CN104788376A - New crystal form of benazepril hydrochloride and preparation method thereof - Google Patents
New crystal form of benazepril hydrochloride and preparation method thereof Download PDFInfo
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- CN104788376A CN104788376A CN201410021563.9A CN201410021563A CN104788376A CN 104788376 A CN104788376 A CN 104788376A CN 201410021563 A CN201410021563 A CN 201410021563A CN 104788376 A CN104788376 A CN 104788376A
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- benazepril hydrochloride
- new crystal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a new crystal form of benazepril hydrochloride and a preparation method and a drug application thereof. According to the crystal form, a sharp heat melting peak begins to appear at 225.6 DEG C. The invention is beneficial to researches on drug bioactivity and bioavailability, etc.
Description
Technical field
The invention belongs to field of medicaments, relate to new crystal of a kind of benazepril hydrochloride and preparation method thereof.
Background technology
Benazepril hydrochloride (English another name: benazepril hydrochloride) being is a kind of angiotensin-convertion enzyme inhibitor, its chemical name is 3-[(1-ethoxycarbonyl-3-phenyl-(1S)-propyl group) is amino] 2,3,4,5-tetrahydrochysene-2-oxo-1H-1-(3S) benzazepine-1-acetic acid hydrochloride, molecular structural formula is as follows:
Form highly active benazeprilat after benazepril hydrochloride hydrolysis, suppress blood angiotensin-converting enzyme, lower the various effects of angiotensinⅡ mediation.Benazeprilat makes peripheral vascular resistance reduce, hypotensive, but does not cause compensatory fluid retention, also can alleviate ventricular afterload, not speed heart rate.In addition, benazeprilat also can improve left ventricular hypertrophy, improves diabetic sugar tolerance.Benazeprilat in vivo oral absorption is rapid, and specific absorption is more than 37%.Oral rear main at hepatic metabolism.The T1/2 of benazepril hydrochloride is about 4h, and protein binding rate is 95%, mainly eliminates through kidney and liver (bile).Light moderate renal insufficiency and liver cirrhosis person can adjust dosage.Severe renal insufficiency person, it is eliminated slowly, should turn dosage down.
Publication number is X-RAY collection of illustrative plates and the preparation method of the benazepril hydrochloride unformed shape that the United States Patent (USP) of US2005/0107359 has disclosed, and the DSC of unformed shape has endothermic melting peak at 76 DEG C.
Publication number is x-ray diffraction pattern and the preparation method of the benazepril hydrochloride crystal form A that the United States Patent (USP) of US2005/0107359 has disclosed;
The patent of publication number to be US2005/0107359 and publication number be WO2006/084761 all discloses x-ray diffraction pattern and the preparation method of benazepril hydrochloride crystal form B; According to WO2006/084761 patent; crystal form B crystal face is 13.6 (vs) apart from d-values; 10.7 (m); 8.8 (s), 6.4 (m), 6.0 (s); 5.9 (s); 5.7 (m), 5.4 (s), 5.3 (s); According to US2005/0107359 patent, crystal form B crystal face is 13.2 (vs) apart from d-values, 10.7 (s), 8.8 (m), 6.4 (m), 5.87 (s), 5.75 (m), 5.35 (m), 5.26 (m), 4.87 (m), 4.66 (s).The x-ray diffraction pattern of crystal form A and crystal form B is all listed in US2005/0107359, sees accompanying drawing 5 and 6.
Those skilled in the art know, and the polymorphic of medicine has become requisite important component part in numerous drug research process and pharmaceutical production quality control and testing process.The bioactive selection of medicine is contributed to a great extent to the polymorphic research of medicine, improve bioavailability and promote clinical efficacy, also contribute to the selection of drug administration approach and design and accelerate the determination of pharmaceutical preparation technology parameter, thus improve pharmaceutical production quality.Same drug crystal forms is different, and its bioavailability possibility significant difference, some crystal formation may have higher stability and the biological activity of Geng Gao than other crystal formations.
We, through constantly research, have invented new crystal of a kind of benazepril hydrochloride and preparation method thereof, have been defined as the C crystal form of benazepril hydrochloride.
Summary of the invention:
The object of the present invention is to provide a kind of new crystal of benazepril hydrochloride, for the research of medicine biological activity, bioavailability etc.
By following experiment and detection method, describe the new crystal of benazepril hydrochloride of the present invention in detail.
One, powder x-ray diffraction: (table 1)
The new crystal of benazepril hydrochloride of the present invention, its condition determination: 40KV, 50mA, beam wavelength CuKa
detected temperatures 25 DEG C, sweep limit 4-40 °, PSD length=2.01 [° 2Th], Divergence Slit Size=0.2500 °, Specimen length=10.00mm, has the absorption peak of following characteristics: table 1
Two, infrared absorption spectrum: table 2
Condition determination: measure infrared absorption spectrum with KBr pressed disc method
Three, differential thermal analysis (DSC):
The new crystal of benazepril hydrochloride of the present invention, its differential thermal analysis (DSC) result shows, starts to occur a sharp-pointed hot melting peak at 225.6 DEG C.
Accompanying drawing illustrates:
Accompanying drawing 1: the x-ray diffraction pattern of benazepril hydrochloride new crystal;
Accompanying drawing 2: the X-ray diffraction detected result of benazepril hydrochloride new crystal;
Accompanying drawing 3: the infrared absorpting light spectra of benazepril hydrochloride new crystal;
Accompanying drawing 4: the differential thermal analysis curve of benazepril hydrochloride new crystal;
Accompanying drawing 5: the X-diffractogram (US2005/0107359) of benazepril hydrochloride crystal form A;
Accompanying drawing 6: the X-diffractogram (US2005/0107359) of benazepril hydrochloride crystal form B.
embodiment
By the following examples, the present invention will be further described, but not as restriction of the present invention.
Embodiment 1:
THF (2300mL) is solvent, with NaOH (33g) for alkali, add (S, S)-hyperphenylalaninemia carboxylic acid, ethyl ester-benzo-aza (ethyl (S)-2-(((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-3-
Yl) amino)-4-phenylbutanoate); concrete structure is shown in patent CN101830850B) (150g) and tetrabutyl ammonium halide (12g); drip chloroacetic acid tert-butyl ester (95g); be stirred to after reacting completely and filter; toluene (400mL) is added after filtrate precipitation; heated and stirred is dissolved, and then passes into hydrogen chloride gas and reacts completely to removing tert. butyl protection group, have solid to produce.Solid filtering drying directly adds acetonitrile afterwards and heats, and after heat filtering, gained solid obtains white crystalline powder after drying, is benazepril hydrochloride new crystal.Its x-ray diffraction pattern, infrared absorpting light spectra and differential thermal analysis curve are shown in accompanying drawing 1,2,3 and 4.
Embodiment 2:
THF (3000mL) is solvent; with KOH (50g) for alkali; add (S; S)-hyperphenylalaninemia carboxylic acid, ethyl ester-benzo-aza (concrete structure is shown in patent CN101830850B) (150g) and tetrabutyl ammonium halide (5g); drip chloroacetic acid tert-butyl ester (95g); be stirred to after reacting completely and filter; toluene (360mL) is added after filtrate precipitation; heated and stirred is dissolved; then passing into hydrogen chloride gas to react completely to removing tert. butyl protection group, having solid to produce.Solid filtering drying directly adds acetonitrile afterwards and heats, and after heat filtering, gained solid obtains white crystalline powder after drying, is benazepril hydrochloride new crystal of the present invention.
Embodiment 3:
Dioxane (2000mL) is solvent; with KOH (50g) for alkali; add (S; S)-hyperphenylalaninemia carboxylic acid, ethyl ester-benzo-aza (concrete structure is shown in patent CN101830850B) (150g) and tetrabutyl ammonium halide (15g); drip bromo-acetic acid tert-butyl (125g); be stirred to after reacting completely and filter; toluene (450mL) is added after filtrate precipitation; heated and stirred is to dissolving; then passing into hydrogen chloride gas to react completely to removing tert. butyl protection group, having solid to produce.Solid filtering drying directly adds acetonitrile afterwards and heats, and after heat filtering, gained solid obtains white crystalline powder after drying, is benazepril hydrochloride new crystal of the present invention.
Claims (1)
1. a preparation method for benazepril hydrochloride new crystal, its step is as follows:
With THF or dioxane for solvent, with NaOH or KOH for alkali, add (S, S)-hyperphenylalaninemia carboxylic acid, ethyl ester-benzazepine (ethyl (S)-2-(((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-3-yl) amino)-4-phenyl-
And tetrabutyl ammonium halide butanoate); drip chloroacetic acid tert-butyl ester or bromo-acetic acid tert-butyl; be stirred to after reacting completely and filter; toluene is added after filtrate precipitation; heated and stirred is dissolved, and then pass into hydrogen chloride gas and react completely to removing tert. butyl protection group, the solid filtering drying produced directly adds acetonitrile afterwards and heats; after heat filtering, gained solid obtains white crystalline powder after drying, is benazepril hydrochloride new crystal.
Described its x-ray diffraction pattern of benazepril hydrochloride new crystal, infrared absorpting light spectra and differential thermal analysis curve are shown in accompanying drawing 1,2,3 and 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410021563.9A CN104788376A (en) | 2014-01-17 | 2014-01-17 | New crystal form of benazepril hydrochloride and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410021563.9A CN104788376A (en) | 2014-01-17 | 2014-01-17 | New crystal form of benazepril hydrochloride and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104788376A true CN104788376A (en) | 2015-07-22 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201410021563.9A Pending CN104788376A (en) | 2014-01-17 | 2014-01-17 | New crystal form of benazepril hydrochloride and preparation method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4575503A (en) * | 1983-02-10 | 1986-03-11 | Ciba-Geigy Corporation | 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids |
| WO2001079176A1 (en) * | 2000-04-18 | 2001-10-25 | Scinopharm Singapore Pte Ltd | Process for preparation of 3-[(1'-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[1]-benzazepine and its derivatives |
| US20050107359A1 (en) * | 2002-07-26 | 2005-05-19 | Van Der Schaaf Paul A. | Crystalline polymorphic and amorphous forms of benazepril hydrochloride |
| WO2005066134A1 (en) * | 2003-12-22 | 2005-07-21 | Novartis Ag | Bis-dicarboxylic acid salts of benazepril and preparation of benazepril via these salts |
| CN103012267A (en) * | 2012-10-11 | 2013-04-03 | 浙江大学 | Novel crystalline object of benazepril hydrochloride and preparation method of crystalline object |
-
2014
- 2014-01-17 CN CN201410021563.9A patent/CN104788376A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4575503A (en) * | 1983-02-10 | 1986-03-11 | Ciba-Geigy Corporation | 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids |
| WO2001079176A1 (en) * | 2000-04-18 | 2001-10-25 | Scinopharm Singapore Pte Ltd | Process for preparation of 3-[(1'-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[1]-benzazepine and its derivatives |
| US20050107359A1 (en) * | 2002-07-26 | 2005-05-19 | Van Der Schaaf Paul A. | Crystalline polymorphic and amorphous forms of benazepril hydrochloride |
| WO2005066134A1 (en) * | 2003-12-22 | 2005-07-21 | Novartis Ag | Bis-dicarboxylic acid salts of benazepril and preparation of benazepril via these salts |
| CN103012267A (en) * | 2012-10-11 | 2013-04-03 | 浙江大学 | Novel crystalline object of benazepril hydrochloride and preparation method of crystalline object |
Non-Patent Citations (4)
| Title |
|---|
| CHING-YAO CHANG等: "Asymmetric synthesis of ACE inhibitor-Benazepril HCl via a bioreductive reaction", 《TETRAHEDRON: ASYMMETRY》 * |
| KAFSSI HASSAN等: "3-[ (1-乙氧羰基-3-苯基丙基)氨基]-2,3,4,5-四氢-2-氧代-1-H-1-苯并氮杂卓-1-乙酸叔丁酯的制备研究", 《化学试剂》 * |
| 何晓强: "盐酸贝那普利的合成", 《中国医药工业杂志》 * |
| 李涛，等: "盐酸贝那普利的合成进展", 《应用化工》 * |
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