CN103897027A - Key intermediate crystal form, preparation method and application of key intermediate crystal form in bortezomib synthesis - Google Patents
Key intermediate crystal form, preparation method and application of key intermediate crystal form in bortezomib synthesis Download PDFInfo
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Abstract
The invention discloses a preparation method of a bortezomib bortezomib (2S)-N-[(1R)]-1-(5,7-dimethyl-1,2,6,2-dioxo aza-boron octane-2-yl)-3-methyl butyl]-3-phenyl-2-pyrazine-2-ylformamido] propanamide (compound II), namely, under gentle reaction conditions, diisopropanolamine is reacted with a crude bortezomib product or a bortezomib boric acid ester compound so as to prepare the compound II. The invention further discloses a novel crystal form A of a midbody II. The crystal form is table in property and is beneficial for purification. The invention further discloses a method for preparing high purity bortezomib from the crystal form A of the compound II with stable properties, and the method is particularly beneficial for industrial purification and refining of bortezomib.
Description
Technical field:
The present invention is specifically related to new crystal of Velcade key intermediate II and preparation method thereof, and uses the new crystal product of Velcade key intermediate II, obtains high purity Velcade bulk drug product through purification refine.
Background technology:
Common neoplastic hematologic disorder mainly comprises each quasi-leukemia, multiple myeloma and malignant lymphoma.Acute leukemia accounts for the 8th of common cancer, and lymphoma is also in top ten, and sickness rate raises year by year, and the whole sickness rate of multiple myeloma accounts for 10% in hematologic malignancies the inside.Hesperian statistical figure are relatively more comprehensive, and the current sickness rate of this three classes tumour all comes the top ten of malignant tumour.
Boric acid compound is an extremely important compounds in organic compound, due to its unique constitutional features, possesses good biological activity and pharmacological action, is widely used in synthetic potential enzyme inhibitors and feedback control drug transport polymkeric substance.Alpha-amino boronic acid analogue also has anti-AIDS and antineoplastic activity (as compd A and B).Based on above-mentioned pharmacology widely and biological activity, in recent years, alpha-amino boronic acid class bioactive molecule has caused the extensive concern of domestic and international biochemist and Pharmaceutical Chemist.All there is following technical barrier in the preparation of boric acid compound: (1) bulk drug synthesis technique complexity, (2) purifying products difficulty is large, (3) poor stability.
Velcade (Bortezomib, B) be a kind of dipeptides ylboronic acid compound, new and effective single-minded proteinase inhibitor, former name: LDP-341 and PS-341, researched and developed by Myogenics company of the U.S. the earliest, within 1999, bought by U.S. Millennium Pharmaceuticals, and obtain the approval list marketing of FDA May 19 in 2003, for injection freeze-dried powder, be used for the treatment of recurrent and Refractory Multiple Myeloma, this kind is in more than 80 the countries and regions list marketing in the whole world at present.This kind was gone on the market in China's approval in 2005, and ratified new indication in 2009 in China---for the treatment of lymphoma mantle cell.
Velcade can specificity suppresses class Quimotrase (Chymotrypsin-like) activity of 26S proteasome in mammalian cell, and a series of signal in cell is sent and exerted an influence, and finally causes cancer cell death.Studies have found that proteasome inhibitor Velcade has following effect: (1) has selective killing effect to malignant cell; (2) there is synergy with other Anticancer drug combination; (3) there is Apoptosis; (4) can induce Bcl-2 overexpressing cell apoptosis.
Velcade is the novel boracic chipal compounds of a class, molecular structure more complicated, and bulk drug synthesis technique is loaded down with trivial details, exists product to be difficult to two large features of purifying, less stable.Because the carbon boron chemical bond in Velcade molecular structure is very easily subject to Oxidative demage, there is DeR, general employing is the means of recrystallization repeatedly, very easily generate a large amount of, be difficult to the degradation impurity of removing, these impurity directly affect the quality of bulk drug, thereby the Velcade purification process of development of new is one of gordian technique of guaranteeing quality product.On the other hand, due to the poor stability of Velcade bulk drug itself, transportation and storage are proposed to higher particular requirement, needed protection and the cryogenic freezing condition of rare gas element.For lowering transportation cost, reduce the impaired risk of quality product in transportation, explore and adopt more excellent transportation and store strategy also to have a very big significance.
Although a large amount of technical literatures discloses the purification process of Velcade,, literature method adopts repeatedly the means of recrystallization mostly, cannot avoid the generation of degraded product, will inevitably increase the manufacturing cost of Velcade.Therefore, the novel purification technique of product of exploitation Velcade, the better transportation of searching and storage strategy are the key subject that promotes Velcade bulk drug manufacturing technology level and guarantee quality product.
At present, people attempt to find and obtain the stable precursor compound of Velcade, on the one hand, are conducive to solve the perishable problem of Velcade bulk drug purifying; On the other hand, be conducive to find a kind of novel Velcade storage, transportation and the new model using, be, by storage, the stable precursor compound of transportation Velcade, changes stable precursor compound into highly purified Velcade by simple method time to be used and uses.Regrettably, existing Velcade precursor compound is boric acid ester compound, all cannot obtain the crystal formation product of stable in properties.Consider the feature of the molecular structure of boric acid compound---the boron atom that contains electron deficiency, easily generate coordination chemistry key with atom (as: nitrogen-atoms) combination with coordination electronics, such coordination chemistry key has the feature of " inner salt ", so just likely obtains the possibility with stable crystal form compound.
Document Org.Lett.2009, has reported in 11,3478-3481 that boric acid ester compound 1 generates and has " inner salt " character compound 3 with diisopropanolamine (DIPA) 2 reaction bonded:
The relevant chemical property that is necessary to study Velcade and has the similar structural characteristics precursor compound II of compound 3, structure is as shown below:
" inner salt " constructional feature that it is special, has determined that this precursor compound likely forms the possibility of certain form crystalline compounds.Need the crystallization condition of careful research stability of compounds crystal formation, study the relevant nature of the stable crystal form of Compound I I, and prepare the technique of high purity Velcade by the crystal formation of stable Compound I I.If above imagination becomes a reality, this technique will overcome Velcade bulk drug purifying, huge shortcoming in storage and transportation, be conducive to set up the new model of the refining purifying of a kind of brand-new Velcade bulk drug, be conducive to reduce from source the cost of Velcade medicine, manufacture cheap medicine and serve extensive patients.
Summary of the invention:
The object of the invention is to overcome the deficiencies in the prior art, prepare first the precursor compound II of Velcade; Illustrate first the new crystal of Velcade key intermediate II, be to provide a kind of Velcade key intermediate---(2S)-N-[(1R)-1-(5,7-dimethyl-1,2,6,2-dioxy azepine boron octane-2-yl)-3-methyl butyl]-3-phenyl-2-pyrazine-2-base formamido-) preparation method of propionic acid amide (Compound I I), and the A type crystal formation of the stable in properties of Compound I I, and utilize the A crystal formation product of Compound I I to prepare high purity Velcade product.The A crystal formation stable in properties of this Compound I I, the utmost point is beneficial to Velcade purification refine, is beneficial to long-term storage under conventional storage and transportation conditions, and the suitability for industrialized production that is beneficial to especially Velcade is carried out.
The invention provides a kind ofly as the preparation method of figure below molecular formula II compound, is stirring reaction in certain solvent by Compound I and diisopropanolamine (DIPA) (III), can obtain Compound I I, as shown below:
This key intermediate II stable in properties, carbon boron chemical bond is difficult for rupture failure, can obtain the intermediate II that purity is higher by recrystallization repeatedly, then prepares highly purified Velcade bulk drug by simple deprotection reaction.
Wherein R
1, R
2for the alkyl of C1～C10, preferably R
1and R
2be connected to:
or R
1and R
2be connected to respectively hydrogen; Wherein action solvent is selected from ethers, C1～C8 alcohols, C3～C8 ketone, C1～C8 ester class, C5～C8 alkanes, C1～C8 haloalkane hydro carbons, one or more in fragrant alkanes; Described solvent is preferentially selected from: t-butyl methyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, ethylene dichloride, normal hexane, Skellysolve A, normal heptane, ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, butanone, ethyl acetate, toluene, benzene, one or more in dimethylbenzene.
The invention discloses the new crystal of Velcade intermediate (II), is A crystal formation:
It is characterized in that, the X-ray powder diffraction pattern of described crystal is 9.08,12.56, and 18.50,21.08,21.63,25.47 diffraction angle (2 θ, °) has characteristic peak, and 2 θ of appointment are respectively accurately or within the scope of exact value ± 0.2 °.
The preparation method of A crystal formation of the present invention, is characterized in that it comprises as the operation of next step or a few step:
(a) formula II compound is scattered in solvent;
(b) stirring and dissolving under certain temperature, filters insolubles;
(c) filtrate, at certain temperature crystallize out, is filtered crystal;
(d) dry at a certain temperature.
The preparation method of formula II compd A crystal formation of the present invention, is characterized in that in step (a), dispersion solvent is selected from ethers, C1～C8 alcohols, C3～C8 ketone, C1～C8 ester class, C5～C8 alkanes, C1～C8 haloalkane hydro carbons, one or more in fragrant alkanes; Described solvent is preferentially selected from: t-butyl methyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, ethylene dichloride, normal hexane, Skellysolve A, normal heptane, ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, butanone, ethyl acetate, toluene, benzene, one or more in dimethylbenzene.
Solvent of the present invention is preferably from ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, ethyl acetate, tetrahydrofuran (THF) and methylene dichloride and mixing solutions thereof.
The preparation method of A crystal formation of the present invention, is characterized in that in step (b), solvent temperature is 20～100 ° of C.
The preparation method of A crystal formation of the present invention, the temperature control that it is characterized in that step (c) filtrate crystallize out is-10～70 ° of C.
The preparation method of A crystal formation of the present invention, is characterized in that the dry temperature of step (d) is 0～100 ° of C.
The purposes of the A crystal formation of Compound I I of the present invention, is characterized in that, described purposes refers to that the A crystal formation of Compound I I, in certain acid system, prepares Velcade under certain temperature condition.
The A crystal formation of use Compound I I of the present invention is prepared Velcade, it is characterized in that, described acid system comprises hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid; Described range of reaction temperature is 0～100 ° of C.
The present invention prepares positively effect and other open source literature comparisons that alpha-crystal form key intermediate II brings for Velcade purifying:
Alpha-crystal form key intermediate II provided by the invention passes through recrystallization; and the productive rate that deprotection obtains highly purified Velcade is all greater than 90%; the refining purifying productive rate of deprotection of patent CN200580017645 is 70%; in patent CN201110300750, the refining productive rate of deprotection is 40%～60%, and in patent CN201210147067, the refining productive rate of deprotection is 67%.
The A crystal formation stable in properties of the key intermediate II of the Velcade that the present invention prepares, under conventional preservation and storage condition, crystal formation and quality have no significant change, and now stability test result of study are summarized as follows.
Stability conditions: get respectively the unformed powder (sample number into spectrum K2) with A crystal formation Velcade key intermediate II (sample number into spectrum K1) and this intermediate, (illumination under following condition respectively, high temperature and high humidity) carry out stability test, test-results is summed up as following table:
Explanation of tables: " 0 ", " 5 ", " 10 " represent the number of days of investigating; " nothing " represents unchanged; " 5% " represents that 5% impurity increases; " 10% " represents that 10% impurity increases
Can find out by above stability test, there is A crystal formation Velcade key intermediate II at high temperature, under the storage condition of high humidity, its related substance is without obvious increase, crystal formation does not change, still the state that keeps stable A crystal formation, the feature of its stable in properties of Velcade key intermediate II of A crystal formation is obviously better than unformed powder.The influence factor test-results of carrying out under the irradiation of high light shows, related substance slightly increases, and crystal formation is unchanged, therefore advises that A crystal formation Velcade key intermediate II keeps in Dark Place.
Velcade key intermediate II provided by the invention (A crystal formation), stable chemical nature, can promote Velcade production of raw medicine, transportation and storage level in the following aspects:
(1), II is more stable than Velcade structure for A crystal formation Velcade key intermediate, has substantially avoided occurring at recrystallization process the problem of degradation impurity, can repeatedly adopt recrystallization operation.
(2), II is very convenient to the conversion of Velcade product for A crystal formation Velcade key intermediate, product purity can reach more than 99%, and productive rate is higher.The deprotection operation (referring to embodiment 14～18) that A crystal formation Velcade key intermediate II just can complete fast in room temperature reaction condition, and obtain high purity Velcade.This purifying products strategy is also higher than the productive rate of other purification process.In this patent embodiment, refining purifying productive rate all exceedes 90%, and the productive rate of the purification process of mentioning in other patents or document is between 40%～70%.(the purifying productive rate of patent CN200580017645 is 70%, and in patent CN201110300750, productive rate is 40%～60%, and in patent CN201210147067, productive rate is 67%).
(3) nature and characteristic, based on A crystal formation Velcade key intermediate II, Velcade bulk drug storage and transportation can adopt more dominant strategy is provided.Due to the unstable of Velcade bulk drug, directly storing and transport this product needs comparatively exacting terms (protection of inert gas, cold condition), has the problem that cost is higher, quality risk is larger.Because of the stable in properties of A crystal formation Velcade key intermediate II and and can be converted into very easily Velcade bulk drug product, can " directly store and transport Velcade bulk drug product mode " and change into indirect storage and the transport strategy of " first store and transport key intermediate II, be converted into again product need to use time ", can effectively lower carrying cost and quality risk.
Accompanying drawing explanation:
Fig. 1 is the powder diagram of the A crystal formation of the Compound I I for preparing of the present invention.
Fig. 2 is the high-efficient liquid phase chromatogram of the high purity Velcade for preparing in embodiment 10.
Embodiment:
Further illustrate the present invention with embodiment below, but the present invention is not limited.
The preparation of Velcade key intermediate II:
Embodiment 1
5.2 grams of compounds ibs (according to patent CN200580017645 preparation) are dissolved in methyl alcohol, add 2.6 grams of diisopropanolamine (DIPA), in stirring at room temperature 24 hours, there is a large amount of solids to separate out, filtration obtains Compound I I crude product, obtains the 4.7 A type crystal formation products (productive rate 97.9%) that digest compound II with methanol wash filter cake.
1HNMR(400MHz，CD
3OD)：δ9.14(s，1H)，8.78(s，1H)，8.68(s，1H)，7.32～7.17(m，5H)，4.23～4.14(m，1H)，4.06～4.04(m，1H)，3.40～3.2(m，2H)，3.19～3.17(m，2H)，3.10～3.06(m，2H)，2.60～2.49(m，1H)，1.55～1.43(m，2H)，1.29～1.21(m，1H)，1.18～1.13(m，3H)，0.97～0.94(m，3H)，0.85～0.82(m，6H)。
Digest compound Ia (according to document J.Am.Chem.Soc.2008 by 4.6,130,6910-6911 preparation) be dissolved in ethyl acetate, add 2.6 grams of diisopropanolamine (DIPA), in stirring at room temperature 12 hours, there is a large amount of solids to separate out, filter and obtain Compound I I crude product, obtain the 4.6 A type crystal formation products (productive rate 95.8%) that digest compound II with ethyl acetate washing leaching cake.
Embodiment 3
Digesting compound Ic (according to patent CN201210147057 preparation) by 4.5 is dissolved in t-butyl methyl ether, add 2.6 grams of diisopropanolamine (DIPA), in stirring at room temperature 24 hours, there is a large amount of solids to separate out, filtration obtains Compound I I crude product, obtains the 4.4 A type crystal formation products (productive rate 91.6%) that digest compound II with t-butyl methyl ether washing leaching cake.
Embodiment 4
By 3.8 grams of Velcades (Id) crude product (according to document Tetrahedron, 2009,65,7105-7108 preparation) be dissolved in ethyl acetate, add 2.6 grams of diisopropanolamine (DIPA), in stirring at room temperature 24 hours, have a large amount of solids to separate out, filtration obtains Compound I I crude product, obtains the 4.72 A type crystal formation products (productive rate 98.3%) that digest compound II with ethyl acetate washing leaching cake.
Velcade key intermediate II prepares A crystal formation product under different crystallization conditions:
Digest compound II by 5 and be scattered in the ethanol of 50mL, reflux 30 minutes in 80 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, waits to separate out a large amount of crystal, filters crystal, dry under 30 ° of C conditions, obtains A crystal formation Velcade key intermediate II.
Embodiment 6
Digest compound II by 5 and be scattered in the methyl alcohol of 50mL, reflux 60 minutes in 60 ° of C, filter a small amount of insolubles, filtrate lets cool to 0 ° of C, waits to separate out a large amount of crystal, filters crystal, dry under 50 ° of C conditions, obtains A crystal formation Velcade key intermediate II.
Embodiment 7
Digest compound II by 5 and be scattered in the trimethyl carbinol of 50mL, reflux 30 minutes in 100 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, waits to separate out a large amount of crystal, filters crystal, dry under 25 ° of C conditions, obtain A crystal formation Velcade key intermediate II.
Embodiment 8
Digesting compound II by 5 is scattered in the acetone of 100mL, reflux 60 minutes in 50 ° of C, filter a small amount of insolubles, filtrate lets cool to-10 ° of C, waits to separate out a large amount of crystal, filters crystal, place crystal in freeze drier pallet, controlling temperature is under 0 ° of C condition, vacuumizes dry 2 hours, obtains A crystal formation Velcade key intermediate II.
Embodiment 9
Digest in the ethyl acetate that compound II is scattered in 100mL 5, reflux 60 minutes in 60 ° of C, filter a small amount of insolubles, filtrate lets cool to 40 ° of C, waits to separate out a large amount of crystal, filters crystal, dry under 50 ° of C conditions, obtain A crystal formation Velcade key intermediate II.
Digest compound II by 5 and be scattered in the tetrahydrofuran (THF) of 50mL, reflux 30 minutes in 70 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, waits to separate out a large amount of crystal, filters crystal, dry under 30 ° of C conditions, obtain A crystal formation Velcade key intermediate II.
Embodiment 11
Digest compound II by 5 and be scattered in the methylene dichloride of 100mL, reflux 60 minutes in 50 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, waits to separate out a large amount of crystal, filters crystal, dry under 30 ° of C conditions, obtain A crystal formation Velcade key intermediate II.
Embodiment 12
Digesting compound II by 5 is scattered in the methylene dichloride and methyl alcohol (1: 1) mixed solvent of 100mL, reflux 60 minutes in 60 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, wait to separate out a large amount of crystal, filter crystal, dry under 35 ° of C conditions, obtain A crystal formation Velcade key intermediate II.
Embodiment 13
Digesting compound II by 5 is scattered in the methylene dichloride and ethanol (1: 1) mixed solvent of 100mL, reflux 30 minutes in 70 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, wait to separate out a large amount of crystal, filter crystal, dry under 30 ° of C conditions, obtain A crystal formation Velcade key intermediate II.
The A crystal formation product of Velcade key intermediate II is converted into high purity Velcade:
Embodiment 14
5 grams of the A crystal formation products of Velcade key intermediate II are placed in to the round-bottomed flask of 100mL, add 30mL methyl alcohol to disperse, then under room temperature condition, be added dropwise to the dilute hydrochloric acid (2mol/mL) of 10mL, under room temperature condition, react approximately 1 hour, with 100mL ethyl acetate dispersion reaction solution, and with three times (50mL × 3) of saturated sodium bicarbonate washing, after use saturated common salt water washing three times (50mL × 3), combined ethyl acetate layer, anhydrous sodium sulfate drying, is concentrated into about 40mL.Place room temperature, have a large amount of crystal to occur, filter crystal, be drying to obtain high purity Velcade.(productive rate 98%, purity 99.96%)
1h NMR (400MHz, CD
3oD): δ 9.16 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 7.31～7.22 (m, 5H), 5.02 (t, J=7.6Hz, 1H), 3.25～3.22 (t, J=6.1Hz, 2H), 2.71～2.65 (t, J=7.6Hz, 1H), 1.42～1.34 (m, 1H), 1.20～1.18 (t, J=7.0Hz, 2H), 0.84～0.83 (m, 6H);
13c NMR (100M Hz, CD
3oD): δ 176.8,165.1,148.8,145.4,144.7,137.0,130.5,129.7,128.2,52.8,40.8,38.5,26.6,23.7,22.0.
Embodiment 15
5 grams of the A crystal formation products of Velcade key intermediate II are placed in to the round-bottomed flask of 100mL, add 30mL ethanol to disperse, then under 0 ° of C condition, be added dropwise to the dilute sulphuric acid (2mol/mL) of 5mL, under room temperature condition, react approximately 1.5 hours, with 100mL ethyl acetate dispersion reaction solution, and with three times (50mL × 3) of saturated sodium bicarbonate washing, after use saturated common salt water washing three times (50mL × 3), combined ethyl acetate layer, anhydrous sodium sulfate drying, is concentrated into about 40mL.Place room temperature, have a large amount of crystal to occur, filter crystal, be drying to obtain high purity Velcade.(productive rate 91%, purity >99%)
Embodiment 16
5 grams of the A crystal formation products of Velcade key intermediate II are placed in to the round-bottomed flask of 100mL, add 30mL methyl alcohol to disperse, then under room temperature condition, be added dropwise to rare nitric acid (2mol/mL) of 10mL, under room temperature condition, react approximately 2 hours, with 100mL ethyl acetate dispersion reaction solution, and with three times (50mL × 3) of saturated sodium bicarbonate washing, after use saturated common salt water washing three times (50mL × 3), combined ethyl acetate layer, anhydrous sodium sulfate drying, is concentrated into about 40mL.Place room temperature, have a large amount of crystal to occur, filter crystal, be drying to obtain high purity Velcade.(productive rate 92%, purity >99%)
Embodiment 17
5 grams of the A crystal formation products of Velcade key intermediate II are placed in to the round-bottomed flask of 100mL, add 30mL methyl alcohol to disperse, then under 60 ° of C conditions, be added dropwise to the dilute phosphoric acid (2mol/mL) of 10mL, under room temperature condition, react approximately 4 hours, with 100mL ethyl acetate dispersion reaction solution, and with three times (50mL × 3) of saturated sodium bicarbonate washing, after use saturated common salt water washing three times (50mL × 3), combined ethyl acetate layer, anhydrous sodium sulfate drying, is concentrated into about 40mL.Place room temperature, have a large amount of crystal to occur, filter crystal, be drying to obtain high purity Velcade.(productive rate 94%, purity >99%)
Embodiment 18
5 grams of the A crystal formation products of Velcade key intermediate II are placed in to the round-bottomed flask of 100mL, add 30mL methyl alcohol to disperse, then under 80 ° of C conditions, be added dropwise to the dilute acetic acid (2mol/mL) of 10mL, under room temperature condition, react approximately 5 hours, with 100mL ethyl acetate dispersion reaction solution, and with three times (50mL × 3) of saturated sodium bicarbonate washing, after use saturated common salt water washing three times (50mL × 3), combined ethyl acetate layer, anhydrous sodium sulfate drying, is concentrated into about 40mL.Place room temperature, have a large amount of crystal to occur, filter crystal, be drying to obtain high purity Velcade.(productive rate 96%, purity >99%)
Claims (10)
1. as a preparation method for figure below molecular formula II compound, the stirring reaction in certain solvent by Compound I and diisopropanolamine (DIPA) (III), can obtain Compound I I, as shown below:
Wherein R
1, R
2for the alkyl of C1～C10, preferably R
1and R
2be connected to:
or R
1and R
2be connected to respectively hydrogen; Wherein action solvent is selected from ethers, C1～C8 alcohols, C3～C8 ketone, C1～C8 ester class, C5～C8 alkanes, C1～C8 haloalkane hydro carbons, one or more in fragrant alkanes; Described solvent is preferentially selected from: t-butyl methyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, ethylene dichloride, normal hexane, Skellysolve A, normal heptane, ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, butanone, ethyl acetate, toluene, benzene, one or more in dimethylbenzene.
2. the A type crystal formation of a compound as shown in figure below molecular formula II:
It is characterized in that, the X-ray powder diffraction pattern of described crystal is 9.08,12.56, and 18.50,21.08,21.63,25.47 diffraction angle (2 θ, °) has characteristic peak, and 2 θ of appointment are respectively accurately or within the scope of exact value ± 0.2 °.
3. a preparation method for A type crystal formation as claimed in claim 2, is characterized in that comprising as the operation of next step or a few step:
(a) formula II compound is scattered in solvent;
(b) stirring and dissolving under certain temperature, filters insolubles;
(c) filtrate, at certain temperature crystallize out, is filtered crystal;
(d) dry at a certain temperature.
4. the preparation method of formula II compd A type crystal formation as claimed in claim 3, it is characterized in that in step (a), dispersion solvent is selected from ethers, C1～C8 alcohols, C3～C8 ketone, C1～C8 ester class, C5～C8 alkanes, C1～C8 haloalkane hydro carbons, one or more in fragrant alkanes; Described solvent is selected from: t-butyl methyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, ethylene dichloride, normal hexane, Skellysolve A, normal heptane, ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, butanone, ethyl acetate, toluene, benzene, one or more in dimethylbenzene.
5. solvent as claimed in claim 4 is preferentially selected from ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, ethyl acetate, tetrahydrofuran (THF) and methylene dichloride and mixing solutions thereof.
6. the preparation method of A type crystal formation as claimed in claim 3, is characterized in that in step (b), solvent temperature is 20～100 ° of C.
7. the preparation method of A type crystal formation as claimed in claim 3, the temperature control that it is characterized in that filtrate crystallize out in step (c) is-10～70 ° of C.
8. the preparation method of A type crystal formation as claimed in claim 3, is characterized in that temperature dry in step (d) is 0～100 ° of C.
9. a purposes for the A type crystal formation of Compound I I as claimed in claim 2, is characterized in that, described purposes refers to that the A type crystal formation of Compound I I, in certain acid system, prepares Velcade under certain temperature condition:
10. the A type crystal formation of use Compound I I as claimed in claim 2 is prepared Velcade, it is characterized in that, described acid system comprises hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid; Described range of reaction temperature is 0～100 ° of C.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10144761B2 (en) | 2015-06-19 | 2018-12-04 | Hanlin Scientific Inc. | Chiral specific boron-containing compounds and their use in treating cancer or amyloidosis |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10144761B2 (en) | 2015-06-19 | 2018-12-04 | Hanlin Scientific Inc. | Chiral specific boron-containing compounds and their use in treating cancer or amyloidosis |
| US11325942B2 (en) | 2015-06-19 | 2022-05-10 | Beijing Artivila Biopharma Co. Ltd. | Chiral specific boron-containing compounds and their use in treating cancer or amyloidosis |
| CN111116711A (en) * | 2018-11-01 | 2020-05-08 | 博谦生技股份有限公司 | Method for preparing bortezomib and intermediate product and crystalline form thereof |
| CN110642881A (en) * | 2019-10-18 | 2020-01-03 | 扬子江药业集团上海海尼药业有限公司 | Bortezomib crystal form M and preparation method and application thereof |
| CN114249796A (en) * | 2021-12-29 | 2022-03-29 | 南京格亚医药科技有限公司 | Carfilzomib key intermediate impurity and preparation method thereof |
| CN114249796B (en) * | 2021-12-29 | 2024-02-27 | 南京格亚医药科技有限公司 | Carfilzomib key intermediate impurity and preparation method thereof |
| CN114644682A (en) * | 2022-03-30 | 2022-06-21 | 海南双成药业股份有限公司 | Preparation method of bortezomib |
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