IE842268L - Process for preparation of nucleoside alkyl-,aralkyl- and¹aryl phosphonites and phosphonates - Google Patents
Process for preparation of nucleoside alkyl-,aralkyl- and¹aryl phosphonites and phosphonatesInfo
- Publication number
- IE842268L IE842268L IE842268A IE226884A IE842268L IE 842268 L IE842268 L IE 842268L IE 842268 A IE842268 A IE 842268A IE 226884 A IE226884 A IE 226884A IE 842268 L IE842268 L IE 842268L
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- IE
- Ireland
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- general formula
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- see diagramm
- compound
- meanings given
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/48—Phosphonous acids R—P(OH)2; Thiophosphonous acids including RHP(=O)(OH); Derivatives thereof
- C07F9/4883—Amides or esteramides thereof, e.g. RP(NR'2)2 or RP(XR')(NR''2) (X = O, S)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
1. Claims for the contracting states : BE, CH, LI, DE, FR, GB, IT, LU, NL, SE A process for the preparation of deoxyribonucleoside phosphonates of the general formula I see diagramm : EP0136543,P14,F1 in which T denotes a protecting group for a primary hydroxyl group, B denotes a nucleoside base radical in which any exoamino group present is protected, G denotes a protecting group for a secondary hydroxyl group, Z denotes oxygen, sulfur or selenium and R denotes alkyl having up to 8 C atoms, cyclohexyl, benzyl, or phenyl which is optionally substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy or trifluoromethyl, characterized in that a difunctional phosphonylating reagent of the general formula II see diagramm : EP0136543,P14,F2 in which X denotes chlorine or Y and Y denotes a group of the formula see diagramm : EP0136543,P14,F3 R**1 and R**2 representing identical or different alkyl or cycloalkyl radicals having up to 8 C atoms, or phenyl radicals, or R**1 and R**2 , together with the nitrogen, representing a saturated or unsaturated heterocyclic ring which can contain further hetero atoms, being reacted with a nucleoside of the general formula III see diagramm : EP0136543,P14,F4 in which T and B have the meanings given above, the resulting compound of the general formula IV see diagramm : EP0136543,P14,F5 being reacted with a compound of the general formula V see diagramm : EP0136543,P15,F1 in which B and G have the meanings given above, and the resulting compounds of the general formula VI see diagramm : EP0136543,P15,F2 in which T, R, B and G have the meanings given above, being oxidatively converted to compound of the general formula I. 1. Claims for the contracting state AT A process for the preparation of deoxyribonucleoside phosphonates of the general formula I see diagramm : EP0136543,P15,F3 in which T denotes a protecting group for a primary hydroxyl group, B denotes a nucleoside base radical in which any exoamino group present is protected, G denotes a protecting group for a secondary hydroxyl group, Z denotes oxygen, sulfur or selenium and R denotes alkyl having up to 8 C atoms, cyclohexyl, benzyl, or phenyl which is optionally substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy or trifluoromethyl, characterized in that a difunctional phosphonylating reagent of the general formula II see diagramm : EP0136543,P16,F1 in which X denotes chlorine or Y and Y denotes a group of the formula see diagramm : EP0136543,P16,F2 R**1 and R**2 representing identical or different alkyl or cycloalkyl radicals having up to 8 C atoms, or phenyl radicals, or R**1 and R**2 , together with the nitrogen, representing a saturated or unsaturated heterocyclic ring which can contain further hetero atoms, being reacted with a nucleoside of the general formula III see diagramm : EP0136543,P16,F3 in which T and B have the meanings given above, the resulting compound of the general formula IV see diagramm : EP0136543,P16,F4 being reacted with a compound of the general formula V see diagramm : EP0136543,P16,F5 in which B and G have the meanings given above, and the resulting compounds of the general formula VI see diagramm : EP0136543,P17,F1 in which T, R, B and G have the meanings given above, being oxidatively converted to compound of the general formula I.
Description
1 H U 4 - 2 - This invention relates to a process for the preparation of nucleoside alkyl-, aralkyl- and ary1-phosphonites and -phosphonates.
Non-ionic analogs of deoxyribonucleic acids (DNA) are important for the investigation of DNA-DNA and DNA-protein interactions. Of particular interest are phos-phonic acid esters of deoxyribonucleotides as a result of their chemical stability and on the basis of their capability to enter into cells and their high resistance to cell nucleases. Hitherto, four different strategies have been described for the synthesis of methylphosphonate analogs ofnucleotides: 1. Ogilvie et al. (M.J. Nemer and K.K. Ogilvie, Tetrahedron Lett. 21, Page 4149 (1980)) prepared a completely protected uridyl-3', 5 1-uridine methylphosphonate by Michaelis-Arbuzov rearrangement of the corresponding phosphite intermediates. This reaction (methyl iodide, 20 hours at 50°C) might not be generally applicable as a result of its drastic conditions, because, for example, methylation of the purine bases is to be expected. 2. Ts'o et al. (F.S. Miller, J. Yano, E. Yano, C. Caroll, K. Jayaraman and P.O.P. Ts'o, Biochemistry 18, 5134 (1979); Proc. Natl. Acad. Sci. USA 73, 1537 (1 981 ); ■P.S. Miller, N. Drean, S.M. Pulford and K.B. McParland, J. Biol. Chem. 225, 9659 (1 980)) developed a synthesis strategy which is analogous to the phosphotriester method in oligonucleotide synthesis. Here, a protected nucleotide 3'-O-methylphosphonic acid ^?-cyanoethyI ester is used as the most important intermediate. This method has the known advantages and disadvantages of the phosphotriester method, the low reactivity of the phosphor us (V) compound being mentioned in particular as a disadvantage. 3. Agarwal et al. (K. L. Agarwal and F. Riftina, Nucl. 5 Acid Res. 6_, 3009 (1979)) used methylphosphonic acid di-chloride as a difunctional phosphonylating agent. In the second step, the chloride has to be activated by means of tetrazole. The crude product obtained can only be purified by efficient chromatography. 10 4. J. Engels and A. Jager, Angew. Chem. Suppl. 1982, 2010, and N.D. Sin ha, V. Grossbruchhaus and H. Ko'ster, Tetrahedron Lett. 2_4, 887 (1 983) used methy I d i ch lorophosphane as the starting material. The latter authors synthesized the nucleotide methylphosphonates on a polymeric support. 15 The products obtained are yet to be characterized.
Whereas the reactivity of the second halogen of methylphosphonic acid dichloride is generally too low and additional activation is necessary, the activity in the case of phosphinic acid dichlorides is if anything too 20 high. Thus, handling difficulties arise (extremely anhydrous medium) and, in addition, the symmetrical phos-phonous acid ester is unavoidably formed.
By contrast, the invention relates to a process for the preparation of deoxyribonucleoside phosphonates of 25 the general formula I 20 (I) - 4 - *-0T$ 0 1 Z = P - R G~0 in which T denotes a protecting group for a primary hydroxyl group, preferably triphenyImethyI ( = Tr), p-anisoyl-5 diphenylmethyl or di(p-anisoyl)phenylmethyl, B denotes a nucleoside base radical in which any exo-amino group present is protected, preferably 1 -thyminyl, 1 -(N-4-benzoyIcytosinyI), 9-(N-6-berizoy l-adeninyl) or 9 - (N-2-isobutyroyIguaninyI), 'i0 G denotes a protecting group for a secondary hydroxy I group, Z denotes oxygen, sulfur or selenium and R denotes alkyl having up to 8 C atoms, cyclohexyl, benzyl,or phenyl optionally substituted by fluorine, 15 chlorine, bromine, lower alkyl, lower alkoxy or tri- f luoromethyI, and preferably denotes methyl, ethyl, phenyl or benzyl, especially methyl, •wherein a difunctional phosphonylating reagent of the general formula II X R- PC Y (II) wherein X denotes chlorine or Y and Y denotes a group of the formula - 5 -R1 VR2 1 ? R 1 and Rc representing identical or different alkyl or cycloalkyl radicals having up to 8 C atoms, or phenyl 1 5 radicals, or R and R , together with the nitrogen, representing a saturated or unsaturated heterocyclic ring which can contain further heteroatoms, is reacted with a nucleoside of the general formula III B r-°XJ (III) H-0 wherein T and D have the meanings given above, preferably 10 at -80 to +100°C, in particular at -20 to 0°C, the resulting compound of the general formula IV T -—O—1/ 0nJ ^Y_j/ (iv) 0 1 R - P y is reacted with a compound of the general formula V B H-°X7 (V) G-0 wherein B and G have the meanings given above, preferably at -20 to +100°C, in particular at room temperature, and the resulting compound of the general formula VI I - 6 - R - ^ B (VI) > The compounds of the general formula I in which 2 denotes sulfur or selenium are new. The intermediates of the general formula IV are also new and form a subject of the i nverit ion. 10 In principle, the radical R in the difunctional phosphcnylating reagent of the general formula II can be any non-cytotoxic organic radical which is inert towards the compounds of the general formulae II to VI and which does not hinder the reactions. 15 Examples of possible groups of the general formula -NR^R^ are: dimethylamino, diethylamino, diisopropyl-amino, methylethyl amino, methylpropylafiiino, methylhexyl-amino, methyIcyc lohexyI amino, methy I benzyI amino, morpholino, pyrrolidine, piperidino, methyI aniIino, dipheny I ami no, 20 imidazolo, triazolo, benzotriazolo and tetrazolo.
The starting materials of the general formula II in which X denotes chlorine can be obtained by reacting the corresponding dichlorophosphane, preferably Riethyldi-chlorophotphane, with a secondary amine of the general 25 formula VII - 7 - H-NR1R2 (VII) 1 ? in which R and R have the meanings given above. Correspondingly, compounds of the general formula II in which X denotes a group of the formula Y are accessible 5 by further reaction with the sane secondary amine or a different secondary amine of the general formula VII. The compounds of the formula II can be purified by vacuum distiIlation.
The reaction of the phosphonylating reagent of the 10 general formula II with a suitably protected nucleoside of the general formula III is carried out in a moderately polar solvent, preferably chloroform, with the exclusion of moisture. Tertiary amines, preferably ethyldiisopropyl- li amine (Hunig's base), can be used as auxiliary bases for 15 this reaction. Working-up is carried out by aqueous extraction and precipitation of the products of the general formula IV with a non-polar solvent such as petroleum ether or pentane. The phosphonous acid ester-amides of the general formula IV obtained in this way precipitate as 20 colorless powders and can be characterized by spectroscopic data such as ^P-NMR or UV and elementary analysis. Furthermore, they can also be converted, by direct oxidation, to the phosphonic acid ester-amides of -the general formula VIII B 25 O (VIII) Z = p — R I Y T, B, Z, R and Y having the meanings given above, which can then be isolated and characterized.
Remarkably, no symmetrical dinucleoside 3',3'-phosphonite is formed within the limit of detection. 5 As shown by '"'p-NMR, the compounds of the general formula I are stable for at least 1 month in powder form, when stored dry and at a maximum of -20°C. This great stability of the phosphonous acid ester-amides is astonishing and emphasizes the value of this method. Its 10 universal applicability in the synthesis of phosphonic acid diesters of nucleosides is shown by the reaction with suitably 3'-protected nucleosides: In this reaction, the 5'-protected nucleoside phosphonites of the general formula IV are dissolved in a 15 moderately polar solvent, preferably acetonitri le, chloroform or tetrahydrofuran, and mixed with the nucleoside of the general formula V (protected in the 31-position) . Suitable protecting groups G in the compounds of the general formula V are acyl groups such as benzoyl, acetyl, 20 pivaloyl or levulonyl, or silyl groups such as t-butyl-dimethy Isi ly I. The reaction is catalyzed by an acid, preferably an azole or amine hydrochloride. Benzotriazole is particularly suitable. It is remarkable that HPLC analysis of the product shows no symmetrical S'^'-isomer 25 and only traces of the 3 ' ,3 '-isomeric phosphonate.
The labile intermediate, namely the phosphonous acid triester of the general formula VI, is oxidized directly to the phosphonate of the general formula I. In addition to the oxidizing agents usually employed for this purpose, such as dinitrogen tetroxide or iodine, peroxides, in particular anhydrous t-butyl hydroperoxide, have proved valuable. The reaction is preferably carried out in a moderately polar solvent, particular preference being 5 afforded to acetonitrile or chloroform. Particular consideration should be given to the known acid-catalyzed transesterification of the diacylalkylphosphonites ( F. W „ Hoffmann, R.G. Roth and T.C. Simmons, J. Amcr. Chem. Soc. 80, 5937 - 40 (1 958)) . 10 The compounds (some of which are already known) 31 1 are characterized by means of P-NMR and H-NMR and also chromatographic comparisons with authentic material.
The compounds of the general formula I in which Z denotes sulfur or selenium are prepared by direct reaction 15 of the compounds of the general formula VI with elemental sulfur or selenium. Stirring with the stoichiometric quantity of sulfur or selenium, in a polar solvent such as tetrahydrofuran, leads to good yields of the corresponding thiophosphonates or seIenophosphonates of the general 20 formula I. Characterization is carried out by means of 31p_NMR and ^ H-NMR as well as elementary analysis.
Because of the presence of a center of asymmetry in the nucleoside moiety and the production of another on the phosphorus, the phosphates of the general formula I 25 exist as mixtures of diastereomers (see Table 6, isomers 1 and 2) .
The isomer ratio, which is close to the statistical ratio of 1:1, is only very slightly influenced by a variation in the parameters such as the solvent, the tern- - 10 - perature and the sequence of addition.
The examples which follow describe the invention in greater detail: Ex amp Ie 1: Starting material HjC-'P CN (CHj) 2^2 5 In a 1000 ml three-necked flask fitted with a dropping funnel and a mechanical stirrer, 125 ml (1.9 mol) of dimethyI amine are introduced into 400 in I of anhydrous diethyl ether and reacted, over a period of 60 minutes, with a solution of 60 ml (0.40 mol) 10 of methyldichlorophosphane in 200 ml of anhydrous ether, while cooling with ice. After stirring for 2 hours at room temperature and for 1 hour at 50°C, the precipitate is filtered off under a protective gas and rinsed twice with 100 ml of ether and the filtrate is concentrated at 15 about 0.1 bar. The remaining residue is rapidly distilled over at 0.5 bar/124°C. Precision distillation with a Vigreux column (50 cm) at 64-65°C/65 mbar gives 36.6 g (66% of theory) of a colorless liquid.
Analysis: Cl^~^ < 0.2% 20 31P-NMR (THF) % = 87 ppm 1H-NMR (COCI3) S = 1.23 ppm (d, 7Hz, P-CU3) % = 2.66 ppm (d, 7Hz, N(CH3)2) Example 2: The S'-tritylnucleosides III (1 mmol) are dissolved 25 in 6 ml of anhydrous chloroform under an inert nitrogen atmosphere nnd H3 CP CN (C ) 2^2 (2 i s added. The reaction is complete after 12 hours at room temperature (stirring) or after only 2 hours if catalytic quantities (0.1 mmol) of collidine hydrochloride are added. - 11 - The solution is then transferred with 100 ml of methylene chloride to a 250 ml separating funnel and extracted twice by shaking with 50 ml of saturated sodium chloride solution (containing 0.1 ml of triethy I amine). The organic phase is dried over anhydrous sodium sulfate and concentrated to a foam. This is stirred for 2 hours with 50 ml of pentane. The residue is filtered off and dissolved in 2 ml of diethyl ether and the solution is slowly added dropwise to 50 ml of thoroughly stirred pentane. The fine precipitate is filtered off and dried to give an 85-95% yield of the compound of the general formula IV (Tables 2 and 3).
The compounds can be identified directly by 31 P nuclear magnetic resonance spectroscopy or, after oxidation with t-butyl hydroperoxide, as phosphonic acid este:— amides of the general formula VIII (Tables 4 and 5).
In the ^P-NMR spectrum, these substances show up to 3% of hydrolyzed product (nucleoside methylphos-phinate), but no detectable quantity of symmetrical di-nucleoside 31,31-phosphonite. This demonstrates the superiority of the method compared with former methods, which always yielded about 5-10% of these products. When stored as dry powders at -20°C, no decomposition can be observed within a month.
The following reagents were also employed analogously: - 12 - „ r I)/N(C2H5>2 ,n ZCHtCIl >,_? n e - pf ii c - * 2 3 ^C1 3 x CI CaHC; N II C - p' 3 HC - P 652 CI 3 ^ CI Example 3: The 5 1 -1rityInucIeoside III (1.00 mmcl) and 1.71 ml (10 mmol) of N, N , N-e t hy Id i i sop ropy I am i ne are 5 introduced into 6 ml of TH F , and 2.,00 mmol of phosphonyla-ting agent II are then slowly added dropwise. After stirring at room temperature overnight, the reaction solution is added dropwise to ice-cold water (50 ml, saturated with NaCl). After extraction with twice 20 ml 10 of methylene chloride, the organic phase is dried with sodium sulfate and the solvent is removed in vacuo.
Further purification is carried out by precipitation as above (Tables 2 and 3).
E xamp le 4; 15 3 *-0-3e nzoy 11 li yrn i d i ne (0.20 mmol) and 1-H-benzo- triazole (0.80 mmol) are dried in a round-bottomed flask and then dissolved in 1.0 ml of dry acetonitrile. The reaction is complete within one minute, a very air-labile and acid-labile phosphonite VI being formed; this is 20 converted directly to the phosphonates I, with 80-90% yield, by oxidation with anhydrous t-butyl hydroperoxide (0.25 mmol) (according to H. Langhals, E. Fritz and J. Mergelsberg, Chen. Ber. 113, 3662 (1980)) dissolved in - 13 - acetonitrile or tetrahydrofuran.
Alternatively/ 30 mg (0.95 mmol) of sulfur are added to 0.7 mmol of VI at -20°C and the mixture is stirred overnight at room temperature. The reaction is generally already complete after a few hours. 20 ml of chloroform are then added and the organic phase is extracted three times by shaking with water. After drying over sodium sulfate and removal of the solvent, a crude product is obtained which is purified by silica gel chromatography to give the compound I in 80-90% yield (Table 6).
A11ernativeIy/ 118 mg (1.5 mmol) of black selenium are added to 0.7 mmol of VI and the mixture is stirred overnight. After working-up (as above), the compound I is obtained in 60% yield (Table 6).
HPLC analysis of the reaction mixture (in the case where Z ~ 0 by comparison with the authentic reference, P.O.P. T1so et al., Biochemistry 18, 5134 (1979)) showed about 1% of the 3',3'-phosphonates and no 5',5'-isomer.
TABLE 1: Conpounds (II) H^C-PXY 1H-NMR (CDClj), cf(ppm) X Y 31 P-NMR £ Cppm)3 ^ B .p.
°C/bar p-ch3 Other protons - Cl ch3 "N\ 6^5 - 141.2b) 44-47/10~8 1.61 d (J=13.1 Hz) 7.41-7.18 3.20 (m, 5H, aromatic H,d (J=8.3 Hz)) - Cl -N(C6H5)2 - 132.2b) 92-44/10-8 1.53 d (J=14 Hz) 7.5-6.9 (m, 10 H, aromatic H) /^N -N ! -N ' -i " NiSsW /=^N "VN yN-S^-NC ~v - 62C) n ^ - 72w _.c) - 91 92/l0~5 CM.p.: 60°C) (M. p.: 110°C) - 81 d) 2.20 d(J=10 Hz) 2.32 d(J=9 Hz) 2.49 d(J=9 Hz) 2.60 d(J=9 Hz) 7.45 (s, 2H) 6.95 (s, 4H) 8.51 (s, 2H) 8.07
Claims (12)
1. A process for the preparation of a deoxyribonucleoside phosphonate of the general formula I O * - P - K E o— ' °' (I) '1 G-0 in v/ h i c h T denotes a protecting group for a primary hydroxyl g roup, B denotes a nucleoside base radical in which one exo-amino group present is protected, G denotes a protecting group for a secondary hydroxyl group, Z denotes oxygen, sulfur or selenium and R denotes alkyl having up to 8 C atoms, cyclohexyl, benzyl, or phenyl optionally substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy or tri-fluoromethyl, which comprises reacting a difunctional phosphonylating reagent of the general formula II X R - ^ Y (II) wherein X denotes chlorine or Y and Y denotes a group of the formula 1 R " 2 x R 10 - 21 - 1 ? R1 and representing identical or different alkyl or cycloalkyl radicals having up to 8 C atoms, or phenyl 1 ? radicals, or R and R , together with the nitrogen, representing a saturated or unsaturated heterocyclic ring which can contain further heteroatoms, with a nucleoside of the general formula III t — o- (iii) H-0 wherein T and B have the meanings given above, reacting the resulting compound of the general formula IV 9 (iv) r - p Y with a compound of the general formula V H-°Or G-0 (v) wherein B and G have the meanings given above, and oxidat-ively converting the resulting compounds of the general formula VI ,o B t—0 15 r~f 0 (vi) 1 R - P B 4-o G—O wherein T, ft, B and G have the meanings given above, to compounds of the general formula - 22 - 1.
2. A process as claimed in claim 1, wherein compounds of the formulae II to IV are used in which T denotes tripheny ImethyI, p-anisoy IdiphenyImethyI or di(p-anisoyl)phenylmethyl, B denotes 1-thyminyl, 1-, 9-(N~ 6-benzoyladeniny I) or 9-(N-2-isobutyroy Iguaniny I) and R denotes methyl, ethyl, phenyl or benzyl.
3. A process as claimed in claim 1 or 2, wherein the compounds of the formulae II and III are reacted at -80 to +100°C.
4. A process as claimed in claim 3, wherein the reaction takes place at -20 to 0°C.
5. A process as claimed in one or more of the preceding claims, wherein the compounds of the formulae IV and V are reacted at -20 to +100°C.,
6. A process as claimed in claim 5, wherein the reaction takes place at room temperature.
7. A process as claimed in one or more of the preceding claims, wherein the compound of the formula VI is oxida-tively converted to a compound of the formula I at -80 to +100°C.
8. A process as claimed in claim 7, wherein the oxidation takes place at -20°C to room temperature.
9. A compound of the formula IV in which T, B, R and Y have the meanings given in claim 1. - 23 -
10. A process as claimed in Claim 1 for the preparation of a deoxyribonucleoside phosphonate of the general formula I given and defined therein, substantially as hereinbefore described and exemplified. 5
11. A deoxyribonucleoside phosphonate of the general formula I given and defined in Claim 1, whenever prepared by a process claimed in preceding claim.
12. A compound of the formula IV according to Claim 9, substantially as hereinbefore described and exemplified. F . R. KELLY & CO . , AGENTS FOR THE APPLICANTS.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833332068 DE3332068A1 (en) | 1983-09-06 | 1983-09-06 | METHOD FOR PRODUCING NUCLEOSIDALKYL, ARALKYL AND ARYLPHOSPHONITES AND PHOSPHONATES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE842268L true IE842268L (en) | 1985-03-06 |
| IE57904B1 IE57904B1 (en) | 1993-05-05 |
Family
ID=6208339
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2268/84A IE57904B1 (en) | 1983-09-06 | 1984-09-05 | Process for the preparation of nucleoside alkyl-,aralkyl-and aryl-phosphonites and-phosphonates |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0136543B1 (en) |
| JP (2) | JPS6072899A (en) |
| AT (1) | ATE38839T1 (en) |
| AU (2) | AU570266B2 (en) |
| CA (1) | CA1235079A (en) |
| DE (2) | DE3332068A1 (en) |
| DK (3) | DK162895C (en) |
| ES (1) | ES535627A0 (en) |
| GR (1) | GR80287B (en) |
| IE (1) | IE57904B1 (en) |
| PT (1) | PT79172B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4959463A (en) * | 1985-10-15 | 1990-09-25 | Genentech, Inc. | Intermediates |
| DE3916871A1 (en) * | 1989-05-24 | 1990-11-29 | Boehringer Mannheim Gmbh | MODIFIED PHOSPHORAMIDITE PROCESS FOR THE PREPARATION OF MODIFIED NUCLEIC ACIDS |
| DE59108644D1 (en) * | 1990-07-02 | 1997-05-07 | Hoechst Ag | Oligonucleotide analogs with terminal 3'-3 'or. 5'-5 'internucleotide linkages |
| US5512668A (en) * | 1991-03-06 | 1996-04-30 | Polish Academy Of Sciences | Solid phase oligonucleotide synthesis using phospholane intermediates |
| EP0652890B1 (en) * | 1992-07-27 | 1998-01-14 | HYBRIDON, Inc. | Oligonucleotide alkylphosphonothioates |
| WO1994015946A1 (en) * | 1993-01-08 | 1994-07-21 | Hybridon, Inc. | Synthesis of dimmer blocks and their use in assembling oligonucleotides |
| US6087491A (en) | 1993-01-08 | 2000-07-11 | Hybridon, Inc. | Extremely high purity oligonucleotides and methods of synthesizing them using dimer blocks |
| CN1121721A (en) * | 1993-01-25 | 1996-05-01 | 海布里顿公司 | Oligonucleotido alky phosphate and alky substituted phosphate |
| DE69527266T2 (en) * | 1994-07-26 | 2003-03-06 | Sony Corp | IMAGE TRANSFER METHOD |
| DK0828749T3 (en) * | 1995-05-26 | 2003-10-27 | Genta Inc | Methods for the Synthesis of Organophosphorus Derivatives |
| AU2739797A (en) * | 1996-05-03 | 1997-11-26 | Hybridon, Inc. | (in situ) preparation of nucleoside phosphoramidites and their use in synthesis of oligonucleotides |
| DE102004049339A1 (en) | 2004-10-08 | 2006-04-13 | Basf Ag | Process for the purification of phosphorus-containing chelate ligands |
| DE102007038930B4 (en) * | 2007-08-13 | 2013-12-05 | Universität Leipzig | New chemical compound and its use in medicine, in particular for use in tumor therapy |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL62834A0 (en) * | 1980-05-14 | 1981-07-31 | Ens Bio Logicals Inc | Polynucleotide synthesis |
| US4415732A (en) * | 1981-03-27 | 1983-11-15 | University Patents, Inc. | Phosphoramidite compounds and processes |
| EP0090789A1 (en) * | 1982-03-26 | 1983-10-05 | Monsanto Company | Chemical DNA synthesis |
| DE3239888A1 (en) * | 1982-10-28 | 1984-05-03 | Hubert Prof. Dr. 2000 Hamburg Köster | METHOD FOR PRODUCING OLIGONUCLEOSIDE PHOSPHONATES |
-
1983
- 1983-09-06 DE DE19833332068 patent/DE3332068A1/en not_active Withdrawn
-
1984
- 1984-08-30 AT AT84110314T patent/ATE38839T1/en not_active IP Right Cessation
- 1984-08-30 EP EP84110314A patent/EP0136543B1/en not_active Expired
- 1984-08-30 DE DE8484110314T patent/DE3475307D1/en not_active Expired
- 1984-09-04 PT PT79172A patent/PT79172B/en active IP Right Revival
- 1984-09-04 GR GR80287A patent/GR80287B/en unknown
- 1984-09-04 ES ES535627A patent/ES535627A0/en active Granted
- 1984-09-05 CA CA000462469A patent/CA1235079A/en not_active Expired
- 1984-09-05 JP JP59184717A patent/JPS6072899A/en active Granted
- 1984-09-05 AU AU32756/84A patent/AU570266B2/en not_active Expired
- 1984-09-05 DK DK424784A patent/DK162895C/en active
- 1984-09-05 IE IE2268/84A patent/IE57904B1/en not_active IP Right Cessation
-
1988
- 1988-02-08 AU AU11384/88A patent/AU601257B2/en not_active Expired
-
1991
- 1991-07-05 DK DK131691A patent/DK167359B1/en active IP Right Grant
- 1991-07-05 DK DK131591A patent/DK166585C/en active
-
1992
- 1992-11-18 JP JP4307481A patent/JPH0662662B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0662662B2 (en) | 1994-08-17 |
| CA1235079A (en) | 1988-04-12 |
| EP0136543A2 (en) | 1985-04-10 |
| DK162895B (en) | 1991-12-23 |
| DK424784A (en) | 1985-03-07 |
| ES8505384A1 (en) | 1985-05-16 |
| DK131691A (en) | 1991-07-05 |
| PT79172B (en) | 1986-09-10 |
| PT79172A (en) | 1984-10-01 |
| ES535627A0 (en) | 1985-05-16 |
| EP0136543B1 (en) | 1988-11-23 |
| EP0136543A3 (en) | 1986-07-16 |
| DK424784D0 (en) | 1984-09-05 |
| DK166585C (en) | 1993-10-25 |
| DK131691D0 (en) | 1991-07-05 |
| GR80287B (en) | 1985-01-07 |
| JPH0531560B2 (en) | 1993-05-12 |
| IE57904B1 (en) | 1993-05-05 |
| DK131591A (en) | 1991-07-05 |
| DK166585B (en) | 1993-06-14 |
| AU3275684A (en) | 1985-03-14 |
| DK131591D0 (en) | 1991-07-05 |
| ATE38839T1 (en) | 1988-12-15 |
| AU570266B2 (en) | 1988-03-10 |
| AU1138488A (en) | 1988-07-14 |
| DE3332068A1 (en) | 1985-03-21 |
| DK162895C (en) | 1992-05-11 |
| DK167359B1 (en) | 1993-10-18 |
| JPH05262787A (en) | 1993-10-12 |
| JPS6072899A (en) | 1985-04-24 |
| DE3475307D1 (en) | 1988-12-29 |
| AU601257B2 (en) | 1990-09-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |