IL105570A - Production of 2',3'-dideoxy-2',3'-didehydronucleosides - Google Patents
Production of 2',3'-dideoxy-2',3'-didehydronucleosidesInfo
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- IL105570A IL105570A IL10557089A IL10557089A IL105570A IL 105570 A IL105570 A IL 105570A IL 10557089 A IL10557089 A IL 10557089A IL 10557089 A IL10557089 A IL 10557089A IL 105570 A IL105570 A IL 105570A
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- dideoxy
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Description
Production of 21 , 31 -dideoxy-2 ' , 3 ' -didehydronucleosides BRISTOL-MYERS SQUIBB COMPANY C: 89204/2 105570/2 BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This application was divided out from Israel Patent Application No. 89693 which relates to an improved process for the production of 2\3'- dideoxy-2,2'-didehydronucleosides.
The present invention provides an alternative improved process for producing the same 2',3'-dideoxy-2,2,-didehydronucleosides.
DESCRIPTION OF THE BACKGROUND AND RELATED REFERENCES Acquired immunodeficiency syndrome (AIDS) is the result of an infection by human immunodeficiency virus(es) (HIV).^ This retrovirus shows a specific tropism for the 2 helper/inducer T cells leading to their depletion. The resultant immunosuppression predisposes -HIV patients to life-threatening opportunistic infections.
Although a present there is no cure for AIDS, one nucleoside derivative, 31 -azido-3 ' -deoxythymidine _(AZT, Retrovir ) , has already proved to be an efficacious agent in the treatment of AIDS in clinical trials and has been licensed by the appropriate regulatory agency for use in 3 patients with AIDS. A number of other chemical and biological agents have been reported to have biological activity against HIV. 2 ' , 3 ' -Dideoxycytidine (ddC), 2 * , 3 ' -dideoxyadenosine. (ddA),4 21 , 3 ' -dideoxy-2 ' , 3 ' -didehydrocytidine (d4C),^ suramine and 6 7 8 9 its analogs, ribavarin, foscarnet, · HPA-23, d-penicillamine, castanospermine, ^ fusidic acid, ^ 13 3 ' -azidoguanosine (AZG), and 3 ' -£luoro-3 '-deoxythymidine 14 ( FDDT) are all reported to be active against HIV.
A number of reports have appeared in the literature which have shown that 2 ' , 3 ' -dideoxy-2 ' , 3 ' -didehydrothymidine (d4T) possesses in vitro activity against HIV in several cell lines. 2 ' , 3 ' -dideoxy-2 ' , 3 ' -didehydrothymidine ( d4T ) has been prepared by Horwitz et al. by two different routes. ' * The"firs¾ of these synthetic routes involves subjecting the 3 ' , 5 ' - anhydro derivative of thymidine to elimination reaction conditions. The second of these routes involves subjecting the 5 ' -O-protected 2, 3 '-anhydro nucleoside derivative of thymidine to ring-opening elimination reaction conditions.
The use of anhydro nucleosides as intermediates for nucleoside synthesis is well precedented in the literature 18 in the art to which the present invention pertains. "^) 105570/2 With the recent discovery of the potency of 2',3'- dideoxy-21 , 3 ' -didehydrothymidine (d4T) as an anti-HIV agent, a process which allows 2 ' , 3 ' -dideoxy-2 ' , 3 ' -didehyd'ro- nucleosides, including d4T, to be prepared cheaply on a large scale becomes important.
The Horwitz route to produce d4T from the 31 , 5 ' -anhydro compound^ is not feasible on a large scale because complete removal of the large volume of DMSO used in scale-up of the Horwitz procedure is very difficult to achieve and requires high vacuum (0.01 mmHg and heating for the temperature range of about 40-50°C) for an extended period of time. These conditions lead to cleavage of the glycosidic bond to give thymine as an undesired side product. ,Also, prolonged exposure to basic conditions, which are required when solvents other than DMSO (e.g. THF, DMF) are used leads to decomposition of d4T to, again, give thymine as an undesired side product.
The alternative Horwitz procedure requires protection of the 5 ' -OH position before formation of the 2 , 5 ' -anhydro- nucleoside. This 2, 5 ' -anhydronucleoside can be opened to give the 5 ' -O-protected nucleoside.
The desired 2 , 3 ' -anhydro. nucleoside can be prepared directly by reacting thymidine with diethyl- (2-chloro-l , 1-2- 19 trifluoroethyl ) amine . 105570/3 SUMMARY OF THE INVENTION This invention provides a process for producing 2',3'-dideoxy- -didehydronucleosides of the formula wherein X, Y, Z and R4 are as defined hereinbelow, in high yields and on a relatively large scale.
DETAILED DESCRIPTION OF THE INVENTION This invention provides a process for producing a 2',3'-dideoxy-2',3'-didehydronucleoside represented by the formula wherein X is N or C-H; Y is C-R5 or N; Z is C-H or N; R4 is OH or NH2; and Rs is H, unsubstituted or halo-substituted alkyl having the formula CnH2nA, or unsubstituted or halo-substituted alkenyl having the formula -(CH2)ra-CH=CHA, wherein m is 0, 1, 2 or 3, n is 1, 2 and 3 and A is H, F, CI, Br or I, comprising the steps of: 105770/1 selected from N and C-H; Y is selected from C-R and N; Z is 4 selected from C-H and N; R is selected from OH and H^ ; and R5 is selected from H, unsubstituted and halo- substituted alkyl having the formula CnEL A, and unsubstituted and halo-substituted alkenyl having the formula C^H^A, wherein n is an integer selected from 1, 2, and 3 and A is selected from H, F, Cl, Br, and I, comprising the steps of: converting a 2 ' -deoxynucleoside represented by the ucleoside intermediate (b) converting in the presence of base selected from non-nucleophi lie and nucleophilic bases said reactive 2 , 3 ' -anhydro-2 ' -deoxynucleoside from etep (a) above to said 2 ' , 3 ' -dideoxy-2 ' 3 ' -didehydronucleoside . 105570/3 As is described above, this invention concerns a process to produce 2',3'-dideoxy-2,,3'-didehydronucleosides wherein the starting material is a 2'-deoxynucleoside; and wherein the base component is derived from an unsubstituted or substituted pyrimidine, or aza-pyrimidine, or deaza-pyrimidine, preferably an unsubstituted or substituted pyrimidine as defined above. Still more preferably, the base moiety is selected from thymine (5-methyl-2,6-dihydroxypyrimidine), cytosine (2-hydroxy-6-aminopyrimidine), uracil (2,6-dihydroxy-pyrimidine), and 5-ethyl- and 5-vinyl- and 5-halovinyl- and 5-halomethyl- and 5-haloethyl-2,6-dihydroxypyrimidin-3-yl. Most preferably the base moiety is thymine. .
In the process according to this invention, the first step involves the preparation of the known reactive 2, 3 ' -anhydro-2 ' -deoxynucleoside intermediate by reacting a starting corresponding 2-deoxynucleoside with a strong base effective to form a 2, 3 ' -anhydro-2 ' -deoxynucleoside. A suitable reagent to accomplish this ring formation is the known reagent, diethyl( 2-chloro-l , 1, 2-trifluoroethyl )amine. This known intermediate has been reacted with nucleophiles to obtain substituted nucleosides such as, for example, 3'-azido-2 ' , 3 ' -dideoxythymidine ( AZ ) .20 The second step of this process involves not nucleophilic addition but, rather, the ring opening reaction of the anhydro ring of the above reactive intermediate.
Suitable reagents to effect this ring opening are either non-nucleophilic bases such as tetrabutyl ammonium fluoride or nucleophilic bases selected from KOtBu, NaOH, KOH and the like.
SCHEME I illustrates schematically typical, representative process according to our present invention, starting from 2 ' -deoxynucleoside and proceeding through the 2,3' -anhydro reactive intermediate .
SCHEME I The problems in the literature methods for producing the desired 21 , 3 ' -dideoxy-2 ' , 3 ' -didehydronucleosides by way of the 2,3'-anhydro reactive intermediate involve the use of diethyl(2-chloro-l, l,2-trifluoroethyl)amine, a fluoramine reagent that is difficult to make and which requires specialized equipment. Alternatively the literature reports a lengthy 4-6tep procedure involving 5 ' -O-tritylation, 3 ' -O-mesylation, detritylation, and anhydro formation. The literature reports formation of various products and side-products other than the desired 2 ' , 31 -dideoxy-2 ' , 3 ' -didehydronucleoside products The specific improvements made in the published route proceding through the 2, 3 '-anhydro reactive intermediate involve the discovery that the use of the reagent, tetrabutyl ammonium fluoride (TBAF), under non-nucleophi lie conditions affords the desired product cleanly and in high yields. Alternatively, the use of KOtBu/DMSO and NaOH/DMF, but not NaCN/DMF or DBU/DMF or NaOH/MeOH or OtBu/BuOH, in place of TBAF in THF or DMF affords the desired product although yields are lower and some undesired side-product (3 ' -epi-thymidine) was obtained with the use of NaOH/DMF.
Thus, the process according to this invention is useful for the preparation of a variety of 2 ' , 3 ' -dideoxy-2 ' , 3 ' -didehydronucleosides, especially pyrimidine nucleosides, having antiviral, antimetabolic, and antineoplastic activity as well as activity against human immunodeficiency virus.
The following examples illustrate but a few representative embodiments of the process according to this invention and are set forth to teach those skilled in the pertinent art how to practice this invention and are not to be construed as limiting in scope. All parts and. percentages are by weight and temperatures are in degrees Celsius unless otherwise specified.
Biological data, including anti-HIV data, of d4T produced by a process according to this invention are set forth in TABLE I. These data are consistent with data published.
\ References 1. (a) Barre-Sinoussi, F; Chermann, J.C.; Rey, R. ; Nugeyre, M.T. Chamaret, S. ; Gruest, C.; Dauguet, C . ; Axler-Blin, C. ; Rouzioux, C; Rozenbaum, W. ; Montagnier, L. Science (Washington, D.C.) 1983, 220, 868-871. (b) Broder, S.; Gallo, R.C. N. Engl. J. Med. 1984, 311, 1292-1297. (c) Eroder, S; Gallo, R.C. Annu. Rev. Immunol. 1985, 3^. 321-336.
. Popovic, M. ; Sarngadharan, M. G.; Read E.; Gallo, R. C. Science (Washington D. C.) 1984, 224, 497-500. (b) Gallo, R. C. ; Sarngadharan, M. G. ; Popovic, M. Shaw, G. M. ; Hahn, B. Wong-Stahl, F. ; Robert-Guroff, M. ; Salahaddian, Z., Markham, P.D. Prog. Allergy 1986, 37, 1-45.
. Fischl, M. A.; Richman, D. D. ; Grieco, M. H. ; Gottlieb, M. S.; Volberding, P. A.; Laskin, 0. L. ; Leedom, J. M. ; Groopman, J. E. Mildvan, D.; Schooley, R. T. ; Jackson, G.G.; Durack, D. T. ; King, D. New Engl. J. Med. , 1987, 317, 185.
Mitsuya, H. ; Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 1911-1915. (a) Lin, T. S. Shinazi, R. ; Chen, M. S.; Kinney- Thomas, E.; Prusoff, W. H. Biochem. Pharmacol. 1987, 36, 311. (b) Balzarini, J.; Pauwels, R.; Herdewijn, P.; De Clercq, E.; Cooney, D. A.; Kang, G-J.; Dalai, M. ; Johns, D.G.; Broder, S. Biochem. Biophys. Res.
Comm. 1986, 140, 735.
Cheson, B. D. ; Levine, A. D. ; Mildvan, D, Kaplan, L.
D.; Wolfe, P.; Rios, A.; Groopman, J.; Gill, P.; Volbdering,, P. A.; Poiesz, B. J.; Gottlieb, M. S.; Holden, H.; Volsky, D. J.; Silver, S. S.; Hawkins,' M.
J. J. Amer. Med. Assoc. 1987, 258, 1347. 89693/2 (a) Balzarini, J.; Mitsuya, H.; De Clercq, E. ; Broder, S. Int. J. Med., 1986, 37 451. (b) McCormick, J.B.; Getchell, J.B; Mitchell, S.W. ; Hicks, D.R. Lancet 1984, ii, 1367. (a) Sarin, P. S. Taguchi , Y. ; Sun, 'D.; Thornton, A.; Gallo, R.C.; Oberg, B. Blochem. Pharmacol. 1985, 3 , 4075. (b) Sandstrom, E. G. ; Kaplan, J. C.; Byington, R. E.; Hirsch, M. s. Lancet 1985, i, 480.
Lane, H.C.; Fauci, A. S. Ann. Intern. Med. 1985, 103, 714.
Chandra, P.; Sarin, P.S. Arznrim-Forsch/Druq Res. 1986, 36, 184.
Tyms, Α.ε.; Berrie, E.M.; Ryder, T. A.; Nash, R. J.; Hegarty, M. P.; Taylor, D. L. ; Mobberley, K. A.; Davis, J. M. ; Bell, E. A.; Jeffries, D. A.; Taylor-Robinson, D.; Fellows, L. E. Lancet 1987, .ii, 1025.
Faber, V.; Newell, A.; Dalgleish, A. G. ; Malkovsky, M. Lancet 1987, ii., 827. (a) ,Hartmann, H. ; Hunsmann, G. ; Eckstein, F. Lancet 1987, i., 40. (b) Baba, M. ; Pauwels , R. ; Balzarini, J.; Herdewiijn, P.; De Clercq, E. Biochem. Biophys. Res.
Comm. 1987, 145, 1080. (a) Herdewijn, P.; Balzarini, J.; De Clercq, E.; Puwels, R. ; Baba, M. ; Broder, S. Vanderhaeghe, H. J.
Med. Chem. 1987, 30, 1270. (b) Mattes, E.; Lehmann, C; Scholz, D. ; von Janta-Lipinski M. ; Gaertner, K. ; Rosenthal, H. A.; Langen, E. Biochem. Biophys. Res.
Comm. 1987, 148, 78. (c) Polski, B. ; Gold, J. M. W. ; Hardy, W.D. ; Baron, P. A.; Zuckermann, E.e.; Chou, T-C. ; Levine, S.M.; Flomenberg, N. ; Wang, L. ; Watanabe, K.
A.; Fox, J. J.; Armstrong, D. 27th ICAAC 1987, Abstract 368, pl61. * (a) Lin, T. S.; Chen, M. S. Gao, Y-S.; Ghazzouli, I.; Prusoff, W. H. J. Med. Chem. 1987, 30, 440. (b) Lin, t. S. ; Shinazi, R. F.; Prusoff, W. H. Biochem.
Pharmacol . 1987, 17, 2713. (c) baba, M. ; Pauwels, R. ; De Clercq, E. ; Desmyter, J.; Vandeputte, M. Blochem . Biophys. Res. Comm. 1987, 142, 128. (d) Balzarini, J. ang, G-J.; Dalai, M. ; Herdewjin, P.; De Clercq, E.; Broder, S.; Johns, D. G. Mol. Pharmacol. 1987, 32, 162 (e) Hamamoto, Y. ; Nakashima, H. ; Matsui, T. ; Matsuda, A.; Ueda, t.; Yamamoto, N. Amtimicrob. Agents Chemother. 1987, 31, 907.
Horwitz, J.; Chua, J. in "Synthetic Procedures in Nucleic Acid Chemistry" (Vol. 1), Zorbach, W. W. ; Tipson R. S. (eds); Interscience , New York, p. 344. Horwitz, J.; Chua, J.; Da Rooge, M. A.; Noel, M. ; Klundt, I. L. J. Org. Chem. 1966, 31., 205.
Fox, J. J.; Miller, N.C. J. Org. Chem., 1963, 28, 936. Kowollik, G.; Gaertner, K. ; Langen, P. Tetrahedron Lett.. 1969, No. 44, 3863.
Glinski, R.P.; Khan, M.S.; Kalamas, R.L.; Sporn, M.B. J. Org. Chem., 1973, 38, 4299.
Davisson, V.J., Davis, D.R., Dixit, V.M. ; Poulter, CD., J. Org. Chem., 1987, 52, 1794; Griffin, B.E.; Jarman, J. ; Reese, C.B.; Sulston, J. Tetrahedron, 1967, 23, 230.
Ando, M. ; Ohhara, H. ; Takase, K. Chem. Lett., 1986, 879.
Jain, T.C.; Jenkins, I.D.; Russell, A.F.; Verheyden, J.P.H.; Moffatt, J.H. , J. Org. Chem., 1974, 3_9, 80. 105570/2 Experimental Melting points were determined on an Electrothermal capillary apparatus and are uncorrected. TLC was performed on silica gel 60 F-254 plates purchased from E. Merck and Co., and column chromatography was performed on flash silica gel (40 uM particle size, Baker), Elemental analysis were performed by the analytical department, Bristol Myers, 1 13 Wallingford. H and C NMR spectra were recorded on a AM360 Bruker NMR spectrometer using tetramethylsilane as the internal standard; chemical shifts are recorded in parts per million. Analytical HPLC was performed on a Waters C18 reverse phase coloumn. 1- (2, 3-Dideoxy-P-D-glcero-pent-2-enofuranosyl) thymine Tetrabutyl ammonium fluoride (0.22 mL, 0.22 mM, 1.0 M) was added to a suspension of the anhydronucleoside ( 25 mg, 0.11 mM) in dry THF (3 mL),. After stirring at 22 ° C for 3 hr, the TLC showed only starting material. The mixture was heated to reflux for 18 hr, at which time the reaction appeared to be complete. After cooling, the solvents were removed in vacuo and the residue was dissolved in CH2Cl2/ eOH/NH4OH (90:10:1). Purification was performed on a 20 mm flash 'chromatography ' column, eluting with CH2Cl2/MeOH/NH4QH (90:10:1). Concentration of the fractions containing the product afforded 18 mg (72%) of d4T Table 1: Comparative in vitro anti-HIV efficacy and cellular toxicitybof AZT and d4T. c d Compound ID (VM) TCID 50 50 AZT 0.45 54.0 d4T 0.33 39.0 (Example p. 15 ) The antiviral test was performed on HIV (LAV train)-infected CEM cells.
The cellular toxicity was measured in CEM cells The 50% inhibitory dose.
The 50% tissue culture inhibitory dose. - 7i - \
Claims (6)
1. A process for producing a 2',3,-dideoxy-2',3'-didehydro- nucleoside represented by the formula wherein X is N or C-H; Y is C-R5 or N; Z is C-H or N; R4 is OH or NH2; and R5 is H, unsubstituted or halo-substituted alkyl having the formula CnH2nA, or unsubstituted and halo-substituted alkenyl having the formula -(CH2)m-CH=CHA, wherein m is 0, 1 , 2 or 3, n is 1, 2 or 3 and A is H, F, CI, Br or I, comprising the steps of: (a) converting a 21 -deoxynucleoside represented by the formula 105770/2 to a reactive 2 , 3 ' -anhydro-2 ' -deoxynucleoside intermediate represented by the formula and (b) converting in the presence of base selected from non-nucleophilic and nucleophilic bases said reactive 2 , 31 -anhydro-21 -deoxynucleoside from step (a) above to said 2 ' , 31 -dideoxy-2 ' , 3 ' -didehydronucleoside .
2. A process according to claim 1 wherein said non-nucleophilic base in step (b) is tetrabutylammonium fluoride (TBAF) .
3.. A process according to claim 1 wherein said nucleophilic base in step (b) is selected from KOtBu, NaOH and KOH. 105770/2
4. ,4. A process according to claim 1 wherein the pyrimidine base is selected from thymine ( 5-methyl-2, 4-dihydroxypyrimidine ) , uracil ( 2 , 4-dihydroxypyrimidine ) , and 5-ethyl- and 5-vinyl- and 5-halovinyl- and 5-halomethyl-and 5-haloethyl-2, 4-dihydroxypyrimid-in-3-yl.
5. A process according to claim 1 wherein the base is thymine.
6. A process for producing 2 ' , 3 ' -dideoxy-2 ' , 3 ' -didehydronucleoside substantially as described herein with reference to the examples . For the Applicants, TNERS IS
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US07/173,473 US4904770A (en) | 1988-03-24 | 1988-03-24 | Production of 2',3'-dideoxy-2',3'-didehydronucleosides |
IL8969389A IL89693A (en) | 1988-03-24 | 1989-03-21 | Production of 2', 3'-dideoxy-2', 3'-didehydronucleosides |
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IL105570A true IL105570A (en) | 1994-08-26 |
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IL10557189A IL105571A (en) | 1988-03-24 | 1989-03-21 | Production of 2'-3'-dideoxy-2'3'- didehydronucleosides |
IL10557089A IL105570A (en) | 1988-03-24 | 1989-03-21 | Production of 2',3'-dideoxy-2',3'-didehydronucleosides |
IL10557289A IL105572A (en) | 1988-03-24 | 1989-03-21 | Production of 2',3'-dideoxy-2', 3'-didehydronucleosides |
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IL10557189A IL105571A (en) | 1988-03-24 | 1989-03-21 | Production of 2'-3'-dideoxy-2'3'- didehydronucleosides |
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IL10557289A IL105572A (en) | 1988-03-24 | 1989-03-21 | Production of 2',3'-dideoxy-2', 3'-didehydronucleosides |
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1989
- 1989-03-21 IL IL10557189A patent/IL105571A/en not_active IP Right Cessation
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IL105571A (en) | 1994-05-30 |
IL105572A (en) | 1994-04-12 |
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