CN108503643B - Process for the preparation of protease inhibitors - Google Patents
Process for the preparation of protease inhibitors Download PDFInfo
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- CN108503643B CN108503643B CN201710110497.6A CN201710110497A CN108503643B CN 108503643 B CN108503643 B CN 108503643B CN 201710110497 A CN201710110497 A CN 201710110497A CN 108503643 B CN108503643 B CN 108503643B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 title claims description 8
- 230000008569 process Effects 0.000 title claims description 5
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 238000003756 stirring Methods 0.000 claims abstract description 33
- 239000000243 solution Substances 0.000 claims abstract description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000012074 organic phase Substances 0.000 claims abstract description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims abstract description 16
- 238000004440 column chromatography Methods 0.000 claims abstract description 16
- 238000001035 drying Methods 0.000 claims abstract description 15
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
- WRXIPCQPHZMXOO-UHFFFAOYSA-N 3,5-dichlorobenzenethiol Chemical compound SC1=CC(Cl)=CC(Cl)=C1 WRXIPCQPHZMXOO-UHFFFAOYSA-N 0.000 claims abstract description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 12
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- 238000005406 washing Methods 0.000 claims abstract description 9
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims abstract description 8
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- 239000012312 sodium hydride Substances 0.000 claims abstract description 8
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- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 6
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- RELMFMZEBKVZJC-UHFFFAOYSA-N 1,2,3-trichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1Cl RELMFMZEBKVZJC-UHFFFAOYSA-N 0.000 claims description 3
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 claims description 3
- 229930024421 Adenine Natural products 0.000 claims description 3
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 3
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- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 3
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- 239000007795 chemical reaction product Substances 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
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- 238000010907 mechanical stirring Methods 0.000 claims description 3
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- 101150065069 Hsp90b1 gene Proteins 0.000 abstract description 4
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- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Abstract
The invention relates to a Grp94 specific Hsp-90 inhibitor, provides a preparation method of a protease inhibitor, solves the blank defects of the preparation method in the prior art, and comprises the following processing steps: putting anhydrous dimethylformamide into a three-neck flask, adding 3, 5-dichlorothiophenol under the protection of nitrogen, stirring to completely dissolve, slowly adding sodium hydride, and stirring at normal temperature to react for 1 hour; then adding 8-bromo-9- (3-isopropylamino) n-propyladenine while stirring, slowly raising the temperature to 150 ℃ after the addition, and carrying out reflux reaction for 6 hours; after the reaction is completed, cooling to room temperature, slowly adding the reaction liquid into water, quenching unreacted sodium hydride, extracting by using a dichloromethane/methanol mixed solution, washing an organic phase by using saturated saline solution and saturated ammonium chloride solution for multiple times, extracting by using saturated sodium bicarbonate for multiple times, drying by using anhydrous magnesium sulfate, carrying out rotary evaporation, and purifying by using column chromatography and a column.
Description
Technical Field
The invention relates to a Grp94 specific Hsp-90 inhibitor, in particular to a preparation method of a protease inhibitor.
Background
Grp-specific inhibitors are a new class of very hot protease inhibitors. Grp (glucose regulated proteins), a class of stress proteins distributed in the lumen of the endoplasmic reticulum, have as major members Grp78 and Grp94, which are involved in the folding of nascent peptide chains during protein synthesis and function as chaperones. Chaperones play an important role in cellular function by ensuring proper folding after protein synthesis and their refolding under conditions of deforming stress, which are an important part of cellular response to stress, and furthermore, by regulating proper folding of various cellular proteins, chaperones play an important role in regulating cellular functions such as cell proliferation and apoptosis. Heat shock proteins (Hsp) are a class of chaperones that accumulate in cells in response to various environmental stresses, such as heat shock, oxidative stress or the presence of alcohols or heavy metals, and in addition to their role in protecting cells from such environmental stresses, Hsp can play an important role as a chaperone for a variety of cellular proteins under stress-free conditions.
Hsp is the same homodimer that has ATPase activity and function in a series of complex interactions with multiple substrate proteins. However, Hsp-90 is unique relative to other chaperones in that most of its known substrate proteins are signal transduction proteins, and therefore Hsp-90 plays an important role in the regulation of cellular signal transduction networks. In particular, the substrate proteins for Hsp-90 include many cancer-associated muteins or overexpressed proteins, such as p53, Bcr-Abl kinase, Raf-1 kinase, Akt kinase, and Npm-Alk kinase. Thus, inhibition of Hsp-90 results in the selective degradation of these important signaling proteins, which are involved in apoptosis, cell proliferation and cell cycle regulation. Thus, because of the important role these signaling proteins play in disease states involving abnormal cell growth, such as cancer, Hsp-90 is an attractive therapeutic target. Therefore, it would be desirable to develop and develop new inhibitors of Hsp-90 activity. (document (a) Patel PD, Yan P, et al; Nat Chem biol.2013, 9(11),677 (b) Argjing, Yangbao, etc.; pharmaceutical Proc. 2015,50(6),640.(c) Zhujiang, Li Huiyu, etc.; tumor prevention and treatment research 2010,37(12),1442, (d) Rohao Ming, Sunwen, etc.; pharmaceutical Proc. 2010,45(7), 813).
Research shows that PU-WS13 as a high-efficiency Grp94 specific Hsp-90 inhibitor can effectively reduce the over-expression of HER2 on the surface of breast cancer cells, can strongly inhibit the activity and survival of human multiple myeloma cells in an in vitro environment, and is a promising novel anticancer medicament in the future. However, there are currently few methods for the preparation of such materials.
Disclosure of Invention
Therefore, in view of the above, the present invention provides a preparation method of a protease inhibitor, which solves the blank defects of the prior art related to the preparation method.
In order to achieve the purpose, the invention is realized by the following technical scheme: the preparation method of the protease inhibitor is characterized by comprising the following processing steps:
putting 200ml of anhydrous dimethylformamide into a three-neck flask, firstly adding 14-16 g of 3, 5-dichlorothiophenol under the protection of nitrogen, stirring to completely dissolve the 3, 5-dichlorothiophenol, then slowly adding 2-3 g of sodium hydride, and stirring to react for 1 hour at normal temperature; then adding 20-24.5 g of 8-bromo-9- (3-isopropylamino) n-propyladenine while stirring, slowly raising the temperature to 150 ℃ after the addition, and carrying out reflux reaction for 6-7 hours;
and cooling to room temperature after complete reaction, slowly adding the reaction liquid into water, quenching unreacted sodium hydride, extracting with a dichloromethane/methanol mixed solution of 10/1, washing an organic phase with saturated saline solution and saturated ammonium chloride solution for multiple times, extracting with saturated sodium bicarbonate for multiple times, drying with anhydrous magnesium sulfate, performing rotary evaporation, and purifying by column chromatography and chromatography to obtain a pure product PU-WS 13.
The further improvement is that: the preparation method of the 3, 5-dichlorothiophenol comprises the following steps:
(1) preparation of 3, 5-dichlorobenzylthiophenol: adding 20-25 ml of dimethyl sulfoxide into a drying reaction bottle, gradually dissolving 2-3 g of trichlorobenzene, 1.37-1.4 g of benzyl mercaptan, 212-215 mg of cuprous iodide, 130-132 mg of benzotriazole and 1.74-1.76 g of potassium tert-butoxide into the dimethyl sulfoxide one by one under stirring, keeping the temperature below 40 ℃, then slowly raising the temperature to 100 ℃, and stirring and reacting for 16 hours under the condition; after the reaction is finished, cooling to room temperature, pouring the reaction liquid into 50-55 ml of sodium bicarbonate solution, extracting with ethyl acetate, drying an organic phase with anhydrous magnesium sulfate, carrying out rotary evaporation to obtain a crude product of 3, 5-dichlorobenzyl thiophenol, and carrying out column chromatography separation and purification on the obtained crude product to obtain a pure product of 3, 5-dichlorobenzyl thiophenol;
(2) then, putting 30-35 ml of anhydrous toluene into a dry reaction bottle, adding 1.5-1.7 g of pure 3, 5-dichlorobenzylthiophenol, stirring until the raw materials are completely dissolved, slowly adding 2.9-3.0 g of solid sodium, and carrying out reflux reaction for 10 hours under the protection of nitrogen; after the reaction is finished, cooling the reaction product to 0 ℃ by using ice water, carefully quenching redundant solid sodium by using ethanol, then adding 80-85 ml of ammonium chloride aqueous solution, adjusting the solution to acidity, extracting by using 50-60 ml of ethyl acetate, drying an organic phase by using anhydrous magnesium sulfate, performing rotary evaporation, and performing column chromatography purification to obtain a pure product of 3, 5-dichlorothiophenol.
The further improvement is that: the preparation method of the 8-bromo-9- (3-isopropylamino) n-propyladenine comprises the following steps:
(1) preparation of 8-bromoadenine:
firstly, adding 40-45 g of adenine into a flask, adding 100-107 ml of liquid bromine under mechanical stirring, wherein the adding process needs to be slow, and then stirring for 3 hours at normal temperature;
after the reaction is finished, adding sodium bisulfite solution to remove redundant liquid bromine, and then adjusting the reaction solution to be neutral by ammonia water to separate out white powdery solid. Filtering, and washing the solid with ice water to obtain 8-bromoadenine;
(2) preparation of 8-bromo-9-bromopropyladenine:
dissolving 8-10 g of 8-bromoadenine in 60-70 ml of dimethylformamide in a three-neck flask, stirring until the 8-bromoadenine is completely dissolved, slowly adding 15-20 g of 1, 3-dibromopropane and 16-20 g of cesium carbonate, raising the temperature to 100 ℃, and stirring for reacting for 16 hours at the temperature;
after the reaction is finished, cooling to room temperature, pouring the mixture into pure water, extracting the mixture by using a dichloromethane/methanol 10/1 mixed solution, washing an organic phase by using a saturated ammonium chloride solution, drying the organic phase by using anhydrous magnesium sulfate, carrying out rotary evaporation, and purifying an obtained crude product by using column chromatography to obtain a pure product 8-bromo-9-bromopropyladenine;
(3) 8-bromo-9- (3-isopropylamino) n-propyladenine:
putting 80ml of dimethylformamide into a flask, slowly adding 5-7 g of 8-bromo-9-bromopropyladenine, 12.5-15 g of isopropylamine and 15-20 ml of triethylamine while stirring, and stirring at normal temperature for 16 hours after the addition;
after the reaction, rotary evaporation is carried out at 40 ℃, redundant isopropylamine and triethylamine are removed, the rest reaction solution is diluted by ethyl acetate, then saturated saline solution and saturated ammonium chloride solution are used for multiple times of extraction, then saturated sodium bicarbonate is used for extraction, the organic phase is dried by anhydrous magnesium sulfate, concentrated and purified by column chromatography, and the pure 8-bromo-9- (3-isopropylamino) n-propyl adenine is obtained.
By adopting the technical scheme, the invention has the beneficial effects that: the preparation method of the PU-WS13 comprises the following steps:
the obtained PU-WS13 has high purity, and the blank of the preparation method of PU-WS13 in the prior art is solved.
Drawings
FIG. 1 is a structural identification map of a protease inhibitor according to an embodiment of the present invention.
Detailed Description
The following detailed description will be provided for the embodiments of the present invention with reference to specific embodiments, so that how to apply the technical means to solve the technical problems and achieve the technical effects can be fully understood and implemented.
Unless otherwise indicated, the techniques employed in the examples are conventional and well known to those skilled in the art, and the reagents and products employed are also commercially available. The source, trade name and if necessary the constituents of the reagents used are indicated at the first appearance.
The embodiment of the invention is as follows:
referring to fig. 1, a method for preparing a protease inhibitor, comprising the following processing steps:
(1) preparation of 3, 5-dichlorobenzylthiophenol:
adding dimethyl sulfoxide (20ml) into a dry reaction bottle, slowly dissolving trichlorobenzene (2g), benzyl mercaptan (1.37g), cuprous iodide (212mg), benzotriazole (132mg) and potassium tert-butoxide (1.74g) into the dimethyl sulfoxide (20ml) one by one under stirring, keeping the temperature below 40 ℃, then slowly raising the temperature to 100 ℃, and stirring to react for 16 hours under the condition;
after the reaction, cooling to room temperature, pouring the reaction liquid into sodium bicarbonate solution (50ml), extracting with ethyl acetate, drying an organic phase with anhydrous magnesium sulfate, carrying out rotary evaporation to obtain a crude product of 3, 5-dichlorobenzyl thiophenol, and carrying out column chromatography separation and purification on the obtained crude product to obtain a pure product of 3, 5-dichlorobenzyl thiophenol, wherein the white solid is 248mg, and the yield is 83.7%;
(2) preparation of 3, 5-dichlorothiophenol:
putting anhydrous toluene (30ml) into a dry reaction bottle, adding 3, 5-dichlorobenzylthiophenol (1.7g), stirring until all raw materials are dissolved, slowly adding solid sodium (2.9g), and carrying out reflux reaction for 10 hours under the protection of nitrogen;
after the reaction is finished, cooling the reaction product to 0 ℃ by using ice water, carefully quenching redundant solid sodium by using ethanol, then adding an ammonium chloride aqueous solution (80ml), adjusting the solution to acidity, extracting the solution by using ethyl acetate (60ml), drying an organic phase by using anhydrous magnesium sulfate, carrying out rotary evaporation, and purifying by using column chromatography to obtain a pure product of 3, 5-dichlorothiophenol, wherein 960mg of white solid is obtained, and the yield is 84.9%;
(3) preparation of 8-bromoadenine:
firstly, adding adenine (40g) into a flask, adding liquid bromine (107ml) under mechanical stirring, wherein the adding process needs to be slow, and then stirring for 3 hours at normal temperature;
after the reaction is finished, adding sodium bisulfite solution to remove redundant liquid bromine, and then adjusting the reaction solution to be neutral by ammonia water to separate out white powdery solid. Filtering, washing the solid with ice water to obtain 8-bromoadenine which is 54g of light yellow solid and has the yield of 85.7 percent;
(4) preparation of 8-bromo-9-bromopropyladenine:
in a three-neck flask, firstly 8-bromoadenine (8g) is dissolved in dimethylformamide (60ml), stirred until the 8-bromoadenine is completely dissolved, then 1, 3-dibromopropane (15g) and cesium carbonate (16g) are slowly added, the temperature is raised to 100 ℃, and the reaction is stirred at the temperature for 16 hours;
after the reaction is finished, cooling to room temperature, pouring the mixture into pure water, extracting the mixture by using a dichloromethane/methanol 10/1 mixed solution (100ml), washing an organic phase by using a saturated ammonium chloride solution, drying the organic phase by using anhydrous magnesium sulfate, carrying out rotary evaporation, and purifying an obtained crude product by using column chromatography to obtain a pure product 8-bromo-9-bromopropyladenine, wherein the white solid is 5.4g, and the yield is 54%;
(5) 8-bromo-9- (3-isopropylamino) n-propyladenine:
80ml of dimethylformamide was placed in a flask, and 8-bromo-9-bromopropyladenine (5g), isopropylamine (12.5g) and triethylamine (15ml) were slowly added with stirring, and after the addition, the mixture was stirred at room temperature for 16 hours;
after the reaction, the reaction solution is first rotary evaporated at 40 ℃ to remove excessive isopropylamine and triethylamine. Diluting the rest reaction solution with ethyl acetate (200ml), extracting with saturated saline solution and saturated ammonium chloride solution for multiple times, extracting with saturated sodium bicarbonate, drying the organic phase with anhydrous magnesium sulfate, concentrating, and purifying with column chromatography to obtain pure 8-bromo-9- (3-isopropylamino) n-propyladenine, which is a white solid 4.08g, 87.7%;
(6) preparation of protease inhibitors:
putting 200ml of anhydrous dimethylformamide into a three-neck flask, firstly adding 14g of 3, 5-dichlorothiophenol under the protection of nitrogen, stirring to completely dissolve the 3, 5-dichlorothiophenol, then slowly adding 3g of sodium hydride, and stirring at normal temperature to react for 1 hour; then adding 8-bromo-9- (3-isopropylamino) n-propyladenine (24.5g) while stirring, slowly raising the temperature to 150 ℃ after the addition, and carrying out reflux reaction for 6 hours;
after the reaction is completed, the reaction solution is cooled to room temperature, the reaction solution is slowly added into water, unreacted sodium hydride is quenched, a dichloromethane/methanol mixed solution is used for extraction, an organic phase is washed by saturated brine and saturated ammonium chloride solution for multiple times, and is extracted by saturated sodium bicarbonate for multiple times, then the mixture is dried by anhydrous magnesium sulfate, rotary evaporation is carried out, column chromatography and column purification are carried out, so that a pure protease inhibitor is obtained, wherein the yield is 83.2 percent, the light yellow solid is 24.8g,1H--NMR(400MHz,DMSO-d6)：8.62-8.65(m,1H)，8.43(s,1H)，8.24-8.26(m,1H)，8.11-8.12(m,1H)，7.50-7.51(m,2H)，7.46-7.47(m,1H),4.38-4.42(t,2H)，3.31(m,1H)，2.90-2.93(m,2H)，2.22-2.26(t,2H)，1.18-1.20(d,6H)。
the above description is only an embodiment utilizing the technical content of the present disclosure, and any modification and variation made by those skilled in the art can be covered by the claims of the present disclosure, and not limited to the embodiments disclosed.
Claims (1)
1. The preparation method of the protease inhibitor is characterized by comprising the following processing steps:
putting 200ml of anhydrous dimethylformamide into a three-neck flask, firstly adding 14-16 g of 3, 5-dichlorothiophenol under the protection of nitrogen, stirring to completely dissolve the 3, 5-dichlorothiophenol, then slowly adding 2-3 g of sodium hydride, and stirring to react for 1 hour at normal temperature; then adding 20-24.5 g of 8-bromo-9- (3-isopropylamino) n-propyladenine while stirring, slowly raising the temperature to 150 ℃ after the addition, and carrying out reflux reaction for 6-7 hours;
after the reaction is completed, cooling to room temperature, slowly adding the reaction liquid into water, quenching unreacted sodium hydride, extracting by using a dichloromethane/methanol 10/1 mixed solution, washing an organic phase by using saturated saline solution and saturated ammonium chloride solution for multiple times, extracting by using saturated sodium bicarbonate for multiple times, drying by using anhydrous magnesium sulfate, carrying out rotary evaporation, and purifying by using column chromatography and a column to obtain a pure product PU-WS 13;
the preparation method of the 3, 5-dichlorothiophenol comprises the following steps:
(1) preparation of 3, 5-dichlorobenzylthiophenol: adding 20-25 ml of dimethyl sulfoxide into a drying reaction bottle, gradually dissolving 2-3 g of trichlorobenzene, 1.37-1.4 g of benzyl mercaptan, 212-215 mg of cuprous iodide, 130-132 mg of benzotriazole and 1.74-1.76 g of potassium tert-butoxide into the dimethyl sulfoxide one by one under stirring, keeping the temperature below 40 ℃, then slowly raising the temperature to 100 ℃, and stirring and reacting for 16 hours under the condition; after the reaction is finished, cooling to room temperature, pouring the reaction liquid into 50-55 ml of sodium bicarbonate solution, extracting with ethyl acetate, drying an organic phase with anhydrous magnesium sulfate, carrying out rotary evaporation to obtain a crude product of 3, 5-dichlorobenzyl thiophenol, and carrying out column chromatography separation and purification on the obtained crude product to obtain a pure product of 3, 5-dichlorobenzyl thiophenol;
(2) then, putting 30-35 ml of anhydrous toluene into a dry reaction bottle, adding 1.5-1.7 g of pure 3, 5-dichlorobenzylthiophenol, stirring until the raw materials are completely dissolved, slowly adding 2.9-3.0 g of solid sodium, and carrying out reflux reaction for 10 hours under the protection of nitrogen; after the reaction is finished, cooling the reaction product to 0 ℃ by using ice water, carefully quenching redundant solid sodium by using ethanol, then adding 80-85 ml of ammonium chloride aqueous solution, adjusting the solution to acidity, extracting by using 50-60 ml of ethyl acetate, drying an organic phase by using anhydrous magnesium sulfate, performing rotary evaporation, and performing column chromatography purification to obtain a pure product of 3, 5-dichlorothiophenol;
the preparation method of the 8-bromo-9- (3-isopropylamino) n-propyladenine comprises the following steps:
a. preparation of 8-bromoadenine:
firstly, adding 40-45 g of adenine into a flask, adding 100-107 ml of liquid bromine under mechanical stirring, wherein the adding process needs to be slow, and then stirring for 3 hours at normal temperature; after the reaction is finished, adding sodium bisulfite solution to remove redundant liquid bromine, and then adjusting the reaction solution to be neutral by ammonia water to separate out white powdery solid; filtering, and washing the solid with ice water to obtain 8-bromoadenine;
b. preparation of 8-bromo-9-bromopropyladenine:
dissolving 8-10 g of 8-bromoadenine in 60-70 ml of dimethylformamide in a three-neck flask, stirring until the 8-bromoadenine is completely dissolved, slowly adding 15-20 g of 1, 3-dibromopropane and 16-20 g of cesium carbonate, raising the temperature to 100 ℃, and stirring for reacting for 16 hours at the temperature; after the reaction is finished, cooling to room temperature, pouring the mixture into pure water, extracting the mixture by using a dichloromethane/methanol 10/1 mixed solution, washing an organic phase by using a saturated ammonium chloride solution, drying the organic phase by using anhydrous magnesium sulfate, carrying out rotary evaporation, and purifying an obtained crude product by using column chromatography to obtain a pure product 8-bromo-9-bromopropyladenine;
c. 8-bromo-9- (3-isopropylamino) n-propyladenine:
putting 80ml of dimethylformamide into a flask, slowly adding 5-7 g of 8-bromo-9-bromopropyladenine, 12.5-15 g of isopropylamine and 15-20 ml of triethylamine while stirring, and stirring at normal temperature for 16 hours after the addition;
after the reaction, the reaction solution is firstly subjected to rotary evaporation at 40 ℃ to remove redundant isopropylamine and triethylamine, the rest reaction solution is diluted by ethyl acetate, then the saturated saline solution and the saturated ammonium chloride solution are used for multiple times of extraction, then the saturated sodium bicarbonate solution is used for extraction, the organic phase is dried by anhydrous magnesium sulfate, concentrated and purified by column chromatography to obtain the pure 8-bromo-9- (3-isopropylamino) n-propyl adenine.
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| CN1420864A (en) * | 2000-04-26 | 2003-05-28 | 住友精化株式会社 | Process for producing bishalophenyl disulfide |
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| CN1420864A (en) * | 2000-04-26 | 2003-05-28 | 住友精化株式会社 | Process for producing bishalophenyl disulfide |
| CN101505762A (en) * | 2005-12-22 | 2009-08-12 | 康福玛医药公司 | Orally active purine-based inhibitors of heat shock protein 90 |
| CN105899503A (en) * | 2013-08-16 | 2016-08-24 | 纪念斯隆-凯特琳癌症中心 | Selective GRP94 inhibitors and uses thereof |
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