CN113121640A - Crystal of monomethyl auristatin E and preparation method thereof - Google Patents
Crystal of monomethyl auristatin E and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 title abstract description 56
- 108010093470 monomethyl auristatin E Proteins 0.000 title description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 51
- 239000002904 solvent Substances 0.000 claims description 48
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 28
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 18
- 239000000562 conjugate Substances 0.000 claims description 15
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- 239000000611 antibody drug conjugate Substances 0.000 claims description 10
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 8
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 101710112752 Cytotoxin Proteins 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 6
- 239000002619 cytotoxin Substances 0.000 claims description 6
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 229920001184 polypeptide Polymers 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- 229940090181 propyl acetate Drugs 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000878 small molecule-drug conjugate Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 1
- -1 methyl auristatin E Chemical compound 0.000 abstract description 16
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000003860 storage Methods 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 2
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- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
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- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 238000003869 coulometry Methods 0.000 description 9
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- 238000002386 leaching Methods 0.000 description 6
- 230000001376 precipitating effect Effects 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000002447 crystallographic data Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
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- 238000002474 experimental method Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
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- 230000001681 protective effect Effects 0.000 description 2
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- 239000012047 saturated solution Substances 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- 102100037709 Desmocollin-3 Human genes 0.000 description 1
- 101000968042 Homo sapiens Desmocollin-2 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000001946 anti-microtubular Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QUCQEUCGKKTEBI-UHFFFAOYSA-N palmatine Chemical class COC1=CC=C2C=C(C3=C(C=C(C(=C3)OC)OC)CC3)[N+]3=CC2=C1OC QUCQEUCGKKTEBI-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
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- 230000005855 radiation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a methyl auristatin E crystal form A, a preparation method thereof, a pharmaceutical composition containing the crystal form A and application of the crystal form A in preparation of a pharmaceutical conjugate. The crystal form A has high purity, good stability and low hygroscopicity, is particularly suitable for industrial application, and overcomes the defects of low purity, poor stability, unsuitability for storage, high requirement on reaction equipment, complex operation and the like when amorphous MMAE is used for preparing a conjugate in the prior art; secondly, the preparation method of the MMAE crystal form A provided by the invention is simple to operate, the prepared crystal form is high in purity and uniform in particle size distribution, the production cost is reduced, and the preparation method is suitable for commercial production amplification.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a methyl auristatin E crystal, a preparation method thereof, a medicinal composition containing the crystal, and application of the crystal forms in preparation of a medicinal conjugate.
Background
Methyl auristatin E (MMAE, structural formula is shown in formula (I)) is a synthetic derivative of palmatine 10, has very effective antimitotic effect, and can inhibit cell division by blocking polymerization of tubulin to realize antitumor purpose. Is as antimicrotubule like vinblastine, but is approximately 200 times as toxic as vinblastine. Because of the toxicity, it is too toxic to be used by direct intravenous drip, and therefore it can only exert its killing power in drug conjugates (ADC drugs). Among the ADC drugs that have been marketed so far, there are Bentuximab developed by Seattle Genetics, Pontolizumab developed by Genentech, and Ennocumab developed by a combination of Seattle Genetics and Astellas, all of which use MMAE as a cytotoxin. At present, in ADC (antibody drug conjugate) and PDC (polypeptide drug conjugate) drugs, MMAE is used as cytotoxin for research.
However, currently commercially available monomethylauristatin E is an amorphous solid, and no reports have been made in any literature or patent on free monomethylauristatin E crystals. Amorphous MMAE is easy to deliquesce and poor in stability, and is not beneficial to long-term storage; in addition, amorphous MMAE also has the problem of low purity, resulting in more impurities in the drug conjugate prepared by using amorphous MMAE, difficult subsequent purification, and affecting the safety and effectiveness of the drug conjugate.
Purification methods of MMAE using reverse phase liquid phase preparation in US2015/23989, CN109200291A are low in yield, complex in operation, and expensive in cost.
Therefore, the development of the MMAE crystal form which has good stability and high purity and is suitable for industrial application has very important significance.
Disclosure of Invention
In order to solve the above problems of the prior art, it is an object of the present invention to provide a high purity crystalline form of MMAE having a structure represented by formula (I), and a method for preparing the same.
Firstly, the invention provides a new crystal form of MMAE, which is named as a crystal form A; specifically, the invention provides a crystal form A of a compound shown as a formula (I), wherein an X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2theta values of 3.8 degrees +/-0.2 degrees, 9.3 degrees +/-0.2 degrees, 9.9 degrees +/-0.2 degrees and 13.2 degrees +/-0.2 degrees,
further preferably, the X-ray powder diffraction pattern of form a also has diffraction peaks at one or more of 2 Θ values of 10.8 ° ± 0.2 °, 11.9 ° ± 0.2 °, 15.3 ° ± 0.2 ° and 16.3 ° ± 0.2 °, more preferably the X-ray powder diffraction pattern of form a also has diffraction peaks at one or two or three or four of 2 Θ values of 10.8 ° ± 0.2 °, 11.9 ° ± 0.2 °, 15.3 ° ± 0.2 ° and 16.3 ° ± 0.2 °.
Further, the X-ray powder diffraction pattern of the crystal form A of the compound shown in the formula (I) also has diffraction peaks at 2theta values of 10.8 degrees +/-0.2 degrees, 11.9 degrees +/-0.2 degrees, 15.3 degrees +/-0.2 degrees and 16.3 degrees +/-0.2 degrees.
Furthermore, the compound shown in the formula (I) of the invention has a crystal form A, and the X-ray powder diffraction pattern of the crystal form A at the 2theta value is as follows: characteristic diffraction peaks are provided at 3.8 degrees +/-0.2 degrees, 9.3 degrees +/-0.2 degrees, 9.9 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees, 11.9 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees, 15.1 degrees +/-0.2 degrees, 15.3 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 18.4 degrees +/-0.2 degrees, 18.6 degrees +/-0.2 degrees, 20.1 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees and 23.0 degrees +/-0.2 degrees.
According to a particular and preferred aspect of the present invention, said compound of formula (I) in crystalline form a has substantially the same X-ray powder diffraction pattern as shown in figure 1 or 2. Further, the X-ray powder diffraction pattern shows at least 14 diffraction peaks whose positions and intensities are shown in FIG. 1 or 2, in which the peak positions are varied within. + -. 0.2 ℃ and the peak intensities are appropriately varied depending on the specific detection conditions.
Preferably, the compound of formula (I) has a Differential Scanning Calorimetry (DSC) pattern with an endothermic peak at 112.81 ℃ + -2 ℃, wherein the DSC pattern is shown in figure 3.
Further, the crystal form A of the compound shown in the formula (I) contains 0-5% (w/w) of water; preferably, the form a contains 1-3% (w/w) of water.
In a second aspect of the invention, there is provided a process for the preparation of form a of the compound of formula (I) comprising the steps of:
A) adding a compound shown in a formula (I) into a first solvent, stirring for dissolving, and optionally adding water to obtain a first mixed system;
B) stirring the first mixed system, and then adding a second solvent into the first mixed system to obtain a second mixed system; preferably, the stirring of the first mixed system is carried out at a temperature of-10 to 10 ℃;
C) stirring the second mixed system, and then adding a third solvent into the second mixed system to obtain a third mixed system; preferably, the stirring of the second mixed system is carried out at a temperature of-10 to 10 ℃;
D) stirring the third mixed system to separate out solid, thus obtaining the solid; preferably, the stirring of the third mixed system is carried out at a temperature of-10 to 10 ℃.
In the above method, preferably, the first solvent of step a) is selected from esters, isopropanol, DMF, or any combination thereof; more preferably, the esters comprise methyl formate, methyl acetate, isopropyl acetate, ethyl acetate, propyl acetate, butyl acetate, or any combination thereof.
Step B) the second solvent is selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, toluene or any combination thereof;
step C) the third solvent is selected from petroleum ether, n-hexane, cyclohexane, methylcyclohexane, n-heptane or any combination thereof.
Further, in the above method, the content of water in the step a) is 0.5 to 4% (w/w) based on the total amount of the first mixed system; preferably, the water content is 1% to 2% (w/w); more preferably the water content is 1-1.5% (w/w); preferably, for example, the water content is 1.1% (w/w), 1.2% (w/w), 1.3% (w/w), 1.4% (w/w), 1.5% (w/w), 1.6% (w/w), 1.7% (w/w), 1.8% (w/w), 1.9% (w/w), or 2% (w/w).
The volume ratio of the first solvent to the second solvent to the third solvent is 1: 1-2: 2.5-7.5, and preferably 1: 1-2: 3-7; more preferably, the volume ratio of the first solvent to the second solvent to the third solvent is 1:1: 3-7, or 1:2: 3-7. In a specific preferred embodiment, the volume ratio of the first solvent to the second solvent to the third solvent is 1:1: 3.
Furthermore, the feeding ratio of the compound shown in the formula (I) to the first solvent is 1: 2.5-7.5 (g/ml); more preferably, the feeding ratio of the compound shown in the formula (I) to the first solvent is 1: 3-7 (g/ml).
Further, in the above method, preferably, the first mixed system is stirred in step B), the seed crystal is added to the first mixed system, the temperature is reduced to-10 to 10 ℃, and then the second solvent is added to obtain a second mixed system. In another more preferred embodiment of the present invention, there is provided a process for the preparation of form a of the compound of formula (I) comprising the steps of:
A) adding a compound shown as a formula (I) into a first solvent, stirring and dissolving, and optionally adding water to obtain a first mixed system; wherein the content of water in the first mixed system is 0.5-4% (w/w) calculated by the total amount of the first mixed system, and the feeding ratio of the compound shown in the formula (I) to the first solvent is 1: 2.5-7.5 (g/ml);
B) stirring the first mixed system, adding seed crystals, continuously stirring at-10 ℃, and then adding a second solvent to obtain a second mixed system; preferably, the volume ratio of the first solvent to the second solvent is 1: 1-2;
C) stirring the mixture at the temperature of-10 ℃, adding a third solvent into the second mixed system to obtain a third mixed system; preferably, the volume ratio of the first solvent to the third solvent is 1: 2.5-7.5;
D) stirring the third mixed system under the condition of stirring at the temperature of-10 ℃ to separate out solids, thus obtaining the solid; preferably, the precipitated solid is filtered, optionally rinsed with a third solvent, and then dried under vacuum to obtain the form a.
In the above process, it is further preferred that the first solvent is selected from methyl formate, methyl acetate, isopropyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropanol, DMF or any combination thereof;
the second solvent is selected from ethyl ether, isopropyl ether, methyl tert-butyl ether, toluene or any combination thereof;
the third solvent is selected from petroleum ether, n-hexane, cyclohexane, methylcyclohexane, n-heptane, or any combination thereof.
In a third aspect of the present invention, there is also provided a pharmaceutical composition comprising the compound of formula (I) provided herein in crystalline form a and a pharmaceutically acceptable carrier.
Preferably, said pharmaceutical composition contains said crystalline form a in an amount of not less than 85%, preferably not less than 90%, preferably not less than 95%, preferably not less than 99%, preferably not less than 99.5%, preferably not less than 99.9%, preferably not less than 99.99% by weight relative to the total amount of compound of formula (I) present in the composition.
In the fourth aspect of the invention, the invention also provides application of the crystal form A of the compound shown in the formula (I) and application thereof in preparing a drug conjugate. Wherein the drug conjugate comprises an antibody drug conjugate, a polypeptide drug conjugate or a small molecule drug conjugate which takes the crystal form A of the compound shown in the formula (I) as cytotoxin. Such as present-tuximab developed by Seattle Genetics, polotuzumab developed by Genentech, and enrobiumab developed in combination with Seattle Genetics and Astellas; also included are currently under-developed ADC (antibody drug conjugates) and PDC (polypeptide drug conjugates) drugs with MMAE as the cytotoxin. Methods for preparing ADC (antibody drug conjugate) and PDC (polypeptide drug conjugate) drugs using MMAE as a cytotoxin using MMAE are known and have been reported in various documents, for example, WO2019183438a1 discloses a method for preparing present cetuximab using MMAE, and WO 2017/025057Al describes a method for preparing polypeptide drug conjugate drugs using MMAE. The disclosures of these documents are incorporated herein by reference.
The invention provides a new crystal form of monomethyl auristatin E and a preparation method thereof, the crystal form has high purity, good stability and low hygroscopicity, is particularly suitable for industrial application, and overcomes the defects of low purity, poor stability, unsuitability for storage, high requirement on reaction equipment, complex operation and the like when amorphous MMAE is used for preparing a conjugate in the prior art; secondly, the preparation method of the MMAE crystal form A provided by the invention is simple to operate, the prepared crystal form is high in purity and uniform in particle size distribution, the production cost is reduced, and the method is suitable for commercial production amplification, and the purity of the MMAE can be improved to more than 99.5%.
The MMAE and the monomethyl auristatin E have the same meanings, and all refer to compounds with the structures shown in the formula (I):
the term "w/w" as used herein means a weight ratio unless otherwise specified.
Drawings
The technical solution of the present application is further explained below with reference to the drawings and the embodiments.
Figure 1 is an X-ray powder diffraction (XRPD) pattern of form a of the compound of formula (I) prepared in example 2;
figure 2 XRPD pattern of form a of the compound of formula (I) prepared in example 3;
FIG. 3 is a DSC of form A of the compound of formula (I);
FIG. 4 is a TGA profile of crystalline form A of the compound of formula (I);
FIG. 5 is an HPLC plot of form A of the compound of formula (I);
FIG. 6 is an XRPD pattern for commercially available sample 1;
FIG. 7 is an XRPD pattern for commercially available sample 2;
FIG. 8 is an XRPD pattern for commercially available sample 3;
FIG. 9 is an HPLC chart of commercial sample 1;
FIG. 10 is an HPLC chart of commercial sample 2;
FIG. 11 is an HPLC chart of commercially available sample 3.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the following examples; it should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. Conditions not indicated in the examples are conventional experimental conditions. The starting material for the compound of formula (I) (i.e. MMAE) used in the present invention may be obtained by commercially available means as an amorphous white powder or by synthesis using a synthetic route known in the art, for example, from CN 109200291A.
The moisture content, unless otherwise specified, was calculated by coulometry.
The seed crystals used in examples 2 to 6 below were crystals A prepared by the method of example 1.
Example 1 preparation of crystalline form A of Monomethylauristatin E
Adding ethyl acetate (2.6mL) into methyl auristatin E (0.65g, HPLC: 98.8%) and stirring until the ethyl acetate is dissolved, adding purified water (28.0mg), stirring uniformly, detecting that the water content is 1.03% by a coulometry method, cooling to 2.5 ℃, stirring for 15-20 h, precipitating a large amount of solid, dropwise adding methyl tert-butyl ether (2.6mL), stirring for 1-2 h, dropwise adding n-heptane (13.0mL), continuously stirring for 2-4 h, filtering, leaching the solid with n-heptane (0.6mL), and drying in vacuum at 40 ℃ to obtain a methyl auristatin E crystal.
Example 2 preparation of crystalline form A of Monomethylauristatin E
Adding ethyl acetate (2.6mL) into methyl auristatin E (0.65g, HPLC: 98.8%) and stirring until the ethyl acetate is dissolved, adding purified water (28.0mg), stirring uniformly, detecting that the water content is 1.03% by a coulometry method, adding seed crystals (25.0mg), cooling to 2.5 ℃, stirring for 15-20 h, precipitating a large amount of solid, dropwise adding methyl tert-butyl ether (2.6mL), stirring for 1-2 h, dropwise adding n-heptane (13.0mL), continuously stirring for 2-4 h, filtering, leaching the solid with n-heptane (0.6mL), and drying in vacuum at 40 ℃ to obtain a methyl auristatin E crystal (0.96g), HPLC: 99.4 percent.
Example 3 preparation of crystalline form A of Monomethylauristatin E
Adding isopropyl acetate (4.0mL) into methyl auristatin E (1.00g, HPLC: 98.8%) and stirring until the isopropyl acetate is dissolved, adding purified water (51.1mg), stirring uniformly, detecting that the water content is 1.21% by a coulometry method, adding seed crystals (40.0mg), cooling to 2.5 ℃, stirring for 15-20 h, precipitating a large amount of solid, dropwise adding methyl tert-butyl ether (4.0mL), stirring for 1-2 h, dropwise adding n-heptane (20.0mL), continuously stirring for 2-4 h, filtering, leaching the solid with n-heptane (1.0mL), and drying in vacuum at 40 ℃ to obtain a methyl auristatin E crystal (0.95g), HPLC: 99.5 percent.
Example 4 preparation of crystalline form A of Monomethylauristatin E
Adding methyl auristatin E (1.00g, HPLC: 95.1%) into a mixed solution (4.0mL) of ethyl acetate and propyl acetate, stirring until the mixture is dissolved, adding purified water (40.2mg), uniformly stirring, detecting that the water content is 0.5% by a coulometry method, adding a seed crystal (40.0mg), cooling to 2.5 ℃, stirring for 15-20 h, precipitating a large amount of solid, dropwise adding methyl tert-butyl ether (6.0mL), stirring for 1-2 h, dropwise adding n-heptane (10.0mL), continuously stirring for 2-4 h, filtering, leaching the solid with n-heptane (1.0mL), and vacuum drying at 40 ℃ to obtain a methyl auristatin E crystal.
Example 5 preparation of crystalline form A of Monomethylauristatin E
Adding butyl acetate (3.0mL) into methyl auristatin E (1.00g, HPLC: 94.9%) and stirring until the butyl acetate is dissolved, adding purified water (51.1mg), stirring uniformly, detecting that the water content is 2% by a coulometry method, adding seed crystals (40.0mg), cooling to 2.5 ℃, stirring for 15-20 h, precipitating a large amount of solid, dropwise adding methyl tert-butyl ether (6.0mL), stirring for 1-2 h, dropwise adding n-heptane (15.0mL), continuously stirring for 2-4 h, filtering, leaching the solid with n-heptane (1.0mL), and drying in vacuum at 40 ℃ to obtain the methyl auristatin E crystal.
Example 6 preparation of crystalline form A of Monomethylauristatin E
Adding methyl formate (4.0mL) into methyl auristatin E (1.00g, HPLC: 97.9%) and stirring until the methyl auristatin E is dissolved, adding purified water (51.1mg), stirring uniformly, detecting that the water content is 1.21% by a coulometry method, adding seed crystals (40.0mg), cooling to 2.5 ℃, stirring for 15-20 h, precipitating a large amount of solid, dropwise adding methyl tert-butyl ether (4.0mL), stirring for 1-2 h, dropwise adding n-heptane (30.0mL), continuously stirring for 2-4 h, filtering, leaching the solid with n-heptane (1.0mL), and vacuum drying at 40 ℃ to obtain the methyl auristatin E crystal.
X-ray powder diffraction analysis (XRP D) was performed on the samples prepared in examples 2 to 6; and the sample prepared in example 2 was subjected to Differential Scanning Calorimetry (DSC) and simultaneous thermal analysis (TGA), in which,
x-ray powder diffraction analysis (XRPD) was collected on Bruker D8 ADVANCE, cuka radiation. The method parameters are as follows:
and (3) a test mode: wide angle;
scanning range: 2-50 °;
step length of test: 0.01 degree/step;
integration time: 0.1 s/step.
XRPD tests show that samples 1-6 prepared in examples 1-6 are all crystals and are named as crystal form A.
The XRPD pattern of the MMAEC crystalline form prepared in example 2 is shown in fig. 1, wherein a total of 39 peaks are shown, the specific diffraction data are shown in table 1, and the characteristic peaks are determined by considering various factors such as d value, low angle, intensity, characteristic line and complete peak shape, and the diffraction peaks at 2theta values of 3.8 ° ± 0.2 °, 9.3 ° ± 0.2 °, 9.9 ° ± 0.2 ° and 13.2 ° ± 0.2 ° are characteristic peaks. Diffraction peaks at 2theta values of 10.8 ° ± 0.2 °, 11.9 ° ± 0.2 °, 15.3 ° ± 0.2 ° and 16.3 ° ± 0.2 ° are important peaks. The diffraction peaks at 2theta values of 15.1 DEG +/-0.2 DEG, 18.4 DEG +/-0.2 DEG, 18.6 DEG +/-0.2 DEG, 20.1 DEG +/-0.2 DEG, 21.6 DEG +/-0.2 DEG and 23.0 DEG +/-0.2 DEG are the secondary important peaks.
TABLE 1
The XRPD pattern of the MMAEC crystal form prepared in example 3 is shown in fig. 2, the specific diffraction data are shown in table 2, and the data are determined by comprehensively considering various factors such as d value, low angle, intensity, characteristic line and complete peak shape, and the 2theta values are diffraction peaks at 3.8 ° ± 0.2 °, 9.3 ° ± 0.2 °, 9.9 ° ± 0.2 ° and 13.2 ° ± 0.2 ° as characteristic peaks. Diffraction peaks at 2theta values of 10.8 ° ± 0.2 °, 11.9 ° ± 0.2 °, 15.3 ° ± 0.2 ° and 16.3 ° ± 0.2 ° are important peaks. The diffraction peaks at 2theta values of 15.1 DEG +/-0.2 DEG, 18.4 DEG +/-0.2 DEG, 18.6 DEG +/-0.2 DEG, 20.1 DEG +/-0.2 DEG, 21.6 DEG +/-0.2 DEG and 23.0 DEG +/-0.2 DEG are the secondary important peaks.
TABLE 2
The XRPD patterns of the MMAE crystal forms prepared in examples 4-6 are substantially the same as those shown in FIGS. 1-2.
The Differential Scanning Calorimetry (DSC) chart of the invention is collected on a TADICOMOVERY DSC25, and the method parameters are as follows:
sample pan: aluminum plate and gland
Temperature range: 25-268 deg.C
Scanning rate: 10 ℃/min
Protective gas: nitrogen gas.
A DSC diagram as shown in figure 3, showing that form a prepared in example 2 shows an endothermic peak at 112.81 ℃.
Simultaneous thermal analysis (TGA) profiles were collected at METTLER TGA/DSC3+/1100F with the following process parameters:
sample pan: alumina oxide
Temperature range: 25-550 deg.C
Scanning rate: 10 ℃/min
Protective gas: nitrogen gas
A TGA profile as shown in figure 4, wherein form a prepared in example 2 is shown to begin with a weight loss at about 305 ℃.
Example 7 hygroscopicity test
Respectively measuring the moisture content of the MMAE crystal form prepared in the embodiment 2 of the invention and 500mg of the purchased amorphous MMAE, and recording the moisture content as the moisture content of the initial condition; then, the sample was placed at 25 ℃ and humidity of 92.5% for 24 hours, and then the moisture content was measured by coulometry, and the measurement results are shown in Table 3.
Table 3, 25 ℃, 92.5% humidity test results:
example 8 MMAE form a versus amorphous MMAE solubility contrast test
Comparing the solubility of the MMAE crystal form A prepared in the embodiment 2 of the invention with that of amorphous MMAE; the MMAE crystal form A and the amorphous MMAE prepared in the embodiment 2 are respectively added into methyl tert-butyl ether at the temperature of 20-25 ℃ to prepare saturated solution, and then the content of the MMAE in the saturated solution is determined by a high performance liquid chromatography after 1 hour and 2 hours. The results of the experiment are shown in table 4.
TABLE 4 solubility contrast test results for MMAE form A and amorphous MMAE
Example 9 stability study of MMAE form A
The MMAE crystal form A prepared in the embodiment 2 of the invention is placed at 40 ℃, and the purity and the moisture are respectively detected by a high performance liquid chromatography and a coulometry method in 1 month and 2 months. The results of the experiment are shown in Table 5.
TABLE 5 stability study results of MMAE form A
Time | Purity of | Moisture content |
Initiation of | 99.42% | 2.7% |
1 month | 99.45% | 2.2% |
2 months old | 99.42% | 2.2% |
Example 10 comparison of MMAE form A to MMAE amorphous purity
MMAE solid prepared in example 2 of the present invention and the crystal form of the sample purchased from 3 different manufacturers were tested by XRPD and the purity of the sample was determined by HPLC method, the results are shown in table 6:
TABLE 6 comparison of amorphous purity of MMAE form A with MMAE
Sample source | Inventive example 2 | |
|
|
Class of crystal forms | Crystal form A | Amorphous form | Amorphous form | Amorphous form |
XRPD pattern | FIG. 1 shows a schematic view of a | FIG. 6 | FIG. 7 | FIG. 8 |
Purity of | 99.40% | 97.90% | 94.90% | 95.10% |
HPLC chart | FIG. 5 | FIG. 9 | FIG. 10 shows a schematic view of a | FIG. 11 |
The MMAE crystal forms prepared in examples 3-6 and the MMAE crystal form prepared in example 2 have similar properties in stability, solubility, and hygroscopicity, and the purity is also improved to different degrees compared to amorphous powder.
In light of the foregoing description of the preferred embodiments according to the present application, it is to be understood that various changes and modifications may be made without departing from the spirit and scope of the invention. The technical scope of the present application is not limited to the contents of the specification, and must be determined according to the scope of the claims.
Claims (14)
1. A crystal form A of a compound shown as a formula (I) is characterized in that an X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2theta values of 3.8 degrees +/-0.2 degrees, 9.3 degrees +/-0.2 degrees, 9.9 degrees +/-0.2 degrees and 13.2 degrees +/-0.2 degrees,
2. form a of the compound of formula (I) according to claim 1 characterized in that it has an X-ray powder diffraction pattern further having diffraction peaks at one or more of 2 Θ values of 10.8 ° ± 0.2 °, 11.9 ° ± 0.2 °, 15.3 ° ± 0.2 ° and 16.3 ° ± 0.2 °;
preferably, the X-ray powder diffraction pattern of the crystal form A also has diffraction peaks at one or two or three or four of the 2theta values of 10.8 +/-0.2 degrees, 11.9 +/-0.2 degrees, 15.3 +/-0.2 degrees and 16.3 +/-0.2 degrees;
more preferably, said form a further has an X-ray powder diffraction pattern having diffraction peaks at 2 Θ values of 10.8 ° ± 0.2 °, 11.9 ° ± 0.2 °, 15.3 ° ± 0.2 ° and 16.3 ° ± 0.2 °.
3. Form a of the compound of formula (I) according to claim 1, characterized in that it has an X-ray powder diffraction pattern at 2 Θ values: diffraction peaks are present at 3.8 ° ± 0.2 °, 9.3 ° ± 0.2 °, 9.9 ° ± 0.2 °, 10.8 ° ± 0.2 °, 11.9 ° ± 0.2 °, 13.2 ° ± 0.2 °, 15.1 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.3 ° ± 0.2 °, 18.4 ° ± 0.2 °, 18.6 ° ± 0.2 °, 20.1 ° ± 0.2 °, 21.6 ° ± 0.2 °, 23.0 ° ± 0.2 °.
4. Form a of the compound of formula (I) according to claim 1, characterized in that it has substantially the same X-ray powder diffraction pattern as shown in figure 1 or figure 2.
5. Form A of a compound of formula (I) according to any one of claims 1 to 4, characterized in that its Differential Scanning Calorimetry (DSC) pattern comprises an endothermic peak at 112.81 ℃ ± 2 ℃.
6. Form A of the compound of formula (I) according to any one of claims 1 to 4, characterized in that it has a DSC profile substantially the same as shown in figure 2.
7. Form A of the compound of formula (I) according to any one of claims 1 to 4, wherein the form A contains 0-5% (w/w) water;
preferably, the form a contains 1-3% (w/w) of water.
8. A process for the preparation of crystalline form a of the compound of formula (I) according to any one of claims 1 to 7, comprising the steps of:
A) adding a compound shown in a formula (I) into a first solvent, stirring for dissolving, and optionally adding water to obtain a first mixed system;
B) stirring the first mixed system, and then adding a second solvent into the first mixed system to obtain a second mixed system;
C) stirring the second mixed system, and then adding a third solvent into the second mixed system to obtain a third mixed system;
D) and stirring the third mixed system to separate out a solid, thus obtaining the catalyst.
Preferably, the first solvent of step a) is selected from methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate, butyl acetate, isopropanol, DMF, or any combination thereof;
more preferably, the second solvent of step B) is selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, toluene or any combination thereof;
more preferably, the third solvent of step C) is selected from petroleum ether, n-hexane, cyclohexane, methylcyclohexane, n-heptane or any combination thereof.
9. The method according to claim 8, wherein the stirring of the first mixed system in the step B) is carried out at a temperature of-10 to 10 ℃;
the stirring second mixed system in the step C) is stirred at the temperature of-10 ℃;
and D), stirring the third mixed system at the temperature of-10 ℃.
10. The method according to claim 9, wherein step a) comprises a water content of 0.5% to 4% (w/w) based on the total amount of the first mixed system; preferably, the water content is 1% to 2% (w/w); more preferably, the water content is 1-1.5% (w/w).
Preferably, the volume ratio of the first solvent to the second solvent to the third solvent is 1: 1-2: 2.5-7.5;
more preferably, the volume ratio of the first solvent to the second solvent to the third solvent is 1: 1-2: 3-7;
more preferably, the volume ratio of the first solvent to the second solvent to the third solvent is 1:1: 3-7, or 1:2: 3-7.
Preferably, the feeding ratio of the compound shown in the formula (I) to the first solvent is 1: 2.5-7.5 (g/ml);
more preferably, the ratio of the weight of the compound represented by formula (I) to the volume of the first solvent is 1:3 to 7 (g/ml).
11. The method according to any one of claims 9 to 10, wherein the step B) is carried out by stirring the first mixed system, adding the seed crystal, cooling to-10 to 10 ℃, and adding the second solvent to obtain the second mixed system.
12. A pharmaceutical composition, which comprises the compound of formula (I) of any one of claims 1 to 7 in crystal form a and a pharmaceutically acceptable carrier.
13. Pharmaceutical composition according to claim 12, characterized in that it contains not less than 85% by weight, preferably not less than 90% by weight, preferably not less than 95% by weight, preferably not less than 99% by weight, preferably not less than 99.5% by weight, more preferably not less than 99.9% by weight of a compound of formula (I) in form a according to claim 1, relative to the total amount of compound of formula (I) present in the composition.
14. Use of crystalline form a of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a pharmaceutical conjugate;
preferably, the drug conjugate comprises an antibody drug conjugate, a polypeptide drug conjugate or a small molecule drug conjugate which takes the crystal form A of the compound shown in the formula (I) as cytotoxin.
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Application publication date: 20210716 Assignee: Tongyi Pharmaceutical (Hefei) Co.,Ltd. Assignor: Tong Yi medicine (Suzhou) Co.,Ltd. Contract record no.: X2024980000028 Denomination of invention: A Crystal and Preparation Method of Methyl Aurestatin E Granted publication date: 20221028 License type: Common License Record date: 20240104 |