CN105820175B - A kind of thienopyrimidines and its preparation method and application - Google Patents

A kind of thienopyrimidines and its preparation method and application Download PDF

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CN105820175B
CN105820175B CN201610228588.5A CN201610228588A CN105820175B CN 105820175 B CN105820175 B CN 105820175B CN 201610228588 A CN201610228588 A CN 201610228588A CN 105820175 B CN105820175 B CN 105820175B
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thienopyrimidines
alkyl
chemical compounds
compound
preparation
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CN105820175A (en
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陈元伟
魏于全
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Sichuan University
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The invention discloses a kind of thienopyrimidines and its preparation method and application.The invention has the benefit that the present invention provides the synthesis of the completely new thienopyrimidines of structure and its in the application of anticancer aspect.Because PI3K-Akt/mTOR signal path plays an important role in the occurrence and development of tumour, it is in close relations with the occurrence and development of the tumours such as breast cancer, gastric cancer, colon and rectum carcinoma, oophoroma, prostate cancer, when PI3K-Akt/mTOR signal path occurs abnormal, it is possible that causing cancer, and thienopyrimidines of the present invention can inhibit the exception of PI3K-Akt/mTOR signal path, to achieve the purpose that prevent and treat cancer.Thienopyrimidines of the present invention provide new strategy and new approaches for oncotherapy, provide new direction and thinking for the research and development of anti-tumor drug.

Description

A kind of thienopyrimidines and its preparation method and application
Technical field
The invention belongs to organic compound synthesis and medical applications technical field, and in particular to a kind of thienopyrimidines Close object and its preparation method and application.
Background technique
Cancer is the first cause of the death of China resident, and with the development of economy with the pollution of environment, the lethality of cancer Constantly rising, is seriously endangering the life and quality of life of people.Currently, people often pass through operation, the method for chemotherapy is controlled Cancer is treated, these methods all cause serious harm to the spirit and body of people.Currently, tumor patient take it is antitumor Drug also largely kills normal cell, such as existing anti-tumor drug either cytotoxin while killing tumour cell Class, all there is toxic side effects for anti-metabolism, antibiosis species or alkaloids.Such as: nausea, canker sore, vomiting, diarrhea, Blood urine, immunity reduction, easy infection, oligoleukocythemia, decrease of platelet etc., cause huge injury to human body.So finding The antineoplastic of high-efficiency low-toxicity is always the target that physicians most ask.
Thienopyrimidines are and standby since it has good curative effect in terms of sterilization, anti-inflammatory, antitumor and cancer By the concern of Pharmaceutical Chemist.
102643272 A of Chinese patent CN discloses a kind of new thieno [3,2-d] pyrimidines, general formula I Are as follows:
And compounds of formula I is described in the drug of preparation treatment and/or pre- anti-cancer and other proliferative diseases Purposes.
Summary of the invention
The object of the present invention is to provide a kind of thienopyrimidines and its preparation method and application.
The purpose of the present invention is achieved through the following technical solutions:
A kind of thienopyrimidines have structure shown in general formula I:
Further, R1Are as follows: halogen, cyano, aldehyde radical, carboxyl ,-C1-C6Alkylamino ,-C1-C6Alkyl-NHC (=O) ,-alkane Base amido ,-alkyl amine group C (=O) alkyl ,-alkyl amine group S (O)2Alkyl ,-alkyl-alkoxy ,-alkyl S (O)2Alkyl ,-alkane Base S (O)2Amido ,-alkoxy-alkyl ,-C (=O) alkyl ,-C (=O) alkoxy ,-C (=O) amido ,-C (=O) amido alkane Oxygroup ,-C (=O) amido S (O2) alkyl ,-C (=O) amido-alkyl-amino ,-alkyl S (O)2Alkyl ,-amido SO2Amido ,-S Alkyl ,-S (O)2Alkyl ,-S (O)2Amido ,-SC (=O) alkyl ,-SC (=O) alkoxy, substituted or unsubstituted C1-C12Alkane Base, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C12Naphthenic base, Substituted or unsubstituted C2-C20Heterocycle, substituted or unsubstituted C6-C20Aryl and substituted or unsubstituted C1-C20Heteroaryl One kind；
R2Are as follows: halogen, trifluoromethyl, nitro ,-C (=O) alkyl ,-C (=O) alkoxy ,-C (=O) amido ,-alkylamine Base ,-amido alkoxy ,-alkyl-amino C (=O) alkyl-amino ,-amido C (=O) alkoxy ,-amido C (=O) amido ,- Amido SO2Alkyl ,-alkoxy ,-OC (=O) alkyl ,-OC (=O) amido ,-OS (O2) alkoxy ,-OP (=O) (alkoxy) ,- OP (alkoxy) ,-SR10,-S (O) alkyl ,-S (O)2Alkyl ,-S (O)2Amido ,-S (O) (alkoxy) ,-S (O)2(alkoxy) ,- SC (=O) alkyl ,-SC (=O) alkoxy ,-SC (=O) amido, substituted or unsubstituted C1-C12Alkyl, it is substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C12Naphthenic base, substituted or unsubstituted C2- C20Heterocycle, substituted or unsubstituted C6-C20Aryl and substituted or unsubstituted C1-C20One kind of heteroaryl；
R3、R4It is identical or different, separately replace selected from unsubstituted aryl or by the 1-5 substituent groups selected from A Aryl；Heteroaryl that is unsubstituted heteroaryl or being replaced by the 1-5 substituent groups selected from A；Unsubstituted naphthenic base is a by 1-5 The naphthenic base that substituent group selected from A replaces；Unsubstituted nitrogenous saturated heterocyclyl is replaced selected from the substituent groups of A by 1-5 Nitrogenous saturated heterocyclyl；Or R3And R4Unsubstituted nitrogenous saturated heterocyclyl is connected to form for N atom adjacent thereto or by 1- The nitrogenous saturated heterocyclyl that 5 substituent groups selected from A replace；
Wherein A is halogen ,-R ,-(CH2) nOR ,-(CH2) nNRR ' ,-COR ,-COOR ,-CONRR ' ,-NHCOR ,-NHCO (CH2) nNRR ' and-SO2One kind of R；
Wherein n is 0,1,2,3 or 4；
R, R ' is identical or different, is separately selected from-H ,-C1-C4Alkyl ,-unsubstituted aryl or by halogen ,-OH ,- COOH、-NH2、-NH-C1-C4Alkyl ,-N (C1-C4Alkyl)2、-CO-C1-C4Alkyl or-COO-C1-C4Alkyl-substituted aryl；- Unsubstituted heterocycle or by halogen ,-C1-C4Alkyl ,-OH ,-O-C1-C4Alkyl ,-COOH ,-NH2、-NH-C1-C4Alkyl ,-N (C1-C4Alkyl)2、-CO-C1-C4Alkyl or-COO-C1-C4Alkyl-substituted heteroaryl；Or R, R ' difference N adjacent thereto Atom is connected, and forms unsubstituted nitrogenous saturated heterocyclyl or by halogen ,-C1-C4Alkyl ,-OH ,-O-C1-C4Alkyl ,- COOH、-NH2、-NH-C1-C4Alkyl ,-N (C1-C4Alkyl)2、-CO-C1-C4Alkyl or-COO-C1-C4It is alkyl-substituted nitrogenous Saturated heterocyclyl；
Further, the step of synthetic method of the thienopyrimidines is as follows: I a compound and urea It carries out annulation and obtains I b compound, I b and phosphorus oxychloride carry out chlorination reaction and obtain I c compound of chlorizate, I c compound I d compound is reacted to obtain with morpholine derivative, I d compound reacts under conditions of acid or alkali with aminated compounds, obtains I eization Object is closed, I e compound obtains chemical compounds I f, chemical compounds I with aldehydes intermediate reaction under the action of grignard reagent or n-BuLi F obtains chemical compounds I through reduction, and synthetic route is as follows:
Further, I e compound obtains chemical compounds I f ' under the action of grignard reagent or n-BuLi with Iod R, changes It closes I f ' of object and reacts generation I with boric acid class or boric acid ester compound, synthetic route is as follows:
In the reaction for generating I can also with I d compound in grignard reagent or n-BuLi under the action of with aldehyde radical or The intermediate reaction of carbonyl obtains chemical compounds I g, chemical compounds I g and obtains chemical compounds I h, I h compound and aminated compounds through reduction Reaction production chemical compounds I or I d compound obtain chemical compounds I g ' under the action of grignard reagent or n-BuLi with Iod R, Chemical compounds I g ' obtains chemical compounds I h through reduction, and I h compound reacts generation I with boric acid class or boric acid ester compound, synthesizes road Line is as follows:
Further, the morpholine derivative are as follows: morpholine, 2,6- thebaine, (2R, 6S)-thebaine, (R)- 3- methyl morpholine.
Further, the aminated compounds are as follows: morpholine, thiomorpholine, indoline, (R) -3- methyl morpholine, 3- hydroxyl Piperidines, (S) -3- methyl morpholine, (2R, 6S)-thebaine, 1- methyl -4- (piperidin-4-yl) piperazine, 2,6- dimethyl Quinoline, substituted or non-substituted aniline.
Further, it is described acid be hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, bicarbonate or Carbonate.
Further, the alkali be sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, zinc hydroxide, sodium carbonate, Potassium carbonate, sodium bicarbonate, saleratus, ammonium hydroxide, methylamine, ethamine, dimethylamine, diethylamine, trimethylamine or triethylamine.
Further, the intermediate with aldehyde radical or carbonyl are as follows: " CHO, wherein R " refers to C to R1-C5Alkyl, C1-C5Ring Alkyl, substituted or non-substituted aryl, substituted or non-substituted heteroaryl or-C1-C6One kind of alkylamino.
Further, the boric acid class or boric acid ester compound are as follows:
Wherein a is boric acid compound, and b is boric acid ester compound；
Wherein R " ' indicates following group: the unsubstituted or aryl, unsubstituted that is replaced by the 1-5 substituent groups selected from B Or the heteroaryl replaced by the 1-5 substituent groups selected from B；
Wherein, B are as follows: halogen ,-R ,-(CH2) nOR ,-(CH2) nNRR ' ,-COR ,-COOR ,-CONRR ' ,-NHCOR ,-NHCO (CH2) nNRR ' or-SO2One kind of R；
Wherein n is 0,1,2,3 or 4.
Further, the thienopyrimidines are preparing the application in curing cancer drug.
The invention has the benefit that the present invention provides the synthesis of the completely new thienopyrimidines of structure and its In the application of anticancer aspect.Because PI3K-Akt/mTOR signal path plays an important role in the occurrence and development of tumour, with mammary gland The occurrence and development of the tumours such as cancer, gastric cancer, colon and rectum carcinoma, oophoroma, prostate cancer are in close relations, work as PI3K-Akt/mTOR When signal path occurs abnormal, it is possible to cause cancer, and thienopyrimidines of the present invention can inhibit The exception of PI3K-Akt/mTOR signal path, to achieve the purpose that prevent and treat cancer.Thieno of the present invention is phonetic Pyridine class compound provides new strategy and new approaches for oncotherapy, provides new direction and think of for the research and development of anti-tumor drug Road.
Specific embodiment
Following embodiment describes 20 kinds of compound I, is indicated respectively with 1-20 digit.
Embodiment one
A kind of thienopyrimidines: (2- ((2S, 6R) -2,6- dimethylated morpholinyl) -4- morpholino thieno [3,2-d] pyrimidine -6- base) methanol preparation: synthetic route is as follows:
The urea of the 3- amino -2- thiophenecarboxylate of 100mmol and 500mmol is placed in microwave reactor 200 DEG C Reaction 30min obtains I b-1 of yellow crystalline compound.It is molten that the I b-1 compound of 50mmol is added to the mixing of 100ml phosphorus oxychloride Obtain I c-1 compound of chlorizate within back flow reaction 10 hours under conditions of 110 DEG C in liquid.By the I c-1 compound of 34mmol It is suspended in 150ml ethyl alcohol, the morpholine of 100mmol is added under the mixing speed of 100r/min, room temperature reaction 2h obtains chemical combination I d-1 of object.(2S, 6R) -2,6- thebaine of the trifluoroacetic acid of chemical compounds I d-1,90mmol of 30mmol, 45mmol is mixed In 100ml n-butanol under conditions of 120 DEG C back flow reaction 3h, obtain chemical compounds I e-1.By the chemical compounds I e-1 of 20mmol Be dissolved in 100ml tetrahydrofuran, nitrogen protection, at -78 DEG C instill 24mmol grignard reagent, it is to be added after in 55r/min Mixing speed under be stirred to react 2h, add 50mlDMF, continue to be stirred to react 4h obtaining chemical compounds I f；Under room temperature, 10mmol chemical compounds I f-1 uses sodium borohydride reduction in methylene chloride, reacts organic phase after the reaction was completed and is washed with saturated common salt It washs 3 times, anhydrous sodium sulfate is dry, and silica gel column chromatography separates to obtain compound as white solid 1.
H1-NMR(CDCl3): δ 7.02 (s, 1H), δ 4.88 (s, 2H), δ 4.50 (d, 2H), δ 3.88 (t, 4H), δ 3.83 (t, 4H), δ 3.67 (q, 2H), δ 2.60 (d, 2H), δ 1.27 (d, 6H).
Embodiment two
A kind of thienopyrimidines: (4- morpholine -2-thio-morpholinyl thieno [3,2-d] pyrimidine-6- base) first The preparation of alcohol: synthetic route is as follows:
On the basis of example 1, by the trifluoroacetic acid of chemical compounds I d-1,30mmol of 10mmol, 15mmol it is thio Morpholine is mixed in 30ml n-butanol back flow reaction 3h under conditions of 120 DEG C, obtains chemical compounds I e-2.By the compound of 20mmol I e-2 is dissolved in 100ml tetrahydrofuran, nitrogen protection, at -78 DEG C instill 8mmol grignard reagent, it is to be added after in 50r/ It is stirred to react 2h under the mixing speed of min, adds 15mlDMF, continues to be stirred to react 4h obtaining chemical compounds I f-2；Room temperature condition Under, 2mmol chemical compounds I f-2 uses sodium borohydride reduction in methylene chloride, reacts organic phase saturated salt solution after the reaction was completed Washing 3 times, anhydrous sodium sulfate is dry, and silica gel column chromatography separates to obtain compound as white solid 2.
H1-NMR(CDCl3): δ 7.04 (s, 1H), δ 4.91 (s, 2H), δ 4.30 (t, 4H), δ 3.87 (t, 4H), δ 3.86 (t, 4H), δ 2.69 (t, 4H).
Embodiment three
A kind of thienopyrimidines: (2- (indoles -1- base) -4- morpholino thieno [3,2-d] pyrimidine -6- base) The preparation of methanol: synthetic route is as follows:
On the basis of example 1, by the trifluoroacetic acid of chemical compounds I d-1,30mmol of 10mmol, the dihydro of 15mmol Indoles is mixed in 30ml n-butanol back flow reaction 3.5h under conditions of 130 DEG C, obtains chemical compounds I e-3.By the chemical combination of 20mmol I e-3 of object is dissolved in 100ml tetrahydrofuran, nitrogen protection, at -78 DEG C instill 8mmol n-BuLi, it is to be added after It is stirred to react 2h under the mixing speed of 60r/min, adds 15mlDMF, continues to be stirred to react 4h obtaining chemical compounds I f-3；Room temperature Under the conditions of, 2mmol chemical compounds I f-3 uses sodium borohydride reduction in methylene chloride, reacts organic phase saturation food after the reaction was completed Salt water washing 3 times, anhydrous sodium sulfate is dry, and silica gel column chromatography separates to obtain compound as white solid 3.
H1-NMR(CDCl3): δ 8.35 (s, 1H), δ 7.07 (s, 1H), δ 7.05 (s, 1H), δ 6.72 (s, 1H), δ 6.05 (s, 1H), δ 4.95 (s, 2H), δ 4.29 (t, 2H), δ 3.97 (t, 4H), δ 3.85 (t, 4H), δ 3.19 (t, 2H).
Example IV
A kind of thienopyrimidines: (S)-(2- (3- methyl morpholine) -4- morpholino thieno [3,2-d] pyrimidine - 6- yl) methanol preparation: preparation method is similar with the preparation method of embodiment one, derivative using suitable morpholine in the preparation It is prepared by object.
H1-NMR(CDCl3): δ 7.02 (s, 1H), δ 4.89 (s, 2H), δ 4.68 (d, 1H), δ 4.28 (d, 1H), δ 3.92 (m, 1H), δ 3.86 (t, 4H), δ 3.83 (t, 4H), δ 3.76 (m, 2H), δ 3.57 (t, 1H), δ 3.26 (m, 1H), δ 1.26 (d, 3H).
Embodiment five
A kind of thienopyrimidines: 1- (6- (methylol) -4- morpholino thieno [3,2-d] pyrimidine -2-base) - 3- hydroxy-piperdine: preparation method is similar with the preparation method of embodiment one, is carried out when preparation using suitable morpholine derivative Preparation.
H1-NMR(CDCl3): δ 6.87 (s, 1H), δ 4.76 (s, 2H), δ 3.83 (t, 4H), δ 3.81 (t, 4H), δ 3.52 (m, 1H), δ 3.2 (d, 2H), δ 2.92 (m, 2H), δ 1.89 (m, 2H), δ 1.66 (m, 2H).
Embodiment six
A kind of thienopyrimidines: (R)-(2- (3- methyl morpholine base) -4- morpholino thieno [3,2-d] is phonetic Pyridine -6- base) methanol preparation: preparation method is similar with the preparation method of embodiment one, and when preparation is spread out using suitable morpholine It is prepared by biology.
H1-NMR(CDCl3): δ 7.02 (s, 1H), δ 4.88 (s, 2H), δ 4.67 (d, 1H), δ 4.25 (d, 1H), δ 3.93 (d, 1H), δ 3.86 (t, 4H), δ 3.83 (t, 4H), δ 3.76 (m, 2H), δ 3.57 (t, 1H), δ 3.26 (m, 1H), δ 1.27 (d, 3H).
Embodiment seven
A kind of thienopyrimidines: the system of 1- (2,4- dimorpholine base thieno [3,2-d] pyrimidine -6- base) ethyl alcohol Standby: synthetic route is as follows:
On the basis of example 1, the morpholine of the hydrochloric acid of the chemical compounds I d-1,30mmol of 10mmol and 15mmol is mixed Back flow reaction obtains chemical compounds I e-4 under conditions of 130 DEG C in 30ml n-butanol；5mmol chemical compounds I e-4 is dissolved in 25ml In tetrahydrofuran, nitrogen protection instills 6mmol grignard reagent at -78 DEG C, it is to be added after 60r/min mixing speed Under be stirred to react 2h, add the dry acetone of 6mmol, continue to be stirred to react 4h obtaining chemical compounds I f-4.Under room temperature, The chemical compounds I f-4 of 1mmol uses sodium borohydride reduction in methylene chloride, reacts organic phase saturated salt solution after the reaction was completed Washing 3 times, anhydrous sodium sulfate is dry, and silica gel column chromatography separates to obtain compound as white solid 7.
H1-NMR(CDCl3): δ 7.02 (s, 1H), δ 5.15 (q, 1H), δ 3.93 (t, 4H), δ 3.86 (t, 4H), δ 3.83 (t, 4H), δ 3.76 (t, 4H), δ 1.62 (d, 3H).
Embodiment eight
A kind of thienopyrimidines: 3- (2- ((2S, 6R) -2,6- dimethylated morpholinyl) -4- morpholino thieno [3,2-d] pyrimidine -6- base) phenol preparation: synthetic route is as follows:
On the basis of example 1, the chemical compounds I e-1 of 10mmol, be dissolved in the dry tetrahydrofuran of 30ml, nitrogen is protected It protects, 12mmol reagent n-butyllithium is added at -78 DEG C, is stirred to react 2h under the mixing speed of 60r/min after to be added, The tetrahydrofuran for being dissolved with 30mmol iodine is added, continues to be stirred to react 4h obtaining chemical compounds I f ' -1.By 8mmol chemical compounds I f '- 1,24mmol3- hydroxy benzenes pinacol borate is in the presence of alkali, is molten with tetrahydrofuran with Pd (II) for catalyst Liquid, nitrogen protection, 110 DEG C are stirred overnight.The mixing of the ethyl acetate and saturated sodium-chloride that are after the reaction was completed 1:1 with volume ratio Liquid extracts reaction solution, with the dry organic phase of anhydrous sodium sulfate, organic phase is then concentrated, silica gel column chromatography separating purification obtains compound 8。
H1-NMR(CDCl3): δ 8.26 (s, 1H), δ 7.95 (d, 1H), δ 7.93 (d, 1H), δ 7.54 (t, 1H), δ 7.46 (s, 1H), δ 4.54 (m, 2H), δ 3.91 (t, 4H), δ 3.87 (t, 4H), δ 3.68 (m, 2H), δ 2.66 (t, 2H), δ 1.68 (d, 6H).
Embodiment nine
A kind of thienopyrimidines: (2- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) -4- morpholino thiophene And [3,2-d] pyrimidine -6- base) methanol preparation: synthetic route is as follows:
On the basis of example 1,10mmol chemical compounds I d-1 is dissolved in the dry tetrahydrofuran of 50ml, nitrogen is protected It protects, 12mmol grignard reagent is instilled at -78 DEG C, is stirred to react 2h under the mixing speed of 60r/min after to be added, then 6mmolDMF is added, continues to be stirred to react 4h obtaining chemical compounds I g-1；7mmol chemical compounds I g-1 is used into boron hydrogen in methylene chloride Change the reduction of sodium room temperature, reacts organic phase after the reaction was completed with saturated common salt water washing 3 times, anhydrous sodium sulfate is dry, silica gel column layer Analysis separates to obtain I h-1 of compound as white solid；By 7mmol chemical compounds I h-1,21mmol 1- methyl -4- (piperidin-4-yl) piperazine, 30mmol hydrochloric acid is mixed in 30ml n-butanol, and back flow reaction 2h obtains compound I under conditions of 130 DEG C.
H1-NMR(CDCl3): δ 7.03 (s, 1H), δ 4.87 (s, 2H), δ 3.85 (t, 4H), δ 3.82 (t, 4H), δ 2.86 (t, 4H), δ 2.80 (d, 2H), δ 2.73 (t, 4H), δ 2.69 (d, 2H), δ 2.69 (t, 1H), δ 2.49 (s, 3H), δ 1.95 (t, 2H), δ 1.53(t,2H)。
Embodiment ten
A kind of thienopyrimidines: 1- (2- ((2S, 6R) -2,6-d dimethylated morpholinyl) -4- morpholino thiophene And [3,2-d] pyrimidine -6- base) ethyl alcohol preparation: preparation method is similar with the preparation method of embodiment nine.
H1-NMR(CDCl3): δ 7.01 (s, 1H), δ 5.15 (q, 1H), δ 4.5 (d, 2H), δ 3.88 (t, 4H), δ 3.83 (t, 4H), δ 3.67 (t, 2H), δ 2.59 (t, 3H), δ 1.63 (d, 2H), δ 1.26 (d, 6H).
Embodiment 11
A kind of thienopyrimidines: (2S, 6R) -2,6- dimethyl -4- (4- morpholinyl -6- (1H- pyrazoles -5- Base) thieno [3,2-d] pyrimidine -2-base) morpholine preparation.
On the basis of embodiment 1,10mmol chemical compounds I e-1 is dissolved in the dry tetrahydrofuran of 30ml, nitrogen is protected It protects, 12mmol reagent n-butyllithium is slowly added dropwise at -78 DEG C, is slowly added dropwise is dissolved in tetrahydrofuran after mixing evenly 30mmol iodine continues to be stirred to react 4h after dripping, saturated sodium bicarbonate solution is added in reaction solution after the reaction was completed, obtains I f'-1.By 8mmol chemical compounds I f ' -1, where ester is in the presence of alkali for 24mmol1H- pyrazoles -3- boric acid frequency, is with Pd (II) Catalyst, using dioxane as solution, nitrogen protection, 110 DEG C are stirred overnight, the acetic acid for being after the reaction was completed 1:1 with volume ratio The mixed liquor of ethyl ester and saturated sodium-chloride extracts reaction solution, and with the dry organic phase of anhydrous sodium sulfate, organic phase, silica gel is then concentrated Column chromatographic isolation and purification obtains compound 11.
H1-NMR(CDCl3): δ 7.45 (d, 1H), δ 7.01 (s, 1H), δ 6.43 (d, 1H), δ 4.5 (d, 2H), δ 3.88 (t, 4H), δ 3.83 (t, 4H), δ 3.67 (t, 2H), δ 1.63 (d, 2H), δ 1.26 (d, 6H).
Embodiment 12
A kind of thienopyrimidines: 1- (2- ((2S, 6R) -2,6- dimethylated morpholinyl) -4- morpholino thieno [3,2-d] pyrimidine -6- base) propyl alcohol.
H1-NMR(CDCl3): δ 7.01 (s, 1H), δ 5.15 (q, 1H), δ 4.5 (d, 2H), δ 3.88 (t, 4H), δ 3.83 (t, 4H), δ 3.67 (t, 2H), δ 1.98 (m, 2H), δ 1.63 (d, 2H), δ 1.26 (d, 6H), δ 0.9 (t, 3H).
Embodiment 13
A kind of thienopyrimidines: 3- (2- ((2S, 6R) -2,6- dimethylated morpholinyl) -4- morpholino thieno [3,2-d] pyrimidine -6- base) phenol.
On the basis of embodiment 11, by the chemical compounds I f ' -1 of 10mmol and 30mmol 2- hydroxy benzenes pinacol borate It is reacted, concrete operation method reference implementation example 11 obtains compound 13.
H1-NMR(CDCl3): δ 7.67 (d, 1H), δ 7.43 (t, 1H), δ 7.20 (t, 1H), δ 7.02 (s, 1H), δ 7.01 (d, 1H), δ 4.54 (m, 2H), δ 3.91 (t, 4H), δ 3.87 (t, 4H), δ 3.68 (m, 2H), δ 2.66 (t, 2H), δ 1.68 (d, 6H).
Embodiment 14
A kind of thienopyrimidines: (2S, 6R) -2,6- dimethyl -4- (4- morpholinyl -6- (pyridine -2- base) thiophene Pheno simultaneously [3,2-d] pyrimidine -2-base) morpholine.
H1-NMR(CDCl3): δ 8.55 (d, 1H), δ 7.83 (t, 1H), δ 7.74 (d, 1H), δ 7.32 (t, 1H), δ 7.02 (s, 1H), δ 4.54 (m, 2H), δ 3.91 (t, 4H), δ 3.87 (t, 4H), δ 3.68 (m, 2H), δ 2.66 (t, 2H), δ 1.68 (d, 6H).
Embodiment 15
A kind of thienopyrimidines: 1- (2- ((2R, 6S) -2,6- dimethylated morpholinyl) -4- morpholino thieno [3,2-d] pyrimidine -6- base) ethyl acrylate preparation.
By the resulting compound 10 of embodiment 10 and acrylic acid, esterification occurs under the conditions of existing for the trifluoroacetic acid and obtains To compound 15.
H1-NMR(CDCl3): δ 7.02 (s, 1H), δ 6.31 (d, 1H), δ 6.03 (t, 1H), δ 5.56 (d, 1H), δ 5.32 (q, 1H), δ 4.5 (d, 2H), δ 3.88 (t, 4H), δ 3.83 (t, 4H), δ 3.67 (t, 2H), δ 1.63 (d, 2H), 1.78 (d, 3H), δ 1.26(d,6H)。
Embodiment 16
A kind of thienopyrimidines: 5- (2- ((2S, 6R) -2,6- dimethylated morpholinyl) -4- morpholino thieno [3,2-d] pyrimidine -6- base) pyridine -2- amine
H1-NMR(CDCl3): δ 8.35 (s, 1H), δ 7.83 (d, 1H), δ 6.74 (d, 1H), δ 7.02 (s, 1H), δ 4.54 (m, 2H), δ 3.91 (t, 4H), δ 3.87 (t, 4H), δ 3.68 (m, 2H), δ 2.66 (t, 2H), δ 1.68 (d, 6H).
Embodiment 17
A kind of thienopyrimidines: 2,6- dimethyl -4- (4- morpholinyl -6- (1 hydrogen-pyrazoles -5- base) thieno [3,2-d] pyrimidine -2-base) morpholine.
H1-NMR(CDCl3): δ 7.45 (d, 1H), δ 7.01 (s, 1H), δ 6.43 (d, 1H), δ 4.5 (d, 2H), δ 3.88 (t, 4H), δ 3.83 (t, 4H), δ 3.67 (t, 2H), δ 2.63 (d, 2H), δ 1.19 (d, 6H).
Embodiment 18
A kind of thienopyrimidines: (2S, 6R) -2,6- dimethyl -4- (7- methyl -4- morpholinyl -6- (1 hydrogen - Pyrazoles -5- base) thieno [3,2-d] pyrimidine -2-base) morpholine preparation.
The mixture of I a-2 and 500mmol urea of 100mmol 3- amino -4- methylthiophene -2- methyl formate is placed in micro- 200 DEG C of reaction 30min obtain chemical compounds I b-2 in wave reactor.50mmol chemical compounds I b-2 is mixed in 100ml phosphorus oxychloride Obtain I c-2 compound of chlorizate within back flow reaction 10 hours in solution.I c-2 compound of 34mmol is suspended in 150ml ethyl alcohol In, agitation and dropping 100mmol morpholine, after morpholine is added dropwise, reacts 2h and obtains chemical compounds I d-2 at room temperature.By 30mmol chemical combination I d-2,90mmol trifluoroacetic acid of object, 45mmol (2S, 6R) -2,6- thebaine are mixed in back flow reaction 3h in 100ml n-butanol Obtain chemical compounds I e-1.I e-5 of 20mmol is dissolved in the dry tetrahydrofuran of 100ml, nitrogen protection, is instilled at -78 DEG C 24mmol reagent n-butyllithium instills the tetrahydrofuran for having dissolved 60mmol iodine after stirring 2h, then reacts 4h and obtain chemical compounds I f'-2.Under room temperature, by 10mmol chemical compounds I f ' -2 and 15mmol 1H- pyrazoles -3- boric acid frequency any ester feelings existing for alkali Under condition, with Pd (II) for catalyst, with tetrahydrofuran solution, nitrogen protection, 110 DEG C be stirred overnight under the conditions of suzuki coupling occurs It even reacts, TCL monitors reaction process.After the reaction was completed reaction solution with volume ratio be 1:1 ethyl acetate and saturated sodium-chloride it is molten Then with the dry organic phase of anhydrous sodium sulfate organic phase is concentrated, silica gel column chromatography separating purification obtains compound in dichloro in liquid extraction Sodium borohydride reduction to be used in methane, reacts organic phase after the reaction was completed with saturated common salt water washing 3 times, anhydrous sodium sulfate is dry, Silica gel column chromatography separates to obtain compound as white solid 20.
H1-NMR(CDCl3): δ 7.45 (d, 1H), δ 6.43 (d, 1H), δ 4.5 (d, 2H), δ 3.88 (t, 4H), δ 3.83 (t, 4H), δ 3.67 (t, 2H), δ 2.63 (d, 2H), δ 2.21 (s, 3H), δ 1.26 (d, 6H).
Inhibited proliferation of the thienopyrimidines of the present invention to Human Prostate Cancer Cells PC3:
Specific embodiment: the Human Prostate Cancer Cells in logarithmic growth phase are inoculated with the density in about 3000/hole In 96 well culture plates, 100 holes μ L/.Every hole concentration sets three multiple holes.And set respective concentration Vehicle controls and cell-free zeroing Hole.Adherent growth adds 100 hole μ L/ of compound or positive control drug (GDC-0941) of the present invention for 24 hours, and cell exists 10%Hyclone fetal calf serum, 37 DEG C, 5%CO2Under the conditions of cultivate 72h.The CCK-8 examination of 20 μ L is added in every hole under the conditions of being protected from light Agent, 37 DEG C, 5%CO2Under the conditions of continue culture 1-4 hours.OD value is measured under microplate reader 450nM wavelength, is obtained in fact by calculating A compound is applied for PC3The IC50 value of cell:
Compound IC50(μM)
GDC-0941 0.328
Embodiment 1 1.051
Embodiment 2 2.255
Embodiment 3 2.693
Embodiment 4 1.321
Embodiment 5 1.148
Embodiment 6 0.815
Embodiment 7 1.918
Embodiment 8 1.062
Embodiment 9 2.178
Embodiment 10 1.381
Embodiment 11 0.068
Embodiment 12 2.972
Embodiment 13 2.489
Embodiment 14 2.753
Embodiment 15 1.447
Embodiment 16 1.343
Embodiment 17 0.093
Embodiment 18 0.718
Test result shows: the compounds of this invention is to Human Prostate Cancer Cells (PC3) there is good inhibited proliferation.
The present invention is not limited to above-mentioned preferred forms, anyone can show that other are various under the inspiration of the present invention The product of form, however, make any variation in its details, it is all that there is technical solution identical or similar to the present application, It is within the scope of the present invention.

Claims (2)

1. a kind of thienopyrimidines, which is characterized in that be the compound of following structural formula:
2. thienopyrimidines described in claim 1 are preparing the application in curing cancer drug.
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