CN105503884A - Method for synthesizing key intermediate of BET protein inhibitor - Google Patents
Method for synthesizing key intermediate of BET protein inhibitor Download PDFInfo
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- CN105503884A CN105503884A CN201610088225.6A CN201610088225A CN105503884A CN 105503884 A CN105503884 A CN 105503884A CN 201610088225 A CN201610088225 A CN 201610088225A CN 105503884 A CN105503884 A CN 105503884A
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- MAVVIXZBENEGPU-UHFFFAOYSA-N CSC(CC1)=Nc2ccccc2C1=O Chemical compound CSC(CC1)=Nc2ccccc2C1=O MAVVIXZBENEGPU-UHFFFAOYSA-N 0.000 description 1
- BSOCBMPQXDFISC-UHFFFAOYSA-N O=C(CC1)c(cccc2)c2NC1=S Chemical compound O=C(CC1)c(cccc2)c2NC1=S BSOCBMPQXDFISC-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
The invention relates to a method for synthesizing a key intermediate of a BET protein inhibitor, in particular to a synthetic method for the key intermediate of 5-aryl triazoloazepine inhibiting BRD4. The method comprises the steps that a methylation reaction is conducted on a compound 1, condensation and ring closing are conducted, and a compound II is obtained; a preparation method of a compound 4 is changed, and the selectivity of a hydrazide reaction is improved by introducing methylthio; compared with the prior art, the reaction condition of a new route is mild, reaction operation is easy, aftertreatment is simple and convenient, purification is not needed during the process, and the three-step yield is up to 80%; compared with the prior art, a purification method of the compound II is changed, the key intermediate II is purified through a crystallization and recrystallization method, the purity is up to 99%, aftertreatment is simplified, resources are saved, and the cost is reduced. The method for synthesizing the key intermediate of the BET protein inhibitor is a brand new industrialized synthetic route, and the method has good methodology significance in developing a new BET protein inhibitor. Please see the formula in the description.
Description
Technical field
The present invention relates to a kind of for the synthesis of BET protein inhibitor, particularly suppress the 5-aryl triazoles of BRD4 and azepine
the synthetic method of key intermediate, be further 1-R
2replace-4,5-dihydro-6H-[1,2,4] triazolo [4,3-a] [1] benzo-aza
the synthetic method of-6-ketone, the invention belongs to organic synthesis field.
Background technology
BET protein family is the 2nd class of BRD protein family, comprises BRD2, BRD3, BRD4 and BRDT.Research display, BET albumen is combined with the acetylated lysine of histone, regulates the genetic transcription relevant to cell cycle and Growth of Cells.The generation of mankind's numerous disease all has close relationship with BET albumen, research finds, comprise in the model of AML, Burkitt lymphoma, multiple myeloma and B cell kemia at hematopoietic system cancer, by the expression disturbing the combination of BRD4 and oncogene MYC can suppress MYC.Therefore, BET protein family, due to the potential value at anti-inflammatory and anti-tumor aspect, becomes one of important target in epigenetic field day by day.
Beyer Co., Ltd develops a kind of new BET protein inhibitor 5-aryl triazoles and azepine
derivative (WO2014048945A1); its structure is as shown in the formula shown in I; effective to multiple myeloma models; the inhibit activities of BRD4 (1) is increased significantly; the interaction between BET albumen (particularly BRD4) and acetylize tissue protein 4 peptide can be stoped, suppress the growth of cancer and tumour cell.
Compound 1-R shown in following formula structure I I
2replace-4,5-dihydro-6H-[1,2,4] triazolo [4,3-a] [1] benzo-aza
-6-ketone is the key intermediate of preparation BET protein inhibitor.
Synthesis for key intermediate compound II only has WO2014048945A1 to report, is shown below.By known compound benzo-aza
diketone and lawesson reagent are obtained by reacting thio lactam Compound II per-2, then react with the hydrazides shown in formula II-3 and generate triazole ring and obtain key intermediate II.When Compound II per-2 and Compound II per-3 react, there is the side reaction that 6 carbonyl groups are converted into acylhydrazone, and when preparing Compound II per by Compound II per-4 pass ring, take propyl carbinol as solvent, need to stir 16 hours under the high temperature of 150 DEG C, severe reaction conditions, operational ton is less, milligram rank is to 24g rank, yield low (from Compound II per-2 to Compound II per two step yield 13.9%-44%), and all adopt silica gel column chromatography method to carry out purifying to Compound II per, be obviously not suitable for industry's enlarging production.
In sum, at present the BET protein inhibitor 5-aryl triazoles of report azepine
the synthetic route of the key intermediate II of derivative I also exists severe reaction conditions, and yield is low, and purifying is loaded down with trivial details waits its amplification factor of production of restriction.Technology is starved of efficient, easy method in producing and prepares intermediate II, for the preparation of BET protein inhibitor I.
Summary of the invention
The object of this invention is to provide a kind of BET protein inhibitor 5-aryl triazoles and azepine
the synthetic method of the intermediate of derivative is further 1-R
2replace-4,5-dihydro-6H-[1,2,4] triazolo [4,3-a] [1] benzo-aza
the synthetic method of-6-ketone compound II.
Wherein, R
1represent hydrogen, hydroxyl, substituted or non-substituted C
1-C
6alkyl, substituted or non-substituted C
3-C
8-cycloalkyl, substituted or non-substituted C
1-C
6alkoxyl group, substituted or non-substituted C
3-C
8heterocyclylalkyl, halogen (herein means fluorine, chlorine, bromine, iodine) etc., be preferably hydrogen, methoxyl group, bromine, 3,5-dimethyl-1,2-oxazole-4-bases, trifluoromethoxy; R
2represent hydrogen, C
1-C
6-alkyl or-NR
5r
6, be preferably methyl, wherein R
5, R
6represent hydrogen or identical or different substituted or non-substituted C independently of one another
1-C
6-alkyl.
Preparation method of the present invention is more specifically described below.However, it should be understood that the present invention is not limited to following given concrete reaction conditions (amount, temperature of reaction, reaction required time etc. as solvent, compound used therefor).
Preparation method of the present invention can represent by following flow process:
1. compound 1 is in the basic conditions, in organic solvent, reacts with methylating reagent, prepares compound 2,
Wherein, R
1definition is as front; Described alkali is selected from salt of wormwood, sodium carbonate, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, the mineral alkalis such as potassium hydroxide, or sodium hydrogen, sodium tert-butoxide, potassium tert.-butoxide, sodium methylate, triethylamine, DBU, pyridine, the organic basess such as DIEA, is preferably salt of wormwood, sodium carbonate; Described alkali and compound 1 equivalence ratio 1 ~ 3:1, be preferably 2:1;
Described methylating reagent is selected from methyl iodide, methyl-sulfate, methylcarbonate, methyl mesylate, trifluoromethayl sulfonic acid methyl esters, is preferably methyl iodide.Described methylating reagent and compound 1 equivalence ratio are 1 ~ 2:1, are preferably 1:1;
Described organic solvent is selected from methyl alcohol, ethanol, acetone, methylene dichloride, tetrahydrofuran (THF), acetonitrile, ether, benzene, toluene, the arbitrary combination of DMF, DMAC, DMSO or above-mentioned solvent, is preferably DMF, DMAC;
Described temperature of reaction is 0 ~ 50 DEG C, is preferably 20 ~ 50 DEG C; Till the described reaction times completes with detection reaction;
Described compound 1 synthesizes with reference to method described in WO2014048945A1.
After reaction terminates, add ethyl acetate by after reacting liquid filtering, and use water, saturated common salt water washing according to this, anhydrous magnesium sulfate drying organic phase, filtering and concentrating obtains crude solid compound 2, and the crude product 2 obtained can be directly used in next step reaction.
2. compound 2 is in organic solvent, reacts prepare compound 4 with compound 3,
Wherein, R
1, R
2definition as front; Described organic solvent is selected from methyl alcohol, ethanol, propyl carbinol, Virahol, toluene, diethylene glycol dimethyl ether, the arbitrary combination of DMF or above-mentioned solvent, is preferably ethanol;
The equivalence ratio of compound 3 and compound 2 is 1.5 ~ 3.5:1, is preferably 2 ~ 3:1;
Till the described reaction times completes with detection reaction;
After reaction terminates, reaction system separates out a large amount of solid, and after filtration, filter cake uses ethanol, washed with diethylether according to this, and vacuum-drying obtains compound as white solid 4, high purity 97%.
3. compound 4 is in acid condition, closes ring in organic solvent and prepares Compound II per,
Wherein, R
1, R
2definition as front; Described acid is selected from acetic acid, tosic acid, trifluoroacetic acid, hydrochloric acid, camphorsulfonic acid, preferred acetic acid; Described organic solvent is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, tetrahydrofuran (THF), DMF, toluene, dimethylbenzene, 1,2-ethylene dichloride, dioxane, acetic acid, trifluoroacetic acid, the arbitrary combination of hydrochloric acid or above-mentioned solvent, preferred acetic acid, propyl carbinol;
After reaction terminates, concentration of reaction solution under vacuum condition, after being down to room temperature, add methyl tertiary butyl ether and sherwood oil mixed solvent, separate out a large amount of faint yellow crude Compound II, after filtration, crude Compound II recrystallization in Virahol is obtained sterling solid chemical compound II, high purity 99%, carries out secondary crystal and prepares sterling solid chemical compound II after crystalline mother solution can concentrate.
The advantage of the inventive method is mainly
1) comparatively prior art, changes the preparation method of compound 4, improve the selectivity of hydrazides reaction, avoiding the side reaction that 6 carbonyl groups existed in prior art are converted into acylhydrazone by introducing methylthio group; Reaction terminates rear crude Compound 4 and separates out in solid, after filtration, can obtain sterling compound 4, high purity 97% successively with ethanol, washed with diethylether filter cake;
2) comparatively prior art, variation route reaction conditions is gentle, and operation is simple, and aftertreatment is easy, and centre does not need purifying, and three step yields are up to 80%;
3) comparatively prior art, changes the purification process of Compound II per, and by the method purifying key intermediate II of crystallization and recrystallization, high purity 99%, while simplifying aftertreatment, has saved resource, reduced cost.
Present method is a brand-new synthetic route capable of being industrialized.Meanwhile, this route has good methodology meaning to the new BET protein inhibitor of exploitation.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, conveniently condition is carried out usually.
Raw material used in embodiment or reagent except special instruction, all commercially.
Room temperature described in embodiment all refers to 20 ~ 35 DEG C.Unless otherwise indicated, the not purified direct use of described reagent.The equal available from commercial supplier of all solvents, such as aldrich (Aldrich), and not treatedly just can to use.Reaction is analyzed by TLC and/or is analyzed by LC-MS, is judged the termination of reacting by the consumption of parent material.The thin-layer chromatography (TLC) analyzed carries out on the sheet glass (EMD chemical company (EMDChemicals)) of pre-coated silica gel 60F2540.25 millimeter plate, with the iodine developing on UV light (254nm) and/or silica gel, and/or heat together with alcohol phospho-molybdic acid, ninidrine solution, potassium permanganate solution or ceric sulfate solution with TLC product dyed thereby.
1H-NMR spectrum is on ten thousand Ruian-Mo Qiuli-VX400 (VarianMercury-VX400) instrument, records under 400MHz operation.
The abbreviation used in the present invention has this area conventional sense, as: DCM represents methylene dichloride, DMSO represents dimethyl sulfoxide (DMSO), DMAC represents N,N-dimethylacetamide, and EA represents ethyl acetate, DBU represents 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene, DIEA represents DIPEA.DMF represents DMF.
Embodiment 1: the preparation of compound 6
Compound 5 (700g, 3.66mol) is dissolved in DMAC (7L), adds salt of wormwood (1kg, 7.32mol), methyl iodide (230ml) is slowly dripped under ice-water bath condition, after dropwising, reaction system is risen to room temperature, and stirring is spent the night.After TLC detection reaction completes, add EA by after reacting liquid filtering, and use water, saturated common salt water washing according to this, anhydrous sodium sulfate drying, concentrate and obtain 2.5kg yellow solid crude product, without the need to purifying, directly carry out next step reaction.
1HNMR(400MHz,CDCl
3):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
Upper step gained compound 6 is dissolved in ethanol (7.5L), add acethydrazide (820g), be stirred to TLC detection reaction under room temperature condition to complete, reaction system separates out a large amount of white solid, after reacting liquid filtering, filter cake uses ethanol, washed with diethylether successively, and vacuum-drying obtains compound as white solid 7 (785g, purity 97%, two step yields 90%).Without the need to being further purified, next step reaction directly can be carried out.
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
Be dissolved in Glacial acetic acid (8L) by upper step gained compound 7, stir under 100 DEG C of conditions and spend the night, TLC detection compound 7 reacts completely.Concentration of reaction solution under vacuum condition, after being down to room temperature, add methyl tertiary butyl ether and sherwood oil mixed solvent, separate out a large amount of faint yellow solid, filter, gained filter cake recrystallization under Virahol condition is obtained faint yellow solid target compound 8, to be weighed as 553g (purity 99%) after solid drying, after crystalline mother solution is concentrated, recrystallisation from isopropanol obtains faint yellow solid target compound 8,105g (purity is 93%) will be weighed as, total recovery 89% after solid drying.
1HNMR(400MHz,CDCl
3):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
By compound 9 (96g, 370mmol) be dissolved in DMF (1L), add sodium carbonate (117.66g, 1.11mol), Methyl triflate (84ml) is slowly dripped under ice-water bath condition, after dropwising, reaction system is risen to room temperature, stirring is spent the night.After TLC detection reaction completes, add EA by after reacting liquid filtering, and use water, saturated common salt water washing according to this, anhydrous sodium sulfate drying, concentrate and obtain 130g yellow solid crude product, without the need to purifying, directly carry out next step reaction.ESI/MS:m/z＝274.04(M+H)
+。
Embodiment 5: the preparation of compound 11
Upper step gained compound 10 is dissolved in propyl carbinol (500mL), add acethydrazide (80g), be stirred to TLC detection reaction under room temperature condition to complete, reaction system separates out a large amount of white solid, after reacting liquid filtering, filter cake uses ethanol, washed with diethylether successively, and vacuum-drying obtains compound as white solid 11 (100.2g, purity 95%, two step yields 86%).Without the need to being further purified, next step reaction directly can be carried out.ESI/MS:m/z＝300.10(M+H)
+。
Embodiment 6: the preparation of compound 12
Be dissolved in propyl carbinol (1L) by upper step gained compound 11, pass into HCl gas 2 hours under room temperature condition, stir under 80 DEG C of conditions and spend the night, TLC detection compound 11 reacts completely.Concentration of reaction solution under vacuum condition, after being down to room temperature, add methyl tertiary butyl ether and sherwood oil mixed solvent, separate out a large amount of faint yellow solid, filter, gained filter cake recrystallization under Virahol condition is obtained faint yellow solid target compound 12,64.5g (purity 97%) will be weighed as after solid drying, after crystalline mother solution is concentrated, recrystallisation from isopropanol obtains faint yellow solid target compound 12,15g (purity is 92%) will be weighed as, total recovery 85.3% after solid drying.
1HNMR(400MHz,CDCl
3):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
By compound 13 (88g, 398mmol) be dissolved in toluene (800mL), add cesium carbonate (130g, 398mmol), methyl iodide (28ml) is slowly dripped under ice-water bath condition, after dropwising, reaction system is risen to 50 DEG C, be stirred to TLC detection reaction and complete.By concentrated after reacting liquid filtering, add EA dilution, and use water, saturated common salt water washing according to this, anhydrous sodium sulfate drying, concentrate and obtain 110g crude solid, without the need to purifying, directly carry out next step reaction.ESI/MS:m/z＝236.10(M+H)
+。
Embodiment 8: the preparation of compound 15
Upper step gained compound 14 is dissolved in Virahol (500L), add acethydrazide (45g), be stirred to TLC detection reaction under room temperature condition to complete, reaction system separates out a large amount of white solid, after reacting liquid filtering, filter cake uses ethanol, washed with diethylether successively, and vacuum-drying obtains compound as white solid 15 (97g, purity 94%, two step yields 88%).Without the need to being further purified, next step reaction directly can be carried out.ESI/MS:m/z＝262.11(M+H)
+。
Embodiment 9: the preparation of compound 16
Be dissolved in by upper step gained compound 15 in ethanol (200mL) and acetic acid (500ml), stir under 80 DEG C of conditions and spend the night, TLC detection compound 15 reacts completely.Concentration of reaction solution under vacuum condition, after being down to room temperature, add methyl tertiary butyl ether and sherwood oil mixed solvent, separate out a large amount of faint yellow solid, filter, gained filter cake recrystallization under Virahol condition is obtained target compound 16, to be weighed as 62.3g (purity 98%) after solid drying, after crystalline mother solution is concentrated, recrystallisation from isopropanol obtains faint yellow solid target compound 16,9.95g (purity is 94%) will be weighed as, total recovery 77% after solid drying.
1HNMR(400MHz,CDCl
3):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).
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. a 1-R
2replace-4,5-dihydro-6H-[1,2,4] triazolo [4,3-a] [1] benzo-aza
the synthetic method of-6-ketone, is characterized in that comprising the following step:
Step 1, compound 1 in the basic conditions, in organic solvent, reacts with methylating reagent, prepares compound 2,
Step 2, compound 2 in organic solvent, reacts with compound 3 and prepares compound 4,
Step 3, compound 4 in acid condition, closes ring in organic solvent and prepares Compound II per,
Wherein, R
1be selected from hydrogen, hydroxyl, substituted or non-substituted C
1-C
6alkyl, substituted or non-substituted C
3-C
8-cycloalkyl, substituted or non-substituted C
1-C
6alkoxyl group, substituted or non-substituted C
3-C
8heterocyclylalkyl, halogen; R
2be selected from hydrogen, C
1-C
6-alkyl or-NR
5r
6, described R
5, R
6represent hydrogen or identical or different substituted or non-substituted C independently of one another
1-C
6-alkyl.
2. synthetic method as claimed in claim 1, is characterized in that, R
1be selected from hydrogen, methoxyl group, trifluoromethoxy, R
2for methyl.
3. synthetic method as claimed in claim 1 or 2, it is characterized in that, in step 1, described alkali is selected from salt of wormwood, sodium carbonate, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, or sodium hydrogen, sodium tert-butoxide, potassium tert.-butoxide, sodium methylate, triethylamine, DBU, pyridine, DIEA.
4. synthetic method as claimed in claim 3, is characterized in that, described alkali and compound 1 equivalence ratio 1 ~ 3:1.
5. synthetic method as claimed in claim 1 or 2, it is characterized in that, in step 1, described methylating reagent is selected from methyl iodide, methyl-sulfate, methylcarbonate, methyl mesylate, trifluoromethayl sulfonic acid methyl esters.
6. synthetic method as claimed in claim 5, it is characterized in that, described methylating reagent and compound 1 equivalence ratio are 1 ~ 2:1.
7. synthetic method as claimed in claim 1 or 2, it is characterized in that, the organic solvent described in step 1 is selected from methyl alcohol, ethanol, acetone, methylene dichloride, tetrahydrofuran (THF), acetonitrile, ether, benzene, toluene, the arbitrary combination of DMF, DMAC, DMSO or above-mentioned solvent.
8. synthetic method as claimed in claim 1 or 2, it is characterized in that, in step 2, described organic solvent is selected from methyl alcohol, ethanol, propyl carbinol, Virahol, toluene, diethylene glycol dimethyl ether, the arbitrary combination of DMF or above-mentioned solvent; The equivalence ratio of compound 3 and compound 2 is 1.5 ~ 3.5:1.
9. synthetic method as claimed in claim 1 or 2, it is characterized in that, in step 3, described acid is selected from acetic acid, tosic acid, trifluoroacetic acid, hydrochloric acid, camphorsulfonic acid, preferred acetic acid; Described organic solvent is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, tetrahydrofuran (THF), DMF, toluene, dimethylbenzene, 1,2-ethylene dichloride, dioxane, acetic acid, trifluoroacetic acid, the arbitrary combination of hydrochloric acid or above-mentioned solvent.
10. synthetic method as claimed in claim 1 or 2, it is characterized in that, in step 3, after reaction terminates, also comprise following treatment step: concentration of reaction solution under vacuum condition, after being down to room temperature, add methyl tertiary butyl ether and sherwood oil mixed solvent, after filtering the solid of separating out, in Virahol, recrystallization is to obtain sterling solid chemical compound II.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115433192A (en) * | 2022-09-23 | 2022-12-06 | 博诺康源(北京)药业科技有限公司 | Method for synthesizing intermediate for preparing BRD4 protein inhibitor |
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| WO2009093009A1 (en) * | 2008-01-21 | 2009-07-30 | Ucb Pharma S.A. | Fused tricyclic thiophene derivatives as mek inhibitors |
| WO2014152621A1 (en) * | 2013-03-14 | 2014-09-25 | Janssen Pharmaceutica Nv | P2x7 modulators |
| CN104781259A (en) * | 2012-09-28 | 2015-07-15 | 拜耳制药股份公司 | Bet protein-inhibiting 5-aryl triazole azepines |
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2016
- 2016-02-17 CN CN201610088225.6A patent/CN105503884B/en active Active
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| WO2009093009A1 (en) * | 2008-01-21 | 2009-07-30 | Ucb Pharma S.A. | Fused tricyclic thiophene derivatives as mek inhibitors |
| CN104781259A (en) * | 2012-09-28 | 2015-07-15 | 拜耳制药股份公司 | Bet protein-inhibiting 5-aryl triazole azepines |
| WO2014152621A1 (en) * | 2013-03-14 | 2014-09-25 | Janssen Pharmaceutica Nv | P2x7 modulators |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115433192A (en) * | 2022-09-23 | 2022-12-06 | 博诺康源(北京)药业科技有限公司 | Method for synthesizing intermediate for preparing BRD4 protein inhibitor |
| CN115433192B (en) * | 2022-09-23 | 2024-01-30 | 博诺康源(北京)药业科技有限公司 | Method for synthesizing intermediate for preparing BRD4 protein inhibitor |
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