CN106632070A - Preparation method for chlorbipram PDE4-inhibitor - Google Patents
Preparation method for chlorbipram PDE4-inhibitor Download PDFInfo
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- CN106632070A CN106632070A CN201611164170.9A CN201611164170A CN106632070A CN 106632070 A CN106632070 A CN 106632070A CN 201611164170 A CN201611164170 A CN 201611164170A CN 106632070 A CN106632070 A CN 106632070A
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- 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
Abstract
The invention discloses a preparation method for a chlorbipram PDE4-inhibitor. The method is capable of using 3-bromine-4-methoxybenzaldehyde as a starting raw material, and synthesizing a target product of E chlorbipram by steps, such as reduction reaction, Suzuki reaction and chlorination. Compared with the prior art, the yield is greatly improved, and the yield is up to 71% proved by experiment. The raw material is easily obtained and cheap, the reaction condition is moderate, the equipment request is low, and the industrial production can be realized. The preparation method is a new efficient and easy way for the synthetic method of the chlorbipram.
Description
Technical field
The present invention relates to a kind of preparation method of PDE4 inhibitor, specially preparation method of the compound chlorine than Pulan.
Background technology
Phosphodiesterase 4 (PDE4) has close relationship with central nervous system and immune function, its 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, is the reason for cause it to list
The side reactions such as the n and V that suppression PDE4 is brought.Compared with first generation PDE4 inhibitor, second generation PDE4 inhibitor has
More preferable therapeutic effect, but the PDE4 inhibitor listing of vomiting is not also avoided that so far.
Develop can avoid n and V react Novel PDE 4 inhibitors in the treatment of depression and cognitive disorder
With good application prospect.CN201210037980.3 Chinese patents disclose a series of PDE4 inhibitor, and prove
Chlorine than Pulan (chlorbipram) the memory sexual dysfunction rat model that hyoscine is induced have change well
Kind effect；Also there is good antidepressant activity to forced swimming and outstanding tail behavioral despair model mice, and adopt 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, the method using after methyl bromide with NH classes compound to being bonded into prepared, reaction scheme
See Scheme 1.Because the side reaction of NBS brominations is more, bromide is unstable, and docking reaction yield is relatively low, and its synthesis has certain
Limitation, is not suitable for the follow-up research and development of the compound.
Scheme 1
The content of the invention
The invention discloses a kind of preparation method of PDE4 inhibitor chlorine than Pulan, it is demonstrated experimentally that the yield of the method is high
Up to 71%.
The synthetic route of this preparation method is：
Comprise the following steps：
(1) with the bromo- 4-methoxybenzaldehydes of 3- as initiation material A, reduction reaction generates the bromo- 4- methoxies of compound B, i.e. 3-
Base phenmethylol；
(2) by compound B and a chlorophenylboronic acid, under the catalysis of palladium salt catalyst, Suzuki reactions are carried out, generates chemical combination
Thing C；
(3) compound C is carried out into chlorination with chlorination reagent, generates compound D；
(4) by starting compound A1With 3,6- dichloro-pyridazines, back flow reaction is heated to, generates compound A2；Compound A2With
Sodium acetate heating reflux reaction, generates compound A3；
(5) by compound D and compound A3In the basic conditions back flow reaction, generates target product E chlorine and compares Pulan.
The preferred NaBH of reducing agent that reduction reaction described in step (1) is adopted4。
The preferred tetra-triphenylphosphine palladium of palladium salt catalyst or palladium or palladium and part urea described in step (2).Four
The rate of charge preferably 1 of triphenylphosphine palladium and compound B:20, the rate of charge preferably 1 of catalyst acetic acid palladium and compound B:30.
Preferred carbon tetrachloride/the triphenylphosphine of chlorination reagent or Cyanuric Chloride/dimethylformamide body described in step (3)
System.
The preferred glycol dimethyl ether of back flow reaction solvent or dimethylformamide described in step (5).
The present invention preparation method relative to prior art, with advantages below：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 gentle, low for equipment requirements, is capable of achieving
Industrialization production.The present invention provides an efficiently easy new way for chlorine than the synthetic method of Pulan.
Figure of description
Fig. 1 is HPLC result figure of the target compound chlorine manufactured in the present embodiment than Pulan.
Specific embodiment
The preparation method of the present invention is further described with reference to embodiment.But the scope of the protection of the present invention is not
It is limited with following examples.
Embodiment 1
(1) 30g raw material As are taken, the bromo- 4-methoxybenzaldehydes of 3- are slowly added in batches NaBH48-10g, in ethanol
Reaction.Reacted by TLC monitoring.After reaction completely, ethanol is removed, extraction merges organic phase, and anhydrous sodium sulfate drying is spin-dried for
The bromo- 4- methoxy benzyl alcohols 30.0g of white solid 3- are obtained, product carries out the next step, yield by need not purifying>98%.
(2) the bromo- 4- methoxy benzyl alcohols 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.Treat that solid all dissolves, remove 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
Aqueous sodium persulfate falls palladium salt after being dried with suction filtration gear, is spin-dried for, and obtains micro- yellow thick liquid compound C11.46g, and product need not be purified
The next step, yield can be carried out>95%.
(3) compound C11.5g (converting by sterling), plus carbon tetrachloride 7.4g are taken, triphenylphosphine 11.0g is dividedly in some parts,
In dichloromethane, stirring at normal temperature, TLC detection reactions.After having reacted, concentration of reaction solution, post separation removal of impurities obtains water white transparency oily
Liquid compound D, 11.1g, yield 90%.
(4) 31.2g compound A are added1With 28.2g 3.6- dichloro-pyridazines in ethanol, backflow is heated to, TLC monitoring is anti-
Should, after reaction terminates, decompression spins off ethanol and obtains crude product, recrystallizes, and obtains yellow solid compound A244g, yield 84.3%.Take
50g compound A obtained above2With acetic acid/sodium acetate, agitating heating backflow, TLC detections.Reaction removes sodium acetate after terminating,
Acetic acid is removed under reduced pressure, with the faint yellow solid compound A of ethyl alcohol recrystallization3, yield 92%.
(5) 11.0g A are taken3In 100mL round-bottomed flasks, 11.0g compound D, 14.5g Anhydrous potassium carbonates, solvent are added
Glycol dimethyl ether, backflow.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%.Jing said methods, calculate total recovery for 67.5%.
Embodiment 2：
On the basis of embodiment 1, other steps are constant, and step (2) method is changed into below scheme in embodiment 1：Take 10g
The bromo- 4- methoxy benzyl alcohols of compound B, 3-, chlorophenylboronic acid 8.6g between addition, potassium carbonate 18.8g, urea 82.8mg, palladium
210mg, isopropanol/water solvent 100mL, is stirred at room temperature.Treat that solid all dissolves, remove the oxygen in reaction system, anaerobic is anti-
Should, heating, after react, decompression spins off isopropanol and part water, is then extracted with ethyl acetate, merging organic layer, with anhydrous
Sodium sulphate falls palladium salt after being dried with suction filtration gear, is spin-dried for, and obtains micro- yellow thick liquid compound C, 11.46g, yield>95%.This enforcement
The total recovery of example is 65.5%.
Embodiment 3：
On the basis of embodiment 1, other steps are constant, and step (3) method is changed into below scheme in embodiment 1：8.13g
Cyanuric Chloride, is slowly stirred addition DMF, and or so half an hour is stirred at room temperature, and adds dry dichloromethane, stirs, and adds
Raw material C 11.5g, are stirred at room temperature 4-8 hours.Rear organic layer is reacted to be washed with saturation NaCl, has been dried organic layer, decompression has been spin-dried for.
The method essence of crude product post separation is put, and obtains colourless oily chlorizate, i.e. compound D, 11.6g (yield 95%).It is computed
Total recovery is 71%.
Embodiment 4：
On the basis of embodiment 1, other steps are constant, and step (5) method is changed into below scheme in embodiment 1:Take
11.0g A3 add 11.0g compound D, 14.5g Anhydrous potassium carbonates, solvent dimethylformamide in 100mL round-bottomed flasks
(DMF), flow back.It is eluant, eluent with ethyl acetate/petroleum ether after having reacted, post separation obtains compound as white solid E14.4g,
Yield 72%.Total recovery is computed for 64.8%.
The experiment proved that：Palladium salt catalyst described in step (2) is 1 with the rate of charge of compound B:The scope of 10-100
It is interior, preferable yield can be all obtained, yield is more than 64%.
Target compound E by obtained by above-described embodiment method, data characterization is：
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 results are 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 preparation method of the present invention and the target product of synthetic method disclosed in CN201210037980.3 Chinese patents
Yield is relatively shown in Table 2., it is apparent that using the inventive method, it is anti-as the steps of initiation material Jing tetra- with the bromo- 4-methoxybenzaldehydes of 3-
Should, final chlorine can reach 71% than the total recovery of Pulan, and general yield is also up to 64-71%.And CN201210037980.3
Number synthetic method disclosed in Chinese patent, yield only has 45%.
Table 2
The synthetic method of this patent protection, shown embodiment has certain representativeness, but not merely office
Limit is in described case method.The coupling reaction that especially wherein Pd is catalyzed, reaction condition is not limited to Pd (PPh3)4, Pd
(OAc)2And the reaction condition of addition different ligands, Different Alkali and solvent；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 and present inventive concept identical synthesis side
Method, all should fall under the scope of the present invention.
Claims (7)
1. preparation method of a kind of PDE4 inhibitor chlorine than Pulan, it is characterised in that comprise the following steps：
(1) with the bromo- 4-methoxybenzaldehydes of 3- as initiation material A, reduction reaction generates the bromo- 4- methoxybenzenes of compound B, i.e. 3-
Methyl alcohol；
(2) by compound B and a chlorophenylboronic acid, under the catalysis of palladium salt catalyst, Suzuki reactions are carried out, generates compound C；
(3) compound C is carried out into chlorination with chlorination reagent, generates compound D；
(4) by starting compound A1With 3,6- dichloro-pyridazines, back flow reaction is heated to, generates compound A2；Compound A2With acetic acid
Sodium heating reflux reaction, generates compound A3；
(5) by compound D and compound A3In the basic conditions back flow reaction, generates target product E chlorine and compares Pulan.
Reaction scheme is：
2. preparation method as claimed in claim 1, it is characterised in that including step in detail below：
(1) with the bromo- 4-methoxybenzaldehydes of 3- as initiation material A, room temperature carries out reduction reaction, after reaction completely, except solvent,
Extraction concentration, obtains compound B；
(2) compound B and a chlorophenylboronic acid, under anaerobic, using palladium salt catalyst or palladium salt/part in alkalescence condition
Under, there is Suzuki reactions, after reaction completely, except catalyst, mixture extraction point liquid is obtained, it is concentrated to give compound C；
(3) compound C chlorination reagents carry out chlorination, and after reaction completely, concentration of reaction solution, pillar layer separation obtains compound D；
(4) by starting compound A1 and 3,6- dichloro-pyridazine, back flow reaction is heated to, after reaction terminates, except solvent afforded crude material, weight
Crystallization, obtains compound A2；Compound A2 is heated to reflux with sodium acetate in acetic acid, after reaction terminates, except sodium acetate and acetic acid, weight
Crystallize to obtain compound A-13；
(5) compound D and compound A-13 are flowed back in a solvent in the basic conditions, after having reacted, with ethyl acetate/petroleum ether
For eluant, eluent, pillar layer separation obtains target product E, i.e. chlorine and compares Pulan.
3. the preparation method as described in claims 1 or 2, it is characterised in that：What the reduction reaction described in step (1) was adopted goes back
Former agent is：NaBH4。
4. the preparation method as described in claims 1 or 2, it is characterised in that：Palladium salt catalyst described in step (2) is：Palladium
Salt adds ligand system or palladium catalyst compound.
5. preparation method as claimed in claim 4, it is characterised in that：Palladium salt catalyst described in step (2) and compound B
Rate of charge be 1:10-100.
6. the preparation method as described in claims 1 or 2, it is characterised in that：Chlorination reagent described in step (3) is four chlorinations
Carbon/triphenylphosphine or Cyanuric Chloride/dimethylformamide or thionyl chloride etc..
7. the preparation method as described in claims 1 or 2, it is characterised in that：Back flow reaction solvent described in step (5) is second
Glycol dimethyl ether or dimethylformamide.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111808029A (en) * | 2020-08-31 | 2020-10-23 | 兰晟生物医药(苏州)有限公司 | Preparation method of PDE4 inhibitor clobiplane |
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| CN102603676A (en) * | 2012-02-20 | 2012-07-25 | 徐江平 | Phosphodiesterase 4 inhibitor capable of avoiding vomiting reaction |
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2016
- 2016-12-16 CN CN201611164170.9A patent/CN106632070B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603676A (en) * | 2012-02-20 | 2012-07-25 | 徐江平 | Phosphodiesterase 4 inhibitor capable of avoiding vomiting reaction |
Non-Patent Citations (6)
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| AMY DALBY ET AL.: "A concise synthesis of biaryl PDE4D allosteric modulators", 《TETRAHEDRON LETTERS》 * |
| HUACHEN LIU ET AL.: "The design, synthesis, and anti-tumor mechanism study of N-phosphoryl amino acid modified resveratrol analogues", 《BIOORG. MED. CHEM.》 * |
| LIDIA DE LUCA ET AL.: "An Efficient Route to Alkyl Chlorides from Alcohols Using the Complex TCT/DMF", 《ORG. LETT.》 * |
| MIGUEL GUERRERO ET AL.: "SAR analysis of novel non-peptidic NPBWR1 (GPR7) antagonists", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111808029A (en) * | 2020-08-31 | 2020-10-23 | 兰晟生物医药(苏州)有限公司 | Preparation method of PDE4 inhibitor clobiplane |
| CN114105884A (en) * | 2020-08-31 | 2022-03-01 | 兰晟生物医药(苏州)有限公司 | Preparation method and crystal form of PDE4 inhibitor clobiplane |
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