EP0195805A1 - Procede de preparation de 2-desoxyuridine - Google Patents

Procede de preparation de 2-desoxyuridine

Info

Publication number
EP0195805A1
EP0195805A1 EP85904767A EP85904767A EP0195805A1 EP 0195805 A1 EP0195805 A1 EP 0195805A1 EP 85904767 A EP85904767 A EP 85904767A EP 85904767 A EP85904767 A EP 85904767A EP 0195805 A1 EP0195805 A1 EP 0195805A1
Authority
EP
European Patent Office
Prior art keywords
group
deoxy
methyl
benzyl
mixture
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP85904767A
Other languages
German (de)
English (en)
Other versions
EP0195805A4 (fr
Inventor
James E. Ollman
Ralph J. Depasquale
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PCR Inc
Original Assignee
PCR Inc
SCM Corp
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.)
Filing date
Publication date
Application filed by PCR Inc, SCM Corp filed Critical PCR Inc
Publication of EP0195805A1 publication Critical patent/EP0195805A1/fr
Publication of EP0195805A4 publication Critical patent/EP0195805A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals

Definitions

  • This invention relates to a process for producing a therapeutically active material from 2-deoxyribose, and more particularly, to a method for making a 2-deoxyuridine.
  • This invention was made in response to a need for increasing yields of 2-deoxyuridine materials from below about 8% and consequent very high cost. It has now been found that by using a novel sequence of known organic synthesis reactions one is able to produce 2-deoxy uridine materials in substantially higher yield and thus at much lower cost. This process utilizes fewer steps than heretofore used in the production of such derivatives.
  • Preferred aiibodiments of the present invention contain a new step which is both unexpected and surprising in terms of the fact that it proceeds well. All indications were that it would not be likely that a sugar be.aring an acid labile protecting group, such as a trityl protected ribofuranoside or a silyl protected ribofuranoside, could be acid condensed with a silylated uracil in an acid catalyzed condensation reaction to form directly a 2-deoxyuridine. Both these protecting groups are regarded as acid sensitive (i.e., easily removed by acid) and the condensation catalyst is a Lewis acid (Friedel-Crafts catalyst) which converts to a Bronsted acid (strong acid) on work up.
  • an acid labile protecting group such as a trityl protected ribofuranoside or a silyl protected ribofuranoside
  • the present invention is a process for making a 2-deoxyuridine. It comprises the steps of (a) protecting the primary hydroxyl group of an alkyl 2-deoxyribofuranoside with a protecting group selected from triphenyl methyl, substituted triphenyl methyl, and silyl radicals to form a blocked alkyl 5-0-"protected"-2deoxyribofuranoside; (b) introducing a hydrocarbyl group (e.g., lower alkyl, or arylalkyl) at the 3-0 position to form a alkyl 3-0hydrocarbyl-5-0-"protected"-2-deoxyribofuranoside; (c) condensing a silyluracil with the product of step (b) in the presence of a solvent and a Lewis acid or a Bronsted acid to form a crude 2-deoxyuridine; and optionally (d) deprotecting the protected group in said crude 2deoxyuridine to form 3'-O-hydrocarby
  • the final 2deoxyuridine is usually obtained as a mixture of alpha and beta anomers. These are preferably for pharmaceutical purposes, isolated from one another. Other pharmaceutically acceptable derivatives may be made in a known manner.
  • the trityl group which is a preferred protecting group for hydrocarbylation, may be replaced with other protecting groups to form a 3-O-hydrocarbyl-5-Oprotected"-2-deoxyribofuranosyl-X wherein X is 1-O-alkyl, 1-O-acyl or 1-halo and the condensation with the silyluracil effected in a manner shown below.
  • a C 1 -C 4 alkyl group e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.
  • a C 1 -C 4 alkoxy group e.g., methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, etc.
  • an aryl group e.g., phenyl, tolyl, etc.
  • a nitro group a halo group, e.g., chloro, bromo, fluoro, iodo, an acyl group, e.g., acetyl, benzoyl; trifluoromethyl, etc.
  • the secondary OH adjacent the hetrocyclic oxygen in (I) reacts readily with what may be considered a protecting compound such as a lower alkyl alcohol (C 1 -C 4 ), e.g., methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, etc., a lower (C 1 -C 4 ) acyl group, e.g., acetyl, or a halogen, e.g., chlorine.
  • HCl acidified
  • the next step in the process is to protect the primary 5-OH group with a protecting radical, e.g., silyl or , preferably a trityl radical, by replacing the hydrogen of the primary hydroxyl group as follows:
  • a protecting radical e.g., silyl or , preferably a trityl radical
  • inert preferably aprotic solvents
  • aprotic solvents may be used in the syntheses described herein in place of chloroform, e.g., methylene chloride, carbon tetrachloride, benzene, toluene, acetonitrile, ethylene chloride, ethylene dichloride, dioxane, tetrahydrofuran (THF), dimethylformamide, carbon disulfide, chlorobenzene, sulfolane, molten dimethylsulfoxide, etc.
  • chloroform e.g., methylene chloride, carbon tetrachloride, benzene, toluene, acetonitrile, ethylene chloride, ethylene dichloride, dioxane, tetrahydrofuran (THF), dimethylformamide, carbon disulfide, chlorobenzene, sulfolane, molten dimethylsulfoxide, etc.
  • the 5-0-trityl group which may be substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, halo, etc., groups in, for example, the para position, is quite important here if the above product is to be benzylated.
  • the benzylated product itself is novel. After alkylation, it is possible with the addition of a couple of steps to deprotect the tritylated group and replace the protecting group with alkyl, aralkyl, silyl or the like group such as disclosed in the aforesaid book by T. W. Green, supra., and proceed with the synthesis.
  • the protecting group for the primary OH must be trityl or silyl in order to effectively hydrocarbylate, e.g., benzylate, the secondary OH.
  • the trityl group is preferred to the silyl group because of its better selectivity.
  • a mixture of 9.0 g. (0.034 mole) of methyl 5-0-(tbutyldimethylsilyl)-2-deoxyribofuranoside, 15 g (0.19 mole) of benzyl bromide, and 21 g (0.076 mole) silver carbonate in 50 ml dry dimethylformamide or other aprotic solvent is heated at 60°C. under a dry nitrogen atmosphere for five days.
  • the mixture is cooled and the solids filtered.
  • the filtrate is then concentrated at reduced pressure to 30 ml volume. To this is added 20 ml pyridine and the mixture heated at 65°C. for three hours.
  • Example VIII illustrates another hydrocarbylation reaction using a methyl providing agent in lieu of a benzyl providing agent.
  • Methyl3-0-Benzyl-2-Deoxy-5-0-(p-Methoxytrityl)Ribo_furanoside A mixture of 5.0 g (13 mmole) of methyl 2-deoxy-5-0-(pmethoxytrityl)ribofuranoside, 0.5 g (20 mmole) of sodium hydride, and 3.4 g (20 mmole) of benzyl bromide in 50 ml dry tetrahydrofuran was heated at reflux under a dry nitrogen atmosphere for two and one-half hours. The mixture was then stirred at ambient temperature overnight. Pyridine (5 ml) was added and the mixture again heated at reflux for three hours. After being cooled to ambient temperature, the mixture was filtered.
  • the emulsion was vacuum filtered through a pad of filter-aid.
  • the filter was washed with 50 ml of ethyl acetate.
  • the combined filtrate and filter washing was phase separated, the organic layer was washed with 250 ml of deionized water, dried (Na 2 SO 4 ), filtered, and the solvent removed under vacuum (50 mm Hg at 45°C.) affording 14.7g of an orange oil.
  • the filtrate from the isolation of the alpha-anomer was evaporated to dryness affording an orange gummy oil.
  • the oil was triturated with hexane (4 x 100 ml) to remove trityl ethyl ether.
  • the silylated uracil is prepared by reacting uracil with 1.05 to 1.5 equivalents of silylating agent, e.g., trimethylchlorosilane, for each hydroxy, mercapto, or amino group in the uracil compound.
  • silylating agent e.g., trimethylchlorosilane
  • the silylating agent is dissolved in hexamethyldisilazane (0.66 equivalent HMDS to 0.33 equivalent silane) and the uracil/silylating system heated for 5-18 hours.
  • the product is isolated by distillation.
  • Other procedures for forming silylated bases, e.g., silylated uracil will be found in U. S. Patent 4,209,613.
  • pyrimidine (uracil) compound which can be condensed with a tritylated sugar to form a 2-deoxy uridine in accordance herewith is prepared as follows:
  • a mixture of 450 g (2.5 mole) of 5-trifluoromethyluracil, 850 g (5.3 mole) of hexamethyldisilazane (HMDS), and 15 g (0.14 mole) of trimethylchlorosilane was heated at 100-120°C. until the evolution of ammonia ceased ( ⁇ 5 hrs.). The temperature was then raised and a gentle reflux maintained (125-130°C.) for one hour. The excess HMDS was removed by distillation at water aspirator pressure. The product was then vacuum distilled (bp. 60-64oC.
  • the oil was triturated with hexane (4 x 20 ml) and the semi-solid residue taken up in 750 ml of hot toluene. After being cooled overnight in a refrigerator, a gelatinous precipitate formed. This was collected by vacuum filtration, washed with 50 ml fresh toluene and air-dried affording 1.59 g (4.1 mmole, 33%) of the alpha-anomer of the title compound as shown by 1 H NMR and TLC. The filtrate was stripped of solvent under reduced pressure affording 3.7 g of an orange oil.
  • the mixture was stirred at 5°C. for an additional 2-1/2 hours.
  • the reaction was then quenched by slow ( ⁇ 5 min) addition of 10 ml anhydrous methanol while keeping the temperature ⁇ 10°C.
  • the quenched mixture was warmed to ambient temperature and stirred for an additional three hours.
  • the mixture was poured into a 25 ml stirred solution of aqueous 6% sodium bicarbonate.
  • the resulting mixture was extracted with two 25 ml portions of ethyl acetate.
  • the organic extracts were combined and washed with 25 ml of water. After being dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was triturated with 35 ml of .
  • This example illustrates a method for converting the alphaanomer to the beta-anomer.
  • Alpha-3'-O-Benzyl-2'-deoxy-5-trifluoromethyluridine (alphaanomer, 99 + % by HPLC), 5.0 g (0.013 mole), was refluxed for 24 hours with 50 ml hexamethyldisilazane and 2 ml trimethylchlorosilane. The excess reactants were removed by rotary evaporation which was followed by the addition and similar concentration of 2 x 100 ml toluene. The residue was dissolved in 25 ml CH 2 CI 2 .
  • the group for protecting the primary OH group on the 2-deoxyribofuranoside is preferably trityl or substituted trityl. It need not be, and another protecting group, e.g., silyl may be used and then condensation effected with the silyl uracil with CH 3 ON/SnCl 4 , for example. Where alkylation or aralkylation of the 3-0 secondary OH group is to be carried out, a trityl or silyl group is necessary, the trityl group being preferred for the reasons stated above.
  • the trityl or silyl group may be replaced with another protective group such as acyl, alkyl, silyl, etc., prior to the condensation step.
  • This extra step of replacing the trityl or silyl group has not been found to be necessary because of the surprising stability of these protecting groups in the presence of an acid condensation catalyst.
  • Q may be hydrogen, alkyl (C 1 -C 5 ) aryl, substituted aryl, heterocyclic, e.g., pyridyl, or containing a heteroatom such as sulfur, nitrogen or phosphorus.
  • a benzyl or methyl group is preferred.
  • radicals may be substituted with alkoxy, e.g., methoxy, ethoxy, isopropoxy, tbutoxy; nitro; or alkyl, e.g., methyl, ethyl, isopropyl, t-butyl, cyclohexyl, or substituted alkyl, e.g., methoxy methyl, ethoxyethyl, methoxypropyl, chloromethyl, bromomethyl, trifluoromethyl, etc.
  • alkoxy e.g., methoxy, ethoxy, isopropoxy, tbutoxy
  • alkyl e.g., methyl, ethyl, isopropyl, t-butyl, cyclohexyl
  • substituted alkyl e.g., methoxy methyl, ethoxyethyl, methoxypropyl, chloromethyl, bromomethyl, trifluoromethyl, etc.
  • the blocking or protecting group or groups can be removed in the usual way, for example, by means of alcoholic solutions of ammonia or alkali metal alcoholates (sodium ethylate) or aqueous or alcoholic alkali.
  • the beta-anomer can be isolated from the alpha-anomer by high pressure liquid chromatogtaphy.
  • the beta-anomer Example No. XIV is not hygroscopic.
  • the 2'-deoxy-5-substituted uridine derivatives of the present invention are useful as antitumor agents.
  • they are ordinarily combined with a suitable, pharmaceutically acceptable carrier to be prepared as a pharmaceutical preparation having a form suitable for desired administration purposes.
  • the carrier may be, for example, a diluent, a binder, a lubricant, a coloring agent or a disintegrator, which are conventionally used and pharmaceutically acceptable.
  • the pharmaceutical preparation may take a form .of tablet, capsule, granule, powder, liquid or the like for oral administration, as well as a form of injection or the like for non-oral administrations such as intravenous injection.
  • the pharmaceutical preparation may also take a form of suppository for intra-rectal administration.
  • the content of the active ingredient (compound produced by the process of the present invention) per unit form of each pharmaceutical preparation can be appropriately decided so as to be proper for that particular form and is not largely different from those in ordinary pharmaceutical preparations.
  • a preferable content of the active ingredient generally is about 25 to 500 mg per unit.
  • Pharmaceutical preparation of the above forms can be done according to the respective usual methods.
  • each pharmaceutical preparation differs naturally from the condition, the weight, the age and the like of a patient to whom the pharmaceutical preparation is to be administered and, accordingly, cannot be restricted.
  • administration to each adult may be made so that the adult intakes about 100 to 2000 mg of the active ingredient daily.
  • This a ⁇ r ⁇ unt of the active ingredient can be administered by division into doses for administration one to six times a day.
  • an average tumor weight for each administration level of each test compound was determined. This weight was compared with an average tumor weight in control group, and the ratio of tumor enhancement inhibition at each administration level of each test compound compared with control group was calculated. From these calculations, the administration level of each test compound at which the ratio of tumor enh-ancement inhibition become 50% was obtained and the level (amount) was taken as the antitumor activity value of each compound.
  • toxicity values of anti-malignant tumor agents have been calculated on the bases of LD 50 of test animals, in most cases.
  • LD 50 is measured under serious conditions of test animal far deviating from conditions of patient where drugs are actually used and accordingly LD 50 does not represent a practical toxicity of drug. Therefore, in the present test, accumulated toxicity, which well represents the toxicity of anti-malignant tumor agents, was focused on and, as an indication for sensitive detection of the accumulated toxicity, inhibition of weight increase of test animal was measured. That is, when antitumor activity value was determined in the above item (a), the weight of each mouse of each test group for each test compound was measured daily from the day of tumor transplanting, iircnediately before administration.
  • a larger therapeutic index of a compound means that the compound is better balanced in effect and toxicity and more useful.
  • 3'-O-Benzyl-2'-deoxy-5-trifluoromethyl uridine, lactose, crystalline cellulose and corn starch are mixed in the following proportion. Thereto is added a 10%-ethanol solution containing hydroxypropyl cellulose and they are kneaded. Then, by the use of an appropriate granulator, the kneaded mixture is made into granules. After drying, the granules are made uniform so as to have granular size of 12 to 42 mesh. Subsequently, the granules are coated with hydroxypropyl methyl cellulose in the following proportion by the use of a suitable coating machine. The coated granules are again made uniform so as to have granular size of 12 to 42 mesh, whereby a granule product is obtained.
  • 3'-O-Benzyl-2'-deoxy-5-trifluoromethyl uridine, corn starch and calcium cellulose glycolate were mixed in the following proportions. Thereto was added a 10%-ethanol solution containing hydroxypropyl cellulose, and the mixture kneaded. The kneaded mixture was made into granules by the use of an appropriate granulator. After drying, the granules were mixed with magnesium stearate and silicic acid anhydride in the following proportions and then the mixture made into tablets by the use of a suitable tablet machine. The tablets were coated with hydroxypropyl methyl cellulose, whereby an intended tablet product was obtained.
  • Trifluorothyraidine 75 mg/kg. 135 mg/kg.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Saccharide Compounds (AREA)

Abstract

Procédé de préparation de certaines 2-désoxyuridines, consistant à former un 5-0-"protégé"-2-désoxyribofuranoside à substitution d'alkyle, à exécuter l'hydrocarbylation du composé et à condenser le composé hydrocarbylé en présence d'un acide de Lewis ou de Bronsted avec un silyluracile pour former une uridine. Plusieurs ribofuranosides tritylatés sont des composés nouveaux per se.
EP19850904767 1984-09-24 1985-09-19 Procede de preparation de 2-desoxyuridine. Withdrawn EP0195805A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US65345184A 1984-09-24 1984-09-24
US653451 1984-09-24

Publications (2)

Publication Number Publication Date
EP0195805A1 true EP0195805A1 (fr) 1986-10-01
EP0195805A4 EP0195805A4 (fr) 1987-07-09

Family

ID=24620949

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19850904767 Withdrawn EP0195805A4 (fr) 1984-09-24 1985-09-19 Procede de preparation de 2-desoxyuridine.

Country Status (3)

Country Link
EP (1) EP0195805A4 (fr)
JP (1) JPS62500239A (fr)
WO (1) WO1986001801A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1301166C (fr) * 1987-07-21 1992-05-19 John Nicholas Freskos Procede pour la preparation de 2-desoxynucleosides

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3531464A (en) * 1966-10-21 1970-09-29 Us Health Education & Welfare Alternative synthesis of 2'-deoxy-5-(trifluoromethyl)-uridine and the alphaanomer thereof
US3553192A (en) * 1968-07-15 1971-01-05 Robugen Gmbh Substituted (2'-deoxyribosyl) uracil compounds, compositions containing same and process of making and using same
DE2721466A1 (de) * 1977-05-12 1978-11-16 Robugen Gmbh Verfahren zur herstellung von 2'-desoxyribofuranosylnucleosiden
GB1601020A (en) * 1978-04-24 1981-10-21 Stichting Grega Vzw 2'-deoxy-5 (2-halogenovinyl)-uridines
JPS54151987A (en) * 1978-05-17 1979-11-29 Toyama Chem Co Ltd Preparation of 3',5'-disubstituted-2'-deoxy-beta-uridines and 2'-deoxy-beta-urdines
JPS5929699A (ja) * 1982-08-11 1984-02-16 Funai Corp ２′−デオキシ−５−フルオロウリジンのエ−テル誘導体およびその製造方法並びにこれを含有する抗腫瘍剤
JPS601196A (ja) * 1983-06-07 1985-01-07 Daicel Chem Ind Ltd グリコシドの製造方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No relevant documents have been disclosed. *
See also references of WO8601801A1 *

Also Published As

Publication number Publication date
WO1986001801A1 (fr) 1986-03-27
EP0195805A4 (fr) 1987-07-09
JPS62500239A (ja) 1987-01-29

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