WO2010031357A1 - 培美曲塞二酸的新晶型及其制备方法 - Google Patents

培美曲塞二酸的新晶型及其制备方法 Download PDF

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WO2010031357A1
WO2010031357A1 PCT/CN2009/074059 CN2009074059W WO2010031357A1 WO 2010031357 A1 WO2010031357 A1 WO 2010031357A1 CN 2009074059 W CN2009074059 W CN 2009074059W WO 2010031357 A1 WO2010031357 A1 WO 2010031357A1
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pemetrexed
pemetrexed diacid
water
crystal form
acid
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PCT/CN2009/074059
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English (en)
French (fr)
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罗杰
林蒙
朱正勇
罗君来
叶文润
秦咏梅
邓杰
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重庆医药工业研究院有限责任公司
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Priority to US13/120,080 priority Critical patent/US8324382B2/en
Priority to AU2009295094A priority patent/AU2009295094B2/en
Priority to EP09814077.5A priority patent/EP2351755B1/en
Priority to JP2011527193A priority patent/JP5536070B2/ja
Priority to CA2737967A priority patent/CA2737967C/en
Publication of WO2010031357A1 publication Critical patent/WO2010031357A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the field of organic chemistry and pharmacy, in particular to a folic acid antagonist N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]
  • N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d] A new crystalline form of pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (a compound of formula I, ie, Pemetrexed diacid, pemetrexed diacid) and a process for its preparation.
  • Pemetrexed diacid and its derivatives potently inhibit a variety of folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycine
  • TS thymidylate synthase
  • DHFR dihydrofolate reductase
  • GARFT amide ribonucleotide decanoyl transferase
  • its disodium salt, Pemetrexed disodium has been marketed in the United States, the European Union, Canada, China, Japan and other countries for the first-line treatment of malignant pleural mesothelioma and first-line and second-line treatment of non-small cell lung cancer. .
  • pemetrexed disodium In the treatment of malignant pleural mesothelioma, pemetrexed disodium is currently the only chemotherapy drug listed; in the second-line treatment of non-small cell lung cancer, pemetrexed disodium compared with the previous standard drug docetaxel The efficacy is comparable, but with fewer side effects, it will become the new standard for second-line treatment of non-small cell lung cancer.
  • training Clinical studies of metrozamide disodium in the treatment of breast cancer, colon cancer, pancreatic cancer, head and neck cancer, stomach cancer, bladder cancer, etc. are also underway, and the results are expected.
  • Pemetrexed diacid is an important precursor for the preparation of pemetrexed disodium. Its quality is a study of the prepared pemetrex, and the polymorphism of pemetrexedic acid has also attracted people's attention.
  • Patent US20080045711 discloses seven crystal forms of pemetrexed diacid, including two hydrate crystal forms (crystal form A, crystal form B), and a type of disulfoxide solvate crystal form (crystal form C). ), two ruthenium, osmium-dimercapto amide solvate crystal forms (Form D, Form E), two anhydrate forms (Form F, Form G).
  • the solvent bound in the solvate crystal form C, the crystal form D, and the crystal form E has a higher boiling point (the boiling point of the disulfoxide is 189 ° C, and the boiling point of the ruthenium, ⁇ -dimercapto amide is 156. °C), when used to further prepare pemetrexed disodium, these high boiling solvents may be introduced into the final product, increasing the control burden of the organic residue of the final product; the anhydrate crystal form F and the crystal form G are higher The temperature (160 ⁇ 200 °C) is obtained by drying.
  • the present invention provides three kinds of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrole) having certain X-ray powder diffraction pattern characteristics.
  • the X-ray powder diffraction pattern of the pemetrexedioic acid H crystal form provided by the present invention is characterized by a value of about 9.9 at 2 ⁇ . 12.2. 16.1. , 18.9. 19.8. 22.6. 25.1.
  • the position corresponds to a diffraction peak, and the other 2 ⁇ value is about 6.4. 10.6. 17.1. 18.1. 21.1. 25.8. 27.8. , 30.1.
  • Bit The arrangement also corresponds to a diffraction peak, and the pemetrexed diacid H crystal form has the characteristics represented by the X-ray powder diffraction pattern shown in FIG.
  • the pemetrexed diacid H crystal form provided by the present invention is a hydrate crystal form of pemetrexed diacid having a water content ranging from 5 to 80%.
  • the crystal form (mass content) of the pemetrexed diacid H crystal form provided by the present invention is generally more than 80%, preferably more than 90%.
  • the pemetrexed diacid I crystal form provided by the present invention has the characteristics represented by the X-ray powder diffraction pattern shown in Fig. 2.
  • the pemetrexed diacid I crystal form provided by the present invention is a hydrate crystal form of pemetrexed diacid having a water content ranging from 5 wt to 80 wt%.
  • the crystal form (mass content) of the pemetrexed diacid I crystal form provided by the present invention is generally more than 80%, preferably more than 90%.
  • the X-ray powder diffraction pattern of the pemetrexed diacid hydrate J crystal form provided by the present invention is characterized by a value of about 12.2 at 2 ⁇ . 20.3. 21.3. 28.9. 32.8.
  • the position corresponds to a diffraction peak, and the other 2 ⁇ value is approximately 5.6. , 8.9. 18.4. 19.5. 23.3. 24.5. 25.7. 27.7. 31.4. , 34.2.
  • the position of the plasmon also corresponds to a diffraction peak, and the pemetrexed diacid hydrate J crystal form has the characteristics represented by the X-ray powder diffraction pattern shown in Fig. 3.
  • the pemetrexed diacid hydrate J crystal form has a water content ranging from 5 wt to 80 wt%.
  • the crystal form (mass content) of the pemetrexed diacid hydrate J crystal form provided by the present invention is generally more than 80%, preferably more than 90%.
  • the water content of the present invention was determined by a METTLER TOLEDO Model DL31 Karl Fischer Moisture Analyzer.
  • Representative X-ray powder diffraction patterns of pemetrexed diacid H crystal form, I crystal form and J crystal form provided by the present invention are shown in the accompanying drawings.
  • "Representative X-ray powder diffraction pattern” means that the X-ray powder diffraction characteristics of this crystal form conform to the overall morphology of the diffraction peaks in this spectrum, and it is understood that during the X-ray powder diffraction test, Subject to a variety of factors, such as the particle size of the test sample, the method of processing the sample, the instrument, test parameters, test operations, etc., the X-ray measured by the same crystal form The peak position and peak intensity of the diffraction peak of the powder diffraction pattern will be different. In some cases, some diffraction peaks will not appear at all. The difference is that the experimental error of the diffraction peak 2 ⁇ value can be ⁇ 0.4. , usually 0.2°.
  • the invention also provides a preparation method of the above three new crystal forms of pemetrexed diacid.
  • the present invention provides a method for preparing a pemetrexedic acid H crystal form, which comprises culturing pemetrexed diacid from a mixed solution comprising pemetrexed diacid, water and a solvent dissolved in water. Crystallize out. Specifically, the pemetrexed salt (including dry or wet) is dissolved in a mixed solvent of water and a solvent dissolved in water, and the pH is adjusted to 1 to 2.5 to crystallize the crystal of pemetrexed diacid; Or pemetrexed diacid (including dry or wet) is directly dissolved in a mixed solvent of water and a solvent soluble in water, and then crystallized.
  • pemetrexed salt refers to a pemetrexed salt having a certain water solubility, including but not limited to pemetrexed sodium salt, pemetrexed lithium salt, pemetrexed potassium salt. And pemetrexed salt, pemetrexed calcium salt and the like, among which pemetrexed disodium salt is preferred.
  • a solvent which is miscible in water includes ethanol, decyl alcohol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethylene glycol dioxime or the like or a mixture thereof, among which ethanol, acetone is preferred;
  • the volume of the solvent which is miscible in water is generally 0.5 to 3 times, preferably 0.8 to 1.5 times the volume of water; the volume of water is usually 3 to 30 times, preferably 3 to 20 times, the weight of the pemetrexed salt or the diacid.
  • the "pH adjustment" in the preparation method of the H crystal form is achieved by adding an acid including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, sodium hydrogen sulfate, sodium dihydrogen phosphate, citric acid, acetic acid. , oxalic acid, trifluoroacetic acid, hydrazine sulfonic acid, p-toluic acid, benzoic acid, etc., of which hydrochloric acid and acetic acid are preferred; the acid used is generally an aqueous acid solution diluted with water, and the concentration thereof is generally 0.5 to 5 mol/L. ; adjust the pH range to
  • the temperature of the system at the completion of pH adjustment is generally from room temperature to the boiling point of the mixed solution.
  • the pemetrexed diacid is directly dissolved in a mixed solution of water and a solvent dissolved in water, and the dissolution can be promoted by adjusting the pH or heating of the system, and the pH is adjusted to 1 ⁇ 3,
  • the heating temperature is generally 40 °C to the boiling point of the mixed solution.
  • the crystallization is generally carried out under stirring, and the crystallization time is generally 0.2 to 6 hours, preferably 0.3 to 2 hours, and the end temperature of the crystallization is generally 0 ° C to room temperature; in order to further increase the crystallization Rate, a certain amount of water may be added during the crystallization process, and the amount of water added is generally the initial amount of water.
  • the pemetrexed diacid H crystal obtained in the H crystal form preparation method can be used in the art commonly used in the art. Separation, such as filtration, the collected water content of pemetrexed diacid H crystal is generally 40wt ⁇ 80wt%, the crystal can be further dried to reduce its water content, drying is generally carried out under reduced pressure, the temperature is generally 35 ⁇ 70 ° C, the degree of vacuum is generally 0.075 ⁇ 0.098 MPa, and the drying time is generally 10 to 40 hours; after drying, the water content of the pemetrexed diacid H crystal form is generally 5 wt% to 10 wt%.
  • the invention provides a preparation method of pemetrexedioic acid I crystal form, which comprises adjusting the pH of an aqueous solution containing pemetrexed salt having a concentration lower than 0.07 mol/L to 2 ⁇ 3 with an acid to precipitate pemetrex. Sebacic acid crystals.
  • pemetrexed salt is a pemetrexed salt having a certain water solubility, including but not limited to pemetrexed sodium salt, pemetrexed lithium salt, pemetrexed potassium salt, It is preferably pemetrexed salt, pemetrexed calcium salt or the like, of which pemetrexed disodium salt is preferred.
  • the concentration of pemetrexed salt in the "aqueous solution containing a lower concentration of pemetrexed salt” is generally less than 0.07 mol/L, and the pH of the solution is generally 7 to 14.
  • the preparation of the aqueous solution comprises dissolving pemetrexed salt in water or an aqueous alkali solution, or dissolving pemetrexed diacid in an aqueous alkali solution, or using a reaction aqueous solution containing pemetrexed salt; wherein "alkali aqueous solution”
  • the “base” includes, but is not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate.
  • aqueous alkali solution may further include a certain amount of a solvent which is miscible in water, such as ethanol, decyl alcohol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethylene glycol dioxime or the like or a mixture thereof, and their volume It is generally 0.05 to 1 times the volume of the aqueous solution.
  • the “acid” used in the pH adjustment method of Form I includes, but is not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, sodium hydrogen sulfate, sodium dihydrogen phosphate, citric acid, acetic acid, oxalic acid, trifluoroacetic acid. And hydrazine sulfonic acid, p-toluic acid, benzoic acid, and the like, and mixtures thereof, of which hydrochloric acid and acetic acid are preferred.
  • the pH and crystallization temperature are generally -10 to 40 °. Preferably, it is from 0 ° C to room temperature.
  • the crystallization is generally carried out under stirring, and the crystallization time is usually 0.1 to 3 hours, preferably 0.3 to 1 hour.
  • the pemetrexed diacid I crystal obtained in the crystal form preparation method can be separated by a method generally used in the art, such as filtration, and the collected pemetrexed diacid crystals generally have a water content of 40 wt% to 80 wt%, the crystal. Further drying to reduce the water content, drying is generally carried out under reduced pressure, the temperature is generally 35 ⁇ 70 ° C, the degree of vacuum is generally 0.075 ⁇ 0.098 MPa, and the drying time is generally 10 to 40 hours; After overdrying, the water content of pemetrexedioic acid I crystal form is generally from 5 wt% to 10% by weight.
  • the invention provides a preparation method of pemetrexed diacid J crystal form, which comprises adjusting the pH of an aqueous solution containing pemetrexed salt having a concentration higher than 0.07 mol/L to 2 ⁇ 4 with an acid to precipitate pemetrex. Sebacic acid crystals.
  • pemetrexed salt refers to a pemetrexed salt having a certain water solubility, including but not limited to pemetrexed sodium salt, pemetrexed lithium salt, pemetrexed potassium salt. And pemetrexed salt, pemetrexed calcium salt and the like, among which pemetrexed disodium salt is preferred.
  • the concentration of pemetrexed salt in the "aqueous solution containing a higher concentration of pemetrexed salt” is generally higher than 0.07 mol/L, and the pH of the solution is generally 7 to 14.
  • the preparation of the aqueous solution comprises dissolving pemetrexed salt in water or an aqueous alkali solution, or dissolving pemetrexed diacid in an aqueous alkali solution, or using a reaction aqueous solution containing pemetrexed salt; wherein "alkali aqueous solution”
  • the “base” includes, but is not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate.
  • aqueous alkali solution may further include a certain amount of a solvent which is miscible in water, such as ethanol, decyl alcohol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethylene glycol dioxime or the like or a mixture thereof, and their volume It is generally 0.05 to 2 times the volume of the aqueous solution.
  • a solvent which is miscible in water such as ethanol, decyl alcohol, isopropanol, acetone, acetonitrile, tetrahydrofuran, ethylene glycol dioxime or the like or a mixture thereof, and their volume It is generally 0.05 to 2 times the volume of the aqueous solution.
  • the "S history" used in the pH adjustment method of J crystal form includes, but is not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, sodium hydrogen sulfate, sodium dihydrogen phosphate, citric acid, acetic acid, oxalic acid, trifluoro Acetic acid, hydrazine sulfonic acid, p-toluic acid, benzoic acid, and the like, and mixtures thereof, of which hydrochloric acid and acetic acid are preferred.
  • the pH and crystallization temperature are generally -10 to 40 °. Preferably, it is from 0 ° C to room temperature.
  • the crystallizing solution can also be heated and cooled to facilitate crystal growth.
  • the heating temperature is generally 50 to 70 ° C
  • the cooling temperature is generally 0 to room temperature.
  • the crystallization is generally carried out under stirring, and the crystallization time is usually 0.1 to 5 hours, preferably 0.3 to 2 hours.
  • the pemetrexed diacid J crystal obtained in the J crystal form preparation method can be separated by a method generally used in the art, such as filtration, and the collected pemetrexed diacid crystals generally have a water content of 40 wt% to 80 wt%, the crystal. It can be further dried to reduce its water content. Drying is generally carried out under reduced pressure. The temperature is generally 35 to 70 ° C, the degree of vacuum is generally 0.075 to 0.098 MPa, and the drying time is generally 10 to 40 hours. After drying, the culture is carried out.
  • the water content of the meperic acid I crystal form is generally from 5 wt to 10 wt%.
  • Another object of the present invention is to provide the use of the above three new crystalline forms of pemetrexed diacid for the preparation of a pharmaceutically acceptable salt of pemetrexed diacid.
  • This use involves the use of the above three new crystalline forms of pemetrexed diacid with a corresponding base to obtain a pharmaceutically acceptable salt of pemetrexedic acid.
  • the use still further comprises first preparing the novel crystalline pemetrexed diacid of the present invention by the method provided by the present invention, and then reacting it with the corresponding base to obtain a pharmaceutically acceptable salt of pemetrexedioic acid.
  • the invention also provides a method for preparing pemetrexed salt, which comprises adding pemetrexedic acid to an aqueous solvent, dissolving pemetrexed diacid with a corresponding base, and adding a suitable mixture after dissolution.
  • the pharmaceutically acceptable salt of pemetrexedic acid is precipitated in an organic solvent dissolved in water or directly lyophilized to obtain a pharmaceutically acceptable salt of pemetrexed diacid in a lyophilized form, the aqueous solvent comprising water and water A mixed solvent with a suitable organic solvent miscible in water.
  • the "pharmaceutically acceptable salt of pemetrexedic acid” in the above method includes a sodium salt, a potassium salt, a lithium salt, an amine salt and the like of pemetrexedic acid, and preferably pemetrexed disodium.
  • the corresponding base including sodium hydroxide, potassium hydroxide, ammonium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, hydrogen phosphate II Potassium or the like is preferably sodium hydroxide.
  • the pemetrexed diacid when the pemetrexed diacid is dissolved, the "corresponding base is added, and the amount is generally more than twice the molar amount of pemetrexed diacid; after dissolution, according to the prepared pemetrexed salt.
  • pH adjustment such as the preparation of pemetrexed disodium, generally adjust the pH to 7 ⁇ 12.
  • "appropriate water-soluble organic solvent” includes “ethanol, acetone, acetonitrile, isopropanol, tetrahydrofuran, B" when dissolved in a suitable water-soluble organic solvent to precipitate pemetrexed salt.
  • the amount of organic solvent added is generally 2 to 10 times the volume of water.
  • the precipitated pemetrexed salt can be isolated by methods commonly used in the art, such as filtration, and the collected pemetrexed salt can be further dried.
  • the "suitable water-soluble organic solvent” in the “aqueous solvent” should be suitably lyophilized, including t-butanol, Disulfoxide, dioxane, etc., and mixtures thereof.
  • a dispersing agent such as mannitol, lactose, fructose or the like may be added to the solution before lyophilization to enhance the lyophilization effect.
  • pemetrexed diacid and pemetrexed disodium used in the present invention are prepared by the method disclosed in Patent CN200410097284.7.
  • the present invention provides three new crystal forms of pemetrexed diacid (H crystal form, I crystal form and J crystal form).
  • Type has good reproducibility, and the preparation process is simple and easy, and has strong practicability. It is an improved new crystal form of pemetrexedic acid.
  • Figure 1 is an X-ray powder diffraction pattern of pemetrexed diacid H crystal form.
  • Figure 2 is an X-ray powder diffraction pattern of pemetrexed diacid I crystal form.
  • Figure 3 is an X-ray powder diffraction pattern of pemetrexed diacid J crystal form.
  • Example 1 Preparation of pemetrexed diacid H crystal form 5 g of pemetrexed disodium (dry) was dissolved in 50 ml of water, 60 ml of ethanol was added, and 2 mol/L was used. The aqueous hydrochloric acid solution is adjusted to a pH of 1.5 to 2.0, heated and dissolved, stirred and crystallized at room temperature for 1.5 hours, filtered, washed with an appropriate amount of water of pH 4 to 5, and depressurized at 45 to 50 ° C (vacuum degree 0.085 to 0.090 MPa). After drying for 30 hours, pemetrexed diacid H crystal form 2.9 g, water content 7.1%.
  • the pemetrexed diacid produced in this example was measured by X-ray diffraction to be 5.4° and 6.3 at 2 Torr. , 9.8°, 10.6. , 12.1°, 16.1°, 17.1. 18.1. , 19.0°, 19.8°, 21.1. , 22.6°, 23.7°, 24.4°, 25.1. 25.8. , 26.5°, 27.8. , 30.1. 31.1. , 32.4°, 38.5.
  • the position corresponds to a diffraction peak (relative intensity is 10% or more).
  • Example 2 Preparation of pemetrexed diacid H crystal form 8 g of pemetrexed disodium (wet product) was dissolved in 24 ml of water, 24 ml of ethanol was added, and the pH was adjusted to 2.0 to 2.5 with a 1 mol/L hydrochloric acid aqueous solution. The solution was dissolved, and 36 ml of water was added thereto, and the mixture was stirred for 0.5 hour, filtered, and the cake was washed with an appropriate amount of water to obtain a crystal form of pemetrexed diacid H having a water content of about 75%.
  • the pemetrexed diacid obtained in this example was measured by X-ray diffraction to be 6.4 ° and 9.9 at 2 Torr. 10.6. 12.2. 16.1. , 17. , 18.1. , 18.9. 19.8. 21.1. 22.6. 25.1.
  • the 25.8°, 27.8°, and 30.1° positions correspond to diffraction peaks and have an X-ray powder diffraction pattern as shown in Fig. 1.
  • Example 3 Preparation of pemetrexed diacid H crystal form 5 g of pemetrexed diacid (dry product) was added to a mixture of 75 ml of water and 70 ml of acetone, and the pH was adjusted to 1.5 with a 1.5 mol/L hydrochloric acid aqueous solution. 2.0, heating and dissolving, stirring and crystallization for 1 hour, filtering, washing the filter cake with an appropriate amount of water, drying at 55 ⁇ 60 ° C under reduced pressure (vacuum degree 0.090 ⁇ 0.095 MPa) for 15 hours, obtaining pemetrexed diacid H crystal Type 3.2g, water content 8.5%.
  • the pemetrexed diacid obtained in the present example was confirmed to be an H crystal form after being measured by X-ray diffraction.
  • Example 4 Preparation of pemetrexed diacid I crystal form Dissolve 10 g of pemetrexed disodium (dry) in 500 ml of water, cool to 0 ⁇ 5 ° C, adjust the pH of the solution to 4 ⁇ 5 with acetic acid, and add 2 mol/L hydrochloric acid solution to adjust H to 2 ⁇ 3. Continue stirring for 0.5 hours, filter, and wash the filter cake with an appropriate amount of water to obtain a crystal form of pemetrexed diacid I with a water content of about 65%.
  • pemetrexed diacid obtained in this example was measured by X-ray diffraction to have an X-ray powder diffraction pattern as shown in Fig. 2.
  • Example 5 Preparation of pemetrexedioic acid I crystal form 10 g of pemetrexed diacid (wet product) was added to a mixed solvent consisting of 400 ml of water and 100 ml of ethanol, and the system was adjusted with 4 mol/L sodium hydroxide solution.
  • the pemetrexed diacid obtained in this example was confirmed to be in the form of I after being measured by X-ray diffraction.
  • Example 6 Preparation of pemetrexed diacid J crystal form 15 g of pemetrexed disodium (dry) was stirred and dissolved in 375 ml of water, cooled to 0 to 5 ° C, and the pH of the solution was adjusted to 3 to 4 with acetic acid. Continue stirring for about 10 minutes, filter, and wash the filter cake with appropriate amount of water to obtain crystal form J pemetrexed diacid. Dry at 60 ⁇ 65 °C under reduced pressure (vacuum degree 0.090 ⁇ 0.095MPa) for 24 hours. The content of the kojic acid J crystal form was 12.1 g, and the water content was 7.7%.
  • the pemetrexed diacid obtained in this example was measured by X-ray diffraction to be about 8.8 at 2 Torr. 12.1. 17.2. 18.3. 19.4. 20.2. 21.1. 23.1. 24.3. 26.2. 27.6. 28.8. , 30.0. 31.6. 32.7. , 34.1.
  • the 34.8 and 37.6 positions correspond to diffraction peaks (relative intensity is 10% or more).
  • Example 7 Preparation of pemetrexed diacid J crystal form 15 g of pemetrexed disodium (wet product) was stirred and dissolved in 100 ml of water, 40 ml of ethanol was added, and the pH was 2 to 3 with a 1 mol/L hydrochloric acid solution, and stirring was continued. After 0.5 hours, it was filtered, and the filter cake was washed with water in an appropriate amount to obtain a pemetrexed acid J crystal form having a water content of about 50%.
  • the pemetrexed diacid obtained in this example is measured by X-ray diffraction and is about 5.6 ° at 2 ⁇ .
  • Example 8 Preparation of pemetrexed diacid J crystal form 10 g of pemetrexed disodium (dry product) was stirred and dissolved in 100 ml of water, 100 ml of acetone was added, and the pH of the solution was adjusted to 2 to 4 with 2 mol/L hydrochloric acid. After the system precipitates a large amount of solids, the mixture is heated to 60 ⁇ 65 ° C for about 10 minutes, stirred and cooled for about 1.5 hours, filtered, and the filter cake is washed with water to obtain the pemetrexed diacid J crystal form.
  • pemetrexed diacid obtained in the present example was confirmed to be J-type crystal by X-ray diffraction measurement.
  • Example 9 Preparation of pemetrexed disodium salt 5 g of a new crystal form (dry product) of pemetrexed diacid obtained in the above example was added to 35 ml of water, and ⁇ 11 11 was adjusted with a 5 mol/L sodium hydroxide aqueous solution.
  • Example 10 Preparation of pemetrexed disodium sodium 7 g of pemetrexed diacid new crystal form (wet product) obtained in the above example was added to 10 ml of water, with 5mol/L sodium hydroxide solution adjust the pH of the system to 10 ⁇ 11, stir and dissolve, add 44ml of acetonitrile, stir and crystallize at room temperature for about 2 hours, filter, wash and filter with appropriate amount of acetonitrile/water mixture and acetone to wash. Metrozine disodium.
  • Example 11 Preparation of lyophilized pemetrexed disodium sodium 10.8 g of a new crystalline form of pemetrexed diacid (dry product) obtained in the above example was added to 180 ml of water for injection, and adjusted with 2 mol/L sodium hydroxide solution. ⁇ 11 ⁇ 12, stir to dissolve, then adjust the pH to 7.0 ⁇ 8.5 with 2mol/L hydrochloric acid, then make up to 250ml; add mannitol lO.Og, add 0.05% activated carbon, stir for 10 minutes, filter, then filter The sterilization filtration was carried out; the lyophilized bottle was filled in a 12.5 ml/bottle, and lyophilized to obtain lyophilized pemetrexed disodium.
  • the new crystal form of pemetrexedioic acid means H crystal, I crystal, J crystal or a mixture thereof.

Description

培美曲塞二酸的新晶型及其制备方法
本申请要求于 2008年 9月 22日提交中国专利局、 申请号为
200810070345.9、 发明名称为"培美曲塞二酸的新晶型及其制备方法
"的中国专利申请的优先权， 其全部内容通过引用结合在本申请中。
技术领域
本发明涉及有机化学领域和药学领域， 具体涉及叶酸拮抗剂 N-[4-[2-(2-氨 基 -4,7-二氢 -4-氧代 -1H-吡咯并 [2,3-d]嘧啶 -5-基）乙基]苯曱酰基] -L-谷氨酸 (式 I 化合物， 即 Pemetrexed diacid, 培美曲塞二酸)的新晶型及其制备方法。
Figure imgf000003_0001
I
背景技术
培美曲塞二酸及其衍生物作为多靶点叶酸拮抗剂，能强有力地抑制多种叶 酸依赖酶， 包括胸苷酸合成酶 (TS)、 二氢叶酸还原酶 (DHFR)和甘氨酰胺核糖 核苷酸曱酰基转移酶 (GARFT)等， 具有优良的抗肿瘤活性。 目前， 其二钠盐即 培美曲塞二钠 （ Pemetrexed disodium ) 已在美国、 欧盟、 加拿大、 中国、 日本 等国上市， 用于一线治疗恶性胸膜间皮瘤和一线、 二线治疗非小细胞肺癌。 在 恶性胸膜间皮瘤的治疗中，培美曲塞二钠是目前唯一上市的化疗药物； 在非小 细胞肺癌二线治疗中，培美曲塞二钠与此前的标准药物多西紫杉醇相比， 疗效 相当， 但副作用更小， 因此将成为非小细胞肺癌二线治疗的新标准。 此外， 培 美曲塞二钠治疗乳腺癌、 肠癌、 胰腺癌、 头颈部癌、 胃癌、 膀胱癌等的临床研 究也正在进行中， 结果令人期待。
培美曲塞二酸是制备培美曲塞二钠的重要前体，其质量对所制备的培美曲 的研究， 其中培美曲塞二酸的多晶现象也引起了人们的重视， 如专利 US20080045711中公开了培美曲塞二酸的 7种晶型，其中包括两种水合物晶型 (晶型 A、 晶型 B), —种二曱亚砜溶剂合物晶型（晶型 C), 两种 Ν,Ν-二曱基曱 酰胺溶剂合物晶型（晶型 D、 晶型 E), 两种无水物晶型（晶型 F、 晶型 G)。 在这 些晶型中， 溶剂合物晶型 C、 晶型 D、 晶型 E中结合的溶剂沸点较高 (二曱亚 砜沸点为 189°C , Ν,Ν-二曱基曱酰胺沸点为 156°C), 在用于进一步制备培美曲 塞二钠时， 这些高沸点溶剂可能引入终产品，增加了终产品有机残留的控制负 担； 无水物晶型 F和晶型 G是经较高温度 (160〜200°C)干燥而得， 在这样的温 度下， 培美曲塞二酸会发生一定的降解， 不利于产品纯度的保持； 水合物晶型 A和 B虽然克服了前面晶型的不足，但晶型 A的制备收率低 (约 40%), 实用价 值不高； 晶型 B制备时间较长， 仅析晶就需耗时约 18小时， 不利于生产效率 的提高。 因此， 为了克服培美曲塞二酸现有晶型技术的不足， 我们对培美曲塞 二酸多晶现象进行了进一步的研究，在此过程中我们惊喜的发现了几种培美曲 塞二酸新晶型， 这些新晶型制备方法简便， 实用性强， 有利于进一步制备培美 曲塞二钠。 发明内容
本发明的目的在于提供制备工艺简便、 实用性强的培美曲塞二酸新晶型， 以及制备这些新晶形的方法。
为了实现该目的， 本发明提供了三种具有一定 X-射线粉末衍射图谱特征 的 N-[4-[2-(2-氨基 -4,7-二氢 -4-氧代 -1H-吡咯并 [2,3-d]嘧啶 -5-基）乙基]苯曱酰 基] -L-谷氨酸 (培美曲塞二酸)新晶型 (分别定义为 H晶型、 I晶型和 J晶型）。
本发明提供的培美曲塞二酸 H晶型的 X-射线粉末衍射图谱的特征为： 在 2Θ值约为 9.9。、 12.2。、 16.1。、 18.9。、 19.8。、 22.6。、 25.1。的位置对应有衍射峰， 另外 2Θ值约为 6.4。、 10.6。、 17.1。、 18.1。、 21.1。、 25.8。、 27.8。、 30.1。等的位 置也对应有衍射峰， 培美曲塞二酸 H晶型具有如图 1所示的 X-射线粉末衍射 图谱所代表的特征。
本发明提供的培美曲塞二酸 H 晶型是培美曲塞二酸的一种水合物晶型， 其水含量范围为 5〜80%。
本发明提供的培美曲塞二酸 H晶型的晶型含量 (质量含量)一般大于 80%, 优选大于 90%。
本发明提供的培美曲塞二酸 I晶型具有如图 2所示的 X-射线粉末衍射图 谱所代表的特征。
本发明提供的培美曲塞二酸 I晶型是培美曲塞二酸的一种水合物晶型，其 水含量范围为 5 wt〜80wt%。
本发明提供的培美曲塞二酸 I晶型的晶型含量 (质量含量)一般大于 80%, 优选大于 90%。
本发明提供的培美曲塞二酸水合物 J晶型的 X-射线粉末衍射图谱的特征 为： 在 2Θ值约为 12.2。、 20.3。、 21.3。、 28.9。、 32.8。的位置对应有衍射峰， 另 外在 2Θ值约为 5.6。、 8.9。、 18.4。、 19.5。、 23.3。、 24.5。、 25.7。、 27.7。、 31.4。、 34.2。等的位置也对应有衍射峰，培美曲塞二酸水合物 J晶型具有如图 3所示的 X-射线粉末衍射图谱所代表的特征。该培美曲塞二酸水合物 J晶型的水含量范 围为 5wt〜80wt%。
本发明提供的培美曲塞二酸水合物 J晶型的晶型含量 (质量含量)一般大于 80%, 优选大于 90%。
本发明的培美曲塞二酸的 X-射线粉末衍射分析是在 0〜40°C的环境温度及 30%〜80%及环境湿度下， 经 PW1710 BASED X-射线衍射仪的 CuKa源 (α = 1.5406A)测定完成的。 本发明水含量由 METTLER TOLEDO DL31 型 Karl Fischer水分仪测定。
本发明提供的培美曲塞二酸 H晶型、 I晶型和 J晶型代表性的 X-射线粉末 衍射图谱列于附图中。 "代表性的 X-射线粉末衍射图谱"是指本晶型的 X-射线 粉末衍射特征符合本图谱中衍射峰的整体形貌， 可以理解的是在的 X-射线粉 末衍射测试过程中， 由于受到多种因素， 如测试样品的粒度、 测试时样品的处 理方法、 仪器、 测试参数、 测试操作等的影响， 同一种晶型所测得的 X-射线 粉末衍射图谱的衍射峰的出峰位置和峰强度会有一定的差异，某些情况下某些 衍射峰甚至会基本不出现，这些差异即为，衍射峰 2Θ值的实验误差可为 ±0.4。， 一般为士 0.2°。
本发明同时提供了以上三种培美曲塞二酸新晶型的制备方法。
本发明提供了一种培美曲塞二酸 H 晶型的制备方法， 该方法包括使培美 曲塞二酸从包含培美曲塞二酸、 水和混溶于水的溶剂的混合溶液中结晶出来。 具体包括将培美曲塞盐（包括干品或湿品） 溶于水与混溶于水的溶剂组成的混 合溶剂中，调节 pH至 1〜2.5,析晶出培美曲塞二酸晶体；或将培美曲塞二酸 (包 括干品或湿品)直接溶于水与混溶于水的溶剂组成的混合溶剂中， 再析晶。
H晶型制备方法中"培美曲塞盐"是指有一定水溶性的培美曲塞盐， 包括但 不限于培美曲塞钠盐、 培美曲塞锂盐、 培美曲塞钾盐、 培美曲塞胺盐、 培美曲 塞钙盐等， 其中优选培美曲塞二钠盐。
H晶型制备方法中"混溶于水的溶剂，，包括乙醇、 曱醇、 异丙醇、 丙酮、 乙 腈、 四氢呋喃、 乙二醇二曱醚等或它们的混合物， 其中优选乙醇， 丙酮； "混 溶于水的溶剂 "的体积一般为水的 0.5〜3倍， 优选 0.8〜1.5倍； 水的体积一般为 培美曲塞盐或二酸重量的 3〜30倍， 优选 3〜20倍。
H晶型制备方法中"调节 pH"是通过加酸来实现的， 酸包括但不限于盐酸、 氢溴酸、 氢碘酸、 硫酸、 磷酸、 硫酸氢钠、 磷酸二氢钠、 曱酸、 乙酸、 草酸、 三氟乙酸、 曱磺酸、 对曱苯横酸、 苯曱酸等， 其中优选盐酸、 乙酸； 所用的酸 一般为用水稀译后的酸水溶液， 其浓度一般为 0.5〜5mol/L; 调节 pH的范围为
1〜3。 pH调节完毕时体系的温度一般是室温至接近混合溶液沸点。
H 晶型制备方法中 "将培美曲塞二酸直接溶于水与混溶于水的溶剂组成的 混合溶液中，，时可通过调节体系 pH或加热来促进溶解， pH—般调节至 1〜3 , 加热温度一般为 40 °C至接近混合溶液的沸点。
H晶型制备方法中析晶一般在搅拌状态下进行， 析晶时间一般为 0.2〜6小 时， 优选 0.3〜2小时， 析晶的终点温度一般为 0°C至室温； 为了进一步提高析 晶收率， 可在析晶过程中再加入一定量的水， 加入的水量一般为初始水量的
0.5-4倍。
H晶型制备方法中所得的培美曲塞二酸 H晶体可用本技术领域常用的方 法进行分离， 如过滤， 收集的培美曲塞二酸 H 晶体的水含量一般为 40wt〜80wt%, 该晶体可进一步干燥以降低其水含量， 干燥一般在减压状态下 进行， 温度一般为 35〜70°C , 真空度一般为 0.075〜0.098MPa, 干燥时间一般为 10〜40小时； 经过干燥后， 培美曲塞二酸 H晶型的水含量一般为 5wt〜10wt%。 本发明提供了一种培美曲塞二酸 I晶型的制备方法，该方法包括用酸调节 含浓度低于 0.07mol/L培美曲塞盐的水溶液 pH至 2〜3 , 析出培美曲塞二酸晶 体。
I晶型制备方法中"培美曲塞盐"是有一定水溶性的培美曲塞盐， 包括但不 限于培美曲塞钠盐、 培美曲塞锂盐、 培美曲塞钾盐、 培美曲塞胺盐、 培美曲塞 钙盐等， 其中优选培美曲塞二钠盐。
I晶型制备方法中 "含较低浓度培美曲塞盐的水溶液"中培美曲塞盐浓度一 般低于 0.07mol/L, 溶液 pH—般为 7〜14。 该水溶液的制备包括将培美曲塞盐 溶于水或碱水溶液中， 或将培美曲塞二酸溶于碱水溶液中， 或使用含培美曲塞 盐的反应水溶液；其中 "碱水溶液"中的 "碱"包括但不限于氢氧化钠、氢氧化钾、 氢氧化铵、 氢氧化锂、 氢氧化钙、 碳酸钠、 碳酸钾、 磷酸钠、 磷酸钾、 磷酸氢 二钠、 磷酸氢二钾等， 以及它们的混合物， 优选氢氧化钠、 氢氧化钾。 该"碱 水溶液"中还可以包括一定量的混溶于水的溶剂， 如乙醇、 曱醇、 异丙醇、 丙 酮、 乙腈、 四氢呋喃、 乙二醇二曱醚等或它们的混合物， 它们的体积一般是水 溶液体积的 0.05〜1倍。
I晶型制备方法中调 pH所用的 "酸"包括但不限于盐酸、 氢溴酸、 氢碘酸、 硫酸、 磷酸、 硫酸氢钠、 磷酸二氢钠、 曱酸、 乙酸、 草酸、 三氟乙酸、 曱磺酸、 对曱苯横酸、 苯曱酸等， 以及它们混合物， 其中优选盐酸、 乙酸。 调 pH和析 晶的温度一般是-10〜40°。， 优选 0°C至室温。 析晶一般在搅拌状态下进行， 析 晶时间一般为 0.1〜3小时， 优选 0.3〜1小时。
I晶型制备方法中所得的培美曲塞二酸 I晶体可用本技术领域常用的方法 进行分离， 如过滤， 收集的培美曲塞二酸晶体的水含量一般为 40wt〜80wt%, 该晶体可进一步干燥以降低其水含量， 干燥一般在减压状态下进行， 温度一般 为 35〜70°C , 真空度一般为 0.075〜0.098MPa, 干燥时间一般为 10〜40小时； 经 过干燥后， 培美曲塞二酸 I晶型的水含量一般为 5wt〜10wt%。
本发明提供了一种培美曲塞二酸 J晶型的制备方法，该方法包括用酸调节 含浓度高于 0.07mol/L培美曲塞盐的水溶液 pH至 2〜4, 析出培美曲塞二酸晶 体。
J晶型制备方法中"培美曲塞盐"是指有一定水溶性的培美曲塞盐， 包括但 不限于培美曲塞钠盐、 培美曲塞锂盐、 培美曲塞钾盐、 培美曲塞胺盐、 培美曲 塞钙盐等， 其中优选培美曲塞二钠盐。
J晶型制备方法中 "含较高浓度培美曲塞盐的水溶液"中培美曲塞盐浓度一 般高于 0.07 mol/L, 溶液 pH—般为 7〜14。 该水溶液的制备包括将培美曲塞盐 溶于水或碱水溶液中， 或将培美曲塞二酸溶于碱水溶液中， 或使用含培美曲塞 盐的反应水溶液；其中"碱水溶液"中的"碱"包括但不限于氢氧化钠、氢氧化钾、 氢氧化铵、 氢氧化锂、 氢氧化钙、 碳酸钠、 碳酸钾、 磷酸钠、 磷酸钾、 磷酸氢 二钠、 磷酸氢二钾等， 以及它们的混合物， 优选氢氧化钠、 氢氧化钾。 该"碱 水溶液"中还可以包括一定量的混溶于水的溶剂， 如乙醇、 曱醇、 异丙醇、 丙 酮、 乙腈、 四氢呋喃、 乙二醇二曱醚等或它们的混合物， 它们的体积一般是水 溶液体积的 0.05〜2倍。
J晶型制备方法中调 pH所用的 "S史"包括但不限于盐酸、 氢溴酸、 氢碘酸、 硫酸、 磷酸、 硫酸氢钠、 磷酸二氢钠、 曱酸、 乙酸、 草酸、 三氟乙酸、 曱磺酸、 对曱苯横酸、 苯曱酸等， 以及它们混合物， 其中优选盐酸、 乙酸。 调 pH和析 晶的温度一般是-10〜40°。， 优选 0°C至室温。 在析晶过程也可加热、 冷却析晶 液以助于晶体生长， 加热温度一般为 50〜70°C , 冷却温度一般为 0〜室温。 析晶 一般在搅拌状态下进行， 析晶时间一般为 0.1〜5小时， 优选 0.3〜2小时。
J晶型制备方法中所得的培美曲塞二酸 J晶体可用本技术领域常用的方法 进行分离， 如过滤， 收集的培美曲塞二酸晶体的水含量一般为 40wt〜80wt%, 该晶体可进一步干燥以降低其水含量， 干燥一般在减压状态下进行， 温度一般 为 35〜70°C , 真空度一般为 0.075〜0.098MPa, 干燥时间一般为 10〜40小时； 经 过干燥后， 培美曲塞二酸 I晶型的水含量一般为 5wt〜10wt%。
本发明的另一目的是提供了以上三种新晶型培美曲塞二酸用来制备培美 曲塞二酸药物上可接受的盐的用途。 该用途包括用以上三种新晶型培美曲塞二酸与相应的碱作用得到培美曲 塞二酸药物上可接受的盐。该用途还进一步包括用本发明提供的方法先制备本 发明的新晶型培美曲塞二酸，再将其与相应的碱作用得到培美曲塞二酸药物上 可接受的盐。
本发明还提供了一种制备培美曲塞盐的方法，包括将培美曲塞二酸加入到 含水溶剂中，， 用相应的碱使培美曲塞二酸溶解， 溶解后加入适宜的混溶于水 的有机溶剂析出培美曲塞二酸药物上可接受的盐或直接进行冻干得到冻干形 式的培美曲塞二酸药物上可接受的盐， 所述含水溶剂包括水、水与适宜的混溶 于水的有机溶剂的混合溶剂。
上述方法中"培美曲塞二酸药物上可接受的盐"包括培美曲塞二酸的钠盐、 钾盐、 锂盐、 胺盐等， 优选培美曲塞二钠。
上述方法中"相应的碱，，包括氢氧化钠、 氢氧化钾、 氢氧化铵、 氢氧化锂、 氢氧化钙、 碳酸钠、 碳酸钾、 磷酸钠、 磷酸钾、 磷酸氢二钠、 磷酸氢二钾等， 优选氢氧化钠。
上述方法中溶解培美曲塞二酸时加入"相应的碱，，的量一般大于培美曲塞 二酸摩尔量的 2倍；在溶解后，根据所制备的培美曲塞盐的情况进行 pH调节， 如制备培美曲塞二钠时一般调节 pH至 7〜12。
上述方法中 "溶解后加入适宜的混溶于水的有机溶剂析出培美曲塞盐"时， "适宜的混溶于水的有机溶剂"包括乙醇、 丙酮、 乙腈、 异丙醇、 四氢呋喃、 乙 二醇二曱醚等， 以及它们的混合物， 优选乙醇、 丙酮、 乙腈。 有机溶剂的加入 体积量一般为水量的 2〜10倍。 析出的培美曲塞盐可用本技术领域常用的方法 进行分离， 如过滤， 收集的培美曲塞盐可进一步干燥。
上述方法中 "溶解后直接进行冻干得到冻干形式的培美曲塞盐"时， "含水 溶剂"中的"适宜的混溶于水的有机溶剂"应适宜冻干， 包括叔丁醇、 二曱亚砜、 二氧六环等， 以及它们的混合物。 在冻干前， 在溶液中还可加入分散剂， 如甘 露醇、 乳糖、 果糖等， 以增强冻干效果。
本发明所使用 的培美曲塞二酸和培美曲塞二钠是按专利 CN200410097284.7中公开的方法制备的。
总的来说， 本发明提供的培美曲塞二酸三种新晶型 (H晶型、 I晶型和 J晶 型)具有良好的重现性， 而且制备工艺简便易行， 具有较强的实用性， 是培美 曲塞二酸的改进新晶型。 附图说明
图 1是培美曲塞二酸 H晶型的 X-射线粉末衍射图谱。
图 2是培美曲塞二酸 I晶型的 X-射线粉末衍射图谱。
图 3是培美曲塞二酸 J晶型的 X-射线粉末衍射图谱。
具体实施方式
下面将结合实施例对本发明作进一步说明，可以使本领域专业技术人员更 全面的理解本发明， 但不以任何方式限制本发明的范围。 值得一提的是， 这些 实施例是基于实验室规模的， 随着制备规模的扩大， 一些工艺参数将会发生一 定变化， 这在本技术领域是可以理解的。 实施例中使用的术语和缩写具有通常 的含义。 如" g"、 "ml", "mol/L"、 "°C"、 "MPa"、 分别是指克、 毫升、 摩尔 / 升、 摄氏度、 兆帕。
下述实施例采用在下列实验条件下测量培美曲塞二酸的 X射线衍射图谱：
— PW1710 BASED X-射线衍射仪
— CuKa源 （λ=1.5406 Α ) 一管电压： 30kV 一管电流： 30mA ^妻收狭缝： 0.05 一扫描步长： 0.1 一每步时间： 2 s
实施例 1 培美曲塞二酸 H晶型的制备 将培美曲塞二钠 (干品 )5g在水 50ml中溶解， 加入乙醇 60ml, 用 2mol/L 盐酸水溶液调 pH至 1.5〜2.0,加热溶清，在室温度下搅拌析晶 1.5小时，过滤， 用适量 pH4〜5的水洗涤， 在 45〜50°C在减压 (真空度 0.085〜0.090MPa)干燥 30 小时， 得培美曲塞二酸 H晶型 2.9g, 水含量 7.1%。
本实施例制的培美曲塞二酸经 X射线衍射测量后，在 2 Θ为 5.4° 、 6.3。 、 9.8°、 10.6。 、 12.1°、 16.1°、 17.1。 、 18.1。 、 19.0°、 19.8°、 21.1。 、 22.6°、 23.7° 、 24.4° 、 25.1。、 25.8。 、 26.5° 、 27.8。 、 30.1。 、 31.1。 、 32.4° 、 38.5。 位置对应有衍射峰（相对强度为 10%以上）。 实施例 2 培美曲塞二酸 H晶型的制备 将培美曲塞二钠（湿品 )8g在水 24ml中溶解， 加入乙醇 24ml, 用 lmol/L 盐酸水溶液调 pH至 2.0〜2.5, 加热溶清， 再加入水 36ml, 搅拌析晶 0.5小时， 过滤， 用适量水洗滤饼， 得培美曲塞二酸 H晶型， 水含量约 75%。
本实施例制得的培美曲塞二酸经 X射线衍射测量后，在 2 Θ为 6.4° 、9.9。、 10.6。 、 12.2。、 16.1。、 17. 、 18.1。 、 18.9。、 19.8。、 21.1。 、 22.6。、 25.1。、 25.8° 、 27.8° 、 30.1° 位置对应有衍射峰， 具有如图 1所示的 X-射线粉末衍 射图谱。 实施例 3 培美曲塞二酸 H晶型的制备 将培美曲塞二酸 (干品 )5g加入到水 75ml 和丙酮 70ml 的混合液中， 用 1.5mol/L盐酸水溶液调 pH至 1.5〜2.0, 加热溶清， 搅拌析晶 1小时， 过滤， 用 适量水洗滤饼， 在 55〜60°C在减压 (真空度 0.090〜0.095MPa)干燥 15小时， 得 培美曲塞二酸 H晶型 3.2g, 水含量 8.5%。
本实施例制得的培美曲塞二酸经 X射线衍射测量后， 确认为 H晶型。 实施例 4 培美曲塞二酸 I晶型的制备 将培美曲塞二钠 (干品）10g在水 500ml中溶解， 冷却至 0〜5°C , 用乙酸调 溶液的 pH至 4〜5, 再加 2mol/L的盐酸溶液调 H至 2〜3 , 继续搅拌 0.5小时， 过滤， 用适量水洗涤滤饼， 得培美曲塞二酸 I晶型， 水含量约 65%。
本实施例制得的培美曲塞二酸经 X射线衍射测量后， 具有如图 2所示的 X-射线粉末衍射图谱。 实施例 5 培美曲塞二酸 I晶型的制备 将培美曲塞二酸 (湿品）10g加入到由水 400ml和乙醇 100ml组成的混合溶 剂中， 用 4mol/L氢氧化钠溶液调体系 pH至 11〜12, 搅拌溶解， 用 2mol/L的 盐酸溶液调 pH至 2〜3 ,继续搅拌 1小时，过滤，用适量水洗涤滤饼，在 45〜50°C 下减压 (真空度 0.085〜0.090MPa)干燥 35小时， 得培美曲塞二酸 I晶型 3.7g, 水含量 6.7%。
本实施例制得的培美曲塞二酸经 X射线衍射测量后， 确认为 I晶型。
实施例 6 培美曲塞二酸 J晶型的制备 将培美曲塞二钠 (干品）15g在水 375ml中搅拌溶解， 冷却至 0〜5°C , 用乙 酸调溶液 pH为 3〜4, 继续搅拌约 10分钟， 过滤， 滤饼适量水洗涤， 得晶型 J 培美曲塞二酸， 在 60〜65°C下减压 (真空度 0.090〜0.095MPa)干燥 24小时， 得 培美曲塞二酸 J晶型 12.1g, 水含量 7.7%。
本实施例制得的培美曲塞二酸经 X射线衍射测量后， 在 2 Θ约为 8.8。、 12.1。、 17.2。 、 18.3。 、 19.4。、 20.2。、 21.1。 、 23.1。 、 24.3。、 26.2。、 27.6。 、 28.8。、 30.0。 、 31.6。、 32.7。 、 34.1。 、 34.8、 37.6位置对应有衍射峰（相对 强度为 10%以上）。
实施例 7 培美曲塞二酸 J晶型的制备 将培美曲塞二钠 (湿品）15g在水 100ml 中搅拌溶解， 加入乙醇 40ml, 用 lmol/L的盐酸溶液 pH为 2〜3 , 继续搅拌约 0.5小时， 过滤， 滤饼适量水洗涤， 得培美曲塞二酸 J晶型， 水含量约 50%。
本实施例制得的培美曲塞二酸经 X射线衍射测量后， 在 2 Θ约为 5.6° 、
8.9°、 12.2°、 18.4° 、 19.5°、 20.3°、 21.3° 、 23.3° 、 24.5°、 25.7°、 27.7。 、 28.9。、 31.4。、 32.8。 位置对应有衍射峰， 衍射图如图 3所示。
实施例 8 培美曲塞二酸 J晶型的制备 将培美曲塞二钠 (干品）10g在水 100ml中搅拌溶解， 加入丙酮 100ml, 用 2mol/L的盐酸调溶液 pH为 3〜4, 体系析出大量固体后升温至 60〜65°C搅拌约 10分钟， 搅拌冷却降温约 1.5小时， 过滤， 滤饼适量水洗涤， 得培美曲塞二酸 J晶型。
本实施例制得的培美曲塞二酸经 X射线衍射测量后， 确认为 J型晶。 实施例 9 培美曲塞二钠的制备 将上述实施例得到的培美曲塞二酸新晶型 (干品 )5g加入到水 35ml中， 用 5mol/L氢氧化钠水溶液调 ρΗ11〜12, 搅拌溶解， 再用 2mol/L的盐酸回调 pH 至 8〜9； 将混合液加热至 40〜45°C , 加入丙酮 170ml, 搅拌冷却析晶约 1.5小 时， 过滤， 滤饼用适量丙酮洗涤， 在 50°C下减压 (真空度 0.090〜0.095)干燥 24 小时， 得培美曲塞二钠 5.3g。 实施例 10 培美曲塞二钠的制备 将上述实施例得到的培美曲塞二酸新晶型（湿品 )7g加入到水 10ml中， 用 5mol/L氢氧化钠溶液调体系 pH至 10〜11 , 搅拌溶清， 加入乙腈 44ml, 在室温 下搅拌析晶约 2小时， 过滤， 洗滤用适量乙腈 /水混合液及丙酮洗涤， 得培美 曲塞二钠。 实施例 11 冻干培美曲塞二钠的制备 将上述实施例得到的培美曲塞二酸新晶型（干品）10.8g 加入到注射用水 180ml中， 用 2mol/L氢氧化钠溶液调 ρΗ11〜12, 搅拌溶解， 再用 2mol/L的盐 酸回调 pH至 7.0〜8.5, 然后定容至 250ml; 加入甘露醇 lO.Og, 加入 0.05%活性 碳， 搅拌 10分钟， 过滤， 然后再对滤液进行除菌过滤； 以 12.5ml/瓶灌装入冻 干瓶中， 冷冻干燥， 得冻干培美曲塞二钠。 实施例 9-11 中， 培美曲塞二酸新晶型是指 H晶、 I晶、 J晶或它们的混 合物。 前面已经详述了本发明， 包括其优选的实施方案。 但是， 应当明白， 考虑 到本发明公开的内容，本领域技术人员可在下述权利要求书的精神范围内对本 发明进行改变和 /或改进， 这些改进和润饰也应视为本发明的保护范围。

Claims

权 利 要 求
1、培美曲塞二酸的 H晶型， 该晶型的 X-射线粉末衍射图谱在 2Θ值约为 9.9°、 12.2。、 16.1。、 18.9。、 19.8。、 22.6。、 25.1。的位置对应有衍射峰。
2、 根据权利要求 1所述的培美曲塞二酸的 H晶型， 其特征在于， 其含水量的 范围为 5 wt%〜80wt%。
3、 一种培美曲塞二酸 H晶型的制备方法， 其特征在于， 包括使培美曲塞二酸 从包含培美曲塞二酸、 水和混溶于水的溶剂的混合溶液中结晶出来。
4、 根据权利要求 3所述的制备方法， 其特征在于， 所述使培美曲塞二酸从包 含培美曲塞二酸、 水和混溶于水的溶剂的混合溶液中结晶出来具体为：
将培美曲塞盐溶于水与混溶于水的溶剂组成的混合溶剂中， 调节 pH 至
1-2.5 , 析晶出培美曲塞二酸晶体； 或将培美曲塞二酸直接溶于水与混溶于水 的溶剂组成的混合溶剂中， 再析晶。
5、 根据权利要求 1所述的培美曲塞二酸晶型用于与相应的碱作用制备培美曲 塞二酸药物上可接受的盐的用途。
6、 根据权利要求 5所述的用途， 其特征在于， 培美曲塞二酸晶型用于与相应 的碱作用制备培美曲塞二酸药物上可接受的盐的用途包括：
将培美曲塞二酸加入到含水溶剂， 用相应的碱使培美曲塞二酸溶解， 溶解 后加入适宜的混溶于水的有机溶剂析出培美曲塞二酸药物上可接受的盐或直 接进行冻干得到冻干形式的培美曲塞二酸药物上可接受的盐，所述含水溶剂包 括：
水、 水与适宜的混溶于水的有机溶剂的混合溶剂中。
7、 权利要求 5或 6所述的用途， 其特征在于， 所述相应的碱是氢氧化钠， 所 述培美曲塞二酸药物上可接受的盐是培美曲塞二钠。
8、 培美曲塞二酸的 I晶型， 该晶型具有如图 2所示的 X-射线粉末衍射图谱所 代表的特征。
9、 根据权利要求 8所述的培美曲塞二酸的 I晶型， 其特征在于， 其含水量范 围为 5wt%〜80wt%。
10、一种培美曲塞二酸 I晶型的制备方法，包括用酸调节含浓度低于 0.07mol/L 培美曲塞盐的水溶液 pH至 2〜3 , 析出培美曲塞二酸晶体。
11、 根据权利要求 10所述的制备方法， 其特征在于， 所述水溶液还可进一步 包含一种混溶于水的溶剂。
12、根据权利要求 8所述的培美曲塞二酸晶型用于与相应的碱作用制备培美曲 塞二酸药物上可接受的盐的用途。
13、 根据权利要求 12所述的用途， 其特征在于， 所述培美曲塞二酸晶型用于 与相应的碱作用制备培美曲塞二酸药物上可接受的盐的用途包括：
将培美曲塞二酸加入到含水溶剂， 用相应的碱使培美曲塞二酸溶解， 溶解 后加入适宜的混溶于水的有机溶剂析出培美曲塞二酸药物上可接受的盐或直 接进行冻干得到冻干形式的培美曲塞二酸药物上可接受的盐，所述含水溶剂包 括：
水、 水与适宜的混溶于水的有机溶剂的混合溶剂中。
14、 权利要求 12或 13所述的用途， 其特征在于， 所述相应的碱是氢氧化钠， 培美曲塞二酸药物上可接受的盐是培美曲塞二钠。
15、 培美曲塞二酸水合物的 J晶型， 该晶型的 X-射线粉末衍射图谱在 2Θ值约 为 12.2。、 20.3。、 21.3。、 28.9。、 32.8。的位置对应有衍射峰。
16、 根据权利要求 15所述的培美曲塞二酸晶型， 其特征在于， 其含水量范围 为 5wt%〜80wt%。
17、一种培美曲塞二酸 J晶型的制备方法，包括用酸调节含浓度高于 0.07mol/L 培美曲塞盐的水溶液 pH至 2〜4, 析出培美曲塞二酸晶体。
18、 权利要求 17所述的制备方法， 其特征在于， 所述的水溶液还可进一步包 含一种混溶于水的溶剂。
19、 权利要求 15所述的培美曲塞二酸晶型用于与相应的碱作用制备培美曲塞 二酸药物上可接受的盐的用途。
20、 根据权利要求 19所述的用途， 其特征在于， 所述培美曲塞二酸晶型用于 与相应的碱作用制备培美曲塞二酸药物上可接受的盐的用途包括：
将培美曲塞二酸加入到含水溶剂中， 用相应的碱使培美曲塞二酸溶解， 溶 解后加入适宜的混溶于水的有机溶剂析出培美曲塞二酸药物上可接受的盐或 直接进行冻干得到冻干形式的培美曲塞二酸药物上可接受的盐，所述含水溶剂 包括： 水、 水与适宜的混溶于水的有机溶剂的混合溶剂中。
21、 权利要求 19或 20所述的用途， 其特征在于， 所述相应的碱是氢氧化钠, 所述培美曲塞二酸药物上可接受的盐是培美曲塞二钠。
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