JPH02311473A - Condensed cyclic lactone and its production - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> and R<2> are each protective group for H and OH). EXAMPLE:[3a-S(3a-alpha,6a-alpha)[-3,3a,6,6a-hexahydro-4-(t-butyldimeth ylsilyl)oxy-6a-(4- methoxyphenyl)oxymethyl-2H-cyclopenta[b]furan-2-one of formula II. USE:Expected as an active ingredient of medicines or pesticides, similar to a group of Corey lactones of formula III (R',R''=R<1>, R2) known as the synthetic intermediates for prostaglandins having strong physiological activity and didemnenones of formulas IV, V,etc., known for their cytotoxicity. PREPARATION:A compound of formula VI (X is halogen, acyloxy or sulfonyloxy) or its optically active modification is treated with a base such as diazabicyclononene in a solvent such as THF to obtain the objective compound of the formula I or its optically active modification.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a new f! Regarding the cyclic rhone and the method for producing the same, the general formula [■]: Further, the optically active substance thereof, the general formula (Ia): and the general formula (Ib): \. A novel ring-fused lactone and the ring-fused lactone represented by , (wherein R'' and R2 represent a hydrogen atom or a hydroxyl group protecting group, and R1 and R2 may be the same or different from each other) This invention relates to a method for producing lactones.

``The conventional method for producing prostaglandins is to produce prostaglandin type E from a cyclopentanone derivative without a substituent at the β-position [M., J., Weis et al. (M
, J. Veiss) et al., Journal, Organic, Chemistry (Journal Organlc C
hemistry) Vol. 44, p. 1439, 1979], a method for producing prostaglandin type F from a compound represented by the following formula (A) OCR, OCH, Ph [G., Stark et al., Journal.

American, Chemical, Social Tea (J, Am.

Chew, Soc, ), vol. 97, 4745.626
0 (1975)], and a number of intermediates have also been proposed, including various cyclopentanone derivatives (Terazu, Sakai, Yamamoto, "Prostaglandin and related physiologically active substances” 89~
92 pages, 1981).

Furthermore, the development of new intermediates derived from new types of prostaglandins is desired.

In order to meet the above requirements, the inventor of the present invention has made the following general formula [■] as a result of intensive studies.

In particular, the optically active substance represented by the following general formula [■a] or [
(b) (In the formula, R1 and R'' represent a hydrogen atom or a hydroxyl group protecting group, R1 and R2 may be the same or different from each other, and X represents a halogen atom, an acyloxy group, or a sulfonyloxy group. When using the following general formula (1), especially the above general formulas (Ila) and (nb) as a starting material, by treating a compound represented by the following general formula ([a]) with a base, the following general formula ([a) or [Ib] \OR'' (wherein R1 and R2 represent a hydrogen atom or a hydroxyl group protecting group, and R'' and R2 may be the same or different from each other.) was found to be obtained in good yield.The above-mentioned novel ring-fused lactone thus obtained has the following general formula CB) R'0mi (wherein R'' and R''' are hydrogen Cory lactone, which represents a protective group for an atom or a hydroxyl group, and R' and R11 may be the same or different, has strong physiological activity and is known as an important synthetic intermediate for prostaglandins. Similar to a group of compounds known as cytotoxic didemnenones represented by general formulas (C) or (D) below, they are expected to be active ingredients in medicines and agricultural chemicals, especially prostaglandins and didemnenones. The present invention has been completed based on the discovery that it is useful as a synthetic intermediate for compounds such as the following.6 Therefore, the present invention provides a novel ring-fused lactone represented by the above formula and a method for producing the same.

The present invention will be explained in more detail below.

As mentioned above, the novel ring-fused lactone according to the present invention is
It is represented by the following general formula [1], which is represented by the following general formula (I a) or (Ib) \OR" (wherein R" and R3 represent a hydrogen atom or a hydroxyl group protecting group, and R and R2 may be the same or different from each other).
The compound represented by the formula a) and the compound represented by the formula (Ib) are in an enantiomeric relationship with each other.

Here, as the protecting group for the hydroxyl group of R1 and R', a trialkylsilyl group (for example, trimethylsilyl 3, t-butyldimethylsilyl group, phenyldimethylsilyl group),
Alkoxyalkyl groups (e.g. methoxymethyl group, ethoxyethyl group, tetrahydropyranyl group), aralkyloxyalkyl groups (e.g. benzyloxymethyl group),
Examples thereof include trityl group, aryl group (for example, p-chlorophenyl group, yP-methoxyphenyl group, 9-anthryl group), and further acyl group (for example, acetyl group, p-phenylbenzoyl group, p-nitrobenzoyl group).

The ring-fused lactone represented by the above general formula [1] is.

The following formula [■]: (In the formula, R1 and R2 represent a hydrogen atom or a hydroxyl group protecting group, and R1 and R2 may be the same or different from each other. Also, X is a halogen atom, an acyloxy group, or a sulfonyloxy It can be synthesized by treating a compound represented by ) with a base. In this case, optically active substances of the general formulas (Ia) and [1b] can be synthesized, respectively, by using a compound represented by the following formula %(). In addition, in the above method, R1
, If R2 is a hydroxyl-protecting group, it can be deprotected in the final step.Here, in the above formula (n), examples of the halogen atom of X include a chlorine atom, a bromine atom, an iodine atom, etc. However, it is preferable to use an iodine atom because it is easy to prepare, and examples of the acyloxy group of X include acetoxy group, trifluoroacetoxy group, etc., and examples of the sulfonyloxy group of Examples include oxy groups and the like.

Bases used in the above treatment include alkali metal alkoxides such as sodium ethoxide, sodium methoxide, potassium t-butoxide, diazabicycloundecene (DBU), diazabicyclononene (DBN), diazabicyclooctane (DBO), etc. ), I'liethylamine,
Amines such as pyridine and 4-dimethylaminopyridine are used.

In addition, as conditions for performing the above-mentioned base treatment, it is preferable to use a solvent in an inert gas atmosphere, and in this case, the solvent may include tetrahydrofuran (THF). The reaction temperature is 70 to 90°C. , especially about 8
The temperature is preferably 0°C, and the reaction time is usually 4 to 1
It is one hour.

In addition, the compounds of the above formulas (II al, (Il b)) are compounds known in the literature [
E] (Literature: N, A. Norman et al., Tetrahedron Letters, p. 3275 (1976)), a method of opening the lactone using an alkali, converting it to iodolactonization with KI-1, and introducing a protecting group therein, etc. It can be obtained by

(E) In formula C, Ri and R2 have the same meanings as Rh and R2 above. It is useful as a synthetic intermediate for various new types of prostaglandins.

Furthermore, according to the method for producing a ring-fused lactone of the present invention, the ring-fused lactone can be synthesized in good yield, and when prostaglandins and didemnenones are produced using this as an intermediate, these can be manufactured at low cost.

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to examples and reference examples, but the present invention is not limited to the following examples.

(Example) (3a-R(3a-a, 6a-CI)) -3,3a
.

6.6a-tetrahydro-4-hydroxymethyl-2H
-Cyclopenta(b)furan-2-one(1)319■
(2,06+++ crystall) and triphenylphosphine 8
09■ (3,09a+mol) and p-methoxyphenol 256■ (3,09mmol) were dissolved in 4.4d of dried methylene chloride, and diethyl azodicarbon a (DEAD) was added to this at room temperature under an argon atmosphere.
578 mg (3,09 mmol) in dry methylene chloride 4.4+n! The solution dissolved in Q was added dropwise and stirred for 3 hours.

4 mQ of water was added to separate the layers, the methylene chloride layer was taken, and the remaining aqueous layer was extracted with 2 d of methylene chloride each.

The methylene chloride layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The residue was subjected to column chromatography (15 g of silica gel,
Purified with hexane-ethyl acetate (volume ratio 7:1)) and purified with (
3a-R (3a-a.

6a-α)) 3,3a,6,6a-tetrahydro-
4-(4'-methoxyphenyl)oxymethyl-2H-
Cyclopenta(b)furan-2-one(2)398,t
Obtained as colorless crystals. Yield 74%.

IR (liquid paraffin): 1750ai-'NM
R (CDCQ3): δ 6.82 (s, 4H),
5.80 (s, 1B), 5.20 (+++, I
H), 4.55 (s, 2H).

3.18 (s, 3H), 2.75 (m, 51
1) MS (m/e): 260 (P), 1
24 (100) High resolution MS (m/e): Calculated value 260.1048 (C,,11□,O,(M”
) Actual value 260.1054 Melting point 64-66℃ (Ethyl acetate-hexane) Compound (
2) 6691 mg (2.57 mmol) was dissolved in 6 m+2 methanol, and 1.12 mm of a 30% aqueous solution of caustic soda was added dropwise thereto at room temperature, followed by stirring for 10.5 hours. Methanol was distilled off under reduced pressure, 3 mu of water was added, and the mixture was washed twice with 1 portion of ether. 10% hydrochloric acid was added dropwise to the resulting aqueous layer to adjust the pH to 4 to 5, followed by extraction three times with methylene chloride SmQ each.

Combine the methylene chloride layers and wash with saturated saline.

After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain colorless crystals (carboxylic acid).

The above carboxylic acid was dissolved in a 4% aqueous solution of caustic soda, and the pH was adjusted to 7 by blowing carbon dioxide gas into the solution.

To this, 4.42g of potassium iodide (26,6Ω+a+
After dropping a solution of 2.46 g (9.68 mmol) of iodine and 7 nl of water at 0 to 5°C,
The mixture was stirred at 0-5° C. for 60 hours under an argon stream.

10 ml of methylene chloride was added to this, and sodium sulfite was further added until the reaction liquid returned to pale yellow.

Separate the methylene chloride layer, and the remaining aqueous layer is diluted with methylene chloride 5.
Each rnQ was extracted three times. Combine the methylene chloride layers,
After washing with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain colorless crystals (iodo-lactone). This one is IR (liquid paraffin): 17
Lactonization was confirmed at 50 cm-1.

The above iodolactone compound was dissolved in dimethylformamide (DMF).
) 3rn1, 425 ml of t-butyldimethylsilyl chloride (2,83+++u+ol) and 448 mg (6,58 mol+ol) of imidazole were added thereto, and the mixture was stirred at 35°C under an argon atmosphere for 12 hours. water 5
After adding IILQ, it was extracted twice with 10 d each of ether. The ether layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The residue was subjected to column chromatography (45 g of silica gel,
Hexane-diethyl ether (volume ratio 19:l)) to purify [3a-8(3a-a, 6a-CI))-3,3
a, 4,5,6゜6a-hexahydro-4-(t-butyldimethylsilyl)oxy-6-iotho6a-(4'
-Me1-xyphenyl)oxymethyl-2H-cyclopenta(b) Furan-2-one (3) 1.08 g was obtained as a colorless caramel. Yield 81%.

IR (liquid paraffin): 1750cm-”NM
R (CDCJ, ): δ 6J4 (s, 4H), 4
．． 47 (+m, :lI), 4.14 (s, E)
, 3.77 (s+ 38).

2.83 (m, 311), 2.32 (m, 2
H), 0.90 (s, 9N).

0.10 (s, 6H) MS (m/e): 518 (M”), 1
24 (100) High resolution MS (m/e): Calculated value 51δ, 0986 (CziHaxOsSiI
(as M”) Actual value 518.0961 1.08 g of the iodolactone body (3) obtained above (2
, 07 mmol) in tetrahydrofuran (THF) 12
1,5-diazabicyclo-5-nonene (D
BN) (311 mg (2,5 On+mol)) was added dropwise thereto, and the mixture was heated under reflux for 11 hours under an argon stream. After adding 3 d of water and 20 d of ether and separating the ether layer, the remaining aqueous layer was extracted twice with 5 ml of ether each. Combine the ether layers and wash with water.

After washing with saturated saline, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (35 g of silica gel, hexane-ethyl acetate (volume ratio 94:6)) to obtain (3a-5 (3a
-a, 6a-(E)) -3,3a,6,6a-hexahydro-4-(t-butyldimethylsilyl)oxy-6
a-(4'-methoxyphenyl)oxymethyl-2H-
Cyclopenta[b]furan-2-one (3) 657mg
was obtained as colorless crystals. Yield 81%.

Melting point: 93-94°C (diethyl ether-petroleum ether) IR (CHCII3): 1770co+-”N
MR (CDCl2,500MH2): δ6.82 (s
, 4H), 6.04 (dd, LH, J=16.
1.18) 1z), 5.94 (dd, IH, J=
6.1.1Hz), 4.90(ddd, 1)1.
J=7.3.1.8.1. Ez), 4.14 (d.

IH, J=9.7)1z), 3.95 (d, LH
,,l=9.7Hz).

3.77 (s, 31), 3.20 (ddd,
IH, J: 10, 8.7.3゜6.0Hz), 3.0
0 (dd, IH,, C10, 3, 6Hz), 2.
63(dd, 1)1. JJ8, 3.10.811z
), 0.91 (s, 911).

0.11 (s, 3H), 0.10 (s, 3)
1) MS (m/e): 390 (M”),
333.209.181゜165, 125 (10
0), 124.123 high resolution MS (m/e)
: Calculated value 390.1862 (C2,H,l,0.Si
(M”) L 1: ) Actual value 390.189 Elemental analysis: Calculated value C, 64,58%, H, 7,74% (c2.H
3, O, Si) Actual value C, 64,43%, H, 7,68% TLCRF
= 0.655 (ethyl acetate:hexane=1:1)RF==0.3
57 (diethyl ether:hexane=1=1) [Reference example] i, z, l, 3,3.3-hexamethyldisilazane 21
8 mg (1.35 mmol) of dried THF
Dissolved in 3.5aQ and heated at -78℃ under an argon stream to n~butyllithium (Low/ν%, hexane solution) 8G
14 (1,35 mmol) was added dropwise and stirred for 30 minutes, followed by lactone (4) 350II synthesized in the above example.
A solution of g (0.90 mmol) dissolved in dry THF6.0+aQ was added dropwise at -78°C and stirred for 1 hour. Next, acrolein 60.3mg (1.08m+5oL)
was added dropwise at -78°C, and after stirring for 1 hour, 3 mQ of saturated ammonium chloride water was added dropwise at -78°C, and the temperature was gradually returned to room temperature. After separating the organic layer, the aqueous layer was extracted three times with three portions of ether, the organic layer and the ether layer were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow oil ( lactone alcohol form) was obtained.

This product was dissolved in dried methylene chloride 6,2-, and at 0°C under an argon stream, 226 μm of triethylamine (
2, 23a+u+ol) and 133 mg of methanesulfonyl chloride (1, 16a++++ol) were added dropwise in this order, followed by stirring at room temperature for 12 hours. Water was added dropwise to separate the mixture, and the aqueous layer was extracted three times with 4 mQ of methylene chloride each time. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a pale yellow oil (lactone mesyloxy compound).

Dissolve this in dried THF6.2-
8-Diazabicyclo(5,4,0)-7-undecene (
DBU) 277■ (1,79u+a+ol) was dropped,
The mixture was heated under reflux for 1 hour under an argon stream.

After cooling, 2IILQ of water was added dropwise to separate the layers, and the aqueous layer was further extracted three times with 2d portions of ether. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography (silica gel 20
g p hexane-ether (95:5 by volume)) to give Z (3a-3(3a-α, 6a-α))-
3,3a,6,6a-tetrahydro-3-propenylidene-4-(butyldimethylsilyl)oxy-6a-
(4″-methoxyphenyl)oxymethyl-2H-cyclopenta(b) furan-2-one (Z-(5)) 21
o (yield 55%) and E-[3a-8 (3a-a, 6
a-α)]-]3,3a,6,6a-tetrahydro3-
Propenylidene-4-(t-butyldimethylsilyl)oxy-6a-(4'-methoxyphenyl)oxymethyl-2H-cyclopenta(b)furan-2-one (E-(
5)) 99■ (yield 26%) was obtained.

Lyo5J: m p 105-106.5°C (diethyl ether-hexane) (a) o+ 142° (C = 0.990. CHCl
l3) I R (CHCffi,): 1740an
-1HMR (CDCL, 500MH2): δ7,80 (ddd, IH, J=17.3.11,
5.10Hz), 6.80(s, 4H), 6°6
1 (dd, IH, J=11.5.1.811z).

6.07 (dd, IH, J=5.5.1.8Hz)
, 5.97 (dd.

ltl, J=5.5.1.2)1z), 5.50
(d, ill, J-10Hz).

5.49 (d, lft, J=17.3Hz),
5.03 (ddd, l)I.

J=7.5. 1.8. 1.21(z), 4.11
(d, 11(, J=9.8Hz), 4.01
(d, lfl, J:9.8Hz), 3.75 (
s, 31().

3.65 (dd, 01. J=7.5.1.8tl
z), 0.87 (s.

9)1), 0.12 (s, 61()MS (+
s/e): 428 (M”), 371.29
1.219°124, 123.73 (100) High resolution MS (m/e): Calculated value 428.2019 (C24It320.Si
(as M”) Actual value 428.2000 Elemental analysis: Calculated value C, 67,26%, H, 7,74% (Cx 4
Hx z O2S l) Actual value C, 67, 34
%, H, 7,57%2 ratio 51-: m p 1
23-124°C (diethyl ether-hexane) [(m]o+205.3° (C=0.990.CHC
l1. )IR(CHCl3): 1740cm
-”NMR (CDCI!, 500MH2): 67
．． 24 (dd, IN, J=11.5.211z)
, 6.80 (s, 411).

6.48 (ddd, LH, J=16.5. 11.
5. 1011z), 6,13(dd, LH,J
=5.5. 1.811z), 6.06 (d,
ill, , C5,51(z), 5.68 (d,
01. J=16.5Hz), 5.58(d.

LH, J=10Hz), 5.05 (dd, IH
, J=7.5. 1.811z).

4.08 (d, 18. J=9.8Hz), 4
．． 01 (d, ill, J=9.8Hz), 3
．． 76 (s, 31(), 3.75 (dd,
IH, J = 7.5.2.21 (z), 0.8 (s
, 91(), 0.06 (s, 311).

0.04 (s, 3f() MS (m/e): 428 (M”), 3
71. 291. 219°124, 123.73
(100) High resolution MS (m/e): Calculated value 428.2019 (C,, H320sSi (
Actual value 428.2012 Elemental analysis: Calculated value C, 67,26%, H, 7,53% (C,)
(As 320JSi) Actual value C, 67,04%, H, 7,46% Procedural amendment (Own ship July 11, 1999 1, Indication of incident 1999 Patent Application No. 135579 2, Title of invention Ring-fused lactones and their manufacturing method 3, and their relationship to the amended case Patent applicant Address: 3-7-1 Kanda Nishiki-cho, Chiyoda-ku, Tokyo Name (398) Takeo Nakai Daba Create, Representative of Nissan Chemical Industries, Ltd. Building 5N Episode 11 (545) 6454
Name Patent Attorney (7930) Takashi Kojima 6 Contents of amendment (1) r3.09ga in the third line from the bottom of page 17 of the specification
ol J is corrected to r2.06+1sol.

(2) On page 26, line 1 There is a certain thing I am corrected.

that's all

Claims (1)

[Claims] 1. General formula [I]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R^1 and R^2 represent a hydrogen atom or a protecting group for a hydroxyl group, and R ^1 and R^2 may be the same or different.) A fused ring lactone. 2. General formula [I a]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I a] Or general formula [I b]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I b] (In the formula, R ^1 and R^2 represent a hydrogen atom or a protecting group for a hydroxyl group, and R^1 and R^2 may be the same or different from each other.) A condensed ring lactone represented by: 3. General formula [II]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, R^1 and R^2 represent a hydrogen atom or a protecting group for a hydroxyl group, and R^1 and R^2 may be the same or different from each other, and X represents a halogen atom, an acyloxy group, or a sulfonyloxy group) is treated with a base to obtain the ring-fused lactone of claim 1. A method for producing a ring-fused lactone, characterized in that it obtains a ring-fused lactone. 4. General formula [IIa]: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IIa] Or general formula [IIb]: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IIb] (In the formula, R^1 and R ^2 represents a hydrogen atom or a protecting group for a hydroxyl group, R^1 and R^2 may be the same or different from each other, and X represents a halogen atom, an acyloxy group, or a sulfonyloxy group. 3. A method for producing a ring-fused lactone, which comprises treating a compound containing a compound with a base to obtain the ring-fused lactone according to claim 2.