WO1988003146A1

WO1988003146A1 - Novel 5'-o-acyl-5-fluorouridines and process for their preparation

Info

Publication number: WO1988003146A1
Application number: PCT/JP1986/000533
Authority: WO
Inventors: Yoshitaka Inamoto; Shinji Kawai; Takeshi Endo
Original assignee: Fuji Kagaku Kogyo Kabushiki Kaisha
Priority date: 1985-04-22
Filing date: 1986-10-21
Publication date: 1988-05-05
Also published as: JPS61246196A

Abstract

Novel 5'-o-acyl-5-fluorouridine compounds represented by general formula (I), and pharmaceutically acceptable salts thereof useful as drugs, particularly oncostatic drugs, antiviral drugs, and immunosuppressive drugs, and process for their preparation. In formula (I), n represents an integer of 6 to 14, and R represents a compound of formula (II) or (III), wherein R1 and R2 may be the same or different and each represents hydrogen or lower alkyl, R3 represents hydrogen or carboxy, and R4 represents C5-20 alkyl.

Description

Specification

New 5'—0—acyl—5—fluoropolymer and its manufacturing method

Conventional technology

5-Fluoro-peridine is a compound synthesized in 1959] (see US Patent No. 2,885,396), which is known to have antineoplastic activity. Despite its excellent antineoplastic activity, it has not been put to practical use until now because of its strong side effects. In addition, many attempts have been made to solve the above-mentioned drawbacks by using 5 -fluorouridine as various derivatives]). Nos. 64, 280, 82, 079, 83, .378, 52, 183, etc.). However, at present, anything that can be put to practical use has not yet been obtained.

Disclosure of the invention

The present inventors have synthesized various novel 5-fluorinated 5'-0-ester compounds and searched for compounds that can be put to practical use. As a compound, we succeeded in providing the 5-5-acyl-5-full-periodine derivative described below. This new compound has the general formula (I) 0

In the formula, 6 represents an integer of L4, and R is

C¾ 00 CR ₄

I

Or

CH ₂ —

CHOO CR4

0

II R,

/

CH ₂ -0-P-0-CH {> CH-N

OH 3

(In the above formula, ₂ , R ₂ are the same or different and are hydrogen or lower alkyl group, R ₃ is hydrogen or carboxy group, is an alkyl group having 5 to 20 carbon atoms. 5'- 0-acyl-5-fluoridin and its physiologically acceptable salts. The novel compound according to the present invention is a compound useful as a medicament, particularly as an antineoplastic agent, an antiviral agent, or an immunosuppressant.

As can be clearly seen from Tables 1 and 2 at the end of these compounds, these compounds inhibit mouse leukemia cells (L-1 1210). The average survival time of transplanted DF _X Queima window scan, we describe a method for manufacturing the novel compounds according to c then present invention have an outstanding ¾ antineoplastic action will leave extending control 2.5 times or more O

According to the present invention, 5 — 0 — acyl — 5 — fluororesin is represented by the general formula (Π)

0

[In the formula, ： is from 6 to: 14! Represents ^, where ^ is

CH ₂ 00CR ₄ CH-

0

II

CH ₂ -0-P-0H

OH or

C¾

CH00CR ₄

0

II '' C¾-0-P-0H

OH

(The above equation is the same as described above.)

5'—0—asyl—5—fluorinated invitation General formula legs on conductor

N-CH-CH ₂ 0H dn)

/ /

[(Where Ri,, are as already mentioned))]]

By reacting the amines represented by

^> o

The above reaction is carried out in an organic solvent in the presence of a condensing agent at a temperature of 50 or less.

In this case, examples of the organic solvent used include anhydrous non-protonic solvents, and examples thereof include benzene, tonolene, xylene, and cyclone. Noremetane, Dichloromethane, Chloroform, Dimethyl noreformamide, -Dimethylacetamide, Hydroxyl acid, Ether, Tetrahydrofuran, Dioxan, and Hi. And a resin. Examples of the condensing agent used in the above reaction are P-toluenesulfonyl chloride and trisobroche. Lelu-zen-sur-chlorite, meta-nucleate, le-sur-ni-chlorite, etc., or le-sur-le-chlorite Lolium and dichloride are available, such as olevozimidide, zionyl chloride and oxyphosphorus chloride.

The molar ratio of each reaction component used in the above reaction is calculated based on the general formula (1) based on 1 mol of 5'-0-acyl-5-fluoropyridine derivative represented by the general formula (Π). The amounts of amines and condensing agents represented by | Π) are about 1 to 3 moles each. After completion of the reaction, the obtained reaction product is purified by silica gel caramuk π-matograph, or the like.

The obtained 5-0-acyl-5-fluoro-π-pyridine derivative represented by the general formula (I) is as desired! ) Is converted to various acid addition salts. Alternatively, these pharmacologically acceptable salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, etc., methansulfonic acid, paratoluenesulfonic acid, etc. And salts with alkali metals such as sodium and potassium.

The pharmacologically 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, 'After purification of the reaction product, it can be further converted to a salt by treating it with another acid or alkali.

When the above reaction is carried out, a secondary reaction other than the intended reaction often occurs, so that the side reaction is prevented. It is recommended to add a group, a carboxyl group and a z- or amino-protecting group, and to remove those protecting groups after the reaction.

In the general formula (H), 5 '— 0 — acyl — 5-Fluoro peridine derivative, the site that can cause secondary reactions other than the intended reaction is ribo. It is one of the hydroxyl groups at the 2nd and 3rd position of the silyl group and the hydroxyl group in the phosphoric acid group. The hydroxyl group at the 2nd and 3rd position of the ribosyl group is, for example, isobromo. Riden, ethoxylation It can be protected by an alkylidene group such as redene or a benzylidene group. The hydroxyl group in the phosphoric acid group is an alkyl group having a substituent such as 2,2,2-trino, rosinethyl, cyanoethyl, and phenylsulphonylethyl. It can be protected with a kill group, a chlorophenyl group, a benzyl group, or a nitropenzyl group.

On the other hand, in the case of the amines of the general formula (HI), when both the amino group and and are both hydrogen atoms, the side group of the ¾ group is a side reaction other than the intended reaction. It is the site where it occurs. Examples of the amino-protecting group include, but are not limited to, butoxycarbonyl, trichloroethoxycarbonyl, and phenyloxycarbonyl. Rubo, -ru group etc. Examples of the protective group for a carboxyl group include a lower alkyl group such as a methyl group and an ethyl group. These Q protecting groups can be easily removed individually or simultaneously with other protecting groups after the completion of the reaction, if necessary, according to a conventional method for removing a protecting group. You. For example, the protecting groups at the 2- and 3-positions of the ribosyl group are treated by acid treatment or reduction] 3, and the protecting groups of phosphoric acid are treated by alkyl treatment or reduction! ), The amino-protecting group and the carboxyl-protecting group are each removed by reduction.

5 of the general formula (H) is one of the starting material - 0 - § Sil _-5 monounsaturated Ruo b c Li di down derivatives is also a novel compound. For example, in the general formula (Π), (Ma)

C H-

0

CHg -O-P-OH

OH

[(Where R4 is already mentioned):

5 — 0 — acyl — 5 — fluorinated pyridine derivative is a derivative of glycerin, which has a protecting group at the 1-position, and 3-carboxylate. Condensation of the 5-year-old rouridine with a dicarboxylate ester, followed by: removal of the 1-position protecting group of glycerin, followed by further removal of the 1-position. -? In this case, the protecting group at the 1-position of glycerin includes a benzyl group, a nitrobenzene group, an alkyl phenyl benzyl group, and a Lekoxyphen phenyl group, e. Examples include a cholyl group and a trialkylsilyl group. Phosphorus oxychloride, 2,2,2-trik mouth lotic acid, lorophosphate, cyano ethinoleic acid for phosphorylation at position 3ホホホフ, ロホ口ホホホホホホホホホホホホホフフフフThe reaction may be carried out using a phosphoric acid compound, such as 1,2,2,2,2,2-trichloroethylene. Nozzle chlorofolate, kuronoref jirokurohofeto, henino kuronohosuhoto When reacted with a phosphoric acid compound such as ethanol, the hydroxyl group of the phosphoric acid is protected to form 5, —0—anl—5—fluoroperidine A derivative is obtained.

The other starting materials, amides of the general formula, are concrete examples of ethanolamine, N-methylethanol-one-reamine'N-N, IT—Dimethylaminoethanol, Min, Serine, N—Methyl Serine, Ν, N—Dimethyl Serine.

The compound of the general formula (I) according to the present invention can be produced by a method other than the methods described above. One of the methods is to prepare the 5-0-acyl-5-fluoroperidine derivative of the general formula (Ε) before reacting the linoleic compound. Intermediates, amines of the general formula, phosphorous oxychloride, 2,2,2-trik, chlorophyll, phosphine, phosphine Σ σ σ フ, ロフフホホホホフスフフフフフフフフフフフフホホフフフThis is a method for simultaneously anti-JS with phosphorus compounds such as space. Examples are shown below, and the present invention is described in more detail.

'' Example 1

(1) No, Idrogen 1 (2,2,2—Trichloro) ethyl — [3—Lumitoyl 1 2 — {13 — (2 ', 3' — 0 - Lee Seo profile ^non-zero Li Devon one 5 - off Ruo Russia click Li di down one 5 '- 0 - i Lumpur mosquito Le ball - two Lumpur) Application Benefits decanoate i Lumpur)] one 1 - grayed Li Se Mouth phosphate

. 1 9 3 ^ arsenide ⁰ to re di emissions solution 15 / ^ of, 2, 4, 6 - Application Benefits Lee Seo Bed B arsenide. Rubensensle Hoyurk mouth lid 1.12 was added and stirred.溶液 in this solution? After adding 1.45 ^ mino ethanol, the mixture was left overnight. Concentrate the reaction solution under reduced pressure Then, the obtained residue was dissolved in 200 ml of black hole pores, and 100 ^ of an aqueous solution of 0.6 ^ carbonated water was added and distributed. After the organic layer was dried and filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in a small amount of porcine and adsorbed on a column of 5XIOC772. Cloth mouth: carbon tetrachloride (1: 1) Ι: ^, etc. Cloth mouth containing three methanol: tetrachloride carbon (1: 1) 1 Eluted in the eluate. The eluate is separated and purified, and the (2,2,2,3,2,3,2,3,2,3,2) -trichloroethylene (3—zS) Mitoyl — 2 — {13 — (2 3, — ◦ — Isobrohi. Liden — 5 — Fluoro resin 1 5 ′ — 0 — Dirkarbonyl ) Triglycerol}]-11-glycerophosphine 1.80 (yield 79.9%) was obtained.

_{[¾NMR (CDC ^ 3, PPm)} : 7.45 (. D, J = 5.98, © lysine _{H s), 7.34 (s,} C 6 H 5 CH 3 -0C0-), 5.75 (, © lysine I¾), 5.1 - 5.4 (m, — CH ₂ CHCH ₃ NH-), 5.12 (s, C ₆ H ₅ C¾-OCO- 4.6-4.9 (m, ゥ lysine ¾ ,,), 4 · 58 (d, d ',' J = 6.65, = 1 · 1,

-OCHgCC ^ a), 4.1 — 4.4 (m, ゥ lysine H ₄ ,, -CH ₂ CHCH _2- , 0C C¾N <), 3.4-3.6 (m, — 0C¾C¾N <), 2.2-2.45 (m, —0- C0C¾-), 1.58, 1.35 (s , s, CH 3 CH 3), 1.26 (¾e, - C¾ one), 0.88 (¾t, -C¾) . ]

(2) Dissolve 1.80 ^ of the phosphoric ester obtained in the above (1) in a mixture of 90% acetic acid solution 15 and ethyl acetate 5, add zinc dust 2 ^ and add room temperature. For 2 hours. Concentrate the reaction mixture, and add 40 parts of hydrochloric acid 5 and 100 parts did. After drying the organic layer, the filtrate is concentrated under reduced pressure, and the residue is dissolved in a small amount of chloroform and adsorbed on a silica gel 5X3 COT column. 1 l — 5 ° h methanol Z Z mouth Hydrogen 1 (2-2 ng) (3) (Normitomiyl) 2 — {13 — (2 3'—0 — Isobrohi. Fluorine resin — 5'—0 — ilcarbole) tridecanol)) 1 1 — grease mouth phosphet 1.55 ^ (943% yield) I got

_{C ¾NME (CD 3 0D, ppm} ); 7.81 (i, J "= 6.47, © lysine Eta _6),

_{_{7.33 (s, C S H 5}} CH 2 - 0C0-), 5 77 (<i, © lysine H), 5.1 - 5.3 (m , - C¾CHC¾-), 5.09 (s, C 6 H 5 C¾- 0C0-) , HOD Overlap (リジン Lysine H, Η ₃ '), .3.9—4.3 · 3 (m, リジン Lysine H ₄ , — C¾CHCH ₂ —, 0C¾CHN く), 3:39 (t, — 0CH ₃ — C¾N く) , 2.2—2.45 (m,-0— C0C —), 1.54, 1.34 (s, s, C 1. C¾), 1.28 (s, -C¾-), 0.89 (¾t, -C¾) ₀ ]

(3) The ester 1.55 ^ obtained in the above (2) was dissolved in a 20% aqueous solution of acetic acid in 90% trifluor acid 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 with 30 / ^ isobronol, and dissolved in a small amount of porosity. Adsorbed to 6 cm Q column. Black mouth home 200m £! ), The methanol was increased by 0.5% each, and elution was carried out using 200 each up to the 5th metal Z-hole. The solution is reduced and hydrogen-(2-phenolic acid-rubonil-amino)----------------------------------------2 ― {13 — (5 — phenolic oleone 1 5 — dicarboyl, nil) tridecanol)) 1 1 — griss mouth

-0.93 ^ (62.0% yield) was obtained.

_{[¾iNMH (CDC 3, ppm):} 7.88 (. D, J = 6.83, © lysine _{H 6), 5 7.33 (¾s} , C 6 H 5 C¾-0C0-) ¾ 5.80 (ά, Urijin !!), 5.1 5 · 25 (m, —C¾CHC¾—), 5 · 09 (s, C ₆ C¾—OCO-), 3.9-4.4 (m, ゥ lysine H ₂ ,, ゥ ', lysine; ，, Η ₅ ', -CH ₃ _{_{CHCH 2 -, -0CH 3 - CH}} 2 N rather), Overlap in _{_{CD 3 0D (- 0C¾ CH 2}} N rather), 2.2 - 2.5 (m, - 0 - COCH 2 -), 1.28 (, - CH 3 -) , 0.89 (, -CH ₃ ). ]

(4) Dissolve the ester 0.93 ^ obtained in the above (3) in methanol 50, add 10 rad / carbon o. ₃₅ ^, and in a stream of hydrogen

Agitated for 2 hours. The reaction solution is filtered, concentrated under reduced pressure, and the residue is made into a powder form with a diethyl ether, and the desired hydrogen 121-aminoaminoethyl — [3 — nomyl Il — 21 — {13- (5 — Fluoro resin 1 5 ′ — 0 — ylcarbonyl) tridecanol))]-1 — Gricellojo Suite 730? (89.7% yield).

[丽_{R (CDC z: CD 3 0D} = 1: 1, ppm); 7.84 (i, J = 6.35, © lysine H _6), 5.87 (¾s, Urijin H), 5.1 - 5.3 (m ,

_{-C¾ CHC¾-) Λ 3.8 - 5.0 (} m, Urijin ¾ I, Urijin H, ¾ to single _{_{_{CH 2 CHCH 2 -, -0CH 2}}} C¾N <), CD 3 0D to _{_{Overlap (-0CH 2 CH 2 N <}} ), 2.2-2.5 (m, -0-C0C¾-), 1 · 27 (W s, -C¾-), 0.89 (¾t, -c¾). ]

Elemental analysis _{_{_{_{[C 44 H 77 N 3 0 15}}}} FP as. 0.45 CHC] CHN

Actual value () 53.73 8.01 4.31

Calculated value) 53.83 7.87 4.24

Example 2

Hydrogen 1 (2,2,2 — Tricro mouth) Etch 1 (3

- des Cats Bruno I le one 2 - {9 - (2 ^7, 3 ⁷ - 0 -. I Seo Bed B arsenide Li Devon one 5 - Full O b c Li di down one 5 '- 0 over I le Ca (Nonyl))] 1-grease port The phosphite 3.0 is used as a starting material, and the same procedure as in Example 1 is carried out (2-pentylol). (2), 2,2—trichloroethylene 1 [3—decanoyl 2— {9— (2 ', 3- 0-Disopro Ridden 1 5 — Phenoleuridine 1 5'—0 — Dinosaur Carbonyl) Nona Noinore)))-1 scan off e - DOO 3.23 (87.9% _{yield) C ^ NMR (CDC 3,} ppm); 7.47 (i, J = 6.1, © lysine _{H 6), 7.33 (, C} 6 H 5 C¾-0C0-),

5.74 (ゥ lysine Η), 5.1 — 5.35 (m, -C¾ CHCH ₂ -FH-), 5.11 (s, C _S H ₅ CH ₃ — 0 CO—), 4.65--5.0 (m, リジン lysine: £, ¾ ') 4.59 (i, d, J = 6 · 59, = 0.97, — 0C¾CC) _¾ 4.1-4.45 (m, ゥ lysine ,,, -CHgCHCHg-, — 0Ci¾ C¾Noku), 3.4—3.55 (m, — 0C¾C¾N tool), 2.2 - 2.5 (m, - 0C0- C¾ -), 1.57, 1.35 (s, a, CH 3 CH 3), 1.26 (¾s, one _{CH 3 -), 0.88 (¾ΐ} , one ^c ¾). ), HYROGEN — (2 ?????????????????????????????????????????????????????????????????? Sobrino ⁰ Ridene 1 5 — Fluorouridine 1 5, — 0 — Dilcarbo-Nore) Nona Nol)) 1 1 — Reset n phosphate 2.29 (83.2% yield) [NMR

_{(CD 3 0D: CDC ^ s} = 1: 1, ppm); 7.65 (, J = 6 · 11, © lysine emissions _{Η 6), 7.33 (¾s,} C 6 H 5 C¾0C0-)% 5.77 (¾d, J = 1.95, ゥ lysine!), 5.1-5.35 (m, -C¾CH-CH _3- ), 5.09 (s, C ₆ C ₂ -OCO-), 4.7-5.05 (m, リジン lysine H, H ₃ ,) , 3.85—

4.4 (m, ゥ lysine Η ₅ ', -C¾ CHC¾-, 0CH ₃ CH ₂ N <), Overlap (— OC¾ C¾N) to CD ₃ OD, 2.2-2.5 (m, —0— CO— CH ₂ —) , 1.57, 1.36 (s, 8 , CH 3 C), 1 · 28 (¾ s, - C¾-), 0.88 (¾t, - C¾;). ], Hydrogen-1 (2—Penziloxybonylamino) ethyl— [3—Decanyl—2— {9— (5 Fluororesin — 5 — 0 — ylcarbanol / nonanol)) — 1 — Glycet mouth phosphate 1. '69 ^ (yield 67 · 2%) C NMR (C¾0D: CDC ₃ = 1: 1, pm); 7.83 (, J = 6.59, ゥ lysine H ₆ ), 7.32 (¾s, C ₆ H ₅ C¾ 0C0-),

5.83 (¾d, © lysine), 5.1 - 5.35 (m, -C¾CH-CH 3 -), 5.09 (s, C 6 H 5 C¾- 0C0-), 3.9 - 4.5 (m, © lysine ¾ ,, Urijin H ' _{^{_{, S 5 f, - CH 3}}} CHCH 3 -, -0C¾ C¾ N <), CD 3 0D to _{Over- lap (- 0C¾CH 3 N <} ), 2.2 - 2.5 (m, - OC 0 C¾ -), 1.28 (¾s , One C¾ one), 0.88 (tt, -C¾). ] 2-Aminoethyl-[3-Decanoyl-2-{9-(5-Fluorologin 1 5 '_ 0 — Ilcarbo, nil) nonano nore})-1 1—Glyce mouth phosphet 1.03 (yield 71.2%) was obtained.

_{[¾NMR (CDC ^ s: CD 3} 0D = 1: 1, ppm); 7.84 (. D, J = 6.35, © lysine ¾), 5.85 (¾s, © lysine !!), 5.2 - 5.45 (m , (Construction 4)

-C¾CHC¾-) 4.0 — 5.0 (m, ゥ lysine!, !!, ゥ lysine H's, !!!, — C CHC¾—, — OCH ₂ C¾N く) — CD ₅ 0D \ [Overlap (― OC¾C¾N ”く), 2.2 -2.6 (m, -OCOC¾-) 1.29 (¾s, -C¾-), 0.89 (¾,

-c¾). ]

Elemental analysis (as C _{3 4} ₇ N ₃ 0 ₁₅ FP1.55 CHC)

C_ H N_

3.23 6.21 4.63.

Calculated value) 3.44 6.00 4.28

Example 3

Hydrogen — (2,2,2 — Trichloro) ethyl (3 — Sterol — 2 — {13-(S ^ S'—0 — Isobro) H. Ridden 1 5 — Fluoro resin 1 5 '— 0 — Filcanolebon) tri-decanoyl}] 1-1 Glyceros Using 44 ^ as a starting material, as in Example 1, (2— ぺ

(2), 2,2,2 Tricycloethyl [3—Stearoyl 2— {13— (2 3'—0—Isobroch.Ridden-1 5—Fluoro-Rizin-1 5'—0-ylcarbonyl) Tridecanol)) 1 1—g Li cell opening Bo scan full e one DOO 2.07 (51.7% rate) ^{[X HNMR (CDC, pm);} 7.45 (. d, J = 5.86, Urijin _{H s), 7.3 (¾s,} C 6 H 5 -C¾-0C0 -.) 5.76 (Urijin H), 5.35 - 5.5 (m , one NH-), 5, 1 -5.35 ( m, - C¾CHC¾- NH-), 5.12 (s, C 6 Ii 5 C¾- OCO-), 4.7 —

4.9 (m, ゥ lysine !, Ε ₃ '), 4.58 (<i, d, J = 6.59, = 1.22, -0C3CC ^ 3), 4.1 — 4.4 (m, ゥ lysine Η ₅ ', -CH ₂₎ CHCH _2- , — 0C C¾N く), 3.4 — 3.6 (m, — 0C¾— C¾N く), 2.2 — 2.45 (m, — OCO-C¾-1), 1.58, 1.35 (s, s, C¾ CH ₃ ), 1.25 (s, -CH _2- ), 0.88 (¾t, C¾-) ₀ ], Nee (2—Pengel-aged bonbon amino) ethyl [3-stealoil — 2 — {13- (2 ', 3'—0—a Sopropylidene — 5 — Fluoro resin 1 5 — 0 — ylcarbonyl) tridecanol)] — 1 grease mouth e over preparative 1.87 ^ (yield 10 ") _{[¾NMR (CD 5 0D: CDC =} 1: 1, ppm); 7.67 (J = 6.1, Urijin _{H e), 7.32 (¾s,} C 6 H g C¾0C0-), 5.77 (¾d., J = 1.95, ゥ lysine), 5.1 — 5.3 (m,

— C¾CHC¾-), 5.09 (s, C ₆ H ₅ C¾C0—), 4.7-5.0 (m, ゥ resin, Η;) 3.8 — 4.4 (m, m lysine Η — C¾CHC¾—, — 0CH ₃ CH ₃ N ), 3.63 (t, -0C¾C¾N <), 2.2-2.45 (m, -0C0C¾— C —), 1.57, 1.36 (s, s, CH ₃ C¾), 1.27 (¾s, one C¾ one), 0.89 (¾t, CH _3- ) ₀ ] and Hydrogen— (2—Penzinoleoxycarbo, Nilamino) ethyl (3—Stearoil 2) — {13-(5 — Fluoro resin 1 5 — — 〇 — ylcarbonyl) tridecanol)] 1 1 1.51 ^ (83.8% yield) of [^ NMR (CD ₃ 0D:

DC ₃ = 1: 1, ppm); 7.83 (i, J = 6.35, lysine H ₆ ), 7.32 (¾s, C ₆ H ₅ — CH ₂ 0—), 5.83 (t> s, ゥ lysine), 5.1 — 5.25 (m, one C¾CHC¾-), 5.08 (s, C ₆ H ₅ CH ₃ -C0-), 3.8-4.4

(M, © lysine !!, E _zeta Urijin ^{_{Η ^, ¾ 7, -CH 2}} CHCH 2 -, -0CH 2 CH 2 N <). CD 3 0D to Overlap (- 0C CH ₂ N rather) _¾ 2. 2-2 · .5 (m, —0— C0CH _2- ), 1.27 (¾s, -C¾-), 0.89 (¾t, CH ₃ —). 2) Amino ethyl [3—Stearoy Lou 2 1 {13-(5 — Fluoro resin — 5 — 0 — Dilucarbino) Tridecanoyl))] — 1 — Griserojos 0.84 ^ (yield 63.5%) was obtained.

[Negation _{R (CD 3 0D: CDC £} 3 = 2: 1, Ppm): 7.82 (i, J = 6 - 35, © Lysine: ¾), 5.84 (s, © lysine), 5.1 - 5.4 (m,

— CH ₂ CHCH ₂ —), 4.0-4.9 (m, ゥ lysine ,, Έ _ζ ', ゥ lysine ，, one C¾CHC¾—, — OC¾C¾N¾), Overlap (-0C¾CH ₂ N <) on CD _S OD 2.25 — 2 · 5 (m, — OCOC¾—), i.27 (¾s, — C¾—), 0.89 (¾t, C¾—) ₀ :

Elemental analysis! : C _4SH _{8; L} 0 ₁₅ N ₃ B · As 1.25 CHC]

C_ H

Actual value) 50.64 7.49 4.00-Calculated value () 50.88 "7.43 3.77-'—' Example 4

Hydrogen-1 (2,2,2—trichloro) ethyl [3 lumi tol 2 — {13 — (2 3'—0 — isobrohi. Ridden-1 5 — Fluoridin-1 5 '— 0-ylcarbonyl) tridecanol)) 1 1 — Grease mouth 1.61 ^ Ethyl was used as a starting material and was prepared in the same manner as in Example 1 (2)-(2-benzyloxycarbonyl-amino-2) -pentyloxycarbanol (2)ー 2,2 2-Trichlorethylene 「3 {ミ — — 2 — {13 — (^ 3 '— 0 — ソブリデ — — 5 — 5 — Fluoro Uridine — 5 '— 0 — ylcarbonyl) tridecanol)) 1 1 — grise mouth phosphate 1.59 ^ (yield 76.8%) C ^ NR (CDC ^ ₃ , ppm); 7.43 (d, J = 6.1, Urijin H6), 7.33 (¾s, C 6 H 5 -C¾-0C0-), 5.7- 5.9 (m, Urijin !!), 5.20, 5 .11 ( s, s, C 6 CH 2 〇_C0-), 3.9 — 5.0 (m, peridine ¾ ', ¾', one OC¾CC ₃ , peridine

One C CHC¾-, One OC¾ CH ₃ N), 2.2 _ 2.4 (m, —OCO—C-), 1.57, 1.33 (s, s, C¾ C¾), 1.25 (¾s, — C¾—), 0.88 (TDt , C¾ 一). ), Hydrogen— (2 — ^^ Angel-aged carbohydrate, Nilamino-1 2—Penzilox-carbo, Nil)ー〔3 — Lumitoyl — 2 — {13-(2 ⁷ , 3 '-0-imbroin. Riden 1 5 — Fluoro resin 1 5 ′ — 0 — I le Ca Le ball - Le) Application Benefits decanoate I le)] one 1 Hague Li cell opening host scan full e over preparative 0.94 (65.1% yield) of _{[NMR (CD 3 0D: CDC =} 1: 1, pm ); 7.75 (d., J = 6.35, peridine Η ₆ ), 7.35, 7.32 (be, C ₆ H ₅ — CH ₂ — OCO—), 5.79 (J = 2.2, peridine),

5.1, 5.21 (s, C ₆ H ₅ C¾0C0-), Overlap (ゥ Lys!, Η ₃ '), 3.9-4.4 (m, ゥ Resin H' H ^, -C¾ CHCH _2- , — 0CH ₂ CH ₃ N),

_{2.2 - 2.4 (m, -0C0CH 2} -), 1 .56, 1 .37 (s, s, C¾ C¾), 1.28 (¾s, -C¾-), 0.88 (¾t, - CH 3 0 ], high- de Lojen (2 — Penguin Loki Carbo, Nil Aminor '21 Penguin Lone Kishikarubo, Nil) Talmi to Ino 1 2-{13-(5-Fluoro resin-5 '-0-Dilcarbo, Nil) Tridecanol)]-1- grayed Li Se port host scan off error one DOO 0.57 ^ (62.3% yield) of _{[^ NMR (CD 3 0D: CDCz} 3 = 1: 1, ppm); 7,88 (d, J = 6.59, © lysine H ₆ ), 7.33, 7.32 (s, C _S H ₅ — C¾— OCO—), 5.80 (t, peridine), 5.11, 5.21 (s, C ₆ ¾ C¾OC0 —), 3.9 — 4.5 (m, peridine ¾, , H ^, ゥリジ N ¾,! ! — C¾CHC¾—, — 0C¾C¾ ¥ く, 2,2—2.4 (m,

—0C0C¾—), 1.26 (¾s, — C¾—), 0.88 (, C—). ), The target is, Idrogen 1 (2—Amino 2—Carboxy) Jet / Ray [3—Lumitoyl—2 1 {13 1 ( 5-Fluoro-uridine-5-0-ylurbonyl / tridecanol))-1-1 glyceric phosphate 0.21 ^ (yield 45.5 ^) I got

_{[¾NMR (CD 3 0D: CDC ^} s = 1: 1, m); 7,86 (i, J = 6.59, Urijin Η _6), 5.82 (¾s, Urijin 11), CD ₃ 0DiC Overlap (one 0C¾C¾N <) , 2.4 (m, — 0C0C¾—), 1.26 (s, — C¾—), 0.88 (¾, C¾—). ]

Elemental analysis CC ₄₅ H ₇₇ 0 ₁₇ N ₃ FP1.75 CHC '0.5 ¾0)

_C ii N

(Measured) 6.79 6.70 3.50

Calculated value) 6.78 6.99 3.77

Example 5

Hydogen-1 (2,2,2-trice mouth) ethyl 1 [3—Stearoil 2— {13— (2 ', 3'-0] Soro hydrid ⁰ 5-Fluoro resin '1. 1-carbon) (tri-carbon) 1-1 Gloss mouth G. Using 2.92 f as a starting material, and in the same manner as in Example 1 (2 ぺ-ジ-キ-シ-カ-ル-ボ-ボ-ボボ-ボ-ボ-力-力-力-ボ-力-ボ-ボボボ) Chill [3 — Steer port. Thread 2 — {13— (2 3'— 0 — Isobrown ⁰ Ridden 1 5 — Phenolone port 一 Resin 1 5 '— 0 — Gilbo, nil) tridecanoyl))-1 1-grease Se B E scan off e one DOO 4.10 ^ (8% yield) of [NMR (CDC, ppm); 7.42 (. D, J = 6.1, © lysine _{H 6), 7.33 (¾s,} C 6 H 5 C¾- 0C0 —), 5.7 — 5.9 (m, ゥ lysine), 5.19, 5.11 (s, s, C6 C¾—0C0—), 3.9-5.0 (m, ゥ lysine ¾ -0C¾CC ^ ₃ , ゥ lysine!) , — C¾CHC¾—, — 0C¾C N), 2.2-2.4 (m, -0—C0CH ₂ —), 1.57, 1.34 (s, s, CH ₃ CH ₃ ), 1.25 (¾s, -CH _2- ) , 0.88 (¾, — C¾). ), Hydrogen-1 (2-Pencil-aged Nishi-Amino 1- 2-Age-aged Kishika-no-Revo, Nil) 3 — Sterilization 2 — {13 — (2 3'— 0 — Isobroghi. Riden — 5 — Fluoro-Regine 1 5 ′ — 0 — Dilka Le ball two Lumpur) Application Benefits de mosquito Roh I Lumpur)] - 1 - grayed Li cell ^ b e scan full-et-one door 1.85 (yield 'rate of 48..1%) ^{_{[X HNMR (CD 5 0D: CD¾}} = 1 : 1, PPm); 7.75 ( d, J = 6.35, © lysine H _6), 7.34, 7.32 (I _{_{_{s, C 6 H 5 CH 2}}} 0C0-), 5.77 (4, J = 2.2, © lysine ^ ), 5.1, 5.21 (s, C ₆ H ₅ CH ₂ -0C0-) Overlap (Overlysine,), 3.9 — 4.4 (m, lysine H, ζ,

— C¾CHCH ₃ —, — 0C C¾N), 2.2-2.4 (-0-C0C¾-), 1.55, 1.37 (β, s, CH ₃ C¾), 1.28 (s, -CH _2- ), 0.89 (tt,- CH ₃ ). ] And Hydogen — (2? Old age carbonil amine 2 — penge old age carbonil) ヱ Chil — [3 — Stealth roll 2 _ {13-(5-full-growth one-5 '-0-karkapo, nil) tridecanoyl))]-1- grayed Li cell b e scan off e one DOO 1.25 ^ (71.3% yield) of _{_{[¾NMR (CD 3 0D: CD 3}} = 1: 1, ppm); 7.88 (^ = 6.59, © lysine H _6), 7.34, 7.32 [S, C ₆ H ₅ CH ₃ -0C0-), 5.81 (bs, ゥ lysine Η '), 5.11, 5.20 (s, C ₆ H ₅ CH _S — OCO—), 3.9-4.5 (m, ゥ lysine H, H, ゥ lysine H ^, H ₅ ,, — C¾CHC¾—, — 0C¾CH ₂ N rather), 2.2 - 2 · 4 ( m, - 0C0C -), 1.28 (¾s, -C¾-) 0.89 (¾, -CH 3 :). ], And the target HIROGEN 1 (2—Amino 21—Carbo-Kishi) ethyl— [3—Steadyl—2— {13— (5— Fluorigin — 5'10 — ylcarbonyl) tridecanoyl))) — 1 — Glyceros phosphet 700 (86% yield) Was.

[Awakening: _{R (CDC ^ s: CD 3} 0Ii = 1: 1, pm); 7.85 (cL, J = 6.59, Urijin Hs), 5.83 (s, Urijin) Overlap in CDsOD (- 0C CH.ir rather), _{2.4 (m, -0C0CH 2 -)} 1.28 (s, - C¾), 0.89 (¾t, -CH 3). ]

Elemental analysis [CH _{81 3} 0 ₁₇ FP 'as 0.6 CHC]

― C Η N

52.78 7.86 4.08

Calculated value) 52.85 7.60 3.88

Example 6 '

Hydrogen — (2,2,2—Trichloro) ethyl (3—Butyloil—2—13— (2 ⁷ , Ζ'-0) Ridden-1 5 — Fluoro-Ridin-1 5, —0 — Dirka norevo, 2) Tridecanyl))]-1 — Glysee mouth phosphate 5.66 ^ [¾ abdominal _{R (CD 5 0D: CDC =} 1: 1, ppm): 7.72 ^ i, ^ = 6.1, Urijin), 5.78 (Urijin;), 5.1 - 5.4 (m,

One CH ₂ CH0CH _a ―), 4.0-5.1 (m, ゥ Lysine Η ^ ', E _s , -0C¾CC ^ ₃ , ゥ Lysine !, Hg', -CH ₂ CHCH _3- , One CH ₂ C¾N く), 2.2 -2.4 (m, —0—C0-CH _2- ), 1.57, 1.37 (s, s, CH ₃ C), 1.28 (¾s, -CH ₂ -) _% 0.95 (¾t, CH _3- ). ) As a starting material, and in the same manner as in Example 1 (2-pentylaminocarbonyl) —2,2,2—trichlorethyl RU [3 — Butyroyl — 2 — (13 — (2 3 — 0 — Isobrohi. Liden — 5 — Full-yearly Rawdin — 5 '— 0 — Le ball d Le) Application Benefits des Cats Bruno I le)] one 1 - grayed Li cell b e scan off e one DOO 5.61 ^ (82.8% yield) of _{[^ NMR (C CZ 3, ppm} ); 7.45 (d, 0 "= 5.86, ゥ lysine H _s ). 7.34 (¾s, C ₆ H ₅ -C¾-0C0-), 5.76 (¾d, ゥ lysine:), 5.1-5.4 (m, -CH ₂ CHCH ₃ -NH-) _¾ 5.11 (e, C ₆ H ₅ C¾-0C0-) _¾

4.65 — 4.95 (m, ゥ Lysine ¾ ¾ ₃ '), 4.58 (d, d, J = 6.59, J = 0.98, -0C¾CCz ₃ ), 4.1 — 4.4 (m, ゥ Lysine H,,, —CH ₃ CHCH _2- , -0CH ₂ C¾ N <), 3 · 4-3.6. (M, -0CH ₂ CH ₂ N <), 2.2-2.45 (m, —〇C0— C¾—), 1.57, 1.35 (s, s, CH ₃ CH ₃ ), 1.25 (te, — CH ₂ —), 0.94 (¾t, CH _3- ). ], Hydogen (2—Penzinol Kishikarbo, Niramino) Technology [3—Petit Lou 2— {13- (2 3 — 0 — Isobrohi, Riden — 5 — Fluoro-resin 1, 5, — 0 — Dilcarbo, Nil) Tridecanyl)) 1 1 — Glyce mouth phosphate

2, 95 ^ (62.2% _{yield) ^ NMR (CD 3 0D:} CDC ^ 3 = 1: 1, ppm); 7.83 (, J = 6.59, © lysine H _s), 7.33 (,

_{_{_{C 6 H 5 CH 3 0C0-)}}} Λ 5.76 (¾ci, Urijin), 5.1 - 5.3 (m, -C¾CHC -), 5.09 (s, C 6 H 5 C¾C0-), Overlap ( © lysine

¾ '), 3.9-4.4 (m, peridine -CH ₂ CHC¾-, — 0CH ₃ C¾N <), Overlap (—0C¾ CN 2.2 2.2-2.45 (m, - 0C0C¾C¾-), 1 .53, 1 .34 (s, s, CH 5 C), 1 .29 (¾s, - C¾ _{one), 0.94 (t, CH 3} -). ) And hydrogen — (Z—Penziolocarbonil amino) ethyl — (3—Petyroyl 2 — {13—— (5—Fluoro) Polystyrene — 5 '— 0 — ylcarbonyl) tridecanol)) 1 1 — Glyce mouth phosfet 1/90 (yield 67.3%) [yield 67.3%) _{¾ MR (CD 3 0D: CDC} = 1: 1, ppm); 7.89 (i, J = 6.84, © lysine H _s),

_{_{7.34 (¾s, C 6 H 5}} - C 0-), 5.81 (s, © lysine ¾), 5.1 - 5.3 (m , - C CHC¾ -), 5.09 (s, C 6 H 5 C¾0C0 -), 3.9 - 4 -35 (m, リジン lysine ，, ゥ lysine!, Έ, ₅ ', -C¾CHCH _S- ,

- 0C¾C¾ rather), Overlap in CD _₃ 0D (- 0CH ₃ rather C¾), 2.2 -2.5 (m, -0C0C -), 1.28 ( "bs, -CH 2T) ¾ 0.94 (t, CH 3 -.) ] Was After that, the desired hydrogen 2-amino, chill-[3-petit-oil-2-(13-(5-fluorinated one 5 '-0- (Carbonil) tridecanol}) — 1—glycerophosphine 1.05 (64.9% yield) was obtained.

_{[¾NMR (CD 3 0D: CDC,} 3 = 1: 1, ppm); 7.90 (d, J = 6.84 © lysine H _6), 5.81 (T3S, © lysine !!), 5.1 - 5.5 (m , - CH 3 CHC¾-), 3.9-5.0 (m, peridine H, H, peridine Ξ, —CH ₂ CHC¾—, — 0C¾C¾iloku), Overlap on CD ₃₀ I!

(— 0C¾C N く), 2.2 — 2.5 (m, — 0C0C¾—), l .29 (¾s,

— C-one), 0.95 (C¾—). ]

Elemental analysis (: as _{_{_{C 32 H 53 3 0 15 FP}}} '¾0 ] CHN

(Measured ^) 48.85 6.92 5.40

Calculated value) 48.79 7.04 5.33

Example 7

(I) Hydrogen one (2,2,2 — tricro mouth) ethyl — 3 — steallo 2 — {13 — (2 3 '— 0 — iso Broden.Liden 1 5 — Full-grown raw resin — 5 '— 0-カルカカリ — — 1 1 1 1 — 1 Feat 0.87 ^. It was dissolved in re di down 10 π, 2, 4, 6 - door Li I-Soviet blanking Russia ^non-zero Le Baie down zero emission scan le ho two-Torque Russia Li de 0.48, followed by di main Chi Le § Mi Roh et data We kneaded 0.29 ^ of the knife and left it overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 0 mL of 1 mL of pore-forming holme. A 50% aqueous solution of 0.24 ^ carbonated carbonate was added and distributed. The organic layer was dried, and the solution after filtration was concentrated under reduced pressure. The residue was dissolved in a small amount of black hole holm and adsorbed on a silica gel 5X7 CTZ column. Separate and purify with a linear concentration gradient eluate of 1: 1 4% methanol / col π.Rho-form 1 in 0.32 ^ (yield 37.5%) (2,2 — Dimethylamino) Etchle 2,2,2-tricks. Lochénole — [3—Stearoil 1 2 — {13— (2 3 '— 0 — Isobrohi, Riden — 5 — Fluoro resin — 5 '— 0 — Dircalbonyl) Tride. mouth host scan full e over preparative _{[iHNMR (CDC 3, ppm,;} . 7.45 (oL, J = 5.86, © lysine), 5.78 (d, J = l .95, © lysine), 5.1 - 5.35 (m, -CH ₃ CHCH _3- ), 4.7-4.95 (m, ゥ -lysine) 4.62 (d, 4, J = 6.47, J = 0.73, — OC CC ^ ₃ ), 4.15— 45 (m, — C¾CHC¾—, — 0CH ₂ CH ₃く), 2.72 (t, J = 5.17, — 0CH ₂ C¾N く), 2.2-2.45 (m, — 0— C0CH ₂ —, — N— C¾), 1.57-1.35 (s, s, C¾ CH ₃ ) _¾ 1.26 (¾s, -C¾-), 0.88 (C¾—). ] Was obtained.

(2) Ester 0.36 ^ obtained in the above (1) was dissolved in 90% aqueous acetic acid solution 30 ~ ^, and about 1 ^ of zinc dust was added, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was partitioned by adding 100 ml of clog mouth and 30% hydrochloric acid to 30%. The organic layer is dried and filtered, and then concentrated under reduced pressure.The residue is dissolved in a small amount of cross-section hologram, adsorbed on silica gel 3 x 3 cm column,

700 m £-5 methanol / chloroform 700 ^, then 5 methanol mouth mouth 500 ^ —metanole Z mouth mouth 500 Separation and purification were performed using an eluent with a linear concentration gradient of ^, and 0.16 (yield: 51.5) of the hydrogen mono (2,2-dimethylamino) ethyl [3-Stearo Lee Norre - 2 - i 13 i (2 ^7, 3 ⁷ - 0 - i Seo Bed b Pi Li Den one 5 - off Ruo b © Li di down over 5'- 0 - i le mosquito Le ball d Le) Application Benefits de mosquito Roh I Lumpur)] one 1 - grayed Li cell opening host scan off e over door _{"iHNMR (CD 3 0D: - CDC} 3 = 1: 1,

Pm); 7.58 (i, = 6.1, ゥ lysine), 5.70 (¾s, ゥ lysine¾), 4.95—5.25 (m, one CH ₂ CHC¾—), 4.6 · 4.9 (m, ゥ lysine; ¾ ,,) , 3.8 -4.3 (m, Urijin _{^{H Η 5 7, - C¾CHC¾-,}} - 0C¾CH 2 N rather -), 2.83 (¾s, - OC¾ - C¾ ¥ Ku one N- C), 2.1- 2.4 (m , -0C0CH _2- ), 1.47, 1.27 (s, s, CH ₃ C.¾) and i .18 (¾s, — C¾-0.79 (¾t, C¾-).

(3) The ester 0.16 ^ obtained in the above (2) was replaced with 90% trifluoro vinegar. It was dissolved in an acid aqueous solution t0m and released for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was azeotropically distilled with isobranol 20 under reduced pressure. adsorbed to a cm column. Separate and purify using the eluate with a linear concentration gradient of the hologram hole 1 — 20 methanol holm hole 1 and obtain the desired product, hydrogen — (2,2-dimethyl) Rumino) ethyl [3-stealoil-2-{13- (5-1 fluorocarbon-5 '-10-yl carbo, nil) Tridecanoyl)]-1-1 grice mouth phosphate 120 (yield 80.5%) was obtained.

_{[^ NMR (CD 3 0D: CDCZ} 3 = 1: 1, PPm); 7.84 (. D, J = 6.6, © lysine _{H s), 5.83 (. ¾d} , © lysine ¾), 5.1 - 5.35 (m , - CH ₃ CHCH ₃ —), 3.9-5.0 (m, ゥ lysine H, Έ. _Ζ ', ゥ lysine,, ¾,, -CH ₃ CHCH _a- , 0C¾C¾N く), 2.94 (¾s, 〇C¾C¾N, N-C¾) 2.2-2.5 (m, — 0— C0C¾_), 1.27 (¾s, one C¾), 0.89 (¾t, CH _3- ). ]

Elemental analysis [C ₄₈ H ₈₅ N ₃ 0 ₁₅ FP · 0.4 CHC ₃ · ¾ 0]

C H N

(Measured ^) 54.57 8.50 4.13

Calculated value (54.84 8.31 3.96

Example 8

(1) No, Idrogen-2, 2, 2 — Trichlorethylene — [3-1 {11 — (2, 3, 3'—0 — Isobrohi. 5 — Fluoro resin — 5 '— 0-ylcarbonyl) decanoyl) — 2 — Palmite oil — 1-grease Mouth phosphate 1.0 ^ To dissolve the ^non-zero Li, di down 1?, 2, 4, 6, one door Li I Zob Russia fire. Rubenzensulfonyl chloride 0 · 57 was added and stirred for 30 minutes. To this solution was added N-phenyloxycarbonyl aminoethanol 0 · 74 ^, and the mixture was left overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 100 ml of chloroform at room temperature, and 100 parts of an aqueous solution of 0.29 of carbonated lithium was added and partitioned. After the organic layer is dried and filtered, the filtrate is concentrated and concentrated, and the residue is dissolved in a small amount of black hole holm. B porosity: Shioshidani carbon (1: 1) 1.5 to 15% methanol porosity porosity: Shichidani carbon (1: 1) 1.5 ^ Separation and purification using the eluate, and (2,2-dimethylaminoamino) ethyl 2,2,2—trike mouth rotyl — (: 3— {11— (2 ′, 3 ′) -0-ISOPROPYLIDEN- ₅ -FLUOROLIDIN-1-5-0-ylcarbonyl) ndecanoyl)-2-Lumito innole ] 1—Dari cellophosphate 1.13 f (yield 97.S) @NMR (CDC, ppm); 7.45 (i, J = -6.1, peridine H _s ), 7.34 (¾s, _{_{_{C s H 5 CH 2 0C0-)}}} , 5.76 (i, J = 1.47, Urijin), 5.35- 5.5 (¾, - H-), 5,15— 5.35 (m, -C¾CHCH _3- ) _Λ 5.11 (s, C ₆ H ₅ CH ₂ 0C0-) 4.6-4.9 (m, ゥ lysine !!,), 4.58 (i, cL, J = 6.72, J = 1.22 _s -0-CH ₂ CC ^ ₃ ) 4. 1- 4.4 (21, lysine; ¾, E ₅ , -CH ₂ CHCH _2- , -0CH ₂ CHN <) 3.4—3.6 (m, one OC C¾N <:), 2.2—2.45 (m, -OCOCHg-) 1.57 , 1.35 (s, s, CH ₃ C), 1.25 (s, — C¾—), 0.88 (¾t, CH _3- ). ] Was obtained.

(2) The ester obtained in (1) above 1.13? To a 90% aqueous acetic acid solution , And about 1.0 ^ of zinc dust was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was partitioned by adding 100 mol of chloroform at mouth and 100 M of L0% hydrochloric acid. The organic layer was dried, filtered, concentrated under reduced pressure, dissolved in a 90% aqueous solution of trifluoroacetic acid 50, and allowed to stand at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was azeotropically distilled under reduced pressure with 20% isobutanol. Adsorbed. Separation / purification using a 1.5- 1212 linear methanol gradient with a 1.5--12 methanol cross-hole, and a 0.29 ^ (30% yield) hydride Lojen 1 (25-diphenylcarboxylicylamino) ethyl [3 — {11 — (5 — phenolic) 1-5 ′ — 0 over i Lumpur mosquito Le ball two Lumpur) © down de force Roh i Lumpur) one 2 - 'Mi Norre Mi bet i le'] one 1 - grayed Li cell opening host scan off Est - Doo [ΝΜΕΙ (CD ₃ 0D: CD _{3 = 1:. 1, ppm} ); 7.81 (d, J = 6.6, © lysine _{Η 6), 7.32 (T3s,} C s H 5 CH 3 OC_〇 one), 5.83 (¾s, © lysine 5.1 - 5 .3 (m, — CH ₂ — CHCH ₂ —), 5.09 (s, C _s H ₅ C¾0C0—), 3.8-4.4 (m, リジン lysine ¾ ',

,, — CH ₂ CHCH _2- , 1 0— CH ₂ C¾N く), CD ₃ OD 0 ver lap (-0C¾ C¾ N <) 2.15-2.5 (m, — 0C0— CH ₂ —), 1.2? (¾s, one C 一 —), 0.89 (wa t, CH ₃ —). ] Was obtained.

(3) The ester 0.29 ^ obtained in the above (2) was dissolved in 10 mol / l of the mouth / mouth and ₄₀ ^ of the methanol, and 10% radium / carbon was purified. . The mixture was stirred for 3 hours in a hydrogen stream. The reaction solution was filtered, concentrated under reduced pressure, and the residue was made into a powder in one liter. The target product, 0.24 ^ (yield: 94%), was obtained as a hydrologen — 2 — aminoethyl Le — [3-(11-1 (5-phenolic oleurin-5 '-0-ilcal ^ nil) デ decanol)-21 lumitoyl]-1 —I got a griselo hosfet.

^{[1 HNMR (CDC ^ s: CD} 3 0D = l: 1, pm); 7.83 (d, J = 6.1, © lysine), 5.84 (¾s, © lysine !!), 5.1- 5.4 (m,

_{_{_CH 2 CHCH 2 -), 4.0}} - 4.5 (m, Urijin _{_{¾, Έ 5 ', -CH 3}} -CHCH 2 -., 0- C C¾CN), Overlap f 0- rather C¾C¾ in CD ₃ 0D), 2.2- 2.5 (m,-OCO—C¾—), 1 · 27 (s, one C¾1), 0 · 89 (¾t, CH ₃ —). Elemental analysis [C ₄₃ H ₇₃ N ₃ 0 ₁₅ FP · l.8 CHC ^ ₃ '2 ¾ 0]

C_ H N

Actual) 5-13 7.02 3.67

(Calculated value feg) 45.32 6.84 3.62-Reference example 1

(1) 1,12-Dodecanedyl carboxylate monopopenyl ester 17.3 was dissolved in pyridin 30 to give 2,4,6-trisyl bromo. Lupenzensulfonil mouth lid 20.4 ^ was added and dissolved with stirring. In this solution, add 2 to 1%. Li Devon - 5 - off Ruo b © Li di down 13.6 A solution of the human ⁰ Li di down 20 was added and allowed to stand at room temperature overnight. Cool the reaction solution

A solution prepared by dissolving 400 ml of carbon dioxide rim 10 ^ in water 150 was added and distributed. The mouth opening solution was dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, and the obtained residue is dissolved in a small amount of porcine and absorbed onto 5 x 25 cm of silica gel. 1: 1) 1.5- to 3% metal mouth containing chrome mouth 14: Idani carbon (1-: 1) Separate and purify with an eluate with a linear gradient of 1.5, and use crude 5'-0.1 () 3 $ niloxycarbonylbonil tridecanol.

2 ', 3'-0 — Iso prohi. Redone 5 — You have obtained a full-length resin. This 5 '— 0 — ester was dissolved in Isobrominominal 300 ^ and t0% c. Radium carbon 2 was added, and the mixture was stirred overnight under a hydrogen stream. The reaction solution is filtered, the filtrate is concentrated under reduced pressure, and the obtained residue is dissolved in a small amount of a black hole, adsorbed on a silica gel 5 x 35 cm column, Oral home 1.5 to 5 ° h Separate and purify with an eluent having a linear concentration gradient of 1.5 from the home-form solution containing methanol 1.5-5-(13- Bodily-de-canyl) — 2 3 '— 0 — Diso brochure. Liden-5-fluoropyridine 14.489 (yield 59.1%) was obtained.

^{_{[1 HNMR (CDC 3, ppm)}} ; 7.48 (. D, J = 5.86, Urijin _{H 6), 5.76 (J =} 1.71, Urijin 4.65 - 5.0 (m, Uriji down ,, ¾,), 4.2 - 4.5 (m , Urijin ',), 2.2 - 2.45 ( tt, -CH 2 C00-), 1.58, 1 .36 (s, s, C¾), 1 .26 (¾s, -C¾- :) ].

In the same way, 5 '— 0 — (11 — Carbide decanole) — 2 3, — Isobrohi. Lydene — 5 — Fully-aged Lauridin 5.0 (39.2% yield) [NMR (CDC ^ ₃ , ppm); 7.50 (d, J = 5.93, peridine), 5.77 (¾d, J = 1.98,ゥ lysine), 4.65-5.0 (m, ¾lysine, ¾ '), 4.2 — 4.5 (m, ゥ lysine H ^,), 2.2-2.45 (t, -CH ₂ C00-), 1.57, 1.36 (ss, CH ₃ CH _{3), 1.28 (¾s, -CH} 3 -). ) And ₅ / — o — (9—power box) — 2 3 '— isobrohi. Red One 5 — Off Ruo b © Li di emissions 6.10 (54.9% yield) ■ _{[^ NMRC CDC _ s, ppm)} ; 7.52 (d, J = 5.98, Urijin _{H 6), 5.78 (¾i,} J = 1.83, Urijin ¾), 4.65-5.0 (m, perisine H ₂ ,,), 4.2 — 4.5 (m, perisine), 2.2— 2.45 (t, ― C COO—), 1.57, 1.36 (s, s, CH ₃ CH ₃ 1.30 (¾s, I C-).]].

(2) Pencil glycerin 5.0 ^, h. Lysine 3.3 was dissolved in dichloromethane.SO.71 and cooled on ice. A solution of palmityl chloride P 8.3 ^ dissolved in dichloromethane 10 was added dropwise under ice-cooling and stirring, and the mixture was allowed to stand under cooling (4) for 18 hours. To the reaction solution was added 50% aqueous 10% sodium bicarbonate solution and partitioned. The organic layer was dried over sodium sulfate, and after concentration, the residue was adsorbed on a 5 × 14 on silica gel gel, and the carbon tetrachloride (1: 1) was added. Mouth-opening por- tion containing 1 to 7% methanol—carbon tetrachloride (1: 1). Separation and purification with a 1 饞 linear elution gradient, 3—lumitol — 1 —Pengenole glycerol 5.09 (43.3% yield) was obtained.

C ¾NMR (CDC ^ s, ppm ); 7.31 (¾s, C 6 ¾ CH 2 0-), .54 (s, C 6 H 5 CH 2 0-) 3, 9- 4.2 (m, - QC¾CHC¾- 0C0 - _{), 3.45- 3.55 (C 6 H} 5 C¾ 0-CH 2 -), 2.2 - 2.4 (¾t, -0C0C¾-), 1.26 (¾s, -C¾-), 0.88 (¾t, CH S -). ]

In the same manner, 3—decanoyl-11-pentenyl glycerol (yield 77.9%) [HNMR (CDC, ppm); 7.27 ((s, C ₆ —C¾—0-) , 4.50 (s, C ₆ H ₅ —0—), 3.9-4.2 (m, —0C¾— CH— C¾0C0—), 3.4—3.55 (m, C ₆ H ₅ C¾0— C¾—, 2.2-2.4 (¾t, -0C0C ¾-) _¾ 1.26 (¾s, -CH _3- ) _¾ 0.88 (¾t, CH _3- ). ] And 3-stearyl-1-benzylglycerol (yield 43.5 ^) [^ NMR (CDC ^ ₃ , ppm);

7.32 (¾s, C ₆ 5 — CH ₂ — 0—), 4.55 (s, c ₆ H ₅ — C — 0—), 3.9 1-4 2 (m, 1 0C¾-CH-0C0-), 3.45 — 3.55 (m, C ₆ ¾-CH ₃ C C _), 2.2-2.4 (¾t, — 0-COC ₃ —), 1.26 (s, — C¾-), 0.88 (w t, ¾-) ₀ ) I got

(3) 5, —0— (13—Carboxite tri-canol) — 2,2,3,1 0—Isobroch. Red 1-5 — Fluoro resin 2.19. Dissolved in lysine 20, followed by 2, 4, 6-triisobroche. Lupensensul Honil chloride 1.32 was released. Add this solution to 3 — Angel Glycerol

1.8 ^ It was added to a solution of lysine 20 ^ and left overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in a black hole boiler 400-71. The solution dissolved in ^ was added and distributed. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was dissolved in a small amount of porcelain foam and applied to a column of 5 x 20 cm silica gel. Adsorbed. Elute with 2 £ of black hole solution for separation and purification. 3—palmitoyl 2— [13— (2 3′—0 1 imbroin.才口 '' '' '' '' '' '' '' '' '' ''

(75.6% yield).

_{[^ NMR (CDC ^ 3, PPm} ); 7.45 (d, J = 5.86, © lysine _{H s), 7.31 (¾s,} C fi H 5 -CH g -0-), 5.77 (¾d, J = 1.47, © Resin), 5.1-5.3 (m, CH ₂ — CH— C —), 4.6-4.9 (m, ゥ Lys!,), 4.53 (s, C _e H ₅ C¾— 0—) 4.1-4.5 (m, ゥ Lysine H, H ₅ ,, —CH ₃ —CH—CH ₂ OCO—), 3.59 (<i,-= 5.12, — C¾— o -C¾1 C ₆ H ₅ ), 2.2-2.4 (m, 1 OCOC¾C¾-), 1.57 , 1.35 (s, s, CH ₃ CH ₃ ), 1.25 (s, -C¾), 0.88 (¾t, C —). ]

In the same way, 3 — Decanol — 2 — [9 — (2 ^f , 3 '-0-Isobrohi. Reden-1 5 — Fluorouridine 1 5'— 0 — Le Ca Noreboni Le ■) Bruno nano I le] one 1 -. pen di Le grayed Li cell b over Honoré (44.7% yield) of ^{_{[1 HNMR (CDG 3, ppm)}} - f 7. 7 (d,. J = 5.86, ゥ lysine H ₆ ), 7.31 (¾s, C ₆ H ₅ -C¾0-), 5.76 (i, J = 1.7, ゥ lysine H;), 5 · 1—5.35 (m, CH ₂ CHC¾-),- 6 - 5 · 0 (m, Urijin, Hs'-, 4.54 (s, C 6 H 5 C¾-0-), 4.1 - 4.5 (m, Urijin _{^{_{¾, Η 5 Λ, -CH 2}}} CHC¾-0C0-), '3.59 (d, J = 5.12 , -. C¾- 0C C 6 5), 2.15- 2.45. (m, - 0C0C C¾-) 1.58, 1.35 (s, s, CH 3 C¾), 1 4 26 (¾s, — C¾ 一), 0.87 (it, C¾))), 3 — Stealth roll 2 — [9 — (Ζ, ^ '— 0 — ブ ^ リ⁰デ — 5 — ロResin — 5 '— Pink ) Bruno Nano I le] one 1 ^ emission di Le grayed Li cell B one Le (I ratio 46.3) C ^ iTMR (CDC ^ 3, ppm) ϊ 7.49 (d, J = 6.11, Urijin H _6), 7.30 ( , C ₆ Ci¾0—), 5.77 (¾i, ゥ lysine:), 5.1-5.3 (m, CH ₂ CirCH _2- ), 4.7—5.0 (m, ゥ lysine ^ !!), 4.53 (s, C ₆ ¾C¾— 0—), 4.2— 4,5 (m, perimeter H ₄ ,, — C¾CHC¾— OCO—), 3.59 (cL, J = 5.13,

_{_{_{-CH 2 0C¾-C 6 H 5}}} ), 2.2 - 2.45 (m, -0C0C¾C¾-), 1.57, 1.35 (s, s, CH 3 C), 1.26 (¾s, -C¾-), 0.88 (¾t, CH _3- :). ), 3—Lumithyl 1 2 1 [9— (2 ', 3'-0-Isobrochi. Liden 5—Fluoro resin 1 5'—0— Norecarbo, nil) nonanol] -1-benzylglycerol (55.9% yield) [^ NMR (CDCZs, PPm); 7.45 (d., J = 5.98) , ゥ lysine H ₆ ), 7.31 (¾s, C ₆ H ₅ C¾0-), 5.75 (¾ <i,

J = 1.83, © lysine ¾), 5 - 1 - 5.3 (m, C¾ CH-CH 2 -), 4.6 - 4.9 (m, © _{lysine), 4.54 (s, C 6} H 5 C¾-0-;), 4.2-4.5 (m, ゥ lysine Η ^, Η ^, — CH ₂ CHCH ₂ 0C0—), 3.59 (d, J = 5.25, -CH ₂ -0-CH ₂ C ₆ H ₅ ), 2.2-2.4 (m , — OCOCH ₂ C¾—). 1.57, 1.35 (s, s, C¾CH ₃ ), 1.25 (¾s, -CH _2- ), 0.88 (¾t, C¾— :). ], And 3 - Le Mi Doo Lee le-2 - (-. 2, 3 ⁷ - 0, - Lee Seo profile human Li Devon one 5 - Full O b c re di down one 5 '- 0 over I Lucarbonil) Tride Canol] 1 1? Emissions di Le grayed Li cell B over Honoré (44.9% yield) of _{[¾NMR (CDC 5, ppm);} 7.47 (d, J = 5.86, © lysine _{H 6), 7.31 (¾s,} C 6 H 5 CH 3 0- ), 5.77 (¾d, J = 1 .96, © lysine ^;), 5, 1 - 5.3 (m, CH 3 - CHCH 2 -), 4.7 - 5.2 (m, © lysine), 4.54 (s, C ₆ H ₅ C¾ -0-), 4.2-4.5 (m, ゥ Lysine ¾, -CH ₂ CHC¾-0C0-) _Ύ 3.59

(d, J = 5.12, -CH ₃ -0-C¾C ₆ H ₅ ), 2.2-2.4 (m, -OCO-C CC), 1.57, 1.35 (s, s, CH ₃ C), 1. 26 (¾B,

— C —), 0.88 (¾t, C¾—). ] Was obtained.

(4) 3 — Palm oil 2 — [13 — (2 3 '— Isobroin ⁰ Ridden 1 5 — Full-year roulidine 1 5, — 0 — (Carbol) tridecanoyl) — 1—Penzylglycerol 2.71 ^ is dissolved in glacial acetic acid 200, and 10% paradium carbon 1.55 ^ Was added, and the mixture was stirred in a hydrogen stream for 3 hours. After concentrating the reaction solution by filtration, the residue was decompressed under iso-vacuolane 20. and e. Evaporate azeotropically with lysine 20 ^ to remove water. Dissolved in lysine 50. Next, 2,2,2-trike mouth crochet mouth hood 2.35 ^. The cooled solution was added dropwise to the lysine solution 150, and the mixture was stirred for 1.5 hours. The reaction solution was poured into iced water 200 ^, and extracted with quenching hole 300. The extract is dried and filtered with sodium sulfate, concentrated under reduced pressure, and dried with hydrodyne- (2,2,2-trichloro) ethyl [3—Lumitto Ill 2-{13-(2 3 '-0-lsobrohi ⁰ 0-1-5-Fluoro resin 1 5 ^Λ -0-ylcarbonil) Tride Canyl)]-1-Glycellos: 7-et 1.93 (yield 63.1%).

_{[¾NMR (CDC: CD 3 0D =} 1: 1, pm); 7.71 (J = 6.1, © lysine), 5.73 (i, = 1.8 , © lysine), 5.1- 5.4 (m, CH 2 CH0CH 3 -), 4.0 — 5.0 (m, ゥ Lysine H, H ^, -0- CH ₂ CC ₃ , — C¾CH— C¾—), 2.2 · 2 · 45 (m, — 0C0C¾C¾—), 1.57, 1.37 (s, s , CH ₃ CH ₃ ), 1.28 (¾s, -C¾-), 0.89 (¾t, CH _3- ). ].

In the same way, the dihydrogen— (2,2,2—tricro mouth) ethyl (3—decanoinole—2— {9— (2 3′—0—iso) Propylidene 5 — Fluoro resin 1 5 — 0 — ylcarbonyl) 57.3%) [head _{_{R (CDCX 3: CD 3 0D}} ^ 1: 1, ppm); 7.61 (i, J = 6.1, © lysine ¾), 5.77 (i, J = 2.2, © lysine ), 5.1-5.4 (m, CH ₂ C OCH ₃ —), 4.7 — 5.0 (m, ゥ resin,), 4.1 — 4.6 (m, — 0 — C¾CC ₃ , リジン lysine,

-CH ₂ CHOCH _2- ), 2.2-2.45 (m, -OCOCHg CH _3- ), 1.57, 1.37 (s, s, CH ₃ C¾), l .28 (¾s, -CH _3- ), 0.89 (¾t, CH _3- ) ₀ ], and hydrologen — (2,2,2 — tric mouth) methyl (3 — stearol — 2 — {13-(2, , 3, —0—Isopropylidene-1 5—Fluorolysine-1 5'—0-ylcalbonyl) Tridecanol))-1 1— grayed Li Se port host scan off error one preparative (yield 75.8%) ^{_{[X HNMR (C CZ 3, PPm}} ); 7.45 (i, J = 5.86, Urijin ¾), 5.75 (<id, Urijin), 5.1 - 5.3 (m, CH ₃ CH0CH _2- ), 4.7 — 4.9 (m, peridine ゥ

), 4.45-4.6 (-0-CH ₃ CCZ ₃ ), 4.1-4.4 (ゥ lysine — CH ₃ CH0C¾—), 2.2-2.4, (m, — 0C0C —), 1.57 1.35 (s, s, C¾ CH ₃ ), 1.26 (¾s, -CH _3- ), 0.88 (t, CH _3- ) ₀ ].

Reference example 2

(1) 5, — 0 — (11 — card box) One 2 ', 3 ^/ -in-pro. Red 1 5 — Fluoro resin 5.0. After dissolving in lysine 50, 2,4,6-trisylpropyl pentene sulfol-chloride 3.2 ^ was added and left overnight. The reaction mixture was washed with pentaglycerol 2.3 ^. The solution was added dropwise to the resin solution 30 ^ with stirring for 3 hours and left overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in a black hole chamber 300, to which was added an aqueous solution of carbon dioxide sphere 1.6 ^ 2, and the mixture was partitioned. The extract is dried and filtered with sodium sulfate, and then concentrated under reduced pressure. The residue is dissolved in a small amount of porphyrin and adsorbed on a column of 5 × 25 COT silica gel. Refined fractions were eluted with eluent having a linear concentration gradient of 2 ^ 3, and 3-[11-(2 3 '-0-isobrohi. 1-5, —0—silkybonyl) decanoyl] —1 ^ benzene glycerol 1.48 (yield 22) was obtained.

[ ¹ ΕΝ Π (CDC ₃ , ppm); 7. 47 (, D = 6.11, リジン lysine), 7.31 (be, C _s C¾0—), 5.76 (¾d, リジン lysine H), 4.65-4.95 (m, ゥ lysine,, H ₃ '), 4.55 (s, C _S H ₅ CH ₂ — 0—), 4.2-4.4 (m, リジン Lysine: ¾, H ₅ '), 4.0-4.2 (, — CH ₃ CH- CH _{2 0} CH ₂ C ₆ H ₅ ) _Λ 3.45-3.55 (m , C ₆ CH ₂₀ -C¾-), 2.2-2.45 (m, -OCOC¾C¾-), 1.57, 1.3 (s, s, C¾CH ₃ ), 1.26 (¾s, -C¾-). ]

(2) 1 - [11 - (2 3 '- 0 - Lee Seo profile ^non-zero Li Devon one 5 - off Ruo Russia © Li di down one 5, - 0 - I Le months Norre ball, two Le) ©デ一一 3 3 3 3 3 3 3 3. Resin 20

^ And lumitriyl chloride 0.65 ^ was added dropwise with stirring at room temperature. After the dropwise addition, the mixture was allowed to stand for 10 minutes, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in a clog mouth 150 / ^, and an aqueous solution 150 ^ of carbon sodium 0.6 ^ was added and distributed. The organic layer was dried and filtered, and then concentrated under reduced pressure. The residue was dissolved in a small amount of black hole por- tion and adsorbed on silica 5X25αηΌ column. Eluent (H B port ho le-time, 1.5) was separated and purified by 1 - [11 - (2 ', 3 - 0 - I Seo Bed B arsenide ⁰ Li Devon - ₅ monounsaturated Ruo b c Li di down ¹ "

1-5, 1 ◦ — Dircalpoyl, nil) pentadecanol) 1 2 — Lumil 1 3 — Pengylglycerol 1.18 ^ (yield 59.1) Obtained.

^{_{[1 HNMR (CDC £ 3, ppm}} ); 7.46 (. D, J = 6.11, © lysine H _6), 7.31 (I _{_{_{s, C 6 H 5 CH 3}}} 0-), 5.78 (¾d, © lysine H), 5.1 — 5.35 (m, — C¾ CHC —), 4.7-5.0 (m, リジン -lysine,), 4.54 (s, C ₆ H ₅ CH _g -0-) 4.15-.4 (m, ゥ -lysine H, E ₅ , COO— C —CHC¾), 3.59 (d., J = 5.13, — C¾—0— CH ₂ C ₆ ¾), 2.2-2.45 (m, — 0C0C¾-), 1.58, 1.36 (s, s, CH ₃ C), 1.26 (fs, -CH _2- ), 0.88 (¾t, CH _3- ). ]

(3) 1-11-(2 3, — 0 — Isoprod. Liden — 5 — Fluoro-dorigin 5'-1 0-Carbo, Nil) 1 Dissolving phenol-2 Lumitil 3-Penzinole grease port-Dissolve 1.18 ^. In 30 ^ glacial acetic acid and add 10% Palladium carbon

0.5 ^ was added, and the mixture was stirred at room temperature under a hydrogen stream for 2 hours. After the reaction solution was filtered and concentrated, the residue was purified under reduced pressure. The azeotropic distillation was carried out with 20 ^ of metal and 20 ^ of pyridine. The obtained residue is extracted. Dissolved in Lysine 20 and added dropwise to a 2,2,2 -trik mouth liquid zinc mouth 1.0 ^ pyridine solution i0 ^ of 1.0 ^ under ice-cooling with stirring. . After the dropwise addition, the mixture was stirred for 30 minutes and poured into ice water 100 ^. The aqueous solution was extracted with a cuff mouth 200 ^ (X 2 times), dried, filtered and concentrated under reduced pressure. The residue is dissolved in a small amount of black mouth por- tion, adsorbed on a silica gel column, and the black horn 1 JL 17 ° methanol / cross hole α hole Separation and purification using eluate with a linear concentration gradient of hydridene — (2, 2, 2- Application Benefits click B B) E Ji Honoré chromatography [3 - {11 - (2 3'0 - I Seo Bed B arsenide ⁰ Li Devon one 5 - Full O b c Li di down - 5'0 - I L-carbonyl) decanoyl) — 2 — Lumitoyl) — 1-grise mouth phosphite (yield 74.2%).

_{[^ MR (CDC 3, ppm)} ; 7.46 (. D, ^ = 6.1, Urijin Η _6), 5.75 (¾d, Urijin '), 5.1 - 5.3 (m , - C¾ CH- C¾-), 4.65 - 4.95 ( m, ゥ lysine ¾ Η ₃ '), 4.-4.6 (m, — 0— CH ₂ CC), 4.1 — 4.4 (m, ゥ lysine: -C¾CHCH _3- ) 2.2-2.4 (m, —0C0— C¾C¾-), 1.57, 1.35 (s, s, CH ₃ CH ₃ ), 1.25 (¾ ^s »— CH ₂ —), 0.88 (¾t, — C). ]

Table 1 Life extension rate (1)

Table 2 Life extension rate (2)

Note) Test methods in Tables 1 and 2

Lymphocytic leukemia sac cells were added to 6 CDFo_ mice per group.

IX) Implant ⁵ L-1210 (NIH strains) per intraperitoneal cavity. The administration compound suspended in physiological saline using Tween-80 was administered once a day according to the dosages shown in Tables 1 and 2, and three times on the first, fifth, and ninth days after transplantation It was administered intraperitoneally, and the life extension rate was calculated by the following formula. Life extension rate () = 1 "-C""1 x 100 τ: Average number of days of survival of the compound administration group

c: Average number of days surviving in the non-administration group

Claims

5B Range of request

Ix. Expression

(I)

(Where n is an integer of 6 to 14, R is

C¾00CR CH-

Or-

CH _2-

CHOOCR,

0

II /

C¾ 一 0-P— 0— C¾ CH- I I \.

OH R ■ .3.

(In the above formulas, 、 represents the same or different and represents a hydrogen or lower alkyl group, ¾ represents a hydrogen or carboxy group, and represents an alkyl group having 5 to 20 carbon atoms.)) 5'- 0-acyl 5-fluorouridine and a pharmacologically acceptable salt thereof represented by the formula:

In the general formula (I), R is a formula, CHg 00CR ₄

CH

(In the above formula, Ri, ¾, ¾, and ¾ are as described above.)

The 50-acyl-5-fluoridin and the pharmacologically acceptable salt thereof according to claim 1, which is a group represented by the formula:

3. In the general formula (I), R is a formula,

CH00CR ₄

0

II-i • R,

/

CH _? -0-P-0-CH ₂ CH-N

OH R.

(In the above formula, ¾, ¾, ¾, and ^ are as described above.)

5-0-Acyl-5-Fluoro-pyridine and a pharmacologically acceptable salt thereof according to claim 1, which is a group represented by the formula:

4. General formula,

0

OH OH Wherein a represents an integer of 6 to 14, and R represents

CH ₂ 00 CR ₄ CH-

C¾-0-P-OH o OH or

CH _2-

CH00 CR,

0

II '

C¾ -0-P-0H

OH

(In the above formula, R ₄ represents an alkyl group having 5 to 20 carbon atoms.)]-5′—0—acyl-5—phenolic derivative generally represented by- formula,

(In the above formula, represents the same or different and represents hydrogen or a lower alkyl group, and R ₃ represents hydrogen or a carboxy-yl group).

A general formula characterized by reacting an amine represented by the formula: and converting the obtained reaction product into a salt which is theoretically acceptable, if necessary. 0

[Wherein n represents an integer of 6 to 14, and R is

C¾00CR ₄ CH-

0

/

CH ₈ -0-P-0-CH ₂ CH-N

\

Or

CH _2-

CHOOCR ^ '

0

II /

CH ₃ -0-P-0-CH ₂ CH-N

\

OH R ₃

(In the above formula,! ^, ¾, ¾, and ^ are the same as those described above.)] 5 '-0 -acyl-5-fluoridin and its pharmacologically acceptable salt Production method.