JPS61246196A - 5'-o-acyl-5-fluorouridine and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [n is 6-14; R is group shown by the formula II or formula II (R1 and R2 are H or lower alkyl; R3 is H or carboxyl; R4 is 5-20C alkyl)] and its salt. EXAMPLE:Hydrodien-2-aminoethyl-{ 3-palmitoyl-2-[ 13-(5-fluorouridin-5'-O-ylcar bonyl)tridecanoyl]}-1-glycerophosphate. USE:An anti-malignant tumor agent, etc. PREPARATION:A properly protected compound shown by the formula I (R is group shown by the formula IV or V) is reacted with a properly protected compound shown by the formula VI (e.g., N-benzyloxycarbonylaminoethanol, etc.) in a solvent such as pyridine, etc., in the presence of a condensation agent. The starting raw material is novel and obtained by condensing a compound shown by the formula I (R is H) with a glycerin 3-carboxylic acid ester protected at the 1-position and phosphorylating the 1-position of glycerin.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 5°-0-acyl-5-fluorouridine represented by the general formula, pharmacologically acceptable salts thereof, and methods for producing them.

5-Fluorouridine was synthesized in 1859 (U.S. Patent No. 2,885,31a8), and its anti-malignant tumor activity is already known, but despite its excellent anti-malignant tumor activity, it has strong side effects. However, many attempts have been made to solve this problem by making 5-fluorouridine into various derivatives. Year 84th, 28th
No. 0, No. 82,079, No. 83,378, Japanese Unexamined Patent Publication No. 5
No. 52,183, etc.), but nothing useful has yet been obtained.

In order to solve this problem, the present inventors conducted research on a 5'-0-ester compound of 5-fluorouridine, and
The present invention has now been completed.

5'-0-acyl-5-fluorouridine according to the present invention is a novel compound represented by the general formula, and is useful as a medicine, particularly as an anti-malignant tumor agent, an anti-viral agent, and an immunosuppressant.

As shown in Tables 1 and 2 at the end, the anti-malignant tumor effects of these compounds are as follows:
．． This is indicated by an extension of 5 times or more.

Next, the manufacturing method will be described.

The 5'-0-acyl-5-fluorouridine according to the present invention is a 5'-0-acyl-5-fluorouridine derivative represented by the general formula (I). As described above, R3 can be obtained by reacting amines represented by the following formulas.

The reaction is carried out in an organic solvent in the presence of a condensing agent at a temperature below 50°C.

At this time, anhydrous aprotic solvents are used as organic solvents, examples of which include benzene, toluene, xylene, chloromethane, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, ethyl acetate, ether, tetrahydrofuran, dioxane, pyridine, etc. can be mentioned. Further, as the condensing agent, arylsulfonyl such as P-toluenesulfonyl chloride, triisopropylbenzenesulfonyl chloride, methanesulfonyl chloride, alkylsulfonyl chloride, dicyclocarbodiimide, thionyl chloride, phosphorus oxychloride, etc. can be used.

The molar ratio in the reaction is represented by general formula (I) 5'
The amount of each of the amines represented by formula (II) and the condensing agent is about 1 to 3 moles per mole of the -〇-acyl-5-fluorouridine derivative.

After the reaction, the target compound is obtained by purification by silica gel column chromatography or the like.

Pharmaceutically acceptable salts of these target compounds include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, salts with organic acids such as methanesulfonic acid and paratoluenesulfonic acid, and alkali salts such as sodium and potassium. Examples include salts with metals.

Pharmaceutically acceptable salts of these compounds can also be obtained by coexisting a pharmacologically acceptable acid or alkali in the process of removing various protecting groups described later, or by adding other acids or alkalis after purification. It can also be used as an alkali salt.

In this reaction, unintended reactions often occur, so in order to prevent this, it is recommended to add a protecting group to one or both of the starting materials and remove those protecting groups after the reaction. .

In the 5-0-acyl-5-fluorouridine derivative of general formula (1), the site that causes a reaction other than the intended one is one of the hydroxyl groups at the 2 and 3 positions of the ribosyl group and the hydroxyl group of the phosphoric acid group.
It is individual. The hydroxyl group at the 2 and 3 positions of the ribosyl group can be protected by, for example, a fullkylidene group or benzylidene group such as impropylidene, ethoxyethylidene, or benzylidene. Also, the hydroxyl group in the phosphoric acid group is 2,2.2-
) It can be protected by an alkyl group having a substituent such as rehalogenated ethyl, cyanoethyl, or phenylsulfonylethyl, or by a chlorophenyl group, benzyl group, or nitrobenzyl group.

On the other hand, in the amines of general formula (II), when both the amino group and RIIR2 are hydrogen atoms, the carboxyl group is a site that causes a reaction other than the intended one. Examples of protecting groups for amino groups include t-butoxycarbonyl group, trichloroethoxycarbonyl group, and benzyloxycarbonyl group. Further, examples of the carboxyl group protecting group include lower alkyl groups such as methyl and ethyl, and benzyl groups. These protecting groups can be easily removed individually or simultaneously with other protecting groups after the reaction is completed, depending on the purpose, according to conventional methods.6For example, the protecting group at the 2.3-position of the ribosyl group can be removed by acid treatment or reduction. Accordingly, the phosphoric acid protecting group is removed by alkali treatment or reduction, and the amino group protecting group and the carboxyl group protecting group are removed by reduction.

The 5'-〇-acyl-5-fluorouridine derivative of general formula (I), which is one of the starting materials, is also a new compound 0 For example, in general formula (I), R' is 5゛-〇- The acyl-5-fluorouridine derivative is composed of a 3-Fl-carboxylic acid ester of glycerin having a protecting group at the 1-position and a 5'-0 of 5-fluorouridine.
-dicarboxylic acid ester, then removing the protecting group at the 1-position of glycerin, and then phosphorylating the 1-position. In this case, examples of the protecting group at the 1-position of glycerin include a benzyl group, a nitrobenzyl group, an alkylphenylbenzyl group, an alkoxyphenylbenzyl group, a picolyl group, and a trialkylsilyl group.

To phosphorylate the 3-position, use phosphorus oxychloride, 2,2.2-)
It may be reacted with a phosphoric acid compound such as dichloroethyl dichlorophosphate, cyanoethyl dichlorophosphate, chlorphenylethyl dichlorophosphate, phenylsulfonylethyl dichlorophosphate, etc. At this time, 2,2.2-trichloroethyl dichlorophosphate, cyanethyl dichloro When reacted with a phosphoric acid compound such as phosphate, chlorphenyl dichlorophosphate, phenylsulfonylethyl dichlorophosphate, etc., the hydroxyl group of phosphoric acid is protected and 5°-0-acyl-5-
A fluorouridine derivative is obtained.

The other starting material, the amines of general formula (II), specifically includes ethanolamine, N-methylethanolamine, N,N-dimethylethanolamine, serine,
N-methylserine and N,N-dimethylserine are commonly known.

Note that the target compound of the present invention can also be obtained by a method other than the method using t'c-c:'. One of the methods is to use an intermediate before reacting with a phosphoric acid compound obtained in the process of producing a 5'-0-7silyl-5-fluorouridine derivative of general formula (I) and an amine of general formula (■). This is a method in which phosphorus oxychloride, 2,2.2-) dichloroethyl dichlorophosphate, cyanethyl dichlorophosphate, chlorphenyl dichlorophosphate, phenylsulfonylethyl dichlorophosphate, and other phosphorus compounds are simultaneously reacted. Examples are shown below,
Further, the present invention will be explained in detail.

(Space below) Example 1 (1) Hydrodiene-(2,2,2-)dichloro)ethyl-(3-valmitoyl-2-(13-(2°
, 3-0-inpropylidene-5-fluorouridine-
5°-〇-ylcarbonyl) tridecamyl)〕-〕1
-g1 no cellophosphate 1.93 in pyridine solution 15
1.12 g of 2.4.84 linpropylbenzenesulfonyl chloride was added to m1 and stirred. In this solution, N
-benzyloxycarbonylaminoethanol 1.45
The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 200+Al of chloroform, and 100+*L of an aqueous solution of 0.8g of potassium carbonate was added and distributed. After drying and filtering the organic layer, the filtrate was concentrated under reduced pressure, the residue was dissolved in a small amount of chloroform, and silica gel 5X fo
It was adsorbed on an am column.

Chloroform carbon ditetrachloride (1:1) 3% from IJL
Elution was performed with a linear concentration gradient of methanol/loform:carbon tetrachloride (1:1). The eluate was separated and purified to give (2-benzyloxycarbonyl-amino)ethyl-2,2,2-)lichloroethyl-[3-)ylumitoyl-2113-(2°,3'-Cl-isopropylidene-5- Fluorouridin-5'-〇-ylcarbonyl)tridecanoyl)]-]1-glycerophosphate 1
．． 80 g (yield 79.8%) was obtained.

(l HNMR (GO 7.45 (d, J-5,!1
18. Uridine H6), ? , 34 (bs, C6)
15cH2-OCO-), 5.75 (bd, uridine H1'), 5.1-5.4 (Maro, -CHzC:
H (HIH-), 5.12Cs, C6H3CH
2-OCO-), 4.8-4.9(m, uridine H
2°.

)13'), 4.58(d, d, J-8,85
, Jl-1,1,-0CR2CC1+), 4.1-
4.4 (m, Urisif HJ°, Hs', -CH
2CHCHHz -C)! 3), 1.2θ(bs,
-GHz-) 0.88 (bt, -C:H3),)
(2) 1.80 g of phosphotriester obtained in (1) above
was dissolved in a mixture of 90% acetic acid solution 151 and diethyl ether 51, 2 g of lead powder was added, and the mixture was stirred at room temperature for 2 hours.
Reaction solution 1:! After condensation, 40 ml of 5% hydrochloric acid and 100 ml of chloroform were added to the residue and partitioned.

After drying the organic layer, the filtrate was concentrated under reduced pressure, and the residue was dissolved in a small amount of chloroform, adsorbed on a 5 x 3 cm column of silica gel, and eluted with a linear concentration gradient of chloroform 1M - 5% methanol/chloroform 1 sentence. Separate and purify with liquid/
\Idrodiene-(2-benzyloxycarbonyl-aminoethyl-[3-valmitoyl-2-(13-(2
", 3'-CI-inpropylidene-5-fluorouridin-5'-0-ylcarbonyl)tridecanoyl)]
-]1-Glycerophos, 7.33(bs, (6H
scH2-000-), 5.77 (bd, uridine H1”), 5.1-5.3 (m, -CH2CHC
H2-), 5. H(s, C6H3CH2-OCO-
), )0verlap (Uridine H2″, ) IOD
H3'), 3.9-4.3 (intestine, uridine H4°,
Hso, -CH2CHGH2-, 0CH2CHN()
, 3.39 (t, -0CH2-CH2N)
, 2.2-2.45(m, -Q(:0CH2-),
1.54. 1.34(s, s, CH3CH3
), 1.28 (bg, -CH2-), 0.8
9(bt, -CH3)-) (3) 90 g of the ester obtained in (2) above
% trifluoroacetic acid aqueous solution and at room temperature.
The 0 reaction solution left for 0 minutes was concentrated under reduced pressure, and the residue was azeotropically distilled under reduced pressure with 30 ml of Impro/Kunol, dissolved in a small amount of chloroform, and adsorbed on a silica gel 3X 8c+s column. From chloroform 20G+11, 0.5%
The amount of methanol was increased in increments to 5% methanol/chloroform, and elution was carried out using 20 (1 ml) each. The eluate was concentrated, and /\hydrogen-(2-benzyloxycarbonylamino)ethyl-[3-balmitoyl-2-(
13-(5-fluorouridin-5'-0-ylcarbonyl)tridecanoyl)]-]1-glycerophosphate 0.93g (yield), 7.33(bs, C6H
sCH2-OCO-), 5.80 (bd, uridine H+'), 5.1-5.25 (m, -CH2CH
Hz-), 5.09(s, C6HsCTo-O
CO-), 3.9-4.4 (m, uridine H2゛.

H3°, uridine H4″, H5°, -C)120)
Ic) 12-, -DC) 12-CH2Nc), C
0verlap (-0CHzCH2N() to D300
, 2.2-2.5(m, -0-GOC:Hz-
), 1.28 (bs, -CH2-) 0.89
(bt, -CH3), ) (4) Dissolve 0.93 g of the ester obtained in (3) above in methanol 501, and dissolve 0.35 g of 10% palladium/carbon.
was added and stirred for 2 hours in a hydrogen stream. The reaction solution was filtered and concentrated under reduced pressure. The residue was powdered with diethyl ether to obtain the desired hydrogen 2-aminoethyl-[3-valmitoyl-2-(13- (5-fluorouridine-5゛-0
-ylcarbonyl)tridecanoyl]]-]1-glycerophosphate 730mg (uridine H6),
5.87 (bs, uridine Ij1'), 5.1
-5.3 (layer, -CH2C!ICH2-), 3.
8-5.0(m, uridine H2'I,)13',
uridine)la', Hs', -()j2c)i
cH2-, -0CH2CH2N(), CD300
0verlap (-0CH2082N<).

2.2-2.5(m, -0-COCH2-), 1
．． 27 (bs, -CH2-).

0.89 (bt, -CH5>, ) Elemental analysis CCaaH77N30+5FP ・0.451
As JGh] 9 days Σ Actual value (%) 53.73 8.01 4.31
Calculated value ($) 53.83 7.87 4.24
Example 2 Hydrodiene-(2,2,2-trichloro)ethyl-
[3-decanoyl-2-(9-(2',3'-0-impropylidene-5-fluorouridiSti0-ylfluponyl)nonanoyl))-1-glycerophosphate-
) 3.0 g as the starting material, (2-benzyloxycarbonylamino)ethyl-2 was prepared in the same manner as in Example 1.
,2,2-)lichloroethyl[3-decanoyl-2-
(9-(2′,3°-0-impropylidene-5-fluorouridin-5′-0-ylcarbonyl)nonanoyl))-1-glycerophosphate 3.23 g (yield 87.9%) (IHNMR ((DC4,000 shif,
47 (d.

J~8.1. Uridine Ha), 7.33 (bs
, C6HsC:Hz-QC:0-), 5.74(
bd, uridine H1°), 5.1-5.35(
m.

Jl: 1b (HCTo-NH-), 5.11 (s
, C6HsCH2-0(0-).

4.65-5.0 (m, uridine 82', H3'),
4.59 (d, d.

J=8.59. J-0,97,-QC:H2CC13
), 4.1-4.45 (m.

Uridine Hs", H5', -GH20HCH2-, -
0 (HzCHi<).

3.4-3.55(m, -0(HzCHi(),
2.2-2.5(m, -0CO-C)12-)
, 1.57.1.35(S, s, CH3(ah
), 1.28(bs, -C)12-), 0.
88(bt, -CTo), ), hydrogene-
(2-benzyloxycarbonylamino)ethyl-[3
-decamyl-2-(9-(2°,3'-0-impropylidene-5-fluorouridin-5'-0-ylcarbonyl)nonanoyl))-1-glycerophos 7.33
(bs, Ca)be)120GO-), 5.77
(bd, JJ, 95° uridine H+'), 5.1
-5.35 (m, -CH2O)! -GH2-).

5.0!3(s, (6H5Gil!2-000-),
4.7-5.05 (w, uridine H2°, H3')
, 3.85-4.4 (rin, uridine H4', H
5゜, -CdanzCHCjj2-, O()! z(
HzN), 0var-1 to CD30D
ap(-0GH2CH2N), 2.2-2.5
(m, -0-GO-GHz-).

1.57.1.38 (s, s, CH3CH3),
1.28 (bs.

-CHz-), 0.88 (bt, -CD5)-)
,hydrodiene-(2-benzyloxycarbonylaminol-[3-decanoyl-2-(9-(5-fluorouridin-5'-0-ylcarbonyl)nonanoyl)
) -1, uridine H6), 7.32 (bs,
G6HsCH20GO-), 5.83 (bd, uridine H1°), 5.1-5.35 (厘.-CH2
CH-CH2-), 5. Q9 (3, C6H5G)
12-OCO-), 3.9-4.5 (Cao, Urisif H2',)+3'. ')! J Schiff H4'. H
s', -CH2CH2H2-, -OCH2CH2
Nc), (:, D30n to Overla
p(-0CHzC:Hz-N(), 2.2-2.
5 (m, -QC:QC:Hz-), 1.28
(b.s, -CH2-) 0.88(bt, -
CH3), ) to obtain the desired hydrogen-2-7minoethyl-[3-decamyl-2-(9-(5-fluorouridin-5-゛-〇-ylcarbonyl)nonanoyl)]
)-1-glycerophosphate 1, 0:1 mg (yield 71.2%) was obtained.

(l HN)IR (CDC h:CD300zen1eiwo7.84(d, J-6.35.

Urisif ) 16), 5.85 (bs, Urisi yH1'), 5.2-5.45 (m, -(H2CC
13-), 4.0-5.0(m, uridine H2',
H3', Uridine Ha', Hs', -CHzC
H(Hz-, -0-CH2CH2N(), CD
30D Overlap(-QC:H2CH2N()
.

2, 2-2.8(m, -OCDC)12-), 1
．． 29(bs, -C)12-).

0, H(bt, -CH3), ) Elemental analysis (C:3nHs7N30+sFP-1.55C
As HCh] 9 days N Actual value ($) 43.23 B. 21 4.
83 calculated value (χ) 43.44 8.0G
4.28 Example 3 Hydrodiene-(2,2.2-) IJ chloro)ethyl)Lt-[3-stearoyl-2- (13-(
Using 3.44 g of 2',3'-0-impropylidene-5-fluorouridin-5'-0-ylcarbonyl phosphate (2-benzyloxycarbonyl 7.45 (d, J-5.88, uridine H6)
, 7.34 (b.s.

C61(5-C)12-OCO-), 5.78(M
, uridine Hl").

5, 35-5.5 (m, -NH-), 5.1-5
．． 35(m,-CH214G)lz-NH-), 5
．． 12(s, C6HsCH2-OCO-), 4.
7-4.9 (m.

uridine H2', H3°), 4.58 (d, d,
J-6.59, J-1.22. -0CII2CGh
), 4.1-4.4 (m, uridine Ha"Hs'
, -GH2CHC:H2-, -0CH2CH2N(
), 3.4-3.8 (m.

-0(H2-CH2Nc), 2.2-2.45(
m, -0CO-CH2-).

1.58. 1.35(s, s, CH3CH3
), 1.25(bs, -CH2-), 0.
88(bt, (H3-), ), hydrogen-(
2-benzyloxycarbonylamino)ethyl-[3-
Stearoyl-2-(13-(2°,3'-0-impropylidene-5-fluorouridin-5'-〇-ylcarbonyl)tridecanoyl)]-1-glycerophos7.
32Cbs, CbH5CH20C:0-), 5.
77 (bd, J-1, 95° Urisif H1'),
5.1-5.3 (m, -CIhCHCH2-).

5.09 (3, CbH5CH2GO-), 4.7-
5.0Crs, uridine H7',)13°),
3.8-4.4 (layer, uridine H4'', H5'.

-CH3COCH3-, -0CHzC82N(),
3.83(t, -0GHz-CH2N(),
2.2-2.45(m, -0COCHz-C
H2-), 1.57.1.3BCs, s, C
H3CH3), 1.27 (bs, -CIh-).

0.88 (bt, CH3-), ) and hydrogen-(2-benzyloxycarbonylamino)ethyl-
[3-Stiaroyl-2-(13-(5-fluorouridin-5-゛-〇-ylcarbonyl)tridecanoyl))-1 glycerophosphate 1.51 g (yield 83
．． 8%) [IHNMR ((I)30D:CDCl3-1
? 7.83 (d, J-8, 35° uridine H6),
7.32 (bs, C6H5-111; H; +O-)
, 5.83 (bs, uridine H+'), 5.1
-5.25 (m, -+1; H2CHCH2-), 5
．． 08(s, C6HsCHzOCO-), 3.8
-4.4 (m, uridine H2', H3', uridine H4°, H5', -CH2COCH2-.

-QC:H2CO2N(), 0 for CD30n
verlap(-0(H2C)I2N().

2.2-2.5(m, -0-COCH2-), 1
．． 0(bs, -C:H2-).

0.89 (bt, CTo-), ) to the desired hydrogen-2-amino/ethyl-[3-stearoyl-
0.84 g (yield: 83.5%) of 2-(13-(5-fluorouridin-5'-〇-ylcarbonyl)tridecanoyl)-1-glycerophosphate was obtained.

('HNMR(CD30D:(DCh iris 2zu 7.82
(d, J-8, 35° Uridine H6), 5.84 (
bg, uridine old'), 5.1-5.4 (+a
, -CH3COCH3-), 4.0-4.9Cm
, Uridine H2°, H3', Uridine H4°
, Hs', -CIhCHCH2-, -0-(H2CH
2N(), C[]300 to 0verlap(
-0(H2C)I2N()+2.25-2.5(m,-
0COCTo-), 1.27(bs,-(H2-)
.

0.89 (bt, CH3-,) Elemental analysis (Ca6Hs+0+5N3FP・1.25CH
As Ch] p day Σ ゛Actual value ($) 50.84 7. +9 4.00
Calculated value ($) 50.88 7.43 3.77
Example 4 Hydrodiene-(2,2,2-)lichloro)ethyl-
[3-Valmitoyl-2-(13-(2',3'-
0-isopropylidene-5-fluorouridine-5-0
(2-benzyloxycarbonylamino-2-benzyloxycarbonyl)ethyl-2,2,
2-) Lichloroethyl [3-valmitoyl-2-113
-(2',3°-0-inpropylidene-5-fluorouridin-5'-〇-ylcarbonyl)tridecanoyl)]-]1-glycerophosphate 1.59 g (yield 7
6.8%) ('HNMR(GDC?7.43(d
, J=8.1. 571J Schiff H6), 7.33(
bs, C6Hs-CH2-OC:O-), 5.7
-5.9 (m, uridine H1'), 5.20.
5.11 (s, s, C6H5CH20GO-),
3.9-5.0 (m, uridine H2', H3°, -
0CH2CC+3, uridine H4°, H5', -
CH2CHCH2-, -0CH2CHi(), 2
．． 2-2.4(m, -0CO-CH2-), 1
．． 57,1.33(3,s,Oh CH3), 1
．． 25 (bs, -C:To-), 0.88 (bt
, CH3-), ), hydrogen-(2-benzyloxycarbonylamino-2-benzyloxycarbonyl)ethyl-(3-valmitoyl-2-(+3-(
2',3'-〇-impropylidene-5-fluorouridin-5"-0-ylcarbonyl) tridecayl)
)-1-glycerophosphate 0.94g (Yield Zg
85.1%) ('HNMR(CD 30D:C
DCl 3-1:1); 7.75 (d, J-fl
, 35. Uridine H6), ? , 35, 7.32 (
bs, C6H3-(H2-OCO-), 5.79
(bd, J=2.2, uridine H+'), 5.1
．． 5.21(s, C6HsCH20fj)-),
0verlap (Urisif 82', H3'), 3
．． 8-4.4Cra.

Uridine H4'', Hs', -CH2O (:H2-
, -0CH2CH2N□.

2.2-2.4 (m, -0COCH2-), 1.
5B, 1.37 (s, s.

CH3(83), 1.28(bs, -CH2-)
, 0.88(bt, -CH3),) ,hydrodiene-(2-benzyloxycarbonylamino-2-
Benzyloxycarbonyl)ethyl-[3-valmitoyl-2-(13-(5-fluorouridin-5-0-ylcarbonyl)tridecanoyl)]-]1-glycerophosphate 0.57 g (yield 62.3%) ( 'HN
MR(C:Ih0D:(DCh-1:1); 7.8
8 (d, J-8,59, uridine H6), ? ,3
3.7.32 (s.

CbH5-CH2-OCO-), 5.80 (bd,
Uridine H+')+5.11.5.21(s, (
6Hs(H20GO-), 3.9-4.5(l uridine H2'l H3', uridine Ha'', )Is',
-CH2C)I-CH2-, -0GH2CH2Nc),
2.2-2.4 (m, -0COGTo-).

1.28(bs, -(H2-), 0.88(bt,
CH3-), ) to obtain the desired hydrodiene-(2-amino-2-carboxy)ethyl-[3-valmitoyl
0.21 g (yield: 45.5%) of -2-(13-(5-fluorouridin-5-0-ylcarbonyl)tridecanoyl))-1-glycerophosphate was obtained.

('HNMR(GD30[]:C[]Cl5=1:1)
; 7.8B (d, J-8,59゜uridine H6)
, 5.82 (bs, uridine L').

CD300 to 0verlap (-0CH2CH2
N<-), 2.4(m, -0-COCH2-
), 1.28 (bs, -GHz-), 0.
88 (bt, CH3-),] Elemental analysis ((4sH770+7N3FP・1.750H
As C13・0.5820] and N Actual value ($) 48.79 B, 70 3.5
0 Calculated value ($) 48.78 8.911 3.
77 Example 5 Hydrodiene-(2,2,2-)lichloro)ethyl-
(3-stearoyl-2-(+3-(2°, 3'-0-
Impropylidene-5-fluorouridine"';'-0
-ylcarbonyl)tridecanoyl)]-]1-glycerophosphate 2.92. (2-benzyloxycarbonylamino-2-benzyloxycarbonyl)ethyl-[3-stearoyl-2-(13-(2°, 3'-0-isopropylidene) -5-Fluorouridine-5'-〇-ylcarbonyl tridecayl)]-]1-glycerosphate 4.10 g (yield: 10 g) (IHNMI
II (C:DCr7.42(d, J-tomi8.1.-7
Lysine H6), 7.33 (bs, CbHsCHz
-OCO-), 5.7-5.9 (m-Uridi'H+
'), 5.1!3.5.11 (g, s, CbH
sCHz-OCO-).

3.9-5.0 (m, tsu IJ Schiff H2° + H3°,
-0CH2CCI3. 7Ha', H
s', -CH2CHCH2-, -(]CH2CH2
Nc).

2.2-2.4(m, -0-[0CR2-), 1
．． 57. 1.34 (t, s.

CH3CH3), 1.25(bs, -CH2-)
0.88 (bt.

-CH5), ), hydrogen-(2-benzyloxycarbonylamino-)ethyl-[3-stearoyl-2-(13-(
2'.

3'-〇-inpropylidene-5-fluorouridine-
5-0-ylcarbonyl-glycerophosphate 1.84ig (yield 48.
1%) ('HNXR (CD30D: CDG13-1 So7
．． 75 (d, J=8.35.

One! J Schiff) 16), 7.34, 7.32 (b
s, C6H5CHzOCO-).

5, 77 (bd, J-2.2, uridine H+'),
5.1, 5.21(s, C6H5CH2-OCO
-), Overlap (Urisif H2', H3')
, 3.9-4.4 (m, Urisif H4°, H5
°, -CToCHC:H2-, -OGH2C)I
;Nku), 2.2-2.4(m, -0-Co
(J2-).

1, 55, 1.37 (s, s, CH3 CH3
), 1.28 (bs.

-CH2-), 0.89 (bt, -C:H3),)
and hydrogen-(2-benzyloxycarbonylamino-2-benzyloxycarbonyl)ethyl-[3
-stearoyl-2- (13-(5-fluorouridin-5'-0-ylcarbonyl]tridecanoyl)]
-]1-Guriulischiff H6, ? ．． 34, 7.32
(s, C6H5GHz-OCO-).

5, 81 (bs. Urisif Hl'), 5. +1
．． 5.20 (s.

C6HsCH2-000-), 3.9-4.5 (layer, uridine H2'.

H3°, uridine H4°, Hs', -CH2CH
CH2-, -OCIh-CH2N(), 2.2
-2.4(m, -OCOIII:H2-),
1.28(bs, -CH2-) 0.89(bt
, -C:H3), ) to form the desired hydrogen (2
-7 minnow 2-carboxy)ethyl-[3-stearoyl-2-(13~(5-fluorouridine-5'-0-
ylcarbonyl)tridecanoyl)]-]1-glycerophosphate 700mg (Yield 8θ%) Uridine H6
), 5.83 (bs, old uridine).

CD300 to Overlap (-0C82G)1
2N (), 2.4 (m. -OCO-CH2-)
, 1.28 (bs, -CH2-), 0.89
(bt, -C:)+3).

] Elemental analysis (Cn7Ha+N30uFP・0.6CHC:
As h]! 2 days N Actual value ($) 52,78 7.88 4.08
Calculated value ($) 52.85 7.80 3.88
Example 6 Hytrodiene-(2,2,2-trichloro)ethyl-
[3-butyroyl-2-+ 13-(2', 3'-0-
Impropylidene-5-fluorouridine-5°-0-
Ilkal 7.72 (d, J-&p-H, uridine H6
), 5.7 蓚(bd, Uri Jin H1″),
5.1-5.4(Maro, -(H2CHOCHz
-), 4.0-5.1 (+s, uridine H2',
H3”, -0CH20C13, uridine To', H
s°, -CH2C:HCO2-, -0CH2G)12
N□.

, ,
, 2.2-2.4 also (wear, -〇-Co-CH2-)
, 1.57.1.37Cs, s, CH3CH3
).

1.28(bs, -(Hz-), 0.95(b
(2-benzyloxycarbonylamino)-2,2,2-trichloroethyl-[3-butyroyl-2-(13-(2 ', 3°-0-impropylidene-5-fluorouridin-5'-0-ylcarbonyl)
tridecanoyl) -1), 7.34Cbs,
CbIjs-CHz-OCO-), 5.78 (bd,
Urisif HI'), 5.1-5.4 (m, -C:H
2CHCH2-NH-).

5.11 (s, CH3CH3-OCO-), 4.
85-4.95Cti, Urisif H2', H3°),
4.58 (d, d, J-8,59, J-0,98
°-0CH2CCI3), 4.1-4.4 (g, uridine H4', H5°.

-CHzCHC)lz-, -0CHzG)12N(),
3.4-3. [i(m, -0CH2-CH2
Nc), 2.2-2.45(Peng, -0(0-
GHz-), 1.57°1.35Cs, s,
CH3CH3), 1.25(bs, -CH2-)
.

0.94(bt, CH3-), ), hydrogen-(2-benzyloxycarbonylamino)ethyl-
[3-Butyroyl-2-(13-(2',3°-0-impropylidene-5-fluoroauridin-5'-0-ylcarbonyl)tridecanoyl)]-]1-glycerophosphate 295 g (Yield 82.2%) ('H
NMR (CD30D:C:DChJ:C6■5CH20
(0-), 5.78(bd, uridine H+')・
5.l-5,3(m, -CH2CHCH2-), 5
．． 09(s, (6HscH2co-).

0verlap (uridine H2°, H3'), 3
．． 9-4.4 (m, uridine H4°, Hs'
, -CH2CHCH2-, -0CH2CH2N□.

0verlap(-0GH2C)i? N(), 2
．． 2-2.45(g,--01:0(Hz-CH2-)
, 1.53, 1.34 (s, s, CH3CH3),
1.29(bs, -CH2-), 0.94(
t, CH3->,) and hydrogen-(2-benzyloxycarbonylamino)ethyl-[3-butyroyl-2-(13-(5-fluorouridine-5'-0-
ylcarbonyl) tridecanoyl J-8,84, Urisif H6), 7.34 (bs, C6Hs-CH20
-), 5.81 (bs, uridine old'),
5.1-5.3 (m.

-CHzCHC)lz-), 5.09(s, Cb
H5C; H2OC0-), 3.9-4.35 (m,
uridine) +2', H3', uridine H4°, H5'
, -CH2C:H(Hz-, -0CH2CH2N(
), (0verlap (-0CI) on D30D
(2cHi(), 2.2-2.5(+*, -
0COC:Hz-), 1.28(bs, -CH2
-), 0.94 (t, CHs-)-), the desired hydrogen 2-aminoethyl-[3-butyroyl-2-(+3-(5-fluorouridine-5'-0
-ylcarbonyl)tridecanoyl) -1-glycerophosphate 1.05 g (yield 64.9%) was converted into Urisif H6), 5.81 (bs, Urisif H+')
), 5.1-5.5(II, -CH2CHCH2
-), 3.9-5.0 (m, uridine H2°,
)13', uridine H4' +H5°, -C
H2GHCH2-, -0-CH2CH2N(),
GD300 to 0verlap (-QC:HzCH2
Nc).

2.2-2.5 (m, -0COIII:Hz-),
1.29 (bs, -CH2-).

0.95 (t, CH3-,) Elemental analysis CC3zH53N30rsFP-1420] and Σ Actual value (χ) 48.85 B, 92 5.4
0 calculated value (ri 48.79 7.04 5.33
Example 7 (1) Hydrodiene = (2,2,2-)lichloro)ethyl-[3-stearoyl-2-(13-(2')
, 3°-0-impropylidene-5-fluorouridin-5-0-yltriponyl)1 tridecanoyl1)-1
- 0.87 g of glycerophosphate in 10 layers of pyridine
0.48 g of 2,4.84-liisopropylbenzenesulfonyl chloride was added, followed by 0.29 g of dimethylaminoethanol, and the reaction mixture was stirred overnight and concentrated under reduced pressure.The residue was dissolved in chloroform! Dissolved in 00s+I,
An aqueous solution 501 containing 0.24 g of potassium carbonate was added and distributed. The organic layer was dried, the filtered solution was concentrated under reduced pressure, and the residue was dissolved in a small amount of chloroform and adsorbed on a column of 5×7c layers of silica gel. Separation and purification using a linear concentration gradient eluent of chloroform and 4% methanol/chloroform resulted in 0.36 g (yield 37.5%) of (2,2-dimethylamino)ethyl-2,2,2 -Trichloroethyl-
[3-stearoyl-2-(13-(2°, 3-0-isopropylidene-5-fluorouridin-5-fluorouridin-5'-0-ylcarbonyl)tridecayl)]-]1-glycerophosphate CI HN)IR( C: DC Pumo”?, 45
(d, J-5,88, uridine H6), 5.78 (
d, J-1,95, uridine H+'), 5.1-
5.35 (rin, -CH2CHCH2-), 4.7
-4.95 (horse, uridine H2', H3'), 4
．． 62 (d, d, J=6.47.Jo, 73.-0-C
H2CH2), 4.15-4.45(m, -
CH2CHCH2-, -0CH2-C1 (2N(),
2.72 (t, J-5゜17.-0CH2C
82N(), 2.2-2.45(m, -0-GO
fl; Hz-, -N-CH3), 1.57-1.
35 (s.

s, CH3CH3), 1.26(bs, -CHz
-), 0.88 (bt, CH3-), ) was obtained.

(2) Dissolve 0.38 g of the ester obtained in (1) above in 90% acetic acid aqueous solution 301, add 1 g of zinc powder, stir at room temperature for 30 minutes, concentrate the reaction solution under reduced pressure, and add chloroform to the residue. 1001 and 30 +++ l of 10% hydrochloric acid were added and distributed. After drying and filtering the organic layer, the residue was dissolved in a small amount of chloroform and purified with silica gel 3X3.
Adsorb onto a cm column and add 700ml of chloroform.
% methanol/chloroform 700ml then 5%
Separation and purification were carried out using a linear concentration gradient eluent of methanol/chloroform 500ml to 15% methanol/chloroform 5001 to obtain 0.18 g (yield 51.5%) of hydrogen-(2,2-dimethylamino)ethyl-[3 -stearoyl-2-(13-(2°,3-0-impropylidene-5-fluorourisia 5"-0-ylcarbonyl]-]1-glycerophosphate C' HNMR (O
h On: CDC: h-1 Shishi%'7.58 (d,
J=6. Touridine H6)・5,70(bs, Uridine old'), 4.95-5.25(+*, -CH
2-COCH2-), 4.8-4.9 (layer, uridine H2", H3') + 3, 81.3 (s, uridine H4°, H5°, -C)!zC:H(Hz-.

-QC:H2CH2N(), 2.83(bs,
-OCH2-CH2N<, -N-CH3),
2.1-2.4 (■, -QC:OCHz-),
1.47, 1.27(s, s,
CHI CH3), 1.18(bs, -
CH2-), 0.79 (bt.

CH3-),) was obtained.

(3) Ester O obtained in (2) above. 18g of 30% trifluoroacetic acid aqueous solution log! and left for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was azeotropically distilled with Improper Tool 201 under reduced pressure, dissolved in a small amount of chloroform, and then adsorbed onto a 3 x 2 cm silica gel column. Separation and purification were performed using a linear concentration gradient eluate of chloroform IM-20% methanol/chloroform In to obtain the target product /hydrogen-(2,2-dimethylamino)ethyl-[3-stearoyl-2- (13-(5- Fluorouridin-5'-0-ylcarbonyl)tridecanoyl)]-]1-glycerophosphate 120 mg (
Yield 80.5%) was obtained for uridine H6), 5.83(
bd, uridine Hl'), 5.1-5.35 layers m, -CH2G! ICH2-), 3.9-5.0
(m, uridine H2″+ H3Z uridine H4′
, H5°, -GH2CHCH2 - , O-CH2
CH2N(), 2.94(bs, OCH2C
IhN<, N-CH3).

2, 2-2.5 (■, -0-CO (Hz-), 1
．． 27(bg, -CH2-).

0,89(bt, CH3-), ) Elemental analysis (C4sHss) 13(]]+sFP-0.4
CHC: as hH2O] C Once N Actual value ($) 54.57 8.50 4
．． 13 Calculated value ($) 54.84 8.31
3.98 Example 8 (1) Hydrodiene-2.2.2-trichloroethyl-(3- (11-(2', 3°-0-impropylidene-5-fluorouridine-5'-0- undecanoyl)-2-balmitoyl)-1
-Glycerophosphate 1. Og to 10 liters of pyridine
0.57 g of 2,4.8-triisopropylbenzenesulfonyl chloride was added and stirred for 30 minutes. Add 0.74 g of N-benzyloxycarbonylaminoethanol to this solution, concentrate the reaction mixture under reduced pressure, dissolve the residue in chloroform 1001, add 0.29 g of potassium carbonate in aqueous solution 1001, and divide into 2 parts. did. After drying and filtering the organic layer, the filtrate was concentrated under reduced pressure, and the residue was dissolved in a small amount of chloroform and adsorbed on a silica gel 5 x 5 cm column.
．． 541-5% methanol/chloroform dicarbon chloride 1:1) was separated and purified using a 1.5-liter linear concentration gradient eluent, and (2,2-dimethylamino)ethyl-2,2,2
-)lichloroethyl-[: 3- (1l-(2',
3'-0-inpropylidene-5-fluorouridine-
5″-〇-ylcarbonyl)undecanoyl)-2-valmitoyl]-1-gly(bs, (6Hslll:H2
0GO-), 5-78 (d, J-1,47, uridine H+'), 5.35-5.輯(b, -NH-
), 5.15-5.35 (m, -CH2CHCH2
-), 5.11 (s, CbH5CH20GO-),
4.8-4.8 (layer, uridine H2', H3''),
4.58 (d, d, J-[1,72, J= 1.2
2. -0-C:H2GGh), 4.1-4.4(m
, uridine H4', H5', -CH2CHCTo-
, -0CH2CHN<), 3.4-3.8(m,
-0(HzC)12N(), 2.2-2.
45 (m, -0COL:Hz-), 1.57
, 1.35 (g, s, CH3CH3), 1.25
(bg.

-CH2-), 0.88 (bt, CH3-), ) was obtained.

(2) Dissolve 1.13 g of the ester obtained in (1) above in 90% acetic acid aqueous solution 501, add 1.0 g of zinc powder, stir at room temperature for 30 minutes, concentrate the reaction solution under reduced pressure, and remove the residue. 1,001 parts of chloroform and 1,001 parts of 10% hydrochloric acid were added and distributed. After dry filtration of [j, concentrate under reduced pressure to 80%
Dissolved in 50 ml of triple oroacetic acid aqueous solution and stirred at room temperature for 30 min.
The reaction solution left for one minute was concentrated under reduced pressure, and the residue was subjected to azeotropic distillation under reduced pressure using an Improper Tool 201, then dissolved in chloroform and adsorbed on a 5×2 C₂ column of silica gel.

Chloroform 1.5jl - 12% methanol/chloroform Separate and purify using a 1.5-liter linear concentration gradient eluent to obtain 0.29g (yield 30%) of hydrogen-(
2-benzyloxycarbonylamino)ethyl-[3-
(11-(5-fluorouridin-5-゛-〇-ylcarbonyl)undecamyl)-2-valmitoyl)-1-
Glycerophosphate) (IHNMR (CD30D:C
Dch=1 swamp. 8j 6,6
, 2: Work! (d,
J-Oshigami, Uridine H6), 7. :l(bs.

Ha', )is', -CH2CHGH2-,
-0-CHzGH2N(), CI]301]σ Overlap(-0GH2GH2N(),
2.15-2. ◆(>(m, -0111:0Jl:
Hz-), , , , , ,
, 1.2 seconds (bs, -C:Hz-), 0
．． 89 (bt, (Hz-), ) was obtained.

(3) 0.29 g of the ester obtained in (2) above was dissolved in 101 ml of chloroform and 40 ml of methanol, and 10% palladium-carbon was added. The mixture was stirred for 3 hours in a hydrogen stream.
The reaction solution was filtered and concentrated under reduced pressure, and the residue was powdered in ether to give 0.24 g (yield 34%) of the target product, hydrogenen-2-aminoethyl-[3- (11-(5- Fluorouridine-5'-〇-ylcarbonyl)undecanoyl)-2-balmitoyl C1 Uridine H6),
5.84 (b+, uridine H+'), 5.1
-5.4Cm, -CH2CHCH2-), 4.0
-4.5Cm, uridine Ha', Hs',
-CH2-CH(Hz-, 0-(:Hz CH
2 ON), CD3 0fl Overlap
(0- (H2CH2N(), 2.2-2.5
(+s, -OCO-CH2-), 1.27(
bs, -CH2-), 0.89(bt, CH3
-).

].

Elemental analysis (C:42H73N30+sFP・1.8C:
As HGh・2H20] 9 days N Actual value ($) 45.13 7.02 3.
8? Calculated value (ri 45.32 8.84 3
．． 82 Reference Example 1 (1) 1. Dissolve 3 g of 12-F tecanedicarponic acid monobenzyl ester IL in 3 hl of pyridine, 2.

20.4 g of 4,8-)liisopropylbenzenesulfonyl chloride was added and dissolved with stirring. This solution 13.8
To the reaction solution, add 400ml of chloroform and a solution of log potassium carbonate dissolved in 150ml of water and leave it at room temperature overnight.
distributed. The chloroform solution was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in a small amount of chloroform, adsorbed on silica gel 5X25c+s, and mixed with 1.5 g of chloroform-carbon tetrachloride (1:1) to chloroform-tetrachloride containing 3% methanol. Carbon (1
:1) Separation and purification with a linear concentration gradient eluent of 1.51,
Crude 5'-0-(13-benzyloxycarbonyltridecanoyl)-2',3'-0-inpropylidene-5-
Fluorouridine was obtained. This 5°-0-ester was dissolved in 300 ml of Improper Tool, 2 g of 10% palladium on carbon was added, and the mixture was stirred overnight under a hydrogen stream.

The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the resulting residue was dissolved in a small amount of chloroform, and silica gel 5 x 35 cm
It was adsorbed on a column of 5'-0-(13-carboxytridecanoyl)-2°, and purified with a linear concentration gradient eluent of 1.1 to 1.5 fL of chloroform solution containing 5% methanol. 3°-0-isopropylidene-5-fluorouridi), 5.78 (bd,
J-1,71, uridine H1'), 4.85-5.0
(m, uridine H2', H3'), 4.2-4.
5(II, uridine Ha', Hs'), 2.2-
2.45 (bt, -C■2cOo-), 1.5B
.

1.38(s, s, CH3CH3), 1-28(
bs, -Cj! 2-)-) Similarly, 5'-0-(1
1-carboxyundecano 7.50 (d, J-5,1
13, uridine H6), 5.77 (bd, J-1
, 98, uridine H1'), 4.85-5. G (■
, uridine H2'', H3'), 4.2-4.5(
Iris, uridine H4", Hs').

:', 2-2.45 (bt, -CH3COO-),
1.57, 1.38 (ss.

CH3C! c), 1.28 (bs, -C!!2-)
, ) and 5°-0-(9-carboxynonanoyl)-2
', 3-improviliary), 5.78 (bd, J-
1,83, uridine H1'), 4.85-5.0(
+*, uridine H2°, H3'), 4.2-4
．． 5(m, uridine)14°, )Is'), 2.2
-2.45 (bt, -CH3COO-).

1.5? , 1.38(s, s, C)! 3G
)! 3), 1. (b+, -CH2-),] was obtained.

(2) Benzylglycerin 5.0g, pyridine 3.3g
was dissolved in dichloromethane 501 and cooled with water. 8.3 g of valmitoyl chloride was added to 10 g of dichloromethane while stirring in water.
A 10% aqueous sodium hydrogen carbonate solution (5) was added dropwise to the reaction mixture, which was left to stand for 18 hours under cooling (4°C).
01 was added and distributed. The organic layer was dried with sodium sulfate, and after concentration, the residue was adsorbed onto a 5×14c silica gel column and treated with chloroform-carbon tetrachloride (1:l) from 1 to 7 liters.
% methanol in chloroform-carbon tetrachloride (1:1
) ill with a linear concentration gradient eluate to obtain 3-valmitoyl-1-benzylglycerol 5.0 g (yield -), 3.45-3.55 (yield, C6H3CH2
0-CH2-), 2.2-2.4(bt, -010
OCR2-), 1.28(bs, -CH2-L
O, 88 (bt.

C) 13-), ) 3-decamyl-1-benzylglycerol (yield 77.9%) [IH River (CDC Shiocho 47.2
7 (bs, C6jis-CTo-0-), 4.5
0(s, CbHs(H2-0-), 3.9-4.
2 (section, -0CHz-C:i!-C:!!20GO
-), 3.4-3.55(11,(:6H5(:H
2O-C! ! 2-), 2.2-2.4(bt, -
0COC! l! 2-), 1.26(bs, -G
! ! 2-), 0.88 (bt, CH3-), ) and 3-stearoyl-1-benzylglycerol (yield 43.5%) ('HNMR (GDC Toseri-32(b
s, C6Hs-CH2-0-), 4.55Cs,
C6Hs-CH2-0-), 3.9-4.2(ts
, -0CH2-C! -Printing 20CO-), 3.4
5-3.55 (m, CbHs-CHzO-()!2-)
, 2.2-2.4(bt, -0-GO(:j!
z-), 1.28(bs, -()j?-), 0
．． 88(bt, CH3-)-) was obtained.

(3) Dissolve 2.1 g of 5'-0-(13-carboxytridecanoyl)-2°, 3'-0-isopropylidene-5-fluorouridine in 20 ml of pyridine, followed by 2.4°6- 1.32 g of triisopropylbenzenesulfonyl chloride was added. This solution was mixed with 3-valmitoyl-! - Added 1.8 g of benzylglycerol to a solution of 20 g of pyridine and 1 part of 20 g of pyridine.
A solution of 0.7 g of potassium carbonate dissolved in 1,501 g of water was added and distributed. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting residue was dissolved in a small amount of chloroform and adsorbed onto a 5×20 cm silica gel column. Elute with 2 sentences of chloroform, separate and purify,
3-Valmitoyl-2-(13-(2°, 3°-0-impropylidene-5-fluorouridin-5'-〇-ylcarbonyltridecanoyl-1-benzylglycerol)+6), 7.31( bg.C6Hs-GH
z-0-), 5.77 (bd, J-1, 47, uridine H+'), 5.1-5.3 (intestine, CH2-
CH-CIh-), 4.8-4.9 (m, uridine H2°, H3'), 4.51 (s, C6) 1s
CIh-0-), 4.1-4.5 (layer, uridine H
a', Hs', -CH2-CH-CHzOCO-),
3.59 (d, J-5.12, -CHz-0-
CH2-C6Hs), 2.2-2.4(m, -0
(:OCHzGHz-).

1, 57, 1.35 (g, s, CH3 CH3
), 1.25(bs, -CH2), 0.8
8(bt,CH3-),) Similarly, 3-decanoyl-
2-(9-(2',3'-0-impropylidene-5-fluorouridine-5'-0-7,47(d,J
-5.8 fl, uridine H6), 7.31 (bs,
C6H5-CH20-), 5.76(bd, J
=1.7, uridine H+'), 5.1-5, 35Ct
a, CH2CdanCH2-), 4.8-5.0(1
1, uridine H2', H3'), 4.54(
! l, C6Hs (lb-0-), 4.1-4.5
(m, Urisif H4', H5°, -CH2CHCH2
-000-), 3.59(d, J=5.12,
-CHz-OCH2CbH5), 2.1
5-2.45 (m.

-Of:O(J2GHz-), 1.58, 1.3
5 (s, s, CH3 CH3).

1, 28 (bg, -CH2-), 0.87 (b
t, CH3) ), 3-stearoyl-
2-(9-(2°,3'-0-inpropylidene-5
-Fluorouridin-5'-ylcarbonyl)uridine H6), 7.30 (bs, Cb■scH?o-)
, 5.77 (bd, uridine old'), 5.1-
5.3 (Maro, CH2CHCH2-).

4, 7-5.0 (layer, uridine H2', H3'')
, 4.53 (S.

C6HsCH2-0-), 4.2-4.5Cm,
Uridine Ha', Hs°.

-CH2CHCH2-OCO-), 3.59(d,
J-5.13, -CHzOCIh-C6Hs), 2
．． 2-2.45 (m, -OCOC:H2CTo-),
1.57.

1, 35Cs, s. CH3 CH3), 1.28
(bs, -C:H2-).

0,88(bt, CH3-), ), 3-valmitoyl-2-[9-(2°.3-0-impropylidene-5-fluorouridin-5-0-ylcarbonyl)
7 nanoyl]-1), 7.31(bs, C6HsC
H20-), 5.75 (bd?,;nH+'),
5.1-5.3 (Sono, GH2G!!-CH2-),
4. fli-4.9 (Country, Urisif H2"l H3'
), 4.54 (s, C6HsCH2-0-).

4, 2-4.5 (m.'7! J Schiff Ha", Hs
', -CH2CHCH20CCJ-), 3.59
(d, J=5.25, -CH2-0-CH2c6Hs
), 2.2-2.4(m, -OCO(H2CO2
-), 1.57, 1.35(s, s, (H3CO
3), 1.25(bs, -C:To-), 0
．． 88 (bt, CH3-).

], and] 3-valmitoylu2-(2',3'-0-
Impropylidene-5-fluorouridin-5'-〇-ylcarbonyl) tridecamethyl-1-benzylg-1
, 170-ru (ff144.9%) (IHNMR
(([lCFH2°, H3'), 4.54(s, C
6HsCH2-0-), 4.2-4.5 (m.

Uridine H4°, Hs', -(H2CHCH2-00
0-), 3.5!3(d.

GH2CH2-), 1.57, 1.35 (S, s,
CH3 CH3).

1, 2 (bs, -CTo-), 0.88 (bt
, GHz-), ) were obtained.

(4) 3-valmitoyl-2-C13-(2°,
3′-isopropylidene-5-fluorouridine-5-
0-ylcarbonyl) tridecanoyl-1-benzylglycerol (2.71 g) was dissolved in 200 ml of glacial acetic acid,
Add 1.5 g of 10% palladium on carbon, and add 1.5 g of 10% palladium on carbon.
Stir for hours. After the reaction solution was filtered and condensed, the residue was mixed with 20 ml of inpropanol and 201 pyridine under reduced pressure to remove water, and then dissolved in 50 ml of pyridine.

E. Next, the cooled solution was added dropwise to 150 ml of a pyridine solution containing 2.35 g of 2,2.2-trichloroethyldichlorobuphosphate and stirred for 1.5 hours. The reaction solution was poured into ice water 2001 and extracted with chloroform 3001.

The extract was dry-filtered with sodium sulfate, concentrated under reduced pressure, and hydrodiene-(2°2.2-)lichloro)ethyl-[3-valmitoyl-2-(+3-(2',
3'-0-isopropylidene-5-fluorouridine-
5'-〇-ylcarbonyl) tridecamyl)]-]1
- Glycerophosphate 1.93g (Uridine H6
), 5.7shi(d, J-1,8, uridine H+'
), 5.1-5.4(m, (H2CHOCH2-
), 4.0-5.0 (Seal, uridine H2'+H3°
, -0-C! b CCl3 , -C)! 20H-CI
3z-).

2.2-2.45(*, -0(OCH2GHz-),
1.57. 1.37 (+.

s, CH30H3), 1.28(bg, -C!
! 2-), 0.89 (bt.

CH3-), ) - Similarly, hydrogen-(2,2,2-trichloro)ethyl -[3-decanoyl-2- (9-(2'
, 3°-0-isopropylidene-5-fluorouridin-5°-〇-ylcarbonyl)nonanoyl))-1-
Glycerophosphate (yield 57.3%) ('HN
MR (CDc: lz: 5.77 (d, J 2.2
．． Uridine H+'), 5.1-5.4 (m.

G) 12cHOcH2-), 4.7-5.0 (layer,
Uridine H2ZHz').

/ g 4,
2.2-2.45 (m, -0COCH2CH2-)
.

1.57, 1.37 (g, s, CH3G, To),
1.2u(b3 -C!!2-), 0.89(b
T, G! ! 3-), ), and hydrogen-(
2,2,2-trichloro)ethyl-[3-stearoyl-2-(13-(2',3'-0-inpropylidene-
5-fluorouridine-5″-〇-ylcarbonyl)tride 5.1-5.3(m, CH2(!!0cH2-)
, 4.7-4.9 (m, uridine H2'', H3')
, 4.45-4. El(bd, -0-CH2O(
13).

4.1-4.4 (Uridine H4', H5', -C1
j2CHOC■2-).

Ta ), ] were obtained.

Reference example 2 (1) 5°-0-(11-carboxyundecanoyl 2
°,3°-isopropylidene-5-fluorouridine 5
, 0 g was dissolved in 50 ml of pyridine, 3.2 g of 2,4.8-)lyisobrobylbenzenesulfonyl chloride F was added, and the mixture was heated overnight. This reaction solution was added dropwise to a solution of 2.3 g of benzylglycerol in pyridine 301 under stirring for 3 hours, and the mixture was allowed to stand overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform 3001.

200 ml of an aqueous solution of 1.8 g of potassium carbonate was added and distributed. Dry the extract with sodium sulfate and filter.

Concentrate under reduced pressure and dissolve the residue in a small amount of chloroform.
It was adsorbed on a silica gel 5 x 25 cm column, separated and purified using a linear concentration gradient of 2 parts of chloroform and 2 parts of 2% methanol/chloroform, and 3-(11-(2'
,3'-0-impropylidene-5-fluorouridine-5'-〇-ylcarbonyl)undecanoyl2-1-
1.48 g (yield 22%) of benzylglycerol was obtained.

(IHNMR (GDCr 7.47 (d, J=8.11
, cormorant! J Shin Hb), 7.31 (bs, C6H
sGH20-), 5.7[1(bd. Uridine H+'), 4.85-4.95C, Uridine H2
'． H3').

4, 55(s, (6Hs()12-0-), 4.
2-4.4 (+s, uridine Ha", Hs'),
4.0-4.2(m, -CH3CN-CH20CH
2CbH5), 3.45-3.55 (layer, C
6H5CH20-CH2-), 2.2-2.45
(m, -OCOCH3(H2-), 1.57,
1.34 (s, s, CH3 CH3 1.48 g of fluorouridin-5'-〇-ylcarbonyldecanoyl-3-benzylglycerol was dissolved in 20 ml of pyridine, and 0.85 g of valmitoyl chloride was added under stirring at room temperature. After dropping for 10 minutes, the reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform 1501, and 150 ml of an aqueous solution of 0.6 g of sodium carbonate was added and separated.The organic layer was filtered through drying under reduced pressure. It was concentrated, and the residue was dissolved in a small amount of chloroform and adsorbed on a 5 x 25 cm column of silica gel. It was separated and purified using the eluent (chloroform, 1.51) to obtain 1-(11-(2°, 3°-0-improduced). pyriden-5-fluorouridin-5-゛-〇-ylcarbonyl)
-undecanoyl]-2-palmitoyl-3-benzylglycerol 1.18 g (yield 58.1%),
7.31 (bs, C61l!5CHzO-), 5
．． 78 (bd, Urisif HI'), 5.1-5
．． 35(+*, -CIbCHGH2-), 4-7
-5-0 (Peng, uridine H2°, H3'), 4.
54 (3, (6HsCHz-0-), 4.15-4
．． 4f, uridine H4°, Hs', COO-1! z
-CHCH2), 3.59 (d, J=5.13.
-CH2-O-CH2CbHs).

2.2-2.45(m, -000(H2-),
1.58. 1.3B(s, s.

CH3C)13), 1.28(bs, -CH2-
), 0.88(bt, CHs-1] (3) 1-(11,-(2°,3-0-impropylidene-5-fluorouridin-5′-〇-ylcarbonyl)-undecanoyl Sea 2-Valmitoyl-3-
1.18 g of benzylglycerol was dissolved in glacial acetic acid 301, 0.5 g of 10% palladium on carbon was added, and the reaction solution was stirred at room temperature for 2 hours under a hydrogen stream. The reaction solution was filtered and concentrated, and the residue was dissolved in Impropatool 201 under reduced pressure. It was azeotropically distilled with pyridine 2h+. The obtained residue was dissolved in pyridine 201,
2.2-) Lichloroethyl dichlorophosphate1. O
The mixture was added dropwise to 10 ml of a pyridine solution of 10 g under stirring and cooling with water. After the addition, the mixture was stirred for 30 minutes and poured into 100 ml of ice water. The aqueous solution was extracted with 200+ sl of chloroform (×2), passed through dry filtration, and concentrated under reduced pressure. The residue was dissolved in a small amount of chloroform and adsorbed onto a 5 x 20 column of silica gel.
Hydrogen-(2,2,2-trichloro)ethyl-[:3-(11
-(2',3'-0-inpropylidene-5-fluorouridin-5'-0-ylcarbonyl-valmitoylcou-1-glycerophosphate (yield 7
4.2%).

C I HNMR (GO(: Ministry of Health = 7.46 (d, J
=8.1, uridine H6).

5, 75 (bd, uridine H+'), 5.1-
5.3(m, -CH2CH-CH2-), 4.8
5-4.95 (m, uridine H2'. H3').

4, 4-4.8 (ta, -0-CH2CJz),
4.1-4.4(m, uridine H4', H5', -
CH2CHCH2-), 2.2-2.4(m, -
OGO-YuGH2CH2-), 1.57,1.35(,!l,
s, CH3 CTo), 1.21)(b+,-
[Jz-); 0.88 (bt, -CH3)-) Note)
Test method as shown in Tables 1 and 2 Lymphocytic leukemia tumor cells L-1210 (NIH strain) were added to 6 GDF strain mice per group at IX 105
Implant intraperitoneally. The administered compound suspended in physiological saline using Tween-80 was administered once a day according to the dosage shown in Tables 1 and 2, on the 1st, 5th, and 9th day after transplantation.
The drug was administered intraperitoneally, and the life extension rate was calculated using the following formula.

T: Average survival days of the compound administration group C: Average survival days of the non-administration group Patent applicant Fuji Chemical Co., Ltd. Procedural amendment (voluntary) July ZS day 1, 1985 Display of JS Patent application No. 1985 No. 85911? Title of the invention 5-0-acyl-5-fluorouridine and 3 Relationship with the case of the person making the amendment Patent applicant postal code 930-03 4 Date of amendment order Originator 5 Details of the invention in the specification to be amended "Explanation" column method.

3. Detailed Description of the Invention The present invention relates to 5'-0-acyl-5-fluorouridine represented by the general formula, pharmacologically acceptable salts thereof, and methods for producing them.

5-Fluorouridine was synthesized in 1958 (U.S. Patent No. 2,885,398), and its anti-malignant tumor activity is already known, but despite its excellent anti-malignant tumor activity, it has strong side effects. However, many attempts have been made to solve this problem by making 5-fluorouridine into various derivatives. Year 84,280
No. 82,079, No. 83,378, Japanese Unexamined Patent Publication No. 1973
No. 52,183, etc.), but nothing useful has been obtained yet.

In order to solve this problem, the present inventors conducted research on a 5°-0-ester compound of 5-fluorouridine, and
The present invention has now been completed.

5°-0-acyl-5-fluorouridine according to the present invention is a novel compound represented by the general formula, and is useful as a medicine, particularly as an anti-malignant tumor agent, an antiviral agent, and an immunosuppressant.

As shown in Tables 1 and 2 at the end of the table, the anti-malignant tumorigenic effects of these compounds are shown in Tables 1 and 2 below. This is indicated by an extension of .5 times or more.

Next, the manufacturing method will be described.

5'-0-acyl-5-fluorouridine according to the present invention can be obtained by reacting a 5'-0-acyl-5-fluorouridine derivative represented by general formula (I) with an amine represented by general formula (II). It can be obtained by

The reaction is carried out in an organic solvent in the presence of a condensing agent at a temperature below 50°C.

At this time, anhydrous aprotic solvents are used as organic solvents, examples of which include benzene, toluene, xylene, chloromethane, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, ethyl acetate, ether, tetrahydrofuran, dioxane, pyridine, etc. can be mentioned. As the condensing agent, 7-arylsulfonyl such as pi-mylenesulfonyl chloride, triisopropylbenzenesulfonyl chloride, methanesulfonyl chloride, alkylsulfonyl chloride, dicyclocarbodiimide, thionyl chloride, phosphorus oxychloride, etc. can be used.

The molar ratio in the reaction is represented by general formula (I) 5'
The amount of each of the amines represented by formula (II) and the condensing agent is approximately 1 to 3 moles per mole of the -O-acyl-5-fluorouridine derivative.

After the reaction, the target compound is obtained by purification by silica gel column chromatography or the like.

Examples of pharmacologically acceptable salts of these target compounds include hydrochloric acid,! In addition to salts with inorganic acids such as acid, nitric acid, and organic acids such as methanesulfonic acid and para-toluenesulfonic acid, salts with alkalis such as sodium and potassium can be mentioned.

Pharmaceutically acceptable salts of these compounds can be obtained by coexisting a pharmacologically acceptable acid or alkali in the step of removing various protecting groups described later, or can be obtained by adding another acid or alkali after purification. It can also be used as salt.

In this reaction, unintended reactions often occur, so in order to prevent this, it is preferable to add a protecting group to one or both of the starting materials and remove those protecting groups after one reaction.

In the 5-0-acyl-5-fluorouridine derivative of general formula (I), the site that causes a reaction other than the intended one is the hydroxyl group at the 2.3-position of the ribosyl group and one of the hydroxyl groups of the phosphoric acid group.
It is individual. The 2- and 3-position hydroxyl groups of the ribosyl group can be protected by, for example, a fullkylidene group or benzylidene group such as impropylidene, ethoxyethylidene, or benzylidene, or the hydroxyl group in the phosphoric acid group +f2.2.2
-) It can be protected by an alkyl group having a substituent such as rehalogenated ethyl, cyanoethyl, or phenylsulfonylethyl, or by a chlorophenyl group, benzyl group, or nitrobenzyl group.

On the other hand, in the amines of general formula (II), the amine 7 group and the carboxyl group when both R1 and R2 are hydrogen atoms are sites that cause unintended reactions. Examples of protecting groups for amine groups include t-butoxycarbonyl group, trichloroethoxycarbonyl group, and benzyloxycarbonyl group. Further, examples of M-retaining groups for carboxyl groups include lower alkyl groups such as methyl and ethyl, and benzyl groups. These protecting groups can be easily removed after the reaction is completed, either individually or simultaneously with other protecting groups depending on the purpose.For example, the protecting group at the 2.3 position of the ribosyl group can be removed by acid treatment or reduction. Accordingly, the phosphoric acid protecting group is removed by alkali treatment or reduction, and the amino group protecting group and the carboxyl group protecting group are removed by reduction.

The 5'-0-acyl-5-fluorouridine derivative of the general formula (I), which is one of the starting materials, is also a new compound. For example, in the general formula (I), R' is H (wherein R4 is already The 5'-0-acyl-5-fluorouridine derivative is obtained by condensing a 3-carboxylic acid ester of glycerin having a protecting group at the 1-position with a 5'-0-dicarboxylic acid ester of 5-fluorouridine. then add 1 part of glycerin
It can be obtained by further phosphorylating the 1-position after removing the position-protecting group. In this case, examples of the protecting group at the 1-position of glycerin include a benzyl group, a nitrobenzyl group, an alkylphenylbenzyl group, an alkoxyphenylbenzyl group, a picolyl group, and a trialkylsilyl group. To phosphorylate the 3-position, use phosphorus oxychloride, 2,2.2-trichloroethyl dichlorophosphate, cyanethyl dichlorophosphate, chlorphenylethyl dichlorophosphate, phenylsulfonylethyl dichlorophosph, -
It is sufficient to react with a phosphoric acid compound such as
, 2.2-) When reacted with a phosphoric acid compound such as dichloroethyl dichlorophosphate, cyanoethyl dichlorophosphate, chlorphenyl dichlorophosphate, or phenylsulfonylethyl dichlorophosphate, the hydroxyl group of phosphoric acid becomes 5'-〇- in a protected form. An acylu-5-fluorouridine derivative is obtained.

The other starting material, the amines of general formula (II), specifically includes ethanolamine, N-methylethanolamine, N,N-dimethylethanolamine, serine,
N-methylserine and N,N-dimethylserine are commonly known.

Note that the target compound of the present invention can also be obtained by methods other than those described above. One of the methods is
The intermediate before reacting the phosphoric acid compound obtained in the process of producing the 5°-0-acyl-5-fluorouridine derivative of general formula (I), the amines of general formula (n), and the phosphorus oxychloride , 2,2.2-trichloroethyl dichlorophosphate, cyanoethyl dichlorophosphate, chlorphenyl dichlorophosphate, phenylsulfonylethyl dichlorophosphate, and other phosphorus compounds are simultaneously reacted. Examples will be shown below to further explain the present invention in detail.

(Left below) Example 1 (+) Hydrodiene-(2,2,2-) 1)
')rollo)ethyl-[3-valmitoyl-2-(13
-(2',3°-0-impropylidene-5-fluorouridin-5°-0-ylcarbonyl)tridecanoyl)-1-glycerophosphate-) To 1.93 g of pyridine solution 151, 2.4 .8-) 1.12 g of lyisopropylbenzenesulfonyl chloride was added and stirred.

1.45 g of N-benzyloxycarbonylaminoethanol was added to this solution, and the reaction solution was heated overnight under reduced pressure to eR1i! The resulting residue was dissolved in chloroform 2001, and an aqueous solution 1001 containing 0.6 g of potassium carbonate was added thereto for distribution. The organic layer was filtered through drying, the filtrate was concentrated under reduced pressure, the residue was dissolved in a small amount of chloroform, and silica gel 5X
It was adsorbed on a loc+s column.

Elution was performed with a linear concentration gradient of 1 part chloroform carbon ditetrachloride (1:1) to 1 part chloroform carbon ditetrachloride (1:l) containing 3% methanol. The eluate was separated and purified to give (2-benzyloxycarbonyl-amino)ethyl-2,2,2-trichloroethyl-[3-valmitoyl-2-(13-(2", 3°-0-isopropylidene-5 -Fluorouridin-5'-0-ylcarbonyl phosphate 1.80 g (yield 78.9%) was obtained.

(IHNMR (GDCh. ppm); 7.45 (d
, J-5.98, uridine H6), 7.34
(bs, CH30H3-000-), 5.75(
bd, uridine H+'), 5.1-! 5.4 (m,
-CI20HCH2H-).

5, 12(S, (6HscTo-000-), 4
．． 8-4.9 (m, uridine H2'. H3'),
4.58 (d. d, J Proverbs 8.85, J
-1.1, -0-CH2CC13), 4.1-
4.4(+1, uridine H4'+ H5'+ -C
I2CC13-, OCHzCH2N), 3
．． 4-3.8(+*, -0(:I2-GH2N()
, 2.2-2.45(m, -0-COCH2
-), 1.58.

1, 35 (s, s, CH30H3), 1.28
(bs, -CH2-).

0,88(bt, -CH3)- ) (2) 1.80 g of the phosphotriester obtained in (1) above
was dissolved in a mixture of 151 parts of a 90% acetic acid solution and 51 parts of diethyl ether, 2 g of zinc dust was added thereto, and the mixture was stirred at room temperature for 2 hours.
The reaction solution was concentrated, and 401 parts of 5% hydrochloric acid and 100 parts of chloroform were added to the residue and partitioned.

After drying the organic layer, the filtrate was concentrated under reduced pressure, and the residue was dissolved in a small amount of chloroform, adsorbed on a 5 x 3 cm column of silica gel, and eluted with a linear concentration gradient of chloroform 11-5% methanol/chloroform 1 sentence. Separate and refine the solution to obtain hydrodiene-(2-penzyloxyluponylamino)ethyl-[3-valmitoyl-2- (+3-
(2',3'-0-inpropylidene-5-fluorouridin-5'-0-ylcarbonylphen) 1.55 g (yield 94.3%) was obtained.

(I) INMR (CD30[1, ppm); 7.8
1 (d, J-8.47, Urisif H6), 7.3
3(bs, (:6HsCH2-OCO-), 5.
77 (bd.

uridine H+'), 5.1-5.3 (intestine, -CH
2 0H (+12 −).

5, 09 (s, C6Hslll:I2-OCO-),
Overlap to HOD (Uridine H2°, H3')
, 3.9-4.3 (m, uridine H4'.

Hs', -CI20HCH2-, OCH2CH
Nku), 3.39(t, -OCH2-CH2
NO, 2.2-2.45(m, -QC:O(Jh
-), 1.54.

1, 34 (s, s, GHx CH:), 1.
28(bs, -G)I2-).

0,89(bt, -CH3), ) (3) 1.55 g of the ester obtained in (2) above was added to 90
% trifluoroacetic acid aqueous solution and left at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was azeotropically distilled under reduced pressure using an Improper Tool 301, dissolved in a small amount of chloroform, and adsorbed onto a 3×6 cm silica gel column. From 200 ml of chloroform, increase methanol in 0.5% increments until 5% methanol/chloroform.
Elution was performed using 200 ml of each sample. The eluate was concentrated and hydrodiene-(2-benzyloxycarbonylamino)ethyl-[3-valmitoyl-2- (13-
(5-fluorouridine-5°-〇-ylcarbonyl)
tridecamethyl)]-]1-glycerophosphate 0
．． 93g (yield 62.0%) was obtained.

('HN)IR(C[lCI3, ppm); 7.8
8 (d, JJ.83, uridine H6), 7.
33(bs, C6HsCH2-Ofj)-), 5
．． 80 (bd, uridine H+'), 5.1-5.2
5(m, -CI20HCH2-).

5,09(s, (6Hs(lb-OCO-), 3
．． 9-4.4 (i uridine H2°, H3', uridine H
a', H5', -CH20HCH2-, -0(l
b-CHzN(), Overl to CD30[]
ap(-0CH2CH2N).

2, 2-2.5(m, -0-(OIL:I2-),
1.28 (bs, -082-).

0,89(bt, -(I3), ) (4) Dissolve 0.93 g of the ester obtained in (3) above in methanol 501, and add 0.35 g of 10% palladium/carbon.
The reaction solution was stirred for 2 hours in a hydrogen stream, concentrated under reduced pressure through filtration, and the residue was powdered with diethyl ether to obtain the desired hydrogen 2-aminoethyl-[3-valmitoyl-2-(13 -(5-fluorouridin-5'-〇-ylcarbonyl)tridecanoyl)]-]1-glycerophosphate 730+sg (yield 89.7%) was obtained.

('HNMR(CD111:l+:CD300-1:1
．． ppll); 7.84 (d, J-fi, 35.
Uridine H6), 5.87 (bS, Uridine H
+'), 5.1-5.3(m, -CH2C!1l
ll:H2-), 3.8-5.0(m, Tsu'Jjin H2", H3°, Uridine Hs", H5', -
C: IhCHCIh-, -tlc82C82N(),
CD3. 0verlap to OD (-〇CH2C
H2-N(), 2.2-2.5(m, -0C
OCHz-), 1.27(bg, -CH2-
), 0.89 (bt, -1ll:H3),) elemental analysis (C4aH71N30+sFP mO,45(H
Cl2 Toshiko] Actual measured value ($) 53.73 8.01 4.31
Calculated value (X) 53.83 7.87 4.24
Example 2 Hydrodiene-(2,2,2-trichloro)ethyl-
3.0 g (2-benzyloxycarbonylamino)ethyl-2,2,2-)lichloroethyl[3-decanoyl-
2-(9-(2',3'-0-inpropylidene-5
-Fluorouridin-5'-〇-ylcarbonyl)7nanoyl 1) -i-Chryserophosphate 3.23g
(Yield 87.8%) ('HNMR(CDGh
, ppll); 7.47 (d, J-8,1, uridine H6), 7.33 (bs.

C6H3 (H2-000-), 5.74 (bd,
uridine H1').

5.1-5.35(m, -CHzCHC:H2-NH
-), 5.11(S, C6Hs-CH20GO-
), 4.85-5.0 (m, uridine H2',
H3').

4, j9 (d, d, JJ, 59. J-0,97,
-0CHzC:Oh).

4.1-4.45 (m, uridine Ha', Hs',
-CHzCHCH2-.

-0CHZCH2Nc), 3.4-3.55 (layer, -0CH2C82N().

2.2-2.5 (m, -0CO-CH2-), 1.
57, 1.35 (s, s.

CH3CH3), 1.28(bs, -CH2-)
, 0.88(bt, -(JJ3), ) , Hydrodiene-(2-benzyloxycarbonylamino)ethyl-[3-decanoyl-2-(9-(2',3'-
0-isopropylidene-5-fluorouridine-5-0
-ylcarbonyl)nonanoyl)]-]1-glycerophosphate 2.62g (yield 83.2%) ('H)
IMR (CD30D:CDGh=1:1.ppll)
;7, fi5(d, J-6,11, uridine H6),
7.33 (bs.

C6HsCIbOCO-), 5.77 (bd, J
-1,95, uridine H+'), 5.1-5.35
(wear, -(H2C!i-CH2-), 5.09(
S.

C6Hs()h-QC:0-), 4.7-5.05
(m, uridine H2゛.

H3'), 3.85-4.4 (11, uridine H4
°, )15', -[)j2-CH・C! l! 2-
, OC:H-2GH2N(), CD300
to 0verlap(-0-CkhCH2N<),
2.2-2.5 (trust, -0COGH2-),
1.57°1.38 (s, s, CH3CH3)
, 1.28 (bs, -CH2-).

0.88(bt, Jl:H3), ), Hydrodiene-(2-benzyloxycarbonylaminocanoyl-2-(9-(5-fluorouridine-5')
-0-ylcarbonyl)nonanoyl't)-1-glycerophosphate 1.89g (yield 67, 2%)
(IHNMR(CD30D:C:DCh-1:1,
ppm); 7.83 (d. J=18.59, uridine H6), 7.32 (bs, CbH5CH20
CO-), 5.83 (bd, uridine H1')
, 5.1-5.35(m, -CH2CHCH2-
), 5.09 (3CbHsCH2-OCO-),
3.9-4.5Cm, uridine H2°, H3'
, uridine H4°, H5', -CH20GH2
-, -OCH2 CH2 Ng), CD3
00 to Overlap(-0CH2CH2-Nc
), 2.2-2.5(m, -OCOCH2-
), 1.28(bs, -CH2-) 0.
88 (bt, -C:H3), ) to obtain the desired hydrodiene-2-aminoethyl-[3-decanoyl-2-(9
-(5-fluorouridin-5-0-ylcarbonyl)
7 nanoyl)-1-glycerophosphate 1,03
mg (yield 71.2%).

('HNMR(GDC13:GDxOD-1:1.p
pll); 7.84 (d, J-8, 35, Uriji y
H6), 5.85(bs, uridine H1°
), 5.2-5.45(m, -CH2CHCH2-
), 4.0-5. OCm, uridine H2', H3°,
Uridine Hs'. Hs', -CH2Cl-CH2-
, -0-CH2(JhNc), GD30[1
Overlap(-0CH2CHzN<), 2
．． 2-2.6 (layer, -0000H2-), 1
．． 29(bS, -CH2-), 0.89(b
t, -CH5)-) Elemental analysis CC3aH57N30+5
As FP-1,55cHG13] and N Actual value ($) 43.23 B, 21 4. E
13 Calculated value ($) 43.44 B, 00 4
．． 28 Example 3 Hydrodiene-(2,2,2-1-lichloro)ethyl-
[3-stearoyl-2-(13-(2', 3'-0
-Impropylidene-5-fluorouridine-5'-0
(2-benzyloxycarbonylamino)ethyl-2,2,2-)lichloroethyl[3] using 3.44 g of 1-glycerophosphate as the starting material. -stearoyl-2-(13-(2°,3'-0-impropylidene-5-fluorouridin-5°-0-ylcarbonylphe-) 2.0?g (yield 51.7%) ( I
HNMR (C[lCIs.

ppm); 7.45 (d, J-5.88, uridine H6), 7.34 (bs, (,6il!s-C
H2-0 (0-), 5.76 (bd, uridine H!
゛), 5.35-5.5(m, -N)I-),
5.1-5.35(m,-CH2Cjl!-CH2
NH-), 5.12 (g, C6H5CH2-OCO
-), 4.7-4.9 (layer, uridine H2°,
H3'), 4.58 (d, d, J stomach E1.59
.

J=1.22, -OCToCC]x), 4.1-
4.4(m, uridine H4',85', -CH2CHC
Hz-, -QC:H2C)t2Nc), 3.4-
3.8 (amount, -OCTo-1082N), 2.
2-2.45 (m, -000-CHH?-).

1, 58, 1.35 (s.s, CH3 CH3)
, 1.25(bs,-CH2-)+0.
88 (bt. (H3-), ), hydrogen-(
2-benzyloxycarbonylamino)ethyl-[3-
Stearoyl-2- (13-(2', 3'-0-
Impropylidene-5-fluorouridine-5゛-0-
ylcarbonyl)tridecanoyl)-1-glycerophosphate 1.87g (yield 104%) C
'HNMR (CD300:(DC13=1:1
, Pp intestine); 7.6? (d, J-6.1, Uridine H6), 7.32 (bs, (6i!scHzO
GO-), 5.77 (bd. J-1, 95, uridine H+'), 5.1-5.3 (layer. -CH2C
;HCIh-), 5. Oil(s, C6H5C
HzGO-), 4.7-5.0 (m, uridine H2
'', H3'), 3.11-4.4 (, uridine H4°, H5゛, -CH2CHCH2-, -
OCHzGHzN(), 3.83(t,
-OCIh-CIhN〈), 2.2-2.45(
m,-0(OCH2-(,Hz-),'-",
1.38 (s, s, CH3 GHz), 1.
27 (bs, -CH.-).

o. a9(bt, CH3-), ) and hydrogen-(2-benzyloxycarbonylamino)ethyl-
[3-Stiaroyl-2-(13-(5-fluorouridin-5°-〇-ylcarbonyl)tridecanoyl))-1-glycerophosphate 1.51 g (
Yield 83.8%) CIHNMR ((lhOD:CDCI
z-1:1, ppm); 7.83 (d, J-6
, 35, uridine H6), 7.12 (bs, G
6H! l-(Hz0-).

5, 83 (bs, uridine H+'), 5.1-
5.25 (m, -CH2-CHGH2-), 5.
08(s, C6H5CH20GO-), 3.8-
4.4Cm, uridine H2', H3°, uridine H4°
, H5", -C))2-C)If,Hz-, -
OCH2(:H2N(), Over to IJ30D
lap(-0-CH2C)12N<), 2.2-
2.5(a, -0-COCHz-), 1.2
7(bs, -CH2-), 0.89(bt, C
H3-), ) to the desired hydrogen-2-aminoethyl-[3-stearoyl-2- ( +3-(5-
Fluorouridine-5°-〇-ylcarbonyl) tridecayl)]-]1-glycerophosphate 0.84g
A yield of 63.5% was obtained.

(IHNXR((D30D:(Def3-2:1.p
pm); 7.82 (d, J-8, 35, uridine H6), 5.84 (bs, uridine Hl'),
5.1-5.4(m, -C)IzCH(Hz-),
4.0-4-9(m, uridine H2", H3",
Uridine Hs', H5°, -CH2 CHCH2-
, -0-CH2(H2Nc), CD:+OD
Overlap (-0CH2-CH2Nc),
2.25-2.5 (m, -OCOCHz-),
1.27 (bs.

-CH2-), 0.89(bt, CH3-,
) Elemental analysis CG46HsIo+sN3FP4.25CH
C13] c H Σ Actual measurement value (ri 50.64 7.48 4.0
0 calculated value ($) 50.88 7.43 3
．． 77 Example 4 Hydrodiene-(2,2.2-)lichloro)ethyl-
[3-Pa) L, Mitoi At -2- ( +3-(
2°,3'-0-inpropylidene-5-fluorouridin-5'-0-ylcarbonyl)tridecanoyl
(2-benzyloxycarbonylamino-2-benzyloxycarbonyl)ethyl-2.2.2-)lichloroethyl [ 3-palmitoyl-2-(13-(2',3°-〇-impropylidene-5-fluorouridin-5'-0-ylcarbonyl)tridecayl)]-]1-glycerophosphate 1.59 g (yield rate 76.8%) ('HNMR
(COCH3, PP11); 7.43 (d, J-
f3.1. C') Schiff H6), 7.33(b
g, Cb'45-CH2-0CO-), 5.7-
5.8 (+s, uridine H+'), 5.20°5.11 (s, s, (aHsc:H?0CO-),
3.9-5.0 (m, uridine H2°, H3
', -0111:HzCCb, Uridine H4',
H5゜, -CH2CHCH2-, -0CH2GH
2N(), 2.2-2.4(m, -0-CO
C: H2-), 1.57, 1.33 (s, s,
CIh CH3), 1.25(bs, -CH2-
), 0.88(bt, CH3-), ),
Hydrodiene-(2-benzyloxycarbonylamino=2-benzyloxycarbonyl)ethyl-[3-valmitoyl-2-(13-(2°, 3'-0-impropylidene-5-fluorouridine-5°- 0.94 g (yield 65.1%) [:'HN
MR (CD30D:CDCI=-1:1); 7.7
5 (d, J-8,35, uridine H6).

7.35.7.32(bs, (6Hs-CH2-OC
O-), 5.79 (bd, J-2,2, Urisif H1'), 5.1.5.21 (s, C6H5CH
20CQ-), 0verlap (uridine H2',
)! 3'), 3.9=4.4 (votes, Uridine H
4°, Hs', -CH2CHCH2-, -0-CH
2CH2N<), 2.2-2.4(+1.-0
COC:H2-), 1.58°1.37(3,s
, CH3CH3), 1.28(bs, -(H2-
).

0.88(bt, -CH5), ) , Hydrodiene=(2-benzyloxycarbonylamino-carbonyl(13-(5-fluorouridin-5-0-ylcarbonyl)tridecanoyl))]-]1-glycerophosphate 0 .57g (yield 62.3%) (IHNMR(C
D30D:GO(:lz-1:1); 7.88(d
, J-8.5L Uridine H6).

? ．． 33, 7.32Cs. C6Hs-CH2-00
0-), 5.80 (bd, Urisif HI°), 5
．． 11, 5.21 (g, f: 6HscH20GO-
).

3, 9-4.5 (R. Uridine H2', H3', Uridine') Hto.

Hs', -CH2CHCH2-, -OCH2C
H2Nc), 2.2-2.4 (intestinal.

-OC01J2-), 1.26(bs, -CH2
-), 0.88 (bt, CH3-), ] to the desired hydrogen-(2-amino-2-carboxy)
Ethyl-[3-valmitoyl-2- (13-(5-
Fluorouridine-5'-0-ylcarbonyl)tridecanoyl))-1-glycerophosphate o. 21g (
Yield 4585%) was obtained ('HNMR (CD30D:
(DCI3-1:1); 7.88 (d, J-8.
59.

Uridine H6), 5.82 (bg, Uridine YH
1').

CD30D to Overlap (-0CHzC82N
(-), 2.4(m, -o-GOC:H2-
), 1.28(bs, -(H2-), 0
．． 88(bt, CH3-),] Elemental analysis (GasH170+zN3FP・t.75(J
As c13・0.5820] 9 Dan Σ Real m Ii ($) 46.79
[i. 70 3.50 Calculated value ($) 4B
．． 78 e. 993.77 Example 5 Hydrodiene-(2,2,2-trichloro)ethyl-
(3-stearoyl-2- (13-(2", 3'-
0-Impropylidene-5-fluorouridine-5'-
(2-benzyloxycarbonylamino-2-benzyloxycarbonyl-[3-steakyl-2- (13-(2°,3'-0-isopropylidene-5-fluorouridin-5'-0-yl carbonyl phosphate 4.10 g (yield 108%) (I
HNMR (CDCh. pps); 7.42 (d,
J = 8.1, Urisif H6) 17, 33 (bs, C
6HsCHz-0(0-), 5.7-5.9(m,
uridine H1°), 5.19, 5.11(s,
s, C6HsCH2-OCO-).

3, 9-5.0 (+s, uridine H2', H3'
, -ocH2cc+3.

Uridine H4°, H5°, -CIhCHCH2-,
-OCHzCH2Nc).

2, 2-2.4 (m, -0-COCH2-), 1
．． 57, 1.34 (s, s.

CH3 CH3), 1.25(bs, -(H2
-), 0.88 (bt.

-CH3)-), hydrogen-(2-benzyloxycarbonylamino-2-benzyloxycarbonyl)ethyl-[3-stearoyl-2-(13-(2
°.

3”-0-inpropylidene-5-fluorouridine-
5°-0-ylcarbonyl)tridecanoyl)]-]1
-Glycerophosphate 1- 1.85g (yield 48.
1%)('HNMR(CD30D:(,DCh-1:1
, PP11): 7.75 (d, J-8, 35,
Uridine H6), ? ．． 34, 7.32 (bs,
C6HsCH2-CCO-), 5.77 (bd,
J-2.2, uridine H1°).

5, 1, 5.21 (s. C6HsCH2-QC:O
-), Overlap (uridine H2'', H3'
), 3.9-4.4 (m, uridine H4゛.

H5', -CH2C)IcL-, -0GH2C)1
2N (), 2.2-2.4 (m.

-0-COC)12-), 1.55. 1.37 (
s, s, CH30H3)・1.28(bs, -C
H2-), 0.89(bt, -CH3), ) and /\hydrogen-(2-benzyloxycarbonylamino-2-benzyloxycarbonyl)ethyl-[3
-stearoyl-2-(13-(5-fluoroeurolysine-5″-0-ylcarbonyl)tridecanoyl)]
-]1-glycerophosphate 1.25g (yield 7
1.3%) ('HNMR(G[130D:GDCh
=1:l, pp+s); 7.88(d.

J cloud 8.59. Uridine H6), 7.34.7.3
2(s, G6Hs-f:1b-OCO-), 5.
8L (bs, uridine [1'), 5.11゜5
．． 20(s, C5HsCH2-OCO-), 3.
9-4.5 (m, uridine H2°, H3°, uridine H4°, )Is', -CHzCHCIh-.

-QC) 120H2N<), 2-2-2.4(*
, -0COCH2-), 1.28(bs,
-GHz-) 0.89 (bt, -CH5), ]
The desired hydrogen-(2-amino-2-carboxy)ethyl-[3-stearoyl-2-(13-(
5-fluorouridin-5'-〇-ylcarbonyl)tridecanoyl)]-]1-glycerophosphate 700
A layer g yield of 86%) was obtained.

('HNMR(f:DCI3:CD0Dl!1:1.
Ppm); 7.85 (d, J-8,59, uridine H6), 5.83 (bs, uridine Ht'),
C[130D 0verlap(-0CHz(
H2Nc), 2.4(s, -0-COGHz
-), 1.28 (bs, -CH2-), 0.
89(bt, -C)+3),] Elemental analysis (C47) 1su130+7FP・0. [HG
h] 9 days Σ Actual value ($) 52.78 7.88 4.08
Calculation ga(X) 52.85 7.80 3.8
8 Example 6 Hydrodiene-(2,2,2-)lichloro)ethyl-
[3-Butyroyl-2-113-(2',3'-0-impropylidene-5-fluorouridine-5'-0-l)-1-gI nocellophosphate 5 ．． fi8g (IHN
NR (CDzOn: (DClx-L: 1. ppm)
; 7.72 (d, J-El, 1. uridine) + 6)
, 5.78 (bd.

uridine H+'), 5.1-5.4C layer, -CH
2C) lOCH2-).

4.0-5.1 (m, uridine 82", H3',
-0CH20CI3゜Uridine Ha', Hs°, -
CIhCHCH2-, -0GH2GToNO.

2.2-2.4 (+a, -0-Co-CH2-),
1.57. 1.37 (+, s.

CH3CH3), 1.28 (bs, -GHz-),
Using 0.95(bt, CH3-),] as the starting material, Lte(2-benzyloxycarbonylamino, 2.2-trichloroethyl-[3-
Butyroyl-2-(13-(2',3'-0-impropylidene-5-fluorouridin-5'-0-ylcarbonyl)tridecayl)]-]1-glycerophosphate 5.61 g (yield B2. 8%) C l)
INMR (CDGh, pp Otori): 7.45
(d, J-5, 88, uridine H6), 7.3
4(bs, [6Hs-C:H2-QGO-), 5
．． 78 (bd, uridine old'), 5.1-5.
4(s,-GHzCIiC:H2-NH-), 5.
11(g, 6HscH2-t)ICO-).

4,85-C95(+*, uridine H2'.)13
'), 4.58 (d.

d, J=8.5J JJ. 9B, -OGlbCCh
), 4.1-4.4 (m.

Uridine H4°, H5", -CIhCHCH2-,
-OCH20H2N<).

3, 4-3.8Cm, -OCHz-CH2N<),
2.2-2.45 (layer, -OCO-CH2-
), 1.57, 1.35Cs, s, CH3
CH3), 1.25(bx, -CH2-),
0.94 (bt. CTo-), ), Hydrodiene-(2-benzyloxycarbonylaminotyl-[3
-Butyroyl-2- (13-(2°,3°-0-isopropylidene-5-fluorouridin-5°-〇-ylcarbonyl)tridecanoyl))-1-g1-nocellophosphate) 2.95 g (Yield B2.2 %) (
IHNMR (CD30D:CDGI:+-11:1.
PP layer); 7.83 (d, J-6.59,
Uridine H6), 7.33(bs, Cbbs
cu2oco-), 5.78 (bd, uridine H+
'), 5.1-5.3((-CHHzCHCHz-)
.

5, H(s, C6H5GH2GO-), Over
lap (one noji y) 12°.

)13'), 3.9-4.4 (■, Uridine H4°
．． )Is', -C)12C)1-C)12-,
-QC) 12CI(2%(), Overlap(
-0CHzGH2Nc).

2, 2-2.45(m, -OCOcH2-(H2-)
, 1.53, 1.34(s;s, CH3 CH
3), 1.29(bs, -CH2-), 0
．． 84 (t.

CH3-) , ) and 1/ /\hydrodiene-(2
-benzyloxycarbonylamino)ethyl-[3-butyroyl-2-(13-(5-fluorouridin-5'-0-ylcarbonyl sulfate 1.9 og (yield 67, 3%) ('HN
MR (GD30D:GDCh=1:1, ppm);
7.89 (d, J wealth 8.84, Tsu1 Nojin) 1a)
, 7.34(bg, (6Hs-CH20-), 5
．． 81 (bs, uridine H+'), 5.1-5.3
(m, -CH2C)IC)12-), 5. H(s
．． Ca) lscH20GO-), 3.9-4.3
5 (m, uridine) + 2', H3°, uridine H
4', H5', -CH2CHCH2-.

−0CH2CH2N(), ([h 00
0verlap(-0CH2C:HzN(), 2.
2-2.5(m, -0(:0CHz-), 1.
28 (bs, -GHz-).

0.94(t, CH3-), ) to form the desired hydrogen-2-aminoethyl-[3-butyroyl-2-
1.05 g (yield 64.9%) of (13-(5-fluorouridin-5-0-ylcarbonyl)tridecanoyl)-1-glycerophosphate was obtained.

('HNMR(CD30D:CDCl3-1:1.p
pm); 7.90 (d, J-8,84, Urisif H6), 5.81 (bg, Uridine H1'),
5.1-! 5.5 (Peng, -CH2CHCH2
-), 3.9-5.0 (layer, uridine H7'
, H3', Uridine H4', H5°, -CH2C
HCH2-, -0-CH2CH2N(), CD3
0verlap(-0(H2-(J2N()
, 2.2-2.5Cm, -0COCHz-)
, 1.29 (bs.

-(J2-), 0.95(t, CH3-)-) elemental analysis (as 111:32Hs3N30+5FP-HzO] and Σ Actual value (1) 48.85 fl, 92 5.
40 Calculated value ($) 48.79 7.04 5.
33 Example 7 (1) Hydrodiene-(2,2,24lichloro)
Ethyl-(3-stearoyl-2-(13-(2°, 3
'-0-inpropylidene-5-fluorouridine-5
°-0-ylcarbonyl)tridecanoyl)]-]1-
0.87 g of glycerophosphate was dissolved in 101 g of pyridine, 0.48 g of 2,4.8-)lyisoprobylbenzenesulfonyl chloride was added, followed by 0.29 g of dimethylaminoethanol, and the reacted solution was stirred overnight under reduced pressure. After concentration, the residue 5 was dissolved in chloroform 1001, and an aqueous solution 501 containing 0.24 g of potassium carbonate was added thereto for distribution. The organic layer was dried, the filtered filtrate was concentrated under reduced pressure, and the residue was dissolved in a small amount of chloroform and adsorbed on a column of 5×7 C layers of silica gel. Separate and purify using a linear concentration gradient eluate of 1 part chloroform to 4% methanol/1 part chloroform,
0.3j1g (yield 37.5%) of (2,2-dimethylamino)ethyl-2,2,2-trichloroethyl-[3
-stearoyl-2-(13-(2', 3'-0-inpropylidene-5-fluorouridin-5'-0-ylcarbonyl)tridecanoyl)]-]1-glycerophosphate IHNMR (CDCh, ppm); 7
．． 45 (d, J=5-88.uridine Hs), 5
．． 78 (d, J=1.95.Uridine H1").

5.1-5.35 (m, -GH2G court (H2-),
4.7-4.9j (intestine/uridine H2', H3°),
4.62 (d, d, J-8,47, J-0.7
3゜-0CH2CGIx), 4.15-4.45
(layer, -CH2CH-CH2-, -0-CH2CH
2N<), 2.72(t, J-5,17,-
0CH2-111: Hi<).

2.2-2.45(+s, -0-COCH2-, -N
-C:H3), 1.57-1.35C3,S, C
D3 (83), 1.28 (bg, -GHz-)
, 0.88 (bt.

CH3-),) was obtained.

(2) Dissolve 0.38 g of the ester obtained in step (1) above in 90% aqueous acetic acid solution, add zinc dust tg, stir at room temperature for 30 minutes, concentrate the reaction solution under reduced pressure, and add chloroform to the residue. 1001 and 30 liters of 10% hydrochloric acid were added and distributed. The Ja layer was filtered through drying and concentrated under reduced pressure, and the residue was dissolved in a small amount of chloroform and adsorbed on a 3x3 cm column of silica gel. Separation and purification were carried out using a linear concentration gradient eluate of 50 hl of chloroform and 15% methanol/chloroform 5001 to obtain 18 g (yield 51.5%) of hydrogen-(
2,2-dimethylamino)ethyl-[3-stearoyl-2-(13-(2',3°-0-inpropylidene-
5-fluorouridin-5-0-ylcarbonyl)tridecanoyl)]-]1-glycerophosphate' H
NMRCCD300:GDCh-1:1. PPI)
; 7.58 (d, J-8,1, uridine H6),
5.70 (bs, uridine H1°), 4.9
5-5.25 (m.

-CH2-CHCIh-), 4.8-4.9 (gourd,
Uridine H2', H3゜), 3.8-4.3(+
*, Uridine H4', H5', -CIhCH-C
H2-, -0GH2GHzN(), 2.83(b
s, -0CHz-111:H2Nc.

-N(Ih), 2.1-2.4(m, -0COC
Hz-), 1.47.1.27Cs, s, CD
3 CH3), 1.18(bg, -(:H2-)
, 0.79 (bt, (H3-),) was obtained.

(3) Dissolve 0.18 g of the ester obtained in (2) above in 101 ml of 90% trifluoroacetic acid aqueous solution, stirrup for 30 minutes, concentrate the reaction solution under reduced pressure, and add the residue to 20 ml of Improper Tool under reduced pressure. The product was co-distilled, dissolved in a small amount of chloroform, and then adsorbed onto a 3 x 20 inch column of silica gel. Separation and purification were performed using a linear concentration gradient of chloroform li and 20% methanol/chloroform to obtain the target product, hydrodiene-(2,2-dimethylamino)ethyl-[3-stearoyl-2-(+3-(5 -fluorouridine-5°-0-ylcarbonyl)tridecanoyl
)-1-glycerophosphate-) 12hg (yield 80.5%) was obtained.

(')IMMR(C1)30D:CDC13-1:1.
Pp Sodium); 7.84 (d, J-6,6, Uridine H
6), 5.83 (bd, uridine H1°),
5.1-5.35 (m, -CH2CHCH2-),
3.9-5.0Cm, Uridine H2°TH:”! Uridine H4', H5', -CHzCHCkh-, -0C
H2CIhN<), 2.94(bs, -0C
HzCH2N<, NC; I3), 2.2-2
．． 5(■, -0CO(82-), 1.27(bS,
-(Hz-), 0.89 (bt, CH3-),) Elemental analysis (C48) 185N3015FP・0.4C)l
As c+3・H2O] 9 days N Actual value ($) 54.57 8.50 4.1
3 Calculated value ($) 54.84. 8.31 3.
98 Example 8 (1) Hydrodiene-2,2,2-)lichloroethyl-(3-(I+-(2', 3'-0-inpropylidene-5-fluorouridin-5-0-ylcarbonyl)
1.0 g of undecanoyl)-2-valmitoyl]-1-glycerophosphate was dissolved in 10 ml of pyridine,
0.57 g of 2,4.81-lyinpropylbenzenesulfonyl chloride was added and stirred for 30 minutes. Add 0.7 N-benzyloxycarbonylaminoethanol to this solution.
The reaction solution was concentrated under reduced pressure, the residue was dissolved in 100 ml of chloroform, and potassium carbonate was added.
．． 100 μl of an aqueous solution of 29 g was added and distributed. After drying and filtering the organic layer, the filtrate was concentrated under reduced pressure, and the residue was dissolved in a small amount of chloroform, adsorbed on a column of 5 x 5 C layers of silica gel, and mixed with chloroform carbon ditetrachloride (1:1) for 1.5 grams.
5% methanol/chloroform dicarbon chloride 1:1)
1. Separate and purify with a linear concentration gradient eluate of 5 sentences, (2,
2-dimethylamino)ethyl-2,2,2-)lichloroethyl-(3-(1l-(2°,3'-0-impropylidene-5-fluorouridin-5'-0-ylcarbonyl)undecanoyl)- 1.13 g (yield $97.8%) of 2-valmitoyl-1-glycerophos 7,-
(IHNMR (CDCI3.ppm); 7.45
(d, J-8,1, uridine H6).

7.34 (bs, C6HsC)I20GO-), 5.
78(d, J=1.47.uridine)I+'),
5.35-5.5(b, -NH-), 5.15-
5.35Cps, -CH2G! ICH2-), 5
．． 11(s, C6)1sGH20(0-).

4.8-4.9 (m, uridine H2', H3')
, 4.58 (d, d.

J=8.72. J-1,22,-0-CH2CCIx
), 4-1-4.4 (m.

Uridine Hs', Hs', -GH2C)lcH? −
, -0CR2C[N□.

3.4-3.6(m, -QC:)I2C)lzN(
), 2.2-2.45(m, -0(0-C)
12-), 1.57.1.35(3,s, CH3
CH3), 1.25 (bs, -C:Hz-),
0.88 (bt, CH3-), ) was obtained.

(2) The ester obtained in (1) above! , 13g was dissolved in 90% acetic acid aqueous solution 501, 1.0g of zinc powder was added, and the reaction solution was stirred at room temperature for 30 minutes.The reaction solution was condensed under reduced pressure, and the residue was mixed with 100ml of chloroform and 10% tml! tHo.

1 was added and distributed. After drying and filtering the organic layer, it was concentrated under reduced pressure, dissolved in 5 ml of 90% trifluoroacetic acid aqueous solution, and left to stand at room temperature for 30 minutes. The reaction solution was condensed under reduced pressure with C, and the residue was azeotropically distilled with 20 ml of isopropamel under reduced pressure. After distillation, it was dissolved in chloroform and adsorbed onto a 5×2c column of silica gel. Chloroform 1.51-12% methanol/chloroform 1.5 fL linear concentration gradient eluent was used to separate and purify 0.29 g (yield 30%) of hydrogen-(2-benzyloxycarbonylamino)ethyl-[3 -(11-(5-fluorouridine-5°-0-
ylcarbonyl)undecanoyl)-2-balmitoyl-1-glycerophosphate (')INMR(C[3
DD: CDCh 1:l.

ppm); 7.81 (d, J11t3.8.uridine H6), 7.32 (bs, G6HsCH20
GO-), 5.83 (bs, UridiyH1')
.

5.1-5.3(m, -111:Hz-CHCH2-
), 5.09(s, (6HsCH2-OCO-)
, 3.8-4.4(m, uridine H2', I(
3°, Ha”.

Hs', -CIhCHCH2-, -0-CHzCH
2N<), CD30[1 to 0verlap(-Q
()12(!2Nku), 2.15-2.5(+s
, -0COCH2-), 1.27(bs, -
C) 12-), 0.89(bt, CH3-), )
I got it.

(3) 0.29 g of the ester obtained in (2) above was added to 101 g of chloroform. It was dissolved in methanol 401 and 10% palladium-carbon was added. The reaction mixture was stirred for 3 hours in a hydrogen stream, concentrated under reduced pressure through filtration, and the residue was pulverized in ether to obtain 0.24 g (yield 94%) of the desired product, hydrogenen-2-aminoethyl- [3-(1l-(5-fluorouridin-5'-0-ylcarbonyl)undecanoyl)-2-valmitoyl-1-glycerophosphate was obtained.

('HNMR(CDCh:(IbOD-1+l, pp
s+); 7.83 (d, J-6, l, uridine H6), 5.84 (bs, uridine H1°)
, 5.1-5.4 (layer, -CH2CH2H2
->, 4.0-4.5C11, Uridine H4"+
H5', -CH2-CHCHz-, 0-CH2CH2
CN).

0verlap (0-C:H2GHzN<
), 2.2-2.5 (m.

-0COcH2-), 1.27(bs, -CH2
-), 0.811 (bt.

CH3-), ) - Elemental analysis (Cs 2 H7 N3015FP/1.8C
:IC:13・2H20] 9 days N Actual value ($) 45.13 7.02 3. f1
7 Calculated value ($) 45.32 B, 84 3.
82 Reference Example 1 (1) 17.3 g of 1.12-dodecanedicarboxylic acid mono/benzyl ester was dissolved in pyridine 301 and heated to 2.4.
8-) Liisoprobyl sulfonyl chloride 2
0.4 g was added and dissolved under stirring. In this solution, 2', 3
'-Isopropylidene-5-fluorouridine 13.8
A solution prepared by dissolving 20 g of pyridine in 20 ml of pyridine was added, and 400 ml of chloroform was added to the reaction solution, which was left overnight at room temperature.
A solution of 10 g of potassium liate dissolved in 1,501 parts of water was added and distributed. The chloroform solution was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in a small amount of chloroform, adsorbed on 5×25 ml of silica gel, and diluted with 1.5 ml of chloroform-carbon tetrachloride (1:1).
The crude 5°-0-(13-benzyloxycarbonyltridecanoyl)- 2',3'-0-impropylidene-5-fluorouridine was obtained. This 5°-0-ester was dissolved in Impropatool 3001, 2 g of 10% palladium on carbon was added, and the 0 reaction solution was stirred overnight under a hydrogen stream. The 5°-0-ester was then concentrated under reduced pressure. 5'-0 was dissolved in a small amount of chloroform, adsorbed on a silica gel 5 x 35 cm column, and separated and purified using a linear concentration gradient eluent of 1.5 m of chloroform to 1.5 m of chloroform solution containing 5% methanol. -(13-carboxytridecanoyl)-2°,3'-0-inpropylidene-5
-Fluorouridine 14.48g (yield 58.1%)
I got it.

('HNMR (CDOh, 22 layers); 7.48 (
d, J-5,88, uridine H6), 5.7[1
(bd, J"1.71. Uridine H+').

4.85-5.0 (m, uriji y12°, H3'
), 4.2-4.5 (m.

Uridine H4', H5'), 2.2-2.45 (
bt, -CH2COO-), 1.58.1.38
(s, s, C!l!s CHs), 1.26(
bs.

-C:H2-), ) Similarly, 5'-0-(11-carboxyundecanoyl)-2',3'-isopropylidene-5-fluorouridine 5.0 ((yield 38.2%) (l HNM
R(CDCI3.

pp ■); 7.50 (d, J-5,93, Uridine H6), 5.77 (bd, J Maro 1.98. Uridine H+'), 4.85-5.0 (m, Uridine H2' , H3°), 4.2-4.5 (Uridine H4°).

Hs'), 2.2-2.45(bt, -CH2
COO-), 1.57, 1.38Css, C! l
! x CH3), 1.28 (bs, -C:)j2-
), ) and 5'-〇-(9-carboxynonanoyl)-
2°, 3°-isopropylidene-5-fluorouridine 8.10 g (yield 54.9%) ('HNMR((D
CI3. pp+s); 7.52(d, J=5.H
.

Uridine H6), 5.78 (bd, J-1,83
, uridine H+'), 4.85-5.0 (■, uridine H2', H3'), 4.2-4.5 (s, uridine H4°+H5') + 2.2-2.45 (bt
.

-Ill:1i2C00-), 1.57. 1.
38(s, s, CH2O)13).

1.30 (bs, -C:Q2-), ) was obtained.

(2) Benzylglycerin 5. Og, pyridine 3.3g
was dissolved in dichloromethane 501 and cooled on ice. 8.3 g of valmitoyl chloride was added to 10 g of dichloromethane while stirring in water.
A 10% aqueous sodium hydrogen carbonate solution (5) was added dropwise to the reaction mixture, which was left to stand for 18 hours under cooling (4°C).
01 was added and distributed. The organic layer was dried with sodium sulfate, and after concentration, the residue was adsorbed on a 5 x 14 cm silica gel column and mixed with chloroform-carbon tetrachloride (1:1) to chloroform-carbon tetrachloride (1:1) containing 7% methanol.
1) Separation and purification using the linear concentration gradient eluate of step 11 yielded 5.0 g of 3-norumitoyl-l-benzylglycerol (yield 43.3%).

C'HNMR (CrJCI3.ppm); 7.31
(BS, C6 So5cHz).

4.54(s, C6)1sC)I20-), 3.
9-4.2 (m, -0CHzCHC!!z-000-
), 3.45-3.55 (m, C6HsCH20
-(42-), 2.2-2.4(bt, -0CO
Hz-), 1.28 (bg, -142-),
0.88 (bt, CHs-), ) Similarly, 3-decanoyl-1-benzylglycerol (yield 77.9%) (IHNMR (CDCh,
PP厘);7.27(bS, (6HscHzo-)
, 4.50 (s, C6HsCQ20-), 3
．． 9-4.2(m, -0CTo-C!-C:j!20
GO-), 3.4-3.55(m, (, aHsc
H20-C)I2-), 2.2-2.4(bt,
-0CO-CH2-), 1.26 (bg, -C!
z-), 0.88 (bt, C!!3-)-] and]
3-stearoyl-1-benzylglycerol yield 43
．． 5%) ('HNMR (CDCl2.ppm);
7.32 (bs, C6!1s-GHz-0-),
4.55 (s, C6H3-C:I2-0-).

3.9-4.2 (layer, -ocu2-c Kano C giant 20G
O-), 3.45-3.55(m, CbH5-
CHzO-CHz-), 2.2-2.4(bt,
-000()! z-).

1.28 (bs, -Cjiz-), 0.88 (bt
, C! l! 3-),) were obtained.

(3) Dissolve 2.1 g of 5'-(1-(13-carboxytridecanoyl 2', 3'-0-impropylidene-5-fluorouridine) in pyridine 201, followed by 2.4.

6-Triimprobylbenzenesulfonyl chloride 1.
Added 32g. This solution was mixed with 3-valmitoyl-1-
1.8 g of benzylglycerol was added to a solution dissolved in pyridine 201, and the mixture was incubated overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 4001 parts of chloroform, and a solution of 0.7 K of potassium carbonate in 150 parts of water was added and partitioned. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting residue was dissolved in a small amount of chloroform and adsorbed onto a 5×20 ml column of silica gel. Separation and purification by elution with 2 fL of chloroform yielded 3-valmitoyl-2-(13-(2',3'-0-impropylidene-5-fluorouridin-5'-0-ylcarbonyl)tridecanoyl]-1-benzylglycerol. 2
, 71g (yield 75.8%) was obtained.

(' HNMR (CDCl2. between PP); 7.
45 (d, J-5.88, uridine H6), 7.
31 (bg, Cb■s-CH2-0-), 5.7
7 (bd・Jmaro 1.47, uridine)l+'),
5.1-5.3 (layer, CHzCHC)12-),
4.8-4.9 (+s, uridine H2° + H3'),
4.53 (S, 06H5GHz-0-), 4.1
-4.5(m, uridine H4' + I5', -C
H2-CH-C:HzO(0-), 3.58(d
,J-! i. 12, -CH2-0-CH2-C6Hs)
, 2.2-2.4 (layer, -OCOCToC
H2-).

1, 57, 1.35 (s, s, CH3
1:I3), 1.25(bs, -C
T.

), 0.88(bt,CH3-),) Similarly, 3-decanoyl-2-(9-(2',3'-0-
Impropylidene-5-fluorouridine-5'-C
I-ylcarbonyl) nonanoylcy 1-benzylglycerol (yield 44.7%) ('HNMR (CI)
C13, pp+*); 7.47 (d, J-5.
88, Uridine H6), 7.31 (bs.

C6 de s-CHz0-), 5.78 (bd. J-
1.7, uridine H1''), 5.1-5.35 (
m, CH2(4CH2-), 4.6-5. O
Cm, Uriji y) 12°, 8
3'), 4.54(s. (6Hs
C) 12-0-).

4, 1-4.5 (m, uridine H4°, Hs',
-CH2C)lCH2-0-GO-), 3.59
(d, J~5.12, -CHzOCHz(6Hs)
.

2, 1! i-2.45(厘、-GCOCH2C)12-
), 1.5B, 1.35(s, s, C
H3 CH3), 1.28 (bs, -CH.-)
, 0.87 (bt.

CH3)), 3-stearoyl-2- [9-(2'
, 3'-0-isopropylidene-5-fluorouridin-51-ylcarbonyl)nonanoylcy-1-benzylglycerol (yield 4B.3%) ('HNMR(C
:DCh. ppm) near, ζ9(d, J-8.11
, uridine H6), ? ．． 30 (bg.

(6HsGHzo-), 5.77 (bd. Uridine Hl'), 5.1-5.3 (m, C)12
cl (GHz-), 4.7-5.0 (m, uIJ
JinH2°, H3'), 4.53(s, C6Hs
CH2-0-), 4.2-4.5(m, uridine H
4°, H5°, -CH2CHCH2-0(0-),
3.58 (d, J=5.13, -CHzOCHz
-C6Hs), 2.2-2.45(+e, -0-
COCH2CH2-), 1.57, 1.35(s
, s, CH3 CH3).

1, 26(bs, -C)12-), 0.88(b
t, CH3-), ), 3-valmitoyl-2
- (9-(2',3'-0-impropylidene-
5-fluorouridin-5'-〇-ylcarbonyl)7
nanoyl]-1-benzylglycerol (yield 55.9
%) ('HNMR (GDCh. ppm); 7
．． 45 (d.

J-5.98, uridine) +6), 7.31 (bs
, Cb body 5C) I20-).

5, 75 (bd. J-1.83, uridine H+'
), 5.1-5.3(m, C)12G)! -GH
z-), 4.8-4.9 (m, uridine H2゛.

H3'), 4.54 (s. C6HsCH2-0-)
, 4.2-4.5(m, 1 no ji yH4',
Hs °, -CToCHC:HzOC:0
-), 3.59 (d.

J=5.25. -CH2-0-GHz (6Hs),
2.2-2.4(m, -0-CO(H2GH2-
), 1.57. 1.35 (s, s, CH
3CH3).

1.25 (bs, -CH2-), 0.88 (bt
, CH3-), ), and 3-valmitoyl-2-
(2',3'-0-inpropylidene-5-fluorouridin-5'-0-ylcarbonyl)tritecanoyl]
-1-penzylclycerol (yield 44.3%) (
'HNMR (C[Gh, ppm); 7.47 (d.

J=5.8fi, Wow! J Shin H6), 7.31
(bs, G51l!5GH20-).

5.77 (bd, J-1,98, uridine H+'),
5.1-5.3(rx, CH2-CH2CH2-
), 4.7-5.2 (Rin, Uridine H2'.

)13'), 4.54Cs, CH2CH2-0-)
, 4.2-4.5 (m, tsu IJ Schiff H4', H5"
, -CH2CH2H2-OCO-), 3.59(
d, J=5.12. -CH2-O-CH2CH2)
, 2.2-2.4(m, -0CO-CH2C
H2-), 1.57.1.35(s, s, [J
3 (H3).

1.28 (bs, -CH2-), 0.88 (bt
, CH+-),) were obtained.

(4) 3-valmitoyl-2-(13-(2', 3
'-Isopropylidene-5-fluorouridine-5'-
〇-ylcarbonyl)tridecanoylc-1-benzylglycerol (2.71 g) was dissolved in glacial acetic acid 2001, and 1
After adding 1.5 g of 0% palladium on carbon and stirring in a hydrogen stream for 3 hours, the reaction solution was filtered and concentrated. Dissolved.

Next, the cooled solution was added dropwise to a pyridine solution 1501 containing 2.35 g of 2,2.21-lichloroethyl dichlorophosphate, and the solution was stirred for 1.5 hours.
1 and extracted with chloroform 3001. The extract was dried and filtered over sodium sulfate, concentrated under reduced pressure, and hydrogenated (2,2゜2-trichloro)ethyl-
[3-Valmitoyl-2-(13-C2°, 3°-0
-Impropylidene-5-fluorouridine-5'=-
1.93 g (yield: 63.1%) of 0-ylcarbonyl]tridecanoyl)]-]1-glycerophosphate was obtained.

(R to IHN (C[CIz:CD30D-1:l, P
7.71 (d, J-6,1, uridine H
6), 5.73 (d, J=1.8. Uridine H+'), 5.1-5.4 (m, ()12()!
0CHz-), 4.0-5.0 (Uridine H
2', H3°, -0-CH2CH2+ -CH2CH
-Cj! 2-), 2.2-2.45(m, -0C
OCIhCH2-), 1.57°1.37(s,
s, CH3CH3), 1.28(bs, -Ci
i2-).

0.89 (bt, [Jh-), ].

Similarly, hydrogen-(2,2,2-trichloro)ethyl-[3-deca/yl-2-(9-(2',3
'-0-inpropylidene-5-fluorouridine-5
-0-ylcarbonyllophosphate (yield 57.3%) (l HNM
R (CDCl2:CD30[]-1:1, PP layer);
7. flll(d, J-8.1, uridine H6
), 5.77 (d, J-2.2, uridine H
l'), 5.1-5, 4(m, GH2CHO(
H2-), 4.7-5.0(+*, Uridine H
2', H3'), 4.1-4.8 (11,-0-G
H2GC13, uridine H4°, Hs', -()!
20HO(H2-), 2.2-2.45(m, -
0111:0-CH2CH2-), 1.57,
1.37 (s, s, CH3 CH3).

1, 28(bs, -CH32-L [1.89(b
t, CH3-L ), and hydrogen-(2,
2.2-) 1) Chloro)ethyl-[3-stearoyl-2- (13-(2',3'-Q-impropylidene-5-fluorouridin-5'-o-ylcarbonyl)tridecanoyl)) -1-glycerophosphate (
Yield 75.8%) (R CCDC I3 to IHN
, PP layer) near, 45 (d, J-5.88, uridine H6), 5.75 (dd. JII2, 2,
Uridine old') + 5.1-5.3(m, CIhC
HOCHz-), 4.7-4.8 (m. Uridine H
2', H3'), 4.45-4.8(bd, -0
-C: HzCCI3), 4.1-4.4 (uridine H4', HS', -Cdan2CHOc!!2-),
2.2-2.4 (layer, -QC:OCTo-).

1, 57, 1.35 (s, s, CH3 CH.)
, 1.28(bs, -CH2-), o. se
(bt, c3-), ) was obtained.

Reference Example 2 (1) 5.0 g of 5'-0-(11-carboxyundecanoyl)-2°,3'-isopropylidene-5-fluorouridine was dissolved in 5 hl of pyridine, and 2.4.8
- triisopropylbenzenesulfonyl chloride t'3
．． Added 2g and set it up overnight. This reaction solution was added dropwise to a solution of 2.3 g of benzylglycerol in pyridine 301 under stirring for 3 hours, and the mixture was allowed to stand overnight. Concentrate the reaction solution under reduced pressure,
The residue was dissolved in chloroform 3001.

An aqueous solution 2001 containing 1.6 g of potassium carbonate was added and distributed. The extract was filtered through drying over sodium sulfate, concentrated under reduced pressure, and the residue was dissolved in a small amount of chloroform, absorbed onto a 5 x 25 cm column of silica gel, and diluted with chloroform 2-2.
% methanol/chloroform. Separate and purify with 2 linear concentration gradient eluents to obtain 3-C1l-(2°, 3°-0
-Impropylidene-5-fluorouridin-5"-0-ylcarbonyl)undecanoyl-1-benzylglycerol 1.48 g (yield 22%) was obtained.

(R to IHN (CDCl2.pp layer); 7-47
(d, J mackerel f1.11. uridine [6), 7.3
1(bs, C6dan5cHz(1-), 5.78(
bd.

Uridine H1°), 4.65-4.95 (Country, Uridine H2°.

H3'), 4.55 (3, C6HsCH2-0-),
4.2-4.4 (m, uridine H4", H5°),
4.0-4.2 (■, -CH2CH-CIh 0-
CH2G6)1s), 3.45-3.55(m,
1:6HscH20-CH2-).

2.2-2.45 (fat, -0COCHzCH2-),
1.57.1.34 (s, s, CH3CH3)
, 1.28(bg, -CH2-), )(2)
1-(11-(2',3'-0-isopropylidene-
1.48 g of 5-fluorouridin-5'-0-ylcarbonyl)undecanoyl]-3-benzylglycerol
was dissolved in pyridine 201, and 0.85 g of valmitoyl chloride was added dropwise with stirring at room temperature. After the dropwise addition, the solution was left to stand for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform 150.
An aqueous solution of 0.6 g of sodium carbonate dissolved in 1501
was added and distributed. The organic layer was concentrated under reduced pressure through dry filtration, the residue was dissolved in a small amount of chloroform, and silica gel 5X
It was adsorbed onto a 25 cm column. Eluate (chloroform,
Separate and purify 1- (1l-(2°, 3-
0-Impropylidene-5-fluorouridine-5°-
1.18 g (yield: 59.1%) of 0-ylcarbonyl-undecanoyl-2-valmitoyl-3-benzylglycerol was obtained.

(IHNMR (CDCh, PP layer); 7.4B
(d, J wealth 8.11. uridine H6), 7.31
(bs, Cb!l!5CHzO-), 5.78(
bd.

uridine H+'), 5.1-5.35(m, -C
H2CH2H2-).

4.7-5.0 (layer, uridine H2', H3'),
4.54 (g.

C6) 1sc)+2-0-), 4.15-4.4(
Intestine, uridine Hs', Is', C0O-CH2-C
HCFh), 3.59(d, J-5,13,-C
H2-0-GHz (6Hs), 2.2-2.45(
■, -0COCHz-), 1.58°1.313(
s, s, CH3CH3), 1.26(bS,
-CH2-).

0.88 (bt, CH3-,) (3) l (1l-(2°, l'-Q-isopropylidene-5-fluorouridin-5'-o-ylcarbonyl)-undecanoyl-2-valmitoyl -3-<
y Dissolve 1.18 g of silk glycerol in 301 g of glacial acetic acid, add 0.5 g of 10% palladium on carbon, and stir at room temperature under a hydrogen stream for 2 hours. After filtering and concentrating the reaction solution, the residue was poured into 20 ml of Impropatool under reduced pressure. , and co-distilled with 2 liters of pyridine. The obtained residue was dissolved in 20 ml of pyridine, and added dropwise to a solution of 1.0 g of 2,2.2-trichloroethyldichlorobosphate in 1.0 g of pyridine under stirring and cooling with ice. Added to. Add the aqueous solution to chloroform 200+*I (x 2 times)
The extract was extracted with water, filtered through drying, and concentrated under reduced pressure. The residue was dissolved in a small amount of chloroform, adsorbed on a 5×2 cm column of silica gel, and purified using a linear gradient eluate of chloroform In-7% methanol/chloroporm to obtain hydrodiene-(2,2,2- trichloro)ethyl-(3
-(1l-(2',3'-0-inpropylidene-5-
Fluorourisia 5'-0-ylcarbonyl)undecamyl)-2-valmitoyl]-1-glycerophosphate (yield 74.2%) was obtained.

('HNMR(CDGh, ppm); 7.4B(
d, J=8.1. Uridine H6), 5.75
(bd, uridine H1°), 5.1-5.3Cta
, -CH3CN-CIh-), 4.85-4.9
5(ts, uridine H2°, )+3'), 4.4
-'4.8 (intestine, -0-C)]2CCh), 4.
1-4.4 (intestine, uridine H4”, H5”, (:
H2CO (Hz-).

2.2-2.4(m, -000-CH2CH2-),
1.57.1.35 (s, s, , CH3CH3)
, 1.25(bs, -CH2-), 0.88
(bt.

-CH5),) Table 1 Life extension rate (1)
(%) Table 2 Life extension rate (2) (
%) Note) Table 19 Test method in Table 2 Lymphocytic leukemia tumor cells L-1210 (NIH strain) were added to 6 CDFI mice per group at 1X105 (1
Implant intraperitoneally. The administration compound suspended in physiological saline using TI#eah-80 was administered once a day according to the dosage shown in Tables 1 and 2 on the 1st, 5th, and 9th day after transplantation.
The drug was administered intraperitoneally, and the life extension rate was calculated using the following formula.

T: Average survival days of compound administration group C: Average survival days of non-administered group

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, n is an integer from 5 to 14, and R represents ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or. (In the above formula, R_1 and R_2 are the same or different and represent hydrogen or a lower alkyl group, R_3 represents hydrogen or a carboxyl group, and R_4 represents an alkyl group having 5 to 20 carbon atoms)] 5'-0-acyl- 5-Fluorouridine and its pharmacologically acceptable salts. General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, n represents an integer from 6 to 14, and R represents. (In the above formula, R_1, R_2, R_3, and R_4 are as described above.)] 5'-acyl-5-fluorouridine and a pharmacologically acceptable salt thereof according to claim 1, represented by the following. 3. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, n represents an integer from 8 to 14, and R represents ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼. (In the above formula, R_1, R_2, R_3, and R_4 are as described above.) 5'-acyl-5-fluorouridine and a pharmacologically acceptable salt thereof according to claim 1. 4. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, n represents an integer from 6 to 14, R' is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the above formula, R_4 represents an alkyl group having 5 to 20 carbon atoms)] 5'-0-acyl-5-fluorousin derivatives represented by the general formula ▲ have mathematical formulas, chemical formulas, tables, etc. (In the formula, R_1 and R_2 are the same or different and represent hydrogen or a lower alkyl group, and R_3 represents hydrogen or a carboxyl group.) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, n represents an integer from 6 to 14, and R is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( In the above formula, R_1, R_2, R_3, and R_4 are as described above)] A method for producing 5'-0-acyl-5-fluorousin and a pharmacologically acceptable salt thereof.