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2
To a 500 mL 3-necked baffled flask was added 5 g of 2-[(4-tetrahydro-2-furoyl)-1-piperazinyl]-4-amino-6,7-di-methoxyquinazoline (terazosin free base, 1). The flask was rotated with an electric motor to mix the powder and a stream of dry nitrogen was passed over the mixed powder for 2 minutes. The flow of nitrogen was replaced with a flow of hydrogen chloride for 45 min. The flow of hydrogen chloride was stopped for 40 minutes and restarted and maintained for an additional 25 minutes. Hydrogen chloride gas was passed over the powder for a further 1 hour after which, the hydrogen chloride flow was discontinued and replaced with a stream of nitrogen for 2 minutes. The excess HCl was then removed from the powder in vacuo at 60° C. over night. The product obtained was 2-[(4-tetrahydro-2-furoyl)-1-piperazinyl]-4-amino-6,7-di-methoxyquinazoline hydrochloride having 1 equivalent hydrogen chloride and characterized by the powder X-Ray diffractogram shown in FIG. 3. 1H NMR (300 MHz, DMSO-d6) δ 1.75-1.90 (m, 2H), 1.95-2.15 (m, 2H), 3.50-4.00 (m, 16H), 4.76 (dd, J=7.4, 5.6 Hz, 1H), 7.50 (s, 1H), 7.74 (s, 1H), 8.70 (s, 1H), 8.91 (s, 1H), 12.22 (s, 1H).
With hydrogenchloride In ethanol; water at 60 - 65℃; for 0.25h;
III
Stage IIIPreparation of 1-(4-amino6,7-dimethoxyquinazolin-2-yl)-4[[(2RS)-2,3,4,5-tetrahydrofuran-2-yl]carbonyl]piperazine hydrochloride (Terazosin hydrochloride)A mixture of Terazosin base (80 g, 0.207 mol), ethanol (1106 ml), DM water (94 ml) was heated to 60-65° C. and hydrochloric acid (20.50 g, 36.8% w/w) was added at 60-65° C. The resulting clear solution was treated with carbon (2.40 g) at 60-65° C. for 15 min. Carbon was removed by filtration and the residue was washed with preheated 8% v/v aqueous ethanol (2×80 ml, 60-65° C.). The filtrate was cooled and stirred at 0-5° C. for 4 hrs. The product was filtered, washed with precooled 8% v/v aqueous ethanol (2×80 ml, 0-5° C.) and dried at 45-50° C. under reduced pressure to obtain 85 g of Terazosin hydrochloride dihydrate, having purity 99.87% and Prazosin 0.02% (HPLC).
With hydrogenchloride; potassium hydrogencarbonate In methanol; 2-methoxy-ethanol
1 2-[4-(Tetrahydro-2-furoyl)piperazinyl]-4-amino-6,7-dimethoxyquinazoline hydrochloride
2-[4-(Tetrahydro-2-furoyl)piperazinyl]-4-amino-6,7-dimethoxyquinazoline hydrochloride To 7.00 g 2-chloro-4-amino-6,7-dimethoxyquinazoline (Lancaster Synthesis) in 50 ml methoxyethanol was added 10.8 g, tetrahydrofurolylpiperazine, and the mixture refluxed 3 hours. The clear solution was concentrated and an aqueous solution of potassium bicarbonate was added. The resultant solid that formed was filtered and washed with water. It was then added to methanol and the resulting suspension was acidified with a solution of hydrogen chloride in isopropyl alcohol. The resulting solution was concentrated and the residue crystallized from isopropyl alcohol giving 8.12 g. of product, m.p. 278°-279° C..
With hydrogenchloride; potassium hydrogencarbonate In methanol; 2-methoxy-ethanol
1 2[4-(Tetrahydro-2-furoyl)piperazinyl]-4-amino-6,7-dimethoxyquinazoline hydrochloride
2[4-(Tetrahydro-2-furoyl)piperazinyl]-4-amino-6,7-dimethoxyquinazoline hydrochloride To 7.00 g 2-chloro-4-amino-6,7-dimethoxyquinazoline (Lancaster Synthesis) in 50 ml methoxyethanol was added 10.8 g, tetrahydrofurolylpiperazine, and the mixture refluxed 3 hours. The clear solution was concentrated and an aqueous solution of potassium bicarbonate was added. The resultant solid that formed was filtered and washed with water. It was then added to methanol and the resulting suspension was acidified with a solution of hydrogen chloride in isopropyl alcohol. The resulting solution was concentrated and the residue crystallized from isopropyl alcohol giving 8.12 g. of product, mp 278°-279° C.
With hydrogenchloride; potassium hydrogencarbonate In methanol; 2-methoxy-ethanol
1 2[4-(Tetrahydro-2-furoyl)piperazinyl]-4-amino-6,7-dimethoxyquinazoline hydrochloride
2[4-(Tetrahydro-2-furoyl)piperazinyl]-4-amino-6,7-dimethoxyquinazoline hydrochloride To 7.00 g 2-chloro-4-amino-6,7-dimethoxyquinazoline (Lancaster Synthesis) in 50 ml methoxyethanol was added 10.8 g, tetrahydrofurolylpiperazine, and the mixture refluxed 3 hours. The clear solution was concentrated and an aqueous solution of potassium bicarbonate was added. The resultant solid that formed was filtered and washed with water. It was then added to methanol and the resulting suspension was acidified with a solution of hydrogen chloride in isopropyl alcohol. The resulting solution was concentrated and the residue crystallized from isopropyl alcohol giving 8.12 g. of product, m.p. 278°-279° C.
5 Preparation of Terazosin Monohydrochloride (Form I) from Terazosin Monohydrochloride Methanolate
EXAMPLE 5 Preparation of Terazosin Monohydrochloride (Form I) from Terazosin Monohydrochloride Methanolate Terazosin monohydrochloride methanolate (1.06 g, 23 mmol) was dissolved in approximately 10 mL of hot absolute ethanol in a 250 mL Edenmeyer flask. The solution was slowly cooled to ambient temperature and allowed to stand undisturbed overnight. The precipitated solids were collected by vacuum filtration on a Buchner funnel and washed with dry acetone to yield 0.76 g (1.8 mmol, 77.9%) of terazosin monohydrochloride which was shown by its powder x-ray diffraction pattern to conform to the non-solvated Form I crystalline polymorph.
0.390 g (0.92 mmol, 54.1%)
6 Preparation of Teraosin Monohydrochloride (Form II) from Terazosin Monohydrochloride Methanolate
EXAMPLE 6 Preparation of Teraosin Monohydrochloride (Form II) from Terazosin Monohydrochloride Methanolate To a 100 mL round-bottom flask containing 0.760 g (1.7 mmol) of terazosin monohydrochloride methanolate were added 25 mL of absolute ethanol. The flask was fitted with a reflux condenser and the slurry was heated under reflux for approximately 24 hours. The mixture was cooled and the precipitated solids collected to yield 0.390 g (0.92 mmol, 54.1%) of terazosin monohydrochloride which was shown by its powder x-ray diffraction pattern to conform to the non-solvated Form II crystalline polymorph.
1.9 g (4.5 mmol, 97.4%)
7 Preparation of Terazosin Monohydrochloride (Form III) from Terazosin Monohydrochloride Methanolate--Treatment with Acetone
EXAMPLE 7 Preparation of Terazosin Monohydrochloride (Form III) from Terazosin Monohydrochloride Methanolate--Treatment with Acetone To a 250 mL round-bottomed flask containing crystalline 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(tetrahydro-2-furoyl)piperazine monohydrochloride methanolate (2.1 g, 4.6 mmol) was added 50 mL of dry acetone. The resulting slurry was stirred and heated at 50° C. for ten minutes. Following this treatment, the solution was cooled in an ice bath for thirty minutes after which the precipitated solid was collected by filtration to yield 1.9 g (4.5 mmol, 97.4%) of terazosin monohydrochloride which was shown by its powder x-ray diffraction pattern to conform to the non-solvated Form III crystalline polymorph.
0.66 g (1.6 mmol, 64.8%)
8 Preparation of Terazosin Monohydrochloride (Form III) from Teramzosin Monohydrochloride Methanolate--Treatment with Ethanol
EXAMPLE 8 Preparation of Terazosin Monohydrochloride (Form III) from Teramzosin Monohydrochloride Methanolate--Treatment with Ethanol To a 100 mL round-bottomed flask containing crystalline 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(tetrahydro-2-furoyl)piperazine monohydrochloride methanolate (1.1 g, 2.4 mmol) was added 50 mL of absolute ethanol. The resulting slurry was stirred and heated at 50° C. for thirty minutes. Following this treatment, the solution was cooled in an ice bath for thirty minutes after which the precipitated solid was collected by filtration to yield 0.66 g (1.6 mmol, 64.8%) of terazosin monohydrochloride which was shown by its powder x-ray diffraction pattern to conform to the non-solvated Form III crystalline polymorph.
1.79 g (4.2 mmol, 95.9%)
9 Preparation of Terazosin Monohydrochloride (Form III) from Terazosin Monohydrochloride Methanolate--Treatment with Methyl Ethyl Ketone
EXAMPLE 9 Preparation of Terazosin Monohydrochloride (Form III) from Terazosin Monohydrochloride Methanolate--Treatment with Methyl Ethyl Ketone To a 250 mL round-bottomed flask containing crystalline 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(tetrahydro-2-furoyl)piperazine monohydrochloride methanolate (2.01 g, 4.4 mmol) was added 50 mL of methyl ethyl ketone (2butane). The resulting slurry was stirred and heated at 50° C. for thirty minutes. Following this treatment, the solution was cooled in an ice bath for thirty minutes after which the precipitated solid was collected by filtration to yield 1.79 g (4.2 mmol, 95.9%) of terazosin monohydrochloride which was shown by its powder x-ray diffraction pattern to conform to the non-solvated Form III crystalline polymorph.
Yield
Reaction Conditions
Operation in experiment
90.9%
4 Preparation of the Anhydrous Crystalline Polymorph of Terazosin Monohydrochloride of This Invention--Reflux Method
EXAMPLE 4 Preparation of the Anhydrous Crystalline Polymorph of Terazosin Monohydrochloride of This Invention--Reflux Method To a 500-mL round-bottom flask containing 5.19 g (0.011 mol) of terazosin monohydrochloride dihydrate was added 250 mL of dry acetone and several glass boiling beads. The flask was fitted with a Dean-Stark trap and reflux condensor. The heterogenous mixture was heated under reflux for five days. After cooling, the undissolved white solid remaining in the flask was collected by vacuum filtration to yield 4.3 g (0.010 mol, 90.9% yield) of the anhydrous crystalline polymorph of terazosin of this invention. The material was found by its powder x-ray diffraction pattern to be free of both the prior art anhydrous crystalline modification and the dihydrate form.
60.9 g (0.143 mol, 93.5%)
3 Preparation of the Anhydrous Crystalline Polymorph of Terazosin Monohydrochloride of This Invention--Reflux Method
EXAMPLE 3 Preparation of the Anhydrous Crystalline Polymorph of Terazosin Monohydrochloride of This Invention--Reflux Method To a 2-liter round-bottom flask containing 71.0 g (0.15 mol) of terazosin monohydrochloride dihydrate was added 1300 mL of absolute ethanol, a stirring bar and several glass boiling beads. The flask was fitted with a Dean-Stark trap and reflux condensor. The heterogenous mixture was heated under reflux for two days. After cooling, the undissolved white solid remaining in the flask was collected by vacuum filtration and washed with dry acetone to yield 60.9 g (0.143 mol, 93.5%) of the anhydrous crystalline polymorph of terazosin of this invention. The material was found by its powder x-ray diffraction pattern to be free of both the prior art anhydrous crystalline modification and the dihydrate form.
5
[ 23680-84-4 ]
[ 63074-07-7 ]
1-(4-amino-6,7-dimethoxy-2-quinaolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride[ No CAS ]
terazosin hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98.7 g (0.233 tool, 93%)
With concentrated aqueous hydrochloric acid In ethanol; 2-methoxy-ethanol
3 Step 1- Preparation of Anhydrous 1-(4-amino-6,7-dimethoxy-2-quinaolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride
Step 1- Preparation of Anhydrous 1-(4-amino-6,7-dimethoxy-2-quinaolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride A slurry of 60 grams (0.25 mol) of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 55.3 g (0.3 tool) of 1-(2-tetrahydrofuroyl)piperazine and 175 grams of 2-methoxyethanol was heated, under a nitrogen atmosphere with mechanical stirring, to 120°-123° C. for eight hours. The slurry was then cooled to 70° C. and 140 ml of 3A 200 proof ethanol was added. The resulting mixture was heated to 60°-70° C. for one hour and then cooled to 0°-5° C. To the cooled solution was added 2.5 g of concentrated aqueous hydrochloric acid in 12 ml of 3A 200 proof ethanol. This mixture was kept at -5°-5° C. for one and one-half hours after which the precipitated solid was collected by filtration and washed with 50 ml of cold 3A 200 proof ethanol to yield 98.7 g (0.233 tool, 93%) of anhydrous 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride of a previously unknown crystalline modification.
3
Take 10g terazosin hydrochloride raw materials evenly spread in the dish, placed in the oven, 90 damage 36 hours. Then,The samples were dissolved in methanol-water solution with 90% methanol concentration, stirred for 20 minutes, filtered through a suction funnelThe filtrate was collected by filtration and concentrated under reduced pressure to give 6.4 g of a concentrate. The concentrate was then dissolved in 8 ml of methanol and treated with 8 g of a granule having a particle size of 100 to 200Objective To prepare a silica gel column using silica gel as the separation silica gel with 120 g of 200 to 300 mesh normal phase silica gelChromatographic separation, with a volume ratio of 6: 1 chloroform-methanol mixed solvent isocratic elution, the eighth column volume of eluate collected, decompressionThe crude product was then concentrated in acetonitrile to a concentration of 90% in acetonitrile, and the crude product was dissolved in a reverse phase silica gel columnThe stationary phase was octadecylsilane bonded silica gel, the mobile phase consisted of acetonitrile-water with 90% acetonitrile concentration,. The eluent of the 7th column volume was collected, concentrated under reduced pressure and lyophilized to give 3.8 g of a pale yellow powder. HPLC normalizationOf the purity of more than 99%.
With 4-dimethylaminopyridine; triethylamine In N,N-dimethyl-formamide
1.2.2.1 2.1 Synthesis of terazosin hydrochloride hapten T-SG
Combine terazosin hydrochloride (1mol), succinic anhydride (1.3mol), triethylamine (1.5mol), 4-dimethylaminopyridine (DMAP) (0.5mol) with solvent N,N-dimethylformamide (DMF, 5ml) reaction, separation and purification to obtain the hapten T-SG.The synthetic route of the hapten T-SG is shown in Figure 2.
With Cs2CO3; sodium iodide In N,N-dimethyl-formamide at 70℃;
1.1.1.1 1.1 Synthesis of terazosin hydrochloride hapten T-2C
Terazosin hydrochloride (1 mol), ethyl bromoacetate (1.2 mol), cesium carbonate (4 mol) and sodium iodide (0.2 mol) were mixed with solvent N,N-dimethylformamide (DMF, 5 mL) in 70 Stir overnight at ; use the separation and purification reactant, dissolve the separated and purified reactant in 5 mL of methanol, then add 1 mol/L aqueous sodium hydroxide solution and stir at room temperature for 3 to 5 h. After the reaction, the concentration is 1 mol/L. L hydrochloric acid to adjust the pH to 6-7 to obtain the hapten T-2C.The synthetic route of the hapten T-2C is shown in Figure 1.
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