WO2010120074A2 - Procédé pour préparer de l'adéfovir dipivoxil cristallin et butanolate d'adéfovir dipivoxil utilisé dans celui-ci - Google Patents

Procédé pour préparer de l'adéfovir dipivoxil cristallin et butanolate d'adéfovir dipivoxil utilisé dans celui-ci Download PDF

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Publication number
WO2010120074A2
WO2010120074A2 PCT/KR2010/002233 KR2010002233W WO2010120074A2 WO 2010120074 A2 WO2010120074 A2 WO 2010120074A2 KR 2010002233 W KR2010002233 W KR 2010002233W WO 2010120074 A2 WO2010120074 A2 WO 2010120074A2
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WO
WIPO (PCT)
Prior art keywords
adefovir dipivoxil
butanolate
crystals
butanol
butyl
Prior art date
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PCT/KR2010/002233
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English (en)
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WO2010120074A3 (fr
Inventor
Hee Sook Oh
Eun Young Byun
Suk Man Jang
Tae Hee Ha
Han Kyong Kim
Kwee Hyun Suh
Gwan Sun Lee
Original Assignee
Hanmi Pharm. Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Hanmi Pharm. Co., Ltd. filed Critical Hanmi Pharm. Co., Ltd.
Publication of WO2010120074A2 publication Critical patent/WO2010120074A2/fr
Publication of WO2010120074A3 publication Critical patent/WO2010120074A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a method for preparing pure crystalline adefovir dipivoxil, i.e., pure Form V crystals of adefovir dipivoxil; and adefovir dipivoxil butanolate used therein.
  • Adefovir dipivoxil (hereinafter referred to as "AD"), 9- [2- [ ⁇ bis(pivaloyloxy)-methoxy ⁇ phosphinyl]methoxy]ethyl adenine, is a nucleotide- analogue reverse transcriptase inhibitor which exhibits strong in vivo antiviral activity toward HIV and hepatitis B virus (HBV), and it is disclosed as an ester prodrug of AD in EP Patent No. 0 481 214.
  • AD Adefovir dipivoxil
  • AD is converted within a body to adefovir, a chemically synthesized nucleotide-analogue of adenosine 5-monophosphate, having inhibitory activity against DNA polymerases of hepatitis B virus.
  • AD is an active ingredient of drug formulation HepseraTM which is commercially available in the treatment of infection of chronic hepatitis B virus.
  • AD exists in at least six distinct crystalline forms, "Form 0" (anhydrous crystals), “Form I” (another anhydrous crystals), “Form II” (di-hydrate crystals), “Form III” (methanol solvate crystals), “Form IV” (fumarate or its complex crystals), and “Form V” (another anhydrous crystals), crystal Form I, Form II, Form III and Form IV being described in International Patent Publication No. WO 99/04774; crystal Form V, in Chinese Patent Publication Nos. 1,396,170, 1,498,890, 1,506,371 and 1,435,420; and crystal Form 0, in Chinese Patent Publication No. 1,935,818.
  • the crystal forms can be identified by its X-ray diffraction (XRD) pattern in which 2 theta values (2 ⁇ ) represent interplanar angles, d values which mean interplanar distances, and melting endothermic peaks as shown in differential scanning calorimetry (DSC).
  • XRD X-ray diffraction
  • Form I crystals of AD have a characteristic melting endothermic peak between 99.0 and 104.0 ° C ;
  • Form II crystals thereof between 65.0 and 70.0 ° C ;
  • Form V crystals thereof between 93.0 and 98.0 °C ;
  • Form 0 crystals thereof between 80.0 and 85.0 ° C .
  • Form V crystals which are often referred to as "Form E crystals" are the most useful in the preparation of a pharmaceutical composition, as described in Chinese Patent Publication No. 1,435,420.
  • Form V crystals of AD have been typically prepared by any one of various methods such as concentrating a solution of AD dissolved in methanol (see Chinese Patent Publication No. 1,396,170), allowing AD to be precipitated in an aqueous alcohol solution (see Chinese Patent Publication No. 1,498,890), spray-drying a solution of AD dissolved in ethanol (see Chinese Patent Publication No. 1,506,371), and concentrating a solution of AD dissolved in acetone, ethylacetate or isopropanol (see Chinese Patent Publication No. 1,435,420).
  • a method for preparing Form V crystals of adefovir dipivoxil comprising:
  • adefovir dipivoxil butanolate of formula (I) used as an intermediate in the preparation of Form V crystals of adefovir dipivoxil:
  • R is 1 -butyl or 2-butyl; and n is 0.5 ⁇ 0.05.
  • FIGs. 1 and 2 differential scanning calorimetry (DSC) and X-ray diffraction (XRD) spectra, respectively, of crystalline adefovir dipivoxil hemi- 1 -butanolate obtained in Examples 1 to 8;
  • FIGs. 3 and 4 DSC and XRD spectra, respectively, of crystalline adefovir dipivoxil hemi-2-butanolate obtained in Examples 9 and 10;
  • FIG. 5 a DSC spectrum of Form V crystals of adefovir dipivoxil obtained in Examples 11 and 12;
  • FIG. 6 a DSC spectrum of Form V crystals of adefovir dipivoxil obtained in Comparative Example 1. Best Mode for Carrying Out the Invention
  • Adefovir dipivoxil butanolate of formula (I), a novel crystalline solvate, is hemi-butanolate formed by a combination of 1 molecule of adefovir dipivoxil and about 0.5 molecule of butanol as a solvent.
  • crystalline adefovir dipivoxil butanolate is prepared by dissolving adefovir dipivoxil in butanol, cooling the resulting solution, and then isolating crystals formed thereupon by filtration.
  • adefovir dipivoxil refers to refined crystal Form 0, Form I, Form II, Form III, Form IV, Form V, any mixture of the six forms of crystals, a non-crystalline or amorphous form of adefovir dipivoxil, or a crude product obtained from a conventional manufacturing process thereof.
  • the crude adefovir dipivoxil may be a mixture of various combinations of crystal Form 0, Form I, Form II, Form III, Form IV and Form V.
  • Butanol employed in step (a) may be 1 -butanol or 2-butanol.
  • Use of 1- butanol and 2-butanol lead to generations of adefovir dipivoxil 1 -butanolate (R is 1 -butyl) and adefovir dipivoxil 2-butanolate (R is 2-butyl), respectively.
  • Butanol may be preferably used in an amount ranging from 0.5 to 5 m£ based on 1 g weight of adefovir dipivoxil, but not limited thereto.
  • the dissolution of adefovir dipivoxil in butanol may be conducted at a temperature ranging from 40 ° C to the boiling point of the used solvent, preferably from 40 to 50 ° C .
  • the resulting solution is preferably cooled to a temperature ranging from -10 to 25 °C, more preferably to room temperature, for a period sufficient to precipitate butanolate crystals of adefovir dipivoxil.
  • the precipitated crystals are filtered, washed and dried in a conventional manner to give crystalline adefovir dipivoxil butanolate.
  • di-n-butyl ether may be further added thereto.
  • Di-n-butyl ether may be preferably used in an amount ranging from 1 to 5 ro ⁇ based on 1 ml volume of butanol.
  • the crystalline adefovir dipivoxil butanolate obtained in step (a) of the present invention has a purity of 98% or higher, the purity of 98% being a value typically accepted in a pharmaceutical field. If necessary, the adefovir dipivoxil butanolate crystals thus obtained may be further purified by recrystallization from said butanol solvent, e.g., to the purity extent of 99% or higher.
  • Form V crystals of adefovir dipivoxil are prepared by dissolving the adefovir dipivoxil butanolate obtained in step (a) in ethyl acetate, adding the resulting solution to diethyl ether, cooling the resulting mixture, and then isolating crystals formed thereupon by filtration.
  • Ethyl acetate may be preferably used in an amount ranging from 3 to 5 m£ based on 1 g weight of adefovir dipivoxil butanolate, but not limited thereto.
  • the dissolution of adefovir dipivoxil butanolate in ethyl acetate may be conducted at a temperature ranging from 40 ° C to the boiling point of the used solvent, preferably from 40 to 50 ° C .
  • Form V crystals of adefovir dipivoxil is formed by adding the resulting solution to diethyl ether, wherein diethyl ether may be preferably used in an amount ranging from 5 to 15 m# based on 1 m-C volume of ethyl acetate. In case of using diethyl ether in an amount less than 5 mi, undesirable crystal forms such as Form I crystals of adefovir dipivoxil may be formed.
  • the resulting mixture is preferably cooled to a temperature ranging from
  • a seed of Form V crystals of adefovir dipivoxil may be further added to the diethyl ether solution.
  • Such a crystal Form V seed may be previously obtained by any of various methods, and be used in an amount ranging from 0.01 to 0.20 g, preferably from 0.05 to 0.10 g, based on 1 g of adefovir dipivoxil.
  • the Form V crystals of adefovir dipivoxil obtained in accordance with the present invention have a high purity of 99% or higher, the purity of 99% being a value typically accepted in a pharmaceutical field and of a very pure state.
  • Adefovir dipivoxil butanolate of formula (I) used as an intermediate in the inventive method, a novel crystalline solvate, has a butanol content of about 6.2 to about 7.6% when measured with gas chromatography (GC), proton nuclear magnetic resonance spectroscopy (IH-NMR), or loss on drying (LOD), wherein its calculated butanol content value is 6.88%.
  • the measured butanol content range means that butanol is present in an amount ranging from 0.45 to 0.55 mole equivalents based on 1 mole of adefovir dipivoxil. .
  • Adefovir dipivoxil hemi-1 -butanolate shows characteristic peaks having a relative intensity of at least 10% at 2 ⁇ values of 7.9 ⁇ 0.2°, 8.5 ⁇ 0.2°, 14.1 ⁇ 0.2°, 14.3 ⁇ 0.2°, 14.8 ⁇ 0.2°, 16.1 ⁇ 0.2°, 19.7 ⁇ 0.2°, 20.6 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.1 ⁇ 0.2° and 22.9 ⁇ 0.2° in its X-ray diffraction (XRD) spectrum, as shown in FIG. 2.
  • XRD X-ray diffraction
  • adefovir dipivoxil hemi-1 -butanolate has a first characteristic endothermic transition peak due to deviation of butanol at the temperature range of about 45 to 52 ° C and a second characteristic melting endothermic transition peak at the temperature range of about 73 to 77 °C, as described in FIG. 1.
  • Adefovir dipivoxil hemi-2-butanolate shows characteristic peaks having a relative intensity (Ul 0 x 100, %) of at least 10% at 2 ⁇ values of 8.1 ⁇ 0.2°, 8.6 ⁇ 0.2°, 14.3 ⁇ 0.2°, 14.8 ⁇ 0.2°, 16.3 ⁇ 0.2°, 16.9 ⁇ 0.2°, 19.2 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.7 ⁇ 0.2°, 22.3 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.2 ⁇ 0.2°, 24.9 ⁇ 0.2°, 27.2 ⁇ 0.2° and 30.0 ⁇ 0.2° in its XRD spectrum, as shown in FIG. 4.
  • adefovir dipivoxil hemi-2-butanolate has a first characteristic endothermic transition peak due to deviation of butanol at the temperature range of about 48 to 55 ° C and a second characteristic melting endothermic transition peak at the temperature range of about 76 to 80 ° C, as represented in FIG. 3.
  • Form V crystals of adefovir dipivoxil of a high purity in terms of chemistry and crystallography can be prepared in a reproducible manner.
  • Adefovir dipivoxil is converted within a body to adefovir which acts to interference DNA polymerases of hepatitis B virus, inhibiting duplication thereof (see [J. E. Starrett et al., J. Med. Chem.(l994) 37: 1857-1864]). Accordingly, adefovir dipivoxil is useful in treating infection of mammal hepatitis B virus, especially human hepatitis B virus.
  • the present invention also provides a pharmaceutical composition for treating hepatitis B virus comprising Form V crystals of adefovir dipivoxil as an active ingredient together with a pharmaceutically acceptable carrier, diluent, or excipient.
  • the pharmaceutical composition according to the present invention may be administered to a patient in an effective amount via various routes, e.g., an oral or non-oral route.
  • the inventive composition is prepared in the oral administration form such as a capsule, a tablet and a powder.
  • Form V crystals of adefovir dipivoxil may be formulated with a pharmaceutically acceptable carrier, diluent, or excipient, regardless of the administration form.
  • suitable carriers, diluents and excipients are as follows: excipients such as starches, sugar, lactose, dextrin, mannitol, sorbitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, Arabic gum, amylopectin, light anhydrous silicic acid, and synthetic aluminum silicate; fillers or extending agents such as calcium phosphate and silica derivatives; binding agents such as starches, sugar, mannitol, trehalose, dextrin, amylopectin, sucrose, gluten, Arabic gum, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, cellulose derivatives including hydroxypropyl cellulose or hydroxypropyl methyl cellulose
  • compositions comprising an effective amount of Form V crystals of adefovir dipivoxil together with additives such as said carrier, diluent, and excipient, may be prepared in accordance with any of the conventional procedures (see ⁇ Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 19 th Edition, 1995]).
  • the inventive pharmaceutical composition may comprise Form V crystals of adefovir dipivoxil as an active ingredient in an amount of 0.1 to 95% by weight, preferably 1 to 70% by weight, based on the total weight of the composition.
  • the inventive pharmaceutical composition can be administered in a single dose or in divided doses per one day, and a typical daily dose of Form V crystals of adefovir dipivoxil for a mammal including human may range from about 1 to 50 mg/kg body weight.
  • the DSC curve was obtained by a STA S-1000 differential scanning calorimeter (Scinco Co. Ltd., Korea) at a rate of +10 ° C/min.
  • the aqueous layer was extracted with 4500m£ of isopropyl acetate.
  • the organic layers were combined, washed twice with each of 4500m£ of water, dried over 18Og of magnesium sulfate, and then concentrated under a reduced pressure to obtain 108Og of crude adefovir dipivoxil (yield 66%, chemical purity 85%).
  • Example 1 Preparation of adefovir dipivoxil hemi-1-butanolate
  • Example 1 Preparation of adefovir dipivoxil hemi-1-butanolate
  • Example 7 Preparation of adefovir dipivoxil hemi-1-butanolate 5g of Form 0 crystals of adefovir dipivoxil obtained according to the procedure disclosed in European Patent Publication No. 0,481,214 was added to lOmi of 1-butanol and heated to 5O 0 C to complete its dissolution. 20m£ of din-butyl ether was added thereto. The reaction mixture was cooled to room temperature and stirred for 6 hours. The precipitated solid was filtered and dried at room temperature to obtain 4.5g of the title compound (yield 83%). The analysis data of the compound thus obtained are listed below. m.p. : 72-75 ° C (melt) chemical purity : 99.3% loss on drying (LOD) : 7.0%
  • Example 9 Preparation of adefovir dipivoxil hemi-2-butanolate>
  • Example 9 Preparation of adefovir dipivoxil hemi-2-butanolate
  • IR (KBr pellet, cm “1 ) : 3330(br), 3198(br), 2964, 1759, 1740, 1653, 1596, 1576, 1482, 1417, 1264, 1170, 1132, 1065, 988, 957, 900, 823.
  • Example 10 Preparation of adefovir dipivoxil hemi-2-butanolate 5Og of crude adefovir dipivoxil obtained in Reference Example 1 was added to 50mi of 2-butanol and heated to 5O 0 C to complete its dissolution. 100m£ of di-n-butyl ether was added thereto. The reaction mixture was cooled to room temperature and stirred for 12 hours. The precipitated solid was filtered and dried at room temperature to obtain 33g of the title compound (yield 62%). The analysis data of the compound thus obtained are listed below. m.p. : 77-80 °C (melt) chemical purity : 99.7%
  • Example 12 Preparation of Form V crystals of adefovir dipivoxil
  • Comparative Example 1 Preparation of Form V crystals of adefovir dipivoxil according to the method disclosed in Chinese Patent Publication No. 1,396,170
  • the method of the present invention is capable of providing higher purity Form V crystals of adefovir dipivoxil from various forms of adefovir dipivoxil, as compared with the conventional method.
  • AD means adefovir dipivoxil

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Saccharide Compounds (AREA)

Abstract

Selon la présente invention, des cristaux de forme V pure d'adéfovir dipivoxil peuvent être préparés par un procédé à rendement élevé comprenant les étapes de dissolution d'adéfovir dipivoxil dans du butanol, de refroidissement de la solution résultante pour obtenir du butanolate d'adéfovir dipivoxil cristallin, de dissolution du butanolate d'adéfovir dipivoxil dans de l'acétate d'éthyle, et d'ajout de la solution résultante à de l'éther diéthylique.
PCT/KR2010/002233 2009-04-13 2010-04-12 Procédé pour préparer de l'adéfovir dipivoxil cristallin et butanolate d'adéfovir dipivoxil utilisé dans celui-ci WO2010120074A2 (fr)

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KR1020090031807A KR20100113302A (ko) 2009-04-13 2009-04-13 결정형 아데포비어 디피복실의 제조방법 및 이에 사용되는 아데포비어 디피복실 부탄올레이트
KR10-2009-0031807 2009-04-13

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999004774A2 (fr) * 1997-07-25 1999-02-04 Gilead Sciences, Inc. Compositions d'analogue de nucleotide
US7417036B2 (en) * 2002-11-12 2008-08-26 Tianjin Kinsly Pharmaceutical Co. Ltd. Crystal form of adefovir dipivoxil and its preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999004774A2 (fr) * 1997-07-25 1999-02-04 Gilead Sciences, Inc. Compositions d'analogue de nucleotide
US7417036B2 (en) * 2002-11-12 2008-08-26 Tianjin Kinsly Pharmaceutical Co. Ltd. Crystal form of adefovir dipivoxil and its preparation

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KR20100113302A (ko) 2010-10-21

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