JPS6330494A - Hapten containing x-antigen determining group and production thereof - Google Patents

Abstract

NEW MATERIAL:A hapten shown by formula I [R<1> is H or acetyl; R<2> is OH, acetyloxy or benzyloxy; R<3> is -CH2OH, -CH2OCONH(CH2)7CO2R<6> (R<6> is methyl or ethyl); R<4> is -NHAc; R<5> is OH, acetyloxy or benzyloxy]. EXAMPLE:A compound shown by formula II. USE:A hapten containing X-antigen determining group. A monoclonal antibody prepared from the hapten is applicable to diagnosis, examination and treatment for various cancers. PREPARATION:A compound shown by formula III is treated in the presence of OsO4 and NaIO4 to give an aldehydeo compound and the reaction product is treated with NaBH4, etc., to give the example compound.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel hapten having an X-antigenic determinant and a method for producing the same.

[Conventional technology]

Recently, it has been revealed that cell surface glycoproteins and glycolipids play important functions in cell physiology. Cell physiology here refers to cell differentiation, development, morphogenesis, tumor transformation, etc.

In addition, abnormal sugar chains that are not normally found in cells that have undergone cancerous changes are present. It has become known that the non-reducing end of the abnormal sugar chain contains blood group substances (Lewis a, b, X, Y, etc.). Among them, some of the abnormal glycolipids isolated and identified from adenocarcinomas of the colon and liver have X-
It has been reported that the determinant has a repeating structure (
S, Iakomori et al., J. Bi
o, Chem, 246.1192 (1971);
257.14865 (1982); 259.4672
(1984); 259.10511 (1984)].

From these facts, it is of various significance to provide haptens having X-determinants as their antigenic determinants and having various spacers. That is, it provides an effective means for elucidating the biological functions of abnormal carbohydrates caused by cancerous changes in cells. Furthermore, it becomes possible to apply monoclonal antibodies produced from haptens to diagnosis, testing, and treatment of various cancers.

[Object of the Invention] An object of the present invention is to provide a novel hapten having an X-antigenic determinant and a method for producing the same.

[Structure of the invention]

That is, the present invention relates to a hapten having an X-antigenic determinant represented by the general formula [I].

(However, R1 is a hydrogen atom or an acetyl group, and R2
is a hydroxyl group, an acetyloxy group, or a benzyloxy group, and R3 is a -CH2OH group or -CH2OCONH (C
H,)? CO□R'(R' is a methyl group or an ethyl group), R4 is a -NHAc group, and R5
is a hydroxyl group, an acetyloxy group or a benzyloxy group. ) Specific examples of the present invention are shown below.

Compound (1) R' = HSR" = R' = OH.

R' = NHAc.

R3=-CH2OCONH(CH2)7CO-Me compound (7) R'=Ac, R'=R5=BnO1R
'=NHAc, R3=CH20H compound (8)
R' = Ac, R2 = R5 = BnO1R' = N
HAc.

R3=-CH20CONH(CF(,)tcO2Et compound (9) R'=Ac, R2=R5=OAc.

R' = NHAc.

R3=-CH2OCONH(CH2)tcO2Et The method for producing the compounds (1), (7), (8), and (9) of the present invention is shown below based on Scheme 1.

[Production method of compound (7): Compound (2) → (3)-(4
)→(5)→(6)→(7)] Compound (7) is compound (2) [in general formula [I], R'
=Ac, R' =R5=BnO, R' =-CH=CH
2, R' = -NPhth] as a raw material, a compound (3
), (4), (5), and (6). However, in this specification, r-NPhthJ represents an N-phthaloyl group.

Compound (3) R'=Ac, R2=R5=BnO1R3
=-CHO1R' =-NPhth compound (4) R'
=Ac, R2=R5=BnO1R3=-CH20H,R
'=-NPhth compound (5) R'=^c, R'=
R5=BnO1R3=-CH, OEE.

R'=-NPhth Compound (6) R'=Ac, R2=R5=BnO.

R3=-CH20EE, R'=-NHAc but EE
represents an ethoxyethyl group (the same applies below).

(4) Synthesis of Compound (3) from Compound (2) Starting compound (2), which is a trisaccharide, can be obtained, for example, by the following method.

That is, allyl 6-benzyl-2-deoxy 2-phthalimido-β-D-glucopyranoside (A) and 2.3,4
．． '6-Citler 0-acetyl-α-D-galactosyltrichloroacetylimidate (B) was dissolved in l(g(CN
)2, HgBra, molecular sieve, Ag2CO
3, AgCl104, ^gO3O2cF3, (CH3)
1 to 1 at -30° to 150°C in the presence of a glycosidation catalyst such as 7CO3O, CF, BF3・Btz○, etc.
By reacting for about 20 hours, compound (C)
is obtained. At this time, along with compound (C), its isomers (C' ) (β1→3) and (C') (α1→3)
It also occurs as a by-product.

The obtained trisaccharide (C) and 1-3-methyl-7-cose (
D) in the presence of the above glycosidation catalyst such as molecular sieve in a solvent such as ether at -30°C to 150°C.
The reaction is carried out at ℃ for about 1 to 120 hours to obtain trisaccharide (2).

An example of the above process is shown in Scheme 2.

Compound (3) oxidizes compound (2) to convert R3 to -CH-
Obtained by converting CH2 to -CHO.

The oxidation reaction can be carried out using, for example, an oxidizing agent of ○1.050. /Na
About -10 to 6 in the presence of a mixed solvent of methanol, ethanol, dioxane, THF, etc. and water using l○1 etc.
The reaction is carried out at 0° C. for about 5 minutes to 24 hours, preferably under stirring. Compound (3) can be obtained as a pure product by purifying the obtained reaction product by a commonly used purification means such as column chromatography.

■Synthesis of compound (4) from compound (3) Compound (4) is produced by reducing compound (3) and converting R3 from -CH0 to -CH20.
She is humiliated by making him H.

The reduction reaction is DIBALC(i-[)u)-J
H], 1, iMaroH < , LiB) (4, NaBH < ,
Using a reducing agent such as NaBCN83, in the presence of a solvent such as methanol, ethanol, n-propanol, THF, dioxane, toluene, etc., at approximately -10°C to 60°C for approximately 5 minutes ~
It can be carried out under 24 hour conditions.

In addition, since the reduction reaction proceeds almost quantitatively, it is possible to obtain the compound (4) with good purity without purifying the reaction product. However, if desired, the reaction product can also be purified by a continuous light method.

■Synthesis of compound (5) from compound (4) Compound (5) is the synthesis of compound (5) by converting R3 of compound (4) from -CH2OH to -CH20EE.
It can be obtained by That is, compound (4) and CH2
=CH20 in the presence of PPTS, p-TsOH, etc., using a solvent such as methylene chloride, dichloroethane, THF, dioxane, toluene, etc., at -10 to 60 °C for about 5 minutes to 24 hours. Ru. The reaction product is preferably purified by known purification means, such as column chromatography, and then used as a raw material for the next step.

■Synthesis of Compound (6) from Compound (5) Compound (5) is first synthesized in the presence of a solvent such as methanol or ethanol.
React with hydrazine at 100°C for about 1 hour to 3 days. In this case, it is preferable to use an ethanol solution of hydrazine (for example, 2% 1 (2N NH2-[!tOH)), and to carry out the reaction under stirring and reflux.

Then, after the reaction solvent is distilled off (under reduced pressure), the remaining reaction product is acetylated. Acetylation is carried out by stirring the above reaction product and 8c2o/Py/4-DMΔP in a solvent such as dichloromethane, dichloroethane, chloroform, THF, ) toluene at about -10 to 60°C for about 5 minutes to 24 hours. Implemented. The obtained reaction product can be converted into a pure compound (6) by known purification means such as column chromatography, if desired.

(4) Synthesis of compound (7) from compound (6) Compound (7) can be obtained by acidifying compound (6). The acidification is carried out using, for example, an ion exchange resin such as 5% AcOH, 0.5NHα, Amberlyst 15, etc., in a solvent such as water, methanol, ethanol, THF, dioxane, etc., to about -10 to 60% °C, about 5 minutes to 24
It is carried out under the condition of time.

[Method for producing compound (8): Compound (7) → (8)] Compound (8) is produced by converting R3 of compound (7) from -CH2OH to -C
H20CONH(C)(2), obtained by converting to C○zBt. That is, the reaction involves compound (7) and OCN
(CH,)7CO7Et in a solvent such as benzene, toluene, xylene, THF, dioxane, etc.
The reaction is carried out at a temperature of about 5 minutes to 24 hours, preferably with stirring.

[Production method of compound (9): Compounds (8)-(9)] Compound (9) is obtained by reducing compound (8) and then acetylating it.

First, compound (8) is reduced using a Pd catalyst (for example, 10%
The reaction is carried out using hydrogen using Pd-C), Rh catalyst, Pt catalyst, etc. At that time, methanol, ethanol, acetic acid, etc. are used as the solvent, the pressure is 1 to 5 atm, the temperature is 20 to 60°C,
Time: Conducted for 1 hour to 3 days. After the reaction is complete, the catalyst and solvent are removed from the reaction mixture.

Next, the reaction product after removing the catalyst etc. and AC20/Py/4
-DMAP in a solvent such as dichloromethane, dichloroethane, chloroform, THF, ) toluene, etc., from about -10 to
The reaction is carried out at a temperature of 100° C. for about 5 minutes to 24 hours with stirring. A pure compound (9) can be obtained by purifying the reaction product by a known purification means such as column chromatography.

[Production method of compound (1): Compound (9)→(1)] Compound (1) is obtained by transesterification of compound (9) with alkali methoxide.

The transesterification reaction is carried out using, for example, NaOMe in a solvent such as methanol, ethanol, THF, dioxane, etc.
It is carried out by stirring at a temperature of 10°C to 60°C for about 5 minutes to 24 hours. The obtained reaction product can be purified by known means such as column chromatography to obtain pure compound (1).

〔Usefulness〕

The novel hapten of the present invention provides an effective means for elucidating the biological functions of abnormal carbohydrates through cancerous changes in cells, and furthermore, monoclonal antibodies produced from the hapten can be used for diagnosis, testing, and treatment of various cancers. It is useful in that it can also be applied to therapy.

The present invention will be explained in more detail below with reference to Reference Examples and Examples.

Reference Example 1 Compound (C) and its isomers (C') and (C')
Synthesis of compound (A) 1310mg (3mM) and compound (
B) 1770mg (3.6mM) was dissolved in 30ml of dichloroxthane and thoroughly dried beforehand. M, 3.4A
Pour into a brown bottle containing 3g under a stream of argon gas, -
Cool to 23°C. This reaction solution contains BP*-Bi120.36mj! was added dropwise and stirred for 4 hours.

The reaction mixture is filtered, the filtrate is washed with saturated brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residual oil was purified by column chromatography (ethyl acetate/
The product was purified using hexane (developed with 1/1 hexane) to obtain three isomers.

(C) Nia 60 mg (yield 33%), Rf-0,60 (
Ethyl acetate/n-hexane-372) elemental analysis value (C3
8843NO+6・'AH20=778, 771) Theoretical value C: 58.60. H:5.69. N:
1.80 Actual value C: 58.40. H:5.56.
N: 1.80 optical rotation [α]. +1541° (C=
1.12 CHα3)ill, H-1a, J
=8.5)1z), 5.22-5.05(m,
2H.

-Ctl=珂h), 2.13~1.91(4X s
, 4x3H,4x-OAc) (C'): 50mg (yield 2.2%), Rf = 0.52
(Ethyl acetate/n-hexane-3/2) 4.98 (m,
2H, -Ctl=fJh), 5.05(d, LH
, H-1a.

J=8.2Hz)', 4.4Hd, IH,H-1h
, J=7.9Hz).

2.13.2, 03.1.88.1.45 (4xS,
4 x 3H.

4X0Ac) (C'): 680 mg (yield 29%), Rf = 0.40
(Ethyl acetate/n-hexane = 3/2) Elemental analysis W1
(C38H43N O12・'AH20=778, 77
1) Theoretical value C: 58.60. H:5.69. N
: 1.80 actual value C: 58.50. H:5.59
．． N: 1.76 optical rotation [α]. +98.1° (C
=0.67 CHα3)TsukuH), 5.7~5.6
(m, LH, F-C'H2), 5.18 (d,
LH, H-1a, J=8.3Hz), 5.1
5'5.02 (m, 2ft.

-CH-1*), 5.03(d, IH, Hlb
, J=4.5tlz).

1.99. 1.98. 1.97. 1.83 (4x
S, 4 x 31 (.

4 X0Ac) Reference Example 2 Synthetic trisaccharide (C) of compound (2) 154 mg (0.2 mt, l) and 1
139 mg of 3-methyl-L-fucose (D) was dissolved in anhydrous ether 6- and thoroughly dried in advance.
The mixture was injected into a brown three-way flask containing 500 mg of 4A under an argon gas stream. To this reaction solution, 70 μl of methyl triflate was added dropwise under ice cooling, and the mixture was stirred overnight.

The reaction mixture was filtered, and the filtrate was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residual oil was purified by column chromatography (ethyl acetate/
Developed with hexane-1/6) to produce an oily product of 182m
g (yield 76.8%) was crystallized from methanol.

[Properties of compound (2)] m, p, 164-5°C Rf = 0.56 (ethyl acetate/n-hexane-1/1)
Elemental analysis value (CssH71N○2o=1186.285
) Theoretical value C: 65.81. H:6.03.
N: 1.18 Actual value C: 66.20. H:6
．． 16. N: 1.24NMR(δ):
7.8-7.0 (m, 9H, Aromachi CDα Kotoku H), 5.7-5.6 (m, Lft, -
]-CL), 5.10(d, LH, H-1a, J
=8.5Hz), 2.02.2.00.1.951.
82 (4xS, 4x3)1. 4 xOAc),
1.19(d, 3H.

CH3,, J=6.6Hz) Reference Example 3 Synthetic trisaccharide (2H, Og (0,843mM) of compound (3) was dissolved in a water-dioxane mixed solution (10mf!/20mj), and osmium tetra 3 ml of 0.39 M oxide solution in dioxane was added. While stirring at room temperature, 400 mg of sodium metaperiodate powder was added and stirred for 1 hour. The reaction solution was extracted with ethyl acetate, and then added with water and saturated brine. After washing, dry combustion was performed using magnesium sulfate, and the solvent was distilled off under reduced pressure.The oily residue was purified by column chromatography (developed with ethyl acetate/toluene-1/1) to obtain an oily substance 74.
0 mg (yield 74%).

Elemental analysis value (Cs=HasN○2.=1188.2
57) Theoretical value C: 64.69. H:5.8
5. N: 1.1B actual value C: 64.64.
H:5.78. N: 1.18 optical rotation [α
]. -7,0° (C=0,60 CH(1,)Rf
= 0.37 (ethyl acetate/toluene = 1/1) NMR (
δ) CDα3 (PPM) 9.56 (s, lft, −[: upper 0), 7
．． 8-7.0 (m, 24H, aromatic proton), 5.11 (d, LH, tl-1a.

J=8.67Hz), 2.01.2.00.1.94
．． 1.82 (4xs, 4 x3H, 4x-OCOCH
3), 1.19(d, 3H.

-CL, J=6.58Hz) Reference Example 4 Synthesis of Compound (4) 215 mg (0.18 mM) of Compound (3) was mixed with n-propyl alcohol 51TF1! The mixture was dissolved in water, and ethyl acetate was added thereto three times warmly. Add 0.0% sodium borohydride to this solution under water cooling. 1 ml of I M n-propyl alcohol solution was added and stirred for 1 hour. The reaction solution was extracted with ethyl acetate, washed successively with water and saturated brine, dried with magnesium sulfate, and evaporated under reduced pressure to obtain 210 mg of an oily substance.
(yield 98%). Rf=0.52 (ethyl acetate/
Toluene-2/1) This product was led to the next reaction without being purified.

NMR (δ) CDα3 (PPM) 7, 8-7.0 (m, 24H, A07 tech),
5.13 (d.

LH, H-1a, J=8.54Hz), 1.19.
2.00.1.98゜1.94.1.83 (4xs,
4x3H, 4x 0COCH3).

1.19(d, 3H, -C)I3. J=6.41)
1z) Reference Example 5 Synthesis of Compound (5) 119mg (0.1mM) of Compound (4) was mixed with 72mg (1mM) of ethyl vinyl ether and 2ml of dichloromethane.
! A catalytic amount of pyridinium, p-)luenesulfonic acid (PPTS) was added thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was extracted with chloroform, washed with water, dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residual oil was purified by column chromatography (developed with ethyl acetate/toluene = 1/2) to obtain 98 mg of oil.
(yield 76.1%).

Rf=0.61 (ethyl acetate/toluene-1/1)NM
R(δ)CDCi! -(PPM) 7, 7-7, 0 (m, 24H, A07 tech).

2.0.1.99. 1.94. 1.82 (4Xs,
4X3H.

4 x-OCOCL).

1゜19 (d, 3H, CL, , J: 6.4Hz
) Reference Example 6 Synthesis of Compound (6) 91 mg (0,072 mM) of Compound (5) was mixed with 5 mj of 2% hydrazine hydrate-ethanol! The mixture was dissolved in water and stirred under reflux overnight. The reaction solvent was distilled off under reduced pressure, and the residual oil was
Acetic anhydride/pyridine/4-dimethylaminopyridine (0
,5+n1/0.5 mi! /catalyst amount),
Stirred for 3 hours. After diluting the reaction solution with ethyl acetate, IN
After sequentially washing with hydrochloric acid and saturated brine, drying over magnesium sulfate, distilling off the solvent under reduced pressure, and column chromatography of the oily residue (developed with ethyl acetate/toluene-2/1).
56.5 mg (yield 67%) of an oily substance was obtained.

Rf=0.34 (ethyl acetate/toluene=3/1)NM
R(δ)CDα3 (PPM) 7,5-7.1 (m, 20H, A07 tech),
5.83 (d.

IH, -Nll, J=6Hz), 2.0-1.
8<5Xs, 5x3H.

5 x-OCOCH3), 1.19(d, 3H,-
C)13. J=6.4 Example 1 Synthesis of Compound (7) 56 mg (0,0477 mM) of Compound (6) was added to 2 mf of methanol! 50 mg of Amberlyst was added thereto, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, insoluble matter was filtered off, and the filtrate was distilled off under reduced pressure. Oily substance 46.7mg
(Yield 89%) Rf=0.17 (ethyl acetate) Optical rotation [α]. -48,6° (C=0.56C
Hα3) Elemental analysis value (C5, H,, No2°・H2O-
1120, 222) Theoretical value C: 62.19. H:6.57. N:
1.25 Actual value C: 62.43. H:5.43.
N: 1.25HMR(δ)CDα3(PPM) 7, 45-7.25 (m, 20H, A07 tech)
, 6.28 (d, IH, -N le J=8.54Hz
), 2.03. 1.99゜1.97.1.89(
5xs, 5x3H, 5xCOCH,)1.07(d,
3f1. -CH,, J=6.41Hz) Example 2 Synthesis of compound (8) Azelaic acid ethyl ester 40mg (0.18m
M ), diphenylphosphoryl azide 50 mg (0,1
8 m M ), and triethylamine 25 mg (0,2
4mM) was dissolved in 2rrIi of toluene, stirred at room temperature for 30 minutes, and then stirred under reflux for 1 hour. After cooling, 50 mg (0,045 mM) of compound (7) was added to this reaction solution,
The mixture was stirred under reflux overnight. After washing the reaction solution with water, the reaction solution was dried with magnesium sulfate, the solvent was distilled off under reduced pressure, and the residual oil was purified by column chromatography (ethyl acetate/toluene = 2/l).
17.5 mg of oily product (yield: 29.5 mg)
7%).

Rf=0.38 (ethyl butyrate/toluene=4/l) optical rotation [α1. -27.0° (C=0.8 CHα3
) NMIR (, δ) CDα3 (PPM) 7, 5-7.
1 (m, 20H, a07 tech), 5.9 (d
.

LH,NH,J=8flz), 3.1(m, 2H,
-N1).

2.3 (t, 2H, -CJiiCL, J=7Hz)
, 2.05-1.8 (5x9.5 x3H, 5XCD
C'+43), 1.27(t, 3H.

CO□CH2 assistant. , J=7Hz), 1.20(d,
311. −[:and,.

J: 6 Hz) Example 3 Synthesis of compound (9) Under hydrogen gas flow, 15.7 mg of compound (8) (0,
An ethanol solution 2- of OL 2mM) and 20 mg of 10% Pd-C was stirred at room temperature overnight. After the reaction was completed, the catalyst was filtered off, the ethanol was concentrated, and the residual oil was mixed with acetic anhydride/pyridine/4-dimethylaminopyridine (0,3
rn! 10.3 mi! /catalytic amount) at room temperature,
Stirred for 5 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with IN hydrochloric acid and saturated brine, dried over magnesium sulfate, the solvent was distilled off, and the oily residue was purified by column chromatography (developed with toluene/acetone = 3/1). ) to obtain 10.0 mg (yield 74%) of an oily substance.

Rf=0.48()Luene/acetone-3/2) Optical rotation [α:]11-64.8' (C=0.5 CH
α3) NMR (δ) CDα, (PPM) 5.88 (d, LH, -NH, J = 8.24Hz),
3.14 (m, 2H.

NCH2-), 2-29(t, 211.-CLC
[128t, J=7.63Hz), 2.20-1.
95 (9Xs, 9x31 (, 9x-COCL).

1.25(t, 3H, -CLCI(21, J=7.0
IHz).

1.20 (d, 3H, -CL, J=6.41Hz)
Example 4 Synthesis of Compound (1) 9.6 mg (o, o O 85 mM) of Compound (9) was added to a methanol solution (2-) with 0.0. 0.2 mi' of IN sodium methylate methanol solution was added and stirred overnight. After adding Amberlyst 15 to the reaction solution and making it neutral,
It was filtered and the filtrate was evaporated under reduced pressure. The residue was purified using Sephadex G-10 (developed with distilled water) and then freeze-dried to obtain 6.6 mg (100%) of compound (1).

Rf=0.55 (n-butanol/ethanol/water=2
/1/1) Optical rotation [α] D ~ 53.4° (C = 0.32 methanol) NMR (δ) D20 (PPM) 5.10 (d, LH, H-1c, as acetone = 2.22PPM) J=3.97
Hz), 4.78 (q.

IH, H-5c, J=6.72Hz), 4.57(
d, LH, H-1a.

J=7.63Hz), 4.44 (d, IH
, H-1b, J=7.94Hz)3.10(t,
2tL NC) I2-, J=7. Kano z), 2.38
(t, 2H, -1, hcO□Me, J=7.321
(z), 2.00(s, 3H.

Claims (11)

[Claims] (1) A hapten having an X-antigenic determinant represented by the general formula [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (However, R^1 is a hydrogen atom or an acetyl group, and R
^2 is a hydroxyl group, acetyloxy group or penciloxy group, and R^3 is -CH_2OH group or -CH_2OC
ONH (CH_2), CO_2R^6 (R^6 is a methyl group or an ethyl group), and R_4 is -NHAc
group, and R^5 is a hydroxyl group, an acetyloxy group, or a benzyloxy group. ) (2) Compound (6) represented by the general formula [I] (wherein R^1 is an acetyl group, R^2 is a benzyloxy group, and R^3 is a -CH_2OEE group (however, EE is (represents an ethoxyethyl group), and R^4 is -N
HAc group and R^5 is a benzyloxy group) is reacted with an acidic substance to form a compound (7) represented by the general formula [I] (wherein R^1 is an acetyl group, R^2 is a benzyloxy group, R^3 is a -CH_2OH group, R^4 is a -NHAc group, and RS is a benzyloxy group). ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (3) The manufacturing method according to claim (2), wherein the acidic substance is an H-type ion exchange resin. (4) The production method according to claim (2), wherein the acidic substance is an inorganic acid or an organic acid. (5) Compound (7) represented by the general formula [I] (wherein R^1 is an acetyl group, R^2 is a benzyloxy group, R^3 is a -CH_2OH group, and R^
4 is -NHAc group and R^5 is benzyloxy group) as OCN(CH_2)_7CO_2C_2H_5
Compound (8) represented by the general formula [I] (wherein R^1 is an acetyl group,
R^2 is a benzyloxy group, and R^3 is -CH_2
OCONH (CH_2)_7CO_2C_2H_5 group, R^4 is -NHAc group, R^5 is benzyloxy group). ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (6) Compound (8) represented by the general formula [I] (wherein R^1 is an acetyl group, R^2 is a benzyloxy group, and R^3 is -CH_2OCONH(CH_2)_7CO_2C_2
General formula [I] consisting of reducing H_5, R^4 is a -NHAc group, and R^5 is a benzyloxy group), and then acetylating the obtained reduction product
Compound (9) represented by (wherein R^1 is an acetyl group, R^2 is an acetyloxy group, and R^3
-CH_2OCONH(CH_2)_7CO_2C_2
H_5, R^4 is -NHAc group, R^5 is acetyloxy group). ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (7) The production method according to claim (6), wherein the reduction is carried out using hydrogen in the presence of a reduction catalyst. (8) The production method according to claim (7), wherein the reduction catalyst is a Rh catalyst, a Pt catalyst, or a Pd catalyst. (9) Acetylation is carried out using a system of acetic anhydride, pyridine and 4-dimethylaminopyridine.
6) Manufacturing method described in section 6). (10) Compound (9) of general formula [I] (wherein R^1 is an acetyl group, R^2 is an acetyloxy group, and R^3 is -CH_2OCONH(CH_2)_7CO_2C_2
H_5 group, R^4 is -NHAc group, R^5
is an acetyloxy group) with an alkali methoxide (where R^1 is a hydrogen atom and R^
2 is a hydroxyl group, and R^3 is -CH_2OCONH(CH_2)_7CO_2CH_
3 groups, R^4 is -NHAc group, and R^5 is hydroxyl group). (11) The production method according to claim (10), using NaOCH_3 as the alkali methoxide.