CN106496259A - A kind of boracic intermediate and its application in medical industry - Google Patents
A kind of boracic intermediate and its application in medical industry Download PDFInfo
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Abstract
The invention discloses the preparation method of a kind of boracic new intermediate I and boracic medicine MLN9708.The new boracic intermediate compound I for utilizing fluorination reagent to prepare disclosed by the invention is used for the preparation of antitumor drug MLN9708, intermediate stable chemical nature in normal temperature air, it is easy to recrystallization purifying, using the intermediate under alkaline reagent and silica reagent effect, antitumor drug MLN9708 is prepared with citric acid single step reaction.The synthesis route, does not have special requirement to production equipment, and reaction condition is gentle, and all of raw material is commercially available prod, and the process route is especially suitable for industrialized production.
Description
Technical field：
Present invention relates particularly to a kind of preparation technology of boracic medicine, discloses a kind of new boracic intermediate and in preparation technology in the boracic product
Application in industrialized production.
Background technology：
Proteasome is the important component part of Ubiquitin-proteasome system, is responsible for the regulation and degraded of most cells internal protein, protein elder generation
By ubiquitin (polypeptide) labelling, then recognized by proteasome and degraded.Proteasome is in terms of cell cycle, cell propagation and apoptosis are adjusted
Play central role.First generation proteasome inhibitor bortezomib (Bortezomib) etc. has been applied to clinical multiple myeloma treatment, tool
There are the growth of suppression kinds of tumor cells and Apoptosis.Ixazomib citrate (MLN9708) be based on bortezomib on the basis of the second filial generation
Proteasome inhibitor, is dipeptides Leucine boric acid that nitrogen end is capped, suppresses chymotrypsin (β 5) hydrolytic sites of 20S proteasomes.
MLN9708 is the oral protein enzyme body inhibitor of first entrance III clinical trial phases, can prevent multiple regulation and control eggs by protease inhibition body
White degeneration, acts on many A signal pathways of cell, apoptosis-induced.2 III clinical trial phases show that MLN9708 combines lenalidomide and ground
The light chain type amyloidosis patient of Sai meter Song treatment recurrence/refractory MM patients and Combined with Dexamethasone treatment recurrence/refractory has preferably treatment
Effect.The I/II clinical trial phases carried out in the U.S. show that MLN9708 combines 62 first visit MM patients' of lenalidomide and dexamethasone in treatment
Complete incidence graph or extraordinary part remission rate are 76%, and this Regimen Chemotherapy toleration is good, occur without 4 grades of toxic reactions.
MLN970 is a kind of oral protein enzyme body inhibitor, is developed for recurrent or intractable systemic light chain type amyloidosis
(ALamyloidosis) treatment.The medicine is that FDA authorizes first proteasome inhibitor and the AL amyloidosis for breaking through that Sex therapy is assert
Experimental drug, can kill tumor cell by the synthesis of blocking tumor cell desired protein.MLN9708 is treated with the situation of selling well of Wu Tian companies
Method Velcade is similar with the Kyprolis principles of Amgen, but the attraction of the medicine is that MLN9708 is a kind of oral therapies.
Boron-containing compound is important drug candidate compound storehouse, and such medicine is received in metabolic disease, antibiotic and antitumor drug exploitation always
Extensive concern is arrived, as follows：
In boron-containing compound " carbon boron " chemical bond not as " carbon carbon " chemical bond stable, therefore, the preparation of boron-containing compound is always chemist and faces
Significant challenge, understand in the same manner, the synthetically prepared always great sciences problems of MLN9708, the purification refine problem of MLN9708 is the product
The difficult point of product production cost control.As the preparation technology difficult point of bortezomib, under general hot conditionss, carbon boron chemical bond is easily broken off, and makes
The method avoided in the purifying process of MLN9708 as far as possible using high-temperature digestion recrystallization is obtained, so purification to MLN9708 proposes bigger
How challenge, avoid, using recrystallization means purification MLN9708, annoying chemist always as far as possible.
The preparation method and main purification method of compound V is indicated in patent CN102066386：
Above patent CN102066386 carries out coupling reaction using intermediate VII and intermediate VIII and obtains compound VI, and compound VI is oily
Compound, the not purified next step that direct plunges into react, and in mixed solvent (methanol/hexane), carry out boric acid ester exchange using 2- methyl-props boric acid
Deprotection obtains the crude oil of compound V, then, knot that compound V is prepared using the method for the anti-phase crystallize of the less normal heptane of polarity
Brilliant, it is clear that the method cannot remove the numerous impurity introduced in preparation technology.
Above method haves the shortcomings that many：
1st, the extremely difficult purification of oily intermediate VI, the extremely difficult removal of byproduct of reaction impurity.Intermediate VI is oily compound, and the intermediate cannot adopt
Purification is carried out with the technique of recrystallization or " room temperature beating ".
2nd, compound V hardly possiblies purification, the extremely difficult removal of byproduct of reaction impurity.Patent CN102066386 does not disclose the purification process of compound V,
Only it is method that compound V is changed into crystalline state product from oil product, the method cannot remove the impurity introduced in compound V preparation technologies.
3rd, the quality of finished product IV is determined by the quality of compound V, but compound V cannot remove numerous impurity.Patent CN102066386
The preparation technology of disclosed MLN9708 can be seen that finished product MLN9708 and is prepared into using the method that compound V is coupled with one step of citric acid
Arrive, do not adopt any purification process, therefore, the quality of finished product MLN9708 is determined by two raw material V and citric acid, finally by V's
Quality determines.
Compound II stability is disclosed in patent WO2012177835 and is better than compound V, but the patent documentation does not disclose stable compound
How II is changed into compound I.
In sum, in existing open source literature, the purification strategy of product MLN9708 cannot remove process contaminants, and therefore, prepared by exploitation and searching
The preparation technology and purification schemes of MLN9708, always medical industry circle need the sciences problems for overcoming.
Content of the invention：
It is an object of the invention to overcoming in existing MLN9708 synthesis techniques, many deficiencies to bortezomib crude drug purification, the present invention is not only
The new synthetic route of a MLN9708 is provided, and also invented the key intermediate in a kind of MLN9708 synthesis, the intermediate exists
Exist under room temperature condition in solid form, the method beneficial to recrystallization can remove most of technique to its purification to the recrystallization of the key intermediate
Impurity, then, then is converted into MLN9708 through simple chemical reaction process, the method using raw material cheap and simple be easy to get, equipment is not had
There is special requirement, be room temperature reaction, be very beneficial for industrialized production MLN9708.
The present invention provides a kind of new key intermediate for preparing boron-containing compound MLN9708 shown in formula I：
Wherein, in Formulas I, Y is selected from hydrogen, lithium, sodium, potassium, caesium.
The preparation method of compound I of the present invention, it is characterised in that including the compound II that will be shown below, at a certain temperature, one
In fixed solvent, using certain fluorination reagent, reaction obtains compound I：
Wherein, Y is defined as above described, R1, R2It is independently the alkyl or hydrogen of C1～C6, or R1And R2Alkane circulus is connected and composed,
It is selected from：Or, R1, R2Knot is connected and composed with boron atom
Structure：
Method of the present invention, it is characterised in that described range of reaction temperature is 30～100 DEG C, preferred range is 10～80 DEG C.
Method of the present invention, it is characterised in that described solvent is selected from water, ethers, C1～C8 alcohols, C3～C8 ketones, C1～C8 esters
Class, C5～C8 alkanes, C1～C8 alkyl halide hydro carbons, one or more in fragrant alkanes；Described solvent is preferably selected from：Water, tertiary fourth
Ylmethyl ether, ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, dichloroethanes, normal hexane, pentane, positive heptan
Alkane, ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, acetone, ethyl acetate, one or more in toluene and water mixed solvent.
Fluorination reagent of the present invention be CsF, HF aqueous solutions, KF, KHF2, it preferably is selected from KHF2, HF aqueous solutions.
The present invention provides a kind of method for preparing boron-containing compound MLN9708 by compound I, it is characterised in that at a certain temperature, necessarily
Reaction dissolvent in, compound I base reagent and silica reagent effect under, obtain MLN9708 with citric acid cyclization,
Method of the present invention, it is characterised in that described range of reaction temperature is 30～100 DEG C, preferred range is 10～80 DEG C.
Method of the present invention, it is characterised in that described solvent is selected from water, ethers, C1～C8 alcohols, C3～C8 ketones, C1～C8 esters
Class, C5～C8 alkanes, C1～C8 alkyl halide hydro carbons, one or more in fragrant alkanes；Described solvent is preferably selected from：Water, tertiary fourth
Ylmethyl ether, ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, dichloroethanes, normal hexane, pentane, positive heptan
Alkane, ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, acetone, ethyl acetate, one or more in toluene and water mixed solvent.
Method of the present invention, it is characterised in that described " base reagent " is to include organic base and inorganic base, wherein, organic base is selected from triethylamine,
Diisopropyl methyl ethylamine；Inorganic base is selected from Lithium hydrate, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, carbonic acid
Hydrogen potassium；Described " base reagent " is to include trimethylsilyl chloride silicon, Silicon chloride..
Method of the present invention, it is characterised in that described " base reagent " is to include that organic base and inorganic base, organic base preferably are selected from triethylamine；Nothing
Machine alkali preferably is selected from sodium carbonate, potassium carbonate；Described " base reagent " is to include trimethylsilyl chloride silicon, Silicon chloride..
In sum, beneficial effects of the present invention：
(1), a kind of new key intermediate I for preparing MLN9708 is provided.In existing patent documentation and document, MLN9708 prepares work
In skill route, deprotection prepares the intermediate of bortezomib and is grease at ambient temperature, it is difficult to carry out purification to which, accordingly, it is possible to by work
Most of impurity in skill is brought in finished product, brings difficulty to the purification of MLN9708.The invention provides a kind of MLN9708 is new
Key intermediate I, the intermediate are present at ambient temperature in solid form, through experimental verification, in certain recrystallisation solvent, the intermediate
Can exist with certain crystal formation, in the method purification I of the recrystallization that can be by commonly using in industrialization, so most of process contaminants exist
Remove in the operation of recrystallization, the purification difficulty of such MLN9708 is substantially reduced.
(2) raw material for, preparing new intermediate I is cheap and easy to get, simple to operate, does not have particular/special requirement to equipment, is especially suitable for industrialized production and opens
Exhibition.The raw material that the preparation of crucial intermediate compound I is used is inexpensively, and the chemical products being easy to get, reaction are carried out at ambient temperature, and reaction is set
For without special requirement, the production of the intermediate is particularly suitable for industrialization.
(3) the MLN9708 product purities for, being prepared using the new key intermediate are high.The invention provides one by new key
The method that intermediate compound I synthesizes MLN9708.Due to having used new key intermediate I, can be obtained by the method purification of recrystallization more high-purity
The key intermediate I of degree, then using the key intermediate I synthesis MLN9708 with higher degree, the process contaminants of introducing are few so that system
Standby MLN9708 purifying products are convenient, and purity is high.
Specific embodiment：
Further illustrate the present invention below with embodiment, but the present invention is not intended to be limited thereto.
1 4- of embodiment (R, S)-(carboxymethyl group) -2- ((R) -1- (2- (2,5- dichlorobenzoylaminos) acetylamino) -3- methyl butyls) -6- oxos -1,3,2- two
Oxa- borine -4- formic acid
Step 1：N-2,5- dichloro-benzoyl-L- glycine methyl esters
By 2,5- dichlorobenzoic acids (9.1g, 47.6mmol), L- glycine methyl ester hydrochlorides (6.0g, 47.5mmol), TBTU (18.4g, 57.3mmol)
0 DEG C is cooled to the mixture of tetrahydrofuran (250mL), 30min is stirred, starts Deca diisopropylethylamine (23.6mL, 143.2mmol).
After completion of dropping, room temperature is slowly increased to, reaction is overnight.Through TLC monitorings reaction completely, concentration of reaction solution, and ethyl acetate is added, use respectively full
With sodium bicarbonate aqueous solution, aqueous citric acid solution, water and saturated common salt water washing, anhydrous sodium sulfate drying, N-2,5- dichloros is filtered and is concentrated to give
Benzoyl-L- glycine methyl ester crude products are standby.
Step 2：N-2,5- dichloro-benzoyl-L- glycine
Gained N-2 in step 1,5- dichloro-benzoyl-L- glycine methyl ester crude products are dissolved in acetone (100mL), 0 DEG C is cooled to, Deca 2N hydrogen
Lithium oxide aqueous solution (25mL), after completion of dropping, is warmed to room temperature (20-30 DEG C) and is stirred overnight.Through TLC monitorings reaction completely, concentration is anti-
Liquid is answered, and adds water, be extracted with ethyl acetate three times, water layer is adjusted pH to 2-3 or so with concentrated hydrochloric acid, is extracted with ethyl acetate twice, organic
Layer is washed 2 times with water and saturated common salt respectively, and anhydrous sodium sulfate drying filters and be concentrated to give N-2,5- dichloro-benzoyl-L- glycine 6.0g, is received
Rate 50.8%.1H NMR(400MHz,DMSO-d6):δ=12.71 (s, 1H), 8.90 (s, 1H), 7.57 7.55 (m, 2H), 7.50 7.47 (m,
1H), 3.93 (d, J=10.5Hz, 2H).
Step 3：N-2,5- dichloro-benzoyls-L- glycine-L-Leu pinacol borate
Prepared by reference literature CN102066386 coupling methods：By N-2,5- dichloro-benzoyls-L- glycine (81.0g, 326.5mmol), (R) -3-
Methyl isophthalic acid-pinacol diester boryl -1- butyl amine hydrochlorates (81.5g, 326.5mmol), TBTU (110.1g, 342.8mmol) and dichloromethane
(1.5L) mixture is cooled to 0 DEG C, stirs 30min, starts Deca diisopropylethylamine (161.9mL, 979.5mM, 3.0eq).Deca
After finishing, room temperature is slowly increased to, reaction is overnight.Water, 1% phosphate aqueous solution, saturated sodium bicarbonate water are used completely, respectively through TLC monitorings reaction
Solution, water and saturated common salt water washing, anhydrous sodium sulfate drying, filter and concentrate and be standby.
Step 4：Bis- chloro- N- of 2,5- [2- ([(1R) -3- methyl isophthalic acids-([1,3,6,2] dioxaborinate -2- bases) butyl] amino) -2- oxoethyls] Benzoylamide
Toward step 3, gained partial concentration grease 10g (not purified direct plungeing into next reaction, calculate with pure material 10g) adds acetic acid
Ethyl ester (100mL) and diethanolamine (4.7g, 45.1mmol), are stirred overnight at room temperature, and filter, and ethyl acetate is washed, and is dried to obtain target product
9.0g, yield about 92.7%.1H NMR(400MHz,MeOD):δ=7.88 7.57 (m, 1H), 7.62 7.17 (m, 2H), 4.01 3.85 (m,
4H),3.86–3.77(m,1H),3.74–3.65(m,1H),3.44–3.35(m,1H),3.31–3.20(m,2H),2.98–2.86(m,2H),2.84
–2.77(m,1H),1.74–1.59(m,1H),1.59–1.48(m,1H),1.44–1.29(m,1H),1.00–0.85(m,6H)；13C NMR(101
MHz,MeOD):δ=169.40,167.59,136.97,132.65,131.21,130.94,129.21,128.72,62.71,62.57,50.83,50.37,
42.88,39.18,24.92,22.93,20.30.MS(ESI),m/z:430.15 (it is calculated as C18H27BCl2N3O4:430.15([M+H]+)).
Step 5：The preparation of compound I-a：
The compound 1-7 obtained in step 4 is amounted to 9g (20mmol) and is dissolved in methanol (100ml), the KHF with addition 4M under room temperature condition2
Aqueous solution (10ml), is then stirred at room temperature reaction 2h, and TLC detects reaction process, after the completion of question response, crosses filter solid, is washed using methanol,
Solid chemical compound I-a is obtained final product, under the conditions of 40 DEG C, drying under reduced pressure obtains final product target solids product Compound I-a, target product recrystallization in methyl alcohol
Obtain product 7.2g (yield 85.7%).1H NMR(400MHz,DMSO)δ8.97–8.63(m,1H),7.69–7.42(m,3H),6.55–
6.29(m,1H),3.88–3.65(m,2H),2.98–2.75(m,1H),1.66–1.39(m,1H),1.24–1.03(m,2H),0.89–0.67(m,
6H).13C NMR(101MHz,DMSO)δ167.17,165.53,138.59,132.07,131.83,131.10,129.23,129.05,43.32,
42.57,25.08,24.50,22.92.MS m/z calcd for C14H17BCl2F3N2O2([M-K+]-)383.07,found 383.03.
Step 6：4- (R, S)-(carboxymethyl group) -2- ((R) -1- (2- (2,5- dichlorobenzoylaminos) acetylamino) -3- methyl butyls) -6- oxo -1,3,2- dioxa boron
Alkane -4- formic acid
The compound I-a that step 5 is obtained amounts to 7g (16mmol), becomes suspension using acetonitrile (50ml) dispersing and dissolving, is subsequently adding three
Ethamine (5ml), one adds the ethyl acetate solution of citric acid (3.08g, 16mmol), solution room temperature stirring reaction 30min mixed above,
At ambient temperature, add under trimethylsilyl chloride 7.8g, with room temperature condition and react 8h, that is, there are a large amount of solids to produce, cross filter solid, use acetic acid second
Ester is washed, and under the conditions of 40 DEG C, drying under reduced pressure obtains final product target solids product MLN9708 and amounts to 8.0g, yield 96.7%.1H NMR(400MHz,
DMSO-d6):δ=10.71 (s, 1H), 9.19 8.97 (m, 1H), 7.69 7.62 (m, 1H), 7.60 7.50 (m, 2H), 4.27 (s, 2H), 3.07
2.52 (m, 6H), 1.78 1.58 (m, 1H), 1.44 1.13 (m, 2H), 0.87 (d, J=6.4Hz, 6H)；13C NMR(101MHz,
DMSO-d6):δ=178.34,176.39,170.99,166.10,137.37,132.11,132.03,131.55,129.50,129.41,76.63,43.46,
41.33,38.65,25.35,24.11,21.79.MS(ESI),m/z:539.24 (it is calculated as C20H23BCl2N2O9Na:539.08([M+Na]+)).
Embodiment 2
The compound 1-6 obtained in embodiment 1 is amounted to 5g (11.3mmol) and is dissolved in methanol (100ml), with addition 4M under room temperature condition
KHF2Aqueous solution (15ml), is then stirred at room temperature reaction 2h, and TLC detects reaction process, after the completion of question response, crosses filter solid, using methanol
Washing, obtains final product solid chemical compound I-b, and under the conditions of 50 DEG C, drying under reduced pressure obtains final product target solids product Compound I-a, and the target product is in methyl alcohol
It is recrystallized to give product 3.9g (yield 84.7%).
Compound I-b obtained above is amounted to 3g (7.3mmol), suspension is become using acetonitrile (25ml) dispersing and dissolving, three second are subsequently adding
Amine (5ml), adds the ethyl acetate solution of citric acid (1.4g, 7.3mmol), and solution room temperature stirring reaction 30min mixed above, in room temperature
Under the conditions of, to add and 8h is reacted under Silicon chloride. 5.3g, with room temperature condition, that is, there are a large amount of solids to produce, cross filter solid, washed with ethyl acetate, in
Under the conditions of 40 DEG C, drying under reduced pressure obtains final product target solids product MLN9708 and amounts to 3.3g, yield 86.6%.
Embodiment 3
Compound 1-6 is prepared according to embodiment 1 and amounts to 10g (22.5mmol), add ethyl acetate (100ml) and N- methyl imido diethyls
Sour (compound 3-1,3.31g, 22.5mmol), is stirred overnight at room temperature, and filters, and ethyl acetate is washed, and is dried to obtain target product 9.5g, yield
89.4%.
Compound 3-2 obtained above is amounted to 9g (19.0mmol) and is dissolved in methanol (100ml), the KHF with addition 4M under room temperature condition2Water
Solution (15ml), is then stirred at room temperature reaction 2h, and TLC detects reaction process, after the completion of question response, crosses filter solid, is washed using methanol, i.e.,
Solid chemical compound I-a is obtained, under the conditions of 50 DEG C, drying under reduced pressure obtains final product target solids product Compound I-a, and recrystallization is obtained the target product in methyl alcohol
Arrive product 6.9g (yield 85.9%).
Compound I-a obtained above is amounted to 6g (14.2mmol), suspension is become using acetonitrile (100ml) dispersing and dissolving, three are subsequently adding
Ethamine (5ml), adds the ethyl acetate solution of citric acid (3.0g, 15.6mmol), solution room temperature stirring reaction 30min mixed above,
Under room temperature condition, to add and 8h is reacted under trimethylsilyl chloride 6.8g, with room temperature condition, that is, there are a large amount of solids to produce, cross filter solid, use ethyl acetate
Washing, under the conditions of 40 DEG C, drying under reduced pressure obtains final product target solids product MLN9708 and amounts to 7.0g, yield 95.7%.
Embodiment 4
Amount to 20g (40.4mmol) according to the compound 4-1 that literature method (CN102066386) is prepared and be dissolved in methanol (200ml), with
The KHF of 4M is added under room temperature condition2Aqueous solution (50ml), is then stirred at room temperature reaction 2h, and TLC detects reaction process, after the completion of question response,
Filter solid is crossed, is washed using methanol, obtain final product solid chemical compound I-a, under the conditions of 50 DEG C, drying under reduced pressure obtains final product target solids product Compound I-a,
The target product is recrystallized to give product 12.3g (yield 72.3%) in methyl alcohol.
Compound I-a obtained above is amounted to 10g (23mmol), suspension is become using acetonitrile (100ml) dispersing and dissolving, three are subsequently adding
Ethamine (15ml), adds the ethyl acetate solution of citric acid (5g, 26mmol), and solution room temperature stirring reaction 30min mixed above, in room
Under the conditions of temperature, to add and 8h is reacted under trimethylsilyl chloride 11.2g, with room temperature condition, that is, there are a large amount of solids to produce, cross filter solid, use ethyl acetate
Washing, under the conditions of 40 DEG C, drying under reduced pressure obtains final product target solids product MLN9708 and amounts to 10.2g, yield 85.8%.
Embodiment 5
By N-2,5- dichloro-benzoyls-L- glycine (2.5g, 10mmol), compound 5-1 (2.6g, 10mmol) (according to patent CN201210011233.2
Prepared by disclosed method), the mixture of TBTU (3.4g, 10mM) and dichloromethane (50mL) be cooled to 0 DEG C, stir 30min, beginning
Deca diisopropylethylamine (5mL).After completion of dropping, room temperature is slowly increased to, reaction is overnight.Through TLC monitorings reaction completely, respectively with water,
1% phosphate aqueous solution, saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing, anhydrous sodium sulfate drying, filter and concentrate.
Compound 5-2 derived above is dissolved in methanol (250ml), the KHF with addition 4M under room temperature condition2Aqueous solution (10ml), then room
Warm stirring reaction 2h, TLC detect reaction process, after the completion of question response, cross filter solid, are washed using methanol, obtain final product solid chemical compound I-a, in
Under the conditions of 50 DEG C, drying under reduced pressure obtains final product target solids product Compound I-a, and the target product is recrystallized to give product 3.0g (yields in methyl alcohol
70.9%).
Compound I-a obtained above is amounted to 2g (4.7mmol), suspension is become using acetonitrile (25ml) dispersing and dissolving, three second are subsequently adding
Amine (5ml), adds the ethyl acetate solution of citric acid (1g, 5.2mmol), and solution room temperature stirring reaction 30min mixed above, in room temperature
Under the conditions of, to add and 8h is reacted under trimethylsilyl chloride 2.3g, with room temperature condition, that is, there are a large amount of solids to produce, cross filter solid, washed with ethyl acetate,
Under the conditions of 40 DEG C, drying under reduced pressure obtains final product target solids product MLN9708 and amounts to 2.2g, yield 91.7%.
Embodiment 6
Will be (public according to patent CN201310258650.1 to N-2,5- dichloro-benzoyls-L- glycine (2.5g, 10mmol), 6-1 (3.2g, 10mmol)
Prepared by the method opened), the mixture of TBTU (3.4g, 10mmol) and dichloromethane (50mL) be cooled to 0 DEG C, stirring 30min starts to drip
Plus diisopropylethylamine (5mL).After completion of dropping, room temperature is slowly increased to, reaction is overnight.Through TLC monitorings reaction completely, respectively with water, 1%
Phosphate aqueous solution, saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing, anhydrous sodium sulfate drying, filter and concentrate.
Compound 6-2 derived above is amounted to and is dissolved in methanol (50ml), the KHF with addition 4M under room temperature condition2Aqueous solution (10ml), in
It is that reaction 2h is stirred at room temperature, TLC detects reaction process, after the completion of question response, crosses filter solid, washed using methanol, obtain final product solid chemical compound I-a,
Under the conditions of 50 DEG C, drying under reduced pressure obtains final product target solids product Compound I-a, and the target product is recrystallized to give product 3.6g (yields in methyl alcohol
85.1%).
Compound I-a obtained above is amounted to 3g (7.1mmol), suspension is become using acetonitrile (50ml) dispersing and dissolving, three second are subsequently adding
Amine (5ml), adds the ethyl acetate solution of citric acid (1.5g, 7.8mmol), and solution room temperature stirring reaction 30min mixed above, in room temperature
Under the conditions of, to add and 8h is reacted under trimethylsilyl chloride 3.4g, with room temperature condition, that is, there are a large amount of solids to produce, cross filter solid, washed with ethyl acetate,
Under the conditions of 40 DEG C, drying under reduced pressure obtains final product target solids product MLN9708 and amounts to 3.0g, yield 81.7%.
Although many aspects and different embodiments of the present invention, art technology is described in detail by above-mentioned specific embodiment and embodiment
Personnel will be easy to predict the method for the invention, reaction condition and can be had appropriate change and adjustment based on above-mentioned teaching, specific to adapt to
Need and practical situation, and these changes and adjustment are thought within the scope of the invention, i.e., in claim limited range.
Claims (10)
1. a kind of new key intermediate for preparing boron-containing compound MLN9708 shown in formula I：
Wherein, in Formulas I, Y is selected from hydrogen, lithium, sodium, potassium, caesium.
2. the preparation method of compound I according to claim 1, it is characterised in that including the compound II that will be shown below, certain
At a temperature of, in certain solvent, using certain fluorination reagent, reaction obtains compound I：
Wherein, Y is defined with claim 1, R1, R2It is independently the alkyl or hydrogen of C1～C6, or R1And R2Connect and compose alkane ring-type
Structure, is selected from：
Or, R1, R2Structure is connected and composed with boron atom：
3. method according to claim 2, it is characterised in that described range of reaction temperature is 30～100 DEG C, preferred range is
10～80 DEG C.
4. method according to claim 2, it is characterised in that described solvent is selected from water, ethers, C1～C8 alcohols, C3～C8 ketones,
C1～C8 esters, C5～C8 alkanes, C1～C8 alkyl halide hydro carbons, one or more in fragrant alkanes；Described solvent is preferably selected from：
Water, t-butyl methyl ether, ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, dichloroethanes, normal hexane, positive penta
Alkane, normal heptane, ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, acetone, ethyl acetate, one or more in toluene and water mixed solvent.
5. the fluorination reagent described in be CsF, HF aqueous solutions, KF, KHF2, it preferably is selected from KHF2, HF aqueous solutions.
6. a kind of method that boron-containing compound MLN9708 is prepared by compound I, it is characterised in that at a certain temperature, certain reaction is molten
In agent, compound I obtains MLN9708 with citric acid cyclization under base reagent and silica reagent effect,
7. method according to claim 6, it is characterised in that described range of reaction temperature is 30～100 DEG C, preferred range is
10～80 DEG C.
8. method according to claim 6, it is characterised in that described solvent is selected from water, ethers, C1～C8 alcohols, C3～C8 ketones,
C1～C8 esters, C5～C8 alkanes, C1～C8 alkyl halide hydro carbons, one or more in fragrant alkanes；Described solvent is preferably selected from：
Water, t-butyl methyl ether, ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, dichloroethanes, normal hexane, positive penta
Alkane, normal heptane, ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, acetone, ethyl acetate, one or more in toluene and water mixed solvent.
9. method according to claim 6, it is characterised in that described " base reagent " is to include organic base and inorganic base, wherein, organic
Alkali is selected from triethylamine, diisopropyl methyl ethylamine；Inorganic base be selected from Lithium hydrate, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate,
Sodium bicarbonate, potassium bicarbonate；Described " base reagent " is to include trimethylsilyl chloride silicon, Silicon chloride..
10. method according to claim 6, it is characterised in that described " base reagent " is to include organic base and inorganic base, and organic base is excellent
It is selected from triethylamine；Inorganic base preferably is selected from sodium carbonate, potassium carbonate；Described " base reagent " is to include trimethylsilyl chloride silicon, Silicon chloride..
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