CN105669647B - A kind of synthetic method of histone methylase EZH2 inhibitor intermediates - Google Patents
A kind of synthetic method of histone methylase EZH2 inhibitor intermediates Download PDFInfo
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- 0 C[C@@](C1CCNCC1)O* Chemical compound C[C@@](C1CCNCC1)O* 0.000 description 2
- STNLQJRBZHAGSO-UHFFFAOYSA-N CC(C1CCNCC1)=O Chemical compound CC(C1CCNCC1)=O STNLQJRBZHAGSO-UHFFFAOYSA-N 0.000 description 1
- HNSFAXPMNOFMQI-LURJTMIESA-N C[C@@H](C1CCOCC1)O Chemical compound C[C@@H](C1CCOCC1)O HNSFAXPMNOFMQI-LURJTMIESA-N 0.000 description 1
- WQBPRTUBQKFRKZ-UHFFFAOYSA-N Cc1c(C(OC)=O)c2ccccc2[nH]1 Chemical compound Cc1c(C(OC)=O)c2ccccc2[nH]1 WQBPRTUBQKFRKZ-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
The present invention relates to a kind of synthetic method of the intermediate compound I of histone methylase EZH2 inhibitor; this method is raw material with compound 1; compound I is obtained by reduction, sulfonylation, substitution and hydrolysis; the operation is simple, convenient post-treatment, and centre need not purify; total recovery is high; environmental-friendly, reaction raw materials are simple and easy to get, are adapted to industrial production.
Description
Technical field
The present invention relates to a kind of histone methylase EZH2 (enhancer of zeste homolog 2) inhibitor
The synthetic method of intermediate, belongs to organic synthesis field.
Background technology
Histone methylase EZH2 is the main ingredient of PcG protein complexes, is H3K27 methylation catalytic enzymes, it with
Histone methylated modification is related, suppresses compound (PRC) by forming polycomb with other PcG albumen and performance transcription suppression
Make and use, play an important roll in the generation of embryonic development, cell differentiation and tumour.EZH2 has dnmt rna, group egg
The regulating and controlling effect of white deacetylase, participates in the Transcription inhibition of target gene and promotes the propagation of cell, and its gene participated in sinks
There are reciprocation for the gene silencing mechanism and the acetylation modification of histone that silent mechanism is participated in dnmt rna.Swollen
EZH2 is a series of transcription inhibitory factor of target genes of the special height silence including tumor suppressor gene in oncocyte.
EZH2 can activate stem cell specific gene and regulation and control many tumor suppressor gene such as p16, p27 and BRCA18.
EZH2 high expression in kinds of tumors tissue, as prostate cancer, breast cancer, carcinoma of urinary bladder, colorectal cancer, hepatocellular carcinoma,
Lymthoma etc., and it is related to the progress of tumour and prognosis to find that EZH2 expression is increased.It is a kind of new that this suggests that it is likely to become
Tumor markers, while as the novel targets of gene therapy.Wherein, the R type isomers of representational compound CPI169 has
Preferable bioactivity, can suppress the catalytic activity of PRC2, IC50<1nM, moreover it is possible to reduce H3K27me3 cellular levels, EC50For
70nM。
Compound I (structure is shown below) and -2 (1H) -one salt of 3- (amino methyl) -4- methoxyl group -6- picolines
Hydrochlorate can prepare EZH2 inhibitor Cs PI169, CPI360 and its similar compound by conventional condensation method.
Wherein, Z NH, NBoc, O, S, SO2.It is less for the report of the synthetic method of compound I,
WO2014124418A1, WO2015010078A2, WO2015023915A1 and organic letters, 2014 (16),
Method (being shown below) disclosed in 4114-4117, using I-6 as starting material prepare compound I, wherein compound I-3
Preparation need to use Grignard Reagent, reaction system requires harsh, and product chiral selectivity is not high, it is necessary to by further tearing open
Point purifying is to obtain the compound I-2 of single configuration, but it is low to purify yield, with (R)-tert-butyl group 4- (1- amino-ethyls) piperidines-
Exemplified by the purifying of 1- carboxylic acid tert-butyl esters, by the way that the enrichment of single chiral compound is carried out into the method that salt dissociates again with mandelic acid,
But purify yield only 44%；By during compound I-2 prepare compound I-1, it is necessary to use ruthenium or porpezite expensive, be not easy to obtain
Metal catalyst so that the synthesis cost of compound I greatly improves, and severe reaction conditions, needs lower 110 DEG C of inert gas conditions to stir
Mix 12 it is small when, need to isolate and purify compound I by silica gel column chromatography separation method after reaction, be unfavorable for
Technique is amplified.
Therefore need to develop a kind of new synthetic method of compound I, the method route that this patent provides is short, operation letter
Single, high income, ee values are high, security is good, and environmental-friendly, cost is low, are conducive to technology production.
The content of the invention
The object of the present invention is to provide a kind of synthetic method of compound described in logical formula (I) below.
Wherein, Z NH, NBoc, O, S, SO2。
The synthetic method of compound I of the present invention can be represented with below scheme：
Wherein, Z is as defined above.
More specifically, preparation method of the invention includes following process：
1) step 1：In organic solvent, compound 1 obtains compound 2 by reduction；
The reducing agent may be selected from (R) -2- methyl-CBS- oxazaborolidines, (S) -2- methyl-CBS- oxazaborolidines, and (R) -
MeCBS- borane dimethylsulf iotades, (S)-MeCBS- borane dimethylsulf iotades, double (4- isopropyl methyls phenyl) ruthenium-(±) -2 of dichloro,
2'- bis- (two-p-methylphenyl phosphine) -1,1'- dinaphthalenes, the double diphenyl phosphines of ruthenous chloride -1,1'- dinaphthalene -2,2'-, sodium borohydride, boron hydrogen
Change lithium, tetrahydrochysene lithium aluminium, palladium/carbon, palladium dydroxide/carbon, platinum/carbon, platinum oxide, platinum/alundum (Al2O3), diethylaniline borane, boron
One or more in alkane dimethyl sulphide, preferably (R)-MeCBS- borane dimethylsulf iotades, (S)-MeCBS- borane dimethylsulf iotades.Institute
The molar ratio for stating reducing agent and compound 1 is 0.1~2:1.The solvent that the reaction uses is methanol, ethanol, tetrahydrofuran, first
One or more in benzene, preferably tetrahydrofuran；The reaction time is untill detecting reaction and complete；The reaction temperature
For -10~35 DEG C.
2) step 2：Compound 2 in alkaline conditions, obtains compound 3 with methylsufonyl chloride；
The reaction can be the conventional method and condition of the such reaction in this area, and the alkali may be selected from triethylamine, N,
N- diisopropylethylamine, pyridine, 4-dimethylaminopyridine diisopropylamine, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, hydrogen
Sodium oxide molybdena, potassium hydroxide, the preferably one or more in sodium hydrogen, triethylamine.The reaction time using detect reaction completion as
Only.
3) step 3：Compound 3 and compound 4 pass through nucleophilic displacement of fluorine prepare compound 5；
The nucleophilic displacement process and condition can be the conventional method and condition of the such reaction in this area, the alkali
It may be selected from sodium hydrogen, two (trimethyl silicon substrate) lithium amides, potassium carbonate, sodium carbonate, the one or more in cesium carbonate, the solvent
For n,N-Dimethylformamide, the one or two of n,N-Dimethylaniline.The reaction temperature be 80~130 DEG C, preferably 100
~120 DEG C.The reaction time is untill detecting reaction and complete.
The compound 4 can be by commercially available, or refers to Organic Letters, 2013,15 (2), 362-365
Shown in method be made.
4) step 4：Compound 5 hydrolyzes prepare compound I；
The nucleophilic displacement process and condition can be the conventional method and condition of the such reaction in this area.
The advantages of the method for the present invention, essentially consists in：
1. a kind of synthetic method for preparing histone methylase EZH2 inhibitor key intermediates I is disclosed, wherein, Z
For NH, NBoc, O, S, SO2；
2. intermediate compound I is easily obtained by compound 1 by reduction, sulfonylation, substitution, hydrolysis, the operation
Simply, convenient post-treatment, centre need not purify, and four-step reaction high income is up to 73%；
3. (the e.e. values of compound 2 of high e.e. values are obtained by chiral reduction compound 1>92%), to reach to key
The chiral control of intermediate compound I；
4. this method operation is simple, environmental-friendly, reaction raw materials are simple and easy to get, are adapted to industrial production；
This method is a brand-new synthetic route capable of being industrialized.Meanwhile the route is to developing new histone methyl
Changing enzyme inhibitor has good methodology meaning.
Specific embodiment
With reference to specific embodiment, the present invention is further explained.It is to be understood that these embodiments are merely to illustrate the present invention
Rather than limit the scope of the invention.The experimental method of actual conditions is not specified in the following example, usually according to conventional strip
Part carries 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, the reagent directly makes without further purification
With.All solvents are purchased from commercialization supplier, such as aldrich (Aldrich), and just can be used without processing.Reaction
Analyzed by TLC and/or analyzed by LC-MS, the termination of reaction is judged by the consumption of starting material.The thin layer of analysis
Chromatography (TLC) is the glass plate (EMD chemical companies (EMD in 60 0.25 millimeter of plate of F254 of pre-coated silica gel
Chemicals carried out on)), with the iodine developing on UV light (254nm) and/or silica gel, and/or with TLC product dyed therebies such as alcohol phosphorus
Molybdic acid, ninhydrin solution, liquor potassic permanganate or ceric sulfate solution heat together.
1H-NMR spectrums are on ten thousand Ruian-Mo Qiuli-VX400 (Varian Mercury-VX400) instrument, are grasped in 400MHz
Make lower record.
The abbreviation used in the present invention has this area conventional sense, such as：DCM represents dichloromethane, and DMF represents N, N- bis-
Methylformamide.
The preparation of 1 compound 7 of embodiment
Compound 6 (652g, 2.87mol) is dissolved in methanol (1.5L), be added portionwise under ice bath sodium borohydride (108.6g,
2.87mol) and keep 0-5 DEG C of temperature of reaction system, be warmed to room temperature stirring 0.5 it is small when.After reaction system is concentrated, water is added
(3L) and methyl tertiary butyl ether(MTBE) (3L) are layered, and water mutually uses methyl tertiary butyl ether(MTBE) (1.5L × 3), merge organic phase, salt water washing, sulphur
Sour sodium drying, filtering and concentrating obtains colorless oil compound 7 (655g), without being further purified, is directly used in and reacts in next step.
1H NMR(400MHz,CDCl3):δ4.30-4.00(m,2H),3.65-3.50(m,1H),2.75-2.54(m,2H),
1.84-1.75(m,1H),1.64-1.53(m,1H),1.43(s,9H),1.42-1.32(m,1H),1.26-1.08(m,5H).
The preparation of 2 compound 8 of embodiment
Compound 7 (655g, 2.86mol) is dissolved in dichloromethane (3.93L), at room temperature triethylamine (598mL,
4.29mol), after reaction system being cooled to 0 DEG C, methylsufonyl chloride (392.6g, 3.43mol) is instilled dropwise, after being added dropwise,
When stirring 0.5 is small under the conditions of 0 DEG C.Reaction solution is used into HCl (1N, 1.5L), water (2.0L) saturated sodium carbonate (2L) and brine respectively
(3L) is washed, and anhydrous sodium sulfate drying organic phase, is concentrated to give yellow oily compound 8 (815g), without further after filtering
Purifying, is directly used in and reacts in next step.
1H NMR(400MHz,CDCl3):δ4.66-4.56(m,1H),4.28-4.04(m,2H),2.98(s,3H),2.75-
2.55 (m, 2H), 1.80-1.56 (m, 3H), 1.42 (s, 9H), 1.40-1.36 (d, 3H, J=6.4Hz), 1.33-1.14 (m,
2H).
The preparation of 3 compound 9 of embodiment
Cesium carbonate (844g, 2.59mol) is added to the n,N-Dimethylaniline of compound 4 (70g, 0.37mol)
(700mL), 120 DEG C are warming up under nitrogen protection by compound.By the N of compound 8 (170.6g, 0.555mol), N- dimethyl
Aniline (700mL) is instilled in reaction system, and after being added dropwise, the reaction was complete to raw material for the 120 DEG C of stirrings of reaction system constant temperature.Will be anti-
Answer system to be down to room temperature, add methyl tertiary butyl ether(MTBE) (1.5L), stirring is filtered after ten minutes.Water (2.5L) is added in filtrate, and
With methyl tertiary butyl ether(MTBE) (1L × 3).Merge organic phase and washed with brine (2L), anhydrous sodium sulfate drying, filtering and concentrating obtains
Yellow oily crude Compound 9 (630g crude products), without being further purified, is directly used in and reacts in next step.
The preparation of 4 compound 10 of embodiment
Compound 9 (790g crude products) is dissolved in ethanol (3.16L), be added dropwise at room temperature sodium hydroxide solution (6N,
1.23L), it is stirred at reflux after being added dropwise overnight.Reaction solution is concentrated into 1.2L, adds water (1L) and methyl tertiary butyl ether(MTBE) (2L)
Stirring stratification after five minutes, organic phase are stripped with water (500mL × 3), merge water phase, and with methyl tertiary butyl ether(MTBE) (1L ×
4) wash, salt acid for adjusting pH is added in 0~10 DEG C of water phase to 2~3, there are a large amount of solids to separate out.Add ethyl acetate (3L) stirring
To separating out, solid is entirely molten, and after being layered liquid separation, water is mutually extracted with ethyl acetate (2L), merges organic phase, and washed with saturated common salt
Wash, anhydrous sodium sulfate drying, filtering and concentrating, obtains crude Compound 10, is crushed at room temperature with methyl tertiary butyl ether(MTBE) (500mL) thick
Product obtain white solid sterling compound 10 (114g, from compound 6 to 10 four-step reaction total recovery 72.6% of compound).
1H NMR(400MHz,DMSO):δ8.05-7.97(m,1H),7.65-7.58(m,1H),7.13-7.05(m,2H),
4.28-4.14(m,1H),4.10-3.92(m,1H),3.86-3.68(m,1H),2.73(s,3H),2.48-2.30(m,2H),
1.98-1.86 (s, 1H), 1.59-1.54 (d, 3H, J=6.8Hz), 1.37 (s, 9H), 1.29-1.15 (m, 2H), 1.00-0.85
(m,2H).
The preparation of 5 compound 11 of embodiment
Under nitrogen protection, (R)-MeCBS (2.64L, 2.64mol) is added to borane dimethylsulf iotade at -10~0 DEG C
In tetrahydrofuran (10L) solution of (880mL, 8.8mol), cryogenic conditions are kept, compound 6 (2kg, 8.8mol) is dripped dropwise
It is added in reaction system, after being added dropwise, 0 DEG C of reaction system stirs 10 minutes.Sequentially add water (10L) and hydrochloric acid (1N,
1.5L) be quenched reaction, when stirring 1 is small after, extracted with methyl tertiary butyl ether(MTBE) (4L × 3), merge organic phase, and use saturated salt solution
(6L) is washed, and anhydrous sodium sulfate drying, filtering and concentrating obtains crude white solid compound 11.Petroleum ether (5L) powder is used at room temperature
Filtered after when broken crude product stirring 1 is small, be dried to obtain white solid sterling compound 11 (1.98kg, yield 98%, 95%ee).
1H NMR(400MHz,CDCl3):δ4.25-4.05(m,2H),3.65-3.50(m,1H),2.75-2.5(m,2H),
1.85-1.75(m,1H),1.63-1.50(m,1H),1.48-1.30(m,10H),1.28-1.10(m,5H).
The preparation of 6 compound 12 of embodiment
At room temperature, compound 11 (1.5kg, 6.54mol) is dissolved in dry dichloromethane (9L), adds N, N- bis-
Wopropyl ethyl amine (1.69kg, 13.08mol), is cooled to 0 DEG C by reaction solution, under nitrogen protection, methylsufonyl chloride is added dropwise
(1124g, 9.81mol), after being added dropwise, when reaction system keeps 0 DEG C of stirring 0.5 small, the reaction was complete for raw material.Reaction solution is successively
Washed with hydrochloric acid (1N, 1.5L), water (2L), saturated sodium carbonate (2L) and saline solution (3L).Organic phase is dried with anhydrous sodium sulfate,
Filtering, concentration, obtains yellow oily compound 12 (1.85kg, yield 92%).
1H NMR(400MHz,CDCl3):δ4.70-4.58(m,1H),4.30-4.05(m,2H),3.00(m,3H),2.78-
2.58 (m, 2H), 1.85-1.58 (m, 3H), 1.45 (s, 9H), 1.43-1.36 (d, 3H, J=6.4Hz), 1.35-1.15 (m,
2H).
The preparation of 7 compound 13 of embodiment
Sodium carbonate (1.01kg, 9.52mol) is added to the n,N-Dimethylformamide of compound 4 (120g, 634mmol)
In the solution of (2L), reaction system is warming up to 80 DEG C, adds the n,N-Dimethylformamide of compound 12 (390g, 1.268mol)
(400mL) solution, reaction system are kept for 80 DEG C and are stirred overnight.It is cooled to room temperature, adds methyl tertiary butyl ether(MTBE) (2L), stirs 10 points
Filtered after clock.Water (2.5L) layering is added in filtrate, water is mutually extracted with methyl tertiary butyl ether(MTBE) (1.5L × 3), merges organic phase, and
Washed with brine (2L), anhydrous sodium sulfate drying, filtering and concentrating obtains yellow oily compound 13 (1.2kg crude products), directly uses
In in next step.
The preparation of 8 compound 14 of embodiment
Compound 13 (1.2kg crude products) obtained by previous step is dissolved in ethanol (4.8L), is stirred at room temperature down, is added dropwise
Enter lithium hydroxide solution (6N, 2.5L), reaction solution is stirred overnight at room temperature, the reaction was complete for raw material, and reaction solution is concentrated into
1.28L, adds water (1.5L) and methyl tertiary butyl ether(MTBE) (3L), stirs stratification after five minutes.Organic phase is with water (700mL × 3)
Extraction, merges water phase, with methyl tertiary butyl ether(MTBE) (1.5L × 4) washings phase.Saturation hydrochloric acid is added under ice-water bath, in water phase to adjust
PH is 2~3, and a large amount of solids separate out, and adds dichloromethane (1.5L) and is all dissolved to solid, stands liquid separation, water mutually uses dichloromethane
Alkane (1.5L × 2) extracts, and merges organic phase, is washed with saturated salt solution (3L), and anhydrous sodium sulfate drying, is concentrated to give crude product
Compound.By this crude product in petroleum ether/vinyl acetate (5:1,1L) crushed in mixed dissolution, filtration drying obtains yellow powder
Sterling compound 14 (182g, from compound 6 to 14 4 step yield 68% of compound).
1HNMR(400MHz,DMSO):δ8.05-7.97(m,1H),7.65-7.58(m,1H),7.13-7.05(m,2H),
4.28-4.14(m,1H),4.10-3.92(m,1H),3.86-3.68(m,1H),2.73(s,3H),2.48-2.30(m,2H),
1.98-1.86 (s, 1H), 1.59-1.54 (d, 3H, J=6.8Hz), 1.37 (s, 9H), 1.29-1.15 (m, 2H), 1.00-0.85
(m,2H).
The preparation of 9 compound 16 of embodiment
Under nitrogen protection, (R)-MeCBS (718.3mL, 1M toluene solution) is added to borane dimethylsulf iotade by -10~0 DEG C
In tetrahydrofuran (4.6L) solution of (718.3mL, 7.183mol).Cryogenic conditions are kept, being instilled dropwise into reaction system will
Compound 15 (920g, 7.183mol).After being added dropwise, reaction system stirs 10 minutes at 0~5 DEG C.Delay under the conditions of -5~0 DEG C
Reaction is quenched in the slow hydrochloric acid (2N, 4L) that adds, persistently stir 6 it is small when after add sodium chloride to saturation, addition methyl tertiary butyl ether(MTBE)
(2L) stirring is filtered after five minutes, and filter cake is rinsed with methyl tertiary butyl ether(MTBE) (2L).Filtrate stratification, water mutually use methyl tertbutyl
Ether extraction in water phase until can't detect target product.Merge organic phase, and washed with saturated salt solution (5L), anhydrous sodium sulfate
Dry, filtering and concentrating obtains faint yellow crude oil compound 16 (846g), without being further purified, can be directly used in next step
Reaction, the e.e. values of compound 16 are measured by the derivatization reaction in embodiment 10.
1HNMR(400MHz,CDCl3):δ4.07-3.94(m,2H),3.60-3.52(m,1H),3.43-3.32(m,2H),
1.82-1.72 (m, 1H), 1.58-1.28 (m, 4H), 1.22-1.15 (d, 3H, J=6.4Hz)
The preparation of 10 compound 17 of embodiment
Under nitrogen protection, DMF (5ml) solution of 16 (0.3g, 2.3mmol) is cooled to 0-10 DEG C, adds sodium hydrogen
After (110mg, 2.76mmol), reaction system stirs 10 minutes after being warming up to room temperature, be added dropwise cylite (0.39g,
2.3mmol), nitrogen protection under be stirred at room temperature 1-2 it is small when.Reaction system is down to 0 DEG C, adds saturated aqueous ammonium chloride
Reaction is quenched in (15mL), and methyl tertiary butyl ether(MTBE) (15ml × 3) extraction, merges organic phase, and washed with saturated salt solution (15ml × 2)
Wash, anhydrous magnesium sulfate drying, column chromatography (EA after filtering and concentrating:PE=1:50~1:20) isolated colorless oil compound 17
(0.4g, yield 80%, 92%ee)
The preparation of 11 compound 18 of embodiment
Compound 16 (740g, 5.69mol) is dissolved in dichloromethane (8.5L), addition triethylamine (2.3kg,
22.76mol).Reaction solution is cooled to 0~5 DEG C, under nitrogen protection, methylsufonyl chloride (1.3kg, 11.38mol) is slowly added dropwise,
After being added dropwise, when reaction system keeps low temperature stirring 2 small.Reaction solution is respectively with hydrochloric acid (1N, 8L), water (8L), unsaturated carbonate
Hydrogen sodium water solution (8L), saturated salt solution (8L) washing, anhydrous sodium sulfate drying, filtering and concentrating obtain light brown crude oil
18 (800g), without being further purified, can be directly used for reacting in next step.
1HNMR(400MHz,CDCl3):δ4.68-4.52(m,1H),4.05-3.95(m,2H),3.40-3.25(m,2H),
2.99(s,3H),1.85-1.30(m,8H).
The preparation of 11 compound 19 of embodiment
Compound 4 (102g, 539.5mmol) and potassium carbonate (745.2g, 5.4mol) are dissolved in N, accelerine
In (2L).Under 110 DEG C of nitrogen protections, it is added dropwise the N of compound 18 (168.75g, 809.3mmol), N- dropwise into reaction solution
Dimethylaniline (500mL) solution, after being added dropwise, reaction system is warming up to 110 DEG C, when stirring 1 is small after, reaction system is dropped
To room temperature, add ethyl acetate (2.5L) stirring and filter after five minutes, filter cake is washed with ethyl acetate.Saturation is added into filtrate
Aqueous ammonium chloride solution (2.5L), stirring stratification after ten minutes, and with ethyl acetate (1L × 3) aqueous phase extracted.Merge organic
Phase, is washed with water (2L), saturated salt solution (2L) successively, and anhydrous sodium sulfate drying, filtering and concentrating obtains light brown oil crude product
Compound, column chromatography (ethyl acetate：Petroleum ether=1:10) yellow foamy solid, is obtained.By this foaming solid in acetic acid
Ethyl ester/petroleum ether (1L, v/v=1:10) crushing, stirring is stayed overnight in system, and filtering, is concentrated to give light yellow solid Compound 19
(113.8g)。
1HNMR(400MHz,CDCl3):δ8.33-8.25(m,1H),7.54-7.47(m,1H),7.25-7.15(m,2H),
4.25-4.05 (m, 2H), 3.85-3.75 (m, 4H), 3.55-3.35 (m, 2H), 2.82 (s, 3H), 1.70-1.63 (d, 3H, J=
6.8Hz),1.55-1.35(m,3H),1.20-1.12(m,2H).
The preparation of 12 compound 20 of embodiment
At room temperature, potassium hydroxide solution (6N, 103mL) is added to the ethanol of compound 19 (65g, 215.6mmol)
In (260mL) solution, after being added dropwise, system is refluxed overnight.After reaction, reaction system is concentrated into 100mL, uses water
(100mL) dilutes, and with methyl tertiary butyl ether(MTBE) (300mL × 4) washings phase.Water is mutually cooled to 0~10 DEG C, is slowly added to salt
Sour condition pH to 2~3, a large amount of white solids separate out, and filtering, filter cake is washed with water (50mL × 2).Solid is dissolved in acetic acid second
In ester (800mL), and washed with water (200mL × 2), anhydrous sodium sulfate drying, filtering and concentrating obtains yellow solid compound 20
(5.9g, from compound 15 to 20 four-step reaction total recovery 60% of compound).
1HNMR(400MHz,CDCl3):δ8.33-8.25(m,1H),7.54-7.47(m,1H),7.25-7.15(m,2H),
4.25-4.05 (m, 2H), 3.85-3.75 (m, 1H), 3.55-3.35 (m, 2H), 2.82 (s, 3H), 1.70-1.63 (d, 3H, J=
6.8Hz),1.55-1.35(m,3H),1.20-1.12(m,2H).
All documents that the present invention refers to are incorporated herein by reference, and are individually drawn just as each document
It is used as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can be with
The present invention is made various changes or modifications, such equivalent forms equally fall within the model that the application the appended claims are limited
Enclose.
Claims (7)
1. a kind of synthetic method of histone methylase EZH2 inhibitor midbody compounds I, it is characterised in that including following
Step：
Step 1, compound 1 is instilled in the organic solvent of reducing agent dropwise, reduction obtains compound 2；The reducing agent is selected from
(R)-MeCBS-borane dimethylsulf iotade；
Step 2, compound 2 is reacted in alkaline conditions with methylsufonyl chloride, obtains compound 3；
Step 3, in organic solvent, compound 3 and compound 4 obtain compound 5 by nucleophilic displacement of fluorine；
Step 4, compound 5 hydrolyzes prepare compound I；
Wherein Z is NH, NBoc, O, S, SO2。
2. preparation method as claimed in claim 1, it is characterised in that in step 1, the reducing agent and mole of compound 1
Than for 0.1~2:1, the organic solvent is selected from one or both of tetrahydrofuran or toluene；The reaction temperature for -10~
0℃。
3. preparation method as claimed in claim 1, it is characterised in that in step 1, comprise the following steps：After the completion of reaction, -5
Hydrochloric acid reaction is slowly added under the conditions of~0 DEG C, is filtered after adding methyl tertiary butyl ether(MTBE) stirring；After filtrate layered, water is mutually used
Methyl tertiary butyl ether(MTBE) extraction in water phase until can't detect target product；Merge organic phase, and with saturated common salt water washing, filtrate
Filtering and concentrating obtains compound 2 after drying.
4. preparation method as claimed in claim 1, it is characterised in that in step 2, the alkali may be selected from triethylamine, N, N- bis-
Wopropyl ethyl amine, pyridine, 4-dimethylaminopyridine diisopropylamine, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, hydroxide
Sodium, potassium hydroxide, the one or more in sodium hydrogen.
5. preparation method as claimed in claim 1, it is characterised in that in step 3, which can add alkali, and alkali used is optional
From sodium hydrogen, two (trimethyl silicon substrate) lithium amides, potassium carbonate, sodium carbonate, the one or more in cesium carbonate.
6. preparation method as claimed in claim 1, it is characterised in that in step 3, the solvent is N, N- dimethyl formyls
Amine, the one or two of n,N-Dimethylaniline.
7. preparation method as claimed in claim 1, it is characterised in that in step 3, reaction temperature is 80~130 DEG C.
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|---|---|---|---|---|
| WO2015010078A2 (en) * | 2013-07-19 | 2015-01-22 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
| WO2015023915A1 (en) * | 2013-08-15 | 2015-02-19 | Constellation Pharmaceuticals, Inc. | Indole derivatives as modulators of methyl modifying enzymes, compositions and uses thereof |
| CN105102446A (en) * | 2013-02-11 | 2015-11-25 | 星座制药公司 | Modulators of methyl modifying enzymes, compositions and uses thereof |
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2016
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105102446A (en) * | 2013-02-11 | 2015-11-25 | 星座制药公司 | Modulators of methyl modifying enzymes, compositions and uses thereof |
| WO2015010078A2 (en) * | 2013-07-19 | 2015-01-22 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
| WO2015023915A1 (en) * | 2013-08-15 | 2015-02-19 | Constellation Pharmaceuticals, Inc. | Indole derivatives as modulators of methyl modifying enzymes, compositions and uses thereof |
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| A Practical Synthesis of Indoles via a Pd-Catalyzed C−N Ring Formation;Rishi G. Vaswani,et al.;《Org. Lett.》;20140728;4114-4117 * |
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