CN107011322A - A kind of high-purity dehydrophenylahistin class compound prepares purification process - Google Patents
A kind of high-purity dehydrophenylahistin class compound prepares purification process Download PDFInfo
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Abstract
Purification process is prepared the invention provides a kind of high-purity dehydrophenylahistin class compound, its purpose essentially consists in removing transisomer.The present invention relates to (the 3Z for preparing high-purity, 6Z) 3 benzylidene 6 ((base of 5 tert-butyl group 1H imidazoles 4) methylene) piperazine 2,5 diketone monohydrates and (3Z, 6Z) 3 benzylidene 6 ((base of 5 tert-butyl group 1H imidazoles 4) deuterated methylene) piperazine 2,5 diketone monohydrates, the purity of obtained product is more than 99.5%, and trans-isomer content is less than 0.1%；The present invention relates to related important intermediate 5 simultaneously（The tert-butyl group）The preparation purifying of the Ethyl formate of 1H imidazoles 4 and the diketone of Isosorbide-5-Nitrae diacetyl piperazine 2,5, so as to reduce production cost, reduce post-processing difficulty, makes technique more conform to the requirement of industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, it is related to a kind of system of high-purity dehydrophenylahistin class compound
Standby purification process.
Background technology
Dehydrophenylahistin class compound (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls)
Methylene) structural formula of piperazine-2,5-dione is：
The compound is also known as Plinabulin (KPU-2, NPI-2358), is a kind of tubulin binding agent, bent from ocean
Low molecule the Cyclic dipeptides phenylahistin or halimide of mould synthesis of derivatives.It can be incorporated into tubulin
Near colchicin binding site, with good antitumor activity, especially in terms of non-small cell lung cancer, the medicine 2015 years
The second half year carries out three phases clinic in the U.S., and its Chinese medicine Pune cloth woods is also dense molten with injection Pune cloth woods in China
Liquid application is clinical, is examining at present.
(3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine-2,5-dione is photosensitive
Property it is stronger, especially in the solution, so can be produced in the preparation method that original grinds patent report, more ((3E, 6Z) -3- benzene is sub-
Methyl -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine -2,5- diketone isomers, the isomers is difficult to remove, this
Also bring problem to follow-up preparation, more can on medicine declaring and clinical safety produces influence, therefore prepare high-purity
(3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine-2,5-dione have it is important
Meaning.
Deuterated dehydrophenylahistin class compound (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazoles -
4- yls) deuterated methylene) piperazine -2,5- diketone is a kind of novel tubulin bonding agent, for its preparation method and in preparation
Application in anti-tumor drug, present invention applicant has applied for patent of invention, and number of patent application is 201510293269.8.But
((3E, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazoles -4- of certain content are also provided in its preparation method provided
Base) deuterated methylene) generation of piperazine-2,5-dione isomers.
Meanwhile, at present on (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine
What piperazine -2,5- diketone was reported prepare, and purification process is complex, and the column chromatography purifying of which part intermediate constrains the medicine
The industrialized production of thing, therefore it is significant to set up the technique of a set of suitable industrialized production.
The content of the invention
Object of the present invention is to provide a kind of preparation purifying side of high-purity dehydrophenylahistin class compound
Method, and in particular to high-purity (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine -2,
5- diketone and (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated methylene) piperazine-2,5-dione
Purifying process and its important intermediate prepare purification process.
For achieving the above object, the present invention is achieved using following technical scheme：
A kind of high-purity dehydrophenylahistin class compound prepares purification process, the dehydrophenylahistin class
Compound has formula（I）Shown structure,
（I）
Formula（I）Middle R1The polysubstituted substituent that five substitutions are not waited is substituted onto for one on phenyl ring, substituent is selected from hydrogen atom, deuterium
Atom, halogen atom, hydroxyl, methoxyl group, amino, phenyl, aminomethyl phenyl, C1-C24 alkyl, C2-C24 alkenyls, C2-C24
Alkynyl, aryl alkyl, heterocyclic aryl alkyl, C1-C24 acyl group, C1-C24 alkoxy, carboxyl, carboxylic acid ester groups, amide groups,
N- is monosubstituted or the disubstituted amide groups of N, N-, sulfonic group, sulfonate group, sulfoamido, N- substituted sulfonamides base, alkoxy, virtue
Base alkoxy, alkylthio group, cyano group, amino, the amino of substitution, nitro；Cycloalkyl, cycloalkenyl group, aromatic radical, substitution aromatic radical,
Fragrant heterocyclic radical, aryloxy group, aroyl, epoxy radicals, ring acyl group, fragrant sulfenyl, arylsulfonyl；
R2For hydrogen atom or D-atom, R3For hydrogen atom or D-atom；
X1For oxygen atom or sulphur atom, X2For oxygen atom or sulphur atom；
X3For-NH, oxygen atom or sulphur atom；
The purification process for preparing comprises the following steps：By formula（I）The crude compound is placed in brown bottle, heating condition
Lower addition isopropanol or ethanol or n-butanol add water and do not have crystal precipitation, be placed at 15-30 DEG C up to being completely dissolved,
Cooling crystallization is stirred, through suction filtration, washs and dry, obtains high-purity dehydrophenylahistin class compound.
Further：By (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated methylene) piperazine
Piperazine -2,5- diketone crude product is placed in brown bottle, is added isopropanol and is done under solvent, heating condition to being completely dissolved, adds water, institute
Volume ratio with isopropyl alcohol and water is VIsopropanol：VWater=1:5 to 100:1, it is placed at 15-30 DEG C, stirs cooling crystallization, through suction filtration, wash
Wash and dry, obtain high-purity (3Z, 6Z) -3- benzylidene -6- ((uncles 5- that faint yellow solid is less than 0.1 % for content of isomer
Butyl -1H- imidazol-4 yls) deuterated methylene) piperazine-2,5-dione monohydrate.
Further：The volume ratio of the isopropyl alcohol and water is VIsopropanol：VWater=5：2.
Further：Compound (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine
The preparation method of piperazine -2,5- diketone crude products is：
In the basic conditions, isocyano acid B ester, trimethyl acetic anhydride cyclization obtain 5-（The tert-butyl group）Oxazole -4- Ethyl formates；
Then by 5-（The tert-butyl group）The heating of oxazole -4- Ethyl formates formamide solvent is converted to imidazole ring, then hydrogenated aluminium lithium
Reduction, manganese dioxide obtains 5-（The tert-butyl group）- 1H- imidazoles -4- formaldehyde；By glycine anhydride acetic anhydride solvent dissolve 1,
4- diacetyl piperazine -2,5- diketone；
In the basic conditions, by 5-（The tert-butyl group）- 1H- imidazoles -4- formaldehyde is condensed with Isosorbide-5-Nitrae-diacetyl piperazine -2,5- diketone,
(3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine -2 are obtained with benzaldehyde again,
5- diketone crude products.
Further：By (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine -
2,5- diketone crude products are placed in brown bottle, are added isopropanol and are done under solvent, heating condition to being completely dissolved, add water, used
The volume ratio of isopropyl alcohol and water is VIsopropanol：VWater=1:10 to 100:1, it is placed at 15-30 DEG C, stirs cooling crystallization, through suction filtration, wash
Wash and dry, obtain high-purity (3Z, 6Z) -3- benzylidene -6- ((uncles 5- that faint yellow solid is less than 0.1 % for content of isomer
Butyl -1H- imidazol-4 yls) methylene) piperazine-2,5-dione monohydrate.
Further：The volume ratio of the isopropyl alcohol and water is VIsopropanol：VWater=5：2.
Further：The 5-（The tert-butyl group）- 1H- imidazoles -4- Ethyl formates are purified by following steps：By 5-
（The tert-butyl group）- 1H- oxazole -4- Ethyl formates and formamide heating response, after reaction terminates, mother liquor cooling, with sodium carbonate and stone
Oily ether is extracted and divided except petroleum ether layer impurity, is extracted through ethyl acetate, merges organic phase, then through washing, drying and be concentrated under reduced pressure
Concentrate is obtained, stirring to pulp is poured into water while hot, has solid precipitation, suction filtration, washing, vacuum drying obtain institute of the product for purifying
State 5-（The tert-butyl group）- 1H- imidazoles -4- Ethyl formates.
Further：1,4- diacetyl piperazines -2,5- the diketone is purified by following steps：By glycine anhydride
With acetic anhydride back flow reaction, after reaction terminates, mother liquor is cooled to room temperature, is concentrated under reduced pressure and steams solvent, concentrate dichloromethane
Dissolving, diatomite filtering, be concentrated under reduced pressure removing dichloromethane, and with re-crystallizing in ethyl acetate, low temperature crystallization, filtering is dry to produce
Thing is the 1,4- diacetyl piperazines -2,5- diketone of purifying.
Advantages of the present invention and have the technical effect that：For what is produced in dehydrophenylahistin class preparation of compounds
The problem of transisomer hardly possible is removed, the invention provides a kind of high-purity dehydrophenylahistin compounds purifying side
Method, especially (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine -2,5- diketone and
Preparing for (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated methylene) piperazine-2,5-dione is pure
Change method, this method solvent for use be by many experiments screen obtain, easily obtained with solvent for use, method is simple to operate,
The features such as high income, favorable reproducibility, obtained transisomer is less than 0.1 %, and this carries out medicine Shen for such compound
Report and safety evaluatio all have great importance.
Meanwhile, the invention, which is additionally provided, prepares dehydrophenylahistin class compound intermediate therefor 5-（The tert-butyl group）-
1H- imidazoles -4- Ethyl formates and N, N- diacetyl piperazine -2,5- diketone prepare purifying process, solve in the middle of both
Body is more beneficial for the industrialization production of such compound, improves yield, reduce into by crossing the problem that post is purified, this method
This.
Cis-product transisomer.
Brief description of the drawings
Fig. 1 is high-purity of the present invention (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated Asias
Methyl) HPLC spectrogram of the piperazine-2,5-dione monohydrate under 254 nm wavelength；
Fig. 2 is high-purity of the present invention (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated methylenes
Base) piperazine-2,5-dione monohydrate thermogravimetric analysis figure；
Fig. 3 is high-purity of the present invention (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine
HPLC spectrogram of the piperazine -2,5- diketone monohydrate under 254 nm wavelength；
Fig. 4 is high-purity of the present invention (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine
The thermogravimetric analysis figure of piperazine -2,5- diketone monohydrates.
Embodiment
Technical scheme is further described in detail below in conjunction with specific embodiment.
Embodiment 1
(3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated methylene) piperazine-2,5-dione crude product
Preparation
Its specific preparation process comprises the following steps：
1）(Z) preparation of -1- acetyl group -3- ((5- (tert-butyl group) -1H- imidazol-4 yls) deuterated methylene) piperazine-2,5-dione
By 10.00 g（65.29 mmol）5-（The tert-butyl group）The deuterated formaldehyde of -1H- imidazoles -4- is added to 50 mL DMF, adds
25.88 g（130.59 mmol）N, N- diacetyl piperazine -2,5- diketone nitrogen protection exhaust three times, adds 31.91 g
（97.94 mmol）Cesium carbonate, nitrogen protects exhaust three times, at room temperature the h of lucifuge stirring reaction 20.Reaction solution is poured into frozen water
In (400 mL), suction filtration, filter cake uses water (200 mL * 2), petroleum ether successively：Ethyl acetate=8:1 (200 mL) is washed, filter cake
With ethanol and dichloromethane ultrasonic disperse, insoluble matter is filtered off, is concentrated under reduced pressure, absolute ethyl alcohol band water.Ethyl acetate is used again（250
mL）Mashing.Yellow-brown solid (Z) -1- acetyl group -3- ((5- (tert-butyl group) -1H- imidazol-4 yls) deuterated methylene) piperazine -
The g of 2,5- diketone 8.96, the % of yield 47.11.
2）(3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated methylene) piperazine -2,5- two
The preparation of ketone crude product
By 8.84 g（30.33 mmol）(Z) -1- acetyl group -3- ((5- (tert-butyl group) -1H- imidazol-4 yls) deuterated methylene)
Piperazine -2,5- diketone is added to 25 mL DMF, adds 4.83 g（45.51 mmol）Benzaldehyde nitrogen protection three gas of row,
Add the g of cesium carbonate 14.82（45.49 mmol）Nitrogen protection three gas of row, temperature programming to 50 DEG C of stirring reaction 24h.Will be anti-
Liquid is answered to be poured into frozen water（300 mL）In, suction filtration, filter cake is successively with 200 mL*2 water, 200 mL petroleum ethers：Ethyl acetate=8:1 washes,
Filter cake ethanol（50 mL）And ethyl acetate（160 mL）Ultrasonic disperse, filters off insoluble matter, is concentrated under reduced pressure, absolute ethyl alcohol band water.
150 mL ethyl acetate ultrasonic disperses, are statically placed in -30 DEG C overnight.Suction filtration, filter cake glacial acetic acid ethyl ester（50 mL）Washing, is obtained
The g of greenish yellow solid 6.66, yield 65.09%.
Embodiment 2
High-purity (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated methylene) piperazine -2,5- two
The preparation of ketone monohydrate
Crude product described in 2.0 g embodiments 1 is placed in brown bottle, added under heating condition 125 mL isopropanols to completely it is molten
Solution, adding the mL of water 50 does not have crystal precipitation, is placed at room temperature, stirs cooling crystallization, suction filtration, isopropanol：Water=1:1 filter wash
Cake, dries, obtains the g of yellow powdery solid 1.642, the % of yield 78.13, purity of the product under 254 nm is 99.94 %,
Wherein isomers ((3E, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated methylene) piperazine -2,5-
Diketone is 0.06 %, sees Fig. 1.1H NMR (500 MHz, dmso) δ 12.22 (brs,2H), 10.00 (brs, 1H),
7.82 (d, J = 12.7 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.7 Hz,
2H), 7.30 (t, J = 7.4 Hz, 1H), 6.73 (s, 1H), 1.37 (s, 9H)。MS (ESI) m/z
338.1715 (M + H)+ (calcd for C19H20DN4O2)。
Products therefrom is (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated methylene) piperazine
The monohydrate of piperazine -2,5- diketone, test moisture is 5.314 %, and Fig. 2 supports for the data of thermogravimetric analysis collection of illustrative plates.Wherein
Elementary analysis see the table below 1：
Table 1 (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated methylene) piperazine-2,5-dione
The Elemental analysis data of monohydrate
| Sample ID | Test value（%） | Theoretical value（%） |
| (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine-2,5-dione monohydrate | C:64.19 N:15.78 H:6.24 | C:64.21 N:15.76 H:6.27 |
Embodiment 3
The system of (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine-2,5-dione crude product
Preparation Method
Its specific preparation process technique comprises the following steps：
1）5-（The tert-butyl group）The preparation of oxazole -4- Ethyl formates
By 90 g（796 mmol）Isocyano acid B ester is added to 1000 mL tetrahydrofurans, and 145 g are slowly added dropwise（955
mmol）DBU, is then added dropwise 178 g（955 mmol）Trimethyl acetic anhydride, drop finishes the h of stirring reaction 48 at room temperature.Reaction is finished, and is subtracted
Pressure concentration.Extraction, plus appropriate 1500 mL dichloromethane, successively with the % sodium carbonate of 800 mL 10, the % citric acids of 800 mL 10,
800 mL saturated common salts are washed, and 1000 mL dichloromethane strip aqueous are twice.Merge organic phase, anhydrous sodium sulfate drying, half
Suction filtration after hour, is concentrated under reduced pressure.Cross silica gel (200 ~ 300 mesh）Post (EA:PE=1:10、1:8、1:5）, obtaining the g of yellow liquid 177 is
The 5-（The tert-butyl group）Oxazole -4- Ethyl formates, the % of yield 113.
2）5-（The tert-butyl group）The preparation of -1H- imidazoles -4- Ethyl formates
By 157 g（796 mmol) 5-（The tert-butyl group）- 1H- oxazole -4- Ethyl formates are added to 717 g（15.914 mmol）Formyl
Amine, 180 DEG C of oil bath is stirred at reflux 30 h of reaction.Room temperature is cooled to, is extracted, the % sodium carbonate of 800 mL 10 is added, 500 are added
ML petroleum ether extractions simultaneously discard organic layer, then use ethyl acetate（1000 mL*3）Extraction three times, merges organic phase and is eaten with saturation
Salt solution（800 mL*2）Wash twice, aqueous phase ethyl acetate（500 mL*2）Back extraction twice, merges organic phase anhydrous sodium sulfate and done
It is dry.Suction filtration, is concentrated under reduced pressure.Mashing, adds the stirring of 1000 mL water, suction filtration, filter cake washing, 50 DEG C of vacuum drying.Obtain khaki
The g of solid 71 is the 5-（The tert-butyl group）- 1H- imidazoles -4- Ethyl formates, the % of yield 45.
3）5-（The tert-butyl group）The preparation of -1H- imidazoles -4- methanol
In -10 DEG C of cold hydrazines, by 40 g（1054 mmol）Lithium aluminium hydride reduction is added in 300 dry mL tetrahydrofurans, will be used
70 g of 200 mL tetrahydrofurans dissolving（357 mmol）5-（The tert-butyl group）- 1H- imidazoles -4- Ethyl formates are slowly dropped to hydrogen
In the dirty solution for changing aluminium lithium, the Bi Yizhi h of stirring reaction 3 at room temperature are dripped.Reaction is quenched in frozen water, and appropriate ice is measured with measuring cup, will
Reaction solution is instilled dropwise.Suction filtration, filter cake uses water successively（1000 mL*2) wash twice, tetrahydrofuran（500 mL*2）Wash twice, nothing
Water-ethanol（500 mL*2）Wash twice, be concentrated under reduced pressure, absolute ethyl alcohol band water.It is the 5- to obtain the g of faint yellow solid 51（Tertiary fourth
Base）- 1H- imidazoles -4- methanol, the % of yield 93.
4）5-（The tert-butyl group）The preparation of -1H- imidazoles -4- formaldehyde
By 50 g（324 mmol）5-（The tert-butyl group）- 1H- imidazoles -4- methanol is added in 500 mL dichloromethane, adds 282 g
（3242 mmol）Manganese dioxide, the at room temperature h of stirring reaction 24.Suction filtration, plus diatomite, filter cake absolute ethyl alcohol（500 mL*3）
Wash three times, be concentrated under reduced pressure.It is the 5- to obtain the g of faint yellow solid 43（The tert-butyl group）- 1H- imidazoles -4- formaldehyde, the % of yield 87.
5）The preparation of N, N- diacetyl piperazine -2,5- diketone
By 50 g（438 mmol）Glycine anhydride is added to 179 g（1753 mmol）Acetic anhydride in, as under 155 DEG C of oil baths
30 h of reaction are stirred at reflux, are concentrated under reduced pressure.Dissolved again with dichloromethane, paving diatomite and the molten filtering of silica gel, filter cake dichloromethane
Alkane is eluted, and is concentrated under reduced pressure, 70 DEG C are used ethyl acetate dissolving-recrystallization, obtains the g of brown solid 74 for the N, N- diacetyl piperazines
Piperazine -2,5- diketone, the % of yield 85.
6）(Z) preparation of -1- acetyl group -3- ((5- (tert-butyl group) -1H- imidazol-4 yls) methylene) piperazine-2,5-dione
By 1 g（6.5 mmol）5-（The tert-butyl group）- 1H- imidazoles -4- formaldehyde is added to 7 mL DMF, adds 2.59 g（13
mmol）N, N- diacetyl piperazine -2,5- diketone nitrogen protection three gas of row, add 3.19 g（9.8 mmol）Cesium carbonate, nitrogen
Gas shielded arranges three gas, at room temperature the h of lucifuge stirring reaction 20.Reaction solution is poured into (100 mL) frozen water, suction filtration, filter cake according to
Secondary use water (100 mL * 2), petroleum ether：Ethyl acetate=8:1 (90 mL) is washed, filter cake ethanol and dichloromethane ultrasound point
Dissipate, filter off insoluble matter, be concentrated under reduced pressure, absolute ethyl alcohol band water.Ethyl acetate is used again（50 mL）Mashing, obtain yellow-brown solid (Z)-
1- acetyl group -3- ((5- (tert-butyl group) -1H- imidazol-4 yls) methylene) piperazine -2,5- diketone 0.89 g, the % of yield 46.9.
7）(3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine-2,5-dione is thick
The preparation of product
By 0.85 g（2.9 mmol）(Z) -1- acetyl group -3- ((5- (tert-butyl group) -1H- imidazol-4 yls) methylene) piperazine -2,
5- diketone is added to DMF, adds 0.56 g（5.25 mmol）Benzaldehyde nitrogen protection three gas of row, add cesium carbonate 0.95
g（2.9 mmol）Nitrogen protection three gas of row, temperature programming to 80 DEG C of lucifuge stirring reaction 24h.Reaction solution is poured into frozen water
（100 mL）In, suction filtration, filter cake is successively with 100 mL*2 water, 90 mL petroleum ethers：Ethyl acetate=8:1 washes, filter cake ethanol（30
mL）And ethyl acetate（100 mL）Ultrasonic disperse, filters off insoluble matter, is concentrated under reduced pressure, absolute ethyl alcohol band water.50 mL acetic acid second
Ester disperses, and is statically placed in -30 DEG C overnight, suction filtration, filter cake glacial acetic acid ethyl ester（5 mL）Washing, obtains the g of crude material 0.73.
Embodiment 4
High-purity (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine-2,5-dione one
The preparation of hydrate
Crude product described in 0.73 g is placed in brown bottle, 45 mL isopropanols are added under heating condition to being completely dissolved, water is added
18 mL do not have crystal precipitation, are placed at room temperature, stir cooling crystallization, suction filtration, isopropanol：Water=1:1 filter wash cake, dries, obtains yellow
The g of color pulverulent solids 0.59, yield 76.71%, product under 254 nm purity be 99.91 %, wherein isomers ((3E, 6Z)-
3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine -2,5- diketone is 0.09 %, as shown in Figure 3；1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 12.22 (s, 1H), 10.00 (s, 1H), 7.84
(s, 1H), 7.52 (d, J = 8 Hz, 2H), 7.39 (t, J = 8 Hz, 2H), 7.32 (t, J = 8 Hz,
1H), 6.86 (s, 1H), 6.73 (s, 1H), 1.37 (s, 9H); MS (ESI) m/z 337.1659 (M + H)+
(calcd for C19H21N4O2)。
Products therefrom is (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine -2,
The monohydrate of 5- diketone, test moisture is 5.326 %, and Fig. 4 is the support data of thermogravimetric analysis spectrogram.
Embodiment 5
Intermediate 5-（The tert-butyl group）The preparation of -1H- imidazoles -4- Ethyl formates
By 157 g（796 mmol) 5-（The tert-butyl group）- 1H- oxazole -4- Ethyl formates are added to 717 g（15.91 mmol）Formyl
Amine, 180 DEG C of oil bath is stirred at reflux 30 h of reaction.Room temperature is cooled to, is extracted, the % sodium carbonate of 800 mL 10 is added, 500 are added
ML petroleum ether extractions simultaneously discard organic layer, then use ethyl acetate（1000 mL*3）Extraction three times, merges organic phase and is eaten with saturation
Salt solution（800*2）Wash twice, aqueous phase ethyl acetate（500 mL*2）Back extraction twice, merges organic phase anhydrous sodium sulfate drying.
Suction filtration, is concentrated under reduced pressure.Mashing, adds the stirring of 1000 mL water, suction filtration, filter cake washing, 50 DEG C of vacuum drying.Obtain khaki solid
5- (tert-butyl group) -1H- imidazoles -4- Ethyl formates 71 g, the % of yield 45.
Embodiment 6
The preparation of intermediate N, N- diacetyl piperazine -2,5- diketone
By 50 g（438 mmol）Glycine anhydride is added to 179 g（1753 mmol）Acetic anhydride in, as under 155 DEG C of oil baths
30 h of reaction are stirred at reflux, are concentrated under reduced pressure.Dissolved again with dichloromethane, paving diatomite and the molten filtering of silica gel, filter cake dichloromethane
Alkane is eluted, and is concentrated under reduced pressure, 70 DEG C are used ethyl acetate dissolving-recrystallization, is obtained brown solid N, N- diacetyl piperazine -2,5- diketone
74 g, the % of yield 85.
The above embodiments are merely illustrative of the technical solutions of the present invention, rather than is limited；Although with reference to foregoing reality
Apply example the present invention is described in detail, for the person of ordinary skill of the art, can still implement to foregoing
Technical scheme described in example is modified, or carries out equivalent substitution to which part technical characteristic；And these are changed or replaced
Change, the essence of appropriate technical solution is departed from the spirit and scope of claimed technical solution of the invention.
Claims (8)
1. a kind of high-purity dehydrophenylahistin class compound prepares purification process, it is characterised in that：The dehydrobenzene
Base ahistins class compound has formula（I）Shown structure：
（I）
Formula（I）Middle R1The polysubstituted substituent that five substitutions are not waited is substituted onto for one on phenyl ring, substituent is selected from hydrogen atom, deuterium
Atom, halogen atom, hydroxyl, methoxyl group, amino, phenyl, aminomethyl phenyl, C1-C24 alkyl, C2-C24 alkenyls, C2-C24
Alkynyl, aryl alkyl, heterocyclic aryl alkyl, C1-C24 acyl group, C1-C24 alkoxy, carboxyl, carboxylic acid ester groups, amide groups,
N- is monosubstituted or the disubstituted amide groups of N, N-, sulfonic group, sulfonate group, sulfoamido, N- substituted sulfonamides base, alkoxy, virtue
Base alkoxy, alkylthio group, cyano group, amino, the amino of substitution, nitro；Cycloalkyl, cycloalkenyl group, aromatic radical, substitution aromatic radical,
Fragrant heterocyclic radical, aryloxy group, aroyl, epoxy radicals, ring acyl group, fragrant sulfenyl, arylsulfonyl；
R2For hydrogen atom or D-atom, R3For hydrogen atom or D-atom；
X1For oxygen atom or sulphur atom, X2For oxygen atom or sulphur atom；
X3For-NH, oxygen atom or sulphur atom；
The purification process for preparing comprises the following steps：By formula（I）The crude compound is placed in brown bottle, heating condition
Lower addition isopropanol or methanol or ethanol or n-butanol add water and do not have crystal precipitation, be placed in 15-30 up to being completely dissolved
At DEG C, cooling crystallization is stirred, through suction filtration, washs and dry, obtains high-purity dehydrophenylahistin class compound.
2. high-purity dehydrophenylahistin class compound according to claim 1 prepares purification process, its feature
It is：By (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) deuterated methylene) piperazine-2,5-dione
Crude product is placed in brown bottle, is added isopropanol and is done under solvent, heating condition to being completely dissolved, adds water, isopropanol used and
The volume ratio of water is VIsopropanol：VWater=1:5 to 100:1, it is placed at 15-30 DEG C, stirs cooling crystallization, through suction filtration, washs and dry,
Faint yellow solid be trans-isomer content be less than 0.1 % high-purity (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl groups -
1H- imidazol-4 yls) deuterated methylene) piperazine-2,5-dione monohydrate.
3. high-purity dehydrophenylahistin class compound according to claim 2 prepares purification process, its feature
It is：The volume ratio of the isopropyl alcohol and water is VIsopropanol：VWater=5：2.
4. high-purity dehydrophenylahistin class compound according to claim 1 prepares purification process, its feature
It is：Compound (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine-2,5-dione
The preparation method of crude product is：
In the basic conditions, isocyano acid B ester, trimethyl acetic anhydride cyclization obtain 5-（The tert-butyl group）Oxazole -4- Ethyl formates；
Then by 5-（The tert-butyl group）The heating of oxazole -4- Ethyl formates formamide solvent is converted to imidazole ring, then hydrogenated aluminium lithium
Reduction, manganese dioxide obtains 5-（The tert-butyl group）- 1H- imidazoles -4- formaldehyde；By glycine anhydride acetic anhydride solvent dissolve 1,
4- diacetyl piperazine -2,5- diketone；
In the basic conditions, by 5-（The tert-butyl group）- 1H- imidazoles -4- formaldehyde is condensed with Isosorbide-5-Nitrae-diacetyl piperazine -2,5- diketone,
(3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine -2 are obtained with benzaldehyde again,
5- diketone crude products.
5. high-purity dehydrophenylahistin class compound according to claim 4 prepares purification process, its feature
It is：By (3Z, 6Z) -3- benzylidenes -6- ((the 5- tert-butyl group -1H- imidazol-4 yls) methylene) piperazine-2,5-dione crude product
It is placed in brown bottle, adds isopropanol and do under solvent, heating condition to being completely dissolved, add water, isopropyl alcohol and water used
Volume ratio is VIsopropanol：VWater=1:10 to 100:1, it is placed at 15-30 DEG C, stirs cooling crystallization, through suction filtration, washs and dry, obtain light
Yellow solid is high-purity (3Z, 6Z) -3- benzylidenes-the 6- ((the 5- tert-butyl groups -1H- that trans-isomer content is less than 0.1 %
Imidazol-4 yl) methylene) piperazine-2,5-dione monohydrate.
6. high-purity dehydrophenylahistin class compound according to claim 5 prepares purification process, its feature
It is：The volume ratio of the isopropyl alcohol and water is VIsopropanol：VWater=5:2。
7. high-purity dehydrophenylahistin class compound according to claim 4 prepares purification process, its feature
It is the 5-（The tert-butyl group）- 1H- imidazoles -4- Ethyl formates are purified by following steps：By 5-（The tert-butyl group）- 1H- Evil
Azoles -4- Ethyl formates and formamide heating response, after reaction terminates, mother liquor cooling with sodium carbonate and petroleum ether extraction and point is removed
Petroleum ether layer impurity, is extracted through ethyl acetate, merges organic phase, then through washing, the dry and concentrate that is concentrated under reduced pressure to obtain, fall while hot
Enter stirring to pulp in water, have solid precipitation, suction filtration, washing, vacuum drying obtain the 5- of the product for purifying（The tert-butyl group）-1H-
Imidazoles -4- Ethyl formates.
8. high-purity dehydrophenylahistin class compound according to claim 4 prepares purification process, its feature
It is that the 1,4- diacetyl piperazines -2,5- diketone is purified by following steps：Glycine anhydride and acetic anhydride are flowed back
Reaction, after reaction terminates, mother liquor is cooled to room temperature, is concentrated under reduced pressure and steams solvent, and concentrate dichloromethane dissolves, diatomite mistake
Filter, be concentrated under reduced pressure removing dichloromethane, and with re-crystallizing in ethyl acetate, low temperature crystallization, filtering is dry that product is the described of purifying
1,4- diacetyl piperazine -2,5- diketone.
Priority Applications (9)
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| CN201610664088.6A CN107011322B (en) | 2016-08-12 | 2016-08-12 | Preparation and purification method of dehydrophenylahistine compound |
| PCT/CN2017/094066 WO2018028420A1 (en) | 2016-08-12 | 2017-07-24 | Polycrystalline form of dehydrophenylahistin-like compound, and manufacturing and purification method and application thereof. |
| US16/325,166 US10851086B2 (en) | 2016-08-12 | 2017-07-24 | Polycrystalline form of dehydrophenylahistin-like compound, and manufacturing and purification method and application thereof |
| CN202111486744.5A CN114276332B (en) | 2016-08-12 | 2017-07-24 | Polymorphic form of dehydrogenated phenyl-achyranthes and its preparing and purifying process and application |
| CN201780049392.2A CN109563079B (en) | 2016-08-12 | 2017-07-24 | Polymorphic form of dehydrophenylahistine compound, preparation and purification method and application thereof |
| EP22175200.9A EP4089085B1 (en) | 2016-08-12 | 2017-07-24 | Manufacturing and purification method of polycrystalline form of dehydrophenylahistin-like compound |
| EP17838550.6A EP3498702B1 (en) | 2016-08-12 | 2017-07-24 | Polycrystalline form of dehydrophenylahistin-like compound, and manufacturing and purification method and application thereof |
| US16/995,098 US11608325B2 (en) | 2016-08-12 | 2020-08-17 | Polycrystalline form of dehydrophenylahistin-like compound, and manufacturing and purification method and application thereof |
| US16/995,045 US11578057B2 (en) | 2016-08-12 | 2020-08-17 | Polycrystalline form of dehydrophenylahistin-like compound, and manufacturing and purification method and application thereof |
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| CN114349740A (en) * | 2022-01-17 | 2022-04-15 | 中国海洋大学 | Preparation method and application of tubulin inhibitor plinabulin isomer impurity |
| WO2023274316A1 (en) * | 2021-06-29 | 2023-01-05 | 深圳华泓海洋生物医药有限公司 | Application of deuterated plinabulin in preparing drug for treating neutropenia |
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| CN1684955A (en) * | 2002-08-02 | 2005-10-19 | 尼瑞斯药品公司 | Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof |
| CN101633655A (en) * | 2002-08-02 | 2010-01-27 | 尼瑞斯药品公司 | Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof |
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| CN101633655A (en) * | 2002-08-02 | 2010-01-27 | 尼瑞斯药品公司 | Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023274316A1 (en) * | 2021-06-29 | 2023-01-05 | 深圳华泓海洋生物医药有限公司 | Application of deuterated plinabulin in preparing drug for treating neutropenia |
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