L227691
`
`PATENT SPECIFICATION
`
`(11)
`
`1227691
`
`NO DRAWINGS
`(22) Filed 24 April. 1969
`(21) Application No. 21132/69
`(31) Convention Application No. 3399
`(32) Filed 8 May 1968in
`(33) Czechoslovakia (CS)
`(45) Complete Specification published 7 April 1971
`(51) International Classification C 07 d 99/04
`(52) Index at acceptance
`C2C 173—199—272 177—271—-279215 247 250 252 253
`25Y 28X 30Y 321 322 323 32¥ 351 352 360 361
`362 36Y 3A12A4A 3A12A4B 3A12B2 3A12C4
`652 670 672 761 766 790 LK
`
`
`
`(54) A PROCESS FOR PREPARING
`1-GLYCOSYL-5-AZACYTOSINES
`
`(71)|We, CESKOSLOVENSKA AKADEMIE
`A mutagenic effect of 5 - azacytidine has
`VED, a Corporation organised and existing
`been reported. Furthermore, 5 - azacytidine
`under the laws of Czechoslovakia of No. 3
`suppresses the formation of inductive enzymes
`Narodni, Prague 1, Czechoslovakia, do here-
`in mammalian cells and regeneration of rat
`by declare the invention, for which we pray
`liver after heptatectomy and, on the other
`that a patent may be granted to us, and the
`hand, protects mice against
`the effects of
`method by which it is to be performed, to be
`X-rays.
`particularly described in and by the following
`5 - Aza ~ 2’ - deoxycytidine, similarly to
`statement : —
`5 - azacytidine, suppresses considerably the
`This invention relates to a process for pre-
`formation
`of
`experimental
`leukemia
`and
`paring 1 - glycosyl . 5 - azacytosines.
`shows, even at low concentrations, significant
`More particularly this invention relates to
`bacteriostatic properties.
`a process for preparing 1 - glycosyl
`- 5 -
`A similar biological activity can be expec-
`azacytosines of the general formula I:
`ted also with some further 1 - glycosyl - 5 -
`azacytosines.
`- glycosyl - 5 ~
`1
`The preparation of
`azacytosines was
`previously
`reported
`in
`British patent specifications Nos. 1,046,181
`and 1,050,899. Per-acylglycosyl
`isocyanates
`are added to O - alkylisoureas or S - alkyl -
`isothioureas to produce the corresponding per-
`acylglycosylisobiurets or peracylglycosyliso -
`thiobiurets. Condensation of the latter com-
`pounds with ortho-esters of aliphatic acids
`affords 1 - per - acylglycosyl - 4 - alkoxy -
`i, 2 - dihydro - 1, 3, 5 - triazin - 2 -
`ones or 1 - per - acylglycosyl- 4 - alkylthio -
`1, 2 - dihydro - 1, 3, 5 - triazin - 2 ~ ones,.
`the treatment of which with ammonia or
`amines in alcohols produces the 1 - glycosyl -
`5 - azacytosines. One disadvantage of this
`procedure is that the reaction of ammonia
`or amines with 1 - per - acylglycosyl - 4 -
`alkoxy (or alkylthio) - 1, 2 - dihydro - 1,
`3, 5 ~ triazine - 2 - ones usually produces the
`required 1 - glycosyl - 5 - azacytosines in
`very low yields because of the instability of
`the aforementioned intermediates under ami-
`nation conditions.
`Furthermore,
`the 4 -
`alkylthio derivatives: are Jess stable than the
`corresponding 4-alkoxy derivatives arid their
`reactivity towards ammonia or amines is very’
`low,
`:
`An object of
`invention ig to
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`the present
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`10
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`
`Re
`
`yom
`
`wherein R* designates a glycosyl residue, R?
`designates a hydrogen atom or an alkyl group
`having from 1 to 4 carbon atoms and R*® and
`R*, which are identical or different, designate
`hydrocarbon atoms, alkyl groups having from:
`1 to 4 carbon atoms or aralkyl groups: hav-
`ing from 7 to 10 carbon atoms.
`Two compounds of the above type show
`significant biological effects, namely, 1 - f -
`D - ribofuranosy!
`- 4 - amino - 1, 2 -
`dihydzo - 1, 3, 5 - triazin - 2 - one (or 5 -
`azacytidine) and 1 - (2 - deoxy - B - D -
`ribofuranosyl) - 4 - amino - 1, 2 - dihydro-
`1, 3, 5 - triazine - 2 - one (or 5 - aza -
`2’ - deoxycytidine). 5 - Azacytidine, a pyrim-
`idine antimetabolite, in low concentrations in-
`hibits bacterial growth and exhibits a high
`antileukemic effect with mice. In the case of
`V. faba merisfen, 5-azacytidine causes a mito-
`sal
`innibition and chromosomal aberrations.
`
`[Price 25p]
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0001
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0001
`
`

`

`1,227,691
`
`general
`formula I preferably is performed
`obviate or mitigate the aforesaid disadvan-
`without isolation of the alkoxytriazinoneof the
`tages.
`general formula IIT.
`We have discovered that the free 1 - gly -
`Hence further according to the present in-
`cosyl - 4 - alkoxy - 1, 2 - dihydro - 1,
`vention there is provided a process for the
`3, 5 - triazine - 2 - ones are much more
`preparation of a 1 - glycosyl - 5 ~ aza -
`stable than their per-acyl derivatives.
`The
`cytosine of the general formula I, comprising
`amination of 1 - glycosyl - 4 - alkoxy -
`effecting reaction of a compoundof the general
`1, 2 - dihydro - 1, 3, 5 - triazine - 2 -
`formula IT
`ones is very rapid and affords high yields of
`the required 1 - glycosyl - 5 - azacytosines.
`The free 1 - glycosyl - 4 - alkoxy - 1,
`y
`2 - dihydro - 1, 3, 5 ~ triazine - 2 - ones
`rb (2)
`are readily accessible by alcoholysis of the
`corresponding per-acyl derivatives as well as
`by alcoholysis of 1 - per - acylglycosyl -4-
`15
`°
`alkylthio - 1, 2 - dihydro - 1, 3, 5 - triazin -
`2 - ones which, in this special case, is accom-
`panied by a conversion of the 4 - alkylthio
`group to the 4 - alkoxy group.
`According to the present invention there is
`provided a process for preparing a 1 - gly -
`cosyl - 5 - azacytosine of the general formula
`I defined above comprising effecting reaction
`of a 1 - glycosyl - 4 - alkoxy - 1,2 -
`dihydro - 1, 3, 5 - triazin - 2 - one of the
`general formula II
`or®
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`XA
`
`|R
`
`wherein R? is as defined for general formula I,
`R® designates a per - acylglycosyl residue
`wherein the acyl group has from 2 to 10
`carbon atoms and X designates an alkoxy
`or alkylthio group having from 1 to 4 car-
`bon atoms, with an alkali metal alkoxide hav-~
`ing from 1 to 6 carbon atoms, preferably
`in methanol,
`thus effecting the formation of
`a1 - glycosyl - 4 - alkoxy - 1,2 - dihydro -
`1,3,5 - triazin - 2 - one of the general formula
`it
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`10
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`ore
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`Ay
`Be SO
`
`(3)
`
`wherein R? and R? are as defined for general
`formula I and R® designates an alkyl group
`having from 1 to 6 carbon atoms, and effect-
`ing reaction of the alkoxytriazinone of the
`general
`formula III with ammonia or an
`amine of the general formula IV
`
`R°—NH—R*
`
`IV
`
`wherein R® and R‘ are as defined above for
`general formula I.
`The reaction of compounds of the general
`formula IT with the alkali metal alkoxide pre-
`ferably is performed at room temperature, pre-
`ferably in an alkanol containing from 1 to
`6 carbon atoms, and morepreferably in meth-
`anol. This reaction preferably is carried out
`in the absence of atmospheric moisture. In
`the case of alkylthio derivatives, optimum
`yields are obtained with the use of 1.2 moles
`of the alkoxide per 1 mole of the starting
`compound.
`The reaction of the alkoxytriazinone of the
`general
`formula III with ammonia or an
`amine of the general formula IV preferably
`is performed at
`room temperature, prefer-
`ably in the medium of an alkanol containing
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`(3)
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`0
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`N“
`
`R
`
`wherein R* and R? are as defined for general
`formula I and R® is an alkyl group having
`from 1 to 6 carbon atoms, with ammonia or
`an amine of the general formula IV
`
`R?—NH—R*
`
`IV
`
`wherein R* and R¢ are as defined for general
`formula I.
`The alkoxytriazinone of the general formula
`III may be prepared by effecting reaction
`of an alkali metal alkoxide having from 1
`to 6 carbon atoms with a compound of the
`general formula II
`
`(2)
`
`xA
`
`y
`Hs
`
`|R
`
`DS
`
`wherein R? is as defined for general formula
`I, R® is a peracylglycosyl group wherein the
`acyl group has from 2 to 10 carbon atoms
`and X is an alkoxy or alkylthio group hav-
`ing from 1 to 4 carbon atoms.
`Conversion of the alkoxytriazinone or the
`alkylthiotriazinone of the general formula II
`to the 1 - glycosyl - 5 ~ azacytosine of the
`
`35
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0002
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0002
`
`

`

`1,227,691
`3
`eee
`from 1 to 6 carbon atoms, and more prefer-
`is fitted to the reaction vessel) until the start-
`ably in methanol.
`ing compound dissolves (3 minutes). The
`The conversion of the compound of the
`resulting solution is allowed to stand for 45
`general formula II to the 1 - glycosyl - 5 -
`minutes
`at
`room temperature
`after
`30
`azacytosine of
`the general
`formula I may
`minutes, the product begins to deposit} and
`be performed in one step, namely, by the
`for 12 hours in a refrigerator at —10° C.
`simultaneous action of the alkali metal alk-
`The crystals are collected with suction, washed
`oxide and of an alkanol solution of ammonia
`with methanol and dried under reduced pres-
`or an amine of the general formula IV.
`sure. A yield of 0.162 ¢ (66.4%) of 5 - aza -
`The invention will be illustrated further
`cytidine, m.p. 232—234° C (decomposition),
`by the following examples, although it is not
`is obtained,
`limited thereto,
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`5 - Azacytidine
`(1 - 8 - D - Ribofuranosyl - 4 - amino -
`1, 2 - dihydro - 1, 3,5 - triazin - 2 - one)
`
`15
`
`EXAMPLE 1
`A mixture of 1 -
`(2, 3, 5 - tri - O -
`benzoyl
`- @ ~ D ~ ribofuranosyl)
`- 4 -
`methylthic - 1, 2 - dihydro - 1, 3, 5 -
`triazin - 2 ~ one 0.5875 g), absolute methanol
`(5 ml) and a normal methanolic sodium meth-
`oxide solution (1.2 mi) is stirred at room
`temperature with the exclusion of atmospheric
`moisture (a guard tube filled with potassium
`hydroxide pellets is fitted to the reaction ves-
`sel). The starting compound passes into solu-
`tion in the course of 5 minutes. The result-
`ing solution is allowed to stand at room tem-
`perature for 45 minutes and then the cations
`are removed by passage of the solution through
`a column packed with 10 ml of a weakly
`acidic cation exchange resin in the H* form:
`prewashed with water and methanol. The
`methanolic effluent
`(60 ml)
`is evaporated
`under reduced pressure at 30° C,
`the resi-
`due is dissolved in methanol (20 ml) and the
`solution once again is evaporated. The resi-
`dual crude crystalline 1 - B - D - ribo -
`furanosyl - 4 - methoxy - 1, 2 - dihydro -
`1, 3, 5 - triazin - 2 - one is dissolved (with-
`out any additional purification)
`in a 10%
`solution of dry ammonia in absolute meth-
`anol (4 ml) and the whole reaction mixture
`is allowed to stand in a stoppered flask for
`30 minutes at room temperature (the product
`begins to deposit in the course of 5 minutes)
`and for 12 hours in a refrigerator at —10°
`GC. The resulting 5 - azacytidine is collected
`with suction, washed with methanol and dried’
`under reduced pressure. A yield of 0.216 ¢
`(88.6%) of 5 - azacytidine, m.p. 232—234°
`C (decomposition), is obtained.
`
`EXAMPLE 2
`A mixture of 1 - 2, 3, 5 - tri - O -
`benzoyl - 8 - D - ribofuranosyl) . 4 - methyl -
`thio - 1, 2 - dihydro - 1, 3, 5 - triazin -
`2 - one (0.5875 g), a 10% solution of dry
`ammonia in methanol 4 ml} and a normal
`methanolic sodium methoxide solution (1.2
`ml) is stirred at room temperature with the
`exclusion ot atmospheric moisture (a guard
`tube filled with potassium hydroxide pellets
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`EXAMPLE 3
`A mixture of 1 - (2, 3,5 - ti -O ~
`benzoyl
`- @ ~ D -
`ribofuranosyl)
`- 4 -
`methoxy - 1, 2 - dihydro - 1, 3, 5 - triazin -
`2 ~ one (0.5715 g), absolute methanol (5 ml)
`and a normal methanolic sodium methoxide
`solution (1 ml) is stirred at room temperature
`with the exclusion of atmospheric moisture
`(a guard tubefilled with potassium hydroxide
`pellets is fitted to the reaction vessel) until
`the starting compound dissolves (5 minutes),
`and the resulting solution is allowed to stand
`for ene hour at room temperature and then
`is processed as in Example 1. A yield of
`0.219 g (89.7%) of 5 - azacytidine, mp.
`232—~234° C (decomposition), is obtained.
`
`EXAMPLE 4
`A mixture of 1 - (2, 3, 5 - tri - O-
`benzoyl - 8 - D- ribofuranosyl) - 4 - meth -
`oxy - 1, 2 - dihydro - 1, 3, 5 - triazin - 2 -
`one (0.5715 g), at 10% solution of dry
`ammonia in methanol (4 ml) and a normal
`methanolic sodium methoxide solution (1 ml)
`is stirred at room temperature with the exclu-
`sion of atmospheric moisture (a guard tube
`filled with potassium hydroxide pellets is
`fitted to the reaction vessel) until the starting
`compound dissolves (5 minutes), Work-up of
`the resulting solution is performed as in Ex-
`ample 2. A yield of 0.174 g (71.3%) of 5 -
`azacytidine, m.p. 232—234° C (decomposi-
`tion),
`is obtained.
`
`5 - Aza.- 2’ - deoxycytidine
`1 - 2 ~ Deoxy - 8 - D - ribofuranosyl) -
`4 - amino - 1, 2 - dihydro - 1, 3, 5 -
`triazine . 2 - one
`
`EXAMPLE 5
`A mixture of 1 - 3,5 - di- O- p-
`toluyl - 2 - deoxy - 8 - D - ribofuranosyl) -
`4 - methylthio - 1, 2 - dihydro - 1, 3, 5 -
`triazin - 2 - one (0.4956 g), absolute meth-
`anol (10 ml) and a normal methanolic sodium
`methoxide solution (1.2 ml) is stirred mag-
`netically at room temperature with the exclu-
`sion of atmospheric moisture (a guard tube
`filled with potassium hydroxide pellets is fit-
`ted to the reaction vessel) for 2 hours and:
`45 minutes (after 2 hours, the starting com-
`pound dissolves), The cations are then re-
`moved by passing the resulting solution
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`120
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0003
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0003
`
`

`

`-
`
`1 - B - D - Ribofuranosyl - 4 - methoxy -
`1, 2 - dihydro - 1, 3, 5 - triazine - 2 - one
`
`EXAMPLE 9
`A mixture of 1 - (2, 3, 5 - ti - O -
`benzoy! - 8 - D - ribofuranosyl) - 4 - methyl -
`thio - 1, 2 - dihydro - 1, 3, 5 - triazine - 2 -
`one (0.5875 g), absolute methanol (5 mil) and
`a normal methanolic sodium methoxide solu-
`tion (1.2 ml) is stirred at room temperature
`with the exclusion of atmospheric moisture
`(a guard tube filled with potassium hydroxide
`pellets is fitted to the reaction vessel) until
`the starting compound dissolves (5 minutes).
`The resulting solution is allowed to stand at
`room temperature for an additional 40 minutes
`and is processed as described in Example 1.
`The crude crystalline product is recrystallised
`from absolute methanol. A yield of 0.210 g
`(81%) of 1 - 6 - D- ribofuranosyl - 4 -
`methoxy - 1, 2 - dihydro - 1, 3, 5 - triazin -
`2 - one, mp. 177—179° C,
`is obtained.
`1 - 8 - D - Ribofuranosyl - 4 - methylamino-
`1, 2 - dihydro - 1, 3, 5 - triazin - 2 - one
`
`EXAMPLE 10
`A mixture of 1 - 8 - D - ribofuranosyl - 4 -
`methoxy - 1, 2 - dihydro - 1, 3, 5 - triazin -
`2 - one (0.259 g) and a 7% solution of dry
`methylamine in absolute methanol (2 mi) is
`stirred at room temperature with the exclu-
`sion of atmospheric moisture (a guard tube
`filled with potassium hydroxide pellets is
`fitted to the reaction vessel) for 5 minutes,
`kept at room temperature for an additional 10
`minutes and finally in a refrigerator at —10°
`C for 15 minutes. The crystals are collected
`with suction, washed with ice-cool methanol
`and dried under reduced pressure. A yield of
`0.210 g (81.4%) of 1 - B- D- ribofuranosyl-
`4. methylamine - 1, 2 - dihydro- 1,3,5-
`triazine - 2 - one, m.p. 148—150° C.,
`is
`obtained.
`
`4
`
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`ib)
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`1,227,691
`.
`-
`4 ~ methoxy - 1, 2 - dihydro - 1, 3, 5 -
`through a column of a weakly acidic cation
`triazine - 2 - one (0.4796 g) a 10% solution
`exchange resin (10 ml) in the H* form (pre-
`of dry ammonia in methanol (4 ml) and a
`washed with water and methanol). The meth-
`normal methanolic sedium methoxide solu-
`anolic effluent
`is evaporated under reduced
`tion (1.0 ml) is stirred magnetically at room
`pressure at 30° C, the residue is dissolved in
`temperature with the exclusion of atmospheric
`methanol (10 ml) and the solution once more
`moisture (a guard tube filled with potassium
`is evaporated. The resulting crude viscous 1 -
`70
`hydroxide pellets is fitted to the reaction ves-
`(2 - deoxy - & - D- tibofuranosyl) -4-
`sel) until the starting compound dissolves (45
`methoxy - 1, 2 - dihydro - 1, 3, 5 - tri -
`minutes). The reaction mixture then is pro-
`azine - 2 - one is dissolved in a 10% solu-
`cessed as described in Example 6. A yield
`tion of dry ammonia in methanol (2 ml) and
`of 0.120 g (52.7%) of 5 - aza - 2’ - deoxy -
`the resu'jing reaction mixture is allowed to
`cytidine, m.p. 198—199° C (resolidification),
`stand in a stoppered flask for 30 minutes at
`is obtained.
`room temperature (after 15 minutes, the cry-
`stalline product begins to separate) and for
`12
`hours
`in
`a
`fegrigerator
`at —10°
`C. The
`crystals
`are
`collected, washed
`with methanol and dried under reduced pres-
`sure. A yield of 0.180 g (79%) of 5 - aza -
`2’ . deoxycytidine, m.p. 196—198° C (resoli-
`dification),
`is obtained.
`
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`EXAMPLE 6
`A mixture of 1 - 3, 5 - di- O- p-
`toluyl - 2 - deoxy - 8 - D - ribofuranosyl) -
`4 - methylthio
`- 1, 2 - dihydro - 1, 3,5 -
`triazine - 2 - one (0.4956 g), a 10% solu-
`tion of dry ammonia in methanol (4 ml) and
`a normal methanolic sodium methoxide solu-
`tion (1.2 ml) is stirred magnetically at room
`temperature with the exclusion of atmospheric
`moisture (a guard tubefilled with potassium
`hydroxide pellets is fitted to the reaction ves-
`sel) until the starting compound dissolves (45
`minutes). The resulting solution is allowed to
`stand at room temperature for 1 hour (dur-
`ing this period of time, the crystalline product
`begins to separate) and then in a refrigerator
`at —10° for an additional 12 hours. The
`crystals are collected with suction, washed
`with methanol and dried under reduced pres-
`sure. A yield of 0.132 g (58%) of 5 - aza -
`2’ - deoxycytidine, m.p. 198—199° C(resoli-
`dification), is obtained.
`
`EXAMPLE 7
`A mixture of 1 - G,5-di- O-p-
`toluyl - 2 ~ deoxy - 8 - D - ribofuranosyl) -
`4 - methoxy - 1, 2 - dihydro - 1, 3,5 -
`triazine - 2 - one (0.4796 g), absolute meth-
`anol (10 ml) and a normal methanolic sodium
`methoxide solution (1 ml) is stirred magnetic-
`ally at room temperautre with the exclusion
`of atmospheric moisture (a guard tube filled
`with potassium hydroxide pellets is fitted to
`the reaction vessel) until
`the starting com-
`pound dissolves (45 minutes). The reaction
`mixture then is processed as described in
`Example 6. A yield of 0.120 g (52.7%) of
`5 ~ azo - 2’ - deoxycytidine, m.p. 198—199°
`C (resolidification),
`is obtained.
`EXAMPLE 8
`A mixture of 1 - 3,5 - di- O- p-
`toluyl - 2 - deoxy - B - D - ribofuranosyl -
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`60
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`1 - @ - D - Ribofuranosyl - 4 - dimethy! -
`amino - 1, 2 - dihydro - 1, 3, 5 - triazine -
`2 - one
`
`120
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0004
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0004
`
`

`

`1,227,691
`
`
`
`EXAMPLE 11
`A mixture of 1 - @ - D - ribofuranosyl - 4 -
`methoxy - 1, 2 - dihydro - 1, 3, 5 - triazin -
`2 - one (0.259 g) and a 7% solution of dry
`dimethylamine in absolute methanol (2 ml) is
`stirred at room temperature with the exclusion
`of atmospheric moisture (potassium hydroxide
`guard tube) for 5 minutes, kept at the same
`temperature for additional 15 minutes and
`evaporated under reduced pressure at 30° C.
`The residue is ccevaporated with absolute
`methanol
`(5 ml) and finally dissolved in
`absolute ethanol (1 ml). The solution is cooled
`and stirred with a sharp edged rod to deposit
`crystals which are kept in a refrigerator at
`10° C overnight, collected with suction,
`washed with ethanol and dried under reduced
`pressure. A yield of 0.216 g (79.4%) of
`1. 8 -D - ribofuranosyl - 4 - dimethyl -
`amine - 1, 2 - dihydro - 1, 3, 5 - triazin -
`2 - one, m.p. 128—130° C, is obtained.
`
`WHAT WE CLAIM IS:—
`1. A process for preparing 1 - glycosyl -
`5 - azacytosine of the general formula I
`
`2. A process as claimed in claim 1, wherein
`the alkoxytriazinone of the general formula
`III is prepared by effecting reaction of an
`alkali metal alkoxide having from 1
`to 6
`carbon atoms with a compound ofthe general
`formula IT
`
`(2)
`
`bs
`wherein R? is as defined for general formula
`I, R® is a per-acylglycosyl group wherein the
`acyl grouphas from 2 to 10 carbon atoms and
`X is an alkoxy or alkylthio group having from
`1 to 4 carbon atoms.
`3. A process for the preparation of a 1 -
`glycosyl - 5 - azacytosine of the general for-
`mula I defined in claim 1, comprising effect-
`ing reaction of a compound of the general
`formula II
`
`(1)
`
`©)
`
`45
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`5
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`10
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`25
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`30
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`35
`
`wherein R* designates a glycosyl residue, R?
`designates a hydrogen atom or an alkyl group
`having from 1 to 4 carbon atoms and R?
`and R*, which are identical or different, desig-
`nate hydrogen atoms, alkyl groups having from
`1 to 4 carbon atomsor aralkyl groups having
`from 7 to 10 carbon atoms, comprising effect-
`ing reaction of a 1 - glycosyl - 4 - alkoxy -
`1, 2 - dihydro - 1, 3, 5 - triazin - 2 - one
`of the general formula ITI
`
`(3)
`
`wherein R* and R? are as defined for general
`formula I and R* is an alkyl grouphaving
`from 1 to 6 carbon atoms, with ammonia or
`am amine of the general formula IV
`
`40
`
`R’—NH—R!*
`
`IV
`
`wherein R® and R* are as defined for general
`formula JI,
`
`wherein R?is as defined in claim 1 for general
`formula I, R* designates a per-acylglycosyl
`residue wherein the acyl group has from 2 to
`10 carbon atoms and X designates an alkoxy
`or alkylthio group having from 1 to 4 carbon
`atoms, with an alkali metal alkoxide having
`from 1 to 6 carbon atoms, thus effecting the
`formation of a 1 - glycosyl - 4 - alkoxy -
`1, 2 ~ dihydro - 1, 3, 5 - triazin - 2 - one
`of the general formula III
`
`(3)
`
`wherein R* and R? are as defined in claim 1
`for general formula I and R® designates an
`alkyl group having from 1 to 6 carbon atoms,
`and effecting reaction of the alkoxytriazinone
`of the general formula IIE with ammonia or
`an amine of the general formula formula IV
`
`R°—NH—R*
`
`IV
`
`wherein R* and R‘ are as defined in claim 1
`for general formula I.
`4. A process as claimed in Claim 2 or
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0005
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0005
`
`

`

`6
`
`5
`
`10
`
`25
`
`30
`
`1,227,691
`in the absence of atmospheric
`claim 3 wherein the reaction between the
`carried out
`- compound of general formula TI and the alkali moisture.
`metal alkoxide is carried out in a medium
`11. A process as claimed in any one of
`of an alkanol having from 1 to 6 carbon
`claims 2, 3 and 4, or in any one of the claims
`atoms.
`5 to 10 as as appendant to any one of the
`5. A process as claimed in any one of
`claims 2, 3 and 4, wherein conversion of the
`claims 1 to 4 wherein the reaction of the
`compound of general formula II to the 1 -
`alkoxytriazinone of general formula III with
`glycosyl - 5 - azacytosine of general formula
`the ammonia cr amine of general formula IV I is carried out in one step by the simulta-
`is carried out
`in a medium of an alkanol
`neous action of the alkali metal alkoxide and
`having from 1 to 6 carbon atoms.
`an alkanol solution of the ammonia or amine
`6. A process as claimed in claim 4 or
`of general formula IV.
`claim 5, wherein the alkanol is methanol.
`12. A process for preparing a 1 - glycosyl -
`7. A process as claimed in any one of claims
`5 - azacytosine according to claim 1, substan-
`15 2, 3 and 4 or
`in claim 5 or claim 6 as
`tially as hereinbefore described.
`appendant to any one of claims 2, 3 and 4,
`13. A process for preparing a 1 - glycosyl -
`wherein in the compound of general formula
`5 - azacytosine according to claim 3, substan-
`II X is an alkylthio group and the molar
`tially as hereinbefore described.
`ratio of the compoundof the general formula
`14. A process for the preparation of al -
`20 Il to the alkali metal alkoxide is 1:1.2.
`glycosyl - 5 - azacytosine as described in any
`8. A process as claimed in any one of the
`one of the Examples 1 to 9.
`preceding claims, wherein the reaction of the
`15. A process for the preparation of a 1 -
`alkoxytriazinone of general formula III with
`glycosyl - 5 - azacytosine according to Ex-
`the ammonia or amine of general formula IV ample 10 or Example 11.
`is performed at room temperature.
`16. A 1 - glycosyl - 5 - azacytosine when-
`9, A process as claimed in any one of
`ever prepared by the process claimed in any
`claims 2, 3 and 4, or in any one of claims
`one of Claims 1 to 15.
`5 to 8 as appendant to any one of claims 2,
`3 and 4, wherein the reaction of the compound
`FITZPATRICKS,
`of
`the general formula II with the alkali
`Chartered Patent Agents,
`metal alkoxide is carried out at room tem-
`14-18 Cadogan Street,
`perature.
`Glasgow, C.2.
`10. A process as claimed in claim 9, where-
`and
`in the reaction of the compound of the general
`27 Chancery Lane,
`
`35 London, WC2A INF.eeeeeeformula II with the alkali metal alkoxide is
`Printed for Her Majesty’s Stationery Office, by the Courier Press, Leamington Spa, 1971.
`Published by The Patent Office, 25 Southampton Buildings, London, WCYA LAY, from
`which copies may be obtained.
`
`
`
`6
`
`40
`
`45
`
`50
`
`55
`
`60
`
`-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0006
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1025-0006
`
`