CN106946780A - A kind of synthetic method of Oxcarbazepine - Google Patents
A kind of synthetic method of Oxcarbazepine Download PDFInfo
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- CN106946780A CN106946780A CN201710071299.3A CN201710071299A CN106946780A CN 106946780 A CN106946780 A CN 106946780A CN 201710071299 A CN201710071299 A CN 201710071299A CN 106946780 A CN106946780 A CN 106946780A
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- Prior art keywords
- formyl
- iminodibenzyl
- oxcarbazepine
- synthetic method
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- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229960001816 oxcarbazepine Drugs 0.000 title claims abstract description 45
- 238000010189 synthetic method Methods 0.000 title claims abstract description 19
- -1 iminodibenzyl formyl chloride Chemical compound 0.000 claims abstract description 36
- ZSMRRZONCYIFNB-UHFFFAOYSA-N 6,11-dihydro-5h-benzo[b][1]benzazepine Chemical group C1CC2=CC=CC=C2NC2=CC=CC=C12 ZSMRRZONCYIFNB-UHFFFAOYSA-N 0.000 claims abstract description 30
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 18
- 230000007062 hydrolysis Effects 0.000 claims abstract description 17
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 17
- 238000004176 ammonification Methods 0.000 claims abstract description 16
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 16
- 238000006704 dehydrohalogenation reaction Methods 0.000 claims abstract description 15
- 238000010992 reflux Methods 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 239000000463 material Substances 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 150000004820 halides Chemical class 0.000 claims abstract description 7
- 239000003999 initiator Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 7
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 7
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 7
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical class BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 3
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical class ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 11
- 230000000977 initiatory effect Effects 0.000 abstract description 9
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical class ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 abstract description 2
- 150000002367 halogens Chemical class 0.000 abstract description 2
- VIQDTRXYTKXIMM-UHFFFAOYSA-N 5h-benzo[d][1]benzazepine Chemical compound N1C=CC2=CC=CC=C2C2=CC=CC=C12 VIQDTRXYTKXIMM-UHFFFAOYSA-N 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 125000005843 halogen group Chemical group 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- 239000007789 gas Substances 0.000 description 9
- UAQSLQPUFQWDAU-UHFFFAOYSA-N BrC1=CC=CC2=C1C1=C(C=CN2)C=CC=C1 Chemical class BrC1=CC=CC2=C1C1=C(C=CN2)C=CC=C1 UAQSLQPUFQWDAU-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 229960000623 carbamazepine Drugs 0.000 description 6
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 6
- 238000009413 insulation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000000630 rising effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- BGTBBBFTOBFVIR-YPKPFQOOSA-N (Z)-3-(chloroamino)-2,3-diphenylprop-2-enoyl chloride Chemical compound C=1C=CC=CC=1C(/NCl)=C(/C(Cl)=O)C1=CC=CC=C1 BGTBBBFTOBFVIR-YPKPFQOOSA-N 0.000 description 3
- LCGTWRLJTMHIQZ-UHFFFAOYSA-N 5H-dibenzo[b,f]azepine Chemical compound C1=CC2=CC=CC=C2NC2=CC=CC=C21 LCGTWRLJTMHIQZ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000005695 dehalogenation reaction Methods 0.000 description 2
- 238000007269 dehydrobromination reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- WKTPWBMBJFHTMV-UHFFFAOYSA-N C(C(C)C)#N.[N] Chemical compound C(C(C)C)#N.[N] WKTPWBMBJFHTMV-UHFFFAOYSA-N 0.000 description 1
- 208000001654 Drug Resistant Epilepsy Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-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
- 208000019022 Mood disease Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- GNHQSAUHXKRQMC-UHFFFAOYSA-N benzene;chlorine Chemical compound [Cl].C1=CC=CC=C1 GNHQSAUHXKRQMC-UHFFFAOYSA-N 0.000 description 1
- VOGJJBHRUDVEFM-UHFFFAOYSA-N clodantoin Chemical compound CCCCC(CC)C1NC(=O)N(SC(Cl)(Cl)Cl)C1=O VOGJJBHRUDVEFM-UHFFFAOYSA-N 0.000 description 1
- 229960004208 clodantoin Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229940053180 other antiepileptics in atc Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- 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
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The present invention relates to a kind of synthetic method of Oxcarbazepine, it passes sequentially through formyl chlorination, double halo dehydrohalogenations, ammonification and hydrolysis and Oxcarbazepine is made using iminodibenzyl as raw material；The product of formyl chlorination is iminodibenzyl formyl chloride, wherein, described pair of halo dehydrohalogenation is specially：Iminodibenzyl formyl chloride and halide reagent are reacted into 3-6 hours to obtain disubstituted halogenated products in 80 DEG C-reflux temperature under organic solvent and initiator existence condition, 8-16 hours dehydrohalogenations are then reacted at a reflux temperature and generate 10 halogen 5HDibenzazepine 5 formyl chlorides of Zhuo.This method has initiation material cheap and easy to get, and processing step is short, high income, low cost and other advantages.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of Oxcarbazepine（OCBZ）Synthetic method, especially
It is, using iminodibenzyl as raw material, to pass through the reaction synthesis oka such as formyl chlorination, disubstituted halogenation dehydrohalogenation, ammonification, hydrolysis
The new method in Xiping.
Background technology
Oxcarbazepine（Oxcarbazepine, OCBZ）The entitled 10,11- dihydros -10- oxo -5H- dibenzo of chemistry [b,
F] azatropylidene -5- formyl ammonia, structural formula is as follows, is a kind of newer antiepileptic, to epilepsy curative effect better than Karma west
It is flat, shared not with other antiepileptics and occur to intersect adverse reaction.In the past few years, some countries are had in the world use oka
Xiping, which substitutes carbamazepine, to be used to treat intractable epilepsy, intractable trigeminal neuralgia and affective disorders, is achieved good
Good effect.
On the synthetic method of Oxcarbazepine, document is reported for work more.It is summed up, mainly has：The carbamazepine method of route 1
（JP56073066）, using carbamazepine as raw material, Oxcarbazepine is solved through the double halos of addition, elimination of water, the method initiation material valency
Lattice are high, and process route is long（Plus synthesis carbamazepine, if being counted from iminodibenzyl, also chloride, bromination, dehydrobromination,
Ammonolysis, totally 7 step）, cause high cost；The iminostilbene carbonyl chloride method of route 2（CN100999497A）, using iminostilbene carbonyl chloride as
Raw material, with double halogen substitutions, ammonification, hydrolyzes to obtain Oxcarbazepine, and it is long that the method equally exists initiation material price height, process route（If
Counted from iminodibenzyl, also chloride, bromination, dehydrobromination totally 6 step, production cost is high；Route 3（CN101314590A）
With 5- cyano group -10- nitros 5H- dibenzazepine is raw material, and to reduce, hydrolyze and to obtain Oxcarbazepine, the route initiation material is difficult
.The reaction equation difference of three kinds of routes is as follows：
Route 1：Oxcarbazepine is synthesized by initiation material of carbamazepine；
Route 2：Oxcarbazepine is synthesized by initiation material of iminostilbene carbonyl chloride；
Route 3：With 5- cyano group -10- nitros 5H- dibenzazepine Zhuo is Material synthesis Oxcarbazepine.
The content of the invention
Present invention aims to overcome that prior art defect is there is provided a kind of new Oxcarbazepine synthetic method, this method with
Iminodibenzyl is raw material, and Oxcarbazepine, tool is made through formyl chlorination, double halo dehydrohalogenations, ammonification and hydrolysis four-step reaction
There is reaction scheme short, initiation material is cheap and easy to get, the advantages of easy to operate.
To achieve the above object, the present invention is adopted the following technical scheme that：
A kind of synthetic method of Oxcarbazepine, it passes sequentially through formyl chlorination, double halo dehalogenations using iminodibenzyl as raw material
Oxcarbazepine is made in hydrogen, ammonification and hydrolysis；The product of formyl chlorination is iminodibenzyl formyl chloride, wherein, described pair of halo takes off
Hydrogen halides is specially：By iminodibenzyl formyl chloride and halide reagent under organic solvent and initiator existence condition in 80 DEG C-
Reflux temperature（Preferable temperature is 90-100 DEG C）Reaction obtains disubstituted halogenated products in 3-6 hours, then in reflux temperature（About
120-125 DEG C）Under the conditions of 8-16 hour dehydrohalogenations of reaction generate 10- halogen -5H- dibenzazepine Zhuo -5- formyl chlorides.
Halide reagent used is chlorine, bromine, N- chlorosuccinimides, N- bromo-succinimides, two chlordantoins
Or C5H6Br2N2O2 etc.；Preferably C5H6Br2N2O2, halide reagent consumption is 1.05-1.3 times of theoretical amount, the very few reaction of consumption
Not exclusively, consumption excessively causes to waste, and optimal consumption is 1.15 times of theoretical amount.Initiator used be azo isobutyronitrile or
Benzoyl peroxide etc., initiator amount is the 1-3% of iminodibenzyl weight, preferably 2%.Organic solvent used is chlorine
Benzene, consumption is 3-8 times of iminodibenzyl weight, preferably the 5 of iminodibenzyl weight times.
The formyl chlorination is specially：By raw material iminodibenzyl and triphosgene or phosgene（It is preferred that triphosgene）In solvent chlorine
In 100 DEG C-reflux temperature under benzene existence condition（Preferable temperature is 110-115 DEG C）Reaction obtains iminodibenzyl in 3-6 hours
Formyl chloride；Wherein, iminodibenzyl and triphosgene mol ratio are 1：0.35-0.5, most ratio of greater inequality are 1：0.4；Iminodibenzyl with
Phosgene mol ratio is 1：1.1-1.5, most ratio of greater inequality are 1：1.2.Solvent chlorobenzene consumption is 3-8 times of iminodibenzyl weight, most
Excellent consumption is 5 times of iminodibenzyl weight.
The ammonification is specially：By 10- halogen -5H- dibenzazepine Zhuo -5- formyl chlorides and aminating agent solvent methanol,
In 40-80 DEG C under ethanol or chlorobenzene existence condition（50-60 DEG C of preferable temperature）Aminating reaction obtains 10- halogen -5H- in 6-10 hours
Dibenzazepine Zhuo -5- formyl ammonia.Aminating agent used is liquefied ammonia or ammoniacal liquor, and aminating agent consumption is the 4-8 of theoretical amount
Times, optimal consumption is 6 times.Ammonification solvent for use is methanol, ethanol or chlorobenzene, and preferred alcohol, solvent load is iminodibenzyl
4-8 times of weight, preferably 5 times.
The hydrolysis is specially：By aminate 10- halogen -5H- dibenzazepine Zhuo -5- formyl ammonia is in acid in 10-50
℃（30-35 DEG C of preferable temperature）Hydrolysis 40-60 hours, it is post-treated to obtain Oxcarbazepine.Acid used can be quality
Concentration 90-96% sulfuric acid or concentrated hydrochloric acid, preferred mass concentration 90-96% sulfuric acid.Sulfuric acid dosage is 10- halogen -5H- hexichol
And 6-15 times of azatropylidene -5- formyl ammonia weight, hydrochloric acid consumption is 10- halogen -5H- dibenzazepine Zhuo -5- formyl ammonia weight
8-20 times.
The present invention is using iminodibenzyl as initiation material, and synthesis Oxcarbazepine OCBZ reaction equation is as follows, wherein, X=
Cl or Br.
Compared to the prior art, the innovative point and advantage of synthetic method of the present invention are：1）Using iminodibenzyl as starting
Raw material, is made Oxcarbazepine, innovatively from double halo dehalogenations through formyl chlorination, double halo dehydrohalogenations, ammonification and hydrolysis
Change hydrogen step and make it that whole synthesis technique is greatly shortened, cheap and easy to get with initiation material, processing step is short, high income, cost
Low advantage；2）Carbamazepine can be made with Oxcarbazepine since same raw material, former steps simplify behaviour using method for the treatment of different things alike
Make, reduce labor intensity, be adapted to industrialized production.
Embodiment
Technical scheme is further discussed in detail with reference to embodiments, but protection scope of the present invention
It is not limited thereto.
Embodiment 1
A kind of synthetic method of Oxcarbazepine, it comprises the following steps：
1）Formyl chlorination prepares iminodibenzyl formyl chloride：
Iminodibenzyl 50g is added in reaction bulb（0.256mol）, chlorobenzene 250g, be slowly passed through phosgene after being warming up to 100 DEG C
30.1g（0.307mol）, and tail gas is absorbed with sodium hydroxide solution, lead to after finishing and temperature is raised to 110 ~ 115 DEG C of insulations instead again
Answer 4 hours, obtain the chlorobenzene solution of iminodibenzyl formyl chloride, remove chlorobenzene about 200g under reduced pressure, cool to room temperature, separate out light green solid
Body, filtering, dry iminodibenzyl formyl chloride light green solid about 53g, yield 80%.Chlorobenzene mother liquor can be applied mechanically, and apply mechanically mother liquor
Yield is up to 99 ~ 100% afterwards.
2）Double halo dehydrohalogenations prepare the bromo- 5H- dibenzazepines Zhuo -5- formyl chlorides of 10-：
Iminodibenzyl formyl chloride 66g is added into reaction bulb（0.256mol）, N- bromo-succinimides 114g
（0.642mol）, azo isobutyronitrile 0.5g, chlorobenzene 250g are slowly added to 80 DEG C, and tail gas is absorbed with sodium hydroxide solution, protect
Temperature reaction adds azo isobutyronitrile 0.2g after 4 hours, and temperature rising reflux adds 0.2g in every 4 hours later, adds 3 times, reacted altogether
Boiled off after and room temperature is down to after chlorobenzene obtains the bromo- 5H- dibenzazepines Zhuo -5- formyl chloride crude products of 10-, directly carry out the next step.
3）Ammonification prepares the bromo- 5H- dibenzazepines Zhuo -5- formyl ammonia of 10-：
To step 2）The 10- bromo- 5 of gainedHEthanol 250g, ammoniacal liquor 114ml are added in-dibenzazepine Zhuo -5- formyl chloride crude products
（About 1.536mol）, 40 ~ 50 DEG C are heated to, stirring is warming up to 50 ~ 60 DEG C after 3 hours, stir 5 hours, be cooled to room temperature, separated out
Yellow solid, is filtered, washing, dry 10- bromo- 5H- dibenzazepine Zhuo -5- formyl ammonia 59g（0.187mol）, yield 73%
（In terms of iminodibenzyl）.
4）Hydrolysis prepares Oxcarbazepine：
By 10- bromo- 5H- dibenzazepine Zhuo -5- formyl ammonia 59g（0.187mol）Add in reaction bulb, add 96% sulfuric acid
Reaction solution, is poured into and is made up of frozen water 4000ml and chloroform 1000ml by 550g by reaction solution after hydrolysis being stirred at room temperature 50 hours
System in, stir 30 minutes, separate organic layer, water layer is extracted 2 times with chloroform, each 500ml, merge organic layer, nothing
Decompression steams chloroform to there is solid precipitation after aqueous sodium persulfate is dried, and is cooled to 0 DEG C, separates out yellow solid, filter, dries, obtain
Oxcarbazepine crude product 37.8g（0.139mol）, yield 80.2%.Oxcarbazepine crude product 35g is put into reaction bulb, methanol is added
250ml, activated carbon 1g, flow back 30 minutes, filter while hot, and filtrate is down to room temperature, separate out solid, and filtering is light yellow admittedly dry
Body product Oxcarbazepine 29g, yield 83%, HPLC contents more than 99%.IR (KBr compressing tablets)：3468(s), 3340(s), 1685
(vs), 1653(vs), 1594(m), 1586(m), 1489(m), 1444(m), 1563(s), 1408(s), 771(s)；
Elementary analysis：C71.52% H4.83% N11.08% (theoretical values：C15H12N2O2C71.42% H4.79% N11.10%)；1H
NMR(400 MHz, CDCl3) δ: 3.86(d, 1H), 4.47(d, 1H), 5.04(s, 2H), 7.34-7.42(m,
4H), 7.51(t, 1H), 7.60(t, 1H), 7.67(d, 1H), 8.11(d, 1H)；13C NMR(400 MHz,
CDCl3) δ: 48.5, 126.7, 128.3, 128.4, 128.6, 129.54, 129.56, 129.7, 133.7,
133.9, 142.1, 144.3, 155.6, 192.4；MS (m/z, EI): 253, 236, 210.
Embodiment 2
A kind of synthetic method of Oxcarbazepine, it comprises the following steps：
1）Formyl chlorination prepares iminodibenzyl formyl chloride：Be the same as Example 1；
2）Double halo dehydrohalogenations prepare the bromo- 5H- dibenzazepines Zhuo -5- formyl chlorides of 10-：
Iminodibenzyl formyl chloride 62.2g is added in reaction bulb（0.256mol）, chlorobenzene 250g, be warming up to 80 DEG C, add even
Nitrogen isobutyronitrile 0.5g, is slowly added dropwise bromine 94.1g（1.178mol）, rate of addition do not escape out return duct as degree using bromine, and by tail
Gas is absorbed with sodium hydroxide solution, and 2 hours are incubated after completion of dropping, adds azo isobutyronitrile 0.2g, temperature rising reflux, later every 4
Hour 0.2g is added, added altogether 3 times, boiled off after the completion of reaction and room temperature is down to after chlorobenzene obtains 10- bromo- 5H- dibenzazepine Zhuo -5-
Formyl chloride crude product, directly carries out the next step；
3）Ammonification prepares the bromo- 5H- dibenzazepines Zhuo -5- formyl ammonia of 10-：Be the same as Example 1；
4）Hydrolysis prepares Oxcarbazepine：Be the same as Example 1.
Embodiment 3
A kind of synthetic method of Oxcarbazepine, it comprises the following steps：
1）Formyl chlorination prepares iminodibenzyl formyl chloride：
Iminodibenzyl 50g is added in reaction bulb（0.256mol）, chlorobenzene 250g, triphosgene 30.1g（0.103mol）, slowly add
Heat is absorbed to 100 DEG C, and by tail gas with sodium hydroxide solution, and it is small that temperature is raised into 110 ~ 115 DEG C of insulation reactions 4 again after 30 minutes
When, the chlorobenzene solution that room temperature obtains iminodibenzyl formyl chloride is down to, the next step is directly carried out.
2）Double halo dehydrohalogenations prepare the bromo- 5H- dibenzazepines Zhuo -5- formyl chlorides of 10-：
In step 1）C5H6Br2N2O2 84.1g is added in the iminodibenzyl formyl reaction solution of gained（0.295mol）, benzoyl peroxide
Formyl 0.5g, is slowly added to 80 DEG C, and tail gas is absorbed with sodium hydroxide solution, and insulation reaction adds benzoyl peroxide after 4 hours
Formyl 0.2g, temperature rising reflux is added 0.2g in every 4 hours later, added altogether 3 times, boiled off after the completion of reaction after chlorobenzene 10- is bromo-
5H- dibenzazepine Zhuo -5- formyl chloride crude products, directly carry out the next step；
3）Ammonification prepares the bromo- 5H- dibenzazepines Zhuo -5- formyl ammonia of 10-：Be the same as Example 1；
4）Hydrolysis prepares Oxcarbazepine：Be the same as Example 1.
Embodiment 4
A kind of synthetic method of Oxcarbazepine, it comprises the following steps：
1）Formyl chlorination prepares iminodibenzyl formyl chloride：
Iminodibenzyl 50g is added in reaction bulb（0.256mol）, chlorobenzene 250g, triphosgene 30.1g（0.103mol）, slowly add
Heat is absorbed to 100 DEG C, and by tail gas with sodium hydroxide solution, and it is small that temperature is raised into 110 ~ 115 DEG C of insulation reactions 4 again after 30 minutes
When, the chlorobenzene solution that room temperature obtains iminodibenzyl formyl chloride is down to, the next step is directly carried out.
2）Double halo dehydrohalogenations prepare the chloro- 5H- dibenzazepines Zhuo -5- formyl chlorides of 10-：
Two chlordantoin 58.1g are added in the iminodibenzyl formyl reaction solution obtained by step 1（0.295mol）, benzoyl peroxide first
Acyl 0.5g, is slowly heated to 80 DEG C, and tail gas is absorbed with sodium hydroxide solution, and insulation reaction adds benzoyl peroxide after 4 hours
Formyl 0.2g, temperature rising reflux adds 0.2g in every 4 hours later, adds altogether 3 times, boiled off after the completion of reaction and room temperature is down to after chlorobenzene
Obtain 10- chloro- 5H- dibenzazepine Zhuo -5- formyl chloride crude products, directly carry out the next step.
3）Ammonification prepares the chloro- 5H- dibenzazepines Zhuo -5- formyl ammonia of 10-：
To step 2）Ethanol 250g is added in the chloro- 5H- dibenzazepines Zhuo -5- formyl chloride crude products of 10- of gained, ammonia is slowly passed through
Gas 26g（About 1.536mol）, logical finish be heated to 40 ~ 50 DEG C, and stirring is warming up to 50 ~ 60 DEG C after 3 hours, stir 5 hours, be cooled to
Room temperature, separates out yellow solid, filters, washing, dry 10- chloro- 5H- dibenzazepine Zhuo -5- formyl ammonia 50g
（0.184mol）, yield 72%（In terms of iminodibenzyl）.
4）Hydrolysis prepares Oxcarbazepine：
By 10- chloro- 5H- dibenzazepine Zhuo -5- formyl ammonia 50g（0.184mol）Add in reaction bulb, add concentrated hydrochloric acid 700g,
Reaction solution after hydrolysis being stirred at room temperature 50 hours reaction solution is poured into to the body being made up of frozen water 4000ml and chloroform 1000ml
In system, stir 30 minutes, separate organic layer, water layer is extracted 2 times with chloroform, each 500ml merges organic layer, anhydrous sulphur
Decompression steams chloroform to there is solid precipitation after sour sodium is dried, and is cooled to 0 DEG C, separates out yellow solid, filter, dries, obtain oka
Xiping crude product 36.3g（0.144mol）, yield 78.2%.Oxcarbazepine crude product 35g is put into reaction bulb, methanol is added
250ml, activated carbon 1g, flow back 30 minutes, filter while hot, and filtrate is down to room temperature, separate out solid, and filtering is light yellow admittedly dry
Body product Oxcarbazepine 29g, yield 83%, HPLC contents more than 99%.
Embodiment 5
A kind of synthetic method of Oxcarbazepine, it comprises the following steps：
1）Formyl chlorination prepares iminodibenzyl formyl chloride：Be the same as Example 4；
2）Double halo dehydrohalogenations prepare the chloro- 5H- dibenzazepines Zhuo -5- formyl chlorides of 10-：
N- chlorosuccinimides 78.8g is added in the iminodibenzyl formyl reaction solution obtained by step 1（0.59mol）, mistake
BP 0.5g, is slowly heated to 80 DEG C, and tail gas is absorbed with sodium hydroxide solution, and insulation reaction is added after 4 hours
Benzoyl peroxide 0.2g, temperature rising reflux adds 0.2g in every 4 hours later, adds 3 times, boiled off after the completion of reaction after chlorobenzene altogether
It is down to room temperature and obtains the chloro- 5H- dibenzazepines Zhuo -5- formyl chloride crude products of 10-, directly carries out the next step；
3）Ammonification prepares the chloro- 5H- dibenzazepines Zhuo -5- formyl ammonia of 10-：Be the same as Example 4；
4）Hydrolysis prepares Oxcarbazepine：Be the same as Example 4.
Claims (6)
1. a kind of synthetic method of Oxcarbazepine, it is characterised in that using iminodibenzyl as raw material, pass sequentially through formyl chlorination,
Oxcarbazepine is made in double halo dehydrohalogenations, ammonification and hydrolysis；The product of formyl chlorination is iminodibenzyl formyl chloride, wherein,
Described pair of halo dehydrohalogenation be specially：Be there is into bar in organic solvent and initiator in iminodibenzyl formyl chloride and halide reagent
Disubstituted halogenated products are reacted 3-6 hours to obtain in 80 DEG C-reflux temperature under part, then reaction 8-16 is small at a reflux temperature
When dehydrohalogenation generation 10- halogen -5H- dibenzazepine Zhuo -5- formyl chlorides.
2. the synthetic method of Oxcarbazepine as claimed in claim 1, it is characterised in that halide reagent used be chlorine, bromine,
N- chlorosuccinimides, N- bromo-succinimides, two chlordantoins or C5H6Br2N2O2, halide reagent consumption are theoretical amount
1.05-1.3 times；Initiator used is azo isobutyronitrile or benzoyl peroxide, and initiator amount is iminodibenzyl weight
1-3%.
3. the synthetic method of Oxcarbazepine as claimed in claim 1, it is characterised in that organic solvent used is chlorobenzene, consumption
For 3-8 times of iminodibenzyl weight.
4. the synthetic method of Oxcarbazepine as claimed in claim 1, it is characterised in that described formyl chlorination is specially：By original
Material iminodibenzyl is obtained for 3-6 hours with triphosgene or phosgene under solvent chlorobenzene existence condition in the reaction of 100 DEG C-reflux temperature
Obtain iminodibenzyl formyl chloride；Wherein, iminodibenzyl and triphosgene mol ratio are 1：0.35-0.5, iminodibenzyl and light
Gas mol ratio is 1：1.1-1.5, solvent chlorobenzene consumption is 3-8 times of iminodibenzyl weight.
5. the synthetic method of Oxcarbazepine as claimed in claim 1, it is characterised in that described ammonification is specially：By 10- halogen-
5H- dibenzazepine Zhuo -5- formyl chlorides and aminating agent are under solvent methanol, ethanol or chlorobenzene existence condition in 40-80 DEG C of ammonia
Change reaction and obtain 10- halogen -5H- dibenzazepine Zhuo -5- formyl ammonia in 6-10 hours；Aminating agent used is liquefied ammonia or ammoniacal liquor, ammonia
Change reagent dosage is 4-8 times of theoretical amount.
6. the synthetic method of Oxcarbazepine as claimed in claim 5, it is characterised in that described hydrolysis is specially：Ammonification is produced
Thing 10- halogen -5H- dibenzazepine Zhuo -5- formyl ammonia in acid in 10-50 DEG C of hydrolysis 40-60 hours, it is post-treated
Oxcarbazepine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108863933A (en) * | 2018-06-25 | 2018-11-23 | 江苏鹏鹞药业有限公司 | The method for synthesizing carbamazepine |
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