CN105503884B - A kind of synthetic method for being used to synthesize the key intermediate of BET protein inhibitors - Google Patents
A kind of synthetic method for being used to synthesize the key intermediate of BET protein inhibitors Download PDFInfo
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- CN105503884B CN105503884B CN201610088225.6A CN201610088225A CN105503884B CN 105503884 B CN105503884 B CN 105503884B CN 201610088225 A CN201610088225 A CN 201610088225A CN 105503884 B CN105503884 B CN 105503884B
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
It is used to synthesize BET protein inhibitors the present invention relates to one kind, particularly suppresses BRD4 5 aryl triazoles and azepineKey intermediate synthetic method, compound 1 is through methylation reaction, and condensation, cyclization obtains compound II；The preparation method of compound 4 is changed, the selectivity that hydrazides reacts is improved by introducing methyl mercapto；Compared with prior art, variation route reaction condition is gentle, and operation is simple, and post processing is easy, and centre need not be purified, and three step high incomes are up to 80%；Compared with prior art, compound II purification process is changed, key intermediate II is purified by the method for crystallization and recrystallization, high purity 99% while simplifying post processing, has saved resource, reduced cost.The method of the present invention is a brand-new synthetic route capable of being industrialized, and the inventive method has good methodology meaning to developing new BET protein inhibitors.
Description
Technical field
It is used to synthesize BET protein inhibitors the present invention relates to one kind, particularly suppresses BRD4 5- aryl triazoles and azepineKey intermediate synthetic method, be further 1-R2Substitution -4,5- dihydros -6H- [1,2,4] triazol [4,
3-a] [1] benzo-azaThe synthetic method of -6- ketone, the invention belongs to organic synthesis field.
Background technology
BET protein families are the 2nd classes of BRD protein families, including BRD2, BRD3, BRD4 and BRDT.Studies have shown that BET
Albumen is combined with the acetylated lysine of histone, adjusts the genetic transcription related with cell growth to the cell cycle.The mankind are permitted
The generation of many diseases all has close relationship with BET albumen, and research is found, includes AML, Burkitt in hematopoietic system cancer
In the model of lymthoma, Huppert's disease and B cell acute lymphatic leukemia, by disturbing BRD4 and oncogene MYC
Combination can suppress MYC expression.Therefore, BET protein families are due to the potential value in anti-inflammatory and anti-tumor aspect, day
Benefit is as one of important target in epigenetic field.
Beyer Co., Ltd develops a kind of new BET protein inhibitor 5- aryl triazoles and azepineDerivative
(WO2014048945A1), its structure is effective to multiple myeloma models as shown in following formula I, to the inhibitory activity of BRD4 (1)
Increase significantly, interaction of the BET albumen (particularly BRD4) between the peptide of acetylation histone 4, suppression can be prevented
The growth of cancer processed and tumour cell.
Compound 1-R shown in formula II2Substitution -4,5- dihydros -6H- [1,2,4] triazol [4,3-a] [1] benzene
And azepine- 6- ketone, is the key intermediate for preparing BET protein inhibitors.
Synthesis for key intermediate compound II only has WO2014048945A1 to be reported, is shown below.
By known compound benzo-azaThe reaction of diketone and lawesson reagent obtains thio lactam compound II-2, then with the institute of Formula II -3
The hydrazides reaction generation triazole ring shown obtains key intermediate II.During compound II-2 and compound II-3 reactions, there are 6 carbonyls
Base group is converted into the side reaction of acylhydrazone, and by compound II-4 cyclization prepare compound II when, using n-butanol as solvent, need
To be stirred 16 hours at a high temperature of 150 DEG C, severe reaction conditions, operational ton is smaller, milligram rank is to 24g ranks, and yield is low
(the two step yield 13.9%-44% from compound II-2 to compound II), and using silica gel column chromatography method to compound II
Purified, it is clear that be not suitable for industry's enlarging production.
In summary, the BET protein inhibitor 5- aryl triazoles and azepine reported at presentThe key intermediate of derivative I
II synthetic route has severe reaction conditions, and yield is low, purifies cumbersome wait and restricts its amplification factor of production.Technique metaplasia
Efficient, easy method is highly desirable in production and prepares intermediate II, for preparing BET protein inhibitors I.
The content of the invention
It is an object of the invention to provide a kind of BET protein inhibitors 5- aryl triazoles and azepineThe intermediate of derivative
Synthetic method, is further 1-R2Substitution -4,5- dihydros -6H- [1,2,4] triazol [4,3-a] [1] benzo-aza-
6- assimilation compounds II synthetic method.
Wherein, R1Represent hydrogen, hydroxyl, substituted or non-substituted C1-C6Alkyl, substituted or non-substituted C3-C8- cycloalkanes
Base, substituted or non-substituted C1-C6Alkoxy, substituted or non-substituted C3-C8Heterocyclylalkyl, halogen (herein means fluorine, chlorine,
Bromine, iodine) etc., preferably hydrogen, methoxyl group, bromine, 3,5- dimethyl -1,2- oxazole -4- bases, trifluoromethoxy；R2Represent hydrogen, C1-
C6- alkyl or-NR5R6, preferably methyl, wherein R5、R6Hydrogen or same or different substitution are represented independently of one another or non-are taken
The C in generation1-C6- alkyl.
The preparation method of the present invention is described more particularly below.However, it should be understood that the invention is not limited in given below
The specific reaction condition gone out (such as the time required to the amount of solvent, compound used therefor, reaction temperature, reaction).
The preparation method of the present invention can be represented with below scheme：
1. compound 1 is in the basic conditions, in organic solvent, reacted with methylating reagent, prepare compound 2,
Wherein, R1It is as defined above；The alkali is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium acid carbonate, saleratus, hydrogen-oxygen
Change sodium, the inorganic base such as potassium hydroxide, or sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, triethylamine, DBU, pyridine, DIEA
Deng organic base, preferably potassium carbonate, sodium carbonate；The alkali and the equivalent proportion 1~3 of compound 1:1, preferably 2:1；
Described methylating reagent is selected from iodomethane, dimethyl suflfate, dimethyl carbonate, methyl mesylate, fluoroform
Methylmesylate, preferably iodomethane.The methylating reagent is 1~2 with the equivalent proportion of compound 1:1, preferably 1:1；
Described organic solvent be selected from methanol, ethanol, acetone, dichloromethane, tetrahydrofuran, acetonitrile, ether, benzene, toluene,
Any combination of DMF, DMAC, DMSO or above-mentioned solvent, preferably DMF, DMAC；
The reaction temperature is 0~50 DEG C, preferably 20~50 DEG C；The reaction time is untill detecting that reaction is completed；
The compound 1 method with reference to described in WO2014048945A1 is synthesized.
After reaction terminates, ethyl acetate will be added after reacting liquid filtering, and uses water, saturated common salt water washing according to this, it is anhydrous
Magnesium sulfate dries organic phase, and filtering and concentrating obtains crude solid compound 2, and obtained crude product 2 can be directly used for next step reaction.
2. compound 2 is in organic solvent, prepare compound 4 is reacted with compound 3,
Wherein, R1, R2It is as defined above；The organic solvent is selected from methanol, ethanol, n-butanol, isopropanol, toluene, diethyl
Glycol dimethyl ether, the preferably any combination of DMF or above-mentioned solvents, ethanol；
The equivalent proportion of compound 3 and compound 2 is 1.5~3.5:1, preferably 2~3:1；
The reaction time is untill detecting that reaction is completed；
After reaction terminates, reaction system separates out a large amount of solids, and after filtering, filter cake is washed with ethanol, ether according to this, and vacuum is done
It is dry to obtain compound as white solid 4, high purity 97%.
3. compound 4 is in acid condition, in organic solvent cyclization prepare compound II,
Wherein, R1, R2It is as defined above；It is described acid be selected from acetic acid, p-methyl benzenesulfonic acid, trifluoroacetic acid, hydrochloric acid, camphorsulfonic acid,
It is preferred that acetic acid；The organic solvent be selected from methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, DMF, toluene, dimethylbenzene, 1,
Any combination of 2- dichloroethanes, dioxane, acetic acid, trifluoroacetic acid, hydrochloric acid or above-mentioned solvent, preferably acetic acid, n-butanol；
After reaction terminates, concentration of reaction solution under vacuum condition is down to after room temperature, adds methyl tertiary butyl ether(MTBE) and petroleum ether is mixed
Bonding solvent, separates out a large amount of faint yellow crude Compound II, after filtering, crude Compound II is recrystallized to give in isopropanol pure
Product solid chemical compound II, high purity 99%, crystalline mother solution carries out secondary crystallization after can concentrating and prepares sterling solid chemical compound II.
The advantage of the inventive method is essentially consisted in
1) compared with prior art, change the preparation method of compound 4, the selection that hydrazides reacts is improved by introducing methyl mercapto
Property, it is to avoid 6 carbonyl groups present in prior art are converted into the side reaction of acylhydrazone；Reaction terminates rear crude Compound
4 separate out in solid, after filtering, filter cake is washed with ethanol, ether successively and can obtain sterling compound 4, high purity 97%；
2) compared with prior art, variation route reaction condition is gentle, and operation is simple, and post processing is easy, and centre need not be pure
Change, three step high incomes are up to 80%；
3) compared with prior art, compound II purification process is changed, is purified by the method for crystallization and recrystallization crucial
Intermediate II, high purity 99% while simplifying post processing, has saved resource, has reduced cost.
This method is a brand-new synthetic route capable of being industrialized.Meanwhile, the route suppresses to developing new BET albumen
Agent has good methodology meaning.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part is carried out.
Raw material used or reagent are commercially available in addition to special instruction in embodiment.
Room temperature described in embodiment refers both to 20~35 DEG C.Unless otherwise indicated, described reagent is not purified directly makes
With.All solvents are purchased from commercialization supplier, such as aldrich (Aldrich), and just can be used without processing.Reaction
Analyzed and/or analyzed by LC-MS by TLC, the termination of reaction is judged by the consumption of parent material.The thin layer of analysis
Chromatography (TLC) is the glass plate (EMD chemical companies (EMD Chemicals)) in 60F2540.25 millimeters of plates of pre-coated silica gel
Upper progress, with the iodine developing on UV light (254nm) and/or silica gel, and/or with TLC product dyed therebies such as alcohol phosphomolybdic acid, hydration indenes
Triketone solution, liquor potassic permanganate or ceric sulfate solution are heated together.
1H-NMR spectrums are on ten thousand Ruian-Mo Qiuli-VX400 (Varian Mercury-VX400) instrument, in 400MHz behaviour
Make lower record.
The abbreviation used in the present invention has this area conventional sense, such as：DCM represents dichloromethane, and DMSO represents diformazan
Base sulfoxide, DMAC represents DMA, and EA represents ethyl acetate, and DBU represents 1,8- diazabicyclos [5.4.0] ten
One carbon -7- alkene, DIEA represents DIPEA.DMF represents N,N-dimethylformamide.
Embodiment 1：The preparation of compound 6
Compound 5 (700g, 3.66mol) is dissolved in DMAC (7L), potassium carbonate (1kg, 7.32mol), ice-water bath is added
Under the conditions of be slowly added dropwise after iodomethane (230ml), completion of dropping, reaction system is warmed to room temperature, is stirred overnight.TLC detections are anti-
After the completion of answering, EA will be added after reacting liquid filtering, and uses water, saturated common salt water washing according to this, anhydrous sodium sulfate drying is concentrated to give
To 2.5kg yellow solid crude products, without purifying, next step reaction is directly carried out.
1H NMR(400MHz,CDCl3):δ7.80-7.75(m,1H),7.55-7.49(m,1H),7.21-7.14(m,2H),
3.00-2.94(m,2H),2.77-2.72(m,2H),2.48(s,3H).
Embodiment 2：The preparation of compound 7
Compound 6 obtained by upper step is dissolved in ethanol (7.5L), add stirred under acethydrazide (820g), room temperature condition to
TLC detection reactions are completed, and reaction system separates out a large amount of white solids, and after reacting liquid filtering, filter cake is washed with ethanol, ether successively
Wash, vacuum drying obtains compound as white solid 7 (785g, purity 97%, two step yields 90%).It need not be further purified, can
Directly carry out next step reaction.
1H-NMR(400MHz,DMSO):δ11.24(s,1H),9.82(s,1H),7.75-7.65(m,1H),7.60-7.45
(m,2H),7.15-7.05(m,1H),2.90-2.80(m,2H),2.75-2.63(m,2H),1.99(s,3H).
Embodiment 3：The preparation of compound 8
Compound 7 obtained by upper step is dissolved in glacial acetic acid (8L), is stirred overnight under the conditions of 100 DEG C, TLC detection compounds 7
Reaction is complete.Concentration of reaction solution under vacuum condition, is down to after room temperature, adds methyl tertiary butyl ether(MTBE) and petroleum ether mixed solvent, analysis
Go out a large amount of faint yellow solids, filter, gained filter cake is recrystallized to give faint yellow solid target compound under the conditions of isopropanol
8,553g (purity 99%) is weighed as after solid is dried, after crystalline mother solution is concentrated, recrystallisation from isopropanol obtains pale yellow colored solid
Body target compound 8, is weighed as 105g (purity is 93%), total recovery 89% after solid is dried.
1H NMR(400MHz,CDCl3):δ7.84-7.80(dd,1H),7.76-7.70(dt,1H),7.59-7.53(dt,
1H),7.33-7.28(dd,1H),3.28-3.22(m,2H),3.09-3.03(m,2H),2.55(s,3H).
Embodiment 4：The preparation of compound 10
Compound 9 (96g, 370mmol) is dissolved in DMF (1L), sodium carbonate (117.66g, 1.11mol), frozen water is added
It is slowly added dropwise under the conditions of bath after Methyl triflate (84ml), completion of dropping, reaction system is warmed to room temperature, is stirred overnight.
After the completion of TLC detection reactions, EA will be added after reacting liquid filtering, and uses water, saturated common salt water washing according to this, anhydrous sodium sulfate is done
It is dry, 130g yellow solid crude products are concentrated to give, without purifying, next step reaction are directly carried out.ESI/MS:M/z=274.04 (M
+H)+。
Embodiment 5：The preparation of compound 11
Compound 10 obtained by upper step is dissolved in n-butanol (500mL), adds under acethydrazide (80g), room temperature condition and stirs
Completed to TLC detection reactions, reaction system separates out a large amount of white solids, after reacting liquid filtering, and filter cake uses ethanol, ether successively
Washing, vacuum drying obtains compound as white solid 11 (100.2g, purity 95%, two step yields 86%).Without further pure
Change, can directly carry out next step reaction.ESI/MS:M/z=300.10 (M+H)+。
Embodiment 6：The preparation of compound 12
Compound 11 obtained by upper step is dissolved in n-butanol (1L), HCl gas is passed through under room temperature condition 2 hours, 80 DEG C of bars
It is stirred overnight under part, TLC detection compounds 11 react complete.Concentration of reaction solution under vacuum condition, is down to after room temperature, adds methyl
Tertbutyl ether and petroleum ether mixed solvent, separate out a large amount of faint yellow solids, and filtering ties gained filter cake again under the conditions of isopropanol
Crystalline substance obtains faint yellow solid target compound 12, and 64.5g (purity 97%) is weighed as after solid is dried, crystalline mother solution is concentrated
Afterwards, recrystallisation from isopropanol obtains faint yellow solid target compound 12, and 15g (purity is 92%) is weighed as after solid is dried,
Total recovery 85.3%.
1H NMR(400MHz,CDCl3):δ7.66(d,1H),7.54(dd,1H),7.30(d,1H),3.28-3.22(m,
2H),3.10-3.03(m,2H),2.55(s,3H).
Embodiment 7：The preparation of compound 14
Compound 13 (88g, 398mmol) is dissolved in toluene (800mL), cesium carbonate (130g, 398mmol), ice is added
It is slowly added dropwise under water bath condition after iodomethane (28ml), completion of dropping, reaction system is risen to 50 DEG C, stirring is anti-to TLC detections
It should complete.It will be concentrated after reacting liquid filtering, add EA dilutions, and use water, saturated common salt water washing according to this, anhydrous sodium sulfate is done
It is dry, 110g crude solids are concentrated to give, without purifying, next step reaction are directly carried out.ESI/MS:M/z=236.10 (M+H)+。
Embodiment 8：The preparation of compound 15
Compound 14 obtained by upper step is dissolved in isopropanol (500L), add stirred under acethydrazide (45g), room temperature condition to
TLC detection reactions are completed, and reaction system separates out a large amount of white solids, and after reacting liquid filtering, filter cake is washed with ethanol, ether successively
Wash, vacuum drying obtains compound as white solid 15 (97g, purity 94%, two step yields 88%).It need not be further purified, can
Directly carry out next step reaction.ESI/MS:M/z=262.11 (M+H)+。
Embodiment 9：The preparation of compound 16
Compound 15 obtained by upper step is dissolved in ethanol (200mL) and acetic acid (500ml), is stirred overnight under the conditions of 80 DEG C,
TLC detection compounds 15 react complete.Concentration of reaction solution under vacuum condition, is down to after room temperature, adds methyl tertiary butyl ether(MTBE) and stone
Oily ether mixed solvent, separates out a large amount of faint yellow solids, and gained filter cake is recrystallized to give targeted by filtering under the conditions of isopropanol
Compound 16, is weighed as 62.3g (purity 98%), after crystalline mother solution is concentrated, recrystallisation from isopropanol obtains light after solid is dried
Yellow solid target compound 16, is weighed as 9.95g (purity is 94%), total recovery 77% after solid is dried.
1H NMR(400MHz,CDCl3):δ7.27(bs,1H),7.20(bs,2H),3.92(s,3H),3.28-3.20(m,
2H),3.10-3.00(m,2H),2.53(s,3H).
All documents referred in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can
To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (10)
1. a kind of 1-R2Substitution -4,5- dihydros -6H- [1,2,4] triazol [4,3-a] [1] benzo-azaThe synthesis side of -6- ketone
Method, it is characterised in that comprise the steps of：
Step 1, compound 1 in the basic conditions, in organic solvent, is reacted, prepare compound 2 with methylating reagent,
Step 2, compound 2 in organic solvent, prepare compound 4 is reacted with compound 3,
Step 3, compound 4 in acid condition, cyclization prepare compound II in organic solvent,
Wherein, R1Selected from hydrogen, hydroxyl, substituted or non-substituted C1-C6Alkyl, substituted or non-substituted C3-C8- cycloalkyl, takes
Generation or non-substituted C1-C6Alkoxy, substituted or non-substituted C3-C8Heterocyclylalkyl, halogen；R2Selected from hydrogen, C1-C6- alkane
Base or-NR5R6, the R5、R6Hydrogen or same or different substituted or non-substituted C are represented independently of one another1-C6- alkyl.
2. synthetic method as claimed in claim 1, it is characterised in that R1Selected from hydrogen, methoxyl group, trifluoromethoxy, R2For methyl.
3. synthetic method as claimed in claim 1 or 2, it is characterised in that in step 1, the alkali is selected from potassium carbonate, sodium carbonate,
Cesium carbonate, sodium acid carbonate, saleratus, sodium hydroxide, potassium hydroxide, or sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide,
Triethylamine, DBU, pyridine, DIEA.
4. synthetic method as claimed in claim 3, it is characterised in that the alkali and the equivalent proportion 1~3 of compound 1:1.
5. synthetic method as claimed in claim 1 or 2, it is characterised in that in step 1, described methylating reagent is selected from iodine first
Alkane, dimethyl suflfate, dimethyl carbonate, methyl mesylate, trifluoromethayl sulfonic acid methyl esters.
6. synthetic method as claimed in claim 5, it is characterised in that the methylating reagent is 1~2 with the equivalent proportion of compound 1:
1。
7. synthetic method as claimed in claim 1 or 2, it is characterised in that the organic solvent described in step 1 is selected from methanol, second
Alcohol, acetone, dichloromethane, tetrahydrofuran, acetonitrile, ether, benzene, toluene, DMF, DMAC, any group of DMSO or above-mentioned solvents
Close.
8. synthetic method as claimed in claim 1 or 2, it is characterised in that in step 2, the organic solvent is selected from methanol, second
Alcohol, n-butanol, isopropanol, toluene, diethylene glycol dimethyl ether, any combination of DMF or above-mentioned solvents；Compound 3 and compound 2
Equivalent proportion be 1.5~3.5:1.
9. synthetic method as claimed in claim 1 or 2, it is characterised in that in step 3, the acid is selected from acetic acid, to toluene sulphur
Acid, trifluoroacetic acid, hydrochloric acid, camphorsulfonic acid；The organic solvent be selected from methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran,
Any combination of DMF, toluene, dimethylbenzene, 1,2- dichloroethanes, dioxane, acetic acid, trifluoroacetic acid, hydrochloric acid or above-mentioned solvent.
10. synthetic method as claimed in claim 1 or 2, it is characterised in that in step 3, after reaction terminates, in addition to following place
Manage step：Concentration of reaction solution under vacuum condition, is down to after room temperature, adds methyl tertiary butyl ether(MTBE) and petroleum ether mixed solvent, filtering
After the solid of precipitation, recrystallize to obtain sterling solid chemical compound II in isopropanol.
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| CP02 | Change in the address of a patent holder |
Address after: 3 / F, building 8, No.15 and 16, Lane 1999, zhangheng Road, China (Shanghai) pilot Free Trade Zone, 201203 Patentee after: MEDCHEMEXPRESS CHINA Co.,Ltd. Address before: Room 502, Lane 720, Cailun Road, Zhangjiang High-tech Park, Pudong New Area, Shanghai, 201203 Patentee before: MEDCHEMEXPRESS CHINA Co.,Ltd. |