro-6,7- dihydro(4-hydroxypiperidinyl)methyloxo-1H,-5H- benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate; and (g) collecting S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyl- 1H,-5H-benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate obtained in step (f) by filtration, and optionally washing it with acetone.
2. The process of Claim 1, wherein the substantially pure S-(-)fluoro-6,7-dihydro- 8-(4-hydroxypiperidinyl)methyloxo-1H,-5H-benzo[i,j]quinolizine carboxylic acid L-arginine salt tetrahydrate has a purity of at least 99% w/w as determined by HPLC.
3. The process of Claim 1 or Claim 2, wherein the substantially pure S-(-)fluoro- 6,7-dihydro(4-hydroxypiperidinyl)methyloxo-1H,-5H- benzo[i,j]quinolizinecarboxylic acid L-arginine salt ydrate further contains: (i) less than 0.15% w/w of 9-fluorohydroxymethyl-6,7-dihydrooxo- 1H,5H-benzo [i,j]quinolizine carboxylic acid as determined by HPLC; (ii) less than 0.15% w/w of 8-fluoro(4-hydroxy-piperidinyl)methyl-6,7- dihydrooxo-1H,5H-benzo[i,j]quinolizinecarboxylic acid as determined by HPLC; (iii) less than 0.15% w/w of 8-(4-hydroxypiperidinyl)methyl-6,7-dihydro- 1-oxo-1H, 5H-benzo[i,j]quinolizinecarboxylic acid as determined by HPLC; (iv) less than 0.15% w/w of 8,9-difluoromethyl-6,7-dihydrooxo-1H,5H- benzo[i,j] izinecarboxylic acid as determined by HPLC; (v) less than 0.5% w/w of R-(+)fluoro(4-hydroxy-piperidinyl) methyl-6,7-dihydrooxo-1H,5H-benzo[i,j]quinolizinecarboxylic acid as determined by HPLC; and (vi) bacterial endotoxins in an amount less than 0.35 USP xin Units per
4. The process of any one of Claims 1 to 3, wherein the filtering in step (d) is first med through a 5μ filter and then through a 0.2μ filter.
5. The s of any one of Claims 1 to 4, wherein refluxing in step (e) is carried out for 30 s.
6. The process of any one of Claims 1 to 5, wherein cooling in step (f) is carried out at a temperature between 10 and 15°C.
7. The process of any one of Claims 1 to 6, further comprising vacuum drying S-(-)- 9-fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-1H,-5H- benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate obtained in step (g) at a temperature between 30 and 40°C.
8. S-(-)fluoro-6,7-dihydro(4-hydroxypiperidinyl)methyloxo-1H,-5H- benzo[i,j]quinolizinecarboxylic acid L-arginine salt tetrahydrate prepared by the process of any one of Claims 1 to 7.
9. The process of Claim 1 substantially as hereinbefore described with reference to Example 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2740MU2011 | 2011-09-28 | ||
| IN2740/MUM/2011 | 2011-09-28 | ||
| PCT/IB2012/050074 WO2013046061A1 (en) | 2011-09-28 | 2012-01-06 | Pures-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1h,-5h-benzo[i,j]quinolizine-2- carboxylic acid l-arginine salt tetrahydrate and a process for its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ621358A NZ621358A (en) | 2016-03-31 |
| NZ621358B2 true NZ621358B2 (en) | 2016-07-01 |
Family
ID=
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