CN108794375A - A kind of pabishta intermediate and its synthesis and application - Google Patents
A kind of pabishta intermediate and its synthesis and application Download PDFInfo
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- CN108794375A CN108794375A CN201810796864.7A CN201810796864A CN108794375A CN 108794375 A CN108794375 A CN 108794375A CN 201810796864 A CN201810796864 A CN 201810796864A CN 108794375 A CN108794375 A CN 108794375A
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- 0 *c1ccc(C=O)cc1 Chemical compound *c1ccc(C=O)cc1 0.000 description 1
- RFTNUTJVVFKBNU-UHFFFAOYSA-N CC1=[IH]=C(CCN)C2=CC=CC=CN2N1 Chemical compound CC1=[IH]=C(CCN)C2=CC=CC=CN2N1 RFTNUTJVVFKBNU-UHFFFAOYSA-N 0.000 description 1
- CPVSLHQIPGTMLH-UHFFFAOYSA-N Cc1c(CCN)c2ccccc2[nH]1 Chemical compound Cc1c(CCN)c2ccccc2[nH]1 CPVSLHQIPGTMLH-UHFFFAOYSA-N 0.000 description 1
- AUZKXWUHUYOZFP-UHFFFAOYSA-N Cc1c(CCNCc2ccc(C=O)cc2)c2ccccc2[nH]1 Chemical compound Cc1c(CCNCc2ccc(C=O)cc2)c2ccccc2[nH]1 AUZKXWUHUYOZFP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
Abstract
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of pabishta intermediate and its synthesis and application, the intermediate are obtained by the reaction, raw material is cheap and easy to get, and reaction condition is mild, easy to operate as shown in Formula II with 2- methyltryptamines and 4- chloromethylbenzene formaldehyde；Prepare pabishta by raw material of above-mentioned intermediate, of low cost, reaction step is few, and purity is high, and reaction condition is mild, easy to operate, conducive to pabishta bulk pharmaceutical chemicals quality control and reduce cost.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of pabishta intermediate and its synthesis and application.
Background technology
Pabishta (panobinostat), chemical name are N- hydroxyls -3- [4- [[[2- (2- Methyl-1H-indoles -3-
Base)-ethyl]-amino] methyl] phenyl] -2E-2- acrylamides, chemical constitution is the one of Novartis Co., Ltd's exploitation as shown in formula A
Kind hydroxamic acid micromolecular histone deacetylase enzyme (HDAC) inhibitor, 2 U.S. Yue23Huo food in 2015 and drug prison
Pipe office (FDA) approval listing, is used for the treatment of Huppert's disease, early stage acute myeloid leukaemia, which may delay more
The excessive generation of thick liquid cell in hair property patients with malignant myeloma body, or lead to these dangerous cell deaths,
Currently, the synthetic method of the pabishta of document report mainly has 2 kinds, the first is Novartis Co., Ltd in the patent world
Apply for pabishta compound and preparation method thereof, two documents disclosed in WO02/22577A2 and WO2007/146718A2
Disclosed method is all to obtain pa with azanol reaction again after reaction using 2- methyltryptamines and 4- formyls-methyl cinnamate as raw material
Than department he, reaction route is as follows：
Intermediate 4- formyls-methyl cinnamate that the above method is used is expensive, and yield and purity is not high, is unfavorable for
The quality control of pabishta bulk pharmaceutical chemicals and reduce cost.
Be for second Liu Qian etc. (《Chinese Journal of Pharmaceuticals》, 2011,42 (10), p725-727) disclosed in a kind of pa ratio
His synthetic method is taken charge of, this method is using (E) -4- methyl cinnamic acids methyl esters as raw material, in carbon tetrachloride solvent after NBS bromos,
(E) -3- [4- [[2- (2- Methyl-1H-indole -3- bases) ethylamino-] methyl] phenyl] acrylic acid is obtained by the reaction with 2- methyltryptamines
Methyl ester hydrochloride, rehydrated hydrazinolysis obtain pabishta, and reaction route is as follows：Pabishta is obtained with azanol reaction again,
Reaction route is as follows：
The above method is not only needed using hypertoxic solvent carbon tetrachloride, and also needs in Suzuki coupling reactions to use costliness
Heavy metal catalyst palladium, simultaneous reactions temperature is high, and reaction condition is violent, and yield is not high, is unfavorable for pabishta raw material
The quality control of medicine and reduce cost.
Therefore, exploration one is cheap and easy to get, and easy to operate, reaction condition is mild, environmental-friendly, it is easy to accomplish industrial metaplasia
The synthetic method of the pabishta of production has great importance.
Invention content
It is an object of the present invention to provide a kind of pabishta intermediates, using the pabishta intermediate as raw material system
Standby pabishta, of low cost, reaction step is few, and purity is high, and reaction condition is mild, easy to operate, is conducive to pabishta
The quality control of bulk pharmaceutical chemicals and reduce cost.
It is a further object to provide the preparation method of above-mentioned pabishta intermediate, the method with phenylhydrazine and
The amyl- 2- ketone of 5- chlorine is raw material, after 2- methyltryptamines are made, then is obtained by the reaction with 4- chloromethylbenzene formaldehyde, raw material is cheap and easy to get, instead
Mild condition is answered, it is easy to operate, it is easy to industrialized production.
The present invention's a further object is the method that above-mentioned pabishta intermediate prepares pabishta that provides.
For achieving the above object, the present invention provides following technical scheme：
A kind of pabishta intermediate, shown in structural formula such as formula (II)：
Second aspect, the present invention provide the preparation method of pabishta intermediate, including：0 DEG C~at room temperature, 2- methyl colors
4- halogenated methyl-benzaldehydes are obtained by the reaction shown in amine or its salt and formula (I), and reaction equation is as follows：
In formula, X is halogen；Preferably, X is selected from chlorine, bromine.
In some preferred embodiments, 2- methyltryptamines or the temperature of its salt and 4- halogenated methyl-benzaldehydes reaction are
0 DEG C~10 DEG C.
In some preferred embodiments, 2- methyltryptamines or the molar ratio of its salt and 4- halogenated methyl-benzaldehydes are 2
~5:1；In a further preferred embodiment, 2- methyltryptamines or the molar ratio of its salt and 4- halogenated methyl-benzaldehydes are 3:
1。
In some preferred embodiments, 2- methyltryptamines or the solvent of its salt and 4- halogenated methyl-benzaldehydes reaction are
DMF, it is a discovery of the invention that reaction dissolvent is very big on the influence of the yield of target compound, when use acetonitrile, ethyl acetate, dichloromethane
When the organic solvents such as alkane, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran are reaction dissolvent, it cannot get target compound or targeted at all
Conjunction object yield is relatively low, and impurity is more, when being only solvent with DMF, can obtain the target compound of high yield, high-purity.
In some preferred embodiments, it is added and ties up when 2- methyltryptamines or its salt and 4- halogenated methyl-benzaldehydes react
Sour agent, the acid binding agent are selected from potassium carbonate, potassium hydroxide, sodium hydroxide, saleratus, DIPEA, triethylamine, diethylamine；Into
In one step preferred embodiment, acid binding agent is added when reacting in 2- methyltryptamines or its salt and 4- halogenated methyl-benzaldehydes, described
Acid binding agent is potassium carbonate.
In a specific embodiment, the preparation method of pabishta intermediate, including：It 0 DEG C~10 DEG C, is being added
In the DMF of potassium carbonate, shown in 2- methyltryptamines or its salt and formula (I) formula (II) institute is obtained by the reaction in 4- halogenated methyl-benzaldehydes
Show compound, wherein 2- methyltryptamines or the molar ratio of its salt and 4- halogenated methyl-benzaldehydes are 3:1, reaction equation is as follows：
In formula, X is halogen；Preferably, X is selected from chlorine, bromine.
The third aspect, the present invention provide a kind of preparation method of pabishta, include the following steps：
Step (1)：Under DBU catalysis, pabishta intermediate shown in formula (II) is reacted with compound shown in formula (III),
Compound shown in formula (IV) is made；
Step (2)：Pabishta is made with azanol reaction in compound shown in formula (IV), and reaction equation is as follows,
In formula, R1And R2Independently selected from C1-6Alkyl and hydrogen；Preferably, R1And R2Independently selected from methyl, ethyl, third
Base, isopropyl and hydrogen；It is further preferred that R1And R2Independently selected from methyl and ethyl.
According to the preparation method of pabishta of the present invention, pabishta intermediate and formula shown in formula (II) in step (1)
(III) molar ratio of compound shown in is 1:1.5~3；Preferably, in step (1) pabishta intermediate shown in formula (II) with
The molar ratio of compound shown in formula (III) is 1:2.
According to the preparation method of pabishta of the present invention, pabishta intermediate and DBU shown in formula (II) in step (1)
Molar ratio is not more than 1:2；Preferably, the molar ratio of pabishta intermediate and DBU shown in formula (II) are 1 in step (1):2.
According to the preparation method of pabishta of the present invention, pabishta intermediate and formula shown in formula (II) in step (1)
(III) solvent of the reaction of compound shown in is selected from acetonitrile, dichloromethane, ethyl acetate, 1,4 dioxane, tetrahydrofuran；It is preferred that
Ground, pabishta intermediate shown in formula (II) is acetonitrile with the solvent that compound is reacted shown in formula (III) in step (1).
According to the preparation method of pabishta, pabishta intermediate and formula (III) shown in formula (II) are shown in step (1)
The temperature of compound reaction is room temperature.
In a specific embodiment, the present invention provides a kind of preparation method of pabishta, includes the following steps：
Step (1)：At room temperature, under the catalysis of DBU, pabishta intermediate shown in formula (II) and formula (III) shownization
Object reaction is closed, compound shown in formula (IV) is made, wherein pabishta intermediate shown in formula (II) and chemical combination shown in formula (III)
The molar ratio of object is 1:2, the molar ratio of pabishta intermediate and DBU shown in formula (II) are 1:2；
Step (2)：Pabishta is made with azanol reaction in compound shown in formula (IV), and reaction equation is as follows,
In formula, R1And R2Independently selected from C1-6Alkyl and hydrogen；Preferably, R1And R2Independently selected from methyl, ethyl, third
Base, isopropyl and hydrogen；It is further preferred that R1And R2Independently selected from methyl and ethyl.
It is a discovery of the invention that catalyst DBU and its dosage influence reaction result very big, the present inventor's trial in step (1)
Other basic catalysts, such as sodium hydrogen, potassium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, DIPEA, are all unable to get formula
(IV) compound shown in, only using DBU as basic catalyst, and DBU dosages are no less than among pabishta shown in 2 times of formulas (II)
When body mole, compound can the reaction was complete shown in pabishta intermediate shown in formula (II) and formula (III), obtains formula (IV)
Shown compound.
Pabishta intermediate provided by the invention, using inexpensive 2- methyltryptamines, 4- halogenated methyl-benzaldehydes as raw material,
Reaction condition is mild, easy to operate, is suitble to large-scale production；Pa Bisi is prepared with pabishta intermediate provided by the invention
He, not only reaction step is few, high income, and reaction condition is mild, and without using metallic catalyst, purifying is easy, and is easy to pa
Than the quality control of his bulk pharmaceutical chemicals of department.
Specific embodiment
The preparation of 1 2- methyltryptamines of embodiment
Phenylhydrazine (19.8ml, 200mmol), absolute ethyl alcohol (120ml) are added in 500ml there-necked flasks, are heated to 35 DEG C, N2
The ethanol solution (25ml) of the chloro- 2 pentanones of 5- (25ml, 210mmol) is added dropwise in protection, is added after being warming up to 40 DEG C of reaction 30min
Ethyl alcohol 160ml is to slowly warm up to back flow reaction 4h, and solvent is spin-dried for after suction filtration, and water (50ml) is added to use 2M hydrochloric acid solution tune Ph to acid afterwards
Property, ethyl acetate (50ml*2) extraction discards organic phase, water phase 20%NaOH solution tune pH to alkalinity, ethyl acetate
(50ml*2) is extracted, and merges organic phase, is washed respectively with water (50ml*2) and saturation chlorinated solution (50ml*2), anhydrous sodium sulfate
It is filtered after drying, is spin-dried for obtaining red oil 24.2g, yield 70.1%.
The preparation of 2 4- of embodiment [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] benzaldehyde
By 2- methyltryptamines (0.26g, 1.5mmol), DMF (5ml), potassium carbonate (0.41g, 3mmol) is added sequentially to
In 10ml single port bottles, N2Under protection, the DMF solution (2ml) of 4- bromomethyls benzaldehyde (0.1g, 0.5mmol) is added dropwise.0 DEG C of reaction
3h pours into reaction solution in water (10ml), ethyl acetate (10ml*3) extraction, merges organic phase, uses water (10ml*3) full successively
It washs with sodium chloride solution (10ml*3), is filtered after anhydrous sodium sulfate drying, filtrate decompression is evaporated, and obtains faint yellow solid 0.29g,
Yield 68.0%.
1H NMR(600MHz,DMSO-d6)(δ,ppm):2.30(s,3H),2.72(m,2H),2.82(m,2H),3.76(s,
3H),6.82-6.95(m,2H),7.20(d,1H),7.32(d,1H),7.56(d,2H),7.82(d,2H),9.96(brs,1H),
10.68(s,1H)。
ESI–MS:m/z 293.0[M+H]+。
The preparation of 3 4- of embodiment [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] benzaldehyde
By 2- methyltryptamines (0.17g, 1.0mmol), DMF (5ml), potassium carbonate (0.41g, 3mmol) is added sequentially to
In 10ml single port bottles, N2Under protection, the DMF solution (2ml) of 4- chloromethylbenzenes formaldehyde (0.08g, 0.5mmol) is added dropwise.10 DEG C anti-
3h is answered, reaction solution is poured into water (10ml), ethyl acetate (10ml*3) extraction merges organic phase, uses water (10ml*3) successively
Saturated nacl aqueous solution (10ml*3) washs, and is filtered after anhydrous sodium sulfate drying, filtrate decompression is evaporated, and obtains faint yellow solid
0.26g, yield 60%.
The preparation of 4 4- of embodiment [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] benzaldehyde
By 2- methyltryptamines (0.43g, 2.5mmol), DMF (5ml), potassium carbonate (0.41g, 3mmol) is added sequentially to
In 10ml single port bottles, N2Under protection, the DMF solution (2ml) of 4- bromomethyls benzaldehyde (0.1g, 0.5mmol) is added dropwise.It is anti-at room temperature
3h is answered, reaction solution is poured into water (10ml), ethyl acetate (10ml*3) extraction merges organic phase, uses water (10ml*3) successively
Saturated nacl aqueous solution (10ml*3) washs, and is filtered after anhydrous sodium sulfate drying, filtrate decompression is evaporated, and obtains faint yellow solid
0.30g, yield 70.0%.
Embodiment 5 (E) -3- [4- [[2- (2- Methyl-1H-indole -3-3 bases) ethylamino-] methyl] phenyl] methyl acrylate
Preparation
By phosphonium mesitoyl methyl acetate diethyl (0.7g, 3mmol), lithium chloride (0.06g, 1.5mmol), acetonitrile 4.5ml,
DBU (0.47g, 3mmol) is sequentially added in 50ml eggplant-shape bottles, N215min is stirred at room temperature in protection, and 4- (((2- (2- methyl-is added dropwise
1H- indol-3-yls) ethyl) amino) methyl) benzaldehyde (0.45g, 1.5mmol) acetonitrile (5ml) solution, react 2h, be spin-dried for
Solvent adds water (10ml), ethyl acetate (5ml*3) extraction to merge organic phase, use water (5ml*3) saturated nacl aqueous solution successively
(5ml*3) is washed, and is filtered after anhydrous sodium sulfate drying, filtrate decompression is evaporated, and obtains pale red grease 0.31g, yield 57.2%.
1H NMR(600MHz,DMSO-d6)(δ,ppm):2.34(s,3H),2.92(m,2H),3.17(m,2H),3.74(s,
3H),4.21(t,2H),6.72(d,1H),7.01(m,2H),7.25(d,1H),7.46(d,1H),7.65(d,2H),7.69(d,
1H),7.80(d,2H),9.59(brs,2H),10.90(s,1H)；13C NMR(150MHz,DMSO-d6)(δ,ppm):11.6,
21.0,47.4,49.8,52.0,66.8,105.6,111.0,117.6,118.7,119.0,120.6,128.2,128.9,
130.9,133.1,134.9,135.6,144.2,167.0。
ESI–MS:m/z 349.0[M+H]+。
The preparation of 6 pabishta of embodiment
By (2E) -3- (4- (((2- (2- Methyl-1H-indole -3- bases) ethyl) amino) methyl) phenyl) -2- acrylic acid first
Ester (0.48g, 1.4mmol) is placed in 50ml single port bottles, and the KOH solution (8.2ml, 14mmol) of azanol methanol, N is added2Protection, room
Temperature reaction 4h is filtered with dilute hydrochloric acid solution tune pH7-8, and filter cake is washed with water, dry faint yellow solid 0.3g, yield
62.5%.
1H NMR(600MHz,DMSO-d6)(δ,ppm):2.31(s,3H),2.69(t,2H),2.81(t,2H),3.77(s,
2H),6.45(d,1H),6.90(m,1H),6.95(m,1H),7.22(d,1H),7.38(m,3H),7.44(d,1H),7.49(d,
2H),10.70(brs,1H).；13C NMR(150MHz,CDCl3)(δ,ppm):11.7,24.7,50.0,52.8,108.5,
110.8,117.8,118.4,118.8,120.3,127.7,128.8,128.9,132.2,133.6,135.6,138.6,
142.7,163.2。
ESI–MS:m/z 350.0[M+H]+。
Claims (10)
1. a kind of pabishta intermediate, shown in structural formula such as formula (II)：
2. the preparation method of pabishta intermediate described in claim 1, including：0 DEG C~at room temperature, 2- methyltryptamines or its
4- halogenated methyl-benzaldehydes are obtained by the reaction shown in salt and formula (I), and reaction equation is as follows：
In formula, X is halogen；Preferably, X is selected from chlorine, bromine.
3. the preparation method of pabishta intermediate as claimed in claim 2, it is characterised in that：2- methyltryptamines or its salt and
The temperature of 4- halogenated methyl-benzaldehydes reaction is 0 DEG C~10 DEG C.
4. the preparation method of pabishta intermediate as claimed in claim 2, it is characterised in that：2- methyltryptamines or its salt and
The molar ratio of 4- halogenated methyl-benzaldehydes is 2~5:1；Preferably, 2- methyltryptamines or its salt and 4- halogenated methyl-benzaldehydes
Molar ratio is 3:1.
5. the preparation method of pabishta intermediate as claimed in claim 2, it is characterised in that：2- methyltryptamines or its salt and
The solvent of 4- halogenated methyl-benzaldehydes reaction is DMF.
6. the method that pabishta intermediate described in claim 1 prepares pabishta, includes the following steps：
Step (1)：Under the catalysis of DBU, pabishta intermediate shown in formula (II) is reacted with compound shown in formula (III), system
Obtain compound shown in formula (IV)；
Step (2)：Pabishta is made with azanol reaction in compound shown in formula (IV), and reaction equation is as follows,
In formula, R1And R2Independently selected from C1-6Alkyl and hydrogen；Preferably, R1And R2Independently selected from methyl, ethyl, propyl, isopropyl
Base and hydrogen；It is further preferred that R1And R2Independently selected from methyl and ethyl.
7. the method for preparing pabishta as claimed in claim 6, it is characterised in that：Pa Bisi shown in formula (II) in step (1)
The molar ratio of his intermediate and compound shown in formula (III) is 1:1.5~3；Preferably, pa ratio shown in formula (II) in step (1)
The molar ratio for taking charge of his intermediate and compound shown in formula (III) is 1:2.
8. the method for preparing pabishta as claimed in claim 6, it is characterised in that：Pa Bisi shown in formula (II) in step (1)
The molar ratio of his intermediate and DBU are not more than 1:2；Preferably, pabishta intermediate and DBU shown in formula (II) in step (1)
Molar ratio be 1:2.
9. the method for preparing pabishta as claimed in claim 6, it is characterised in that：Pa Bisi shown in formula (II) in step (1)
His intermediate and the solvent that compound is reacted shown in formula (III) be selected from acetonitrile, dichloromethane, ethyl acetate, 1,4 dioxane,
Tetrahydrofuran；Preferably, pabishta intermediate shown in formula (II) reacts molten with compound shown in formula (III) in step (1)
Agent is acetonitrile.
10. the method for preparing pabishta as claimed in claim 6, it is characterised in that：Pa Bisi shown in formula (II) in step (1)
His intermediate is room temperature with the temperature that compound is reacted shown in formula (III).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110194769A (en) * | 2019-06-19 | 2019-09-03 | 重庆医科大学 | A kind of bis- target spot inhibitor of HDAC, CDK and the preparation method and application thereof |
| CN113387866A (en) * | 2021-06-18 | 2021-09-14 | 山东汇海医药化工有限公司 | Preparation method of panobinostat |
-
2018
- 2018-07-19 CN CN201810796864.7A patent/CN108794375A/en active Pending
Non-Patent Citations (6)
| Title |
|---|
| （美）李杰: "《有机人名反应及机理》", 30 September 2003, 华东理工大学出版社 * |
| （英）卡拉瑟斯等: "《当代有机合成方法》", 31 March 2006, 华东理工大学出版社 * |
| KAORI ANDO ET AL.: "Solvent-free Horner-Wadsworth-Emmons reaction using DBU", 《TETRAHEDRON LETTERS》 * |
| MANKIL JUNG ET AL.: "Design, synthesis, and discovery of stilbene derivatives based on lithospermic acid B as potent protein tyrosine phosphatase 1B inhibitors", 《BIOORG. MED. CHEM. LETT.》 * |
| SHANWEN CHEN ET AL.: "An improved and efficient synthesis of panobinostat", 《JOURNAL OF CHEMICAL RESEARCH》 * |
| 刘倩等: "帕比司他的合成", 《中国医药工业杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110194769A (en) * | 2019-06-19 | 2019-09-03 | 重庆医科大学 | A kind of bis- target spot inhibitor of HDAC, CDK and the preparation method and application thereof |
| CN110194769B (en) * | 2019-06-19 | 2021-12-10 | 重庆医科大学 | HDAC (Histone deacetylase) and CDK (CDK) double-target inhibitor as well as preparation method and application thereof |
| CN113387866A (en) * | 2021-06-18 | 2021-09-14 | 山东汇海医药化工有限公司 | Preparation method of panobinostat |
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