CN109810066A - A kind of synthetic method of the ambroxol hydrochloride in relation to substance - Google Patents
A kind of synthetic method of the ambroxol hydrochloride in relation to substance Download PDFInfo
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- CN109810066A CN109810066A CN201910086874.6A CN201910086874A CN109810066A CN 109810066 A CN109810066 A CN 109810066A CN 201910086874 A CN201910086874 A CN 201910086874A CN 109810066 A CN109810066 A CN 109810066A
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- ambroxol hydrochloride
- synthetic method
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- bromo
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- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229960000985 ambroxol hydrochloride Drugs 0.000 title claims abstract description 26
- 238000010189 synthetic method Methods 0.000 title claims abstract description 19
- 239000000126 substance Substances 0.000 title claims abstract description 15
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 17
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 19
- BEKDPSXQCRHBKJ-UHFFFAOYSA-N 2-bromo-1,4-dihydroquinazoline Chemical compound BrC1=NC2=CC=CC=C2CN1 BEKDPSXQCRHBKJ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 11
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 10
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 8
- 230000003647 oxidation Effects 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 5
- -1 copper ion compound Chemical class 0.000 claims description 5
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 5
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 229910001431 copper ion Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- 239000002609 medium Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 239000010949 copper Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 20
- 239000012535 impurity Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 8
- 238000011109 contamination Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 239000000047 product Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- LGACUMPRRMLUFZ-UHFFFAOYSA-N 1,4-dihydroquinazoline Chemical compound C1=CC=C2CN=CNC2=C1 LGACUMPRRMLUFZ-UHFFFAOYSA-N 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- 206010013786 Dry skin Diseases 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960005174 ambroxol Drugs 0.000 description 6
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229960003280 cupric chloride Drugs 0.000 description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- VFLVUQOSBVPKFA-UHFFFAOYSA-N 6,8-dibromo-1,4-dihydroquinazoline Chemical compound BrC=1C=C2CNC=NC2=C(C=1)Br VFLVUQOSBVPKFA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- ICLHRFYBPXBCPE-UHFFFAOYSA-N 4-(6,8-dibromo-2,4-dihydro-1h-quinazolin-3-yl)cyclohexan-1-ol;hydrochloride Chemical compound Cl.C1CC(O)CCC1N1CC2=CC(Br)=CC(Br)=C2NC1 ICLHRFYBPXBCPE-UHFFFAOYSA-N 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 208000032571 Infant acute respiratory distress syndrome Diseases 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- XBFISNPWDYRTRZ-UHFFFAOYSA-N N.Cl.[Br] Chemical compound N.Cl.[Br] XBFISNPWDYRTRZ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028974 Neonatal respiratory distress syndrome Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000009798 acute exacerbation Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 229940090044 injection Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 201000002652 newborn respiratory distress syndrome Diseases 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012372 quality testing Methods 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
- 208000037975 work-related injury Diseases 0.000 description 1
Abstract
A kind of synthetic method the invention discloses ambroxol hydrochloride in relation to substance, it is related to technical field of organic synthesis, using ambroxol hydrochloride as raw material, elder generation synthesizes 4- (6 through cyclization reaction with formaldehyde, bromo- Isosorbide-5-Nitrae-dihydroquinazoline -3 (the 2H)-yl of 8- bis-)-cyclohexanol HCI, then 4- (6 is synthesized through oxidation reaction, bromo- 3, the 4- dihydroquinazoline -3- base of 8- bis-)-cyclohexanol HCI.Product yield of the present invention can reach 90% or more, so that purity is reached 99% or more simultaneously, meet the requirement as drug contamination levels product, to be conducive to impurity 4- (6 in control ambroxol hydrochloride, bromo- 3, the 4- dihydroquinazoline -3- base of 8- bis-)-cyclohexanol HCI content.
Description
Technical field:
The present invention relates to technical field of organic synthesis, and in particular to a kind of synthetic method of the ambroxol hydrochloride in relation to substance.
Background technique:
Ambroxol hydrochloride is a kind of very strong expectorant of effect, is clinically usually used in secreting abnormal and expectoration with sputum
Acute, the chronic lung disease of dysfunction, such as chronic bronchitis acute exacerbation, asthma type brochitis and bronchial asthma
Eliminating the phlegm treatment；The prophylactic treatment of hand postoperative pulmonary complications；Premature and neonatal infant respiratory distress syndrome
Treatment.For many years, curative for effect, quality is stablized for ambroxol hydrochloride injection clinical application at home and abroad, has obtained market
With the generally approval of consumer, quantity is big, is particularly suitable for critical, postoperative, fasting and other is not suitable for oral trouble
Person, and entered in China various regions medical insurance and work-related injury insurance Drug catalogue.
Entitled trans- -4- [(the 2- amino 3.5- dibromo-benzyl) amino] cyclohexanol hydrochloridumi of chemistry of ambroxol hydrochloride, by
The German big pharmaceutical factory research and development of Boehringer Ingelheim, list, trade name " Mucosolvin ", specification 2ml the beginning of the eighties in Germany:
15mg。
Ambroxol Hydrochloride Glucose Injection can generate degradation impurity 4- (the bromo- 3,4- dihydro of 6,8- bis- in process of production
Quinazoline -3- base)-cyclohexanol, which can significant generation in preparation sterilization process.The garden China Medicine University Li Yuan is using super
Efficient liquid phase-ion trap-flight time tandem mass spectrum has carried out separation preparation, structural characterization to the impurity, it is determined that its chemistry
Structure.
Currently, the synthesis and content scaling method about the impurity have not been reported.In view of the impurity to control hydrochloric acid ammonia bromine
Rope product quality is most important, and its preparation method that can be used as the standard items that those skilled in the art use and quality testing side
Method is still unavailable, thus the acquisition of the contamination levels product have to effective control ambroxol hydrochloride raw material and its quality of the pharmaceutical preparations it is important
Meaning.
Document " Chinese Journal of New Drugs " the 9th phase of volume 15 in 2006, Page708-709 disclose the trans- impurity of ambroxol
The detailed preparation process of the bromo- 3- of 6,8- bis- (trans- -4- hydroxy-cyclohexyl) -1,2,3,4- tetrahydro quinazoline.By ambroxol first
Alcohol and water (volume ratio: methanol/water=3:1) dissolution completely, is slowly dropped into 37% formalin, reacts 10h at room temperature.It will reaction
Liquid is concentrated to dryness, and residue is recrystallized to give product with the solution of petroleum ether-ethyl acetate (volume ratio=2:1).In addition it reports
Column elution is crossed to obtain product with the solution of chloroform-acetone (volume ratio=6:1) using by ambroxol bulk pharmaceutical chemicals crude product.By
Many experiments, it has been found that this method synthesising by-product is more, is isolated and purified with petroleum ether-ethyl acetate (volume ratio=2:1)
Extremely difficult, yield is lower, and obtained product purity is very low, is unable to satisfy and wants as the quality of drug contamination levels product
It asks.
GB1131164A and Synthesis of metabolites of Bisolvon.J.Keck, Liebigs
Ann.Chem.707,107-111 (1967) similarly reports the trans- impurity 6,8- bis- of ambroxol bromo- 3- (trans- -4- hydroxyl ring
Hexyl) -1, the preparation process of 2,3,4- tetrahydro quinazolines, concrete operations are to dissolve ambroxol with methanol, and 40% first is added
Aldehyde is heated to back flow reaction 2h, then cools to room temperature filtering, and filter cake is recrystallized with methanol/ether.But it is sent out in research
Existing, synthesis yield is lower, highest 35%, and separation and purification of products is recrystallized using methanol/ether, and purity is lower, and highest purity is not
To 95%, it is difficult to as drug contamination levels product.
Due to the bromo- 3- of the trans- impurity 6,8- bis- of ambroxol (trans- -4- hydroxy-cyclohexyl) -1 that above-mentioned route is prepared,
2,3,4- tetrahydro quinazoline purity are lower, and therefore, it is difficult to meet the requirement as drug contamination levels product.
Summary of the invention:
Technical problem to be solved by the present invention lies in providing, a kind of product yield high, purity is high and technological operation are simply easy
Synthetic method of the capable ambroxol hydrochloride in relation to substance, made product can satisfy the requirement as drug contamination levels product.
The following technical solution is employed for the technical problems to be solved by the invention to realize:
A kind of synthetic method of the ambroxol hydrochloride in relation to substance, using ambroxol hydrochloride as raw material, elder generation and formaldehyde are anti-through cyclization
Should synthesize 4- (6,8- bis- bromo- Isosorbide-5-Nitrae-dihydroquinazoline -3 (2H)-yl)-cyclohexanol HCI, then through oxidation reaction synthesis 4- (6,
The bromo- 3,4- dihydroquinazoline -3- base of 8- bis-)-cyclohexanol HCI.
The cyclization system of the cyclization reaction is made of formaldehyde and solvent, and solvent is selected from methanol aqueous solution, ethanol water
One of.
The oxidation system of the oxidation reaction is made of oxidant and solvent, oxidant be selected from manganese dioxide, ammonium ceric nitrate,
One of palladium charcoal, solvent are selected from one of methylene chloride, methanol, dioxane, tetrahydrofuran, toluene or a variety of.
The oxidation system of the oxidation reaction is made of ferric trichloride and acid medium.
The acid medium is selected from one of hydrochloric acid solution, acetic acid solution.
The oxidation system of the oxidation reaction is made of divalent copper ion compound, alkaline medium and solvent, and solvent is selected
DMSO (dimethyl sulfoxide).
The divalent copper ion compound is selected from one of copper chloride, copper nitrate, copper bromide.
The alkaline medium selects DBU (11 carbon -7- alkene of 1,8- diazabicylo).
The beneficial effects of the present invention are:
(1) 4- (6,8- bis- bromo- Isosorbide-5-Nitraes-two are made through cyclization reaction with formaldehyde using ambroxol hydrochloride as raw material in the present invention
Hydrogen quinazoline -3 (2H)-yl)-cyclohexanol HCI, solvent is recycled in the last handling process of cyclization reaction, reduce at
This while, reduces wastewater treatment difficulty；
(2) present invention is using oxidation reaction by 4- (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-hexamethylene alkoxide
Hydrochlorate synthesizes 4- (6,8- bis- bromo- 3,4- dihydroquinazoline -3- base)-cyclohexanol HCI, and three kinds of different oxygen have been respectively adopted
Change system farthest improves the conversion of 4- (6,8- bis- bromo- Isosorbide-5-Nitrae-dihydroquinazoline -3 (2H)-yl)-cyclohexanol HCI
The yield of rate and 4- (6,8- bis- bromo- 3,4- dihydroquinazoline -3- base)-cyclohexanol HCI, makes yield can reach 90% or more,
So that purity is reached 99% or more simultaneously, meet the requirement as drug contamination levels product, to be conducive in control ambroxol hydrochloride
The content of impurity 4- (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI.
Detailed description of the invention:
Fig. 1 is the MS map of product 4- of the present invention (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI；
Fig. 2 is intermediate 4- of the present invention (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-cyclohexanol HCI
MS map；
Fig. 3 is product 4- of the present invention (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI1H-NMR
Map；
Fig. 4 is intermediate 4- of the present invention (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-cyclohexanol HCI1H-NMR map；
Fig. 5 is product 4- of the present invention (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI13C-NMR
Map；
Fig. 6 is intermediate 4- of the present invention (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-cyclohexanol HCI13C-
NMR spectra.
Specific embodiment:
In order to be easy to understand the technical means, the creative features, the aims and the efficiencies achieved by the present invention, tie below
Specific embodiment is closed, the present invention is further explained.
Embodiment 1
1, the synthesis of 4- (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-cyclohexanol HCI
By ambroxol hydrochloride (8.3g, 20mmol), methanol (60mL), water (20mL), 250mL round-bottomed flask is sequentially added
In, it is slowly added into 37% formalin (15mL), 25 DEG C of stirring 10h, TLC detection reactions.40 DEG C of decompressions after reaction
Methanol is recycled, cooling crystallization filters, and cold dehydrated alcohol washing, 50 DEG C of dryings obtain white solid, yield 93%, purity
98.6%.
2, the synthesis of 4- (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI
Previous step product (6g, 14mmol), methylene chloride (200mL), ammonium ceric nitrate (19.2g, 35mmol) are successively added
Enter in 250mL round-bottomed flask, 10h, TLC detection reaction is stirred at room temperature.After reaction plus water (100mL), point water intaking layer are used
5% sodium carbonate liquor adjusts pH 7-8, is extracted with ethyl acetate (80mL*3), merges organic layer, and organic layer is with water (50mL*3)
Washing, anhydrous sodium sulfate is dry, and ethyl acetate is recovered under reduced pressure to 10mL, is added with stirring concentrated hydrochloric acid (1mL), cooling crystallization, takes out
Filter, ethyl acetate washing, 50 DEG C of dryings obtain white solid.
Embodiment 2
1, the synthesis of 4- (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-cyclohexanol HCI
With embodiment 1.
2, the synthesis of 4- (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI
Previous step product (6g, 14mmol), methylene chloride (200mL), manganese dioxide (3g, 35mmol) are sequentially added
In 250mL round-bottomed flask, 10h, TLC detection reaction is stirred at room temperature.After reaction plus water (100mL), point water intaking layer, with 5%
Sodium carbonate liquor adjusts pH 7-8, is extracted with ethyl acetate (80mL*3), merges organic layer, and organic layer is washed with water (50mL*3)
It washs, anhydrous sodium sulfate is dry, and ethyl acetate is recovered under reduced pressure to 10mL, is added with stirring concentrated hydrochloric acid (1mL), cooling crystallization, filters,
Ethyl acetate washing, 50 DEG C of dryings obtain white solid.
Embodiment 3
1, the synthesis of 4- (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-cyclohexanol HCI
With embodiment 1.
2, the synthesis of 4- (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI
Previous step product (6g, 14mmol), methylene chloride (200mL), 10% palladium charcoal (5g) are sequentially added into 250mL round bottom
In flask, 10h, TLC detection reaction is stirred at room temperature.After reaction plus water (100mL), point water intaking layer, with 5% sodium carbonate liquor
PH 7-8 is adjusted, is extracted with ethyl acetate (80mL*3), organic layer is merged, organic layer is washed with water (50mL*3), anhydrous slufuric acid
Sodium is dry, and ethyl acetate is recovered under reduced pressure to 10mL, is added with stirring concentrated hydrochloric acid (1mL), cooling crystallization, filters, ethyl acetate is washed
It washs, 50 DEG C of dryings obtain white solid.
Embodiment 4
1, the synthesis of 4- (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-cyclohexanol HCI
With embodiment 1.
2, the synthesis of 4- (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI
By previous step product (6g, 14mmol), ferric chloride (FeCl36H2O) (9.5g, 35mmol), 1% hydrochloric acid solution (30mL) according to
In secondary addition 250mL round-bottomed flask, 10h, TLC detection reaction is stirred at room temperature.After reaction plus water (100mL), point water intaking layer,
PH 7-8 is adjusted with 5% sodium carbonate liquor, is extracted with ethyl acetate (80mL*3), organic layer, organic layer water (50mL* are merged
3) it washing, anhydrous sodium sulfate is dry, and ethyl acetate is recovered under reduced pressure to 10mL, is added with stirring concentrated hydrochloric acid (1mL), cooling crystallization,
It filters, ethyl acetate washing, 50 DEG C of dryings obtain white solid.
Embodiment 5
1, the synthesis of 4- (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-cyclohexanol HCI
With embodiment 1.
2, the synthesis of 4- (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI
By previous step product (6g, 14mmol), DMSO (10mL), anhydrous cupric chloride (4.7g, 35mmol), DBU (2mL) according to
In secondary addition 250mL round-bottomed flask, 10h, TLC detection reaction is stirred at room temperature.After reaction plus water (100mL), point water intaking layer,
PH 7-8 is adjusted with 5% sodium carbonate liquor, is extracted with ethyl acetate (80mL*3), organic layer, organic layer water (50mL* are merged
3) it washing, anhydrous sodium sulfate is dry, and ethyl acetate is recovered under reduced pressure to 10mL, is added with stirring concentrated hydrochloric acid (1mL), cooling crystallization,
It filters, ethyl acetate washing, 50 DEG C of dryings obtain white solid.
Embodiment 6
1, the synthesis of 4- (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-cyclohexanol HCI
With embodiment 1.
2, the synthesis of 4- (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI
Previous step product (6g, 14mmol), DMSO (10mL), copper nitrate (6.6g, 35mmol), DBU (2mL) are successively added
Enter in 250mL round-bottomed flask, 10h, TLC detection reaction is stirred at room temperature.After reaction plus water (100mL), point water intaking layer are used
5% sodium carbonate liquor adjusts pH 7-8, is extracted with ethyl acetate (80mL*3), merges organic layer, and organic layer is with water (50mL*3)
Washing, anhydrous sodium sulfate is dry, and ethyl acetate is recovered under reduced pressure to 10mL, is added with stirring concentrated hydrochloric acid (1mL), cooling crystallization, takes out
Filter, ethyl acetate washing, 50 DEG C of dryings obtain white solid.
Embodiment 7
1, the synthesis of 4- (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-cyclohexanol HCI
With embodiment 1.
2, the synthesis of 4- (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI
Previous step product (6g, 14mmol), DMSO (10mL), copper bromide (7.8g, 35mmol), DBU (2mL) are successively added
Enter in 250mL round-bottomed flask, 10h, TLC detection reaction is stirred at room temperature.After reaction plus water (100mL), point water intaking layer are used
5% sodium carbonate liquor adjusts pH 7-8, is extracted with ethyl acetate (80mL*3), merges organic layer, and organic layer is with water (50mL*3)
Washing, anhydrous sodium sulfate is dry, and ethyl acetate is recovered under reduced pressure to 10mL, is added with stirring concentrated hydrochloric acid (1mL), cooling crystallization, takes out
Filter, ethyl acetate washing, 50 DEG C of dryings obtain white solid.
Reference examples 1
Synthetic method does not add 1% hydrochloric acid solution only with embodiment 4.
Reference examples 2
Synthetic method does not add DBU only with embodiment 5.
Reference examples 3
Synthetic method does not add DBU only with embodiment 6.
Reference examples 4
Synthetic method does not add DBU only with embodiment 7.
Reference examples 5
DBU is only substituted for the sodium hydroxide solution of equimolar amounts with embodiment 5 by synthetic method.
The yield and purity of 1 embodiment 1-8 of table and reference examples 1-3 second step product
| Group | Oxidation system | Yield/% | Purity/% |
| Embodiment 1 | Ammonium ceric nitrate+methylene chloride | 52 | 98.9 |
| Embodiment 2 | Manganese dioxide+methylene chloride | 60 | 98.3 |
| Embodiment 3 | 10% palladium charcoal+methylene chloride | 81 | 98.7 |
| Embodiment 4 | + 1% hydrochloric acid solution of ferric chloride (FeCl36H2O) | 85 | 99.8 |
| Embodiment 5 | Anhydrous cupric chloride+DBU+DMSO | 92 | 99.8 |
| Embodiment 6 | Copper nitrate+DBU+DMSO | 83 | 99.2 |
| Embodiment 7 | Copper bromide+DBU+DMSO | 89 | 98.5 |
| Reference examples 1 | Ferric chloride (FeCl36H2O) | 0 | / |
| Reference examples 2 | Anhydrous cupric chloride+DMSO | 0 | / |
| Reference examples 3 | Copper nitrate+DMSO | 0 | / |
| Reference examples 4 | Copper bromide+DMSO | 0 | / |
| Reference examples 5 | Anhydrous cupric chloride+NaOH+DMSO | 76 | 98.4 |
Characterization of compound data:
4- (bromo- -3 (the 2H)-yl of 1,4- dihydroquinazoline of 6,8- bis-)-cyclohexanol HCI:
Mp:226.8~229.3 DEG C[4]。IR(KBr)υ(cm-1): 3409.13,2912.56,2487.74,1598.35,
1499.56,1068.34,866.90,816.66,669.29；1H-NMR(DMSO-d6,400MHz)ppmδ:1.15-1.18(m,
2H,CH2in cyclohexane),1.58-1.60(m,2H,CH2in cyclohexane),1.89-1.92(m,2H,CH2in
cyclohexane),2.06-2.18(m,2H,CH2in cyclohexane),3.07(m,3H,N-CH),3.34-3.40(m,
1H,O-CH),4.48brs,(3H,1/2CH2and 1/2N-CH2-N),4.67(s,1H,1/2CH2),6.64(s,1H,NH),
7.38 (d, 1H, J=2.0Hz, CH in Ar), 7.67 (d, 1H, J=2.0Hz, CH in Ar), 11.25 (s, 1H, OH)；13C-
NMR(DMSO-d6,100MHz)ppmδ138.33,130.09,110.69,67.83,59.81,59.21,48.16,33.58,
25.44,25.11；ESI-MS(m/z):C14H18Br2N2O,391.0[M+H]+.
4- (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI:
Mp:198.3~199.9 DEG C.IR(KBr),υ,cm-1: 3398.36,2922.35,1599.12,1497.35,
1068.78 855.50,846.69；1H-NMR(DMSO-d6,400MHz)ppmδ:1.19-1.29(m,2H,CH2in
cyclohexane),1.64-1.74(m,2H,CH2in cyclohexane),1.83-1.93(m,4H,2×CH2in
cyclohexane),3.38-3.41N-CH),3.86-3.89(m,1H,O-CH),4.83(s,2H,CH2),7.42(s,1H,CH
In Ar), 7.90 (s, 1H, CH in Ar), 8.25 (s, 1H ,=CH), 11.68 (s, 1H, OH)；13C-NMR(DMSO-d6,
100MHz)ppmδ151.16,134.76,129.62,129.54,122.41,119.16,111.68,67.88,63.46,
43.27,33.96,27.20；ESI-MS(m/z):C14H16Br2N2O,389.1[M+H]+.
The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (8)
1. a kind of synthetic method of ambroxol hydrochloride in relation to substance, it is characterised in that: using ambroxol hydrochloride as raw material, elder generation and formaldehyde
4- (6,8- bis- bromo- Isosorbide-5-Nitrae-dihydroquinazoline -3 (2H)-yl)-cyclohexanol HCI is synthesized through cyclization reaction, then through oxidation reaction
Synthesize 4- (the bromo- 3,4- dihydroquinazoline -3- base of 6,8- bis-)-cyclohexanol HCI.
2. synthetic method of the ambroxol hydrochloride according to claim 1 in relation to substance, it is characterised in that: the cyclization reaction
Cyclization system be made of formaldehyde and solvent, solvent be selected from one of methanol aqueous solution, ethanol water.
3. synthetic method of the ambroxol hydrochloride according to claim 1 in relation to substance, it is characterised in that: the oxidation reaction
Oxidation system be made of oxidant and solvent, oxidant be selected from one of manganese dioxide, ammonium ceric nitrate, palladium charcoal, solvent choosing
From one of methylene chloride, methanol, dioxane, tetrahydrofuran, toluene or a variety of.
4. synthetic method of the ambroxol hydrochloride according to claim 1 in relation to substance, it is characterised in that: the oxidation reaction
Oxidation system be made of ferric trichloride and acid medium.
5. synthetic method of the ambroxol hydrochloride according to claim 4 in relation to substance, it is characterised in that: the acid medium
Selected from one of hydrochloric acid solution, acetic acid solution.
6. synthetic method of the ambroxol hydrochloride according to claim 1 in relation to substance, it is characterised in that: the oxidation reaction
Oxidation system be made of divalent copper ion compound, alkaline medium and solvent, solvent select DMSO.
7. synthetic method of the ambroxol hydrochloride according to claim 6 in relation to substance, it is characterised in that: the divalent copper from
Sub- compound is selected from one of copper chloride, copper nitrate, copper bromide.
8. synthetic method of the ambroxol hydrochloride according to claim 6 in relation to substance, it is characterised in that: the alkaline medium
Select DBU.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110551071A (en) * | 2019-08-29 | 2019-12-10 | 合肥学院 | 2, 4-quinazoline diketone compound and synthetic method and application thereof |
| CN113087672A (en) * | 2021-04-08 | 2021-07-09 | 广州隽沐生物科技股份有限公司 | Preparation method of ambroxol impurity |
-
2019
- 2019-01-29 CN CN201910086874.6A patent/CN109810066A/en active Pending
Non-Patent Citations (2)
| Title |
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| 李园园等: "盐酸氨溴索葡萄糖注射液中未知杂质的分离制备与结构鉴定", 《中国医药工业杂志》 * |
| 陈仕云等: "盐酸氨溴索葡萄糖注射液有关物质的合成", 《化学试剂》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110551071A (en) * | 2019-08-29 | 2019-12-10 | 合肥学院 | 2, 4-quinazoline diketone compound and synthetic method and application thereof |
| CN113087672A (en) * | 2021-04-08 | 2021-07-09 | 广州隽沐生物科技股份有限公司 | Preparation method of ambroxol impurity |
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