DE2748562A1 - 5-FLUORURACIL DERIVATIVES AND PROCESS FOR THE PREPARATION - Google Patents

Description

The present invention relates to a new class of 5-fluorouracil derivatives which contain a glycoside residue and a method for their production.

Certain 5-fluorouraci1 derivatives are known to be anti-tumor agents. For example, the 5-fluorouracil itself (hereinafter referred to as ^M 5-FU ") and the N_ - (2-tetrahydrofuryl) -5-fluorouracil (hereinafter referred to as ^M FT-2O7") should have good anti-tumor activity [R . Duschinksy et al., J. Amer. Chem. Soc. 79_, 4559 (1957) and SA Hiller et al., Dokl. Akad. Nauk. (USSR), 176 "332 (1967)]. There is, however, a need for an agent with as good or better anti-tumor activity than that of the 5-Fü and FT-207, but which has fewer side effects and lower toxicity.

The 5-fluorouracil derivatives of the present invention are compounds of the general formula (I):

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wherein one of the radicals R and R is a hydrogen atom or a hydroxyl protecting group, which can be removed by reduction, and the other is a glycoside residue selected from '

ROJCK?

HR ³

H R3

represents where

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R is selected from hydrogen atoms and acyl groups,

R is selected from groups of the formula -OR (where R is as is defined above), amino groups and protected amino groups; and

R ^{4 is} selected from hydroxyl groups, alkoxy groups, cycloalkoxy groups, aralkoxy groups, aryloxy groups and amino groups of the formula

(in which R and R, which can be the same or different, are each selected from hydrogen atoms, alkyl groups, Cycloalkyl groups, aralkyl groups and aryl groups or R and R together with the nitrogen atom to which they are bonded, a 5- to 7-membered cyclic amino group);

and when R represents an amino group, its pharmaceutical acceptable acid addition salts.

The 5-fluorouracil derivatives of formula (I) can be prepared by adding a compound of formula (II):

(ID

V 8

[wherein one of R and R is a metal ion (as will be explained in more detail below) and the other is a hydroxy-protecting group mean, which is generally the same hydroxy protecting group as that, if desired should be present in the product of formula (I)] with a compound of formula (III):

R ⁹ - X (III)

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[where X is a halogen atom, for example chlorine or bromine, and R ^{9 is} a glycoside radical selected from the group

and

means in which

R * denotes an acyl group and is generally the same Represents acyl group as represented by R in formula (I);

R is selected from groups of the formula -OR * (in which R ^{1 is} as defined above) or represents a protected amino group and generally represents the same protected amino group as defined by R in the product of the formula (I), and

4 ' R is selected from alkoxy groups, cycloalkoxy groups, Aralkoxy groups, aryloxy groups and amino groups, and generally the same such group as them

illustrated by R in the product of formula (I)]

converts to a compound of formula (IV):

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(IV)

(in which one of the radicals R ¹⁰ and R ^{1 is} a hydroxy protecting group and the other is the group R defined above), and optionally subjecting the compound of the formula (IV) to reduction and / or hydrolysis in any order to give the desired To obtain fluorouracil derivative of formula (I).

In the compounds of the above formula (I), preferred include Examples of hydroxy protecting groups that can be achieved by the

1 2
Group R or R can be illustrated: Benzyl groups, which can be unsubstituted or whose phenyl moiety can be substituted by one or more nitro groups and / or halogen atoms, e.g. benzyl itself, o-nitrobenzyl, m-nitrobenzyl, p-nitrobenzyl, o-rchlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, o-fluorobenzyl, m-fluorobenzyl or p-fluorobenzyl; and ß-haloethyl groups, for example 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2,2-dichloroethyl or 2,2-dibromoethyl.

If the group R is an acyl group, it is preferably an aliphatic acyl group having 2 to 4 carbon atoms (e.g. acetyl, n-propionyl, n-butyryl or isobutyryl) or an aromatic acyl group having 7 to 11 carbon atoms (e.g. benzoyl, p-nitrobenzoyl, p-methylbenzoyl, p-methoxybenzoyl or naphthoyl).

When R is a protected amino group, it is preferred that the protecting group can be easily removed by reduction. Such protecting groups include, for example: benzyloxycarbonyl groups, which may be unsubstituted, or their phenyl moiety

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may contain one or more nitro and / or halogen substituents, e.g. benzyloxycarbonyl, o-nitrobenzyloxycarbonyl, m-Ni trobenzyloxycarbonyl, p-lti trobenzyloxycarbony 1, o-chlorobenzyloxycarbonyl, m-chlorobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, m-bromobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, o-pluorbenzyloxycarbonyl, m-fluorobenzyloxycarbonyl or p-fluorobenzyloxycarbonyl, or a β-haloethoxycarbonyl group, e.g., 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2,2-dibroraethoxycarbonyl or 2,2-dichloroethoxycarbonyl.

R preferably denotes a hydroxyl group, a straight-chain or branched alkoxy group with 1 to β carbon atoms, e.g. Methoxy, xthoxy, n-propoxy, xsopropoxy, n-butoxy, isobutoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, sec-hexyloxy, n-heptyloxy, n-octyloxy or 2-xthylhexyloxy; a cycloalkoxy group having 5 to 7 ring carbon atoms, for example cyclopentyloxy, cyclohexyloxy or cycloheptyloxy; an aralkoxy group with 7 to 12 carbon atoms, the aromatic ring of which can be unsubstituted or one or more C.-C ^ -alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl), C ^ -C ^ - Alkoxy groups (for example methoxy, xthoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy) or halogen atoms (for example chlorine, bromine or fluorine) as substituents, such as benzyloxy or phenethyloxy; or an aryloxy group with 6 to 10 carbon atoms, the aromatic ring of which can be unsubstituted, or one or more C ₁ -C ₄ -alkyl groups (for example methyl, ethyl, n-propyl, isopropyl, η-butyl or isobutyl), C ^ -C ^ Alkoxy groups (for example methoxy, xthoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy) or halogen atoms (for example chlorine, bromine or fluorine) as substituents, such as phenyloxy. ·

R is a substituted or unsubstituted amino group of the formula

R ⁵

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5 6 1 (>

so R and R are identical or different and preferably each mean: a hydrogen atom, a straight-chain or branched alkyl group with 1 to 5 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, n-pentyl or isopentyl; a cycloalkyl group with 5 to 7 ring carbon atoms, e.g., cyclopentyl, cyclohexyl or cycloheptyl; an aralkyl group with 7 to 12 carbon atoms, e.g. benzyl or phenethyl, the aromatic ring of which is unsubstituted may be or one or more C 1 -C 4 alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl), Cj-C.-alkoxy groups (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy) or halogen atoms (e.g. chlorine, bromine or fluorine) as substituents can; an aryl group having 6 to 10 carbon atoms, e.g. phenyl, the aromatic ring of which may be unsubstituted or one or more Cj - ^ - alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, η-butyl or isobutyl), C 1-4 alkoxy groups (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy) or halogen atoms (e.g. chlorine, bromine or Fluorine) may contain as substituents; or R and R together with the nitrogen atom to which they are attached can form a cyclic amino group with 5 or 6 ring atoms, e.g. a 1-pyrrolidinyl, piperidino or morpholino group.

Preferred examples of compounds of the present invention are given below; the connections in the following list assigned digits are used to subsequently identify these connections.

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1. 1 - ^ - (5-FIuOr - 1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronic acid · '. ■ ■

2. Methyl-1-0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -ß-D-gluco-

pyranuronate.

3. Ethyl-1-a- (5-fluoro-1H-2-oxopyrimidin-4-yl) -ß-D-6luco-

pyranuronate

4. nr-Propyl-1-O- (5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D _r sl ^uc ° - pyranuronate '.

5. Isopropyl 1 - & - (5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronate

6. n-Butyl-1-Ö- (5-fluoro- ^/ IH-2-oxopyrimidin-4-yi) -ß-D-gluco-

pyranuronate

7. Isobutyl 1-0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronate

8. n-Pentyl-1-0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronate :

9. n-Hexyl-1-0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronate . . ·

10. n-heptyl-1-0- (5-fluorine -1H-2-oxopyrimidin-4-yl) -ß-D _r gluco-

pyranuronate
11 n-octyl-1-O- (5-fluorine -1H-2-oxopyrimidin-4 ~ yl) -ß-D-gluco-

pyranuronate

12. 1-0- (5-Pluoro -1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronamide

13. H, N-dimethyl-1-0- (5-fluoro -1H-2-oxopyrimidin-4-yl) -β-D- glucopyranuronamide

W, H-diethyl-i ~ O- (5-fluoro 1H-2-oxopyrimidin-4-yl) -β-D- glucopyranuronamide

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N-n-Propyl-1-C) - (5-fluoro-ig - ^ - oxopyrimidin - ^ - yl) -ß-D-glucopyranuronamide

16.. N-isopropyl-1- £ - (5-fluoro- ^/ 1H-2-oxopyriiridin-4-yl) -ß-D-gluco-

pyranuronamide.

17.N ~ n-Butyl-1-0 _- (5-fluoro-1H-2-oxopyrimidin-4-yl) -ß-D-gluco-

pyranuronamide

18. If-Isobuty 1-1 - £ - (5 »fluoro - 1H-2-oxopyrimidin-4-yl) -β - ^ - elucopyranuronamide

19. N-n-Pentyl-1-O- (5-fluoro-1H-2-oxopyrimidiii-4-yl) -β-D-glucopyranuronamide

20. N-Benzyl-1 -O- (5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronamide

21. 1 ~ [1-0, - (5-FIuOr - 1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronylI-pyrrolidine .

22. 1- [1-0- (5-FIuOr -1H-2-oxopyrimidin-4-yl) -β-D-gluco-. pyranuronyl] piperidine

2Y. 4- [iO _r (5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronylmorpholine

24. Methyl-1-0 _> - (2-benzyloxy-5-fluoropyrimidin-A'-yl) -2,3,4-tri- ^ -0.-acetyl-β-] D-glucopyranuronate.

25. Ethyl 1-p_ - (2-benzyloxy-5-fluoropyrimidin-4 ~ yl) -2,3,4-tri-O ^ -acetyl-β-D ^ -glucopyranuronate

26.Isopropyl-1- £ - (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4- -tri-ö-acetyl-ß-D-glucopyranuronate

27. N-methyl-1-p _- (2-benzyloxy-5 - fluoropyrimidin - 4-yl) -2,3,4- -O-acetyl-ß -D-glucopyranuronamide

28. lO _r (5-fluoro-lH _r 4-oxopyrimidin-2-yl) -ß-D _r glucopyran-

uronic acid

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Λ-

29. Methyl 1-0- (5-fl ^ or-1H-4-oxopyrimidin-2-yl) -β-D _r glucopyranuronate

30. Ethyl 1-0- (5-fluoro -1H-4-oxopyrimidin-2-yl) -β-D-glucopyranuronate

31. n-Prppyl-1-0- (5-fluorine - 1H-4-oxopyrimidin-2-yl) -β-D-glucopyrazmronate -

32. Isopropyl 1-0- (5-fluoro-1H-4-oxppyrimidin-2-yl) -β-D7-glucopyranuronate

33. n-Butyl-1-O- (5-fluoro-1H- ^z l-oxopyrimidin-2-yl) -β-D-glucopyramironate

34. Isobutyl 1-0- (5-fluoro-1H-4-oxopyrimidin-2-yl) ~ β-B-glucopyranuronate

35. n-Pentyl-1 -O- (5-fluoro-1H _r 4-oxopyrimidin-2-yi) -ß -D-glucopyranuronate '

36. n-Hexyl-1-0- (5-fluorine- ^/ ! Η-4-οχορ3ΤΓίπάάϊη-2 ^ 1) -β-Β-ε1ηοο-pyraziuronat

37. n-Heptyl - ^ - O- (5-fluoro-1H-4-oxopyrimidin-2-yl) j-ß-D-glucopyraimronate '

38. n-Octyl-i-O.-C 5-fluorine - 1H-4-oxopyrimidin-2-yl) -ß-3) -gluco-

pyranuronate 39. l-0 ^ (S-Pluor-lH-A-oxopyrimidin-a-yl) -ß-D _r glucopyran-

uronamide

AO. N, N-Dimethyl-1-O _r (5-fltior-1E-4-oxopyrimidin-2-yl) -β-D-glucopyranxironamide

41. N _l N-diethyl-1-0- (5-fluoro-1H-4-oxopyrimidin-2-yl) -beta-D-glucopyranuronamid

42. Nn-Propyl-1- <M 5-fluoro-1H-4-oxopyrimidin-2-yl) -β-D _r glucopyranuronamide "~

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43. N-Isopropyl-1-0 _- (5-fluoro-1H-4-oxopyrimidin-2-yl) -β-D-glucopyranuronamide

44. N-n-Butyl-1-0- (5-fl-uor-1H-4-oxopyrimidin-2-yl) -β-I) -glucopyranuronamide

45. N-Isobutyl-1-p _- (5-fluoro-1H-4-oxopyrimidin-2-yl) -β-1) -glucopyranuronamide

46. N- n -pentyl-1-p_- (5-fluoro-1H-4-oxopyrimidin-2-yl) -β-D-glucopyranuronamide

47. N-Benzyl-1-0 _- (5-fluoro-1H-4-oxopyrimidin-2-yl) -β-D-glucopyranuronamide

48. 1 - [1 -0- (5-Fluoro-iH-4-oxopyrimidin-2-yl) -β-D-glucopyran uronyl] -pyrrolidine

49. 1- [1-0- (5-Fluor-1H-4-oxopyrimidin-2-yl) -β-D-glucopyranuronyl] piperidine

50. 4- [i-0- (5-fluoro-1H-4-oxopyrimidin-2-yl) -β-D-glucopyranuronyl I-morpholine

51. Methyl-1-0- (4-benzyloxy-5-fluoropyrimidin-2-yl) -2,3,4-tri- - ^ - acetyl-ß-D-glucopyranuronate

52. Xfchyl-1-0- (4-benzyloxy-5-fluoropyrimidin-2-yl) -2,3,4-tri- -O-acetyl-ß-D-glucopyranuronate

53. N-Methyl-1-0- (4-benzyloxy-5-fluoropyriiaidin-2-yl) -β-jD-glucopyranuronamide

5 ^. N-ethyl-1- £ - (4-benzyloxy-5-fluoropyrimidin-2-yl) - ß - ^ -

glucopyranuronamide

55 · P_ - (β-D-glucopyranosyl) -5-fluorouracil ο ~~

56. Ο. - (β-D-galactopyranosyl) -5-fluorouracil

57.0 - (β-D-ribopyranosyl) -5-fluorouracil

2 "~

58. £ - (ß-lD-XylopyranosyD-S-fXuoruracil

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-Ji

59. O ^it - (β-D _r glucopyranosyl) -5-fluorouracil

60. p_ ^{i |} '- (β-D _r Galafctopyranosyl) -5-fluorouracil

61.0 * - (β-D-ribopyranosyl) -5-fluorouracil

62. 0 ^ - (ß-B-xylopyranosyl) -5-fluo2? Uracil

ο ~~ "4

63. 0 - (2,3, ^, e-Tetra-O-acetyl-ß-D-glucopyraiiooylj-O -benzyl-5-

-fluoruracil

64. O - (2,3,4, e-Tetra-O.-acetyl-ß-B-glucopyranosyl) -O -benzyl-5-

-fluoruracil

H. P.

65.0 - (2,3,4,6-Tetra-O-acetyl-ß-D-glucopyranosyl) -O _- -benzyl-5-

-fluoruracil

66. 1-O- (5-PlTior-1H-2-oxopyrimidin-4-yl) -β-D-salaktopyranuro]>. acid

6 ?. ^{Methyl- /} IO- (5-fluoro - 1H-2-oxopyrimidin-4-yl) -ß-D-galactopyranuronate -

68. Xthyl-1-O- (5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D-galakfcopyranuronate

69. n-Propyl-1-0- (5-fluoro - • IH ^ -oxopyrimidin - ^ - yl) -ß-B-galactopyranuronate

70. Isopropyl 1-p _- (5-fluoro - ^/ IH-2-oxopyrimidin-4-yl) -β-D-galactopyranuronate

7iJ. n -Butyl 1-0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D-galactopyranuronate

72. Isobutyl 1-0- (5-fluoro-1H-2-O3-copyrimidin-4-yl) -β-B-galactopyranuronate

73.1-0 _- (5 - Pluoro - 1H-4-oxopyrimidin-2-yl) -ß - ^ - galactopyranuronic acid

74. Methyl 1-0- (5-fluoro-1Hr4-oxopyrimidin-2-yl) -β-D-galactopyranuronate

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75. Ethyl-1-0 .- (5-fluoi-1H-4-qxopyrimidin-2-yl) -β-D-galactopyranuronate

76. n-Propyl-1-0 .- (5-fluoro 1H-4-oxopyrimidin-2-yl) -β-D-ga ^ kfcopyranuronate

77. Isopropyl-iOC ^ -fluoro-1H _r 4-oxop_yrimidin-2-yl) -β- -D-galactopyranuronate

78. n-Butyl-1-0 .- (5-fluoro-1H-4-oxopyrimidin-2-yl) -β-D-galak-fcopyranioronate

79 .. Isobutyl-1-0 .- (5-fluoro-1H-4-oxopyrimidin-2-yl) -β-D-galactopyranuronate

80. Methyl-1-0 _- (2-benzyloxy-5- fluoropyrimidin-4-yl) -2 ~, 3,4-tri-0_-acetyl-ß-D-galaktopyranuronat

81. Ethyl 1-O _r (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4- -tri-O-acetyl-β-D-galactopyranuronate

82. p_ - (2-Amino-2-c3esoxy-β-D-glucopyranosyl) -5-fluorouracil.

83. O - (2-Amino-2-desoKy-ß-D-galactopyranosyl) -5-fluorouracil

H '

84. p_ - (2-Amino-2-ktesoxy-β-D-ribopyranosyl) -5-fluorouracil

85. O - (2-Araino-2-deoxy-β-D-xylopyranosyl) -5-fluorouracil

86. O _- - (2-Amino-2-deoxy-β-] D-gluopyranosyl) -5-fluorouracil

2 ·

87. () - (2-Amino-2-deoxy-β-D _r galaktopyranosyl) -5-fluorouracil

88. £ - (2-Amino-2-deoxy-β-D-ribopyranosyl) -5-fluorouracil

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-J *

89.0 ² - (2-Amino-2-deoxy-β-B-X3rlopyranosyl) -5-fluoro uracil

90. 1-0- (5-fluorine -1H-2-oxopyrimiaine - ^ - ylO-2-amino-2-deoxyß -D-glucopyramironsätire.

91. i_o_ (5-. Piuor-1H-4-oxopyrimidin-2-yl) -2-amino-2-desoocy ^β- srglucopyranuronic acid

92. 1-O- (5-fluoro -1H-2-oxopyximidinr-4-yl) -2-amino-2'-deoxyβ -JD-galactopyramirön acid

93. 1 - <) - (5-FIuOr TiH-4-oxopyrimidin-2-yl) -2-amino-2-deoxyß-jD-galalctopyranuronic acid

O ^ -C? , 4 ₎ 6-tri-O-acetyl-2- <tescDcy-2-trichloroethiioxycar "boiiylaiBin: o-ß-D-glucopyranosyl) -5-fluorouracil

95. 0 ² benzyl-0 - (3,4,6-tri-O _r acetyl-2-desoocy-2-tri "Sthoxy bromo-carbonylamino-ß-D ^ glucopyranosyl) -5-i luorur aci 1

96. Op-Benzyl-O ^ -C 3,4, e-tri-O-acetyl ^ -deoxyHS-1-benzyloxycarbonylamino-β-D _r glucopyranosyl) -5 - luoruracil

97. O ^ O ^-benzyl-2 - (3,4,6-tri-0-acetyl-2-deoxy-2-trichloro Sthoxycarbonylajnino-ß-DrBl ^uco Py ^r aiiosyl.) -5-f 1 luoruraci

98. of-Benzyl-Op-0,4,6-tri-0-acetyl-2- € lesoxy-2 -benzyloxycarbonylamino-β-D-glucopyranosyl) -5-fluorouracil

99. O - (3, ^, G-Tri- ^ acetyl ^ -amino- ^ esoxy- p-D-gluco-

pyranosyl) -5-iluoruiraci 1

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100.0 - (3,4,6-Tri-p-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil

101. Methyl-1-0 _- (2-benzyloxy-5 - fluoropyrimidin-4-yl) -

-β-D-glucopyranuronate

102. 1-O ~ - (2-Benzyloxy -5 - fluoropyrimidin -4-yl) - ß-

- I) - glucopyranuronic acid

103. Methyl 1 -O ₁ - (5-fluoro-IH, -2-oxopyriinidin-4-yl) -2,3,4-tri-0-acetyl-β-D_ -glucopyranuronate

104. Isopropyl-l-p _- (2-t> enzyloxy-5 - fluoropyrimidin-4-yl) - -ß-D - glucopyranuronate

105. Isopentyl-l-p_ - (5-fluoro-lH-2-oxopyrimidin-4-yl) -ß- -B- glucopyranuronate.

106. Cyclohexyl-1-O- (5-fluoro -IH -2-oxopyrimidin-4-yl) -β-D - glucopyranuronate ■

107. N - methyl - 1-0. - (2- ^< benzyloxy-5-fluoropyrimidin-4-yl) - -β- JD - glucopyranuronamide

108. N - methyl-1-2 - (5 - fluoro-1H -2-oxopyrimidin-4 ~ yl) - -ß-D - glucopyranuronamide

109. p_ - (2,3,4,6 - Tetra -O- acetyl-ß-D - glucopyranosyl) - -5-fluorouraci1

110. Q - (2,3,4,6 - Tetra -0, - acetyl - ß-D - glucopyranosy]>

-5-f luor ur ad 1

2 4

111. p_ - Benzyl - 0 - (β-D-glucopyranosyl) -5-fluorouracEL

112. Methyl-1-0 - (4-benzyloxy -5-fluoropyrimidin-2-yl) _ß_ p_ _ glucopyranuronate

113. 1-0- (4-Benzyloxy -5-fluoropyrimidin-2-yl) -β- ^ glucopyranuron acid

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" ⁴ ^ S 2748552,

Methyl-1-0- (5-fluoro-1H-4-oxopyrimidin-2-ylJ-23,4- -tri-O-acetyl ~ ß-D -glucopyranuronate

115. N-methyl-1- 0- (5-fluoro-IB- ^ - oxopyrimidin ^ -yl) -P-D - glucopyrax uronamide

116. Methyl-l-O- (2-benzyloxy-5 - fluoropyrimidin-4-yl) -ß- * -D - galalctopyranuronate

117.1-0- (2-Benzyloxy-5-fluoropyrimidin-4-yl) -ß-D- -galactopyranuronic acid

118. O ² -benzyl-O ⁴ - (3,4,6-tri-O -acetyl-2-amino ^ desa ^ - -ß-ih elucopyranosyl) -5-fluorouracil

119. O, - Benzyl - ti - (2-3ΐηίηο-2-αβ5οχγ-β-Β-9ΐχχ: οργτ3ηο6γ1) -

-5- fluorouracil

"δ. 2

120. O - Benzyl - O - (3,4,6 - tri -O-acetyl ^ -amino ^ -

deoxy-ß-D ^ - glucopyranosyl) -5-fluorouracil

121. Ο / - Benzyl -O - ^ -amino ^ -deoxy-ß-D- glucopyranosyl) - -5-fluorouracil

122. O ² - Benzyl - (Λ- (3,4,6-tfi - ^. Acetyl-2-amino-2-deoxy-

_D_ glucopyranosyl) -5 - fluomracil hydrochloride

123. O * - (3,4,6-Tri-O-acetyl-2-amino-2-desoocy-.ß_D- -glucopyranosyl) -5 - fluorouracil hydrochloride

124.0 ^ - Benzyl-0 - (3,4,6-tri - & - acetyl-2-amino-2-deoxy-ß-O- -glucopyranosyl) -5-fluorouracil - hydrochloride

125. Ö ² - (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D _: - -glucopyranosyl) -5-riuoruracil hydrochloride

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For the preparation of the compounds according to the invention, a Compound of formula (II) as defined above with the compound of formula (III) as defined above is reacted to give a compound of formula (IV). This compound of the formula (IV) is then used if necessary subjected to hydrolysis and / or reduction in any order to give the desired 5-fluorouracil derivative of formula (I).

In the compound of formula (II):

7 8

one of the radicals R and R denotes a metal ion and the other denotes a hydroxyl protecting group. The metal ion can be any monovalent, be a metal-containing ion, wherein the metal itself can be monovalent or polyvalent. Is the metal polyvalent, the metal ion preferably consists of the metal alone, e.g. a silver ion, a mercury ion, Hg ion, or an alkali metal ion, e.g. a sodium or Potassium ion. If the metal is polyvalent, the metal ion contains the metal and one or more anionic ligands, such that the metal ion itself is monovalent. Examples include HgCl and HgBr. Likewise, if the metal is polyvalent is, the compound of formula (II) contain more than one 5-fluorouracil derivative radical, and the metal ion is then to consider it as if it consists of the metal and, with the exception of a remainder, of these residues.

Instead of adding the metal salt of the formula (II) per se the metal salt can be formed in situ from the corresponding free 5-fluorouracil derivative for the reaction mixture.

809818/0980

The reaction can be carried out, for example, by adding mercury cyanide to a solution of the corresponding the free 5-fluorouracil derivative is added and then the compound of the formula (III) is added thereto.

The compound of the formula (III) is a <x -glycosyl halide, in which the halogen atom is preferably chlorine or bromine. This α-glycosyl halide reacts with the compound of Formula (II), it gives the corresponding ß-glycoside of the 5-fluorouracil derivative

The reaction of the compounds (II) and (III) is preferably carried out in the presence of a solvent. Any solvent can be used provided it does not adversely affect the reaction. Examples of suitable solvents are: aromatic hydrocarbons, for example toluene or xylene; dialkylaliphatic acid amides, for example N, N-dimethylformamide or Ν, Ν-dimethylacetamide; Dialkyl sulfoxides, for example dimethyl sulfoxide; Phosphoric acid amides, for example hexamethylphosphoric acid oxisamide; Nitroalkanes, for example nitromethane; and nitriles such as acetonitrile. Although there is no particular restriction on the reaction temperature, the reaction is generally carried out at a temperature of from 0 to 150.degree. If a non-polar solvent is used, the preferred reaction temperature is 100 to 150 ^° C .; if a polar solvent is used, about room temperature is preferred. The time required for the reaction depends mainly on the reaction temperature and the solvent used. However, it generally varies between 5 minutes and 20 hours.

After the reaction has ended, the compound of the formula (IV) obtained can be separated off from the reaction mixture by conventional methods. For example, after filtering off of insoluble substances in the reaction mixture, the solvent is removed by distillation under reduced pressure, and then the residue is extracted with an organic solvent such as chloroform. The extract can

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then washed with water and dried, after which the solvent is removed from the extract by distillation. An organic liquid such as ethanol can be added to the residue thus obtained and the mixture in the Cold, for example, in a refrigerator, to give the desired compound (IV) in the form of crystals.

The compound of the formula (IV) is useful as an intermediate in the synthesis of anti-tumor agents and can be easily by reduction and hydrolysis, which can be carried out in any order, into such anti-tumor agents be transferred.

The hydroxy protecting group in the pyrimidine part and / or the Amino protecting group in the glycoside part can be obtained by reduction be removed by treating the compound of formula (IV) with a reducing agent, preferably in the presence of a solvent, brings in contact. The nature of the reducing agent is taken into account in order to achieve the best possible results the nature of the protecting group to be removed. If the hydroxy protecting group is a substituted one or unsubstituted benzyl group or the amino protecting group a substituted or unsubstituted benzyloxycarbonyl group, the reducing agent is preferably hydrogen and a catalyst such as palladium on carbon. Is the hydroxy protective group a ß-haloethyl group or the amino protective group a ß-haloethoxycarbonyl group, the reducing agent is preferably metallic zinc with an acid (e.g. acetic acid) or an alcohol (e.g. methanol or ethanol). The nature of the solvent used is provided that it has no adverse effect on the reaction exercises, not critical. Suitable solvents include: alcohols such as methanol or ethanol; and ether how Tetrahydrofuran and dioxane. The reaction temperature is not critical, and for the sake of simplicity it is preferred to carry out the reaction at room temperature. The for the implementation

80981 8/0980

Time required varies depending mainly on on the nature of the reducing agent, but is generally 5 to 60 minutes.

After the reaction has ended, the product can be recovered by conventional methods, e.g. after insoluble Substances have been filtered off from the reaction mixture, the solvent by distillation under reduced pressure can be removed and an organic liquid such as ethanol can be added to the residue obtained, after which the mixture is allowed to stand in crystalline form to obtain the desired product.

The hydrolysis reaction, which can be carried out before or after the reduction, can be effected by treating the compound of the formula (IV) or the product obtained by reducing the compound of the formula (IV) with a base in the presence of a solvent to remove the by R * brings acyl group represented in this compound into contact. The base used is preferably ammonia or an alkali metal alcoholate, for example sodium methylate, sodium ethylate or potassium tert-butoxide. Any suitable solvent which does not interfere with the reaction can be used, although it is preferred to use an alcohol such as methanol, ethanol or tert-butanol, or a mixture of one or more of these alcohols with one or more other organic solvents, like Ätherη (e.g. tetrahydrofuran or dioxane), or hydrogen halides (e.g. methylene chloride or chloroform) to be used. The reaction is preferably carried out under anhydrous conditions. It is with regard to the reaction temperature is no particular limitation, and temperatures within the range of -30 to +50 ⁰ C, and bevorzugtesten from ⁰ ° C to about room temperature yield good results. The reaction time varies depending mainly on the reaction temperature *, but it is generally 2 to 20 hours.

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After the reaction has ended, the product can be removed from the reaction mixture can be obtained by conventional methods. For example, the solvent can be removed from the reaction mixture under reduced Pressure to be evaporated and the residue dissolved in a small amount of anhydrous methanol, after which a Addition of chloroform leads to crystals which can be filtered off.

The hydrolysis of the compound (IV) or the by reduction

The product obtained from the compound (IV) in which R is an alkoxy group, a cycloalkoxy group, an aralkoxy group or an aryloxy group to obtain a compound of the formula (I) in which R is a hydroxyl group is preferably carried out at a pH of about 11 using ammonium hydroxide in the presence of a solvent. The nature of the solvent is not subject to any restriction, provided that it does not adversely affect the reaction, the use of a mixture of an alcohol (for example methanol or ethanol) with water being generally preferred. With regard to the Reaktionstempera- also door is "no particular limitation, and the reaction is thus generally carried out at a temperature of -10 ° C to +50 ⁰ C. For convenience, the reaction is preferably carried out at about room temperature · The for the reaction The time required depends mainly on the reaction temperature and is generally 3 to 24 hours.

After the reaction has ended, the product can be recovered by conventional means. For example, the solvent removed from the reaction mixture by distillation under reduced pressure and then the residue through Fractionation can be purified by preparative thin layer chromatography on silica gel. The the product you want containing fraction can be extracted with an organic solvent such as methanol, and then the solvent removed from the extract by distillation. The addition of an organic liquid such as ethanol to the return

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and leaving the mixture in the cold, e.g. in the Refrigerator, gives the desired product in the form of crystals.

If R ⁴ 'is an alkoxy group, a cycloalkoxy group, an aralkoxy group or an aryloxy group, it is preferred to carry out the hydrolysis of the acyl group (R ·) before the reduction.

Compounds of the formula (I) in which R is the group

(in which R and R have the meanings given above) can also be prepared, if desired, in

4 a compound of formula (I) in which R is an alkoxy group means, with an area of the formula R R NH (in which R and R have the meanings given above) in Presence of a solvent "

The nature of the solvent to be used in this reaction is not particularly limited insofar as it does not adversely affect the reaction. In general, it is convenient to use an alcohol such as methanol or ethanol. The reaction temperature is also not critical, and good results are generally obtained at temperatures from ⁰ ° C. to 100 ° C., preferably at about room temperature. The time required for the reaction depends mainly on the reaction temperature, but it is generally 3 to 18 hours and usually 12 to 18 hours when the reaction is carried out at room temperature.

After the reaction has ended, the product can be removed from the reaction mixture separated by conventional methods. For example, the solvent can pass through from the reaction mixture

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Removed distillation under reduced pressure and the desired Product can be obtained by adding an organic liquid such as ethanol to the remaining residue.

The 5-fluorouracil derivatives of formula (I) wherein R is Amino group can be converted into pharmaceutically acceptable acid addition salts by conventional methods will. Examples of suitable salts include the acid addition salts of mineral acids (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid or phosphoric acid) or organic acids (e.g. oxalic acid, succinic acid, maleic acid or citric acid).

The anti-tumor activity of the 5-fluorouracil derivatives according to the invention was examined by the method described in Gann, £ 1, 485-493 (1970), Japan. The results of these tests are given in Tables I to IV below. In each case the test animals used were mice of strain BDF ₁ and the tests were carried out in-

which the mouse was inoculated with L-1210 leukemia cells (1 χ 10).

The day of administration of the active ingredient given in the table corresponds to the number of days after inoculation with the leukemia cells.

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Table I.

Really
material dosage
mg / kg / day Administration s-
Day Meet
chung s-
method By-
Schnitbl.
Survive
ben-
duration
(Days) Ver
better
tion d.
Survive
ben-
duration
t O / \
\ r & J Connection 2
Connection 2 50
100 1,2,5,4,6,7,8,9 ip ■
ip 15.0
16.2 59
98 Connection 2 200 1,2,5,4,6,7 i.p. 15.6 90 control - - -. 8.2 - Connection 2 500 .1 i.p. 11.8 57 Connection 2 250 1 i.p. 9.6 28 control - - - 7.5 - Connection 2 1000 1 p.o. 14.6 74 Connection 2 500 1 p.o. 11.6 38 Connection 2 250 1 p.o. 8.8 5 5-FU 200 1 p.o. 13.2 57 PT-207 1000 1 p.o. 14.0 67 control - - - 8.4 .-

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Table II

Active ingredient dosage
mg / kg / day Meet
chung stag Meet
ching
method By-
sdinittl.
Survive
ben s dong
he (days) improvement
the survival
service life
(%) Connection 59
5-FU
ΙΓΤ-207
control 5OO
125
400 1
1
1 i.p;
i.p.
i.p. 15.0
15.0
11.6
8.0
a 88
88
45 Connection 59
control 5OO 1 p.o. .15.8
8.0 73

cn cn K)

Table III

Active ingredient dosage
tng / Tcg / lag Meet
chung day Meet
ching
method By-
Schnlttl,
Survive
bens last
he (days) Improve
tion of the
Survival
duration
(%) Connection 29
P ₅ U ₂ O?
control 150
100 1-5
■ ·. 1-5 ip.
ip 11.5
11.2
8.5 35
32 Connection 39
PT-207
control 5OO
25O Λ
1 ip
ip 10 »2
10.4
8.5 20th
22nd

-JtI -

Table IV

Active,
material dosage
mg / kg / day Meet
chung stag Meet
chung S-
method By-
average
Survive
ben-
duration
(Days) Verbs
eruption
d.Over
vital
duration
(%) Vbd. 99 500 1 i.p. 15.0 78 5-FU 100 1 i.p. 13.2 81 FT-207 400 1 i.p. 9.2 26th Contr. - - - 7.5 - ■ Vbd. 125 500 1 i.p. 10.6 33 5-FU 100 1 i.p. 13.8 73 FT-207 400 1 i.p. 11.0 38 Contr. - - - 8.0 -

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It is thus illustrated that the invention Compounds have valuable activity against tumors.

The compounds of the invention can be administered by any conventionally used method of administration of anti-tumor agents, such as parenteral Administration, intravenous injection or oral administration in the form of, for example, tablets, capsules, Granules, powders or syrups. The amount to be administered varies depending on the symptoms, age and the body weight of the patient, but it is generally 5 to 50 mg / kg / day in the adult when intravenous Administration and between 200 and 2000 mg per day in adults for oral administration. The connection can be in administered in divided doses one to four times per day.

By U. Bicker in "Nature", 252 . 726 (1976) reports that the combination of glucose with an anti-tumor agent generally tends to increase anti-tumor activity. It has been found that this combination is particularly effective with the 5-fluorouracil derivatives of the formula (I). To illustrate this effect, a piece of lymphoma LS-I tissue with a diameter of about 2 mm was subcutaneously by the method described in Gann, 6-1 ^ 535-539 (1970), Japan, using a trocar in the armpit area of a female mouse of strain DBA / 2 inoculated. The anti-tumor agent (Compound 2 or 5-FU) was administered intraperitoneally at the dose shown in Table V once daily on the 1st, 3rd and 9th day after the inoculation of the Lymphora tissue. The glucose was administered in a 10fc aqueous solution in an amount of 1 ml on the same day as the anti-tumor agent. In Table V, the time of administration of the glucose is given as "0" to express simultaneous administration with the anti-tumor agent, or given as "1", equivalent to administration 1 hour before administration of the anti-tumor agent. Active ingredient. The results obtained are shown in Table V.

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3 *

Table V

Active ingredient dose time
d.glucose
injection Average
Tumor diameter
Day 12 (ram) Inhibition
(*) Connection 2 200 - 10.8 42 Connection 2
+
glucose 200 0 • 0 100 Connection 2
+
glucose 200 1 0 100 Connection 2
+
glucose 100 1 7.5 60 Connection 2
+
glucose 50 1 15.1 29 Connection 2
+
glucose 25th 1 16.2 12th 5-FU
+
glucose 20th 1 4.8 74 control - - 18.5 -

8 098 18/0 980

The results of Table V illustrate that it is preferred to take glucose concurrently with or prior to administration of the .5-fluorouracil derivative of the formula (I) to be administered. The amount of glucose administered is preferably from 400 to 4000 mg / kg / day in adults.

The following examples illustrate the invention.

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yo

Manufacturing

Silver salt of O -benzyl-5-fluorouracil

C6H5CH2O

5.387 g (24.5 mmol) of O-benzyl-5-fluorouracil were suspended in 9OmI of water and then completely dissolved by adding 29.4 ml an aqueous ln sodium hydroxide solution. To the solution added a solution of 4.17 g (24.5 mmol) of silver nitrate in 30 ml of water was added dropwise with stirring, and the mixture was further stirred 15 minutes at room temperature. After the completion of the reaction, the precipitate was collected by filtration with water washed and dried. Further drying for 7 hours at 60 ° C. in the presence of phosphorus pentoxide resulted

2 7.9 g of the desired silver salt of 0 -benzyl-5-fluoro

uracils.

Analysis: C ₁₁ HgO ₂ N

Calculated: C 39.31 H 2.70 N 8.34 F 5.65% Found: 39.14 2.48 8.41 5.78 %

Other metal salts of the 5-fluorouracil derivatives can be used in analog ger way.

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example 1

Methyl 1-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-O-acetyl-β-D-qlucopyranuronate

CH3COO

00CCH ₃

2 7.9 g (24.2 mmol) of the silver salt of 0-benzyl-5-fluorouracil were suspended (prepared as described in the preparation) in 320 ml of dry xylene, after which about 90 ml of solvent removed by distillation using a water separator to remove water in the suspension. The remaining mixture was then allowed to cool. 9.1 g (24.2 mmol) were then added to the suspension obtained Methyl 2,3 ^ -tri-O-acetyl-1-brora-1-deoxy-a-D-glucopyranuronate and then refluxed the mixture for 5 minutes. The mixture was then allowed to cool and filtered insoluble substances. The solvent was removed by distillation under reduced pressure and the The residue dissolved in chloroform. The chloroform solution was successively mixed with 5% (w / w) aqueous sodium hydrogen carbonate solution and 20% (w / w) aqueous sodium chloride solution washed. The washing waters were extracted with chloroform. After combining and drying the Chloroform phases, the solvent was distilled off, whereby a caramel-like residue was obtained. One added this residue is ethanol and then left the mixture to stand overnight at 4? C, 7.3 g of the desired methyl

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1-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-O-acetylß_D_gl _U copyranuronate (compound 24) was obtained in the form of crystals with a melting point of 120 to 121 ° C.

Analysis; ^C 24 ^H 25 ° H ^N 2 ^F

Calculated: C 53.73 H 4.70 N 5.22 F 3.54 %

Found: 53.94 4.56 5.19 3.48 %

UV spectrum:

\ _max (O, In-HCl, CH ₃ OH) 271 nm ( ί 8000) \ _max (CH ₃ OH) 271 nm ( I 7300)

λ (0, In-NaOH, CH-, OH) 270 nm ( L 9000) max J.

Example 2

Methyl 1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D -qlucopyranuronate

C6H5CH2O

6.06 g (11.3 mmol) of methyl 1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-O-acetyl-β-D-glucopyranuronate (prepared as in Example 1) to 70 ml of a 3 ^ volume mixture of anhydrous methanol and methylene chloride. After the mixture had been cooled with ice water, 6.6 ml of an in-methanolic solution of sodium methylate were added and the mixture was stirred immediately thereafter. The mixture was then stirred ^{at 0 °} C. for a further 40 minutes. After completion of the reaction, 2.5 ml of 1 n hydrochloric acid was added

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the mixture to neutralize it and removed that Solvent by distillation. The residue was dissolved in chloroform and then the chloroform solution with water washed and dried over anhydrous magnesium sulfate. The solvent was carried out from the dried solution Distillation removed and 4.46 g of a caramel-like residue was obtained. This residue was subjected to column chromatography on 100 g silica gel using Chloroform containing 2.5% by volume of methanol. The eluate was collected and the solvent by distillation removed. Ethanol was added to the residue and then allowed to stand. The precipitated crystals were through Filtration recovered to give 1.78 g of the desired methyl 1-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) ß-D-glucopyranuronate (Compound 101) in the form of white crystals from F β 159 to 160 ° C. A further 540 mg of secondary crystals were obtained from the mother liquor.

Analysis; ^^ ΐ ^ β ^ ¹ "

Calculated: C 52.68 H 4.67 N 6.83 F 4.63 % Found: 53.05 4.50 6.93 4.41%

UV spectrum:

²⁶⁹

^X max ^(H 2 ^{0) 27} ° ^{nm ( &} 7300)

X _mav (O, In-NaOH) 269 nm (£ 7700) max '

8 09818/0980

2746562

Example 3

Methyl l-0- (5-fluoro-lH-2-oxopyrimidin-4-yl) -β-D-qlucopyran uronate

CH3O.CO T "F -O. 0

2.03 g (4.95 mmol) of methyl 1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-glucopyranuronate were dissolved in 100 ml of anhydrous methanol. The atmosphere in that containing the solution was replaced Reaction vessel by nitrogen and then added 400 mg of 10% by weight palladium on carbon. The atmosphere was again replaced with fresh nitrogen gas and then bubbled with stirring for 15 minutes at atmospheric pressure Hydrogen. After the catalytic reaction was completed, insoluble substances became from the reaction mixture was filtered off and the solvent was then removed by distillation under reduced pressure. Man added ethanol to the precipitated crystals, then filtered the mixture to obtain 1.529 g of the desired methyl 1-0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronate (Compound 2) in the form of white crystals from F = 122 to 124 ° C.

Analysis; C ₁₁ H ₁₃ OgN ₂ F-OjSH ₂ O Calculated: C 40.13 H 4.29 N 8.51 F 5.77% Found: 39.97 4.64 8.44 5.47 %

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UV spectrum;
Nnax ^(H 2 ^{0) 288}

^t5700)

The obtained crystals were made from a 1: 1 volume mixture recrystallized from anhydrous methanol and ethanol to give white needles from P «127 to 128 ° C.

Example 4

1-O- (2-Benzvloxv-5-fluoropvrimidin-4-yl) -β-D-qlucopyranuronic acid

C6H5CH2O

1.025 g (2.5 mmol) of methyl 1- O- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-glucopyranuronate was dissolved (obtained as described in Example 2) in 23 ml of a 6: 3.9: 0.1 volume mixture of methanol, water and concentrated aqueous ammonia. The solution was then stirred at room temperature for 24 hours. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 1.2 g of a caramel-like Residue removed. This residue was a preparation! ven thin layer chromatography on silica gel under Using chloroform containing 35 volumes of methanol as a developing solvent. One the desired Fraction containing compound was extracted with methanol and the solvent was evaporated from the extract. Man added ethanol to the obtained caramel-like residue, and allowed the mixture to stand in a refrigerator overnight.

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The precipitated crystals were collected by filtration, and 724.5 mg of the desired product (compound 102) were obtained in the form of white crystals of melting point 129 to 130 ° C.

Analysis: C ₁₇ H ₁₇ OgN ₂ F ^ H ₂ O Calculated: C 47.23 H 4.90 N 6.48 F 4.39 % Found: 47.77 4.60 6.39 4.00 %

UV spectrum:

λ_ _ν (pH 4.01) 269 nm (t8800)

ItIcUC

λ _{Μ = ν} (H, 0) 269 nm ( V 8400) \ nax ^{(pH 9 '18) 269 nm (} i-8500)

Example 5

5-Fluoro-1H-2-oxopyrimidine-4-vl) -β-D-qlucopyranuronic acid

362 mg of 1- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-glucopyranuronic acid were dissolved in 20 ml of anhydrous methanol. The atmosphere in the reaction vessel containing the solution was replaced by gaseous nitrogen and then added 72.5 mg of 10% by weight palladium on carbon to the solution. One stirred the mixture at room temperature while bubbling gaseous hydrogen into it. After the reaction was finished The catalyst is filtered off from the reaction mixture and the

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27A8562

Solvent removed by distillation under reduced pressure to give a crystalline powder. This Powder was then dissolved in a small volume of ethanol, collected by filtration and washed, giving 254 mg the desired 1- (5-fluoro-1H-2-oxopyrimidin-4-yl) -ß-D-glucopyranuronic acid (Compound 1) in the form of a white powder.

Analysis; ^C ₁₀ ^H 11 ° 8 ^N 2 ^P

Calculated: C 39.2 H 3.62 N 9.15 F 6.20 *

Found: 38.95 3.51 9.01 6.31 %

UV spectrum:
^X max ^(H 2 ^{0) 288 1} ^

Example 6

Methyl 1-0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -2.3.4-tri-O-acetyl-β-D-qlucopyranuronate

CH3COO

OOCCH3

1.2 g of methyl 10- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-O-acetyl-β-D-glucopyranuronate (obtained as described in Example 1) were dissolved in 120 ml of anhydrous methanol. The atmosphere in the reaction vessel containing the solution was replaced with nitrogen, and then 240 mg of 10% by weight

8 09818/0980

Palladium on carbon to the solution. The atmosphere was again replaced with fresh gaseous nitrogen and the mixture was stirred then the mixture for 15 minutes while passing in gaseous hydrogen under atmospheric pressure. After the In the reaction, insoluble substances were removed from the reaction mixture, and the solvent was then removed by distillation removed under reduced pressure. Ethanol was added to the residue obtained and the crystals were recovered by filtering, giving 891 mg of the desired methyl ΙΟ- (5-fluoro-1H-2-oxopyrimidin-4-yl) -2,3,4-tri-O-acetyl-ß-D-glucopyranuronate in the form of white crystals from F = to 117 ° C. A further 106 mg of secondary crystals were obtained from the mother liquor.

Analysis: ^c ₁ 7 ₁ 9 ^H ₁ ^N 2 i ° ^F * ^H 2 °

Calculated: C 43.97 H 4.56 N 6.03 F 4.10% Found: 44.70 4.55 5.89 4.26 %

UV spectrum:

\ nax ^(H 2 ^{0) 288 nra ( S 4800)}

Example 7

1- 0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -β- D-qIucopyranuronami d

8098 18/0980

200 mg of methyl 1-0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -2,3,4-tri-O-acetyl-β-D-glucopyranuronate were dissolved in 20 ml of anhydrous methanol. The solution was saturated with gaseous ammonia while cooling with ice and, after sealing the jar tightly, left to stand in a refrigerator overnight. After completion After the reaction, the solvent was removed from the reaction mixture by distillation under reduced pressure. Methanol was added to the resulting crystalline residue, and then the mixture was filtered, whereby 111 mg of the desired 1- 0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -β_D-glucopyranuronamide (Compound 12) in the form of white crystals from P = 146 to 150 ° C (decomp.).

Analysis; C ₁₀ H ₁₂ O ₇ N ₃ F

Calculated: C 39.35 H 3.96 N 13.77 F 6.22 % Found: 39.10 3.81 13.65 6.12 %

UV spectrum

(H ₀ O) 286 nm (t 9200)

Example 8

Isopropyl-1-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri O-acetyl-ß-D-qlucopyranuronate

C6H5CK2O

(CH & CHOXO CH3COO

809818/0980

3.27 g (10 mmol) of the silver salt of O -benzyl-5-fluorouracil were suspended in 150 ml of dry xylene. To remove the water, about 40 ml of the solvent were distilled at ambient pressure and then allowed the remaining suspension to cool. 4.25 g of isopropyl 2,3,4-tri-O-acety1-1-bromo-1-deoxy-α-D-glucopyranuronate were then added to the suspension and refluxed the mixture for 5 minutes. After the completion of the reaction, the mixture was allowed to cool and filtered precipitated insoluble substances. The solvent was removed by distillation under reduced pressure, leaving a residue which was then dissolved in 100 ml of chloroform. The chloroform solution was washed successively 50 ml of a 5% aqueous sodium hydrogen carbonate solution and 50 ml of a 20% aqueous sodium chloride solution. The washing waters were extracted again with 50 ml of chloroform, and all the chloroform phases were combined and dried. The solvent was removed by distillation, whereby a colorless caramel-like residue was obtained. This residue was then dissolved in ethanol and the solution was left to stand in a refrigerator overnight. The crystals precipitated on standing were collected by filtration, to give 4.97 g of the desired one Isopropyl 1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-O-acetyl-β-D-glucopyranuronate (Compound 26) in the form of white crystals from F = 138 to 139 ° C.

Analysis: ^C ₂ 6 ^H 29 ° 11 ^N 2 ^F

Calculated: C 55.32 H 5.18 N 5.00 F 3.37 % Found: 55.08 5.21 4.93 3.12%

UV spectrum:

^λ η, = _ν < ⁵⁰ * 0, In-HCl, 50 % CH-OH) 270 nm (£ 10 500) ^X raax ⁽⁵ ° ^{% CH} 3 ^OH » ⁵⁰ * ^H 2 ^{0) 27} ° ^{nm (} « ^{10 300 )}

(50 % 0, In-NaOH, 50 % CH ₃ OH) 270 nm (g, 10 800)

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Example 9

Isopropyl 1-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-qluco pyranuronate

(CH ^ CHO-CO

A three-necked flask was charged with 100 ml of anhydrous methanol and then with 0.366 g of metallic sodium. The mixture was cooled to -30 ° C while adding moisture kept away. To the methanolic solution thus obtained 4.50 g of isopropyl 1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-O-acetyl-β-D-glucopyranuronate were added to the sodium methylate and stirred the mixture for 6 hours. After the completion of the reaction, the mixture was neutralized by adding acetic acid and then evaporated to dryness. The residue was dissolved in 100 ml of ethyl acetate and the ethyl acetate solution was twice with a 2.5% (w / w) aqueous Sodium hydrogen carbonate solution or washed with saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate and then removed the solvent by distillation under reduced pressure, whereby a residue remained, which was recrystallized from methanol. The desired isopropyl l-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-glucopyranuronate was obtained (Compound 104) from P β 68 to 59 ° C.

809818/0980

Analysis ^ C ₂₀ H ₂₃ OgN ₂ F * l / 3 H ₂ O

Calculated: C 54.05 H 5.37 N 6.30 F 4.28 % Found: 54.06 5.45 6.24 4.04 %

UV spectrum:

λ (CH-, OH) 270 nm (6 7300)

ΓΠ9 ό

Example 10

Isopropyl 1- 0- (5-fluoro-1H-2-oxopvrimidin-4-yl) -β-D-qlucopyranuronate

(CH ^ CHQJO

0.46 g of isopropyl 1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-glucopyranuronate was dissolved in 40 ml of anhydrous methanol. The atmosphere in that containing the solution was replaced Reaction vessel by gaseous nitrogen and added 52.5 mg of 10% by weight palladium on carbon and then passed gaseous hydrogen under atmospheric pressure. After 23 ml of hydrogen gas was absorbed, the catalyst became removed from the reaction mixture by filtration and then the solvent was distilled off under reduced pressure. After adding anhydrous * methanol to the reaction mixture, crystals precipitated, which were collected by filtration became. The desired isopropyl-1-0-

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(5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronate (Compound 5) from F> 151 to 152 ° C.

Analysis; C ₁₃ H ₁₇ OgN ₂ P ₂ Calculated: C 42.21 H 5.29 N 7.57 F 5.14 % Found: 42.25 5.08 7.63 4.71%

UV spectrum:

λ (pH 6.86, phosphate buffer) 288 hm (£ 5200)

Examples 11-18

Compounds 3, 4, 6, 7, 8, 105, 9 and 106 (identified in the list above) were put into use the procedure described in Examples 8, 9 and 10, except that the isopropyl used in Example 8 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-α-D-glucopyranuronate by the corresponding halosaccharide to give a compound of the following formula

R ¹² OXO

replaced, in which R is as defined in Table VI below. The properties of the compounds obtained are given in Tables VI and VII below.

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Table VI

oo ο co oo

E.g.
No- link
No. R ¹² F ( ⁰ C) UV spectrum: \ _{m = v} (pH 6.86 phosphate buffer) nra ( £ ) 11 KN -CII ₂ CH, 128-130 288 (4900) 12th 4th - (GH ₂ ) ₂ GH ₃ 154-155 288 (5100) 15th 6th - (CHg) ₅ OH ₃ 140-141 288 (5100) 14th 7th -CE ₂ CRi CH ₃ ) 2 156-137 288 (4800) 15th 8th - (CH ₂ ) ^ CH ₃ 126-127 288 (4900) 16 105 - (CH ₂ ) 2CH (CH ₅ ) 2, 126-129 288 (5100) 17th 9 - (CH ₂ ) ₅ -CH ₃ 127-129 288 (5000) 18 · 106 288 (5200)

Table VII

link
No. Pormel Calculated (%) C. H N P. Found (.%) C. H ■ N P. • 3 · G / t 'y3-s \ ςΟοΝρΡ · 2 / 3HoO 41.62 4.75 8.06 5.49 41.32 5.01 7.83 5.73 4th η TT / \ TCT TjI CL / CXt f \
U ₁ 2 · "- /] o ^ Ä 2 ^ *? - ^π · ρ ^ν> ' 42.21 5.29 7.57 5.14 42.14 5.00 7.30 • 5.59 6th O ₁₄ H ₁₉ O ^ -SZ ₅ H ₂ O 43.79 5.62 7.30 4.95 43.62 5.42 • 7.08 5.23 7th C ₁₄ H ₁₉ O ₈ N ₂ PH ₂ O 44.21 5.57 7.37 5.00 44.09 5.47 7.25 5.15 8th ^ t tr ^ \ Ύίτ TP ^^ ctt ^ n 46.75 5.75 7.27 4.73 46.23 5.34 7.22 4.63 105 C ₁ 5 ^Η 21 ^Ο 8 ^Ν 2 ¹ '* ¹ - ^5Η 2 ° 44.67 6.00 6.95 4.71 44.90 5.72 7., 1O .4.60 9 ° ^16H 23 ° 8 ^{] Sr} 2 ^F - ^H 2 ⁰ 47.06 6.17 6.86 4.65 47.04 5.54 6.99 4.50 106 O ₁₆ H ₂₁ O ₈ K ₂ P-LSH ₂ O 46.27 5.82 6.74 4.57 46.22 5.59 6.89 4.62

Example 19

-W-

5C

N-methyl-1-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D -qlucopyranuronamide

C ₆ H ₅ CK ₂ O ^ JL

CH3NH.C0

1.34 g of methyl l-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-O-acetyl-β-D-glucopyranuronate were dissolved in 70 ml of anhydrous methanol. Dry monomethylamine was then brought in during Soak in the solution for 10 to 15 minutes while keeping moisture away. The jar was then closed with a stopper sealed and the solution stirred at OC for 3 hours. After the completion of the reaction, the solvent was removed from the The reaction mixture was removed by distillation under reduced pressure. Anhydrous ethanol was then added to the obtained one Residue and the precipitated crystals were collected by filtration, whereby 538 mg of the desired N-methyl-1-O- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-glucopyranuronamide (Compound 107) of m.p. 159 to 160 ° C. From the mother liquor a further 114 mg of the desired compound were obtained.

Analysis: ^c 18 ^H 20 ° 7 ^N 3 ^F

Calculated: C 52.81 H 4.92 N 10.26 F 4.64 % Found: 52.58 5.11 10.24 4.55%

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UV spectrum;

λ (O, In-HCl) 270 nin (£ 7100)

Max

λ (CH-, ΟΗ) 270 nra <6 7400) max ό

λ (0, In-NaOH) 270 nm (S78OO)

Max

Example 20

N-methyl-1- 0- (5-fluoro-1 H-2-OXopvrimidin-4-yl) -β-D-qluco pyranuronamide

40.9 mg of N-methyl-l-O- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-glucopyranuronamide were dissolved in 5 ml of anhydrous methanol. The atmosphere in that containing the solution was replaced Reaction vessel through gaseous nitrogen, after which 8.2 mg of 10% by weight palladium on carbon were added to the solution and bubbling gaseous hydrogen into the solution for about 5 minutes. After the completion of the reaction, the catalyst became removed from the reaction mixture by filtration and the filtrate evaporated to dryness under reduced pressure, wherein a crystalline residue was obtained. Water ff ei ethanol was added to this residue and then the crystals were recovered by filtering. 13.8 mg of the desired N-methyl-1-0- (5-fluoro-1H ^ 2-oxopyrimidin-4-yl) -β-D-glucopyranuronaroid were obtained (Compound 108) from F> 130 to 140 ° C (decomp.).

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Si

Analysis: C ₁₁ H ₁₄ O ₇ N ₃ F CH ₃ OH

Calculated: C 41.03 H 5.16 N 11.96 F 5.41 %
Found: 39.87 5.13 11.85 5.48 %

UV spectrum:

^{287 nm} <£ 4600)

Example 21

2 .4

O- (2,3,4, e-Tetra-O-acetyl-ß-D-qlucopyranosyl) -0 -benzyl-

5-fluorouracil

C6K5CH2O

ÄC0CH2

1.96 g (6.1 mmol) of the silver salt of 0-benzyl-5-fluorouracil were suspended in 100 ml of anhydrous xylene which had been dehydrated with calcium hydride and then distilled. The mixture was refluxed with about 10 ml of the solvent removed by azeotropic distillation to remove additional water. After the resulting mixture was cooled, 2.51 g (6.1 mmol) of 2,3,4,6-tetra-O-acetyl-aD-glucopyranosyl bromide were added to the mixture, and the mixture was refluxed for 5 minutes. After the
In the reaction, insoluble materials were filtered off, and that

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The filtrate was distilled under reduced pressure to give a caramel-like residue, which was dissolved in 30 ml of ethyl acetate and then washed once with a 5% (w / w) aqueous sodium bicarbonate solution and washed twice with 20 ml of water. The wash waters were 15 ml Ethyl acetate extracted. The combined ethyl acetate solutions were then dried over anhydrous magnesium sulfate and dried under reduced pressure to give a caramel-like color Distilled substance which was dissolved in 15 ml of ethanol. Man let the solution stand, whereupon white crystals precipitated. These crystals were obtained from a mixture of 15 ml of ethanol and 4 ml of benzene recrystallized, whereby 1.986 g of 0 - (2,3,4,6-

Tetra-O-acetyl-ß-D-glucopyranosyl} -0 -benzyl-5-fluorouracil

(Compound 63) from P »140 to 141 ° C.

The mother liquor was further concentrated and dried, and the residue was then subjected to column chromatography Subjected to the use of silica gel eluted with chloroform to obtain various proportions, which have been purified and 274 ml of the desired crystalline Product.

Analysis; ^C 25 ^H 27 ° n ^N 2 ⁱ ' Calculated: C 54.55 H 4.94 N 5, O9 P 3.45%

Found: 54.34 5.08 5.04 3.30%

UV spectrum;

\ nax <°> ^ln - ^{HC3L in} CH ₃ OH) 264 nm (£ 5200) Nnax ^ a ⁰¹ ^ ^{264 nm} (ε-5100) \ nax ( ⁰ J ^ -Na ⁰ H ^ln CH ₃ OH) 265 nm (£ 5500)

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co

Example 22

O ² - (2,3,4, e-rTetra-O-acetyl-β-D-qlucopyranosyl) -5-fluorouracil

Ac = acetyl

550 mg (ImMoI) O - (2,3,4,6-Tetra-0-aCetyl-ß-D-glucopyranosyl) -0 were dissolved -benzyl-5-fluorouracil in 30 ml of anhydrous Methanol. The atmosphere in the reaction vessel containing the solution was then replaced by dry gaseous nitrogen and added 100 ml of 10% by weight palladium on carbon. Gaseous hydrogen was then passed into the solution Room temperature and pressure while shaking the jar until 24 ml of hydrogen was absorbed. After the completion of the reaction, the atmosphere in the vessel was again replaced with fresh nitrogen gas and the catalyst is filtered off. The filtrate was concentrated by evaporation under reduced pressure and then dried, to give a crystalline residue which was dissolved in 45 ml of anhydrous ethanol with heating. One let leave the ethanol solution in a refrigerator overnight, after which crystals separate out. These were filtered off, and 373 mg of white crystals of the desired one were obtained

2
0 - (2,3,4, G-Tetra-O-acetyl-β-D-glucopyranosyl) -5-fluorouracils (Compound 109). These crystals melted at 140 to 142 ° C

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and decomposed to color at 197 to 212 ° C.

Analysis: ^C ₁ 8 ^H 21 ° 11 ^N 2 ^F

Calculated: C 46.96 H 4.60 N 6.09 F 4.13% Found: 47.23 4.90 5.73 3.95%

UV spectrum:

^X max ( ^CH 3 ^m ) 266 nm (ε 6200)

Example 23

ρ
0 - (β-D-glucopyranosyl) -5-fluorouracil

460 mg (1 mmol) of 0- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -5-fluorouracil were dissolved in 25 ml of anhydrous methanol. The solution was then saturated with dry gaseous ammonia and left to stand in a refrigerator for 4 hours at room temperature and then overnight. After completion of the implementation the residue was dissolved in a small volume of methanol. The addition of 10 ml of chloroform to the resulting solution gave a crystalline powdery material which, with obtaining 307 mg of the desired Ö -tß-D-glucopyranosyD-5-fluorouracils (Compound 55) was filtered. This material partially melted at 1Ο3 to 109 ° C and decomposed Bubble formation at 116 to 119 ° C.

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Analysis: C ₁₀ H ₁₃ O ₇ N ₂ F-CH ₃ OH-NH ₃ -H ₂ O

Calculated: C 36.77 H 6.17 N 11.70 F 5.29 % Found: 36.06 5.73 12.07 5.38%

UV spectrum:

λ (0.02m phosphate buffer, pH 6.86) 268 nm (£ 7000)

Example 24

A. 0

0 - (2,3,4, e-Tetra-O-acetyl-ß-D-qlacopyranosyl) -0 -benzyl- 5-fluorouraci1

C6H5CH2O

ÄCÜCH2

l - o. 0

4.91 g (15 mmol) of the silver salt of 0 -benzyl-5-fluorouracil were dissolved in 220 ml of dry xylene. 20 ml of xylene were then distilled off to remove the water. Hereafter added one receives 6.17 g (15 mmoles) of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide to the suspension and the mixture was refluxed for 5 minutes. After the completion of the reaction, a grayish yellow insoluble matter was filtered off, and then the solution concentrated under reduced pressure and dried. The residue was dissolved in 100 ml of ethyl acetate and then the solution once with 70 ml of a 5% (w / w) aqueous sodium hydrogen carbonate solution and washed twice with 70 ml of water. The wash waters were washed several times with 50 ml of ethyl acetate

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extracted and the combined ethyl acetate solutions were dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, whereby a caramel-like substance resulted which was then dissolved in ethanol. The addition of isopropanol to the ethanol solution led to the precipitation of crystals, which were filtered off and

4 were dried, giving 5.795 g of the desired 0 - (2,3,4,6-tetra-O-acetyl-ß-D-glucopyranosyl) -0 -benzyl-5-fluorouracils (compound 65) in the form of white crystals from F = 95 to 96 ° C received.

Analysis: ^C 25 ^H 27 ° il ^N 2 ^P

Calculated: C 54.54 H 4.94 N 5.09 F 3.26 % Found: 54.33 4.92 4.70 3.26 %

UV spectrum: X _mjav (0, In-HCl in CH, OH) 270 mn (E 7200)

(CH, OH) 270 nra (t 7100) (0, In-NaOH in CH, OH) 270 nm (t 8300)

Example 25

4th
0 - (2,3 «4 .e-Tetra-O-acetyl ^ -ß-D-glucopyranosvl) -5-fluorouracil

OAc

Ac β acetyl 809818/0980

One dissolved 5.795 g (10.5 mmol) of O ⁴ - (2,3,4,6-Tetra-O-acetyl) -ß-

D-glucopyranosyl) -0 -benzyl-5-fluorouracil in 130 ml of distilled Tetrahydrofuran. The atmosphere in the reaction vessel containing the solution was then replaced by nitrogen gas replaced, after which 526 mg of 10% by weight palladium on carbon was added to the solution. Hydrogen was fed into it Vial and reduce the mixture with shaking at room temperature and ambient pressure until 254 ml of hydrogen is absorbed had been. The atmosphere in the vessel was again replaced with gaseous nitrogen and more were added 52 mg of palladium on carbon were added and a further 14 ml of gaseous hydrogen were absorbed. After the reaction has ended the atmosphere in the vessel was replaced with gaseous nitrogen and the catalyst was filtered off. The filtrate was concentrated by evaporation under reduced pressure and then dried to give a crystalline residue, to which methanol was added. The obtained crystals were filtered off to give 4.318 g of the desired one 0 - (2,3,4,6-Tetra-0-acetyl-β-D-glucopyranosyl) -5-fluorouracils (Compound 110) from F = 154 to 155 ° C.

Analysis: C - ^^ i ⁰ !! ¹ ^

Calculated: C 46.96 H 4.60 N 6.09 F 4.13%

Found: 46.87 4.6 7 5.93 3.94%

UV spectrum:

λ ™ _v (CHoOH) 288 nm (t 4200)

TTl el λ J

8098 1 8/0980

- -66 -

Example 26

O- (β-D-glucopyranosyl) -5-fluorouracil

2.3 g (5 mmol) of 0- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -5-fluorouracil were dissolved in 125 ml of anhydrous methanol and then saturated the solution with dry ammonia while taking Ice-cooling was stirred for 6 hours and then left to stand in a refrigerator overnight. After the reaction has ended the solvent was distilled off under reduced pressure and anhydrous ethanol are added and this is then also distilled off. The gelatinous substance thus obtained was filtered off and dried to give 1.40 g of the desired one 0 - (ß-D-glucopyranosyD-S-fluorouracils (compound 59) in Form of a white powder from Fs H4 to 115 ° C.

Analysis: C ₁₀ H ₁₃ O ₇ N ₃ F · Ο, 5Η ₂ Ο Calculated: C 39.87 H 4.68 N 9.30 F 6.31 % Found:

39.36 5.02. 9.31 6.13 %

UV spectrum:

(O, O2m phosphate buffer, pH 6.86) 286 nm (6 4600)

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CD,

Example 27

O -Benzyl-0 - (β-D-qlucopyranosyl) -5-fluorouracil

550 mg of O - (2,3,4,6-Tetra-O-acetyl-ß-D-glucopyrano-

syU-0 -benzyl-5-fluorouracil (obtained as described in Example 24) in 100 ml of anhydrous methanol and then saturated the mixture with dry ammonia at room temperature and stirred after tightly sealing the reaction vessel for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, whereby 410 mg of a caramel-like Substance remained by thin-layer chromatography using a fractional silica gel plate subjected, eluted and with a 10 volume%

Purified chloroform solvent containing methanol

2 4

became. 310 mg of the desired 0 -benzyl-0- (ß-D-glucopyranosyl ) -5-fluorouracils (compound 111) in the form of a caramel-like substance, which in thin-layer chromatography gave a single spot, from F = 82 to 83 ° C.

Example 28

4th
Ο - (ß-D-GlucopyranosyD-S-fluorouracil

2 4

310 mg of 0-benzyl-0 - (β-D-glucopyranosyl) -5-fluorouracil were dissolved in 20 ml of anhydrous methanol and added 50 mg of 10% by weight palladium on carbon. The mixture was stirred in

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- W-

Room temperature and ambient pressure under a stream of gaseous Hydrogen · After absorption of 16 ml of hydrogen, the catalyst was filtered off after 5 minutes and then the The solvent was distilled off under reduced pressure to obtain a caramel-like substance which was dissolved in ethanol became. The ethanol solution was left to stand, with crystals precipitating out. These crystals were filtered off to give the desired 0 - (ß-D-glucopyranosyD-S-fluorouracil in the form of a white powder. The properties of this product were identical to the properties in example established connection.

Example 29

Methyl 1- 0- (4-benzyloxy-5-fluoropyrimidin-2-yl) -2,3,4-tri-0-acetyl-β-D-qlucopyranuronate

5.23 g (16 mmol) of silver salt of 0-benzyl-5-fluorouracil were suspended in 250 ml of dry xylene and heated the suspension under reflux. About 50 ml of xylene were then removed through azeotropic distillation to remove the water. 6.35 g (16 mmol) of methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-a-D-glucopyranuronate were added to the remaining suspension and refluxed the mixture for 12 minutes. After the completion of the reaction, the mixture was allowed to cool and removed

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insoluble substances precipitated on standing by filtration. The filtrate was then taken by distillation evaporated to dryness under reduced pressure, leaving a residue which was dissolved in 100 ml of ethyl acetate. the Ethyl acetate solution was then in turn with 50 ml of a 5% strength aqueous sodium bicarbonate solution, 50 ml of a saturated aqueous sodium chloride solution and 50 ml of water. The washed solution then became over anhydrous Magnesium sulfate dried and the solvent was distilled off under reduced pressure, a caramel-like Material remained. A mixture of benzene and ethanol was added to this material, causing crystallization of the material was brought about. 7.107 g of the desired 1-0- (4-benzyloxy-5-fluoropyrimidin-2-yl) -2,3,4-tri-O-acetyl-β-D-glucopyranuronate were obtained (Compound 51) in the form of white powdery crystals. One received another 450 mg of crystals from the mother liquor. The melting point of the product was 141 ° C.

Analysis: ^c ₂ 4 ^H 25 ° ii ^N 2 ^F

Calculated: C 53.73 H 4.70 N 5.22 F 3.54% Found: 54.03 4.68 5.03 3.56%

UV spectrum:

< ⁵⁰ % 0, In-HCl, 50% CH, OH) 264 nm (E 8200)

(50 % CH ₃ OH, 50 % H ₂ O) 264 nm (8 8000) (50 % 0, In-NaOH, 50 % CH ₃ OH) 265.5 nm (& 8200)

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65

Example 30 Methyl-l-O-H-benzyloxy-S-fluoropyrimidine ^ -yD-ß-D-gluco-

pyranuronate

5.9 g (11 mmol) of methyl 1-0- (4-benzyloxy-5-fluoropyrimidin-2-yl) -2,3,4-tri-O-acetyl-β-D-glucopyranuronate were dissolved in a mixture of 18 ml of anhydrous methanol and 12 ml of methylene chloride. 5.5 ml of an in-methanolic sodium methoxide solution were added to the solution while cooling with ice, and the solution was stirred Mix while standing for 1.5 hours. After completion of the reaction, In hydrochloric acid was added to the reaction mixture, to reduce the pH of the solution to about 7. The solvent was then reduced by distillation under reduced pressure Pressure removed. The residue was dissolved in 50 ml of ethyl acetate dissolved and the ethyl acetate solution washed with water and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure to give 5.8 g of crystalline residue. This The residue was subjected to column chromatography using a column containing silica gel (4 × 20 mm) subjected. The chloroform containing 5% by volume of methanol Eluted fractions were collected and the solvent was removed by distillation. One added to that residue obtained in this way to ethanol and received 2.735 g of des

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desired 1- (4-benzyloxy-5-fluoropyrimidin-2-yl) -β-D-glucopyranuronate (Compound 112) in the form of white crystals with a melting point of 146 to 148 ° C.

Analysis: ^c ₁ 8 ^H 19 ° 8 ^N 2 ^F

Calculated: C 52.68 H 4.67 N 6.83 F 4.63% Found: 52.25 4.64 7.03 4.36 %

UV spectrum:

λ (CH ^ OH) 265 nm (£ 7700) max j

Example 31

Methyl l-0- (5-fluoro-lH-4-oxopyrimidin-2-yl) -β-D-qlucopyranuronate

0.65 g of methyl 1- 0- (4-benzyloxy-5-fluoropyrimidin-2-yl) was dissolved ) -ß-D-glucopyranuronate in 20 ml of anhydrous methanol and replaced the atmosphere in the reaction vessel containing the solution by gaseous nitrogen. 130 mg of 10% by weight palladium on carbon were added to the solution and stirred the solution for 8 minutes in a stream of hydrogen. After the completion of the reaction, the catalyst was removed by filtration removed and the solvent was distilled off under reduced pressure. The residue obtained was in a slight Volume of methanol dissolved, and then added to the solution

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acetone was added to precipitate a powder, which was filtered off, giving 47 mg of the desired methyl l-0- (5-fluoro-lH-4-oxopyrimidin-2-yl) -ß-D-glucopyranuronate received. This compound showed by thin layer chromatography on silica gel under development with a solvent system consisting of chloroform containing 30% by volume of methanol, a single stain. The melting point of the product was 142 to 145 ° C (dec.).

i. ^c ii ^H i 3 ° 8 ^N 2 ^{F # 1 >> 5H} 2 °

Calculated: C 38.05 H 4.64 N 8.07 P 5.47 %

Found: 38.70 4.56 7.44 5.00 %

UV spectrum:

(0.02m phosphate buffer, pH 6.86) 267 nm (ε 6400)

Example 32

1-0- (4-Benzyloxy-5-fluoropyrimidin-2-yl) -β-D-qlucopyranuron

acid

821 mg (2.0 mmol) of methyl l-0- (4-benzyloxy-5-fluoropyrimidin-2-yl) -β-D-glucopyranuronate were dissolved (obtained as described in Example 30) in 20 ml of a 6: 3J9: 0.1 volume mixture of methanol, water and concentrated aqueous ammonia. The solution was stirred for 21 hours at room temperature.

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Another 0.2 ml of concentrated aqueous ammonia was then added to the solution to adjust the pH to 10-11. The resulting solution was then stirred for a further 48 hours at room temperature. After the completion of the reaction, the solvent was removed from the reaction mixture by distillation removed under reduced pressure leaving a residue. This residue was in a small volume of methanol dissolved and the product separated off by preparative thin-layer chromatography on silica gel. One collected the product by extraction with methanol, added ethanol and collected the powdery residue obtained Filter, whereby 660 mg of the desired 1- (4-benzyloxy-5-fluoropyrimidin-2-yl) -β-D-glucopyranuronic acid are obtained (Compound 113) in the form of a white powder from F = 155 to 159 ° C (Decomp.) Received.

Analysis; C ₁₇ H ₁₇ OgN ₂ F * 1.5H ₂ O Calculated: C 48.23 H 4.76 N 6.62 F 4.49 % Found: 48.23 5.13 7.06 4.10 %

UV spectrum:

\ _{m = iv} (CH-, OH) 266 nm ( ζ, 7800)

IUcLX 3

Example 33 1- 0- (5-fluoro-1H-4-oxopyrimidin-2-yl) -β-D-qlucopyranuronic acid

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500 mg (1.26 mmol) of 1- (2-benzyioxy-5-fluoropyrimidin-2-yl) -β-D-glucopyranuronic acid were dissolved in 40 ml of anhydrous methanol, and the atmosphere in that containing the solution The reaction vessel was replaced by gaseous nitrogen. 63 mg of 10% by weight palladium on charcoal were added to the solution, and gaseous forms were passed in at room temperature with stirring Hydrogen through the solution until 22.5 ml of hydrogen had been absorbed. After the reaction has ended the catalyst was filtered off from the reaction mixture and the solvent was distilled off under reduced pressure. The powdery residue thus obtained was suspended in anhydrous ethanol, recovered by filtration, with anhydrous Washed ethanol and then dried. 294 mg of the desired l-O- (5-fluoro-lH-4-oxopyridraidin-2-yl) -ß-D-glucopyranuronic acid were obtained (Compound 28) in the form of a white powder from F »146 to 150 ° C (decomp.).

Analysis: C 10 ^{1 1} Il O ₈ N ₂ F.2 / 3C ₂ H ₅ OH • 2 H ₂ O F 5 , 09 % Calculated: C. 36 , 49 H 5.13 N 7, 51 4th , 71 % Found: 36 , 62 4.96 7, 57

UV spectrum;

λ (0.02m phosphate buffer, pH 6.86) 266.5 nm

Example 34

Methyl 1-0- (5-fluoro-1H-4-oxopyrimidin-2-yl) -2,3 «4-tri-O-acetyl [beta] -D-glucopyranuronate

OAc 809818/0980

0.55 g (1.04 mmol) of methyl 1-0- (4-benzyloxy-5-fluoropyriraidin-2-yl) -2,3,4-tri-O-acetyl-ß-D-glucopyranuronate ( obtained as described in Example 29) in 40 ml of anhydrous methanol and replaced the atmosphere in the reaction vessel containing the solution with gaseous nitrogen. _{O 1} II g of 10% by weight palladium on charcoal were then added to the solution and the mixture was stirred for 7 minutes in a stream of gaseous hydrogen. After the completion of the reaction, the catalyst was removed by filtration and then the solvent was distilled off under reduced pressure to leave a residue. This residue was crystallized by adding anhydrous ethanol and gave 378 mg of the desired methyl-1-0- (5-fluoro-1H-4-oxopyrimidin-2-yl) -2,3,4-tri-O-acetyl-β -D-glucopyranuronate (compound 114) in the form of white crystals from F = 165 to 16 7 C.

Analysis: ^{C H} ₁ 7 ₁ 9 ₁₁ ^N ₂ ° ^F

Calculated: C 45.75 H 4.29 N 6.28 F 4.26 % Found: 45.35 4.35 6.32 4.02 %

UV spectrum:

(CH, 0H) 266 nm (£ 6400)

Example 35
1- 0- (5-fluoro-1H-4-oxopyrimidin-2-yl) -β-D-qlucopyranuronamide

809818/0980

357 mg (0.8 mmol) of methyl 1-0- (5-fluoro-1H-4-oxopyriraidin-2-yl) -2,3,4-tri-O-acetyl-β-D-glucopyranuronate were dissolved in
27 ml of anhydrous methanol and then saturated the solution with ammonia by introducing dry ammonia. The resulting mixture was left to stand in the refrigerator overnight. After completion of the reaction, the solution was concentrated by distillation under reduced pressure and the residue in
dissolved in a small volume of methanol. One added to the
Solution 10 ml of chloroform to give a precipitate which was collected by filtration and then suspended in chloroform. The suspension was stirred for 30 minutes
and then filtered to obtain 270 mg of a powder obtained by thin layer chromatography on silica gel with development with 50% by volume of methanol containing
Chloroform showed a single stain. F »120 to 125 ° C (decomp.)

Analysis: C ₁₀ H ₁₂ O ₇ N ₃ FH ₂ O

Calculated: C 37.16 H 4.37 N 13.00 F 5.88 % Found: 37.05 4.23 12.85 5.66 %

UV spectrum: X _max (0.02m phosphate buffer, pH 6.86) 268 nm (£ 6700) Example 36

N-Methy1-1-0- (4-benzyloxy-5-fluoropyrimidin-2-yl) -β-D-qlucopyranuronami d

C ₆ H ₅ CH ₂ O

CH3KK.CO

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Was dissolved 590 mg (I ₁ I mmol) of methyl 1-0- (4-benzyloxy-5-fluoropyrimidine-2-yl) -2,3,4-tri-O-acetyl-ß-D-glucopyranuronate in 40 ml anhydrous methanol. The solution was then saturated with methylamine by sparging dry methylamine into the solution. After closing the vessel containing the mixture with a stopper, the mixture was ^{stirred at 0 °} C. for 35 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue thus obtained was suspended in anhydrous ethanol, and the suspension was then stirred for 30 minutes. The precipitated powders were collected by filtration, washed with anhydrous ethanol and dried to obtain 378 mg of the desired N-methyl-1-0- (4-benzyloxy-5-fluoropyrimidin-2-yl) -β-D-glucopyranuronamide (Compound 53) in the form of a white powder which showed a single spot on thin layer chromatography on silica gel with development with chloroform containing 10% by volume of methanol. F = 181 to 182 ° C (dec.).

Analysis; ^c ₁ 8 ^H 2O ° 7 ^N 3 ^F

Calculated: C 52.81 H 4.92 N 10.27 F 4.64 % Found: 53.16 5.21 10.23 4.34%

UV spectrum:

k _mav (CH-QH) 265 nm (ε 7500)

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Example 37

N-MethYl-1- 0- (5-fluoro-> 1H ~ 4 ~ oxopyrimidin-2-Yl) -β-D-qluco pyranuronamide

300 mg (0.734 mmol) of N-methyl-1- 0- (4-benzyloxy-5-fluoropyrimidin-2-yl) -β-D-glucopyranuronamide were dissolved in 40 ml of anhydrous methanol and the atmosphere in the reaction vessel containing the solution was replaced by gaseous nitrogen. 37 mg of 10% by weight palladium on carbon was then added to the solution and the mixture was stirred while blowing hydrogen gas
passed until 15 ml of hydrogen had been absorbed.
After the completion of the reaction, the catalyst was removed by filtration and the solvent was reduced under reduced pressure
Distilled pressure. The powdery residue thus obtained was suspended in anhydrous ethanol and, after stirring for 30 minutes, collected by filtration. 142 mg of the desired N-methyl-1- 0- (5-fluoro-1H-4-oxopyrimidin-2-yl) -β-D-glucopyranuronamide (compound 115) were obtained in the form of a white
Powder with a melting point of 130 to 135 ° C (decomp.).

Analysis; ^c n ^H 14 ° 7 ^N 3 ^F

Calculated: C 40.25 H 4.61 N 12.80 F 5.79 % Found: 40.53 4.67 12.60 5.85 %

UV spectrum:

^X max (° » ^02m phosphate buffer, pH 6.86) 267 nm (£ 7400)

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7t

Example 38

Methyl 1-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-O-acetyl-β-D -qalactopyranuronate

Ac = acetyl

7.9 g of silver salt of O -benzyl-5-fluorine were suspended

uracils in 320 ml of dry toluene and then removed about 90 ml of solvent by distillation using a water separator to remove the water. The remaining suspension was allowed to cool. 9.1 g of methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-α-D-galactopyranuronate were added and refluxed the mixture for 30 minutes. After the completion of the reaction, insoluble substances were removed by filtration removed and the solvent was distilled off under reduced pressure. The residue was dissolved in 300 ml of ethyl acetate dissolved and the solution obtained successively with 200 ml of water, 300 ml of a 5 percent strength by weight aqueous sodium hydrogen carbonate solution and 200 ml of a 20 percent strength by weight aqueous sodium chloride solution. Each of the Wash water was extracted with 200 ml of ethyl acetate and the ethyl acetate solutions were combined. The United Solutions were dried over anhydrous magnesium sulfate, and then the solvent was distilled off, whereby a caramel-like residue remained. This residue was purified by column chromatography on silica gel using Purified of chloroform as the eluent, 10.1 g of the desired methyl-1-0- (2-benzyloxy-5-fluoro-

809818/0980

75

pyrimidin-4-yl) -2,3,4-tri-O-acetyl-β-D-galactopyranuronate (Compound 80) was obtained as a caramel-like substance which showed a single spot on thin layer chromatography.

Analysis: ^C 24 ^H 25 ° II ^N 2 ^F

Calculated: C 53.73 H 4.70 N 5.22 F 3.54% Found: 53.96 4.55 5.20 3.52 %

UV spectrum:

λ (0,0 In-HCl, CH-OH) 271 nm max ' i

\ nax ^(CH 3 ^{OH) 271 nm}

\ nax (° » ^ln - ^NaOH » CH ₃ OH) 270 nm

Example 39

Methyl 1-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D -qalactopyranuronate

A sodium methylate solution in methanol was prepared by dissolving 0.55 g of metallic sodium in 160 ml of anhydrous methanol and then cooling to -30 ° C. 6.44 g of methyl l-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-0-acetyl-β-D-galactopyranuronate were added to this solution and the mixture was left reacting under anhydrous conditions 6 * hours at -30 ⁰ C. 2.01 g of acetic acid, dissolved in 10 ml of anhydrous methanol, were then added and the neutral

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go

Iitat the mixture. The mixture was then reduced under reduced pressure Pressure evaporated to dryness to give a caramel-like residue which was then dissolved in 90 ml of ethyl acetate and once with 100 ml of an aqueous phosphate buffer solution (pH 7.0) and twice with 60 ml of a 10 percent by weight aqueous sodium chloride solution was washed. Each washing water was extracted with 50 ml of ethyl acetate, and the ethyl acetate solutions were combined and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and after the majority of the ethyl acetate has been removed 50 ml of isopropanol was added to the remaining mixture, and then this solvent was added gradually after removed. After the ethyl acetate odor completely disappeared the precipitated white powdery substance was collected by filtration and dried, whereby 1.8 g of the desired methyl 1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-galactopyranuronate (Compound 116).

Analysis: ^C ₁ 8 ^H 19 ^N 2 ^F 8 °

Calculated: C 52.68 H 4.67 N 6.83 F 4.63 % Found: 52.81 4.50 6.91 4.42%

UV spectrum:

^(H 2 ^{0) 27} ° ^nm

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Example 40 Methvl-l-0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -ß-D-qalakto-

pyranuronate

2.56 g of methyl 1-1-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-galactopyranuronate were dissolved in 90 ml of anhydrous methanol and the mixture was stirred for 15 minutes in a stream of hydrogen. The atmosphere in the reaction vessel was then replaced with nitrogen gas. 300 mg of 10% by weight palladium were then added on charcoal to the solution, and there were 134 ml of gaseous hydrogen at ambient temperature and atmospheric pressure absorbed. The catalyst was then removed by filtration and the solvent removed under reduced pressure a bath temperature below 30 ° C evaporated. When most of the methanol had evaporated, it was added Add 30 ml of ethanol to the residue and continue evaporation. This procedure was repeated twice and collected then a white powdery product by filtration to give 1.1 g of the desired methyl 1-0- (5-fluoro-IH-2-oxopyrimidin-4-yl) -β-D-galactopyranurotate (Compound 67).

Analysis: ^c i ^^ ° ^ ⁱ 2 ^F

Calculated: C 41.26 H 4.09 N 8.75 F 5.93 % Found: 41.55 4.30 8.77 5.99%

8 09818/0980

UV spectrum:

λ (0.02m phosphate buffer, pH 6.86) 288 nm

Example 41

1-0- (2-Benzyloxy-5-fluoropyrimidin-4-yl) -β-D-qalactopyran uronic acid

1.0 g of methyl 1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-galactopyranuronate (obtained as described in Example 39) was dissolved in 23 ml of a 6: 3.9: 0.1 volume mixture of methanol, V / water and concentrated aqueous ammonia and then allowed the solution to stand for 24 hours with stirring. Than the reaction was completed, the solvent was distilled off from the reaction mixture under reduced pressure, whereby 1.1 g of a caramel-like residue remained. This The residue was subjected to a preparative thin-layer chromatography and a fraction containing the desired compound using 35% by volume of methanol containing chloroform as a developing agent. This fraction was extracted with methanol and then the Methanol was evaporated from the extract to give a caramel-like residue. Ethanol was added to the residue and left the mixture to stand in a refrigerator, after which a powdery substance precipitated, which was then filtered was collected and the desired l-0- (2-benzyloxy-5-fluoro

pyrimidin-4-yl) -ß-D-galactopyranuronic acid (compound 117) revealed.

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- T? -

Analysis; C ₁₇ H ₁ ^ OqN ₂ P * 2H ₂ O Calculated: C 47.23 H 4.90 N 6.48 F 4.39 % Found: 47.56 4.51 6 ₄ 32 4.21 %

UV spectrum: \ nax ^(H 2 ^{0) 269 nm}

Example 42

-Fluoro-1H-2-oxopyrimidin-4-yl ^ -ß-D-qalactopyranuronic acid

396 mg of 1- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-galactopyranuronic acid were dissolved in 20 ml of anhydrous methanol and replaced the atmosphere in the reaction vessel with gaseous Nitrogen. 50 mg of 10% by weight palladium on carbon was added to the solution and the mixture was stirred at ambient temperature and ambient pressure while bubbling hydrogen until 22 ml of gaseous hydrogen was absorbed. After completion After the reaction, the catalyst was removed from the reaction mixture by filtration and then the methanol was added distilled off under reduced pressure. When most of the methanol was removed, it became anhydrous ethanol added to the remaining mixture and then continued distilling. The white powdery substance formed was collected by filtration, washed with anhydrous ethanol, and then to give the desired l-0- (5-fluoro-

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1H-2-oxopyrimidin-4-yl) -β-D-galactopyranuronic acid (compound 66) dried

Analysis: ^c ₁₀ ^H ₁₁ ° e ^N 2 ^F Calculated: C 39.22 H 3.62 N 9.15 P 6.20 % Found: 39.45 3.45 9.32 5.95 %

UV spectrum:

λ (0.02m phosphate buffer, pH 6.86) '288 nm

Example 43

0 ² -Benzyl-0 - (3,4, e-tri-O-acetyl - ^ - deoxy - ^ - trichloroethoxy carbonylamino-ß-D-qlucopyranosyl) -5-fluorouracil

NH.CO.OCH2CCI3

23.1 g (71 mmol) of the silver salt of 0-benzyl-5-fluorouracil were suspended in 710 ml of anhydrous toluene which had been dehydrated with calcium hydride and distilled. The suspension was then distilled until 50 ml of toluene had been removed to remove the water by azeotropic distillation. The suspension was allowed to cool to room temperature. A solution of 33.6 g (71 mmol) of 3,4,6-tri-O-acetyl ^ -deoxy ^ -trichloroethoxycarbonylamino ^ -oc-D-glucopyranosyl bromide was added to the suspension in 100 ml of dry toluene and the mixture was refluxed for 15 minutes with stirring. After completion

809818/0980

the reaction, insoluble substances were filtered off and that The filtrate was concentrated by evaporation in vacuo and dried to give a caramel-like residue, dissolved in 500 ml of ethyl acetate and then in turn with 300 ml of a 5 percent strength by weight aqueous sodium hydrogen carbonate solution and washed 500 ml of a saturated aqueous solution of sodium chloride · After filtering off, insoluble Substances, the organic phase was dried with anhydrous magnesium sulfate and then the solvent under evaporated under reduced pressure, 43.2 g of the desired

7 4
th 0 -Benzy1-0 - (3,4,6-tri-O-acetyl-2-deoxy-2-trichloroethoxycarbonylamino-β-D-glucopyranosyl) -5-fluorouracils (compound 94) in the form of a caramel-like substance. This substance was used without further purification in Example 44 below, but purified for analysis by column chromatography on silica gel using chloroform containing 1% by volume of methanol as the eluent.

UV spectrum;

(0, In-HCl in CH, OH) 270 nm (£ 6950)

λ ™ _v (CH-OH) 271 nm (£ 7260) max j

^X max <° » ^ln - ^{NaOH in} CH ₃ OH) 272 nm (£ 7310)

Nuclear Magnetic Resonance Spectrum _{(CDCl 3} ) 6 ppm:

6.30 (doublet, H in 1 * position, ^ ₁ ._ ₂ · ^{s 8} » ^{5 Hz)}

Analysis; C ₂₆ H ₂₇ O ₁₁ N ₃ Cl ₃ F ^ lZa CHCl

Calculated; C 43.77 H 3.81 N 5.81 F 2.56 % Found; 43.88 3.66 6.04 2.56%

8 0 9818/0980

Example 44

2 4

O -Benzyl-0 - (3,4 _< 6-tri-0-acetyl-2-ainino-2-deoxy-ß-D-qluco-

pyranosyl) -5-fluorouracil

CSH5CH2O ^ Λ

ÄC0.CÜ2

43.2 g (63.0 mmol) of the crude obtained in Example 43 was dissolved

2 4
0 -Benzyl-0 - (3,4,6-tri-0-acetyl-2-deoxy-2-trichloroethoxycarbonylamino-β-D-glucopyranosyU-5-fluorouracil in 200 ml of 80% acetic acid. In the meantime suspended 20.4 g (31.5 mmol) of zinc dust in 330 ml of 80% acetic acid were stirred for about 5 minutes and cooled with ice cooling to about 20 ° C. The solution was then added to the suspension with stirring and stirred the mixture was an additional hour and 10 minutes after the addition of 80% acetic acid After the completion of the reaction, insoluble substances were filtered off and then the solvent was evaporated under reduced pressure to give a residue, which was dissolved in 300 ml of ethyl acetate and then in turn with 300 ml of ice water, washed with 500 ml of a 5% strength by weight aqueous sodium hydrogen carbonate solution, with 200 ml of v / ater and with 200 ml of saturated saline solution Magne dried sodium sulfate. The solvent was then distilled off. The residue was dissolved in 200 ml of ethanol and the solution was distilled,

809818/0980

to narrow their volume to about 100 ml, after which they are over Left to stand at about 5 ° C overnight. The crystal precipitated was filtered off and dried to give 14.38 g of the desired one O -Benzyl-0 - (3,4,6-tri-0-acetyl-2-amino-2-deoxyβ-D-glucopyranosyl) -5-fluorouracils (Compound 118) in the form of colorless crystals from P β 141 to 142 ° C.

UV spectrum;

\ nax C ⁰ » ¹ " - ¹ ^ ^{1 in} CH ₃ OH) 270 nm (£ .6900) \ nax ^(CH 3 ^{0H) 271 nm} (t699O)

(0, In-NaOH in CH, OH) 270 nm (£ 6880)

Nuclear Magnetic Resonance Spectrum _{(CDCl 3} ) A ppm:

8.24 (doublet, H in 6-position, Jg _H _ _p = 2.0 Hz) 5.90 (doublet, H in! 'Position, J ₁ I _-2 ' ~ ⁸ ' ^{5 Hz)} 5.40 (Singlet, -CH _-2 -CgH ₅

Analysis; ^c ₂ 3 ^H ₂ 5 ° g ^N 3 ^F

Calculated: C 54.44 H 5.16 N 8.28 P 3.74% Found: 54.18 5.44 8.28 3.45 %

Example 45

0 - (3,4,6-T 5-fluorouracil

0 - (3,4,6-tri-0-acetyl-2-amino-2-deoxy-ß-D-qlucopyranosyl)

Ac β acetyl 809818/0980

517 mg of O-benzyl-0 - (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil were dissolved in 50 ml of anhydrous ethanol. The atmosphere was then replaced with the solution containing reaction vessel by dry gaseous nitrogen, added 50 mg of 10% by weight palladium on carbon and stirred the solution while passing in gaseous hydrogen at atmospheric pressure, up to 20 ml of gaseous hydrogen is absorbed had been. After the completion of the reaction, the catalyst was filtered off and the filtrate was filtered off under reduced pressure concentrated by evaporation. The residue was dissolved in 5 ml of anhydrous methanol, there became 20 ml of anhydrous ethanol was added, and then the solution was concentrated by evaporation under reduced pressure to give crystals which were filtered off and dried. 250 mg of the desired 0 - (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil were obtained (Compound 99) from F = 129 to 130 ° C (decomp.).

UV spectrum:

\ nax ^(CH 3 ^{0H) 291 nm (ε} 5010)

HMR spectrum (Dimethyl sulf ο xyd-d, -) δ ppm:

8.13 (doublet, H in 6-position, J _6R _ _p = 5.5 Hz) 6.06 (doublet, H in 1'-position, J _lt _ ₂ i = ⁸ ° ^Hz >

Analysis: C ₁₆ H ₂₀ O ₉ N ₃ FH ₂ O

Calculated: C 44.14 H 5.09 N 9.65 F 4.36 % - Found: 44.05 4.77 9.39 3.87%

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_. *, _ 27Α8562

Example 46

O A.

O -Benzyl-0 -P ^ .e-tri-O-acetvl-Z-amino ^ -deoxy-ß-D-qlucopyranosyl) -5-fluorouraci! -Hydrochloride 3.04 g (6 mmol) O ² - Benzyl-O ⁴ - (3,4,6-tri-O-acetyl-2-amino-3-deoxy-β-D-glucopyranosyl) -5-fluorouracil, obtained as described in Example 44, in 160 ml of acetone. A solution of 1.96 ml of diethyl ether containing 0.95 equivalents of hydrogen chloride in 40 ml of acetone was added dropwise. After completion of the reaction, the white precipitate formed was filtered off, washed with acetone and dried, whereby 2.67 g of the desired product were obtained in the form of white crystals with an melting point of 171 ° to 172 ° C. (decomp.). The filtrate was concentrated to give a crystalline residue, to which 200 ml of acetone was added. A further 378 mg of the desired product were obtained by filtering off the residue, washing with acetone and drying. This product also had a melting point of 171 to 172 ° C (decomp.).

UV spectrum;

X _{m = iv} (CH, OH) 270 nm (S 7030)

Nuclear Magnetic Resonance Spectrum (dimethylsulfoxy-d _g ) 0 ppm:

8.63 (doublet, H in 6-position, J _6H _ _p = 2.7 Hz) 6.78 (doublet, H in l'-position, J _11-2 I ■ 8 »5 Hz)

Analysis; C ₂₃ H ₂₆ O ₉ N ₃ F-HCl

Calculated: C 50.79 H 5, OO N 7.73 Cl 6.52 F 3.49% Found: 50.84 4.98 7.80 6.55 3.30 %

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do

Example 47

O - (3 _< 4,6-tri-0-acetyl-2-amino-2-deoxv-β-D-qlucopvranosyl) -5-fluorouracil hydrochloride

54.4 mg of 0-benzyl-0 - (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil hydrochloride were dissolved in 50 ml of anhydrous methanol. The atmosphere in the vessel containing the solution was replaced with dry gaseous nitrogen. 50 mg of 10% by weight palladium on carbon were added and hydrogen was passed in while stirring at atmospheric pressure through the solution until 20 ml of hydrogen gas has been absorbed was. After the reaction had ended, the catalyst was filtered off and the filtrate was concentrated to give crystals, which were filtered off, washed with anhydrous ethanol and then dried to give white crystals of the desired 0 - (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -S-fluorouracil hydrochloride from F = 112 to 116 C (dec.).

Analysis; C ₁₆ H ₂₀ O ₉ N ₃ F-HCl-H ₂ O Calculated: C 40.73 H 4.70 N 8.91 Cl 7.51 F 4.03 % Found: 40.66 4.67 9.55 7 .23 3.57 %

Example 48

2 4

O -Benzyl-0 - (2-amino-2-deoxy-β-D-qlucopyranosyl) -5-fluorouracil

809818/0980

- 62 -

2.06 g (4 mmol) of O ² -benzyl-O ⁴ - (3,4,6-tri-O-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil were dissolved in a mixture of 30 ml of anhydrous methanol and 20 ml of methylene chloride and the solution cooled to -35 ° C. 8 ml of in-methanolic sodium methylate solution were added and the mixture was left at a temperature of -30 to -25 ° C. for 2 hours. The solution was then cooled to -40 ° C. and 10 ml of anhydrous methanol in 528 mg of acetic acid were added; a solution of anhydrous methanol in 0.1 ml of acetic acid was added dropwise to adjust the pH to 6 to 7, after which the solvent was evaporated under reduced pressure to give a gel-like residue. To this residue were added 50 ml of O, ln-phosphoric acid buffer solution and 50 ml of ethyl acetate, and the mixture was stirred well to form a precipitate, which was crushed, filtered off, washed each with 20 ml of ethyl acetate and water and then dried to obtain 597 mg of the desired

2 4
0 -Benzyl-0 - (2-amino-2-deoxy-ß-D-glucopyranosyl) -5-fluorouracils in the form of white crystals with a melting point of 124 to 126 ° C (dec.).

UV spectrum;

(CH, OH) 270 nm (t 6930)

Nuclear Magnetic Resonance Spectrum (dimethylsulfoxide-dg) <5 ppm: 8.50 (doublet, H in 6-position, Jg _H _ _p - 2.5 Hz) 5.83 (doublet, H in l'-position, J _{11- 2} t ^{β 8} »° Hz) 5.4O (singlet, -CH _-2 - C ₆ H ₅ )

Analysis; C ₁ -H ₂₀ OgN ₃ F

Calculated: C 53.54 H 5.29 N 11.02 F 4.93 % Found: 53.50 5.45 11.03 4.51%

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dz

Example 49

O- (2-Amino-2-deoxy-β-D-qlucopyranosyl) -5-fluorouracil

2 4
762 mg (2 mmol) of O-benzyl-0 - (2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil were dissolved in 60 ml of anhydrous methanol. The atmosphere in the vessel containing the solution was replaced with dry gaseous nitrogen and then 100 mg of 10% by weight palladium on carbon were added. Hydrogen was bubbled through the solution at room temperature with stirring until 46 ml of hydrogen had been absorbed. After the completion of the reaction, the catalyst was filtered off, and then the filtrate was concentrated by evaporation under reduced pressure to give crystals. A small volume of anhydrous ethanol was added to these and then filtered off

4th
and dried to obtain the desired 0 - (2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil (Compound 82) in the form of white crystals, mp = 120 to 130 ° C (dec.) .

Analysis: C ₁₀ H ₁₄ O ₆ FH ₂ O-CH ₃ OH

Calculated: C 38.71 H 5.91 N 12.31 F 5.57% Found: 38.59 5.62 12.06 5.26%

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Example 50

0 -benzyl-0 carbonylamino-ß-D-qlucopyranosyD-S-fluorouracil

0 -Benzyl-0 - (3 «4 _< 6-tri-0-acetyl ~ 2 - deoxy-2-trichloroethoxY-

KH.CO.OCH2CCI3

Ac β acetyl

10.8 g (33 mmol) of the silver salt of O ⁴ -benzyl-5l fluorouracil were suspended in 330 ml of anhydrous toluene which had been dehydrated with calcium hydride and then distilled. The suspension was then heated in order to distill off about 30 ml of toluene and in this way to remove water by azeotropic distillation. It was then cooled to room temperature. A solution of 17.9 g (33 mmol) of 3,4,6-tri-C) acetyl-2-deoxy-2-trichloroethoxycarbonyllamino-cc-D-glucopyranosyl bromide in 30 ml of anhydrous toluene was then added to the suspension and refluxed the mixture for 30 minutes. After the reaction had ended, a crystalline precipitate was filtered off and the filtrate was distilled under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate and washed once with 150 ml of a 5 percent strength by weight aqueous sodium hydrogen carbonate solution and twice with 200 ml of water. Each of the washing waters was extracted with 50 ml of ethyl acetate, and the ethyl acetate solutions were combined and dried over anhydrous magnesium sulfate. The solvent was then distilled off, and 26.3 g of the desired O ⁴ -benzyl-O ² - were obtained

809818/0980

O ^^ - tri-O-acetyl ^ -deoxy - ^ - trichlorethoxycarbonylaminoß-D-glucopyranosyl) -5-fluorouracils in the form of a raw caramel-like product. For identification purposes, this crude product was analyzed by silica gel chromatography using chloroform containing 1% by volume of methanol as
Eluant purified, but it was used as starting material for Example 51 below without further purification.

UV spectrum:

λ (0, In-HCl in CH ^ OH) 265 nm (ε 6900)

λ (H _o 0 / CH ^ 0H) 265 nm (& 8200)

λ (0, In-NaOH in CH., OH) 266 nm (fc. 8000)

Nuclear Magnetic Resonance Spectrum _{(CDCl 3} ) 6 ppm:

8.48 (doublet, H in 6-position, J _{6R p} = 2.6 Hz) 8.18 (doublet, H in l'-position, J ₁ , _ ₂ ^{= 9} »° ^Hz ^ 5.55 ( Singlet, -CH ₂ -C ₆ H ₅

Analysis: C ₂₆ H ₂₇ O ₁₁ N ₃ Cl ₃ F ₃ VsCHCI O ^ _CH3 OH Calculated: C 44.80 H 4.11 N 5.89 Cl 16.76 F 2.66% Found: 44.63 3 .82 5.57 16.72 2.41 %

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IS

Example 51

4 2

Ο -Benzyl-0 ~ (3,4 _< 6-tri ~ 0-acetyl-2-amino-2-deoxy-ß-D-gluco pyranosyl) -5-fluorouracil

C6K5CK2O

ÄCÖ.CH2

Ac = acetyl

Was suspended 9.8 g (150 mmol) of zinc dust in 250 ml of 80% acetic acid and the mixture was stirred at room temperature and cooled to about 20 ⁰ C. A solution of 20.5 g (30 mmol) of crude 0 -benzyl-0 ² - (3,4, e-tri-O-acetyl ^ -deoxy ^ -trichloroethoxycarbonylaminoß-D-glucopyranosyl) -5 was added to the suspension obtained -fluoruracil, which had been prepared in Example 50, in 80 ml of 80% acetic acid. The mixture was then stirred at room temperature for 2 hours. After the completion of the reaction, insoluble substances were filtered off and the solvent was distilled off under reduced pressure to give a caramel-like residue. This residue was dissolved in 350 ml of ethyl acetate and washed once each time with 300 ml of ice water, 300 ml of an aqueous sodium hydrogen carbonate solution and 300 ml of ice water. Each of the washing waters was extracted with 100 ml of ethyl acetate, and then the ethyl acetate solutions were combined. The United

809818/0980

Solutions were dried over anhydrous magnesium sulfate and then distilling off the solvent to give a residue, which was dissolved in ethanol. The ethanol solution was concentrated to give crystals which

4 were filtered, 10.7 g of the desired 0 -benzyl-

ρ
0 - (3,4, δ-tri-O-acetyl ^ -amino-deoxy-ß-D-glucopyranosyl) -5-fluorouracils (compound 120) of mp = 61-62 ° C.

UV spectrum:

(0, In-HCl in CH-OH) 263.5 nm (£ 8300) (H ₂ O / CH ₃ OH) 265 nm (£ 8200) (0, In-NaOH in CH, .OH) 265 nm (£ 8200)

«5

NMR spectrum (dimethylsulfoxide-d) 6 ppm: 8.49 (doublet, H at the 6 position, Jg _{p H} = 2.6 Hz) 5.94 (doublet, H at the l'-position, J _lt _ ₂ t = ⁸ i ^{5 Hz} > 5.58 (singlet, -CH ₂ -C ₆ H ₅ )

Analysis: C ₂₃ H ₂₆ O ₉ N ₃ FO ₁ SC ₂ H ₅ OH Calculated: C 54.34 H 5.51 N 7.92 F 3.58% Found: 53.91 5.31 8.00 3.50 %

8098 18/0980

Example 52

Ο ² - (3,4 _< 6-tri-0-acetyl-2-amino-2-deoxy-ß-D-qlucopyranosyl)

5-fluorouracil

ÄcO.CH2

Ac = · acetyl

507 mg (1 mmol) of O ⁴ -benzyl-O ² - (3,4,6-tri-O-acetyl-2-amino-2-deoxy-β-D-glucbpyranosyl) -5-fluorouracil were dissolved in 30 ml anhydrous methanol. The atmosphere in the reaction vessel containing the solution was replaced by dry gaseous nitrogen. 50 mg of 10% by weight palladium on carbon was then added to the solution and gaseous hydrogen was bubbled through at room temperature until 23 ml of gaseous hydrogen had been absorbed. After the completion of the reaction, the catalyst was filtered off and then the solvent was distilled off under reduced pressure. To the residue thus obtained, anhydrous methanol was added and the mixture was concentrated by evaporation under reduced pressure to obtain a precipitate. This precipitate was filtered off, washed with anhydrous ethanol and dried

■ 2

net, whereby 283 mg of the desired 0 - (3,4,6-tri-O-acetyl-2-amino-2-deoxy-ß-D-glucopyranosyl) -5-fluorouracils (Compound 100) in the form of a white powder from P = 103 to 104 ° C received.

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UV spectrum;

(CH ₃ OH) 267 nm (£ 6000)

Nuclear Magnetic Resonance Spectrum (Dimethylsulfoxide-d, -) 6 ppm:

7.84 (doublet, H in 6-position, J _{& H} _ _p = 3.7 Hz) 5.97 (doublet, H in 1'-position, J _11-2 I = ⁸ » ^{3 Hz} >

Analysis: C ₁₆ H ₂₀ O ₉ N ₃ F * 0.5H ₂ O

Calculated: C 45.07 H 4.96 N 9.86 F 4.46 % Found: 45.33 5.33 9.93 3.92 %

Example 53

0 -Benzyl-0 - (3 _< 4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-qlTjcopyranosyl) -5-fluorouracil hydrochloride 9.3 g (18.3 mmol ) O ⁴ -Benzyl-O ² - (3,4,6-tri-O-acetyl-2-amino-2-deoxy-ß-D-glucopyranosyl) -5-fluorouracil (obtained as described in Example 51) in a Mixture of 60 ml of acetone and 30 ml of diethyl ether. An ethereal solution containing 1 equivalent of hydrochloric acid was then added to the solution while cooling with ice. After completion of the reaction, about 80 ml of acetone was added to the reaction mixture, whereby crystals were precipitated. These crystals were crushed, filtered off, washed with acetone and then dried, whereby

4 2
8.5 g of the desired 0 -benzyl-0 - (3,4,6-tri-O-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil hydrochloride

in form ■

received.

in the form of white crystals from F = 157 to 159 ° C (decomp.)

UV spectrum:

(CH.OH) 263 nm (ε 7600)

Nuclear Magnetic Resonance Spectrum (methyl sulfoxide-d _g ) <$ ppm: 8.55 (doublet, H in 6-position, J _ßH _ = 2.5 Hz) 6.57 (doublet, H in l'-position, J _{11- 2} , = 8.0 Hz) 5.61 (singlet, -CH ₂ -C ₆ H ₅ )

809818/0980

27A8562

34

Analysis: C ₂₃ H ₂₆ O ₉ N ₃ F-HCl

Calculated: C 50.48 H 5.00 N 7.73 Cl 6.51 F 3.49 % Found: 50.48 5.03 7.55 6.50 3.28 %

0 - (3,4,6-tri-0-acetyl-2-amino-2-deoxy-ß - D-qlucopyranosyl) -

Example 54

O ² - (3,4,6-Tj S-fluorouracil hydrochloride

544 mg (1 mmol) of O ⁴ -benzyl-O ² - (3,4,6-tri-O-acetyl-2-atnino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil hydrochloride were dissolved in 50 ml of anhydrous methanol. The atmosphere in the reaction vessel containing the solution was then replaced by dry gaseous nitrogen. 50 mg of 10% by weight palladium on carbon was added to the solution and then the mixture was stirred at room temperature while bubbling gaseous hydrogen through until 21 ml of gaseous hydrogen had been absorbed. After the completion of the reaction, the catalyst was filtered off, and then the filtrate was concentrated by evaporation under reduced pressure to obtain crystals. A small volume of anhydrous ethanol was then added and the distillation continued. The obtained crystals were filtered off, washed with anhydrous ethanol and then dried to obtain 304 mg of the desired 0 - (3,4,6-tri-O-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5 -fluoruracilhydrochlorids in the form of white crystals from F = 140 to 148 ° C (dec.).

UV spectrum:

\ nax i ^Pnos P ^{nat buffer} »P ^H 6.86) 266 nra (£ 6000)

Nuclear Magnetic Resonance Spectrum (dimethyl sulfoxide-d _g ) 6 ppm:

7.94 (doublet, H in 6-position, J _gH _ _p »3.5 Hz) 6.32 (doublet, H in l'-position, J _11-2 , - 8.0 Hz)

Analysis: C ₁₆ H ₂₀ O ₉ N ₃ F-HCl

Calculated: C 42.35 H 4.66 N 9.26 Cl 7.81 F 4.19 % Found: 42.03 4.56 9.00 7.77 3.83 %

809818/0980

Example 55

A. O

O -Benzyl-0 - (2-aniino-3-deoxy-β-D-qlucopyranosyl) -5-fluorouracil

C6Ü5CH2O

2.18 g (4 tnmol) of O ⁴ -benzyl-O ² - (3,4,6-tri-O-acetyl-2-amino-2-deoxy-ß-D-glucopyranosyl) -5-fluorouracil- hydrochloride (obtained as described in Example 53) in 50 ml of anhydrous methanol and the solution was cooled to -30.degree. The addition of 4 ml (1 equivalent) of an in-methanolic sodium methylate solution resulted in a white precipitate of the free amino compound, which was dissolved by the further addition of 30 ml of methylene chloride. 8 ml (2 equivalents) of a sodium methylate solution in methanol were then added and the mixture was stirred for 3.5 hours at -30 5 ° C. After the solution had cooled to -40 ° C., 10 ml of v / aqueous methanol were added dropwise containing 625 mg (10.4 mmol) of acetic acid. The mixture was then distilled under reduced pressure to obtain a residue, to which 30 ml of an 1 m phosphoric acid buffer solution (pH 6.5) was added to obtain crystals. These crystals were filtered off, washed with water and dried, whereby

4 2
1.53 g of the desired 0 -benzyl-0 - (2-amino-2-deoxy-ß-D-glucopyranosyl) -5-fluorouracil in the form of white crystals with a melting point of 116 ° to 119 ° C. was obtained.

809818/0980

27A8562

UV spectrum:

λ _ν (0, In-HCl) 262 nm ( t 8100) (H ₂ O / CH ₃ OH) 264 nm ( t 7900) (0, In-NaOH) 265 nm (£ 8000)

Nuclear Magnetic Resonance Spectrum (dimethyl sulfoxide-d _g ) 6 ppm:

8.50 (doublet, H in 6-position, 5.80 (doublet, H in l'-position, 5.55 (singlet, -CT ₂ C ₆ H ₅ )

__ _p

■ 2.5 Hz) ^{β 8} » ^{5 Hz)}

Analysis; C ₁₇ H ₂₀ OgN ₃ F'2H ₂ O-Calculated: C 44.29 H 5.30 N 9.12 P 4.12 % Found: 43.76 5.34 9.58 4.29 %

Example 56

0 - (2-Amino-2-deoxy-β-D-qlucopyranosyl) -5-fluorouracil

762 mg (2 mmol) of 0 ⁴ -benzyl-0 ² - (2-amino-2-deoxy-ß-D-glucopyranosyl) -5-fluorouracil were dissolved in 60 ml of anhydrous methanol and the atmosphere in the vessel containing the solution was replaced by dry gaseous nitrogen. 100 mg of 10% by weight palladium on carbon were then added and passed through

809818/0980

- 93--

the solution under atmospheric pressure: and with stirring gaseous Hydrogen until 46 ml of gaseous hydrogen had been absorbed. When the reaction was complete, the catalyst became filtered off and then the filtrate by evaporation under reduced Pressure concentrated to give crystals. 40 ml of anhydrous ethanol were added and the distillation was then continued away. The obtained crystals were filtered off to give 516 mg of the crude product. This crude product was in 80 ml Dissolved anhydrous methanol, and then 30 ml of anhydrous ethanol were added. The solution was then obtained by evaporation concentrated under reduced pressure to give a powder which filtered off, washed with anhydrous ethanol and then dried to give 233 mg of the desired 0 - (2-amino-3-deoxy-β-D-glucopyranosyl) -5-fluorouracils (compound 86) in pure form as a white powdery substance from F = 161 to 165 ° C (decomp.).

UV spectrum;

\ (Phosphate buffer, pH 6.86) 267 nm (S 4400)

Analysis; C.

Calculated; C 34.45 H 5.90 N 10.04 F 4.54 % Found: 34.68 5.76 9.53 4.43 %

809818/0980

Example 57

N-Methyl-1- 0- (2 ^ benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-O-acetyl-β-D-glucopyranuronamide

C6H5CH2O

CH3KUXO

2 3.27 g (10 mmol) of silver salt of 0-benzyl-5-fluorouracil were suspended in 130 ml of dry xylene which had been dehydrated with calcium hydride and distilled. One distilled then approx. 30 ml of solvent using a water separator to remove water from the suspension, and then allowed the remaining mixture to cool. 3.96 g (10 mmol) of 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-N-methyl-cc-D-glucopyranuronamide were then added to the suspension and the mixture was refluxed for 5 minutes. After the reaction has ended insoluble materials were filtered off and the solvent was then distilled off under reduced pressure, leaving a residue. This residue was dissolved in 200 ml of ethyl acetate and then first with a 5 percent by weight aqueous sodium hydrogen carbonate solution and then washed with a 20 percent strength by weight sodium chloride solution. Each of the washing waters was extracted with 100 ml of ethyl acetate. The ethyl acetate solutions were then combined and washed with anhydrous Dried magnesium sulfate. The solvent was removed by distillation to leave a caramel-like residue

809818/0980

to obtain. This residue was used in Example 58 below without further purification. For analytical samples however, portions of the material were purified by column chromatography on silica gel, with chloroform eluted to give the desired N-methyl-1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-O-acetyl-β-D-glucopyranuron amide (compound 27) as a chromatographically pure caramel-like substance.

Analysis: C ₃₄ H ₂₆ O ₁₀ N ₃ F Calculated: C 53.83 H 4.89 N 7.85 F 3.55% Found: 53.59 4.66 7.81 3.31 %

UV spectrum:

\ nax ^(CH 3 ^{OH) 271 nm}

\ nax (° » ^ln - ^{NaOH in} CH ₃ OH) 271 ntn (0, In-HCl in CHoOH) 271 nm

Example 58

N-Methyl-1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-qlucopyranuronamide

To 30 was added 2.67 g (5 mmol) of N-methyl-1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3 ^ -tri-O-acetyl-β-D-glucopyranuronamide ml of a 3: 2 volume mixture of anhydrous methanol and methylene chloride. After the mixture had been cooled with ice water, 2.5 ml of an in-methanolic solution of sodium methylate were added and the mixture was stirred, the stirring being continued at 0 ^° C. for a further 40 minutes. After the reaction had ended, 2.5 ml of in-acetic acid in methanol were added in order to neutralize the reaction mixture, and the solvent was then distilled off under reduced pressure. The residue was dissolved in ethyl acetate and then the solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation to give 1.80 g of a caramel-like residue. This residue became one

8098 18/0980

Silica gel column chromatography using Chloroform containing 10% by volume of methanol as an eluent subjected. The solvent was removed from the collected eluate by distillation under reduced pressure and the residue obtained was dissolved in a small volume of methanol. A small amount of ethanol was then added. The solution was then concentrated to about 30 ml by evaporation under reduced pressure to give the desired N-methyl-1- 0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -β-D-glucopyranuronamide in the form of a white powdery material. The physical properties of this product were completely correct with those of the product obtained in Example 19.

809818/0980

Claims (1)

Claims 1. For use as anti-tumor agents or as intermediates 5-fluorouracil derivatives of the formula (I) suitable for the production of anti-tumor agents: (D 1 2
wherein one of the radicals R and R is a hydrogen atom or a hydroxyl protective group and the other is one of the following glycoside radicals HR ³ OR \ and η means in which R represents a hydrogen atom or an acyl group, R is the group -OR (in which R has the meaning given above), an amino group or a protected one Amino group means and 4th
R is a hydroxy group, an alkoxy group, a cycloalkoxy group, an aralkoxy group, an aryloxy group or an amino group of the formula 809818/0980 ORIGINAL INSPECTED means in which R and R are identical or different and each represents a hydrogen atom, an alkyl group, a Cycloalkyl group, an aralkyl group or an aryl group, or R and R together with the Nitrogen atom to which they are attached represent a 5- to 7-membered cyclic amino group, and when R represents an amino group, its pharmaceutical acceptable salts. 2 · Compounds according to claim 1, characterized in that 1 2
one of the radicals R and R is a hydrogen atom, a benzyl group, a substituted benzyl group with one or more nitro and / or halogen substituents in the phenyl moiety or a β-haloethyl group and the other is one of the glycoside radicals mentioned in which R represents a hydrogen atom, an aliphatic acyl group with 2 to 4 carbon atoms or an aromatic acyl group with 7 to 11 carbon atoms, R is the group -OR (in which R has the meaning given above), an amino group, a benzyloxycarbonylamino group, a substituted benzyloxycarbonylamino group with one or more nitro and / or halogen substituents in the phenyl part or a ß-halogen ether oxycarbonylamino group means and R is a hydroxyl group, a straight-chain or branched alkoxy group with 1 to 8 carbon atoms, a cycloalkoxy group with 5 to 7 ring carbon atoms, an aralkoxy group with 7 to 12 carbon atoms, a substituted aralkoxy group with 7 to 12 carbon atoms (in which the aromatic ring has one or more C ₁ - C ₄ -alkyl, C ₁ -C ₄ -AIkOXy or halogen atom substituents), an aryloxy group with 6 to 10 carbon atoms, a substituted aryloxy group with 6 to 809818/0980 10 carbon atoms (in which the aromatic ring has one or more C ₁ -C ₄ -AllCyI, C ₁ -C ₄ -AlkOXy or halogen atom substituents) or an amino group of the formula wherein R and R are the same or different and each represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, a substituted aralkyl group having 7 to 12 carbon atoms (wherein the aromatic ring has one or more C ₁ -C ₄ -alkyl, C ₁ -C ₄ -AlkOXy or halogen atom substituents), an aryl group with 6 to 10 carbon atoms, a substituted aryl group with 6 to 10 carbon atoms (with one or several C ₁ -C ₄ -C ₁ -C _A alkoxy or halogen atom substituents on the 5 ß aromatic ring) or R and R together with the nitrogen atom to which they are bonded, a Represent 5- to 7-membered cyclic amino group. 3. Compounds according to claim 2, characterized in that 1 2
one of the radicals R and R is a hydrogen atom, a benzyl group or a β-haloethyl group and the other is the glycoside radical mentioned, in which R denotes a hydrogen atom or an acetyl group, R is an -OR group (where R is as defined above), an amino group, a benzyloxycarbonylamino group or a ß-haloethoxycarbonylamino group and 4th
R is a hydroxyl group, a straight-chain or branched alkoxy group having 1 to 8 carbon atoms or an amino group of the formula 809818/0980 represents wherein R and R are the same or different and each represents a hydrogen atom or a straight-chain or branched C 1 -C 6 alkyl group. 4. Compounds according to claim 1, namely: 10- (5-fluoro-1H-2-oxopyrimidin-4-yl) -β-D-glucopyranuronic acid Methyl l-0- (5-fluoro-lH-2-oxopyrimidin-4-yl) -β-D-glucopyranuronate 0 - (β-D-glucopyranosyl) -5-fluorouracil 1-0- (5-Fluoro-1H-4-oxopyrimidin-2-yl) -β-D-glucopyranuronic acid Methyl l-0- (5-fluoro-lH-4-oxopyrimidin-2-yl) -β-D-glucopyranuronate 1-0- (5-fluoro-1H-4-oxopyrimidin-2-yl) -β-D-glucopyranuronamide 0 - (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil or its hydrochloride 2
0 - (3,4,6-tri-0-acetyl-2-amino-2-deoxy-ß-D-glucopyranosyl) - 5-fluorouracil or its hydrochloride 5. Process for the preparation of 5-fluorouracil derivatives, thereby characterized in that a compound of the formula (I) (D 809818/0980 [wherein one of R and R is a hydrogen atom or is a hydroxy protecting group and the other is one of the glycoside residues R0XH2 RO J-O, / H means in which R denotes a hydrogen atom or an acyl group, R is an -OR group (where R is as defined above), represents an amino group or a protected amino group and 4th
R is a hydroxy group, an alkoxy group, a cycloalkoxy group, an aralkoxy group, an aryloxy group or an amino group of the formula means in which R and R, the same or different are each a hydrogen atom, an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group represent or R and R together with the nitrogen atom to which they are attached form a 5- to 7-membered structure mean cyclic aroino group] 809818/0980 - «72 - or, when R represents an amino group, prepare an acid addition salt thereof by: (a) Implementation of a compound of the formula (II): (H) 7 8
(wherein one of R and R is a metal ion and the other is a hydroxy protecting group) with a
Compound of the formula (III): R ⁹ -X (III) [where X is a halogen atom and R is one of the glycoside radicals of the formulas HR ³ ' .1 J-öH OR ¹ around! u N ^ äxF il R , 3 ' represents where 809818/0980 R ^{1 is} an acyl group, R ³ 'is an -OR' group (in which R ^{1 has} the meaning given above) or a protected amino group and R ⁴ 'is an alkoxy group, a cycloalkoxy group, an aralkoxy group, an aryloxy group or an amino group of the formula "5 (in which R and R have the meanings given above)] to obtain a compound of the formula (IV) (IV) iO 11 (in which one of the radicals R and R is a hydroxy protective 9 represents group and the other represents group R), (b) if necessary, subjecting this compound of the formula (IV) to reduction and / or hydrolysis in any desired manner Order to give the compound of formula (I), and (c) if necessary subjecting this compound to formula (I) salt formation to give an acid addition salt thereof. 80981 & / 0980 6. The method according to claim 5, characterized in that the metal ion is a silver, mercury, sodium or potassium ion or the ion is HgCl or HgBr. 7. The method according to claim 5 or 6, characterized-characterized, that step (a) in the presence of a solvent selected from aromatic hydrocarbons, dialkylaliphatic Acid amides, dialkyl sulfoxides, phosphoric acid amides, nitroalkanes and nitriles. 8. The method according to any one of claims 5 to 7, characterized in, that the reaction is carried out at a temperature of 0 to 150 ° C. 9. The method according to claim 8, characterized in that in step (a) a non-polar solvent is used and that this step is carried out at a temperature of 100 to 150 ⁰ C. 10. The method according to claim 8, characterized in that step (a) in the presence of a polar solvent and is carried out at a temperature of about room temperature. 11. The method according to any one of claims 5 to 10, characterized in that that the reduction in stage (b) is carried out with the aid of hydrogen and a catalyst. 12. The method according to claim 11, characterized in that the catalyst is palladium on carbon or activated carbon. 13. The method according to any one of claims 5 to 10, characterized in that that the reduction in step (b) is carried out with the aid of metallic zinc and an acid or an alcohol will. 14. The method according to claim 13, characterized in that the acid is acetic acid. 809818/0980 15. The method according to claim 13, characterized in that the alcohol is methanol or ethanol. 16. The method according to any one of claims 5 to 15, characterized in that the hydrolysis in step (b) with the aid
a base is carried out in the presence of a solvent. 17. The method according to claim 16, characterized in that the base is ammonia or an alkali metal alcoholate. 18. The method according to any one of claims 5 to 17, characterized in, that the salt formation in step (c) is carried out with the aid of hydrochloric acid. 809818/0980