JPS6036474A - Intermediate for production of galantinic acid - Google Patents

Abstract

NEW MATERIAL:An epoxyaminoalcohol derivative of formula I (R<1> is H, acyl, benzyloxycarbonyl, toluenesulfonyl, alkoxycarbonyl; R<2> is H, benzyl, tri-lower- alkylsilyl, tetrahydropyranyl, acyl). EXAMPLE:2-(N-t-Butoxycarbonyl)amino-3,4-epoxy-butanol(1). USE:A preparative intermediate of galantinic acid of formula II (R<2>'' is H, aralkyl; R<3>'' is H, alkyl), which is one of the aminoacids constituting galantin I , an antibiotic. PREPARATION:For example, methionine is protected at its amino group with an appropriate group and esterified at its carboxyl group, then treated with a reducing agent to convert the carboxyl into hydroxymethyl. Then, the S in methionine is converted into sulfoxide, and subjected to thermal decomposition. The resultant product is treated with an epoxidizing agent to give 2-amino-3,4-epoxybutanol derivative, one of the compounds of formula I .

Description

Detailed description of the invention (al Untechnical!l+1) The present invention is based on the general formula (1) (wherein R1 represents a hydrogen atom or a lower acyl group, a benzylox7carbonyl group, a toluenesulfonyl group, an alkoxycarbonyl group, and R2 represents a hydrogen atom, a benzyl group, a tri-lower alkylsilyl group, a tetrahydropyranyl group, or a lower anlu group. This is an intermediate used in I1 for producing galantinic acid of general formula (2), which is one of the constituent amino acids.

R2 (In the formula, R1 is a hydrogen atom, a lower acyl group, a benzyloxy 7
It represents a carbonyl group, a toluenesulfonyl group, or an alkoxycarbonyl group, R2 represents a hydrogen atom, an aralkyl group, and R3 represents a hydrogen atom or a lower alkyl thread. Many unconventional types of amino acids have been found as their constituent amino acids. In particular, novel antibiotics that cannot be predicted are often included. For example, Ecumine (Frtam, ycin,), bo
ttrom, ycin), Irama 4 nn (t lam)
ycin, ) 1;7 and one antibiotic 'tri-amino acid.

This first raru Izou (/L is caused by: 1rlI4ii
It is also thought that it is due to the hydrolysis lIjγ caused by bezotides originating from substances. ・ is a peptide antibiotic galantin I, and・5
ho)'t et al. J, hnttbiot, 28. '
l 22 (1975) 1, and has a unique 1:c<vj structure with a pyran principle in its structure.

The structure of galantin I was analyzed by Shiba et al. [T,
5hiha et al., Pepttie Chem, tstr
y, 113 (1980)], its unique 4'Fj
structure has been revealed.

Galantin■ is active against Durham-positive bacteria, Gram-negative bacteria, and acid-fast bacteria, but its lethality in mice is 50 m9.
/9 (intraperitoneal administration), and has been found to be quite toxic.

The present inventors have discovered that Galantine l's 1'11'!I special 4
He was interested in the production, activity, and toxicity of 1), and completed the present invention in the process of modifying them.

According to the present invention, the epiquinamine alcohol represented by the formula (1) is used as an intermediate to produce the formula (2).
) Galantinic acids represented by ) are produced and shine.

(C) Disclosure of the Invention A novel method for synthesizing galantinic acid, which is a constituent amino acid of galantin I, which is a peptide antibiotic of the present invention, and an epoxy amino alcohol represented by the above formula fi+, which is an 11 essential intermediate for the synthesis of galantinic acid. Visit? ! Regarding one body. Note that galantinic acid itself has activity as an antibacterial agent.

The intermediate epoxy amino alcohol +11 of the present invention can be synthesized as follows.

12+1! ζ: The amino group of methionine, which is a ζ-known acid, is protected by a suitable protecting group, preferably t-butoxycarbonyl, benzyloxycarbonyl, etc. , for example, by treatment with lithium aluminum hydride, which converts it into a hypiroquine methyl group.

The sulfur atoms contained in methionine are then converted to sulfoxide with a weak oxidizing agent, such as sodium periodate.

A 2-vinyl-2-amino alcohol whose amine group is preserved by thermally decomposing the obtained amine group-protected 4-(methylsulfinyl)-2-amino-1-butanol (3) in an organic solvent. (4) is zeroed. The 41N solvent used here is Etquin ethyl ether,
High Buddha point compounds such as dichlorobenzene, cumene, cymene, and mesitylene are preferred.

This amino group is captured by a lower acyl group, alkoxycarbonyl group, benzyloxycarbonyl group, tosyl group, etc., and the hydroxyl group is substituted with a hydrogen atom, benzyl group, tri-lower alkylsilyl group, tetrahydropyranyl group, lower acyl group, etc. 2-vinyl-2-aminobutanol (4)
As shown in Scheme 1, the epoxidizing agent is an epoxidizing agent such as 10-chloroperbenzoic acid, perbenzoic acid, and p-nitrobenzoic acid.
．． Pernotaric acid, peracetic acid or vanadium acenaracetonate-t-butylhydrono! By treating with -oxy V, a 2-amino-6,4-epoxybutanol derivative (1) having an amine group and a hydroxyl group as the above-mentioned substituents is obtained.

In this case, at the same time as the uninvented compound (threo isomer), a very small amount of erythro isomer is also produced as follows: (acedel) Bos = t-butquine carbonyl where 1) I is the compound of the present invention (1 ) is not only a heavy intermediate in the synthesis of galantinic acid hM, but also an intermediate in the synthesis of other antibiotics, such as furanomain, plasticidin-S, ther-crosborin, and aminozaylitol. I will explain the applied aspects of the area (useful and wide-ranging).

This compound (1) can be converted into IVI to synthesize galanthuic acid according to the process shown in Scheme I.

That is, acylation of epoxyamino alfur txt in the presence of a weak base? Preferred examples of weak bases include pyridine and trialkylamine. Examples of the acylating agent include acetic anhydride, acetyl chloride, propionyl chloride, benzoyl chloride 9, and the like. Next, as a method for increasing the number of 6 carbon atoms, there is a method of cleaving epoxide using divinyl cuprate (A). It can be decaptated under acidic conditions (1) When the steel reagent of allyl alcohol and the acylated epoxyamino alfur were reacted, the amide 7 group and the hydroxyl group were properly retained. Amino-1,3,7-)rihydrogineheptene (5), but some of the acyl groups are hydrolyzed under the reaction conditions, and after the reaction treatment, it is further acylated with the above-mentioned acylating agent. It is preferable to do this.

Once obtained here monoheptene (5) is treated with acid, e.g.
)-) Treatment with luenesulfonic acid, hydrochloric acid, etc. to preserve allyl alcohol, remove the radical, and then treat with chromic acid such as pyridinium chlorochromate, Collins reagent, pyridinium dichromate, Jones reagent, etc. Oxidant,
Allyl carbon powder ester is obtained by treating with an oxidizing agent such as silver oxide, manganese dioxide, or potassium permanganate to form an aldehyde, and then treating with activated manganese dioxide in alcohol.

(R depends on the azl-le, for example, in methanol, el
l 3) The obtained alkyl-6-amino-5,7-dihydro-
The 2-hebutenoic acid ester (6) is subjected to a reaction procedure to remove the anol group to form Form I, pyran 1r, 1.

The amino acid that was asked for is an alkali solution, for example, thorium hydroxide. Ester 4' hydrolysis 1 by treatment with potassium hydroxide etc.
4r of r (cy, amino by further treatment with trinoruloacetic acid, -+21 hydrohydric acid, etc.)
(: Galantinic acid (2) can be obtained by removing ii?'i.

Scheme I D-methionine → N-t-Bo (-methionine't-B
oc = t-butoquino is a 4-hydroxy group R1 is a protecting group (4) (R', R2 are the above-mentioned protecting groups) When the compound of the present invention, epoxide ``'' (1), is treated with, for example, an alkyl-・Groups are introduced.

When treated with a dimethyl copper reagent, the amino becomes a ntandiol derivative. Also, dibutyl copper test (I) (river NMR (δ, rn), 0.85 (3H, t, J=6H
z).

1.42 (9H, J), 3.62 (2H, +l] wide,
r), 3.64 (IH, m), 6.88 (I H, m
>,4.50 (2H,,s).

5.15 (IH, ct, J=8H2), Z2s (st
t, s> In this way, it became possible to synthesize many useful substances η such as amino sugar antibiotics and aminozylitol from the compound fi+ of the present invention.

(d) Examples Below, examples are shown in which the compound of the present invention is produced by mail, and a reference example showing the manufacturing process from the compound of the present invention to the final target compound, ganic acid.

Example 1 (2R) -N-t-butoginecarbonyl-2-amino-6-putenol 705■ (filter, 8 mmol)*1
7mA! Commonly understood as methylene chloride, mechchloro is undervalued, 1
Yoka 1'f! ! Add 1.37 g of the mixture and treat with τ crystal under a stream of ♀ air for 15 hours.

The reaction mixture was washed with a 5% potassium carbonate water bath for 1fIIVcf; then extracted with chloroform, washed with saturated brine, added with magnesium hydroxide and dried (kA,!9). The product (threo form) shown in Table 1 was subjected to chromatography (ether) at 291 my
(40%) obtained. Also, 75% (11%) of starting material was recovered.

IR (film * cm-1) 3550+ 169O
NMR (CDC13, δ, p, n) 1.38 (9H,
! >, 2.57 (IH, d-cL, J=5.5.5
．． 0Hz), 2.71 (IH.

ctd, J=4.5.5.0H2), 3.15(I
H, rrL).

5.68-4.0 (3H, m), 4.80 (1)
(,d.

J,,,9Hz) [α]D = +15.6 (C = 0.865.Chloroform) Example 2 The product fl139 OTn& (1,9 mmol) of Example 1 was dissolved in 5me tetrahydrofuran and o' c.
g Triethylamine (0.27ml 1.9
mmol) followed by acetyl chloride (0.21 ml.
Add 2°9ml) and stir for 2 hours (4T). After pouring into water to complete the reaction, extract twice with a needle, add 11 um of furnace water sodium sulfate to the extract, and dry. Anhydrous sodium chloride was separated by dj, concentrated and subjected to silica gel column chromatography (eluent: ether:hexane-1:1) to give the title compound (threo form) 387 m';/ (82% 1
'pl got it.

1, R (CHG13) 1756.1708 box-1HMR
(CDC13, δpprIL) 1.35(9)1.
r), 2.00 (3H, y), 2.55 (IH, d
d,, J=3.5+5.5) 12:64 (I H
, ctd, J=4.5. 5.5), Ro02 (I
H.

m), 4.12(2H,S) Example 3-(N-t-butquincarbonyl)amino-4-
386 ml of penzyloxy-1-butene (11.4 mmol) and 400 my of 90% m-chloro-J4 benzoic acid (2
, 1 mmol) in 7rrLt of methylene chloride and 1
Stir at room temperature for 9 hours. I*k: The liquid was poured into water and extracted with chloroform. The extract was washed with an aqueous solution of potassium carbonate and dried over anhydrous sodium sulfate.

The crude product was purified using silica gel column chromatography using ether:hexane = 1:4 as a Yrt elution solvent to obtain erythro compound 70.21111$ (yield 17.2%).
), 179 m9 of threo bodies (convergence 44%) were obtained.

' H, -NMI ((CDC63, δppm) 1.42
(9H,J), 2.60 (IH,dcl,J=
6゜4.5Hz), 2.72 (IH, t, J=4..5
Hz).

3.20 (I H, m), 5.76 (21 (, m)
, 4.08 (IH, m), 4.54 (2H, S
), , 4.68 (IH.

hrd, J=3H2), 7.30 (5H, -r) Physical properties of erythro form 1H-NMI ((CDC13-, a, , ): 1.4
2 (9H, s), 2.80 (2H, m), 3.
04 (11-1,171), 4.52 (2H,,
? ).

7.60 (5H,-?) Example 4 2-(N-1-butquinecarbonyl)amino-4-notenyl acedate 1o 1my (0.44 mmol),
nL-Black a, 1% 1% 127 m9 to 5m/
! The mixture was dissolved in dichloromethane and stirred at room temperature for 19 hours.

Pour the reaction solution into water, add 11:1 chlorine Σ and add 1 cup.

The extracted material was washed with dilute potassium carbonate water bath solution, then reduced to zero, and the crude product was separated using a phosphoric acid gel column. : 171?, 11 in the table using compounds
7. The compound 66m& (yield 61%) was obtained as a compound of 7R of threo form and erythro form.

Physical properties of threo body 1, R1 (CHC/!3) 1756,1708cm
-”NMRCCDG13.δppm) 1.55 (9
H,s ), 2.00(3H,'L 2.55(1H,
d, d, J=3.5.5.5).

2.64 (if-1, d, d,, J=4.5.5.5
), 3.02 (1H.

”), 4.12 (2H,, r) Physical properties of erythro form 11 (-NMR (CDC13, δ, prrL): 1.4
4 (91 (, -9), 2.09 (3H, y), 2.
68(1)1. m), 2.74 (1H.

rid, J=4.9.5.5Hz), 2.98(IH
, C1, dd.

J=4.5.5.5.6.5H2) Example 5 2-(iq-benzyloxycarbonyl)amino-6
- putenol 300ml (1,36 mmol) and 90
'7? tn-Chloro 1 ha benzoic acid 5n mouth nI! ? (2
, 04 mmol) in 7.5 ml of methylene chloride and at room temperature for 16 hours ('7'-(1-1). The liquid was dried in a furnace using IIum. Separate the 4=i' phase and concentrate.
Further, the product was purified using licage gel column chromatography using ether as a bathing solvent to obtain the title compound 1≧(threo compound) 138+Il& (yield 46%).

'H-IVI So (cLJc63.δ, Engineering): 2.58 (
IH, ctrt, J=3, 4.5) 1z), 2.
62 Cdd, J=4.4.5H2).

ro, 07 (1) (, m ), 3.76 (2H, +I
J Hiro, J=68Z).

4.0 (I H,m,), 5.06 (2H,S
), 7.32 (5H.

S) At the same time, the erythro compound was also removed at a yield of 11%, and the following physical properties were determined.

'+-+-Nw((coax 3. δppm): 2
．． 82 (2H,rn), 6.10 (18,171)
, 3.64 (I H, m), 3.74 (2H,
-' ).

5.08 (21-1, -1=), 7.32 (5H,!>
Example 6 2-(benzyloxycarbonyl)amino-6-butenyl acetate 100+11L; I (0.58 mmol), 90% m-ri o o J4 benzoic acid 11] 91
．． 19 (0.57 mmol) was dissolved in 6 m13 of htA methylene and stirred at room temperature for 65 hours.
1 H-1iMR (CDCd 3.δ, pm): 2
．． 05 (3H, J= ), 2.61 (1H, m),
2.74 (IH, t, J = 4.6), 2.82 (11-
1,”) + 5.10 (2H, S), 7.55 (5H,
S) The elinurobody obtained at the same time exhibited the following physical properties.

'H-NMR (CDCd 3.δ, engineering): 2.07 (3
1-1, S), 2.61 (IH, m), 2.74 (1
H, t, J = 4.6Hz).

3.0 (IH,, m), 5.10 (2H,,?), 7.
35 (5H.

S) Example 7 (2R>-N-<t-butquinecarbonyl)amino-ro-butynol 254n+Q (1.3 mmol) was dissolved in 1 m of methylene chloride, e, and 1 m of trifluoroacetic acid.
1 and treated at room temperature for 15 minutes. Depressurize the U medium'', A1
After leaving, soak the remaining liquid in water and add Dowtx 5.
Adsorb onto 0WX4 (ion exchange resin from Dow Chemical Company). After thoroughly washing with water, it was bathed with 28% ammonia water. The solvent was distilled off under reduced pressure and the amine compound (A159 r=+ri(
07 mmol, yield 54%).

Avan compound (A) 59IRQ (0.7 mmol) was R'r FfF in 1 ml of methanol, and 89 μl of ethyl trifluoroacetate (0.8 mmol, 1.1 mmol)
4t) and l-ethylamine 2111 were added, and the mixture was stirred IW at room temperature for 2 days.

Add water, convert to 7) H2 with an aqueous hydrochloric acid solution, and then extract with ether. Dry the organic layer with aqueous sodium,
71" JJM, reduce the solvent) and evaporate. The crude product obtained in 1) was subjected to silica gel column chromatography (elution solvent: ether) to yield 85 rng (69
%) was obtained.

1H-NMR (CDCl 3.δpprn) 3.72
(2H, d, J=5.5H2), 5.0~5.5
(2H.

m), 5.85(1)1. ddd, J=5.5.10,
14Hz) 2-(N-1-lifluoroacetyl)amino-3-butynol 85■ (0.47 mmol) and 90%
133 m9 (0.7 mmol) of m-chloroperbenzoic acid was dissolved in 5 ml of methylene chloride and purified by silica gel column chromatography at room temperature for 19 hours (v extrusion solvent).

Yield 68m9C (as threo, erythro mixture).

Threo form: H-NMR (CDCA3.δpp□)2.
58 (I H, d d, J=3.2.3.6H2)
, 2.84(1)1. t, J=-3,2)1Z)
*3.31 (IH, l.

3.8-4.0 (5H, m) Erythro form: H-NMR (CDC13, δpp□)2
．． 88 (I H, dd-, J=3.2. 3.48Z
), 2.93 (1'A, t, J=6.2H2),
3.20 (I H,m ).

3.8-4.0 (3H, m) Example 8 6-(N-1-butoxycarbonyl)amino-4-indyloxy-1-butene 262 m9 (0.9 mmol)
was dissolved in 1 m of methylene chloride, and 1 m of trifluoroacetic acid was dissolved in 1 m of methylene chloride.
1 and stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in water and dissolved in water (Dowex).
Adsorb to 50 W x 4. After washing thoroughly with water, 2
．． Elute with 8% ammonia aqueous solution.

The solvent was removed and distilled off under pressure to obtain amine 9B"!7 (C1.6 mmol). (Yield 58%) Amine 71 (0.4 mmol) was dissolved in 2 ml of methanol.
Dissolved in ethyl trifluoroacetate 56μlc0
．． 44 mmol, 1.1 equivalents) was added and stirred overnight at room temperature. Since the reaction was not completed when checked by TLG, 6 μl of triethylamine was added and stirred for an additional 2 days. Water was added, methanol was distilled off under reduced pressure, and the mixture was adjusted to pH 2 with a dilute aqueous hydrochloric acid solution and extracted with ether. After drying the organic layer over anhydrous sodium sulfate, P was removed and the solvent was distilled off under reduced pressure. The obtained crude product was subjected to licage gel column chromatography (bathing solvent: ether) to obtain the title compound 6.
9.5 m9 was obtained. (66%)”H-NMH(CD
G13. δppm): 3.5b (2H, ti, J=
5Hz).

4゜50 (2H, -?)t 4.65 (I H,
771), 5.0-5.4 (2H, m>, s, 5s
(1H, ttd, t, J=3.5.8.5°1.5H
1), 7.30(5H,,?)3-(N-)lifluoroacetyl)amino-4-benzyloxy-1-butene 7 CJm9 (0,25 mmol), 90% m-chloroperbenzoic acid 75m? (0,38
mmol) in 2 wLl of methylene chloride and stirred for 16 hours at room temperature. The reaction solution was post-treated in the same manner as in Example 6, and a mixed solvent of ether:hexano-4:6 was added to the eluate for silica gel column chromatography.

The title compound 59 as a mixture of threo isomers, 1971 isomers
m9 (yield 80%) was obtained.

Threo body (64m?) “H-NMR (GiJC13, δpprn): 2
．． 82 (2H, m).

6.10 (IH, m), 4.65 (2H, S), 7.3
3(5H,s) 1971 bodies (25m da) ')(-NMJ'((GDGl 3.δp engineering C2,5
7 (IH, dct.

J-2,3,5H2), 2.77 (1H,t, J=3
．． 5H2).

3.24 (IH, m) - 3,60 (2H, d, J = 5
．． 5Hz).

4.36 (111, m,), 4.54 (2H,,?),
7.31 (5M,,r) Example 9 2-(ti-trifluoroacetyl)amino-ro-butynol 57my (0.3mmol) Q, 5'm
7. Add 46.5 μl of triethylamine at 0°C, followed by 64 μl of acetyl chloride (0.48 mmol). ). The mixture was stirred at 0°0 for 1 hour and at room temperature for 60 minutes, water was added, and the mixture was extracted with ether. Purified using silica gel column chromatography to obtain 47 m of 2'-(N-)lifluoroacetyl)amino-ro-butyl acetate. ! It's +.

"H-NMR (CDC13, δP7)ヮ): 2.1 (
38,! ), 4.15 (2N, d, J=5.
5H2).

4.70 (1H, m), 5.0-5.4 (2H
, m), 5.75 (1B, ddd,, J=5.5,
8.148Z) 46 mL of this 2-(f'l-trifluoroacetyl)amino-6-butyl acetate? (0,
2 mmol) and m-rio;il,', 4benzoic acid 59m! 7 (0.3s mol) was dissolved in 2m6 of methylene chloride and stirred at room temperature for 48 hours. The reaction solution was treated in the same manner as in Example 6, and purified using silica gel column chromatography using ether:hegisan-6:1 as a bathing solvent. The title compound (1971 compound, mixture of threo compound) was obtained in 4 filtration (yield: 87%).

Threo body] H-NIJ ((CIX;/3.δ,,-): 2
．． 10 (5M, S C2,55(I H,dd,,
J=2.6.5.6['-z)t2.82(1H
, t, J=6.61(z)s 3.20 CI E(
, m, ) 1971 body 1l-1-Nl edict (GDGl3.δ, yoC2,16(5
H,s).

2.55 (I H, dd, J=2.6.3.6H
z), 2.88 (I H, t, J = 3.61-12
), 3.04 (I H, m) Example 10 2-(N-ρ-Toluensurun J Sunil) -7=,
/-6-butynol 26.4nI9 (Ll, 11 mmol) and 90% m-chloro-perbenzate rt9313my
(0.16 mmol) was dissolved in 1 ml OJ of dichloromethane and stirred for 16 hours at moderate temperature. The reaction solution was purified using preparative chromatography in the same manner as in Example 6. 14.4 m9 (yield 52%) of the title compound was obtained as a mixture of threo and erythro.

Threo body (8,9m9) ”H-NMR (CDCβ3.δ21.yu): 2.42
(3)1. 3).

2.58 (1)(, dd,, J=2.5.4.6H
z ), 2.68(11(,ctd, J=4.3,5
．． 0Hz), 3.10 (IH.

m), 6.5~. 15.75(5)(,m), 5.0
5 (IH, ct.

J = 8Hz), 7.31 (2H, d, J = 8
Hz).

7.95 (2H, d, J=81(z)) 1971 bodies (
5,5~) IH-NMR (CDC43, δppm): 2.43
(3H,s).

2.60 (I H, cLtL, J=2.5.46H
z), 6.03 (IH, “L), 3.14 (1 day, m
, ), 3.50-3.75 (3H, m, ), 5.3
5 (IH, d, J=7.5l-1z).

7.32 (2H, tt, J=8Hz) -7,77
(2M, d.

J=8.01 (Z) Reference Example 1 A divinyl steel reagent solution (5.1 mmol) of tetrahydrofuran was evaporated under a N2 stream at -78°C.

A solution of quinacetate (630+ψ, 2.6 mmol) in tetrahydrofuran (2d) is slowly added dropwise. −
60 minutes at 78℃, 45 minutes at -4'00G, then 4℃
Stir IV2 for 17 hours. Addition of saturated ammonium chloride water bath solution to the reaction
2 times), and the organic layer was dried by adding magnesium sulfate under irrigated water, and concentrated under reduced pressure 6S3. Raw jjy thing 1 (1-OH
,3-OAC) body, (1-OAc, 3-0H) body, (
1. Dissolve in d ml of acetic anhydride and leave at room temperature for 5 hours (a. Pyridine, %
Water 1: The acid was distilled off under reduced pressure and silica gel column chromatography (ether:hexane-4:6) was performed to obtain diacetates 603-9 (yield 51.1%).

IR (Ci (GA3) 1721. 174ro/ff
-'NMRδ0.04 (3H, r), 0.05 (IH,
0.89 (9) 1.8), 1.45 (9H, J),
2.0ro (6H,,r).

6.99 (2k(,' )-4,67(1H,d,J
=8).

5.01 (1) (, m), 5.57 (2H, m,) Mass 4.60 (M++1) Reference Example 2 The product 435 rny of Reference Example 1 was mixed with 5 ml of methanol,
Catalytic amount (5 m9) of 7)-)luenesulfonic acid at room temperature 2
．． After treatment for 5 hours, sodium bicarbonate powder was added to quench the reaction, methanol was distilled off under reduced pressure, and the mixture was subjected to silica gel column chromatography (ether/hexane-9/1) to obtain (28,33)-N-. -Methyl-6-acetoxy-9-human 90quin-3 (El heptenyl acede)
A temperature of 197°C was obtained (66 hours).

Raw material recovery 130■ (60゛) IR (CHC73) 5450, 3350, 1735, 1
716゜17013Gm-"lqMR(cDc13.δ,,rrL) 1.42(9
)i, S), 2.00(ro)(,S), 2.02(
3H,y), 3.70-4,20(58,rn), 5
．． 5-5.8 (21-1, rrL) # Example 1) A methylene chloride solution (51 m) of the product 280111 (0,087 mmol) of Reference Example 2 was soaked at 0°C under a N2 stream.
Pyridinium chlorochromate (566
■, 0.261 mmol) of methylene chloride (5+11)
Drop into the moisture of the water. After stirring at 0° C. for 1 hour and in room τJ for 1 hour, 50 ml of ether, 10 ml of ether, and magnesium acid were added, followed by filtration under reduced pressure.1. J-(:r6°'
, + nai L, then perform silica gel column chromatography 240m9 (86%) (7) (2S, 35) -
N-t-dityl-6-acetoquine-9-ormyl-3 (
E) Hebutenyl acetate was obtained.

2) MWf the above-mentioned production of fl+ J# (155m&, 0.45 mmol) to 15 ml of methanol-#, and
Next, add acetic acid with an IQ of 77 zf, 12.3 9 (・o, +s mmol) of cyanide, and 1.5 g of activated manganese nitride, and stir at room temperature for 5 hours (□, ・; 6. Suction the reaction oil. it' 1f45, extracted with ethyl acetate, b;
F water sulfuric acid) II Add 1 neem and add 1; After condensation under reduced pressure, silica gel column chromatography was carried out using 1 coat (bathing solvent: Conycil/Hexane-1:
1 followed by ether), (2S.

6s>-N-6-butyl-6-acedoquine-9-acetoxy-3(E)hep'thenyl-1-1-1101-1
15 mg (10'yo) of recovered raw material was obtained.

IR (CHC13) 1736.1715□-1 Cloth MR
(CDC13, δ, pm) 1.46 (9H, -?),
2.06 (3H, ri, 2.07 (roH, s), 2.
53 (2B.

t, J=7.2H2), 3.72 (3H,J)
, 3.95-4.10 (3H, m), 4.73
(C1,, J=8.6), 5.15 (IH, m), 5.
89(1)i,cL,J=15.8).

6.85Cdt, 1)1. J-7,2,15,8) Reference Example 4 (23,38)-N-t-butyl-ro-aceto\C9-acetoxy-3(E)hebutenyl acetate 20
3■ (0.54 mmol) in 4rnl Mechnono 1/
Add 7 m9 of potassium carbonate and stir at room temperature for 14 minutes. After adding an ammonium chloride bath solution to the reaction solution, methanol is distilled off under reduced pressure, extraction is performed using ethyl acetate, and anhydrous sulfuric acid (II) is added to dry. After t-1 filtration, the product was concentrated under reduced pressure and subjected to silica gel column chromatography (ether/ethyl acetate = 1/1).
, (2S, 48.58j compound 52m9 (40%) and the title compound 49my (38%) were obtained.

1R (CuCl2) 343U, 1730, 1710c
s, -”NMR (CDC13, δ,, m) 1.45 (
9H,y), 2.10(IH,d(Ad,J=2.5
．． 13), 2.45 (IH.

d(t, J=4.8.1.6), 2.60 (I
H,rid,, J=8.4.16), 5.08(
1H,t, J=11), 3.45(IH,m),
3.56 (IH, dt, J=4.8.11.0).

5.70(roH,'L 3.80(1H,"L 4.0
1 (1F+, ctct, J=4.8. 1 1.0
) Risa Example 5 Galantinic acid 1156 m& The product produced in Example 4 (0.2 ml 1 mol) was dissolved in 5 m/m of methanol, and 1% K.
Add 22 ml (0.39 lmol) of OH and stir at room temperature for 15 hours. After adding water and distilling off M t OH under reduced pressure, the pH was adjusted to 2 with 6% HCl and extracted with ethyl acetate.
After adding Nα2S04 and drying, filter through fJj and concentrate under reduced pressure to give 5
4 mF/(~100%+ (7) (2S, 43°53)-tJ-6-butoxycarbonyl-4-hydroxy-5-aminopyran-2-acetic acid was obtained.

2) Dissolve 16 da of the product from 1) in 1 ml of methylene chloride, add 0.5 rnl of trifluoroacetic acid, and dissolve at room temperature.
Process for 5 minutes. After distilling off the bathwater under reduced pressure, DOWEX (
Dower) 50 W x 4, 2.8%
Bathed with ammonia water. The fractions positive for ninhydrin reaction were collected and the solvent was distilled off under reduced pressure to obtain crystals of galantinin solution of 8.5 rv, 0 [α] = +2.64 (c
=1.06. Ho)2 NMR (D20.δppm> 1.47 (6αH, d
, t, J2, 3α=J ~12.0. J3C1
,3β-12,5), 2.173α・4 (6βH,ddd, J2.3β=2.4 J3β,
4 = 56*J3ct, 3β=12.5)t 2.
38 (1'H, dcL, J1/, 2""6.2r
J, t,, t = 16.8), 2.45 (1
'H, dcL*J, =7.7. J, ,=16
ε5), 6.12 (s-H.

1 -2 1 -1 11-1. cat J4.5=J5.6/=11.0
．． J5.6 (1=5.0), 6.47 (6β-H, I
H, t, J=1 1.0).

3.87 (2-Ht,;Jl[-H,2)1. m)
, 4.14 (6α, -1-1, cod, J5.6° ~
5.0? J6 (1,6β=11.0) (g) Industrial field of application Evaxyamino alcohol derivative of the present invention (a constituent amino acid of galantin I, an excellent antibiotic)
A useful intermediate for the production of lantinine narcosis, as well as for the synthesis of other antibiotics, such as furanomycin, plasticidin-S, the icros 71" phosphorus, amino→noik 1) toll, etc. It is believed that it is useful for the body as well, and is used in the antibiotic manufacturing field (・
It will be widely used.

(4 other people)

Claims (1)

[Scope of Claims] fi+ -1 functional formula (wherein R1 represents a hydrogen atom, a low-strength anhydrous group, a penzyloxycarbonyl group, a toluenesulfonyl group, an alkoxycarbonyl group, and R2 represents a hydrogen atom, a benzyl group, a l-
I+lower alkyl group represents a tetrahydropyranyl group or a lower anru group. ) Epoxyamino alfur 841 body represented by