EP1165548A1 - Neues verfahren zur herstellung von doxazosin-mesylat in einer als form a bezeichneten kristallmodifikation - Google Patents
Neues verfahren zur herstellung von doxazosin-mesylat in einer als form a bezeichneten kristallmodifikationInfo
- Publication number
- EP1165548A1 EP1165548A1 EP00918763A EP00918763A EP1165548A1 EP 1165548 A1 EP1165548 A1 EP 1165548A1 EP 00918763 A EP00918763 A EP 00918763A EP 00918763 A EP00918763 A EP 00918763A EP 1165548 A1 EP1165548 A1 EP 1165548A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- doxazosin
- doxazosin mesylate
- mesylate
- methanol
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 229960000220 doxazosin mesylate Drugs 0.000 title claims abstract description 42
- VJECBOKJABCYMF-UHFFFAOYSA-N doxazosin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 VJECBOKJABCYMF-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 230000004048 modification Effects 0.000 title claims abstract description 21
- 238000012986 modification Methods 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 57
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 35
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229960001389 doxazosin Drugs 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000013078 crystal Substances 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 239000003495 polar organic solvent Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- 238000010992 reflux Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 238000005169 Debye-Scherrer Methods 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a new process for the preparation of doxazosin mesylate in a crystal modification referred to as Form A.
- Doxazosin 4-amino-2- [4- (1,4-benzodioxan-2-carbonyl) piperazin-l-yl] -6, 7-dimethoxyquinazoline
- the substance is mainly used in the form of the monomesylate.
- a first report on polymorphic forms of doxazosin mesylate has appeared in the Chinese Journal of Medicinal Chemistry 5 (4), 266-270 (1995). Three crystal modifications of the doxazosin mesylate are described there. The various modifications are referred to as modifications A, B and C in the cited reference.
- Modification A is obtained in the recrystallization of doxazosin mesylate from ethanol, while modifications B and C result in the recrystallization of doxazosin mesylate from chloroform or water.
- form A is suitable for use for pharmaceutical purposes.
- the production method for form A of doxazosin mesylate specified in the Chinese Journal of Medicinal Chemistry, which proceeds via recrystallization of doxazosin mesylate from ethanol is not one Method that can be used on an industrial scale to specifically obtain this modification.
- EP-A 849 266 describes a crystal modification of the doxazosin mesylate, referred to as Form III, which is identical to the form A of the doxazosin mesylate.
- EP-A 849 266 also describes a process for producing form A of the doxazosin mesylate, which starts from doxazosin.
- Doxazosin is preferably reacted in an organic solvent such as ethyl acetate in the heat with acetic acid to form doxazosin acetate.
- the hot solution is filtered, methanesulfonic acid is added and, if necessary, stirred until it crystallizes.
- the precipitate is separated off (modification D of the doxazosin mesylate), washed with methanol and heated in a moist state in ethanol. After cooling, the resulting modification A of the doxazosin mesylate is isolated.
- the process is also successful if only methane sulfonic acid is used to dissolve doxazosin in methanol.
- Form A of the doxazosin mesylate As far as the other two methods for producing Form A of the doxazosin mesylate mentioned above are concerned, they are likely to be usable on a larger scale. But they are both very expensive. In both cases, the production of Form A of the doxazosin mesylate is not possible simply by treating doxazosin with methanesulfonic acid. Rather, in the case of the method from EP 849 266 from doxazosin, the acetate must first be prepared with acetic acid, to which methanesulfonic acid is added in solution. Here, a solvent adduct crystallizes out, which must be isolated. Only heating this adduct in a lower alcohol then gives the desired form A of the doxazosin mesylate.
- doxazosin and methanesulfonic acid are first used to produce a form of doxazosin mesylate, referred to as modification D, which must be isolated. It is only after heating this form D in ethanol that the desired form A of the doxazosin mesylate is obtained.
- modification D a form of doxazosin mesylate
- a simple process, which can be used on an industrial scale, for the preparation of doxazosin mesylate of modification A has now been found.
- the invention relates to a process for the preparation of doxazosin mesylate in modification A, which consists in dissolving doxazosin with methanesulfonic acid in a mixture of an aprotic, polar organic solvent and methanol and, if appropriate, filtering the resulting solution, optionally with doxazosin -Mesylate crystals of Form A inoculated, heated, the resulting product isolated after cooling, washed with an organic solvent and dried.
- doxazosin To react doxazosin with methanesulfonic acid, the two substances are used in a molar ratio of about 1: 1. A small molar excess of the sulfonic acid is preferably used (up to about 10%).
- Suitable aprotic, polar organic solvents are, for example, N, N-dimethylformamide and in particular N-methyl-2-pyrrolidone.
- the ratio of doxazosin to methanol to aprotic polar organic solvent is about 1: (5 to 15): (1.5 to 4), preferably about 1: (8 to 12): (2 to 3). If the solution obtained by adding methanesulfonic acid to the mixture of doxazosin, methanol and aprotic, polar organic solvent is cloudy, it is advisable to remove the cloudiness, for example by filtration. If cloudiness is to be removed, for example by filtration, it is advisable to add part of the methanol only after the filtration.
- the clear solution obtained after adding methanesulfonic acid to the mixture of doxazosin, methanol and aprotic, polar organic solvent, if appropriate after filtering, is subsequently heated, preferably after inoculation with crystals of doxazosin mesylate of the form A. It is preferably carried out with heating to the reflux temperature.
- the reaction mixture is usually heated to this temperature for 3 to 9 hours, preferably 4 to 6 hours.
- the crystal suspension formed is then cooled to room temperature and stirred for a short time at room temperature.
- the solid product (modification A of the doxazosin mesylate) is then isolated, especially with an organic solvent, preferably a lower alkyl alcohol preferably methanol, washed and dried in a conventional manner, for example in vacuo.
- the new process provides doxazosin mesylate of modification A in a very simple manner in a total yield of over 85%.
- the purity of modification A obtained by the new process is excellent.
- a major advantage of the new process is that a solution is formed after the methanesulfonic acid has been added. This makes it possible to remove any foreign particles that may be present by filtration.
- Fig. 1-3 reproduced data for the Debye-Scherrer X-ray diffractogram, the differential scanning thermogram and the IR spectrum determined.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19912063A DE19912063A1 (de) | 1999-03-18 | 1999-03-18 | Neues Verfahren zur Herstellung von Doxazosin-Mesylat in einer als Form A bezeichneten Kristallmodifikation |
| DE19912063 | 1999-03-18 | ||
| PCT/EP2000/001939 WO2000056731A1 (de) | 1999-03-18 | 2000-03-06 | Neues verfahren zur herstellung von doxazosin-mesylat in einer als form a bezeichneten kristallmodifikation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1165548A1 true EP1165548A1 (de) | 2002-01-02 |
Family
ID=7901411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00918763A Withdrawn EP1165548A1 (de) | 1999-03-18 | 2000-03-06 | Neues verfahren zur herstellung von doxazosin-mesylat in einer als form a bezeichneten kristallmodifikation |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1165548A1 (ja) |
| JP (1) | JP2002540109A (ja) |
| KR (1) | KR20010113753A (ja) |
| CN (1) | CN1352643A (ja) |
| AU (1) | AU3960800A (ja) |
| CA (1) | CA2367903A1 (ja) |
| CZ (1) | CZ20013347A3 (ja) |
| DE (1) | DE19912063A1 (ja) |
| HU (1) | HUP0200663A2 (ja) |
| IL (1) | IL144944A0 (ja) |
| PL (1) | PL350088A1 (ja) |
| TR (1) | TR200102730T2 (ja) |
| WO (1) | WO2000056731A1 (ja) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19912573A1 (de) * | 1999-03-19 | 2000-09-21 | Knoll Ag | Arzneimittel, enthaltend Doxazosin-Mesylat der Kristallmodifikaton D |
| CA2706372A1 (en) | 2007-12-24 | 2009-07-02 | Cipla Limited | Crystalline polymorph of doxazosin mesylate (form iv) and process for preparation thereof |
| CN109988158A (zh) * | 2018-01-03 | 2019-07-09 | 合肥立方制药股份有限公司 | X晶型、含有x晶型的多沙唑嗪甲磺酸盐及其制备方法和用途 |
| CN111303130B (zh) * | 2018-12-11 | 2021-09-14 | 合肥立方制药股份有限公司 | 一种多沙唑嗪甲磺酸盐晶型、其制备方法及用途 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1287588B1 (it) * | 1996-12-13 | 1998-08-06 | Alfa Chem Ital | Forma cristallina del doxazosin mesilato e processo per la sua produzione |
| PT849266E (pt) * | 1996-12-20 | 2007-03-30 | Heumann Pcs Gmbh | Nova forma polimorfa de mesilato de doxazosina (forma iii) |
| DE19800214A1 (de) * | 1998-01-06 | 1999-07-15 | Knoll Ag | Verfahren zur Herstellung von Doxazosin-Mcsylat in einer als Form A bezeichneten Kristallmodifikation und ein Zwischenprodukt dafür |
-
1999
- 1999-03-18 DE DE19912063A patent/DE19912063A1/de not_active Withdrawn
-
2000
- 2000-03-06 PL PL00350088A patent/PL350088A1/xx unknown
- 2000-03-06 JP JP2000606592A patent/JP2002540109A/ja active Pending
- 2000-03-06 HU HU0200663A patent/HUP0200663A2/hu unknown
- 2000-03-06 TR TR2001/02730T patent/TR200102730T2/xx unknown
- 2000-03-06 WO PCT/EP2000/001939 patent/WO2000056731A1/de not_active Application Discontinuation
- 2000-03-06 CZ CZ20013347A patent/CZ20013347A3/cs unknown
- 2000-03-06 AU AU39608/00A patent/AU3960800A/en not_active Abandoned
- 2000-03-06 IL IL14494400A patent/IL144944A0/xx unknown
- 2000-03-06 KR KR1020017011780A patent/KR20010113753A/ko not_active Application Discontinuation
- 2000-03-06 CA CA002367903A patent/CA2367903A1/en not_active Abandoned
- 2000-03-06 CN CN00805209A patent/CN1352643A/zh active Pending
- 2000-03-06 EP EP00918763A patent/EP1165548A1/de not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO0056731A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| PL350088A1 (en) | 2002-11-04 |
| KR20010113753A (ko) | 2001-12-28 |
| TR200102730T2 (tr) | 2002-06-21 |
| CZ20013347A3 (cs) | 2002-01-16 |
| JP2002540109A (ja) | 2002-11-26 |
| DE19912063A1 (de) | 2000-09-21 |
| IL144944A0 (en) | 2002-06-30 |
| WO2000056731A1 (de) | 2000-09-28 |
| AU3960800A (en) | 2000-10-09 |
| CN1352643A (zh) | 2002-06-05 |
| HUP0200663A2 (en) | 2002-08-28 |
| CA2367903A1 (en) | 2000-09-28 |
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| 18D | Application deemed to be withdrawn |
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