CN110372612A - A kind of preparation method of bortezomib derivative - Google Patents
A kind of preparation method of bortezomib derivative Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method of bortezomib derivative, the bortezomib derivative is indicated by following formula 1:The bortezomib derivative is a kind of important impurity of generation during bortezomib synthesis process and/or storage.By the preparation method according to the application, above-mentioned bortezomib derivative can be made with higher yield.
Description
Technical field
The present invention relates to medicine synthesis and analysis fields, and in particular, to a kind of preparation method of bortezomib derivative.
Background technique
Bortezomib (Bortezomib, PS-341), scientific name: [(1R)-3- methyl-1-[[(2S)-1- oxygen-3- phenyl-2-
[(pyrazine formyl) amino] propyl] amino] butyl]-boric acid, No. CAS: 179324-69-7, molecular formula: C19H25BN4O4, molecule
Amount: 384.24, it is a kind of anticancer drug, the treatment suitable for Huppert's disease and lymphoma mantle cell.Bortezomib is also
For the first proteasome inhibitor of the mankind, inhibit 20S proteasome (20S by targeted serine-threonine residue
Proteasome), to destroy the cell cycle, induce cell apoptosis and inhibit nuclear factor NF- κ B.Compared with classic chemotherapy,
Bortezomib can reach higher complete incidence graph, can significantly extend the existence of tumor patient, clinical efficacy is definite, toxic side effect
It is small, it is not easy to cause drug resistance, and still have good therapeutic effect to the patient with kidney function damage and undesirable cell genetics characteristics.It is tied
Structure formula is as follows:
In order to guarantee patient medication quality and safety, side effect is reduced, is reinforced miscellaneous to being generated in product synthesis process
Quality Research and detection are of great significance.In particular, for human administration's security consideration, in a kind of active pharmaceutical ingredient
(API) it before product commercialization, needs to establish the identification of non-feature impurity in toxicology by country and international management organization
Extremely low lower limit.
The impurity of drug refers to present in drug without therapeutic effect or influences the stability of drug, curative effect or even right
The harmful substance of health of human body.The research of drug, production, storage and in terms of, it is necessary to keep the pure of drug
Degree, reduces the impurity of drug, just can guarantee the validity and safety of drug in this way.The impurity contained in drug is to influence drug
The principal element of purity has more than the impurity of limitation as contained in drug, it is possible to change physicochemical constant, appearance character generates
Variation, and influence the stability of drug；Impurity, which increases, also necessarily makes the content of drug relatively low or active reduction, toxic side effect are significant
Increase.It therefore, is a very important link for controlling pharmaceutical purity, improving drug quality for the research of impurity of the drug.
Summary of the invention
[technical problem]
To solve the above-mentioned problems, the present invention provides a kind of preparation methods of bortezomib derivative, and the boron is for assistant
The important impurity of one kind of generation during rice derivative is bortezomib synthesis process and/or stores.
[technical solution]
According to embodiment of the present invention, a kind of preparation method of bortezomib derivative is provided, the boron replaces
Assistant rice derivative is indicated by following formula 1:
Wherein, the preparation method comprises the following steps:
(a) the progress amidation process of compound 1 is carried out into prepare compound 2:
(b) the progress methylation reaction of compound 3 is carried out into prepare compound 4:
(c) compound 4 is subjected to hydroxyl protection reaction and carrys out prepare compound 5:
(d) reaction is hydrolyzed in compound 5 and carrys out prepare compound 6:
(e) the progress acyl chloride reaction of compound 6 is carried out into prepare compound 7:
(f) compound 7 and compound 2 are subjected to condensation reaction and carry out prepare compound 8:
(g) compound 8 is subjected to dehydroxylation protection reaction to prepare the bortezomib derivative:
The bortezomib derivative molecular formula is C19H22N4O4, molecular weight 370.16 is the conjunction in drug bortezomib
At the important impurity of the one kind generated during process and/or storage.By being synthesized to it, can more accurately detect
Its content in bortezomib product, and its physiological action to human body can be specified, it is replaced to targetedly improve boron
The drug effect of rice is helped, and reduces side effect.
In step (a), the condition of the condensation reaction can be with are as follows: with methylene chloride (DCM), n,N-Dimethylformamide
(DMF) or tetrahydrofuran (THF) is solvent, in the presence of n,N-diisopropylethylamine (DIEA) or triethylamine (TEA), with
HATU (2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphate) or EDCl (1- (3- dimethylamino third
Base) -3- ethyl-carbodiimide hydrochloride) it is that catalyst reacts 2 to 12 hours with ammonium hydroxide or ammonium salt at room temperature.Wherein, relatively
In compound 1, the amount of n,N-diisopropylethylamine or triethylamine can be 3.0 molar equivalents, and the amount of HATU or EDCl can be
NH in 1.5 molar equivalents and ammonium hydroxide or ammonium salt3Amount can be 1.5 to 3.0 molar equivalents.
It can be amide groups by the converting carboxylate groups of compound 1, to generate compound 2 in the amidation process.
In step (b), the condition of the methylation reaction can be with are as follows: using methanol as solvent, in Me2SO4Or H2SO4's
In the presence of react at room temperature 16 hours；Alternatively, using methylene chloride or tetrahydrofuran as solvent, using methanol as methylating reagent,
It is reacted at room temperature 5 to 16 hours in the presence of HATU or EDCl；Alternatively, with n,N-Dimethylformamide (DMF) for solvent, in K2CO3
It is reacted at room temperature 16 hours in the presence of MeI.
In the methylation reaction, the carboxyl of compound 3 is replaced by methyl and generates methoxycarbonyl group, to obtain chemical combination
Object 4.
In step (c), the condition of hydroxyl protection reaction can be with are as follows: with methylene chloride, dichloroethanes (DCE) or four
Hydrogen furans (THF) is solvent, with TBSOTf (tert-butyl dimethyl silyl triflate) or TBSCl (tert-butyldimethylsilyl chloride
Silane) it is hydroxy-protecting agent, in the presence of pyridine, react at room temperature 1 to 16 hour, preferably 16 hours.Wherein, relative to chemical combination
Object 4, the amount of pyridine can be that the amount of 3.0 molar equivalents and TBSOTf or TBSCl can be 2.5 molar equivalents.
In hydroxyl protection reaction, the hydroxyl of compound 4 is reacted with TBSOTf or TBSCl generates compound 5, thus
Influence of the hydroxyl to following reaction is avoided, and in the appropriate stage, deprotection reaction can also be carried out to restore hydroxyl.
In step (d), the condition of the hydrolysis can be with are as follows: with MeOH/H2O、THF/H2O or MeOH/THF/H2O
For solvent, in the presence of NaOH or LiOH, room temperature is to reacting 1 to 16 hour at 50 DEG C, wherein preferably 40 DEG C of reaction temperature, instead
Preferably 16 hours between seasonable.Wherein, relative to compound 5, the amount of NaOH or LiOH can be 1.5 molar equivalents.
In the hydrolysis, the methoxycarbonyl group (i.e. carbomethoxy) of compound 5 is hydrolyzed demethylating, to be changed
Close object 6.
In step (e), the condition of the acyl chloride reaction can be with are as follows: using methylene chloride or tetrahydrofuran as solvent, with
Thionyl chloride or oxalyl chloride are chloride reagent, in room temperature to reacting 16 hours at 40 DEG C.
In the acyl chloride reaction, the carboxyl of compound 6 forms chlorine acyl group, to obtain compound 7.
In step (f), the condition of the condensation reaction can be with are as follows: by compound 2 be dissolved in n,N-Dimethylformamide or
In tetrahydrofuran, it is added after NaH in room temperature to react at 50 DEG C 0.5 hour, it is small to react 1 at room temperature for addition compound 7 later
When；Alternatively, compound 2 and compound 7 are dissolved in n,N-Dimethylformamide or tetrahydrofuran, in the presence of triethyl amine,
It reacts 8 to 16 hours at room temperature.Wherein, relative to compound 2, the amount of compound 7 can be 1.0 molar equivalents, the amount of NaH
The amount that can be 2.0 molar equivalents and triethylamine can be 3.0 molar equivalents.
In the condensation reaction, the acid chloride groups of compound 7 and the amide group of compound 2 are condensed, thus raw
At compound 8.
In step (g), the condition of dehydroxylation protection reaction can be with are as follows: with tetrahydrofuran or methylene chloride is molten
Agent reacts at room temperature 1 to 16 hour, preferably 1 hour in the presence of tetrabutyl ammonium fluoride (TBAF)；Alternatively, using methanol as solvent,
The back flow reaction 1 to 16 hour in the presence of cesium fluoride.Wherein, relative to compound 8, the amount of tetrabutyl ammonium fluoride can be
The amount of 1.0 molar equivalents and cesium fluoride can be 3.0 molar equivalents.
In dehydroxylation protection reaction, the hydroxyl being protected is restored, and spreads out to generate the bortezomib
Biology.
[beneficial effect]
By the preparation method according to the application, above-mentioned bortezomib derivative can be made with higher yield.
Detailed description of the invention
Fig. 1 is that the nuclear-magnetism of the bortezomib derivative according to prepared by the preparation method of the embodiment of the application is total
Shake spectrogram.
Fig. 2 a and 2b are the bortezomib derivative according to prepared by the preparation method of the embodiment of the application
LCMS spectrogram.
Specific embodiment
Hereinafter, preferred embodiment is provided to more fully understand the present invention.However, these embodiments are only used for
Improving eyesight, and be not intended to the present invention being now set to these embodiments.
Reagent
(S) -3- phenyl -2- [(pyrazine -2- carbonyl) amino] propionic acid, No. CAS: 114457-94-2, purity 97% is purchased from
Shanghai Hao Hong biological medicine Science and Technology Ltd.；
2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphate (HATU), No. CAS: 148893-
10-1, purity 98% are purchased from Shanghai Hao Hong biological medicine Science and Technology Ltd.；
3-Hydroxy-3-methylbutyric acid, No. CAS: 625-08-1, purity 97% has purchased from the white great biological medicine science and technology in Shanghai
Limit company；
Tert-butyl dimethyl silyl triflate (TBSOTf), No. CAS: 69739-34-0, purity 97% is purchased from Shanghai
Hao Hong biological medicine Science and Technology Ltd.；
Thionyl chloride (SOCl2), No. CAS: 7719-09-7, it is purchased from the smooth Science and Technology Co., Ltd. of upper Haitai；
NaH, No. CAS: 7646-69-7, it is purchased from the smooth Science and Technology Co., Ltd. of upper Haitai；
Tetrabutyl ammonium fluoride (TBAF), tetrahydrofuran solution, No. CAS: 429-41-4, have purchased from the smooth scientific and technological share of upper Haitai
Limit company；
Other conventional reagents are purchased from Tianjin great Mao chemical reagent factory.
Instrument
Nuclear Magnetic Resonance, model: III HD 300 of AVANCE, manufacturing company: the limited public affairs of Brooker (Beijing) technological service
Department；
Liquid chromatograph-mass spectrometer (LCMS), model: LCMS-2020, manufacturing company: Japanese Shimadzu instrument company.
Embodiment
Embodiment 1
(a) the progress amidation process of compound 1 is carried out into prepare compound 2:
By (S) -3- phenyl -2- [(pyrazine -2- carbonyl) amino] propionic acid (compound 1) (5.0g, 18.4mmol, 1.0eq)
It is dissolved in methylene chloride (200mL), n,N-diisopropylethylamine (7.14g, 55.3mmol, 3.0eq) and HATU is added
30min is stirred at room temperature in (10.51g, 27.7mmol, 1.5eq), later be added ammonium hydroxide (3.76g, 25%/W, 55.3mmol,
3.0eq), it reacts at room temperature 2.5 hours.Later, the brine It (100mL × 3) reaction solution being saturated, then with anhydrous
Na2SO4Dry, vacuum rotary steam is to remove solvent.Gained crude product is purified by silica gel column chromatography, and obtains yellow solid (compound 2)
4.3g, yield 86.3%.
(b) the progress methylation reaction of compound 3 is carried out into prepare compound 4:
3-Hydroxy-3-methylbutyric acid (compound 3) (20g, 0.17mol, 1.0eq) is dissolved in methanol (200mL), is added
H2SO4After (3mL), reaction 16 hours is stirred at room temperature.Later, then reaction solution vacuum rotary steam is used into ethyl acetate to remove solvent
Then (200mL) dissolution, acquired solution use anhydrous Na with saturated common salt water washing (150mL × 3)2SO4It is dry, then vacuum rotary steam
To remove solvent.Gained crude product is purified by silica gel column chromatography, and obtains light yellow oil (compound 4) 7.6g, yield 33.8%.
(c) compound 4 is subjected to hydroxyl protection reaction and carrys out prepare compound 5:
Compound 4 (5.0g, 37.8mmol, 1.0eq) and pyridine (8.97g, 114.0mmol, 3.0eq) are dissolved in dichloromethane
In alkane (200mL) and -10 DEG C are cooled to, TBSOTf (25.0g, 94.6mmol, 2.5eq) then is added, warms naturally to room temperature
And it reacts 16 hours.Later, by reaction solution vacuum rotary steam to remove solvent, ethyl acetate (200mL) dissolution, acquired solution is added
(100mL × 1), NH is washed with water4Cl saturated solution washs (100mL × 3) and saturated common salt water washing (100mL × 1).
Then anhydrous Na is used2SO4It is dry, then vacuum rotary steam is to remove solvent.Gained crude product is purified by silica gel column chromatography, and obtains yellow oil
Shape object (compound 5) 7.6g, yield 81.5%.
(d) reaction is hydrolyzed in compound 5 and carrys out prepare compound 6:
Compound 5 (7.6g, 30.8mmol, 1.0eq) is dissolved in methanol (20mL), THF (20mL) and H2O's (20mL) is mixed
In bonding solvent, it is added NaOH (1.85g, 46.3mmol, 1.5eq), is reacted 16 hours at 40 DEG C.Later, reaction solution is depressurized
To remove solvent, then plus water (50mL) dilutes revolving, then (50mL × 2) are extracted with ethyl acetate to remove impurity.By gained
Water phase be cooled to 0 DEG C, be added 2M hydrochloric acid solution adjust pH to 4~5, (100mL × 3) are then extracted with ethyl acetate.It closes
And organic phase then uses anhydrous Na with saturated common salt water washing (150mL)2SO4Drying, then vacuum rotary steam are obtained with removing solvent
To light yellow oil (compound 6) 4.9g, yield 68.4%.
(e) the progress acyl chloride reaction of compound 6 is carried out into prepare compound 7:
Compound 6 (2.0g, 8.59mmol, 1.0eq) is added in methylene chloride (50mL), is cooled to 0 DEG C, is added
SOCl2(10mL) then heats to 40 DEG C and reacts 16 hours.Later, reaction solution vacuum rotary steam is added anhydrous with removing solvent
Methylene chloride (10mL), vacuum rotary steam are repeated 3 times, and obtain colorless oil (compound 7) 2.1g, yield 97.3%.
(f) compound 7 and compound 2 are subjected to condensation reaction and carry out prepare compound 8:
Compound 2 (2.0g, 7.43mmol, 1.0eq) is dissolved in tetrahydrofuran (30mL), NaH is added at 0 DEG C
(0.59g, 60%/W, 14.8mmol, 2eq) is warming up to 50 DEG C and reacts 0.5 hour, be then cooled to 0 DEG C again, compound 7 is added
Reaction 1 hour is stirred at room temperature in tetrahydrofuran (20mL) solution of (1.86g, 7.43mmol, 1.0eq).Later, into reaction solution
Water (10mL) is added to extract reaction of going out, then (30mL × 2) are extracted with ethyl acetate.Merge organic phase, with saturated common salt water washing
(20mL), uses anhydrous Na2SO4Drying, then vacuum rotary steam obtain light yellow oil (compound 8) 3.2g to remove solvent, receive
Rate 89.4%.
(g) compound 8 is subjected to dehydroxylation protection reaction to prepare the bortezomib derivative:
Compound 8 (3.2g, 6.56mmol, 1.0eq) is dissolved in tetrahydrofuran (20mL), TBAF (6.6mL, 1M is added
Tetrahydrofuran solution, 6.56mmol, 1.0eq), it reacts at room temperature 1 hour.Later, by reaction solution vacuum rotary steam to remove solvent, institute
It obtains crude product to be purified by silica gel column chromatography, obtains white solid (bortezomib derivative) 705mg, yield 28.7%.
Embodiment 2
(a) the progress amidation process of compound 1 is carried out into prepare compound 2:
By (S) -3- phenyl -2- [(pyrazine -2- carbonyl) amino] propionic acid (compound 1) (5.0g, 18.4mmol, 1.0eq)
Be dissolved in n,N-Dimethylformamide (200mL), be added triethylamine (5.60g, 55.3mmol, 3.0eq) and EDCl (5.30g,
27.7mmol, 1.5eq), 30min is stirred at room temperature, ammonium hydroxide (3.76g, 25%/W, 55.3mmol, 3.0eq) is added later, room
Temperature reaction 2.5 hours.Later, the brine It (100mL × 3) reaction solution being saturated, then uses anhydrous Na2SO4It is dry,
Vacuum rotary steam is to remove solvent.Gained crude product is purified by silica gel column chromatography, and obtains yellow solid (compound 2) 4.05g, yield
81.3%.
(b) the progress methylation reaction of compound 3 is carried out into prepare compound 4:
3-Hydroxy-3-methylbutyric acid (compound 3) (20g, 170mmol, 1.0eq) is dissolved in methylene chloride (400mL),
Be added triethylamine (51.5g, 510mmol, 3.0eq), methanol (16.3g, 510mmol, 3.0eq) and HATU (95.6g,
254mmol, 1.5eq) after, reaction 16 hours is stirred at room temperature.Later, reaction solution washs (200mL with saturated sodium bicarbonate aqueous solution
× 3) anhydrous Na, is then used2SO4Dry, vacuum rotary steam is to remove solvent.Gained crude product is purified by silica gel column chromatography, and is obtained yellowish
Color grease (compound 4) 9.80g, yield 43.8%.
(c) compound 4 is subjected to hydroxyl protection reaction and carrys out prepare compound 5:
Compound 4 (5.0g, 37.83mmol, 1.0eq) and pyridine (8.97g, 113.50mmol, 3.0eq) are dissolved in dichloro
In ethane (200mL) and -10 DEG C are cooled to, TBSOTf (25.00g, 94.58mmol, 2.5eq) then is added, warms naturally to
Room temperature is simultaneously reacted 8 hours.Later, by reaction solution vacuum rotary steam to remove solvent, ethyl acetate (200mL) dissolution, gained is added
(100mL × 1), NH is washed with water in solution4Cl saturated solution wash (100mL × 3) and saturated common salt water washing (100mL ×
1).Then anhydrous Na is used2SO4It is dry, then vacuum rotary steam is to remove solvent.Gained crude product is purified by silica gel column chromatography, and obtains yellow
Grease (compound 5) 7.15g, yield 76.7%.
(d) reaction is hydrolyzed in compound 5 and carrys out prepare compound 6:
Compound 5 (7.15g, 29.0mmol, 1.0eq) is dissolved in the in the mixed solvent of methanol (35mL) and water (35mL),
It is added LiOH (1.04g, 43.5mmol, 1.5eq), reacts 12 hours at room temperature.Later, by reaction solution vacuum rotary steam to remove
Solvent, then plus water (70mL) dilutes, then (70mL × 2) are extracted with ethyl acetate to remove impurity.Resulting water phase is cooling
To 0 DEG C, the hydrochloric acid solution that 2M is added adjusts pH to 4~5, and (70mL × 3) are then extracted with ethyl acetate.Merge organic phase, uses
Saturated common salt water washing (140mL), then uses anhydrous Na2SO4Drying, then vacuum rotary steam obtain faint yellow oily to remove solvent
Object (compound 6) 4.25g, yield 63.0%.
(e) the progress acyl chloride reaction of compound 6 is carried out into prepare compound 7:
Compound 6 (4.25g, 18.3mmol, 1.0eq) is added in tetrahydrofuran (50mL), is cooled to 0 DEG C, is added
SOCl2(20mL) then heats to 40 DEG C and reacts 16 hours.Later, reaction solution vacuum rotary steam is added anhydrous with removing solvent
Tetrahydrofuran (20mL), vacuum rotary steam are repeated 3 times, and obtain colorless oil (compound 7) 4.35g, yield 94.8%.
(f) compound 7 and compound 2 are subjected to condensation reaction and carry out prepare compound 8:
Compound 2 (2.0g, 7.4mmol, 1.0eq) is dissolved in n,N-Dimethylformamide (30mL), is added at 0 DEG C
NaH (0.59g, 60%/W, 14.8mmol, 2eq) is warming up to room temperature reaction 0.5 hour, is then cooled to 0 DEG C again, and chemical combination is added
Reaction 1 hour is stirred at room temperature in n,N-Dimethylformamide (20mL) solution of object 7 (1.86g, 7.4mmol, 1.0eq).Later,
Water (10mL) is added into reaction solution to extract reaction of going out, ethyl acetate extraction (150mL) is added, with saturated common salt water washing
(50mL×3).Organic phase anhydrous Na2SO4Drying, then vacuum rotary steam obtain light yellow oil (compound to remove solvent
8) 2.30g, yield 64.1%.
(g) compound 8 is subjected to dehydroxylation protection reaction to prepare the bortezomib derivative:
Compound 8 (2.30g, 4.75mmol, 1.0eq) is dissolved in methylene chloride (20mL), TBAF (4.8mL, 1M is added
Tetrahydrofuran solution, 4.75mmol, 1.0eq), it reacts at room temperature 5 hours.Later, by reaction solution vacuum rotary steam to remove solvent, institute
It obtains crude product to be purified by silica gel column chromatography, obtains white solid (bortezomib derivative) 540mg, yield 30.7%.
Embodiment 3
(a) the progress amidation process of compound 1 is carried out into prepare compound 2:
By (S) -3- phenyl -2- [(pyrazine -2- carbonyl) amino] propionic acid (compound 1) (5.0g, 18.4mmol, 1.0eq)
Be dissolved in n,N-Dimethylformamide (200mL), be added triethylamine (5.60g, 55.3mmol, 3.0eq) and HATU (10.5g,
27.7mmol, 1.5eq), 30min is stirred at room temperature, ammonium chloride (1.48g, 27.7mmol, 1.5eq) is added later, room temperature reaction
12 hours.Later, the brine It (100mL × 3) reaction solution being saturated, then uses anhydrous Na2SO4It is dry, vacuum rotary steam
To remove solvent.Gained crude product is purified by silica gel column chromatography, and obtains yellow solid (compound 2) 4.40g, yield 88.3%.
(b) the progress methylation reaction of compound 3 is carried out into prepare compound 4:
3-Hydroxy-3-methylbutyric acid (compound 3) (20g, 170mmol, 1.0eq) is dissolved in tetrahydrofuran (200mL),
After methanol (27.1g, 847mmol, 5.0eq) and EDCl (39.0g, 203mmol, 1.2eq) is added, reaction 6 hours is stirred at room temperature.
Later, by reaction solution vacuum rotary steam to remove solvent, gained crude product is purified by silica gel column chromatography, and is obtained light yellow oil and (is changed
Close object 4) 7.05g, yield 31.5%.
(c) compound 4 is subjected to hydroxyl protection reaction and carrys out prepare compound 5:
Compound 4 (5.0g, 37.8mmol, 1.0eq) and pyridine (8.97g, 114mmol, 3.0eq) are dissolved in tetrahydrofuran
In (200mL) and -10 DEG C are cooled to, TBSCl (14.3g, 94.6mmol, 2.5eq) then is added, warms naturally to room temperature and anti-
It answers 12 hours.Later, by reaction solution vacuum rotary steam to remove solvent, ethyl acetate (200mL) dissolution, acquired solution water is added
It washs (100mL), NH4Cl saturated solution washs (100mL × 3) and saturated common salt water washing (100mL).Then with anhydrous
Na2SO4It is dry, then vacuum rotary steam is to remove solvent.Gained crude product is purified by silica gel column chromatography, and obtains yellow oil (compound
5) 4.30g, yield 46.1%.
(d) reaction is hydrolyzed in compound 5 and carrys out prepare compound 6:
Compound 5 (4.30g, 17.4mmol, 1.0eq) is dissolved in THF (25mL) and H2The in the mixed solvent of O (25mL),
It is added NaOH (1.05g, 26.2mmol, 1.5eq), is reacted 8 hours at 60 DEG C.Later, by reaction solution vacuum rotary steam to remove
Solvent, then plus water (50mL) dilutes, then (50mL × 2) are extracted with ethyl acetate to remove impurity.Resulting water phase is cooling
To 0 DEG C, the hydrochloric acid solution that 2M is added adjusts pH to 4~5, and (50mL × 3) are then extracted with ethyl acetate.Merge organic phase, uses
Saturated common salt water washing (50mL), then uses anhydrous Na2SO4Drying, then vacuum rotary steam obtain faint yellow oily to remove solvent
Object (compound 6) 2.05g, yield 50.6%.
(e) the progress acyl chloride reaction of compound 6 is carried out into prepare compound 7:
Compound 6 (2.0g, 8.6mmol, 1.0eq) is added in methylene chloride (50mL), is cooled to 0 DEG C, grass is added
Acyl chlorides (2.18g, 17.2mmol, 2.0eq) and then instills 2 drop DMF, then reacts 16 hours at room temperature.It later, will be anti-
Liquid vacuum rotary steam is answered to remove solvent, is added anhydrous methylene chloride (10mL), vacuum rotary steam is repeated 3 times, and obtains colorless oil
(compound 7) 2.10g, yield 97.3%.
(f) compound 7 and compound 2 are subjected to condensation reaction and carry out prepare compound 8:
Compound 2 (2.0g, 7.4mmol, 1.0eq) and compound 7 (1.86g, 7.4mmol, 1.0eq) are dissolved in tetrahydro furan
It mutters in (50mL), is added triethylamine (2.25g, 22.2mmol, 3.00eq), reaction 12h is stirred at room temperature.Later, into reaction solution
It is added saturated common salt water washing (20mL), uses anhydrous Na2SO4Drying, then vacuum rotary steam obtain faint yellow oily to remove solvent
Object (compound 8) 1.26g, yield 35.1%.
(g) compound 8 is subjected to dehydroxylation protection reaction to prepare the bortezomib derivative:
Compound 8 (1.26g, 2.60mmol, 1.0eq) is dissolved in methanol (25mL), addition cesium fluoride (3.95g,
26.0mmol, 10.0eq), back flow reaction 10 hours.Later, by reaction solution vacuum rotary steam to remove solvent, gained crude product is through silicon
It is gel column chromatography eluting, obtain white solid (bortezomib derivative) 190mg, yield 19.7%.
Nuclear magnetic resonance
(1) deuterated dimethyl sulfoxide (DMSO-d is used6) it is that solvent dissolves bortezomib derivative made from embodiment 1,
It is sent into III HD of AVANCE, 300 type Nuclear Magnetic Resonance to be measured, the nuclear-magnetism for obtaining bortezomib derivative as shown in Figure 1 is total
Shake map, and data are as follows:
1H NMR (300MHz, DMSO-d6) δ 10.82 (s, 1H), 9.11 (d, J=1.5Hz, 1H), 8.89 (d, J=
2.4Hz, 1H), 8.86 (s, 1H), 8.75 (dd, J=2.4Hz, J=1.5Hz, 1H), 7.34-7.14 (m, 5H), 5.33-5.26
(m, 1H), 4.74 (s, 1H), 3.21-3.07 (m, 2H), 2.59 (d, J=2.7Hz, 2H), 1.23 (s, 6H).
LC-MS (LCMS)
Using LCMS-2020 type liquid chromatograph-mass spectrometer, boron made from embodiment 1 is detected using the following conditions
Bortezomib derivative: column model: Shimadzu Shim-pack XR-ODS (50 × 3.0mm, 2.2 μm), mobile phase A: water/
0.05%FA, Mobile phase B: acetonitrile, Detection wavelength: 254nm；Ion source: ESI.Resulting map as shown in figures 2 a and 2b,
In, retention time 1.077min, [M+1]+=371.2.
The nuclear magnetic data of bortezomib derivative made from the preparation method of embodiment according to the present invention 2 and 3 and liquid matter
It is similar to Example 1 to be combined data, therefore is omitted herein.
Claims (10)
1. a kind of preparation method of bortezomib derivative, the bortezomib derivative are indicated by following formula 1:
Wherein, the preparation method comprises the following steps:
(a) the progress amidation process of compound 1 is carried out into prepare compound 2:
(b) the progress methylation reaction of compound 3 is carried out into prepare compound 4:
(c) compound 4 is subjected to hydroxyl protection reaction and carrys out prepare compound 5:
(d) reaction is hydrolyzed in compound 5 and carrys out prepare compound 6:
(e) the progress acyl chloride reaction of compound 6 is carried out into prepare compound 7:
(f) compound 7 and compound 2 are subjected to condensation reaction and carry out prepare compound 8:
(g) compound 8 is subjected to dehydroxylation protection reaction to prepare the bortezomib derivative:
2. preparation method according to claim 1, wherein in step (a), the condition of the condensation reaction are as follows: with two
Chloromethanes, n,N-Dimethylformamide or tetrahydrofuran are solvent, in the presence of n,N-diisopropylethylamine or triethylamine, with
HATU or EDCl is that catalyst reacts 2 to 12 hours with ammonium hydroxide or ammonium salt at room temperature.
3. preparation method according to claim 2, wherein relative to compound 1, n,N-diisopropylethylamine or triethylamine
Amount be 3.0 molar equivalents, the amount of HATU or EDCl are NH in 1.5 molar equivalents and ammonium hydroxide or ammonium salt3Amount be 1.5 to
3.0 molar equivalent.
4. preparation method according to claim 1, wherein in step (b), the condition of the methylation reaction are as follows: with
Methanol is solvent, in Me2SO4Or H2SO4In the presence of react at room temperature 16 hours；Alternatively, being molten with methylene chloride or tetrahydrofuran
Agent reacts at room temperature 5 to 16 hours in the presence of HATU or EDCl using methanol as methylating reagent；Alternatively, with N, N- dimethyl
Formamide is solvent, in K2CO3It is reacted at room temperature 16 hours in the presence of MeI.
5. preparation method according to claim 1, wherein in step (c), the condition of the hydroxyl protection reaction are as follows:
Using methylene chloride, dichloroethanes or tetrahydrofuran as solvent, using TBSOTf or TBSCl as hydroxy-protecting agent, in the presence of pyridine
Under, it reacts at room temperature 1 to 16 hour.
6. preparation method according to claim 5, wherein relative to compound 4, the amount of pyridine is 3.0 molar equivalents, with
And the amount of TBSOTf or TBSCl is 2.5 molar equivalents.
7. preparation method according to claim 1, wherein in step (d), the condition of the hydrolysis are as follows: with
MeOH/H2O、THF/H2O or MeOH/THF/H2O is solvent, in the presence of NaOH or LiOH, room temperature to reaction 1 at 50 DEG C to
16 hours.
8. preparation method according to claim 1, wherein in step (e), the condition of the acyl chloride reaction are as follows: with
Methylene chloride or tetrahydrofuran are solvent, using thionyl chloride or oxalyl chloride as chloride reagent, in room temperature to reacting 16 at 40 DEG C
Hour.
9. preparation method according to claim 1, wherein in step (f), the condition of the condensation reaction are as follows: will change
It closes object 2 to be dissolved in n,N-Dimethylformamide or tetrahydrofuran, be added after NaH in room temperature to reacting 0.5 hour at 50 DEG C, later
Compound 7 is added to react 1 hour at room temperature；Alternatively, compound 2 and compound 7 are dissolved in n,N-Dimethylformamide or four
In hydrogen furans, in the presence of triethyl amine, react 8 to 16 hours at room temperature.
10. preparation method according to claim 1, wherein in step (g), the condition of the dehydroxylation protection reaction
Are as follows: using tetrahydrofuran or methylene chloride as solvent, reacted at room temperature 1 to 16 hour in the presence of tetrabutyl ammonium fluoride；Alternatively, with
Methanol is solvent, the back flow reaction 1 to 16 hour in the presence of cesium fluoride.
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| WO2006040646A1 (en) * | 2004-10-14 | 2006-04-20 | Pfizer, Inc. | Benzimidazole or indole amides as inhibitors of pin1 |
| CN103497233A (en) * | 2013-09-30 | 2014-01-08 | 哈药集团技术中心 | Preparation method for bortezomib |
| CN103554219A (en) * | 2013-10-01 | 2014-02-05 | 昆明贵研药业有限公司 | Method for preparing bortezomib |
| JP2014076948A (en) * | 2011-02-09 | 2014-05-01 | Astellas Pharma Inc | Isoquinoline amide derivative |
| CN109134601A (en) * | 2017-06-15 | 2019-01-04 | 重庆医药工业研究院有限责任公司 | A kind of impurity of bortezomib and preparation method thereof |
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| WO2006040646A1 (en) * | 2004-10-14 | 2006-04-20 | Pfizer, Inc. | Benzimidazole or indole amides as inhibitors of pin1 |
| JP2014076948A (en) * | 2011-02-09 | 2014-05-01 | Astellas Pharma Inc | Isoquinoline amide derivative |
| CN103497233A (en) * | 2013-09-30 | 2014-01-08 | 哈药集团技术中心 | Preparation method for bortezomib |
| CN103554219A (en) * | 2013-10-01 | 2014-02-05 | 昆明贵研药业有限公司 | Method for preparing bortezomib |
| CN109134601A (en) * | 2017-06-15 | 2019-01-04 | 重庆医药工业研究院有限责任公司 | A kind of impurity of bortezomib and preparation method thereof |
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