CN106432227B - A kind of method for preparing pirenzepine hydrochloride key intermediate - Google Patents
A kind of method for preparing pirenzepine hydrochloride key intermediate Download PDFInfo
- Publication number
- CN106432227B CN106432227B CN201610604961.2A CN201610604961A CN106432227B CN 106432227 B CN106432227 B CN 106432227B CN 201610604961 A CN201610604961 A CN 201610604961A CN 106432227 B CN106432227 B CN 106432227B
- Authority
- CN
- China
- Prior art keywords
- carbamic acid
- pyridine radicals
- aniline
- ketone
- reaction
- 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.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- FFNMBRCFFADNAO-UHFFFAOYSA-N pirenzepine hydrochloride Chemical compound [H+].[H+].[Cl-].[Cl-].C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 FFNMBRCFFADNAO-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 229960000293 pirenzepine hydrochloride Drugs 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 40
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims abstract description 26
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229940049706 benzodiazepine Drugs 0.000 claims abstract description 19
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000001475 halogen functional group Chemical group 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims abstract description 7
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 8
- 230000006837 decompression Effects 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052786 argon Inorganic materials 0.000 claims description 7
- 238000009835 boiling Methods 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 239000007789 gas Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000002801 charged material Substances 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000002904 solvent Substances 0.000 abstract description 8
- 230000000977 initiatory effect Effects 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000010189 synthetic method Methods 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 230000008092 positive effect Effects 0.000 abstract description 2
- 238000010025 steaming Methods 0.000 abstract description 2
- 150000002576 ketones Chemical class 0.000 abstract 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- 229960004633 pirenzepine Drugs 0.000 description 6
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- -1 o-amino benzoyl Chemical group 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 2
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 150000005759 2-chloropyridine Chemical class 0.000 description 1
- 150000003929 3-aminopyridines Chemical class 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N acetic acid;palladium Chemical compound [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- BNUZPSHNZDBXSU-UHFFFAOYSA-N aniline methyl formate Chemical group NC1=CC=CC=C1.C(=O)OC BNUZPSHNZDBXSU-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000002012 dioxanes Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000010437 gem Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940102398 methyl anthranilate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of method for preparing pirenzepine hydrochloride key intermediate.For this method using (pyridine radicals of 2 halo 3) carbamic acid and aniline as initiation material, aniline is reaction dissolvent, under alkali and cuprous iodide effect, single step reaction obtains 5, the ketone of 11 dihydro 6H pyridos [2,3 B] [Isosorbide-5-Nitrae] benzodiazepine 6.The positive effect of the present invention is to propose relatively new synthesis 5, 11 dihydro 6H pyridos [2, 3 B] [1, 4] method of the ketone of benzodiazepine 6, this method step is simple, high income is up to more than 99%, aniline is both reaction dissolvent, and raw material, both the reaction of raw material (pyridine radicals of 2 halo 3) carbamic acid can have been made complete, improve reaction yield, it it also avoid the cost increase and environmental pollution come using other solvent banks, and unnecessary aniline is post-processed after steaming and can be continuing with, greatly save cost and protect environment, this synthetic method has good industrial prospect.
Description
Technical field
The present invention relates to a kind of pirenzepine hydrochloride key intermediate 5,11- dihydro -6H- pyridos [2,3-B] [1,4] benzene
And the synthetic method of diaza -6- ketone, belong to pharmaceutical synthesis field.
Background technology
Pirenzepine hydrochloride (1) also known as hydrochloric acid Pirenzepine, it is a kind of selective anticholinergic agent, can selectively be blocked
The plain gill fungus alkali acceptor of parietal cell and effectively gastric acid secretion inhibiting, mitigate hydrochloric acid in gastric juice to oesophagus, the stimulation of stomach and intestine focus, promote disease
The healing of stove inflammation, has been developed to medicament for resisting peptic ulcer.
Prior art synthetic hydrochloric acid hydrochloric acid sends the method in logical sequence Xiping mainly with 2- chlorine-3-aminopyridines and o-amino benzoyl
Sour methyl esters is initial feed, and palladium compound is catalyst, and phosphorus-containing compound is part, and benzene kind solvent is solvent, in the effect of alkali
Lower reaction obtains 5,11- dihydro -6H- pyridos [2,3-B] [1,4] benzodiazepine -6- ketone；5,11- dihydro -6H- pyridos
[2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone in the presence of alkali, is done with one or both of dioxanes or toluene mixture
Solvent, acylation reaction occurs with chloracetyl chloride and obtains N- chloracetyls-benzodiazepine ketone；Finally, then using acetonitrile as solvent,
In the presence of alkali, N- chloracetyls-benzodiazepine ketone reacts to obtain pirenzepine with N methyl piperazine；By anti-into salt
Pirenzepine hydrochloride should be obtained (referring to a kind of method [P] the Jiangsu of synthetic hydrochloric acid pirenzepines of Yang Ying a beautiful gems：
CN103044419A,2013-04-17.).By studying it can be found that 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzene
And diaza -6- ketone is the key intermediate of synthetic hydrochloric acid pirenzepine, therefore, in high yield, low cost, the synthesis 5 of high quality,
11- dihydro -6H- pyridos [2,3-B] [1,4] benzodiazepine -6- ketone is the key of synthetic hydrochloric acid pirenzepine.It is but existing
The deficiencies of cumbersome with the presence of synthetic route reactions steps, supplementary material species is various, and cost is high, and pollution is heavy.
The content of the invention
The problems such as to solve the above problems, i.e. reactions steps are cumbersome, supplementary material species is various, and cost is high, and pollution is heavy, this hair
It is bright to provide a kind of side of synthesis 5,11- dihydro -6H- pyridos [2,3-B] [1,4] benzodiazepine -6- ketone simple to operate
Method.
This method provides a kind of safe efficient, in high yield synthesis 5,11- dihydro -6H- pyridos [2,3-B] [1,4] benzene
And the method for diaza -6- ketone.See reaction equation 1.
The reaction equation that the present invention synthesizes is as follows：
The synthetic method of the present invention 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone, under
State step progress：
Argon gas is protected, successively toward addition (2- halo -3- pyridine radicals) carbamic acid, aniline, alkali and iodate in four-hole boiling flask
It is cuprous, 185 DEG C are warming up to, stirring reaction 5-7 hours, TLC tracking is reacted.It has been reacted that, be cooled to room temperature, filtered, filtrate decompression
Distillation, steams excessive aniline, obtains 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone crude products.Side
Stirring side crude product is washed with water three times, dry, obtain chloro- 5, the 10- dihydros -11H- dibenzo [b, e] of Light yellow crystals 8- [1,
4]-phenodiazine- 11- ketone.
Described (2- halo -3- pyridine radicals) carbamic acid is (2- chloro-3-pyridyls base) carbamic acid, (the bromo- 3- pyridines of 2-
Base) carbamic acid, (the iodo- 3- pyridine radicals of 2-) carbamic acid.
Described alkali is potassium carbonate, cesium carbonate, caustic alcohol.
Described (2- halo -3- pyridine radicals) carbamic acid and the charged material weight volume ratio of aniline are：1:3-1:5g/mL.
(2- halo -3- pyridine radicals) carbamic acid is made by 2- halo -3- aminopyridines and carbon dioxide reaction.
The molar ratio of described (2- halo -3- pyridine radicals) carbamic acid, alkali and catalyst is：1:1.3-1.5:
0.01。
The positive effect of the present invention is to propose the chloro- 5,10- dihydros -11H- dibenzo of relatively new synthesis 8-
[b, e] [1,4]-phenodiazineThe method of -11- ketone, many deficiencies of prior art being overcome, step is simple, only needs single step reaction,
High income is up to more than 99%；Aniline is both reaction dissolvent, and raw material, can both make raw material (2- halo -3- pyridine radicals) amino
Formic acid reaction is complete, improves reaction yield, it also avoid the cost increase and environmental pollution come using other solvent banks, and unnecessary
Aniline post processing steam after can be continuing with, greatly save and cost and protect environment, this synthetic method has good
Industrial prospect.
Embodiment
With specific embodiment, the present invention will be described in detail.Protection scope of the present invention not using embodiment as
Limit, but be defined in the claims.
Comparison example 1：A kind of method of synthetic hydrochloric acid pirenzepine:China, CN201210388731.9 [P] .2013-4-
17.
(1) 300 milliliters of toluene are added in reaction vessel, 257 grams of 2- chlorine-3-aminopyridines are dissolved in toluene,
Stirred with mechanical agitator.Being added thereto 292 grams of potassium tert-butoxide slowly, addition speed is 5% dosage/minute,
Stir.Then 393 grams of methyl anthranilate is added in reaction dissolvent in a manner of being added dropwise, rate of addition is
3% dosage/minute.Reacted 1 hour under conditions of 50 DEG C, after reaction terminates, add 400 milliliters of toluene, 4.49 grams of acetic acid
Palladium and 12.5 grams of dinaphthalene hexichol phosphorus, rise reaction temperature are reacted 24 hours to 110 DEG C.After reaction terminates, decompression boils off solvent, takes out
Filter obtains white solid, then is recrystallized with 50% acetone and 600 milliliters of the mixed solvent of water, filters and is washed with petroleum ether
Wash, be dried to obtain 401 grams of cyclisation intermediate benzodiazepine ketone, product yield 95%, purity 99%.
Comparison example 2：A kind of new method of synthetic hydrochloric acid piperazine human relations Xiping intermediate:China, CN201510075537.9
[P].2015-9-9.
(1) in 1000 milliliters of reaction bulb, 600 milliliters of butanol is added, 100 grams of 2- amino-N- (2- chloropyridines base-
3-) benzamide, 2 milliliters of concentrated sulfuric acids, back flow reaction 3 hours, reaction temperature are 80 DEG C, are cooled to room temperature, filter, are washed with acetone
Wash, 50-60 DEG C is dried in vacuo to obtain 98 grams of faint yellow solid product, yield 98%, purity 99%.
Example 1
Argon gas is protected, successively toward addition (2- chloro-3-pyridyls base) carbamic acid 17.2g (0.1mol), benzene in four-hole boiling flask
Amine 51.6mL, potassium carbonate 18g (0.13mol), cuprous iodide 0.19g (0.001mol) are warming up to 185 DEG C of backflows, stirring reaction 5-
7 hours, TLC tracking reactions.It has been reacted that, be cooled to room temperature, filtered, filtrate decompression distillation, steamed excessive aniline and reuse,
Obtain brown solid 5,11- dihydro -6H- pyridos [2,3-B] [1,4] benzodiazepine -6- ketone crude products.It is washed with water while stirring
Wash crude product three times, dry, obtain light yellow solid 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone
20.89g, yield 99.00%, purity 99.5% (GC).
Example 2
Argon gas is protected, successively toward addition (2- chloro-3-pyridyls base) carbamic acid 17.2g (0.1mol), benzene in four-hole boiling flask
Amine 68.8mL, cesium carbonate 45.6g (0.14mol), cuprous iodide 0.19g (0.001mol) are warming up to 185 DEG C of backflows, stirring reaction
5-7 hours, TLC tracking reactions.It has been reacted that, be cooled to room temperature, filtered, filtrate decompression distillation, steamed excessive aniline and repeat to make
With obtaining brown solid 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone crude products.Use while stirring
Water washing crude product three times, drying, obtains light yellow solid 5, and 11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -
6- ketone 21.00g, yield 99.52%, purity 99.8% (GC).
Example 3
Argon gas is protected, successively toward addition (2- chloro-3-pyridyls base) carbamic acid 17.2g (0.1mol), benzene in four-hole boiling flask
Amine 86mL, caustic alcohol 10.2g (0.15mol), cuprous iodide 0.19g (0.001mol) are warming up to 185 DEG C of backflows, stirring reaction 5-
7 hours, TLC tracking reactions.It has been reacted that, be cooled to room temperature, filtered, filtrate decompression distillation, steamed excessive aniline and reuse,
Obtain brown solid 5,11- dihydro -6H- pyridos [2,3-B] [1,4] benzodiazepine -6- ketone crude products.It is washed with water while stirring
Wash crude product three times, dry, obtain light yellow solid 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone
20.90g, yield 99.05%, purity 99.6% (GC).
Example 4
Argon gas is protected, successively toward addition (the bromo- 3- pyridine radicals of 2-) carbamic acid 21.7g (0.1mol), benzene in four-hole boiling flask
Amine 68.8mL, potassium carbonate 19.3g (0.14mol), cuprous iodide 0.19g (0.001mol) are warming up to 185 DEG C of backflows, stirring reaction
5-7 hours, TLC tracking reactions.It has been reacted that, be cooled to room temperature, filtered, filtrate decompression distillation, steamed excessive aniline and repeat to make
With obtaining brown solid 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone crude products.Use while stirring
Water washing crude product three times, drying, obtains light yellow solid 5, and 11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -
6- ketone 21.04g, yield 99.71%, purity 99.9% (GC).
Example 5
Argon gas is protected, successively toward addition (the iodo- 3- pyridine radicals of 2-) carbamic acid 26.4g (0.1mol), benzene in four-hole boiling flask
Amine 86mL, potassium carbonate 18g (0.13mol), cuprous iodide 0.19g (0.001mol) are warming up to 185 DEG C of backflows, stirring reaction 5-7
Hour, TLC tracking reactions.It has been reacted that, be cooled to room temperature, filtered, filtrate decompression distillation, steamed excessive aniline and reuse,
Obtain brown solid 5,11- dihydro -6H- pyridos [2,3-B] [1,4] benzodiazepine -6- ketone crude products.It is washed with water while stirring
Wash crude product three times, dry, obtain light yellow solid 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone
21.03g, yield 99.66%, purity 99.7% (GC).
Example 4 and comparison example 1-2 is contrasted it can be found that comparison example 1 is with 2- chlorine-3-aminopyridines and adjacent aminobenzene
Methyl formate is initiation material, 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone is synthesized, in reaction
Use expensive and be not easy palladium and the dinaphthalene hexichol phosphorus obtained, added synthesis cost；Total reaction time is more than 24
Hour, high energy consumption, yield only has 95%, and yield is low.Comparison example 2 is that conventional synthesis route is improved, and is with 2- ammonia
Base-N- (2- chloropyridine bases -3-) benzamide is initiation material, although improve after technique overcome original technique high temperature,
The defects such as post processing is complicated, yield is low, but initiation material 2- amino-N- (2- chloropyridine bases -3-) benzamide is not large
Industrialization product, synthesis are using 3- aminopyridines as initiation material, and (Zhang Yun mono- is obtained through chlorination, acylation, reduction three-step reaction
The production method of kind pirenzepine:Jiangsu, CN104744457A [P] .2015-07-01), reaction Central Plains supplementary product kind is more, operation
Complexity, cost is high, and yield is low, and this adds increased 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone
Industrial production cost.For example 4 using (the bromo- 3- pyridine radicals of 2-) carbamic acid and aniline as initiation material, single step reaction obtains 5,
11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone, it is low etc. to overcome high energy consumption in conventional art, yield
Deficiency, high income is up to more than 99%, hence it is evident that higher than prior synthesizing method；Aniline is both reaction dissolvent in reaction, and raw material, both
The reaction of raw material (2- halo -3- pyridine radicals) carbamic acid can be made complete, reaction yield is improved, it also avoid using other solvents
The cost increase and environmental pollution brought, and unnecessary aniline is post-processed after steaming and can be continuing with, and greatlys save cost
With protect environment.
Claims (4)
- A kind of 1. method for preparing pirenzepine hydrochloride key intermediate, it is characterised in that specific prepare is carried out as steps described below Argon gas is protected, successively toward addition (2- halo -3- pyridine radicals) carbamic acid, aniline, alkali and cuprous iodide, heating in four-hole boiling flask To 185 DEG C, stirring reaction 5-7 hours, TLC tracking reactions, react, be cooled to room temperature, filtered, filtrate decompression distillation, steamed Excessive aniline, obtains 5,11- dihydro -6H- pyridos [2,3-B] [Isosorbide-5-Nitrae] benzodiazepine -6- ketone crude products, uses while stirring Water washing crude product three times, drying, obtains chloro- 5,10- dihydros -11H- dibenzo [b, e] [the Isosorbide-5-Nitrae]-phenodiazines of Light yellow crystals 8-- 11- ketone, described alkali are potassium carbonate, cesium carbonate, caustic alcohol.
- 2. the method according to claim 1 for preparing pirenzepine hydrochloride key intermediate, it is characterised in that (the 2- halogen Generation -3- pyridine radicals) carbamic acid is (2- chloro-3-pyridyls base) carbamic acid, (the bromo- 3- pyridine radicals of 2-) carbamic acid, (2- is iodo- 3- pyridine radicals) carbamic acid.
- 3. the method according to claim 1 for preparing pirenzepine hydrochloride key intermediate, it is characterised in that described (2- Halo -3- pyridine radicals) the charged material weight volume ratio of carbamic acid and aniline is：1:3-1:5g/mL.
- 4. the method according to claim 1 for preparing pirenzepine hydrochloride key intermediate, it is characterised in that described (2- Halo -3- pyridine radicals) molar ratio of carbamic acid, alkali and catalyst is：1:1.3-1.5:0.01.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610604961.2A CN106432227B (en) | 2016-07-28 | 2016-07-28 | A kind of method for preparing pirenzepine hydrochloride key intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610604961.2A CN106432227B (en) | 2016-07-28 | 2016-07-28 | A kind of method for preparing pirenzepine hydrochloride key intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106432227A CN106432227A (en) | 2017-02-22 |
| CN106432227B true CN106432227B (en) | 2017-12-05 |
Family
ID=58185102
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610604961.2A Expired - Fee Related CN106432227B (en) | 2016-07-28 | 2016-07-28 | A kind of method for preparing pirenzepine hydrochloride key intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106432227B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111217690B (en) * | 2020-01-20 | 2023-01-13 | 临沂大学 | Preparation method of propafenone hydrochloride and intermediate 2' -hydroxy dihydrochalcone thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1130973B (en) * | 1980-03-17 | 1986-06-18 | Microsules Argentina Sa De S C | PROCESS FOR THE PREPARATION OF DERIVATIVES OF 5,11-DI-HYDRO-6H-PYRID (2,3-B) (1,4) -BENZODIAZEPIN-6-ONE, FINAL AND INTERMEDIATE DERIVATIVES OF SYNTHESIS IN THIS WAY OBTAINED |
| WO2012045194A1 (en) * | 2010-10-09 | 2012-04-12 | Abbott Laboratories | Benzodiazepinones as fak inhibitors for treatment of cancer |
| CN103044419A (en) * | 2012-09-04 | 2013-04-17 | 苏州弘森药业有限公司 | Method for synthesizing pirenzepine hydrochloride |
| CN104892596A (en) * | 2015-02-12 | 2015-09-09 | 苏州弘森药业有限公司 | Novel method for synthesizing pirenzepine hydrochloride intermediate |
-
2016
- 2016-07-28 CN CN201610604961.2A patent/CN106432227B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN106432227A (en) | 2017-02-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104945299B (en) | A kind of high-efficiency synthesis method of vildagliptin | |
| EP3828170A1 (en) | Method for safely preparing pimavanserin and tartrate salt thereof using triphosgene | |
| CN106966947A (en) | A kind of preparation method of vildagliptin | |
| CN109020881A (en) | A kind of Ah pa replaces the preparation method of Buddhist nun | |
| CN107311907A (en) | A kind of preparation method of vildagliptin isomer impurities | |
| CN107235958A (en) | A kind of synthetic method for preparing PARP inhibitor Niraparib | |
| CN109320498A (en) | The bromo- 1-(3- chloro-2-pyridyl of 3-) -1H- pyrazoles -5- formic acid alkyl ester preparation method | |
| CN102786431A (en) | Preparation method of propacetamol hydrochloride | |
| CN104725335A (en) | Preparation method of high-purity vortioxetine hydrobromide | |
| CN106432227B (en) | A kind of method for preparing pirenzepine hydrochloride key intermediate | |
| CN103012290B (en) | Preparation method of high-purity gefitinib | |
| CN107298678B (en) | Preparation method of bulk drug suvorexant | |
| CN109867673A (en) | A method of synthesis Pabuk former times benefit cloth | |
| CN105218390A (en) | A kind of Propacetamol Hydrochloride preparation technology of improvement | |
| CN104478974B (en) | A kind of 20, the synthetic method of 23-dipiperidino-5-O-mycamino syl-tylono lide | |
| CN111362957B (en) | Preparation method of icotinib key intermediate | |
| CN107383418B (en) | A kind of uvioresistant plastic additive and preparation method thereof | |
| CN106349229B (en) | The preparation method and midbody compound of Lei Dipawei intermediates | |
| CN108299149A (en) | The synthetic method of high-purity O LED intermediate 1- bromine pyrenes | |
| CN108558745A (en) | A kind of pa wins the synthetic method of XiLin intermediate | |
| CN106631828A (en) | Preparation method of bromhexine hydrochloride | |
| CN105315161B (en) | The preparation method of the key intermediate of one class PKB/Akt inhibitor | |
| CN110903211B (en) | Preparation method of L-theanine | |
| CN108409648B (en) | Preparation method of sorafenib tosylate related intermediate | |
| CN106542958A (en) | A kind of preparation method of adjacent Iodoaniline |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20171205 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |