CN106632070B - A kind of preparation method of PDE4 inhibitor chlorine than Pulan - Google Patents
A kind of preparation method of PDE4 inhibitor chlorine than Pulan Download PDFInfo
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- CN106632070B CN106632070B CN201611164170.9A CN201611164170A CN106632070B CN 106632070 B CN106632070 B CN 106632070B CN 201611164170 A CN201611164170 A CN 201611164170A CN 106632070 B CN106632070 B CN 106632070B
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 239000000460 chlorine Substances 0.000 title claims abstract description 16
- 229910052801 chlorine Inorganic materials 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 title claims abstract description 12
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000006722 reduction reaction Methods 0.000 claims abstract description 6
- ODISAUHBLBVQKC-UHFFFAOYSA-N 2-bromo-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(Br)=C1 ODISAUHBLBVQKC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000007858 starting material Substances 0.000 claims abstract description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- 150000002940 palladium Chemical class 0.000 claims description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- ZOQCZTRFTARYGJ-UHFFFAOYSA-N chlorooxy(phenyl)borinic acid Chemical compound ClOB(O)C1=CC=CC=C1 ZOQCZTRFTARYGJ-UHFFFAOYSA-N 0.000 claims description 4
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- GUSWJGOYDXFJSI-UHFFFAOYSA-N 3,6-dichloropyridazine Chemical compound ClC1=CC=C(Cl)N=N1 GUSWJGOYDXFJSI-UHFFFAOYSA-N 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 2
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 claims 1
- BDKZHNJTLHOSDW-UHFFFAOYSA-N [Na].CC(O)=O Chemical compound [Na].CC(O)=O BDKZHNJTLHOSDW-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000012320 chlorinating reagent Substances 0.000 claims 1
- 239000012279 sodium borohydride Substances 0.000 claims 1
- 229910000033 sodium borohydride Inorganic materials 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- 230000006837 decompression Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 3
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
- -1 bromo- 4- methoxy benzyl Chemical group 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- MSHFRERJPWKJFX-UHFFFAOYSA-N para-methoxybenzyl alcohol Natural products COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- ZMKVNEGSOKFNDH-UHFFFAOYSA-N 2-[[3-(3-chlorophenyl)-4-methoxyphenyl]methyl]-6-[2-(2-methoxyphenoxy)ethylamino]pyridazin-3-one Chemical compound COC1=CC=CC=C1OCCNC1=NN(CC=2C=C(C(OC)=CC=2)C=2C=C(Cl)C=CC=2)C(=O)C=C1 ZMKVNEGSOKFNDH-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000008673 vomiting Effects 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
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 201000001880 Sexual dysfunction 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
- 239000003513 alkali Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 229940000041 nervous system drug Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- ZOUWOGOTHLRRLS-UHFFFAOYSA-N palladium;phosphane Chemical compound P.[Pd] ZOUWOGOTHLRRLS-UHFFFAOYSA-N 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 239000011780 sodium chloride Substances 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/22—Nitrogen and oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A kind of preparation method the invention discloses PDE4 inhibitor chlorine than Pulan.This method is using the bromo- 4-methoxybenzaldehyde of 3- as starting material, through reduction reaction, Suzuki reaction, chlorination and etc. synthesis target product E chlorine compare Pulan.Compared with the existing technology, yield is greatly improved this method, the experiment proved that, yield is up to 71%.And raw material is easy to get inexpensive, reaction condition is mild, low for equipment requirements, it can be achieved that industrialization production.The present invention provides an efficient easy approach than the synthetic method of Pulan for chlorine.
Description
Technical field
The present invention relates to a kind of preparation methods of PDE4 inhibitor, specially preparation method of the compound chlorine than Pulan.
Background technique
The function of phosphodiesterase 4 (PDE4) and central nervous system and immune system has close relationship, inhibitor
It is considered as the new anti-inflammatory agent and central nervous system drug candidate for acting on intracellular targets.
First generation PDE4 inhibitor such as rolipram has good antidepressant effect, and the reason of causing it that cannot list is
Inhibit the side reactions such as nausea and vomiting brought by PDE4.Compared with first generation PDE4 inhibitor, second generation PDE4 inhibitor has
Better therapeutic effect, but there are no the PDE4 inhibitor listings for being avoided that vomiting so far.
The Novel PDE 4 inhibitors that can be avoided nausea and vomiting reaction are developed in the treatment of depression and cognitive disorder
It has a good application prospect.CN201210037980.3 Chinese patent discloses a series of PDE4 inhibitor, and proves
Chlorine has than Pulan (chlorbipram) in the memory sexual dysfunction rat model induced hyoscine to be changed well
Kind effect；Also there is good antidepressant activity to forced swimming and outstanding tail behavioral despair model mice, and used than lattice
Dog proves that it only has faint or even vomits nauseous side effect without cause.The patent also also discloses chlorine and compares Pulan
(chlorbipram) synthetic method, this method use methyl bromide after with NH class compound to being bonded into obtained, reaction route
See Scheme 1.Since the brominated side reaction of NBS is more, bromide is unstable, and docking reaction yield is lower, and synthesis has certain
Limitation is not suitable for the subsequent research and development of the compound.
Scheme 1
Summary of the invention
Preparation method the invention discloses a kind of PDE4 inhibitor chlorine than Pulan, it is demonstrated experimentally that the yield of this method is high
Up to 71%.
The synthetic route of this preparation method are as follows:
The following steps are included:
(1) using the bromo- 4-methoxybenzaldehyde of 3- as starting material A, reduction reaction generates compound B, the i.e. bromo- 4- methoxy of 3-
Base benzyl alcohol；
(2) by compound B and chlorophenylboronic acid, under the catalysis of palladium salt catalyst, Suzuki reaction is carried out, generates chemical combination
Object C；
(3) compound C is subjected to chlorination with chlorination reagent, generates compound D；
(4) by raw material compound A1With 3,6- dichloro-pyridazine, it is heated to back flow reaction, generates compound A2；Compound A2With
Sodium acetate heating reflux reaction generates compound A3；
(5) by compound D and compound A3Back flow reaction under alkaline condition generates target product E chlorine and compares Pulan.
The preferred NaBH of reducing agent that reduction reaction described in step (1) uses4。
The preferred tetra-triphenylphosphine palladium of palladium salt catalyst or palladium acetate or palladium acetate described in step (2) and ligand urea.Four
The preferred 1:20 of feed ratio of triphenylphosphine palladium and compound B, the preferred 1:30 of feed ratio of catalyst acetic acid palladium and compound B.
Preferred carbon tetrachloride/the triphenylphosphine of chlorination reagent described in step (3) or Cyanuric Chloride/dimethylformamide body
System.
The preferred glycol dimethyl ether of back flow reaction solvent or dimethylformamide described in step (5).
Preparation method of the invention compared with the existing technology, has the advantage that yield is up to 64-71%, relatively before
Synthetic method yield improves 42.2%-57.8%, and raw material is easy to get inexpensive, and reaction condition is mild, it is low for equipment requirements, it can be achieved that
Industrialization production.The present invention provides an efficient easy new way than the synthetic method of Pulan for chlorine.
Figure of description
Fig. 1 is HPLC result figure of the target compound chlorine manufactured in the present embodiment than Pulan.
Specific embodiment
Preparation method of the invention is further described below with reference to embodiment.But the range of protection of the invention is not
It is limited with following embodiment.
Embodiment 1
(1) 30g raw material A is taken, the bromo- 4-methoxybenzaldehyde of 3- is slowly added to NaBH in batches48-10g, in ethanol
Reaction.It is monitored and is reacted by TLC.After fully reacting, ethyl alcohol is removed, extraction merges organic phase, and anhydrous sodium sulfate is dry, is spin-dried for
The bromo- 4- methoxy benzyl alcohol 30.0g of white solid 3- is obtained, product, which does not need purifying, can carry out the next step, yield > 98%.
(2) the bromo- 4- methoxy benzyl alcohol of 10g 3-, chlorophenylboronic acid 8.6g between addition, potassium carbonate 18.8g, four triphenyls are taken
Phosphine palladium 1.0g, isopropanol/water solvent 100mL, is stirred at room temperature.It is all dissolved to solid, removes the oxygen in reaction system, anaerobic
Reaction, heating, after having reacted, decompression spins off isopropanol and part water, is then extracted with ethyl acetate, and merges organic layer, with nothing
Fall palladium salt with suction filtration gear after aqueous sodium persulfate is dry, be spin-dried for, obtain micro- yellow thick liquid compound C11.46g, product does not need to purify
It can carry out the next step, yield > 95%.
(3) compound C11.5g (converting by sterling) is taken, adds carbon tetrachloride 7.4g, triphenylphosphine 11.0g is added portionwise,
In methylene chloride, stirring at normal temperature, TLC detection reaction.After having reacted, concentration of reaction solution, post separation removal of impurities obtains colorless and transparent oily
Liquid compound D, 11.1g, yield 90%.
(4) add 31.2g compound A1In ethanol with 28.2g 3.6- dichloro-pyridazine, it is heated to flowing back, TLC monitoring is anti-
It answers, after reaction, decompression spins off ethyl alcohol and obtains crude product, recrystallizes, obtains yellow solid compound A244g, yield 84.3%.It takes
50g compound A obtained above2With acetic acid/sodium acetate, agitating and heating reflux, TLC detection.Sodium acetate is removed after reaction,
Acetic acid is removed under reduced pressure, with the faint yellow solid compound A of ethyl alcohol recrystallization3, yield 92%.
(5) 11.0g A is taken3In 100mL round-bottomed flask, 11.0g compound D, 14.5g Anhydrous potassium carbonate, solvent is added
Glycol dimethyl ether, reflux.It is eluant, eluent with ethyl acetate/petroleum ether after having reacted, post separation obtains compound as white solid
E, i.e. chlorine are than Pulan 15g, yield 75%.Through the above method, calculate total recovery be 67.5%.
Embodiment 2:
On the basis of embodiment 1, other steps are constant, and step (2) method becomes following scheme in embodiment 1: taking 10g
The bromo- 4- methoxy benzyl alcohol of compound B, 3-, chlorophenylboronic acid 8.6g between addition, potassium carbonate 18.8g, urea 82.8mg, palladium acetate
210mg, isopropanol/water solvent 100mL, is stirred at room temperature.It is all dissolved to solid, removes the oxygen in reaction system, anaerobic is anti-
It answers, heats, after having reacted, decompression spins off isopropanol and part water, is then extracted with ethyl acetate, and merges organic layer, and use is anhydrous
Fall palladium salt with suction filtration gear after sodium sulphate is dry, be spin-dried for, obtains micro- yellow thick liquid compound C, 11.46g, yield > 95%.This implementation
The total recovery of example is 65.5%.
Embodiment 3:
On the basis of embodiment 1, other steps are constant, and step (3) method becomes following scheme in embodiment 1: 8.13g
Cyanuric Chloride is slowly stirred and DMF is added, or so half an hour is stirred at room temperature, dry methylene chloride is added, stirs evenly, and is added
Raw material C 11.5g is stirred at room temperature 4-8 hours.Organic layer is washed with saturation NaCl after having reacted, and dry organic layer, decompression is spin-dried for.
The method essence of crude product post separation is set, and colourless oily chlorizate, i.e. compound D, 11.6g (yield 95%) are obtained.It is computed
Total recovery is 71%.
Embodiment 4:
On the basis of embodiment 1, other steps are constant, and step (5) method becomes following scheme in embodiment 1: taking
11.0g compound D, 14.5g Anhydrous potassium carbonate, solvent dimethylformamide is added in 100mL round-bottomed flask in 11.0g A3
(DMF), it flows back.It is eluant, eluent with ethyl acetate/petroleum ether after having reacted, post separation obtains compound as white solid E14.4g,
Yield 72%.Being computed total recovery is 64.8%.
The experiment proved that: the feed ratio of palladium salt catalyst described in step (2) and compound B are the range of 1:10-100
It is interior, it all can get preferable yield, yield is 64% or more.
By the resulting target compound E of above-described embodiment method, data characterization are as follows:
ESI-MS:m/z 492.6([M+H])；1H NMR(400MHz,CDCl3) δ 1.26 (s, 1H), 3.62 (t, J=
4.8Hz, 2H), 3.78 (s, 3H), 3.84 (s, 3H), 4.14 (t, J=4.8Hz, 2H), 5.15 (s, 2H), 6.73 (d, J=
8.0Hz, 1H), 6.85-6.96 (m, 6H), 7.36-7.38 (m, 2H), 7.40 (d, J=8.4Hz, 1H), 7.49 (s, 1H)13C
NMR(100MHz,CDCl3)δ41.7,54.3,55.7,55.8,67.6,111.3,112.0,111.8,121.0,122.1,
126.7,127.0,127.7,128.9,129.2,129.5,130.0,130.8,131.5,133.7,140.0,147.6,
147.9,149.7,156.1, and 157.9.HPLC result is as shown in Fig. 1 and table 1.
Table 1
| Peak (#) | Retention time (min) | Peak width (min) | Peak area (mAUs) | Peak area (%) |
| 1 | 1.161 | 0.0511 | 5.74117 | 0.0723 |
| 2 | 2.283 | 0.0692 | 16.69851 | 0.2102 |
| 3 | 8.542 | 0.2159 | 7922.44971 | 99.7176 |
| Total amount | 7944.88939 |
The target product of synthetic method disclosed in preparation method and CN201210037980.3 Chinese patent of the invention
Yield is relatively shown in Table 2., it is apparent that using the method for the present invention, it is anti-through four steps by starting material of the bromo- 4-methoxybenzaldehyde of 3-
It answers, final chlorine can achieve 71% than the total recovery of Pulan, and general yield is also up to 64-71%.And CN201210037980.3
Synthetic method disclosed in number Chinese patent, yield only have 45%.
Table 2
The synthetic method of this patent protection, shown embodiment have certain representativeness, but not merely office
Limit is in the instance method.The coupling reaction of especially wherein Pd catalysis, reaction condition are not limited to Pd (PPh3)4, Pd
(OAc)2And different ligands, the reaction condition of different alkali and solvent is added；The method of benzyl chloride is converted into also not using benzyl alcohol
It is confined to the CCl of examples detailed above4/PPh3With two kinds of reactive modes of Cyanuric Chloride/DMF.All synthesis sides identical with present inventive concept
Method should all be fallen under the scope of the present invention.
Claims (4)
1. a kind of PDE4 inhibitor chlorine is than the preparation method of Pulan, it is characterised in that the following steps are included:
(1) using the bromo- 4-methoxybenzaldehyde of 3- as starting material A, reduction reaction generates compound B, the i.e. bromo- 4- methoxybenzene of 3-
Methanol；
(2) by compound B and chlorophenylboronic acid, under the catalysis of palladium salt catalyst, Suzuki reaction is carried out, generates compound C；
(3) compound C is subjected to chlorination with chlorination reagent, generates compound D；
(4) by raw material compound A1With 3,6- dichloro-pyridazine, it is heated to back flow reaction, generates compound A2；Compound A2With acetic acid
Sodium heating reflux reaction generates compound A3；
(5) by compound D and compound A3, under alkaline condition, using glycol dimethyl ether or dimethylformamide as solvent refluxing
Reaction generates target product E chlorine and compares Pulan；
Reaction route are as follows:
2. preparation method as described in claim 1, it is characterised in that the step (3) method particularly includes: compound C, with
Carbon tetrachloride/triphenylphosphine or Cyanuric Chloride/DMF are chlorinating agent system, carry out chlorination reaction and generate compound D.
3. preparation method as described in claim 1, it is characterised in that palladium salt catalyst described in step (2) is with compound B's
Feed ratio is 1:10-100.
4. the preparation method as described in claims 1 or 2 or 3, it is characterised in that: the reduction of reduction reaction described in step (1)
Agent are as follows: NaBH4。
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