CA2367903A1 - Novel method for producing doxazosin mesylate in a crystalline modification designated as form a - Google Patents
Novel method for producing doxazosin mesylate in a crystalline modification designated as form a Download PDFInfo
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- CA2367903A1 CA2367903A1 CA002367903A CA2367903A CA2367903A1 CA 2367903 A1 CA2367903 A1 CA 2367903A1 CA 002367903 A CA002367903 A CA 002367903A CA 2367903 A CA2367903 A CA 2367903A CA 2367903 A1 CA2367903 A1 CA 2367903A1
- Authority
- CA
- Canada
- 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.)
- Abandoned
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- 229960000220 doxazosin mesylate Drugs 0.000 title claims abstract description 41
- 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 41
- 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 claims abstract description 8
- 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
- 239000013078 crystal Substances 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 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
- 238000001914 filtration Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 238000010899 nucleation Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- 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
- 239000000047 product Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation 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
- 239000000463 material 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
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- -1 methanol or ethanol Chemical compound 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001226 reprecipitation Methods 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (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)
Abstract
The invention relates to a method for producing doxazosin mesylate in the modification A. The method is characterised in that doxazosin and methane sulphonic acid are dissolved in a mixture containing an aprotic, polar organic solvent and methanol. Any clouding in the resulting solution is optionally eliminated. The clear solution thus produced is optionally injected with doxazosin mesylate crystals of form A, heated and isolated after the resulting product has been cooled. Said product is then washed with an organic solvent and dried.
Description
NOVEL METHOD FOR PRODUCING DOXAZOSIN MESYLATE IN A
CRYSTALLINE MODIFICATION DESIGNATED AS A FORM A
The present invention relates to a novel process for preparing doxazosin mesylate in a crystal modification referred to as form A.
Doxazosin (= 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)-piperazin-1-yl]-6,7-dimethoxyquinazoline) is a known substance (Merck-Index 12th edition 1996, No. 3489) which lowers blood pressure. The substance is mainly used in the form of the monomesylate. An initial report of polymorphic forms of doxazosin mesylate appeared in the Chinese Journal of Medicinal Chemistry 5(4), 266-270 (1995). 3 crystal modifications of doxazosin mesylate are described therein. The various modifications are referred to as modifications A, B and C in the reference mentioned. Modification A is obtained on recrystallization of doxazosin mesylate from ethanol, while modifications B and C
result from the recrystallization of doxazosin mesylate from chloroform and water respectively. Although the said reference speaks only of doxazosin, according to the published data the material is doxazosin mesylate.
Of the three forms, only form A is suitable for use for pharmaceutical purposes. The method for preparing form A of doxazosin mesylate indicated in the Chinese Journal of Medicinal Chemistry takes place by a recrystallization of doxazosin mesylate from ethanol which is, however, not a method which can be used on the industrial scale for obtaining specifically this modification.
EP-A 849 266 describes a doxazosin mesylate crystal modification which is referred to as form III and is identical to form A of doxazosin mesylate.
EP-A 849 266 also describes a process for preparing form A of doxazosin mesylate starting from doxazosin. This entails converting doxazosin, preferably in an organic solvent such as ethyl acetate, by heating with acetic acid into doxazosin acetate. The hot solution is filtered, treated with methanesulfonic acid and stirred where appropriate hot until crystallization occurs. The precipitated solvent adduct is removed after cooling and heated moist in a lower alcohol such as methanol or ethanol, the resulting solution is cooled and the crystals which have separated out (= form A of doxazosin mesylate) are removed.
A further process for preparing doxazosin mesylate in modification A is described in PCT Application PCT/EP/9808360 of 18.12.1998. The starting material in this process is likewise doxazosin. To obtain form A of doxazosin mesylate, in this case doxazosin is dissolved with methanesulfonic acid in a mixture of an aprotic, polar organic solvent, for example N,N-dimethylformamide and N-methyl-2-pyrroli.done, and methanol, the solution obtained in this way is freed of turbidity where appropriate, and the resulting clear solution is stirred until no further precipitation occurs. The precipitate is removed (modification D of doxazosin mesylate), washed with methanol and heated in the moist state in ethanol. After cooling, the resulting modification A of doxazosin mesylate is isolated. The process also succeeds if only methanol is used to dissolve doxazosin with the methanesulfonic acid.
The reprecipitation of doxazosin mesylate from ethanol, which is indicated in the Chinese reference cited above for obtaining form A of doxazosin mesylate, is not, as already mentioned, a method which can be used on the industrial scale for obtaining doxazosin mesylate specifically in form A. In addition, this reference does a5 not indicate the preparation of doxazosin mesylate which is used as starting material for preparing the individual forms either.
The two other methods indicated above for preparing form A of doxazosin mesylate could probably be used on a larger scale.
However, both processes are very elaborate. In both cases, form A
is. not prepared simply by treating doxazosin with methanesulfonic acid. On the contrary, the method from EP 849 266 requires firstly preparation from doxazosin and acetic acid of the acetate, which is treated in solution with methanesulfonic acid.
During this process, a solvent adduct crystallizes out and has to be isolated. Only on heating this adduct in a lower alcohol is the required form A of doxazosin mesylate then obtained.
According to PCT/EP 9808360 there is firstly preparation from doxazosin and methanesulfonic acid of a form of doxazosin mesylate which is referred to as modification D and which has to be isolated. Only on subsequent heating of this form D in ethanol is the required form A of doxazosin mesylate obtained.
A simple process which can be used on the industrial scale for preparing doxazosin mesylate of modification A has now been found.
CRYSTALLINE MODIFICATION DESIGNATED AS A FORM A
The present invention relates to a novel process for preparing doxazosin mesylate in a crystal modification referred to as form A.
Doxazosin (= 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)-piperazin-1-yl]-6,7-dimethoxyquinazoline) is a known substance (Merck-Index 12th edition 1996, No. 3489) which lowers blood pressure. The substance is mainly used in the form of the monomesylate. An initial report of polymorphic forms of doxazosin mesylate appeared in the Chinese Journal of Medicinal Chemistry 5(4), 266-270 (1995). 3 crystal modifications of doxazosin mesylate are described therein. The various modifications are referred to as modifications A, B and C in the reference mentioned. Modification A is obtained on recrystallization of doxazosin mesylate from ethanol, while modifications B and C
result from the recrystallization of doxazosin mesylate from chloroform and water respectively. Although the said reference speaks only of doxazosin, according to the published data the material is doxazosin mesylate.
Of the three forms, only form A is suitable for use for pharmaceutical purposes. The method for preparing form A of doxazosin mesylate indicated in the Chinese Journal of Medicinal Chemistry takes place by a recrystallization of doxazosin mesylate from ethanol which is, however, not a method which can be used on the industrial scale for obtaining specifically this modification.
EP-A 849 266 describes a doxazosin mesylate crystal modification which is referred to as form III and is identical to form A of doxazosin mesylate.
EP-A 849 266 also describes a process for preparing form A of doxazosin mesylate starting from doxazosin. This entails converting doxazosin, preferably in an organic solvent such as ethyl acetate, by heating with acetic acid into doxazosin acetate. The hot solution is filtered, treated with methanesulfonic acid and stirred where appropriate hot until crystallization occurs. The precipitated solvent adduct is removed after cooling and heated moist in a lower alcohol such as methanol or ethanol, the resulting solution is cooled and the crystals which have separated out (= form A of doxazosin mesylate) are removed.
A further process for preparing doxazosin mesylate in modification A is described in PCT Application PCT/EP/9808360 of 18.12.1998. The starting material in this process is likewise doxazosin. To obtain form A of doxazosin mesylate, in this case doxazosin is dissolved with methanesulfonic acid in a mixture of an aprotic, polar organic solvent, for example N,N-dimethylformamide and N-methyl-2-pyrroli.done, and methanol, the solution obtained in this way is freed of turbidity where appropriate, and the resulting clear solution is stirred until no further precipitation occurs. The precipitate is removed (modification D of doxazosin mesylate), washed with methanol and heated in the moist state in ethanol. After cooling, the resulting modification A of doxazosin mesylate is isolated. The process also succeeds if only methanol is used to dissolve doxazosin with the methanesulfonic acid.
The reprecipitation of doxazosin mesylate from ethanol, which is indicated in the Chinese reference cited above for obtaining form A of doxazosin mesylate, is not, as already mentioned, a method which can be used on the industrial scale for obtaining doxazosin mesylate specifically in form A. In addition, this reference does a5 not indicate the preparation of doxazosin mesylate which is used as starting material for preparing the individual forms either.
The two other methods indicated above for preparing form A of doxazosin mesylate could probably be used on a larger scale.
However, both processes are very elaborate. In both cases, form A
is. not prepared simply by treating doxazosin with methanesulfonic acid. On the contrary, the method from EP 849 266 requires firstly preparation from doxazosin and acetic acid of the acetate, which is treated in solution with methanesulfonic acid.
During this process, a solvent adduct crystallizes out and has to be isolated. Only on heating this adduct in a lower alcohol is the required form A of doxazosin mesylate then obtained.
According to PCT/EP 9808360 there is firstly preparation from doxazosin and methanesulfonic acid of a form of doxazosin mesylate which is referred to as modification D and which has to be isolated. Only on subsequent heating of this form D in ethanol is the required form A of doxazosin mesylate obtained.
A simple process which can be used on the industrial scale for preparing doxazosin mesylate of modification A has now been found.
The invention relates to a process for preparing doxazosin mesylate in modification A, which comprises dissolving doxazosin with methanesulfonic acid in a mixture of an aprotic polar organic solvent and methanol, and where appropriate filtering the solution obtained thereby, where appropriate seeding with doxazosin mesylate crystals of form A, heating and, after cooling, isolating the resulting product and washing it with an organic solvent and drying it.
To react doxazosin with methanesulfonic acid, the two substances are employed in the molar ratio of about 1:1. A small molar excess (up to about 10~) of the sulfonic acid is preferably used.
Suitable aprotic polar organic solvents are N,N-dimethylformamide and, in particular, N-methyl-2-pyrrolidone. The ratio of doxazosin to methanol to aprotic polar organic solvent (weight/volume/volume) is about l:( (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 turbid, it is advisable to remove the turbidity by, for example, filtration. If turbidity is to be removed, for example by filtration, it is expedient 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, where appropriate after filtration, is subsequently heated, preferably after seeding with crystals of doxazosin mesylate of form A. This heating is preferably to a reflux temperature. The reaction mixture is heated at this temperature as a rule for 3 to 9 hours, preferably 4 to 6 hours.
The resulting suspension of crystals is then cooled to room temperature and subsequently stirred at room temperature for a short time. The solid product (modification A of doxazosin mesylate) is then isolated, washed with an organic solvent, preferably a lower alkyl alcohol, particularly preferably methanol, and dried in a conventional way, e.g. in vacuo.
The novel process provides doxazosin mesylate of modification A
in a very simple manner and in an overall yield of more than 85~.
The purity of the modification A obtained by the novel process is excellent. A considerable advantage of the novel process is also that a solution is produced after the addition of the methanesulfonic acid. This makes it possible to remove, by filtration, any foreign particles present.
To react doxazosin with methanesulfonic acid, the two substances are employed in the molar ratio of about 1:1. A small molar excess (up to about 10~) of the sulfonic acid is preferably used.
Suitable aprotic polar organic solvents are N,N-dimethylformamide and, in particular, N-methyl-2-pyrrolidone. The ratio of doxazosin to methanol to aprotic polar organic solvent (weight/volume/volume) is about l:( (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 turbid, it is advisable to remove the turbidity by, for example, filtration. If turbidity is to be removed, for example by filtration, it is expedient 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, where appropriate after filtration, is subsequently heated, preferably after seeding with crystals of doxazosin mesylate of form A. This heating is preferably to a reflux temperature. The reaction mixture is heated at this temperature as a rule for 3 to 9 hours, preferably 4 to 6 hours.
The resulting suspension of crystals is then cooled to room temperature and subsequently stirred at room temperature for a short time. The solid product (modification A of doxazosin mesylate) is then isolated, washed with an organic solvent, preferably a lower alkyl alcohol, particularly preferably methanol, and dried in a conventional way, e.g. in vacuo.
The novel process provides doxazosin mesylate of modification A
in a very simple manner and in an overall yield of more than 85~.
The purity of the modification A obtained by the novel process is excellent. A considerable advantage of the novel process is also that a solution is produced after the addition of the methanesulfonic acid. This makes it possible to remove, by filtration, any foreign particles present.
Example 1 5.05 g of anhydrous methanesulfonic acid were added with stirring to a mixture of 22.6 g of doxazosin, 45 ml of N-methyl-2-pyrrolidone and 210 ml of methanol in a 500 ml three-neck round-bottom flask. During this, the internal temperature rose to 30°C, and a solution resulted. The reaction mixture was seeded with 0.5 g of doxazosin mesylate of form A, these seed crystals not dissolving. Seeding was followed by heating to the reflux temperature (boiling point 68°C; no solution) and stirring at this temperature for 4 h, during which further crystals formed. This was followed by cooling to room temperature and stirring at this temperature for 15 min. The precipitated product was filtered off by suction, washed 2x with 50 ml of methanol each time and dried at 75°C in vacuo. 24.6 g of doxazosin mesylate in form A were obtained. This corresponds to a yield of 87.8 based on doxazosin employed and subtracting the material used for seeding.
The doxazosin mesylate obtained in this way was used to determine the data shown in Figs. 1-3 for the Debye-Scherrer X-ray diffractogram, the differential scanning thermogram and the IR
spectrum.
ExaxBple 2 5.05 g of anhydrous methanesulfonic acid were added with stirring to a mixture of 22.6 g of doxazosin, 45 ml of N-methyl-2-pyrrolidone and 210 ml of methanol, in a 500 ml three-neck round-bottom flask. During this, the internal temperature rose to 30°C, and a solution resulted. After the addition of methanesulfonic acid was complete, the mixture was heated to the reflux temperature (boiling point 68°C) and stirred at this temperature for 4 h (crystal formation during the stirring at the reflux temperature). This was followed by cooling to room temperature and stirring at this temperature for 15 min.
The precipitated product was filtered off with suction, washed 2x with SO ml of methanol each time and dried at 75°C in vacuo. 23.5 g of doxazosin mesylate of form A were obtained. This corresponds to a yield of 85.7 based on doxazosin employed.
Example 3 5.05 g of anhydrous methanesulfonic acid were added with stirring to a mixture of 22.6 g of doxazosin, 45 ml of N-methyl-2-pyrrolidone and 190 ml of methanol, in a 500 ml three-neck round-bottom flask. During this, the internal ......,..,_............- _.._.. ._ ........ ......__.. .... ....._.....__...,-...._..-...._..._........_ _.,......"....,-........... _ _........ .... ....
..._..___..
temperature rose to 30°C, and a solution resulted. After the addition of methanesulfonic acid was complete, the reaction mixture was filtered into a second 500 ml three-neck round-bottom flask. The filter was then washed with 20 ml of methanol. The 5 combined filtrates were heated to the reflux temperature (boiling point 68°C) and stirred at this temperature for 4 h (crystal formation during the stirring at the reflux temperature). After completion of the stirring time at the reflux temperature, the mixture was cooled to room temperature and stirred at this temperature for 15 min. The precipitated product was filtered off with suction, washed 2x with 50 ml of methanol each time and dried at 75°C in vacuo. 23.4 g of doxazosin mesylate in form A
were obtained. This corresponds to a yield of 85.4 based on doxazosin employed.
The doxazosin mesylate obtained in this way was used to determine the data shown in Figs. 1-3 for the Debye-Scherrer X-ray diffractogram, the differential scanning thermogram and the IR
spectrum.
ExaxBple 2 5.05 g of anhydrous methanesulfonic acid were added with stirring to a mixture of 22.6 g of doxazosin, 45 ml of N-methyl-2-pyrrolidone and 210 ml of methanol, in a 500 ml three-neck round-bottom flask. During this, the internal temperature rose to 30°C, and a solution resulted. After the addition of methanesulfonic acid was complete, the mixture was heated to the reflux temperature (boiling point 68°C) and stirred at this temperature for 4 h (crystal formation during the stirring at the reflux temperature). This was followed by cooling to room temperature and stirring at this temperature for 15 min.
The precipitated product was filtered off with suction, washed 2x with SO ml of methanol each time and dried at 75°C in vacuo. 23.5 g of doxazosin mesylate of form A were obtained. This corresponds to a yield of 85.7 based on doxazosin employed.
Example 3 5.05 g of anhydrous methanesulfonic acid were added with stirring to a mixture of 22.6 g of doxazosin, 45 ml of N-methyl-2-pyrrolidone and 190 ml of methanol, in a 500 ml three-neck round-bottom flask. During this, the internal ......,..,_............- _.._.. ._ ........ ......__.. .... ....._.....__...,-...._..-...._..._........_ _.,......"....,-........... _ _........ .... ....
..._..___..
temperature rose to 30°C, and a solution resulted. After the addition of methanesulfonic acid was complete, the reaction mixture was filtered into a second 500 ml three-neck round-bottom flask. The filter was then washed with 20 ml of methanol. The 5 combined filtrates were heated to the reflux temperature (boiling point 68°C) and stirred at this temperature for 4 h (crystal formation during the stirring at the reflux temperature). After completion of the stirring time at the reflux temperature, the mixture was cooled to room temperature and stirred at this temperature for 15 min. The precipitated product was filtered off with suction, washed 2x with 50 ml of methanol each time and dried at 75°C in vacuo. 23.4 g of doxazosin mesylate in form A
were obtained. This corresponds to a yield of 85.4 based on doxazosin employed.
Claims
We Claim:
A process for preparing doxazosin mesylate in modification A, which comprises dissolving doxazosin with methanesulfonic acid in a mixture of an aprotic polar organic solvent and methanol, where appropriate filtering the solution obtained thereby, where appropriate seeding with doxazosin mesylate crystals of form A, heating and, after cooling, isolating the resulting product and washing it with an organic solvent and drying it.
A process for preparing doxazosin mesylate in modification A, which comprises dissolving doxazosin with methanesulfonic acid in a mixture of an aprotic polar organic solvent and methanol, where appropriate filtering the solution obtained thereby, where appropriate seeding with doxazosin mesylate crystals of form A, heating and, after cooling, isolating the resulting product and washing it with an organic solvent and drying it.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19912063A DE19912063A1 (en) | 1999-03-18 | 1999-03-18 | New process for the preparation of doxazosin mesylate in a crystal modification called Form A. |
| DE19912063.3 | 1999-03-18 | ||
| PCT/EP2000/001939 WO2000056731A1 (en) | 1999-03-18 | 2000-03-06 | Novel method for producing doxazosin mesylate in a crystalline modification designated as form a |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2367903A1 true CA2367903A1 (en) | 2000-09-28 |
Family
ID=7901411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002367903A Abandoned CA2367903A1 (en) | 1999-03-18 | 2000-03-06 | Novel method for producing doxazosin mesylate in a crystalline modification designated as form a |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1165548A1 (en) |
| JP (1) | JP2002540109A (en) |
| KR (1) | KR20010113753A (en) |
| CN (1) | CN1352643A (en) |
| AU (1) | AU3960800A (en) |
| CA (1) | CA2367903A1 (en) |
| CZ (1) | CZ20013347A3 (en) |
| DE (1) | DE19912063A1 (en) |
| HU (1) | HUP0200663A2 (en) |
| IL (1) | IL144944A0 (en) |
| PL (1) | PL350088A1 (en) |
| TR (1) | TR200102730T2 (en) |
| WO (1) | WO2000056731A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19912573A1 (en) * | 1999-03-19 | 2000-09-21 | Knoll Ag | Medicament containing doxazosin mesylate of crystal modification D |
| CA2706372A1 (en) * | 2007-12-24 | 2009-07-02 | Cipla Limited | Crystalline polymorph of doxazosin mesylate (form iv) and process for preparation thereof |
| CN109988158A (en) * | 2018-01-03 | 2019-07-09 | 合肥立方制药股份有限公司 | X crystal form, doxazosin mesylate containing X crystal form and its preparation method and application |
| CN111303130B (en) * | 2018-12-11 | 2021-09-14 | 合肥立方制药股份有限公司 | Doxazosin mesylate crystal form, and preparation method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1287588B1 (en) * | 1996-12-13 | 1998-08-06 | Alfa Chem Ital | CRYSTALLINE FORM OF MESILATE DOXAZOSIN AND PROCESS FOR ITS PRODUCTION |
| EP0849266B8 (en) * | 1996-12-20 | 2007-10-03 | Heumann PCS GmbH | Novel polymorphic form of doxazosin mesylate (form III) |
| DE19800214A1 (en) * | 1998-01-06 | 1999-07-15 | Knoll Ag | Process for the preparation of doxazosin mcsylate in a crystal modification referred to as Form A and an intermediate therefor |
-
1999
- 1999-03-18 DE DE19912063A patent/DE19912063A1/en not_active Withdrawn
-
2000
- 2000-03-06 CN CN00805209A patent/CN1352643A/en active Pending
- 2000-03-06 IL IL14494400A patent/IL144944A0/en unknown
- 2000-03-06 AU AU39608/00A patent/AU3960800A/en not_active Abandoned
- 2000-03-06 EP EP00918763A patent/EP1165548A1/en not_active Withdrawn
- 2000-03-06 WO PCT/EP2000/001939 patent/WO2000056731A1/en not_active Application Discontinuation
- 2000-03-06 TR TR2001/02730T patent/TR200102730T2/en unknown
- 2000-03-06 CA CA002367903A patent/CA2367903A1/en not_active Abandoned
- 2000-03-06 KR KR1020017011780A patent/KR20010113753A/en not_active Application Discontinuation
- 2000-03-06 HU HU0200663A patent/HUP0200663A2/en unknown
- 2000-03-06 JP JP2000606592A patent/JP2002540109A/en active Pending
- 2000-03-06 PL PL00350088A patent/PL350088A1/en unknown
- 2000-03-06 CZ CZ20013347A patent/CZ20013347A3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TR200102730T2 (en) | 2002-06-21 |
| JP2002540109A (en) | 2002-11-26 |
| PL350088A1 (en) | 2002-11-04 |
| KR20010113753A (en) | 2001-12-28 |
| EP1165548A1 (en) | 2002-01-02 |
| WO2000056731A1 (en) | 2000-09-28 |
| CN1352643A (en) | 2002-06-05 |
| DE19912063A1 (en) | 2000-09-21 |
| AU3960800A (en) | 2000-10-09 |
| HUP0200663A2 (en) | 2002-08-28 |
| CZ20013347A3 (en) | 2002-01-16 |
| IL144944A0 (en) | 2002-06-30 |
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| FZDE | Discontinued |