CN102382034A - Synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride - Google Patents
Synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride Download PDFInfo
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- CN102382034A CN102382034A CN2010102788976A CN201010278897A CN102382034A CN 102382034 A CN102382034 A CN 102382034A CN 2010102788976 A CN2010102788976 A CN 2010102788976A CN 201010278897 A CN201010278897 A CN 201010278897A CN 102382034 A CN102382034 A CN 102382034A
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- Prior art keywords
- azabicyclo
- amino
- octane hydrochloride
- formula
- hydrochloric acid
- 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.)
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- WPYNXKFLSQEEFE-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-amine;hydrochloride Chemical compound Cl.C1CCC2CN(N)CC21 WPYNXKFLSQEEFE-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000010189 synthetic method Methods 0.000 title abstract 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 9
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 claims abstract description 9
- 229940007718 zinc hydroxide Drugs 0.000 claims abstract description 9
- 229910021511 zinc hydroxide Inorganic materials 0.000 claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000012065 filter cake Substances 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 5
- ZHVULPDNOFUIML-UHFFFAOYSA-N octane;hydrochloride Chemical compound Cl.CCCCCCCC ZHVULPDNOFUIML-UHFFFAOYSA-N 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- 150000002832 nitroso derivatives Chemical class 0.000 claims description 3
- -1 YLENE Chemical compound 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000005259 measurement Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims 2
- OHQKDJNVNLYHOL-UHFFFAOYSA-N 2,3,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-3a-amine hydrochloride Chemical compound Cl.NC12CNCC2CCC1 OHQKDJNVNLYHOL-UHFFFAOYSA-N 0.000 claims 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 238000000638 solvent extraction Methods 0.000 claims 1
- 239000002699 waste material Substances 0.000 abstract description 5
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 abstract description 4
- 229960000346 gliclazide Drugs 0.000 abstract description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002674 ointment Substances 0.000 abstract description 3
- FSCBDDOKZIRLCN-UHFFFAOYSA-N 2-nitroso-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrole Chemical compound C1CCC2CN(N=O)CC21 FSCBDDOKZIRLCN-UHFFFAOYSA-N 0.000 abstract 1
- 230000003113 alkalizing effect Effects 0.000 abstract 1
- 239000012752 auxiliary agent Substances 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 238000009413 insulation Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- QWHNJUXXYKPLQM-UHFFFAOYSA-N dimethyl cyclopentane Natural products CC1(C)CCCC1 QWHNJUXXYKPLQM-UHFFFAOYSA-N 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a synthetic method of an important intermediate of gliclazide, in particular to the synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride. The N-amino-3-azabicyclo[3,3,0]octane hydrochloride is prepared by the following steps of: reducing N-nitroso-3-azabicyclo[3,3,0]octane through zinc powder and hydrochloric acid, alkalizing and dissociating through potassium hydroxide or sodium hydroxide, extracting through methylbenzene or dimethylbenzene and the like, acidulating through industrial hydrochloric acid to form salts, reducing pressure, reflowing and completely distributing water, cooling and crystallizing. The synthetic method has the advantages of simple process, small alkali consumption, low discharge of wastes, high yield and low cost; and the synthetic method can be used for co-generating zinc hydroxide used as an auxiliary agent of rubber and surgical ointment and is suitable for industrial production.
Description
Technical field
The present invention relates to the compound method of a kind of N-amino-3-azabicyclo [3,3,0] octane hydrochloride, belong to the pharmaceutical intermediate synthesis technical field.
Background technology
GLICLAZIDE B.P. 2000 is at present all over the world, comprises the most widely used antidiabetic drug of China.And N-amino-3-azabicyclo [3,3,0] octane hydrochloride is the important intermediate of synthetic GLICLAZIDE B.P. 2000.
Present domestic patent 200810060128.1N-amino-3-azabicyclo [3,3,0] octane hydrochloride is by N-amino-1, and the reduction of 2-cyclopentanediformylandne makes, and yield is 78.7%; Patent 200810061421.X makes with a kind of adjacent dimethylcyclopentane verivate and hydracid hydrazine reaction, and yield is no more than 85%; The consumption of the synthetic alkali of N-amino-3-azabicyclo [3,3,0] octane hydrochloride is too big in Zhejiang University's master thesis " synthesizing of gliclazide ", forms complex compound, produces a large amount of wastes, and is difficult for handling; And foreign literature J.Med.and Pharm.Chem.5,819 method is to use LiALH
4Reduction-type (II), but its cost is higher; Japanese kokai publication hei 6-41073 be in acetum with zinc powder reduction formula (II), its weak point is to form the zinc acetate colloid, stirs difficulty, and waste is difficult for handling.And above report does not all relate to zinc hydroxide, and the present invention combines above report, and through changing reaction conditions, the consumption and the reduced-pressure backflow that reduce alkali divide water, improves the handicraft product yield and reduces cost, and reduce a large amount of waste of discharging.
Summary of the invention
The technical problem that the present invention solves is, provides a kind of technology simple, can reduce discharging wastes; Significantly improve yield, reduce cost; And the ability coproduction is as the compound method of N-amino-3-azabicyclo [3,3,0] octane hydrochloride of the zinc hydroxide of rubber and surgery ointment auxiliary.
Technical scheme of the present invention is:
(1) a certain proportion of nitroso compound and technical hydrochloric acid are dropped in the reaction flask, in 0～30 ℃ of a certain amount of zinc powder of slow adding, finish under stirring in 10～40 ℃ of reactions 4～8 hours;
(2) reaction finishes after-filtration, and filtrating adds an amount of alkali, and adjust pH is 12～13, and repetition measurement is constant; Continue to stir 2～3 hours, filter, the filter cake water is washed till neutrality, drains; In 70～80 ℃ of oven for drying, promptly get zinc hydroxide, can be used as rubber and surgery ointment auxiliary;
(3) filtrating is extracted 3～5 times with suitable solvent, united extraction liquid and to use the technical hydrochloric acid adjust pH be 1～2, reduced-pressure backflow divides water to the greatest extent, is cooled to below 30 ℃, filter, the filter cake oven dry, N-amino-3-azabicyclo [3,3,0] octane hydrochloride.
Embodiment
Embodiment 1:
100g nitroso-group thing and 450g technical hydrochloric acid are added in the 2000ml reaction flask, stir down in 15 ℃ and repeatedly add the 110g zinc powder on a small quantity, finish, be filtered in the 5000ml reaction flask in 15 ℃ of insulation reaction 7 hours; Add the about 2000ml of 10% sodium hydroxide solution, adjust pH is 12～13, filters, and the washing filter cake is to neutral; Drain, dry zinc hydroxide 130g, filtrating add extracted in toluene 300ml * 4, the about 100g adjust pH of extraction liquid processing industry hydrochloric acid is 1～2; Reduced-pressure backflow divides water to the greatest extent, is cooled to 5 ℃, filters the filter cake oven dry; Get N-amino-3-azabicyclo [3,3,0] octane hydrochloride 112g, yield 96.5%.
Embodiment 2:
120g nitroso-group thing and 550g technical hydrochloric acid are added in the 2000ml reaction flask, stir down in 10 ℃ and repeatedly add the 115g zinc powder on a small quantity, finish, be filtered in the 5000ml reaction flask in 20 ℃ of insulation reaction 5 hours; Add the about 1700ml of 15% potassium hydroxide solution, adjust pH is 12～13, filters, and the washing filter cake is to neutral; Drain, dry zinc hydroxide 158g, filtrating add xylene extraction 350ml * 3, the about 120g adjust pH of extraction liquid processing industry hydrochloric acid is 1～2; Reduced-pressure backflow divides water to the greatest extent, is cooled to 7 ℃, filters the filter cake oven dry; Get N-amino-3-azabicyclo [3,3,0] octane hydrochloride 133.2g, yield 95.6%.
Embodiment 3:
100g nitroso-group thing and 440g technical hydrochloric acid are added in the 2000ml reaction flask, stir down in 10 ℃ and repeatedly add the 95g zinc powder on a small quantity, finish, be filtered in the 5000ml reaction flask in 18 ℃ of insulation reaction 6 hours; Add the about 1900ml of 15% sodium hydroxide solution, adjust pH is 12～13, filters, and the washing filter cake is to neutral; Drain, dry zinc hydroxide 120g, filtrating adds butanone extraction 300ml * 5, the about 105g adjust pH of extraction liquid processing industry hydrochloric acid is 1～2; Reduced-pressure backflow divides water to the greatest extent, is cooled to 3 ℃, filters the filter cake oven dry; Get N-amino-3-azabicyclo [3,3,0] octane hydrochloride 113g, yield 97.4%.
Claims (5)
1.N-the compound method of amino-3-azabicyclo [3,3,0] octane hydrochloride formula (I) is characterized in that:
(1) a certain proportion of nitroso compound formula (II) and technical hydrochloric acid are dropped in the reaction flask, in 0～30 ℃ of a certain amount of zinc powder of slow adding, finish under stirring in 10～40 ℃ of reactions 4～8 hours;
(2) reaction finishes after-filtration, filtrate to add an amount of alkali, and adjust pH to 12～13, repetition measurement is constant, continues to stir 2～3 hours, filters, and the filter cake water is washed till neutrality, drains, and in 70～80 ℃ of oven for drying, gets zinc hydroxide;
(3) filtrate with suitable solvent extraction 3～5 times, united extraction liquid, and with technical hydrochloric acid adjust pH to 1～2, reduced-pressure backflow divides water to the greatest extent, is cooled to below 30 ℃, filters, filter cake is dried, and gets N-amino-3-azabicyclo [3,3,0] octane hydrochloride;
(4) structural formula of formula (I) and formula (II) is:
2. N-amino according to claim 1-3-azabicyclo [3; 3; 0] compound method (1) of octane hydrochloride formula (I), it is characterized in that: the mass ratio of nitroso compound and technical hydrochloric acid and zinc powder is 1.0: 4.1～5.2: 0.93～1.2, the temperature that adds zinc powder is 0～30 ℃; The temperature of reaction is 10～40 ℃, and the reaction times is 4～8 hours.
3. according to claim 1N-amino-3-azabicyclo [3; 3,0] the described alkali of compound method (2) of octane hydrochloride formula (I), it is characterized in that: alkali is meant 3%～40% sodium hydroxide solution, 3%～35% potassium hydroxide solution; The pH that is transferred is 12～13, and filter cake is a zinc hydroxide.
4. according to the described suitable solvent of compound method (3) of claim 1N-amino-3-azabicyclo [3,3,0] octane hydrochloride formula (I), it is characterized in that: toluene, YLENE, butanone, pimelinketone.
5. the described reduced-pressure backflow of compound method (3) according to claim 1N-amino-3-azabicyclo [3,3,0] octane hydrochloride formula (I) divides water, and it is characterized in that: pressure is 200Pa～500Pa, and temperature is no more than 75 ℃, tells until anhydrous.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010278897 CN102382034B (en) | 2010-09-06 | 2010-09-06 | Synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010278897 CN102382034B (en) | 2010-09-06 | 2010-09-06 | Synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride |
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| Publication Number | Publication Date |
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| CN102382034A true CN102382034A (en) | 2012-03-21 |
| CN102382034B CN102382034B (en) | 2013-03-27 |
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| CN 201010278897 Expired - Fee Related CN102382034B (en) | 2010-09-06 | 2010-09-06 | Synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833625A (en) * | 2014-03-21 | 2014-06-04 | 华烁科技股份有限公司 | Post-treatment method of N-amino-3-aza-bicyclo-[3.3.0] octane hydrochloride |
| CN105061293A (en) * | 2015-07-28 | 2015-11-18 | 江苏瑞克医药科技有限公司 | Synthesis method of gliclazide intermediate (amino azacyclo-hydrochloride) |
| CN105985281A (en) * | 2015-02-02 | 2016-10-05 | 浙江九洲药业股份有限公司 | Preparation method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride |
| CN110372568A (en) * | 2019-08-22 | 2019-10-25 | 山东海佑福瑞达制药有限公司 | A kind of crystallization and preparation method thereof of gliclazide intermediate |
| CN113045547A (en) * | 2019-12-27 | 2021-06-29 | 武汉先路医药科技股份有限公司 | Preparation method of azelastine hydrochloride |
| CN116283719A (en) * | 2023-03-28 | 2023-06-23 | 安徽金鼎医药股份有限公司 | Preparation process and preparation system of gliclazide intermediate amino heterocyclic hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0565270A (en) * | 1991-03-14 | 1993-03-19 | Honsyu Kagaku Kogyo Kk | Production of n-amino-3-azabicyclo (3,3,0)octane |
| CN101235011A (en) * | 2008-03-11 | 2008-08-06 | 浙江大学 | N-amino-1,2-cyclopentanediformylimine and preparation method thereof |
-
2010
- 2010-09-06 CN CN 201010278897 patent/CN102382034B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0565270A (en) * | 1991-03-14 | 1993-03-19 | Honsyu Kagaku Kogyo Kk | Production of n-amino-3-azabicyclo (3,3,0)octane |
| CN101235011A (en) * | 2008-03-11 | 2008-08-06 | 浙江大学 | N-amino-1,2-cyclopentanediformylimine and preparation method thereof |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833625A (en) * | 2014-03-21 | 2014-06-04 | 华烁科技股份有限公司 | Post-treatment method of N-amino-3-aza-bicyclo-[3.3.0] octane hydrochloride |
| CN103833625B (en) * | 2014-03-21 | 2016-06-08 | 华烁科技股份有限公司 | The post-treating method of N-amino-3-azabicyclo [3.3.0] octane hydrochloride |
| CN105985281A (en) * | 2015-02-02 | 2016-10-05 | 浙江九洲药业股份有限公司 | Preparation method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride |
| CN105061293A (en) * | 2015-07-28 | 2015-11-18 | 江苏瑞克医药科技有限公司 | Synthesis method of gliclazide intermediate (amino azacyclo-hydrochloride) |
| CN105061293B (en) * | 2015-07-28 | 2017-11-07 | 江苏瑞科医药科技有限公司 | A kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride |
| CN110372568A (en) * | 2019-08-22 | 2019-10-25 | 山东海佑福瑞达制药有限公司 | A kind of crystallization and preparation method thereof of gliclazide intermediate |
| CN113045547A (en) * | 2019-12-27 | 2021-06-29 | 武汉先路医药科技股份有限公司 | Preparation method of azelastine hydrochloride |
| CN113045547B (en) * | 2019-12-27 | 2023-03-28 | 武汉先路医药科技股份有限公司 | Preparation method of azelastine hydrochloride |
| CN116283719A (en) * | 2023-03-28 | 2023-06-23 | 安徽金鼎医药股份有限公司 | Preparation process and preparation system of gliclazide intermediate amino heterocyclic hydrochloride |
| CN116283719B (en) * | 2023-03-28 | 2023-09-08 | 安徽金鼎医药股份有限公司 | Preparation process and preparation system of gliclazide intermediate amino heterocyclic hydrochloride |
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