JPH02250842A - Optically active compound - Google Patents

Abstract

NEW MATERIAL:An optically active compound of formula A (Bn is benzyl; *represents an asymmetric carbon). EXAMPLE:The optically active (R) compound of formula (A)-1. USE:An synthetic intermediate of milbemycin beta2 which occurs in nature and is effective against parasites in domestic animals. PREPARATION:The reaction of the compound of formula 1 with triethyl orthoacetate and pivalic acid gives the compound of formula 2 (Et is ethyl), the product is reduced with diisobutylaluminum hydride to form the compound of formula 3. The product is allowed to react with triphenylphosphine and carbon tetrachloride to give the compound of formula 4. Then, the compound is allowed to react with n-butyl lithium to give the compound of formula (A)-1, which is useful as an intermediate of milbemycin beta2 of formula I (Me is methyl), especially the compound of formula II, which is the upper half moiety of formula I, from the optically active (S) compound of formula 1.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to an optically active compound which is an intermediate for the production of milbemycin β2, which is known to be effective against parasitic diseases of livestock. . More specifically, the present invention relates to an intermediate for producing a compound represented by the following formula (B), which is the northern hemisphere portion of milbemycin β2 represented by the following formula.

Milbemycin β2 (B) (Prior art and problems to be solved) Milbemycin β2 is known as a naturally occurring compound, but generally, naturally occurring compounds with the above-mentioned unique properties are optically active compounds. There are many. These exert their effects in extremely small amounts, but since the amounts produced from nature are also extremely small, extraction from natural products is inefficient and impractical. Therefore, it is of great significance that this product can be mass-produced by synthesis.

(Means for Solving the Problems) The present invention provides an optically active compound represented by the following formula (A>) which is an intermediate for producing milbemycin β2.

That is, the present invention provides that the optically active compound of the present invention has the following formula (A>): (R) form and (S) form.
There are several types of optical isomers, among which milbemycin β2
The intermediate for production is the (R) form.

A method for synthesizing the (R) form of the above formula (A> compound) will be explained according to the following synthetic route. However, in the following, Bn represents a benzyl group and Et represents an ethyl group.

(In the above formula (A>, Bn represents a benzyl group,
The symbol * represents an asymmetric carbon atom).

Compound (A)-1 is obtained. Compound of starting material (
If the optically active (R) form is used as 1), the target compound (S) form of Compound (^)-2 can be obtained in the same manner as above. This product can be expected as a raw material for the synthesis of other useful optically active compounds.

(A>-1) The optically active (S) form of Compound (1), which is the starting material, can be obtained by a known method (Takano, Sekiguchi, Sahara, Ogasawara: 5ynthesis 1987.139).

Compound (1) is reacted with triethyl orthoacetate and pivalic acid to form compound (2), which is reduced with diisobutylaluminum hydride to form compound (3). Next, compound (3) was reacted with triphenylphosphine and carbon tetrabromide to form compound (4), which was then reacted with n-butyllithium (R) (A>- 2. Compound (A)-1 in the (R) form obtained above is converted into compound (7), which is a raw material for producing the compound (B), which is the northern hemisphere portion of milbemycin β2, according to the following synthetic route (1). can be converted.

(A>-1).The above-mentioned optically active epichlorohydrin is one with high optical purity, which is disclosed in Japanese Patent Application Laid-open No. 61-11111, filed by the present applicant.
132196@publication and Japanese Patent Application Laid-open No. 62-6697,
Alternatively, those obtained by the method described in Japanese Patent Application No. 63-284881 can be used.

The compound (B
), in addition to the above compound (7), compound (17) obtained according to the following synthetic route
is used. In the following, TMS represents a trimethylsilyl group, Bn represents a benzyl group, and pH represents a phenyl group.

In the above synthesis reaction, compound (A)-1 is given (R)-(
-)-Epichlorohydrin is reacted to synthesize compound (5), which is treated with a base to form compound (6), which is reacted with acetylene gas to form optically active (4R, 9R)
Compound (7) and TMS The above-mentioned starting material, Compound (8) in the optically active (R) form, can be obtained by a known method (Takano, Sekiguchi, Sake, Ogasawara: 5ynthesis 1987.139).

The above compound (8) is treated with propargyl chloride in the presence of a base such as an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide. Compound (9) is synthesized by reacting with a propargyl halide such as propargyl bromide or propargyl iodide. This compound (9) is converted to compound (10) by reacting with a halogenated trimethylsilane such as trimethylsilane chloride in the presence of a base such as 0-butyllithium, lithium hydride, sodium hydride, or a Grignard reagent.

Compound (10) is rearranged to give compound (11) in the presence of a base such as n-butyllithium in a solvent such as tetrahydrofuran, ethyl ether, or dimethoxyethane, and then this compound (11) is rearranged in a solvent such as tetrahydrofuran, ethyl ether, or dimethoxyethane. , potassium fluoride, hydrogen fluoride, in a solvent such as chloroform, methylene chloride, carbon tetrachloride, etc.
The trimethylsilyl group (TMS) is removed by the action of a fluorine reagent such as tetralobylammonium fluoride to obtain compound (12). The hydroxyl group at the 3-position of this compound (12) is esterified to form a compound (13), which is then treated with a base to be inverted and converted to a compound (14). This is hydrogenated in the presence of platinum (IV) oxide to give compound (15), and further hydrogenolyzed in the presence of palladium hydroxide (II>) to give compound (16).This compound (16)
When treated with acid in the presence of platinum black, it becomes optically active (43,5R)
Compound (17) is obtained.

Compound (B) can be synthesized by the following synthetic route IV using the above compound (7) and the above compound (17) as raw materials. In the following, Bn is a benzyl group, T
BDMS represents t-butyldimethylsilyl group.

(B) In the above reaction, n-butyllithium is added to compound (7) and reacted, and then compound (17) is reacted, and the hydroxyl group is protected with silyl ether to form compound (18). This is reduced to give a cis-olefin, which is then selectively epoxidized, and further reduced to open the ring to give compound (19). When compound (19) is reacted with a fluorine reagent to remove the silyl group, compound (B) and its epimer are obtained. This epimer can be converted to compound (B) by oxidizing it to a spiroketone and then reducing it with hydride. This compound (B) corresponds to the optically active northern hemisphere portion of milbemycin β2 and is an important intermediate for producing milbemycin β2.

The optically active (4R,9
Compound (7) in R) form and optical activity (4S.

Instead of Compound (17) of the 5R) form, the respective optical isomers of the Compound (43.93) (7') and (4R,
53) If compound (17M) is used, 1q of compound (B'), which is an optical isomer of compound (B), will be obtained. In addition, the above (43,93-) compound (7') is Compound (A)- instead of starting compound (A)-1
2, and (S)-(+)-epichlorohydrin was used instead of (R)-(-)-epichlorohydrin used in the reaction from compound (^)-1 to compound (5). It can be manufactured in the same manner as above. Also (4R
, 53) Compound (17M is the compound (17M) in the above synthetic route (■),
(S) in place of the optically active (R) compound (8) of the raw material
It can be obtained by performing the same procedure using a compound of the same type.

(Example) Example 1 <Synthesis of compound (2)> Compound (1) 7,09a (36,9m mof>
Triethyl orthoacetate 30. oa (185
m mol ) and pivalin l! 226mg (2,
21 mmol) was added, a Dean-3 tark apparatus was attached, and the mixture was heated at 140° C. for 12 hours in an argon stream.

Triethyl orthoacetate was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography using 250 g of silica gel to obtain ethyl ether:hexane=1:2.
A colorless oily compound (2>7.
120 (yield 73%) was obtained.

Elemental analysis CIBH2203 CH Theoretical value (%) 73.25 8.45 Analysis value (
%) 73,03 8.511Rνmax
(neat) 1730cm-11H-NMR (CD
α3) δ: 1.07 (3H.

1.24 (3H.

2803-2.04 (3H.

3.97 (2H.

4.12 (2H.

4.49 (2N.

5.54-5.72 (2H.

7, 33 (51°MS m/e: 155 (M” compound (3)
Synthesis > d, J=6.6Hz > t, J=7.1Hz) m) d) a, J-7,1Hz > S, ) m) S) -OBn), 91 (100%) obtained above Compound (2) 6.944g (26,30m mof
) diisobutylaluminum hydride 3.741g (26.30m mol) in toluene 200rd solution
> was added at -90°C in an argon stream, and the mixture was stirred at the same temperature for 1 hour.

After adding 1N hydrochloric acid and extracting with ethyl ether, the ether layer was washed successively with saturated sodium bicarbonate solution and saturated saline solution, and anhydrous W.
Dry with magnesium chloride. After distilling off the solvent under reduced pressure, the obtained residue was subjected to column chromatography using 200 g of silica gel, and the raw material compound (2>1
44 mg (yield 2%) was obtained, and subsequently, 5.0500 mg (yield 88%) of compound (3) as a colorless oil was obtained from a flow of ethyl ether:hexane=1:15→1:19 (volume).

[α)! -20,43° (c= 1.008.
CH(la3) elemental analysis C141-1ta O2 Theoretical value (%) Analytical value (%) IR1,1maX (neat) 'H-NMR (CDC13) δ: 1.09 (3H.

2.30-2.50 (2H.

2.81 (IH.

3.97 (2H.

CH 77,02B, 32 76.62 8.51 1725Cm-1 4.49 (2H, s) 5.50-5.74 (2H, m) 7.33 (5tl, S) 9, γ3
(1M, t, J=2.2tfz) MS
m/e: 218 (M”), 91 (1
00%) C14H+s O2 theoretical value 218.1307 analytical value 218.1287 <Synthesis of compound (4)> Triphenylphosphine 24.03 g (92.68 mm
1 carbon tetrabromide to 90 rIdl methylene chloride solution of
5.37!11 (46.34 mmol) was added under ice-cooling in an argon stream and stirred at the same temperature for 15 minutes.To this was added 5.05 g (23.1 mmol) of the compound (3) obtained above.
A solution of 7 mmol) of methylene chloride in ioml was added at the same temperature and stirred for 1 hour. The mixture was washed successively with diluted diluted with 200 ml of methylene chloride, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the resulting residue 44.94 (1) was dissolved in 300 d of ethyl ether and filtered through a glass filter. After distilling off the solvent under reduced pressure on the filtrate, the obtained residue 13.18 ( 1 was subjected to column chromatography using silica gel 400 (1),
Compound (4>7.67 g (yield: 89%) was obtained from a stream of ethyl ether:hexane=1:15 (volume).

[α] 萱-6.61° (c= 1.048.CHC
l3) IRvmax (neat) 1615cm
-1'H-NMR (CHCl13) δ: 1.05 (3H, d, J=6.4Hz
) 1.95~2.60 (3H, m) 3.99 (2N, m) 4.51 (2H, S) 5.51~5.69 <2tl, m) 6.38
(1H, t, J=7.1Hz)7.33
(5H, S) MS m/e: 374 (M”), 91
(100%) <Synthesis of compound (A)-1> (A)-1 Compound (4) obtained above γ, 61 g (20.3 m
mof) in a 150d solution of n- in tetrahydrofuran.
Butyl lithium (10% W/V n-hexane solution>2
7.5 m (46,8 m mol>) in an argon stream -7
The mixture was added at 8°C and stirred at the same temperature for 30 minutes. 50 d of water was added, extracted with ethyl ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
Column chromatography using silica gel 2001J was carried out to obtain 13.59 g of colorless oily compound (A) (
A yield of 82%) was obtained.

[α] Suga-6.40" (C= 1.000. CH
α3) Elemental analysis C+s Hsa O2 Cto1 Theoretical value (%) 84.07 8.47 Analysis value (
%) 84,34 8.47IR17max
(neat) 2140.3210cm-11H-
NMR (CDα3) δ: 1.12 3H, d, J=6.6Hz
>1.98 1H,t, J=2.4Hz)
2.09-2.28 2H,m) 2.36 1H,m) 4.00 2H,m) 4.51 2H,S) 5.58-5.78 2H,m> 7.33 5)1. S) MS m/e: 214 M”), 91
(100%) The optically active (R> compound (A)-1, which is one of the objects of the present invention obtained in this way,
Subsequently, as shown in the example below, it can be converted to compound (7), which is the raw material for producing compound (B), which is the northern hemisphere portion of milbemycin β2, through compound (5) and then compound (6). . An example of its synthesis is shown below.

<Synthesis of compound (5)> Zirconocene dichloride 1,86a (6,36m mol
) in a methylene chloride suspension of trimethylaluminum 2.
After adding 86 g (39.7 mmol) at room temperature in an argon stream and stirring for 15 minutes, a 5d methylene chloride solution of the compound (^)-11,70a (7.94 mmol) prepared above was added at the same temperature. Stirred for 13 hours. The solvent and trimethylaluminum were distilled off under reduced pressure (15 mmH
After room temperature and 0.5 mm 1 l (II 4 hours at 50° C.), the residue was extracted with n-hexane (15 dX 3 times) and transferred to another container using a cannula. In this container, n-butyl lithium (1.65 mol n-hexane solution>7.
22me (11,91m mol>) in an argon stream -
The mixture was added at 78°C and roughly stirred at -30°C for 30 minutes. ,
At this temperature (R>-(-)-epichlorohydrin 3.6
7g (39.7mnot) was added and stirred at -20°C for 12 hours. After adding 40 rIJl of saturated ammonium chloride water, the mixture was extracted with ethyl ether, washed successively with saturated sodium bicarbonate water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel 100.
The compound (
, 5) 1.750 (yield 68%) was obtained.

[α] 萱+9.80° (c= 1.016. CHα
3) Elemental analysis C-9H2702α CH (j! 70.68 8.43 10.9B 70.67 8.51 10.89 1665, 3450cnr1 Theoretical value (%) Analytical value (%) IRl/maX (neat) 'H -NMR (CDC13) δ: 0.96 (3H.

1.61 (31゜ 2.00 (2H.

2.28 (2H.

2.41 (IH.

d, J=6.3Hz) ・brs) d, J=6.8H2) t, J=7.3H2) d, J=4.9H2゜exchangeable with 020)2.
10-2.52 (IH, m) 3.28-3.88 (3H, m) 3.96 (2N, m) 4.49 (2H, S) 5.13 (1)1. t, J=7.3
H2) 5.43-5.68 (2tl, m) 7.3
3 (5tl, s) Synthesis of compound (6)> Compound (5) obtained above 438mg (1,36m
163 ma (4.07 mmol) of powdered sodium hydroxide was added to a solution of 5d of tetrahydrofuran in an argon stream at room temperature, and the mixture was stirred at the same temperature for 9 hours. After diluting with 60 d of ethyl ether, the mixture was washed three times with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to column chromatography using silica gel 159, and ethyl ether:hexane=
Compound (6) as a colorless oil from a 1:9 (volume) stream
362 mg (yield 93%) was obtained.

[α] 萱-3,35° (C= 1.014. CDC
f3) Elemental analysis Cl9H2BO2 Theoretical value (%) Analytical value (%) IRνmax (neat) 'H-NMR (CDCf3) δ: 0.95 (2H.

1.59 (3H.

1684-2.11 (2H.

2.13-2.40 (2H.

2.47 (IH.

2, 70 (il+.

2.90 (IH.

3.96 (2H.

4.4 & (2tl.

5.15 (IH.

H 79,689゜15 79.61 9.10 1670cnr1 d, J=6.4Hz) S) m) m) dd.

t.

m) d, J=4.9H2) S) t, J-7,1Hz) J=2.7Hz, 5.1Hz) J=4.9Hz) 5.413-5.67 (2H, m>7. 32 (58,3) MS m/e: 285 (M-1>, 9
1 (100%) C19H2502 theory @ 285.
1855 (M”-1>Analysis value 285°1894
(M”-1) Synthesis of compound (7)> Dimethyl sulfoxide 3 (7!) and sodium hydride (6
789 mO (19,7 mm mol) in 0% oil was added at room temperature under a stream of argon and heated to 70 °C until hydrogen evolution stopped (about 50 min). After returning 1 q of green clear solution to room temperature. , concentrated sulfuric acid and acetylene gas passed through a silica gel washing bottle were introduced for 40 minutes.To this was added compound (6) i, 41 g (4,93 m
A solution of 10 mol of dimethyl sulfoxide was added at room temperature and stirred for 4.5 hours. Add 50ml of water to the reaction solution under water cooling.
was added dropwise and extracted with ethyl ether. The ether layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The obtained residue was subjected to column chromatography using silica gel 70 (II), and from the flow of ethyl ether:hexane = 1:4 (volume), pale yellow oily compound (7) was obtained.
1.23 g (yield 80%) was obtained.

bp 196°C (0.5mm1g, Kuge
lrohr) (α) 萱+7.55° (C= 1.03
2. CHα3) Elemental analysis C2182802 C-1 Theoretical value (%) 80.73 9.03 Analysis value (
%) 80.70 9.22IRνmax
(neat) 1670.3310.3460cm-
1'H-NMR (CDC13) δ: 0.97 (3H, d, J=6.6H2
) 1.81 (3N, brs) 1.77-2.10 (3H, m) 2.17 (IH, d, J=5.1tlz.

exchangeable with C20)2.2
3-2.50 (5H, m) 3.75 1H, m) 3.95 2H, m) 4.50 2tl, s) 5.15 1H, t, J=7.1H2)5.
46~5.65 2N, m) 7.33 (51-1, s> MS m/e: 313 (M"+1>, 91
(100%) C21H2802 theoretical value 313.216
7 (M” +1>Analysis value 313.2182 (M
++1> The optically active (4R,9R) compound (7) obtained above is used as a raw material for producing compound (B), which is the northern hemisphere portion of milbemycin β2, as described above.

Next, the other raw material compound (17) for producing the above compound (B) was synthesized as in the following example.

<Synthesis of compound (9)> Compound (8) with optical purity of 100% ee 1.00 g
(5,21 mmol), n-butylammonium hydrogen sulfate 88 mg (0,26 mmol) and 60%
(W/V) Propargyl bromide 3.10a (26
,0 m mof> was added, and the mixture was stirred at room temperature in an argon stream for 26 hours. Water and ethyl ether were added to this, and the ether layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 1q of the residue was subjected to column chromatography using 50 g of silica gel, and ethyl ether:hexane = 1:50 (
0.917 g of colorless oily compound (9) from the stream of
(yield 77%).

bp 130'C (0.2mmt1g, Kuc+
elrohr) [α]″V −85,38″ (c=
1.040. CHCl3) Elemental analysis C+s H
t802 H Theoretical value (%) 78.23 7.88 Analysis value (
%) 77.58 7.90IRvmax
(neat) 2110cm-1'H-NMR (CD
(1!3) δ:1.73 (3tl, dd, J=1.
7Hz.

2.40 (IN, t, J=2.5Hz
) 3.45-3.60 (2N, III) 4.19
(21,t, J=2.5)1z)4.5
0-4.88 (ltl, m) 4.60 (
2H, s) 5.12~6.02 (2N, m) 7.33
(5+1.S) MS m/e: 189 (M" -CH=CH-
CH3).

91 (100%) 6.8Hz <Synthesis of compound (10)> Compound (9) obtained above 10. OOg(43,4
8m mof>tetrahydrofuran solution 92150 Ethylmagnesium bromide-tetrahydrofuran solution 83. '61rd (108.7 mmof) was added under ice-cooling in an argon stream, and after stirring at the same temperature for 3 hours, trimethylsilyl chloride 14.17a (130
．． 4 mmol) was added. Next, 50% of saturated aqueous ammonium chloride was added and extracted with ethyl ether, and the ether layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography using 250 g of silica gel, and ethyl ether:hexane=1:3
Compound (10) as a colorless oil from a stream of 0 (by volume)
12.23a (yield 93%) was obtained.

bp 130℃ (O12mmHg,
l rohr ) [α) V-80.74° (c= 1
．． 018, CI (43 elemental analysis Cl8H2BO2
S i H 71,47 8.66 71,44 8.72 2180 cm-1 Theoretical value (%) Analytical value (%) IR νmaX (neat) 1)-1-NMR (CDα3) δ: 0.18 (9H.

1, 71 (31.

3, 55-3.73 (2H.

4, 18 (2H.

4, 49-4.79 (IH.

4, 60 (2H.

5, 12-6.01 (2H.

7, 34 (5H.

MS m/e: 302 (M" C1BH2BO2 S 1 brs) dd, J=1.4Hz, 7.1Hz) m) d, J=2.9H2) m) S) m) S) ), 91 (100% ) Theoretical value 302.1703 (M”) Analytical value 302.
1711 (M”) <Synthesis of compound (11)> 1 MS 16.0 g of compound (10) obtained above (53
10 m mol> of tetrahydrofuran 200-solution
% (W/V) n-butyllithium 49. 7rd ( 7
9 mmol) was added at -80°C in an argon stream, and the mixture was stirred at the same temperature for 4 hours. After adding 50 d of saturated ammonium chloride water and extracting with ethyl ether, the ether layer was washed successively with saturated sodium bicarbonate water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography using 450 g of silica gel, and a colorless oily compound (11) i4.5 was extracted from a stream of ethyl ether:hexane=1 (volume). .

(yield 90%).

[α] 萱+18.91” (C= 0.624, C
HCe. 3) Elemental analysis Cl8H2BO2S 1 CH 71,478,66 71,298,73 2170, 3400 cm-1 Theoretical value (%) Analytical value (%) IRνmaX (neat) 'H-NMR (CD (J3) δ: 0.17 (9N, brs) 1.12
(3tf, d, J=6.8112)1
．． 86 (IH, d, J=7.4H2゜ex
changeable with D20)2.2
8-2.67 (IH, m) 3.94-4.08 (211, m) 4.24 (1)1. dd, J=6.8H
2,7,4112')4.52 (2N, S
) 5.61~5.82 (21'1. m) 7.33
(5H, S) MS m/e: 301 (M"-1>, 91
(100%) <Synthesis of compound (12)> 1. Compound (11) obtained above 1.77 g (5,86
17.6 rnll of tetra-n-butylammonium fluoride-tetrahydrofuran solution with a concentration of 1.0 mol) in 20 rnl of tetrahydrofuran (17,
6 mmol> was added at the very temperature, and the mixture was stirred for 8 minutes at the same temperature in an argon stream. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography using silica gel 30i), and a colorless oily compound (12) 1. 29Q (
A yield of 96% was obtained.

bp 125℃ (0.2mmHg, Kugel
rohr) [α] 萱+18.15° (C= 1.14
6. CtlCb > IRνmax (neat)
2100.3500cm-1'H-NMR (CD(1
'3) δ:1.12 (3H, d, J=7.1)1
2) t, 82~2.10 (ltf, brs
, exchangeable with 020) 2.30~2.70 (IH, m) 4.26 (IH, dd, J=2.3H2,
5,1H2) 4.51 (2H,S) 5.88~5.82 (2H,m> 7.30 (511,S) MS m/e: 230 (M”), 91
(100%) C1s Hto 02 Theoretical value 230.
1307 (M+) Analysis value 230.1293 (M
) <Synthesis of compound (13)> The compound obtained above (12> 49.3 mg (0,21
Benzoic acid 34.0 mg (0,278 mmol), triphenylphosphine 84.0 mg (0,321 m not ) in a tetrahydrofuran 2d solution of 4 mm01)
and diisopropyl azodicarboxylate 64.9 mg (0
, 321 mmol) were sequentially added under water cooling in an argon stream, and the mixture was stirred at the same temperature for 35 minutes.

The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel 1.
53.4 mg (yield 75%) of compound (13) as a colorless oil was obtained from a flow of ethyl ether:hexane=1:15 (volume).

bp 1N2℃ (0.04mmh,
rohr) [α)9-31.74° (C=t,
008. C3 (1' 3 ) elemental analysis C22H
2203 Cl-1 79,016□63 79.21 6.73 1720, 2130.3290 cm-1 Theoretical value (%) Analytical value (%) IRljmaX (neat) 1H-NMR (CDα3) δ: 1.25 (3N, d, J=6.8
NZ >2.49 (IH, d, J=2.2
H1') 2.78 (111, m> 4.00 (2H, III) 4.47 (20, S) 5.54 (IH, dd, J=2.2H2,
6, IH2) 5.68~5.84 (2N, m>7
．． 30 (5H, S) 7.38-7.70 (3H, m) 7.95-8.16 (2H, m) MS m/e: 334 (M10), 91
(100%) C221-12203 theoretical value 334.1
568 (M”) Analysis value 334.1535 (M
+ ) <Synthesis of compound (14)> Compound (13) obtained above 2.776 g (8,31
1.723 g (12.47 mmol) of potassium carbonate was added to a methanol 20rf11 solution of 1 mmof), and the mixture was stirred for 1 hour at temperature in an argon stream. The solvent was distilled off under reduced pressure, ethyl ether and water were added, and the mixture was shaken.
The ether layer was separated. After washing with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography using 80 g of silica gel. Ethyl ether:hexane=1: Compound (14) as a colorless oil from a stream of 4 (by volume)
1.858 g (yield 97%) was obtained.

bp 162℃ (0.3mmHg,
rohr) (α) 9-15.38° (C= 1.0
14. CHc123) Elemental analysis Css Hto
O2 theoretical value analysis value IRνmax IH-NMR δ: 1.15 1.98 2.47 2.50 IH (%) 78.23 7.88 (%)
78.22 8.03 (neat) 2120.3
280.3380cm-1 (CD(J!3) (3H, d, J=6.8H2) (11,brd, J=5.9H2゜exchange
easy with D20) (IH, d,
J=2.2H2) (IH, m) 4.02 (28, III) 4.22 (Ill, dd, J=2.2t
lz, 5.9Hz >4.52 (2H,
S) 5.65-5.82 (28, III) 7.33 (5H, S) MS m/e: 230 (M”), 91
(100%) C+s H1e O2 theoretical value 230.13
07 (M”) Analysis value 230.1338 (M”
) <Synthesis of compound (15)> Compound (14) obtained above 1.450 g (6,3
A solution of 44 mQ of platinum (IV) dioxide in 10 mg of vinegar Ml-) was suspended and stirred at temperature in a hydrogen stream for 4.5 hours. After filtration through Celite, the solvent was distilled off under reduced pressure to obtain a crude product (Compound (15>>1.55%).

The analysis results of compound (15), which was obtained by purifying the above crude product by silica gel column chromatography, were as follows.

bp 157℃ (0, lmmHg,
l rohr ) [α]″g-7,72° (c= 1
．． 010. CHCf'3) Elemental analysis C15H24
02 IH 76,2210,24 75,8410,64 3340cnrl Theoretical value (%) Analytical value (%) IR1,1lIlaX (neat)11-1-NM
R(CDα3) δ: 0.89 (3H, d.

0.95 (3H, t.

1.08-2.80 (8H, III.

with 02 3.20-3.58 (2H, m) 4.50 (2H, s) 7.32 (5H,s) MS m/e: 236 (M 10).

J=6.6H2) J=7.8Hz > 1N, exchangeable O) 91 (100%) <Synthesis of compound (16)> The crude product obtained above (compound (15)>1.427(
Pd(OH)27 in a 10rnl methanol solution of J
1 mg was suspended and stirred at room temperature in a hydrogen stream for 4.5 hours. After filtration through Celite, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography using 25 (l) of silica gel, ethyl ether:hexane = 2:1 (
Compound (16) 833 mg (yield 98
% (compound (14): 1)).

bp 105℃ (0.2mmf1g, Kugel
rohr) [α] 萱-7.93° (C= 1.008
．． CH (1'3) elemental analysis C881802 CH Theoretical value (%) 65.71 12.41 Analysis value (%) 65.44 12.58IRymax
(neat) 3340cm-1'H-NMR (
CDC13) δ: 0.90 (3H, d, J=6.6H
2) 0.96 (3H, t, J=8.1H
z) 1.08~1.84 (7H, m) 1.76 (2N, s, exchange
easy withD20) 3.36 (IH, ddd, J= 3.9t
! z.

5, IH2,,8,4)12) 3.65 (2H, m') MS m/e: 147 (M"+1>, 70
(100%) CeHsoO2 theoretical value 146.1307
Analysis value 146.1311 <Synthesis of compound (17)> Compound (16) obtained above 740 m (1 (5,06
9 mmol) 10th! Suspend 444 mq of platinum black in emulsion water, add 3 drops of concentrated hydrochloric acid, and stir at 55°C in an oxygen stream for 13 min.
Stir for hours. After adding ethyl ether to this, it was filtered through Celite, and the filtrate was roughly diluted with ethyl ether, and then the ether layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was 850 mg of benzene 15 mf! The solution was heated under a stream of argon under Dean-
The mixture was heated under reflux for 1.5 hours using a 3tark apparatus.

The reaction solution was washed successively with saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure,
The obtained residue was subjected to column chromatography using 25 g of silica gel, and ethyl ether:hexane=1
:Compound (17) from a stream of 4 (volume) 558ma
(yield 78%).

bp 126℃ (17mmHg, Kugelro
hr) (α) 萱+49.32° (C= 1.034.
CHCl3) Elemental analysis C(lH+402 CH Theoretical value (%) 67.57 9.93 Analysis value (
%) 67.28 10.09IR17max
(neat) t730cm-''t-f-NM
R (CDC13) δ: 0.99 (3H, d, J=4.6H7
)1.03 (3H, t, J=5.4H2
) 1.20-2.09 (5H, m> 2.20-2.87 (2H, m) 3.90 (IH, ddd, J=3.4Hz.

6.9l-1z, 9.4Hz) MS m/e: 143 (M" +t), 56
(100%) CBH+402 Theoretical value 142.09
94 (M+) Analysis value 142.0991 (M+
) The thus obtained optically active (48,5R) compound (17) and the optically active (4R,9R) compound (7) are synthesized using the synthetic route I using these as raw materials.
According to V, it can be converted to compound (B), which is the northern hemisphere portion of milbemycin β2, via compound (18) and compound (19).

(Effects of the Invention) The optically active compound of the present invention is important as an intermediate capable of synthesizing naturally occurring milbemycin β2.

Claims (2)

[Claims] (1) An optically active compound represented by the following formula (A). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(A) In the above formula (A), Bn represents a benzyl group, *
The symbol represents an asymmetric carbon atom. (2) The compound of formula (A) according to claim 1 has optical activity (R)
A compound that is a body.