JPS5849336A - Naphthylbutenoic acid derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A naphthylbutenoic acid derivative shown by the formulaI(R is lower alkyl; R<1> is H or lower alkyl; R<2> is H, alkyl or aralkyl). EXAMPLE:4-(3-Acetyl-4-hydroxy-5-methoxy-1-oxo-1,2-dihydro-2-naphthyl)- 2-butenoic acid methyl ester. USE:Useful an an intermediate for synthesizing nanaomycins or frenolicins to be used as a drug such as an antifungal agent. PROCESS:A compoung shown by the formula II is reacted with a compound shown by the formula III (R<3>, R<4>, and R<5> are the same or different alkyl or phenyl) usually at <=0 deg.C preferably in a nitrogen atmosphere in the presence of a Lewis acid, to give a compound shown by the formulaI. The compound shown by the formula II, for example, is obtained by treating an O-acyl derivative at the 4 position of 1,5-dimethoxy-4-hydroxynaphthoquione with boron trifluoride ether complex, and with ammonium ceric nitrate.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention describes the general formula (wherein, violet represents a lower alkyl group, This invention relates to 7-tylbutenoic acid #I, which is represented by the following formula: 1 represents a hydrogen atom or a lower alkyl group, and RR represents a hydrogen atom, an alkyl group, or an aralkyl group, and a method for producing the same.

To explain the above o'iiL definition in more detail, lower alkyl groups include methyl, ethyl, propyl, isoptevir,
Goutyl, tertiary butyl, etc. are □, and aralkyl groups are halodane atoms, alkyl groups, alkoxy groups, etc. as substituents.
Benzyl, phenylethyl, etc., which may have a hydroxyl group, a nitro group, a 1.7-mino group, etc., are used.

Hon f! 4o General compound (I) is a compound represented by the general formula (wherein l and 11 are the same as above) and a compound represented by the general formula (wherein l"aR'-15 is the same or different). is an alkyl group, a 7-ethyl group, and 12 has the same meaning as above. The process proceeds in the presence of a Lewis acid under a nitrogen atmosphere.

The metal compound (I) #i of the present invention, for example, is reacted with tertiary butyldimethylsilyl chloride in the presence of imidazole O, then treated with sodium chloride hydride, and then treated with sodium methoxide) Cyclization and desilylation produce the methyl ester of 0-methylnanaomycin. For example, Tetrahedron Letters,
When treated (according to the method of Ichihara et al. described in II21414469-4472 (1-1 year)), nanaomycin is produced. 7 lenolysine can also be produced from the methyl ester of deoxy-O-methyA77 lenolysine obtained in a similar manner.

ζO, the metal compound of the present invention has value as a synthetic intermediate for metal compounds useful as antifungal agents, and moreover, each step 8
The process proceeds with a yield of 0 or more, and the process requirements are short (and because it uses easily available reagents, it is a highly cost-effective technology, so it is industrially very useful and easy.

The compound of general formula (II) can be, for example, ! , s-dimethoxylate 4-hydoxynaphthoquinone 04 position 〇-abil form was produced, and this was treated with fluorine trifluoride ether complex salt, and then treated with nitric acid 27-liquidium chloride. Good luck.

9. The compound of general formula (1) can be prepared by adding carboxylic acid JUl to the ate complex of, for example, trizenylallylsicune (by esterifying if necessary).
be left behind.

EXAMPLES Hereinafter, the present invention will be explained in detail using examples and reference examples.

Example 1 Under a nitrogen stream, 1-17tyl-5-methoxy-4-natoquinone 23.Q (1,0 mlmol) and 1-
Methyl trizelsilyl-1-butenoate 25711F
(1.1 mmol) of methylene chloride solution was cooled to -71"CK, and while stirring, stannic chloride 14
Add G door l and circle. The resulting deep purple solution was heated to -30°C over one hour cycle, and when kept at this temperature for one hour, it gradually turned yellowish brown. After adding water and repeatedly extracting with ether, the needle layer was washed with water and saturated saline,
Rinse with anhydrous magnesium sulfate (dry).

When the ether was distilled off under reduced pressure, 4-(3-acetyl-4-hydroxy-5-methoxy-1-oxo-
Methyl 2-dihydro-2-su7tyl)-2-butenoate was obtained quantitatively.

1m-IMII (in deuterated chloroform, ICpp meal)] Wealth 11! (all), 2-2 ・~L60(m, 2
M), L4・(s, 311), 11(III), 3.8
5 (s, il, L59 (d e I H-J-161
1x), Li4 (t, t, 1i, z 8, 141 [凰)
Examples Under nitrogen atmosphere, 3-butyryl-S-methoxy-L4-7toquinone 258QF (1,0 ml 1 ol)) and 2
-dimethylphenylsilyl-3-butene methyl 251
Cape (1.1 mmJl) of methylene chloride solution 3.-
The mixture was cooled to 78°C, and 140 ml of stannic chloride was added dropwise. At this time, the yellow solution turned deep purple.

When the temperature of the anti-BS solution was gradually raised and stirred at -30'C for 1 hour, the reaction solution turned yellowish brown.9.

After adding water and extracting with ether, the ether layer was washed with water and dried in a conventional manner, and the ether was dried under reduced pressure.
Methyl methoxy-1-oxo-1,2-dihydro-1-natti-2-butenoate was obtained quantitatively.

'l[-III (in deuterated chloroform, #(pp-Otori)]!
a9fu (t, 3a, Jmyum), 1fu0 (sex,)
II, Jm full5), λ2・~1TO (臘, 4■)
, Li4(-13H), LM(s.

31[), 14)-190(111[), S, 65(d
.

s x I J Tomi t 4! [x ), Lf3 (d
, t, I Hako' Fable 114i)
, l F, - 5 (@, 11 Reference Example Reference System 1 Example of Preparation of Compound (II) (1) 72401 g of Li-dimethoxy-4-hydroxyna 7 (20 mO1, Rapoport et al. J, Org.

(!bsa,,44.1153~2151(1171)
An apricot pellet is made from L5-dihydroxynaphthalene according to the method of K. 11E. ] with pyridine 3- and acetic anhydride 2
- After stirring overnight in a humid room, 4 eJOd of water was added, and the precipitated crystals were separated by F, washed with water, and then dried with phosphorus.

This was recrystallized from a benzene-hexane mixed solvent.
Pure 4-acetoxy-1,! -412 g of dimethoxynaatalene were obtained as colorless platelets.

Melting point 119-121°C, yield 92% O II-IMII (in deuterated chloroform, # (pp))!
131(m, 3i[), 3. B 5 (s, 3 Ti
)%190(@e3H), 6.64-7.00
(m, 3H), 740 (t, 1m1),
7.111 (tl, IH).

Elemental analysis value 80 4102%, H5, 80% Calculated value as C engineering 4"14'4: Q 4L 21%, MS, 73% (■)
S-dimethoxynatsutalene 4404g (1 block, 9 o1
) was heated and melted for about 12 hours, and trifufluoride ether salt was added to it. Ether was vigorously pumped out, and a reddish-brown solid was obtained. After heating for 9 minutes, the mixture was extracted with 200 ml of water and 100 ml of methylene chloride, and the aqueous layer was further extracted with methylene chloride (30 dx once).

Combine the organic layers and wash with water and then saturated saline,
Dry with anhydrous sulfuric acid. After evaporating methylene chloride, apply silica gel Katsumukulimato (developing solution: methylene chloride)
Purification was performed to obtain pure 3-acetyl-4-hydroxy-LS-dimethoxynatutalene. Yield 18
42g (87%), yellow crystals, melting point 133-13SCC
benzene-hexane).

11-IMR (#(pp hazy) in deuterated chloroform) wealth
2-71 (se3!!), l
9 3 (6, 3M), 404 (s*3M),
6.80-6.9 6 (hidden, 3H), 7.
44 (t, 1m, z 8I Atsushi), Fu, Fu) (d, 11 (
.

J-siis), heavy 3L coj@(s, III)
.

Difficult spectrum (caritum bromide method, cm)! 333
5 (s, DI), 1400 (Ym).

Elemental analysis value g C6 block, 91%, 1113% Calculated value as 14'4 Alm 06L2 Hatake%, m 173% (1) 3-acetyl-4-hydroxy-!, 5-dimethoxynatsutalene 412 Misaki (λ, ugliness 01) was dissolved in 1 setonisili #35 mK, and while stirring at room temperature, 1 F of sericum ammonicum nitrate (Ig was dissolved in water at 15 dK) and a solution of 9 was added. After 5 minutes, water hammer was added. Add methylene chloride, shake, separate the methylene chloride layer, and extract the aqueous layer twice with methylene chloride.

The methylene chloride solution was diluted, washed with water, and dried over anhydrous magnesium sulfate. Crude crystals of 7,1-1 cetyl-2-methoxy-L4-nattoquinone emitted from solvent 11 42
Three capes were obtained. Yield 92%.

When this crude crystal was recrystallized from a mixed solvent of ether and hexybane, pure product 353111IF was obtained, 0-membered colored needle crystals.
Melting point 1o 1-10 $'C (decomposed).

11-IIMI (ICpp in deuterated chloroform)]!
1s? (s, 3K), 4.01 (a, 3H), 6.93
(a, III), 7.36 (ltl, J-3, $Its
), F'' S ~ F] Q (m, 2H).

Infrared spectrum (caritum bromide method, country ""'"1) = 1
4@1 (vs), 1655 (Ma1).

Elemental analysis value: 8 C6, 99%, H447%, C11m. Calculated value as 04 8 c 41. @196. Similarly to H411%,
1-Butyryl-5-methoxy-L4-nattoquinone (melting point 100-102°C) was obtained.

lH-1fMR [firi KID Ho/L/A, #(pp
m)):O,? 8(t, 31!, Jeg) Hm), 1.1
3(s@x.

21, Jm) Ifm), 2.90 (t −2' Hs
1M711 m), t 4 (@, 3H),
&92(s, 11), Fu, 1 ・~ Fu, 50(
m, 111), 1.6 0 ~ '1. g
6 (m, 2! [) Infrared spectrum (Calicum bromide tablets, s+-”) t14?6 (v, s), 166 g (v
s), 165S (mas') Elemental analysis value 8 o 1ts1%, Ii 5.73%'15"1
Calculated as 4'4 8 C69, 16%, MS, 4m'M -3-17tyl-5-methoxy-1,4-nattoquinone 49! Misaki (10 liters o 1) of methylene chloride 4 dKfl
j, and Illuminate Hokusin S.Ill (L6mmel) -
Drop it at 11℃, gradually bring it to room temperature, add water, and then
Extraction with ether, treatment of the ether layer in a conventional manner, and distillation of the solvent under reduced pressure yielded crude crystals of droquinone 37911. 9. This was dissolved again in ether,
Excess amount of silver(I) oxide L2? Add g and stir overnight.

After separating the solid F, it was washed with ether, and the ether layer was combined and dried under reduced pressure to obtain 6-acetylnigeron 304 cape as an orange needle-shaped insect with a melting point of 91°C (decomposition) and a yield rate of 9. ＄Porridge'I-wwxc Sumire Kuro pformri, I (pp heavy)]＼! λ6 ・(s, 3 H), F, @2(s, I
K), 7.2 ・～F, FUO (grave, 3M), 11. Fut
(@*tg).

Infrared spectrum (Calicum bromide tablets, cs) $340・(
br, s), 1695 (v@), 1660 (mar).

Elemental analysis value richness C46, 17%, I 192% Calculated value as C1 corridor δ04: C6 table 61%, i L13% Reference example 2 Preparation example of raw material compound (1) -71"CK cooling in an electric atmosphere 12 d of λIM tertiary butyrrhizicum O pentane solution was added to 46 d of Shikutetotsuhyde W7, followed by summer.

Summer, add r,r-tetramethylethylenediamine L7s-9. To this,) 4g 1 * g
Dissolve the solution and add 9-tetrahydro-7 run solution, and then gradually raise the temperature to -30'CK. The formed thick yellow solution was cooled again for 171'CK, and then... A solution of S% triethylaluminum in hequinane was added until the yellow color of the solution disappeared. While keeping the temperature of the reaction solution at -18°C, dry carbon dioxide was continuously added to the solution, and the temperature was slowly raised to 0°C. The reaction solution is then poured into ice-saturated ammonium chloride solution. A 5% hydrochloric acid solution was added until the white solid was completely dissolved to make the solution acidic, and then extracted with ether. The ether layer was separated, washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. When the excavation was analyzed by IH-MMR, 65
325! It is a mixture of IIO ratio. Recrystallization from methylene chloride provided tri->ritzenylsilyl-3-butene L9g. When the mother liquor was subjected to 7 ml of silica gel, an additional 1"Og was obtained. 9.Yield Table: 13gC4
3515>.

This was methylated with diazomethane in ether, and the product was recrystallized from benzene-hexane to obtain 124 g of product M, 1-triphenylsilyl-1-butene methyl. Melt! 96-91°C, yield 4% (based on trizenylsilane).

1 - Ml (weight p in roform, # (ppm)) wealth
Co-33(s, 31ri, 180((1,IH,J-
1-10"), 4.8 Q~5.16 (m, 21 [
), 6.08 (aielM, zxto, team),
? , 2-7.7 (m, III).

Infrared spectrum (caritum bromide method, ts) i.

11th 7th Mer).

In the same manner, methyl 1-dimethylphenylate-putenoate was obtained as a colorless oil from allyldimethyltzenylshikune.

1, - Summer Ml (weight 6w in holm, #(ppm) 1t6
．． 3g(*, 4K>, LIO(&, IH, Iw-161
g), 14Jl (s, 111), 4j4-50-0 (臘, 2M), 5.95 (d, t, IH, J-10
, 1) Hm) , 7.24 ~ 7.50 (m, 5
ir).

Infrared spectrum (liquid film method, (Ill-1) t 17°
20゜610 Reference Example 3 Preparation example of nanaomycin (114-<3-1 cetyl-4-hydroxy-5-methoxy-凰-oxo L2-dihydro-2-natutyl)-
Tertiary butyl dimethylsilyl chloride 378 cape, imidazole 408 w* and dimethyl formamide 211 d were added to 2-butene methyl chloride under a nitrogen stream, and after stirring at room temperature overnight, water was added and extracted with dichloromethane.

After the ether layer was washed with water and dried in a conventional manner, it was subjected to silica dull column chromatography (eluent: methylene hydride) to extract the corresponding l-11F tertiary glythyldimethylsilyl t-oxy compound 3.
Obtained 22 Capes. Colorless needles.

Melting point 1.F~16? ℃. Yield 13%.

11-IMI (weight in form, # (ppm)) snow
& Dish 4 (@e6M), 1.1
0(s,!II), 2J @(s, 31[), 141(
s, 31), 172 (1゜21 * J 4 Hz
), 4 (12 (s, 311), 16 Hatake (4, 11 [, J
-14Hz), 6.80 (cl, IH.

I tom $H edition), t9i (d, t, tH, J tom 6゜14H
s), 7.32(t, IH, Iz
811g), 7, 4'i (IL e
I H, J; a Hz), !
, 4S (s.

1 summer) Infrared spectrum (liquid film method, aR) 366 (br.

-), 11$5 (vs), 1690 (vs) mass spectrum (Otori/・) s, 444 (molecular ion beak) (1) This 1-tertiary gutyldimethylsilyloxy compound 111 Misaki (11 Otori mob) Add 31 wIg of sodium hydride to the methanol solution and stir at room temperature for 1 hour. Add saturated anthonicum chloride solution, extract with 1,000 ml, and extract the ether layer using a conventional method.

After distilling off the ether under reduced pressure, the sample was subjected to silica gel column chromatography (developing solution: methylene chloride enrichment) to obtain 4-[1-tert-butyldimethylsilyloxy-4-human tetrax-3
-(1-Hydroxyethyl)]-5-methoxy-2-su7tyl methyl 1-2-butenoate 11.Misaki was obtained. Yield 94%.

'I-rml (weight in Roliform, # (pp grave)] $L
11(s, LH), (LSI("s, 31[), LSI
(s, 1m), t-42 (a I 3 x -J dew 1
H rin), λ41 (1,3M), 1ma S (6e Z M
.

Jfu01), 444(s, 31ri, t91(虱.

1, L7・((1,11[,7111114111)
.

6.12 ((1, III, J-8Hs), ?,
OS ((1.

t, IH, 7w6, 16Hs), 7.21 (t
, 1 Seal', J m @ [H), 1.45
(6, IH, 1-・Hs), 9.1S (mouth, IH) (l ζO) The compound 60 obtained by K was dissolved in methanol KIl!!! and dissolved in sodium methoxide under stirring at room temperature.・Add LIWIl (as a 26% methanol solution of sodium hydroxide). After stirring for 1 hour, a saturated solution of 1 ton dicum chloride was added and extracted with ether. The ether layer was washed with silica gel by a conventional method. When W is carried out, 5-tertiary goutyldimethylsilyloxy-10-hydoxy-9-methoxy-°1-methyl-3,4-dihydro11-11-nat[λ1-o]bitun-3-yl methyl acetate s7# can be obtained as a mixture of two diastereoisomers.

Yield: 94 Excellent 1 Summer-Summer Ml (in heavy chloroform, # (ppm))! =
lL1 (s, 61), 1.1 (s, 911), 1.4・
(' I J ii, J m) Its), 12-3
．． ,%(m),3,? @ (@ I 3H), 113
(@, 3H), 4J@(s e 3 M), 3-
S Nt 4 (wi * l K ), 5.2 (ya
* 11), 6.70 (a * I H-J max 11 Hz), fu, heat ・ (1, 11 [, J-11
1! fi), fu-6o(asllJWIHm), 9
．． 'lSCmelK>, 9.32 (-11K) (Transformation) To 2wd of an acetonitrile solution of the thus obtained nine mixed-57misaki (L12 mol), add the 27th Likumuan Ningiri ^1fusaki of nitric acid. water! - Dissolved in solution and added the round solution, stirred for S minutes at room temperature, added water and extracted with ether to give the round solution. The ether layer 'l/! After processing according to the law, Bureparaty! Liquid chromatography (developing solution: 8-methylene chloride) Kyoto-separate two diastereomers and 0-methylnanaomycin methyl ester 1lsy were obtained as yellow crystals. Yield 46%. Melting point: 1.42-143°C (recrystallized from methanol).

11-IIMI (# (pp heavy) in heavy chloroform) t
Lis (a, in, z 7 Hg), 112-12 Hatake ・
(ds14, 2 summer * J=2-11, N I m
), λ6・〜Le2Cae2yilzwm4yxsea
ae tl.

J W3-1 e II s), L 73 (s
* 3 H) , 4,0 @(@ I 3 M
), 4.16~t46 (臘, 1 I), L1
1~Lie (臘, IM), Fu, 2・~1.3'4C臘.

1 summer), ? , IO~? , I I (
m', 2 M) infrared spectrum (wave film method, <111) $1735 (ma), 14 $5 (v
s), 1111 (vs) mass spectrum ('10・ma,
relative strength) 83J・(M+, ■), 2 j 7 (10
0), 2j4(H), 241(43) (V) O-methyl nanaoma obtained by K in this manner.

For example, Tetrahedron Recuse, Vol. 21, pages 4469-4472 (19
110) In order to perform a reaction treatment according to the method of KE Sen, Nanao Ishinmu with a melting point of 171-174°C was obtained. Based on NMR data, we can confirm that this is naomycin.

Patent Applicant Kazuhiro Maruyama Patent Applicant Yoshitomi Pharmaceutical Co., Ltd. Agent Patent Attorney Treble Winning Procedural Amendment (Voluntary) July 1979'/u Commissioner of the Patent Office Wakasugi Kazudono 1, Indication of Case 1988 Patent Application No. 12800 2, Name of the invention: 7-methylbutenoic acid derivative and its manufacturing method 3, Relationship with the amended case Patent applicant, address 3-35 Hirano-cho, Higashi-ku, Osaka Address: Higashi-ku, Osaka 3-35 Hirano-cho, page 15, line 7 of the amended statement of contents, ``6-1 Cetyl nigeron'' is corrected to ``Cuacetyl yugron''.

that's all

Claims (1)

[Claims] (1) A naphthylbutenoic acid derivative 0 (formula (In the formula, 18 is a hydrogen atom, an alkyl group, an aralkyl group, 3, 14 and 15 are the same and 9 are different alkyl groups,
Indicates a tsenyl group. ) A method for producing a 7-methylbutenoic acid derivative represented by the general formula (in the formula, the symbols are as defined above and M), the method comprising reacting a metal compound represented by: