JP2596825B2 - Optically active compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (INDUSTRIAL FIELD) The present invention relates to optically active compounds which are intermediates for the milbemycin (Milbemycin) beta ₂ production which is known as being effective in parasitic diseases of livestock . More particularly, to intermediates for making compounds represented by the following formula is a northern hemisphere part of the milbemycin beta ₂ represented by the following formula (B).

The milbemycin beta ₂ (issues to be prior art and resolution) is known as a naturally occurring compound, generally the compounds of the naturally occurring with unique properties such as mentioned above are often optically active form. Although these substances exert their effects in extremely small amounts, the extraction from natural products is inefficient because of the extremely small amounts produced from nature, and their utility is poor. Therefore, it is very significant that this is mass-produced by synthesis.

(SUMMARY for a) the present invention is to provide an optically active compound represented by the following formula as an intermediate for the production of milbemycin beta ₂ (A).

That is, the present invention provides the following formula (A) (In the above formula (A), the symbol * represents an asymmetric carbon atom.) Among the compounds represented by the formula (1), they are trans-form (4S, 5R) optically active compounds.

The compound represented by the above formula (A) has the following four types of optical isomers.

The present invention, the four types of intermediate become trans for milbemycin beta ₂ production of the optical isomers (4S, 5
R) Compounds are provided.

A method for synthesizing the (4S, 5R) compound of the compound of the formula (A) will be described below according to synthesis route I. However, in the following, TM
S represents a trimethylsilyl group, Bn represents a benzyl group, and ph represents a phenyl group.

Optically active (R) compound (1) as the starting material
Can be obtained by known methods (Takano, Sekiguchi, Sato, Ogasawara: Synthesis 1987, 139).

The compound (1) 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 (2) is synthesized by reacting with propargyl halide such as propargyl bromide and iodide propargyl. The compound (2) is reacted with a halogenated trimethylsilane such as trimethylsilane in the presence of a base such as n-butyllithium, lithium hydride, sodium hydride or Grignard reagent to convert the compound into a compound (3). Compound (3) is rearranged in a solvent such as tetrahydrofuran, ethyl ether or dimethoxyethane in the presence of a base such as n-butyllithium to give compound (4), and then compound (4) is converted into tetrahydrofuran, ethyl ether or dimethoxyethane. Fluoride reagents such as potassium fluoride, hydrogen fluoride, and tetra-n-butylammonium fluoride in a solvent such as water, chloroform, methylene chloride, and carbon tetrachloride remove the trimethylsilyl group (TMS) to react with compound (5). I do. The 3-position hydroxyl group of the compound (5) is esterified to give a compound (6), which is then treated with a base to invert the compound (7).
Convert to This is hydrogenated in the presence of platinum (IV) oxide to give compound (8), and further palladium (II) hydroxide
Hydrogenolyses in the presence of to give compound (9). When this compound (9) is treated with an acid in the presence of platinum black, an optically active (4S, 5R) compound (A) -1 is obtained.

Thus obtained optically active (4S, 5R) body of Compound (A) -1 is a raw material for producing the compound is a northern hemisphere part of the milbemycin beta ₂ and (B). In the above synthesis method, (S) was used as the starting compound (1).
When the compound of the form is used, the compound of formula (A) -2 of the optically active (4R, 5S) form can be obtained in the same manner. This can be expected as an optically active compound as a raw material for synthesizing various useful compounds.

As a raw material for preparing the compound is a northern hemisphere part of the milbemycin beta ₂ a (B), in addition to the above-mentioned compound (A) -1, the compounds obtained according to the following synthesis route II (17) is used. In the following, Bn represents a benzyl group and Et represents an ethyl group.

Optically active (S) compound (10) as the starting material
Can be obtained by known methods (Takano, Sekiguchi, Sato, Ogasawara: Synthesis 1987, 139).

Compound (10) is reacted with triethyl orthoacetate and piperic acid to give compound (11), which is reduced with diisobutylaluminum hydride to give compound (12). Next, the compound (12) is reacted with triphenylphosphine and carbon tetrabromide to obtain a compound (13).
-React with butyllithium to give compound (14). Next, compound (14) is reacted with (R)-(-)-epichlorohydrin to synthesize compound (15), which is treated with a base to form compound (16), and acetylene gas is reacted therewith. Thus, the optically active (4R, 9R) compound (17) can be obtained. As the above optically active epichlorohydrin, those having high optical purity are disclosed in Japanese Patent Application Laid-Open No.
And Japanese Patent Application Laid-Open No. Sho 62-6669 or Japanese Patent Application No. 63-2848.
Those obtained by the method described in the specification of Japanese Patent No. 81 can be used.

The compound (B) can be synthesized by using the compound (A) -1 and the compound (17) as raw materials according to the following synthesis route III. In the following, Bn is a benzyl group,
TBDMS represents a t-butyldimethylsilyl group.

In the above reaction, n-butyllithium is added to compound (17) for reaction, then compound (A) -1 is reacted, and the hydroxyl group is protected with silyl ether to give compound (18). This is reduced to a cis olefin, then selectively epoxidized, and further reduced to open the ring to give compound (19). When the compound (19) is reacted with a fluorine reagent to remove the silyl group, the compound (B) and its epimer are obtained. This epimer can be converted to the compound (B) by oxidizing it to a spiro ketone and then reducing it with hydride. The compound (B) is equivalent to the optically active northern part of milbemycin beta _2, is an important intermediate for the production of milbemycin beta _2.

The optical activity (4S, 5
In place of the compound (A) -1 in the R) form and the compound (17) in the optically active (4R, 9R) form, the respective (4R, 5S) compounds (A) -2 and (4S , 9S) compound (1
If 7 ′) is used, compound (B ′) which is an optical isomer of compound (B) can be obtained. The above (4S, 9S) compound (1
7 ′) is the starting compound (10)
Was used in place of (R) -form compound, and (R)-(-) was used in the reaction from compound (14) to compound (15).
It can be produced in the same manner as described above using (S)-(+)-epichlorohydrin instead of -epichlorohydrin.

(Examples) Example 1 <Synthesis of Compound (2)> 1.00 g (5.21mmo) of compound (1) having an optical purity of about 100% ee
l), 88 mg of n-butylammonium hydrogen sulfate (0.26 mmol
l) and 3.10 g (26.0 mm) of propargyl bromide in a mixture of 20 ml of a 60% (W / V) aqueous sodium hydroxide solution under ice-cooling.
ol), and the mixture was stirred at room temperature in an argon stream for 26 hours. Water and ethyl ether were added thereto, and the ether layer was separated, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography using 50 g of silica gel, and 0.917 g of a colorless oily compound (2) was obtained from a stream of ethyl ether: hexane = 1: 50 (volume). (77% yield).

bp 130 ° C (0.2 mmHg, Kugelrohr) ▲ [α] ²⁵ _D ▼ -85.38 ゜ (c = 1.040, CHCl ₃ ) Elemental analysis C ₁₅ H ₁₈ O ₂ CH Theoretical value (%) 78.23 7.88 Analytical value (%) 77.58 ^{7.90 IR νmax (neat) 2110cm -1} 1 H-NMR (CDCl 3) δ: 1.73 (3H, dd, J = 1.7Hz, 6.8Hz) 2.40 (1H, t, J = 2.5Hz) 3.45~3.60 (2H, m) 4.19 (2H, t, J = 2.5 Hz) 4.50 to 4.88 (1H, m) 4.60 (2H, s) 5.12 to 6.02 (2H, m) 7.33 (5H, s) MS m / e: 189 (M ⁺ _{-CH = CH-CH 3),} < synthesis of compound (3)> 91 (100%) To a solution of 10.00 g (43.48 mmol) of the obtained compound (2) in 150 ml of tetrahydrofuran was added 83.61 ml of a 1.3 mol solution of ethyl magnesium bromide in tetrahydrofuran.
(108.7 mmol) in an argon stream under ice cooling, and the mixture was stirred at the same temperature for 3 hours, and then trimethylsilyl chloride 14.1 was added.
7 g (130.4 mmol) were added. Subsequently, 50 ml of a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl ether. The ether layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography using 250 g of silica gel, and ethyl ether: hexane = 1: 30 (by volume).
12.23 g (93% yield) of a colorless oily compound (3) from the stream
I got

bp 130 ° C (0.2 mmHg, Kugelrohr) ▲ [α] ²⁷ _D ▼ -80.74 ゜ (c = 1.018, CHCl ₃ ) Elemental analysis C ₁₈ H ₂₆ O ₂ Si CH Theoretical value (%) 71.47 8.66 Analytical value (%) 71.44 8.72 IR νmax (neat) 2180cm -1 1 H-NMR (CDCl 3) δ: 0.18 (9H, brs) 1.71 (3H, dd, J = 1.4Hz, 7.1Hz) 3.55~3.73 (2H, m) 4.18 ( 2H, d, J = 2.9Hz) 4.49 to 4.79 (1H, m) 4.60 (2H, s) 5.12 to 6.01 (2H, m) 7.34 (5H, s) MS m / e: 302 (M ⁺ ), 91 ( _{100%) C 18 H 26 O} 2 Si theory 302.1703 (M ⁺⁾ analysis value 302.1711 (M ⁺⁾ <synthesis of compound (4)> To a solution of 16.0 g (53 mmol) of the compound (3) obtained above in 200 ml of tetrahydrofuran, 49.7 ml (79 mmol) of 10% (w / v) n-butyllithium was added at -80 ° C in an argon stream to obtain a solution.
The mixture was stirred at the same temperature for hours. 50 ml of a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl ether. The ether layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography using 450 g of silica gel, and 14.5 g of a colorless oily compound (4) was obtained from a stream of ethyl ether: hexane = 1: 7 (volume). (90% yield).

▲ [α] ²⁴ _D ▼ + 18.91 ゜ (c = 0.624, CHCl ₃ ) Elemental analysis C ₁₈ H ₂₆ O ₂ Si CH Theoretical value (%) 71.47 8.66 Analytical value (%) 71.29 8.73 IR νmax (neat) 2170 ^{, 3400cm -1 1 H-NMR (} CDCl 3) δ: 0.17 (9H, brs) 1.12 (3H, d, J = 6.8Hz) 1.86 (1H, d, J = 7.4Hz, exchangeable with D
₂ O) 2.28 to 2.67 (1H, m) 3.94 to 4.08 (2H, m) 4.24 (1H, dd, J = 6.8 Hz, 7.4 Hz) 4.52 (2H, s) 5.67 to 5.82 (2H, m) 7.33 (5H , s) MS m / e: 301 (M ⁺ -1), 91 (100%) <Synthesis of compound (5)> To a solution of 1.77 g (5.86 mmol) of the compound (4) obtained above in 20 ml of tetrahydrofuran, tetrafluorofuran having a concentration of 1.0 mol was added.
n-butylammonium-tetrahydrofuran solution 17.6
ml (17.6 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 8 minutes in a stream of argon. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography using 30 g of silica gel to obtain 1.29 g of a colorless oily compound (5) from a stream of ethyl ether: hexane = 1: 7 (volume). (96% yield).

bp 125 ℃ (0.2mmHg, Kugelrohr) ▲ [α] ²⁶ _D ▼ + 18.15 DEG _{(c = 1.146, CHCl 3)} IR νmax (neat) 2100,3500cm -1 1 H-NMR (CDCl 3) δ: 1.12 ( 3H, d, J = 7.1Hz) 1.82~2.10 (1H, brs, exchangeable with D 2 O) 2.30~2.70 (1H, m) 4.26 (1H, dd, J = 2.3Hz, 5.1Hz) 4.51 (2H, s ) 5.68~5.82 (2H, m) 7.30 (5H, s) MS m / e: 230 (M +), 91 (100%) C 15 H 18 O 2 theory 230.1307 (M ⁺⁾ analysis value 230.1293 (M ⁺ <Synthesis of Compound (6)> To a solution of 49.3 mg (0.214 mmol) of the obtained compound (5) in 2 ml of tetrahydrofuran was added 34.0 mg (0.278 mmol) of benzoic acid.
l), triphenylphosphine 84.0 mg (0.321 mmol) and diisopropyl azodicarboxylate 64.9 mg (0.321 mmol
l) were sequentially added under ice-cooling in a stream of argon, and the mixture was stirred at the same temperature for 35 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography using 15 g of silica gel to obtain 53.4 mg of compound (6) as a colorless oil from a stream of ethyl ether: hexane = 1: 15 (volume). (75% yield).

bp 182 ° C (0.04 mmHg, Kugelrohr) ▲ [α] ²⁵ _D ▼ -31.74 ゜ (c = 1.008, CHCl ₃ ) Elemental analysis C ₂₂ H ₂₂ O ₃ CH Theoretical value (%) 79.01 6.63 Analytical value (%) 79.21 ^{6.73 IR νmax (neat) 1720,2130,3290cm -1} 1 H-NMR (CDCl 3) δ: 1.25 (3H, d, J = 6.8Hz) 2.49 (1H, d, J = 2.2Hz) 2.78 (1H, m ) 4.00 (2H, m) 4.47 (2H, s) 5.54 (1H, dd, J = 2.2Hz, 6.1Hz) 5.68-5.84 (2H, m) 7.30 (5H, s) 7.38-7.70 (3H, m) 7.95 ~8.16 (2H, m) MS m / e: 334 (M +), 91 (100%) synthesis of C ₂₂ H ₂₂ O ₃ theory 334.1568 (M ⁺⁾ analysis value 334.1535 (M ⁺⁾ <compound (7) 〉 1.723 g (12.74 mmol) of potassium carbonate was added to a solution of 2.776 g (8.311 mmol) of the compound (6) obtained above in 20 ml of methanol.
Was added and stirred at room temperature for 1 hour in a stream of argon. The solvent was distilled off under reduced pressure, ethyl ether and water were added, and the mixture was shaken, and the ether layer was separated. Next, the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography using 80 g of silica gel to give ethyl ether: hexane = 1: 1. Colorless oily compound (7) from a stream of 4 (volume)
1.858 g (97% yield) was obtained.

bp 162 ° C. (0.3 mmHg, Kugelrohr) ▲ [α] ²⁵ _D -15.38 ゜ (c = 1.014, CHCl ₃ ) Elemental analysis C ₁₅ H ₁₈ O ₂ CH Theoretical value (%) 78.23 7.88 Analytical value (%) 78.22 ^{8.03 IR νmax (neat) 2120,3280,3380cm -1} 1 H-NMR (CDCl 3) δ: 1.15 (3H, d, J = 6.8Hz) 1.98 (1H, brd, J = 5.9Hz, exchangeable with
_{D 2 O) 2.47 (1H,} d, J = 2.2Hz) 2.50 (1H, m) 4.02 (2H, m) 4.22 (1H, dd, J = 2.2Hz, 5.9Hz) 4.52 (2H, s) 5.65~5.82 (2H, m) 7.33 (5H , s) MS m / e: 230 (M +), 91 (100%) C 15 H 18 O 2 theory 230.1307 (M ⁺⁾ analysis value 230.1338 (M ⁺⁾ <compound ( 8) Synthesis> 44 mg of platinum (IV) oxide was suspended in a solution of 1.450 g (6.30 mmol) of the obtained compound (7) in 10 ml of ethyl acetate, and the mixture was stirred at room temperature in a hydrogen stream for 4.5 hours. After filtration through celite, the solvent was distilled off under reduced pressure to give 1.554 g of a crude product (compound (8)).
I got

The analysis results of the compound (8) obtained by purifying the above crude product by silica gel column chromatography were as follows.

bp 157 ° C (0.1 mmHg, Kugelrohr) ▲ [α] ²² _D ▼ -7.72 ゜ (c = 1.010, CHCl ₃ ) Elemental analysis C ₁₅ H ₂₄ O ₂ CH Theoretical value (%) 76.22 10.24 Analytical value (%) 75.84 ^{10.64 IR νmax (neat) 3340cm -1} 1 H-NMR (CDCl 3) δ: 0.89 (3H, d, J = 6.6Hz) 0.95 (3H, t, J = 7.8Hz) 1.08~2.80 (8H, m, 1H , exchangeable with D ₂ O) 3.20 to 3.58 (2H, m) 4.50 (2H, s) 7.32 (5H, s) MS m / e: 236 (M ⁺ ), 91 (100%) <Synthesis of compound (9) 〉 71 mg of Pd (OH) ₂ was suspended in a solution of 1.427 g of the obtained crude product (compound (8)) in 10 ml of methanol, and the mixture was stirred at room temperature for 4.5 hours in a hydrogen stream. After filtration through celite, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography using 25 g of silica gel to give ethyl ether:
Hexane = 833 mg of compound (9) from a stream of 2: 1 (volume)
(Yield 98% (based on compound (7)) was obtained.

bp 105 ° C (0.2 mmHg, Kugelrohr) ▲ [α] ²⁴ _D ▼ -7.93 ゜ (c = 1.008, CHCl ₃ ) Elemental analysis C ₈ H ₁₈ O ₂ CH Theoretical value (%) 65.71 12.41 Analytical value (%) 65.44 ^{12.58 IR νmax (neat) 3340cm -1} 1 H-NMR (CDCl 3) δ: 0.90 (3H, d, J = 6.6Hz) 0.96 (3H, t, J = 8.1Hz) 1.08~1.84 (7H, m) 1.76 (2H, s, exchangeable with D ₂ O) 3.36 (1H, ddd, J = 3.9Hz, 5.1Hz, 8.4Hz) 3.65 (2H, m) MS m / e: 147 (M ⁺ +1), 70 (100% ) <synthesis of compound _{(a) -1> C 8 H} 18 O 2 theory 146.1307 analysis 146.1311 10m of 740 mg (5.069 mmol) of the compound (9) obtained above
l Suspended 444 mg of platinum black in emulsified water, added 3 drops of concentrated hydrochloric acid,
The mixture was stirred in an oxygen stream at 55 ° C. for 13 hours. Ethyl ether was added thereto, and the mixture was filtered through celite. The filtrate was further diluted with ethyl ether, and the ether layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and a solution of 850 mg of the resulting residue in 15 ml of benzene was added to a stream of Dea in an argon stream.
The mixture was heated under reflux for 1.5 hours with an n-Stark apparatus. The reaction solution was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to column chromatography using 25 g of silica gel, and ethyl ether: hexane = 1: 4 (by volume).
Of the compound (A) -1 (558 mg, yield 78%).

bp 126 ° C (17 mmHg, Kugelrohr) ▲ [α] ²⁶ _D ▼ +49.32 ゜ (c = 1.034, CHCl ₃ ) Elemental analysis C ₈ H ₁₄ O ₂ CH Theoretical value (%) 67.57 9.93 Analytical value (%) 67.28 ^{10.09 IR νmax (neat) 1730cm -1} 1 H-NMR (CDCl 3) δ: 0.99 (3H, d, J = 4.6Hz) 1.03 (3H, t, J = 5.4Hz) 1.20~2.09 (5H, m) 2.20 ~2.87 (2H, m) 3.90 ( 1H, ddd, J = 3.4Hz, 6.9Hz, 9.4Hz) MS m / e: 143 (M + +1), 56 (100%) C 8 H 14 O 2 theory 142.0994 (M ⁺ ) Analytical value 142.0991 (M ⁺ ) Compound (A)-of optically active (4S, 5R) obtained above
1 is used as a raw material for producing a northern part of compounds of the milbemycin beta ₂ (B) is as described above.

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

<Synthesis of Compound (11)> To 7.09 g (36.9 mmol) of compound (10), 30.0 g (185 mmol) of triethyl orthoacetate and 226 mg of pivalic acid (2.
21 mmol), and heated at 140 ° C. for 12 hours in a stream of argon with a Dean-Stark apparatus. The triethyl orthoacetate was distilled off under reduced pressure.
The residue was subjected to column chromatography using 0 g to obtain 7.12 g (yield 73%) of compound (11) as a colorless oil from a stream of ethyl ether: hexane = 1: 20 (volume).

Elemental analysis C ₁₆ H ₂₂ O ₃ C H Theoretical Value (%) 73.25 8.45 Analytical values (%) 73.03 8.51 IR νmax ( neat) 1730cm -1 1 H-NMR (CDCl 3) δ: 1.07 (3H, d, J = 6.6Hz) 1.24 (3H, t, J = 7.1Hz) 2.03 to 2.04 (3H, m) 3.97 (2H, d) 4.12 (2H, q, J = 7.1Hz) 4.49 (2H, s,) 5.54 to 5.72 ( 2H, m) 7.33 (5H, s) MS m / e: 155 (M ⁺ -OBn), 91 (100%) <Synthesis of compound (12)> To a solution of 6.944 g (26.30 mmol) of the obtained compound (11) in 200 ml of toluene, 3.741 g (26.30 mmol) of diisobutylaluminum hydride was added at -90 ° C in an argon stream, followed by stirring at the same temperature for 1 hour. After 1N hydrochloric acid was added and the mixture was extracted with ethyl ether, the ether layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to column chromatography using 200 g of silica gel, and 144 mg of the starting compound (11) (yield) was obtained from a stream of ethyl ether: hexane = 1: 15 (volume). 2%), and 5.050 g (88% yield) of a colorless oily compound (12) was obtained from a stream of ethyl ether: hexane = 1: 15 → 1: 19 (volume).

▲ [α] ²⁶ _D ▼ -20.43 ゜ (c = 1.008, CHCl ₃ ) Elemental analysis C ₁₄ H ₁₈ O ₂ CH Theoretical value (%) 77.02 8.32 Analytical value (%) 76.62 8.51 IR νmax (neat) 1725 cm ^{−1 1} H-NMR (CDCl ₃ ) δ: 1.09 (3H, d, J = 6.6 Hz) 2.30 to 2.50 (2H, m) 2.81 (1H, m) 3.97 (2H, m) 4.49 (2H, s) 5.50 to 5.74 (2H, m) 7.33 (5H , s) 9.73 (1H, t, J = 2.2Hz) MS m / e: 218 (M +), 91 (100%) C 14 H 18 O 2 theory 218.1307 analysis 218.1287 <Synthesis of Compound (13)> 15.37 g (46.34 mmol) of carbon tetrabromide was added to a solution of 24.03 g (92.68 mmol) of triphenylphosphine in 90 ml of methylene chloride under ice-cooling in a stream of argon, and the mixture was stirred at the same temperature for 15 minutes. 5.05 g of the compound (12) obtained above (23.17 mmol
l) A methylene chloride solution (10 ml) was added at the same temperature and stirred for 1 hour. After dilution with 200 ml of methylene chloride, saturated aqueous sodium hydrogen carbonate,
The extract was washed successively with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, 44.94 g of the obtained residue was dissolved in 300 ml of ethyl ether and filtered with a glass filter. The solvent was distilled off under reduced pressure from the filtrate, and the obtained residue was obtained.
13.18 g was subjected to column chromatography using 400 g of silica gel, and ethyl ether: hexane = 1: 15 (volume).
7.67 g (89% yield) of compound (13) was obtained from the stream.

▲ [α] ²⁶ _D ▼ -6.67 DEG _{(c = 1.048, CHCl 3)} IR νmax (neat) 1615cm -1 1 H-NMR (CDCl 3) δ: 1.05 (3H, d, J = 6.4Hz) 1.95~2.60 (3H, m) 3.99 (2H, m) 4.51 (2H, s) 5.51 to 5.69 (2H, m) 6.38 (1H, t, J = 7.1Hz) 7.33 (5H, s) MS m / e: 374 (M ⁺ ), 91 (100%) <Synthesis of compound (14)> In a solution of 7.61 g (20.3 mmol) of the compound (13) obtained above in 150 ml of tetrahydrofuran, n-butyllithium (10
% W / V n-hexane solution) (27.5 ml, 46.8 mmol) was added at -78 ° C in an argon stream, followed by stirring at the same temperature for 30 minutes. Water 50
After adding ml, the mixture was extracted with ethyl ether, washed with brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using 200 g of silica gel, and ethyl ether: hexane = 1: 50 (volume).
3.59 g (82% yield) of a colorless oily compound (14) from the stream
I got

▲ [α] ²⁹ _D ▼ -6.40 ゜ (c = 1.000, CHCl ₃ ) Elemental analysis C ₁₅ H ₁₈ O ₂ CH Theoretical value (%) 84.07 8.47 Analytical value (%) 84.34 8.47 IR νmax (neat) 2140,3210cm _{^{-1 1 H-NMR (CDCl 3}} ) 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 to 5.78 (2H, m) 7.33 (5H, s) MS m / e: 214 (M ⁺ ), 91 (100%) <Synthesis of compound (15)> To a suspension of 1.86 g (6.36 mmol) of zirconocene dichloride in methylene chloride, 2.86 g (39.7 mmol) of trimethylaluminum
Was added at room temperature in an argon stream, and the mixture was stirred for 15 minutes. At the same temperature, a solution of 1.70 g (7.94 mmol) of the compound (14) obtained above in 5 ml of methylene chloride was added, and the mixture was stirred for 13 hours. The solvent and trimethylaluminum were distilled off under reduced pressure (15 mmHg room temperature and
After 0.5 mmHg at 50 ° C for 4 hours, the residue was washed with n-hexane (15 m
1 × 3 times) and transferred to another container using a cannula. Into this container, 7.22 ml (11.91 mmol) of n-butyllithium (1.65 mol of n-hexane solution) was introduced in an argon stream.
The mixture was added at 78 ° C, and further stirred at -30 ° C for 30 minutes. At this temperature, 3.67 g of (R)-(-)-epichlorohydrin (39.7 mm
ol) and stirred at -20 ° C for 12 hours. After adding 40 ml of a saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl ether, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography using 100 g of silica gel, and 1.75 g (yield) of compound (15) was obtained from a stream of ethyl ether: hexane = 1: 9 (volume). 68%).

▲ [α] ²⁴ _D ▼ + 9.80 ゜ (c = 1.016, CHCl ₃ ) Elemental analysis C ₁₉ H ₂₇ O ₂ Cl CHCl Theoretical value (%) 70.68 8.43 10.98 Analytical value (%) 70.67 8.51 10.89 IR νmax ( ^{neat) 1665,3450cm -1 1 H-NMR} (CDCl 3) δ: 0.96 (3H, d, J = 6.3Hz) 1.61 (3H, brs) 2.00 (2H, d, J = 6.8Hz) 2.28 (2H, t , J = 7.3Hz) 2.41 (1H, d, J = 4.9Hz, exchangeable with D ₂
O) 2.10 to 2.52 (1H, m) 3.28 to 3.88 (3H, m) 3.96 (2H, m) 4.49 (2H, s) 5.13 (1H, t, J = 7.3Hz) 5.43 to 5.68 (2H, m) 7.33 (5H, s) <Synthesis of Compound (16)> 163 mg of powdered sodium hydroxide was added to a solution of 438 mg (1.36 mmol) of the compound (15) obtained above in 5 ml of tetrahydrofuran.
(4.07 mmol) at room temperature in an argon stream and stirred at the same temperature for 9 hours. After dilution with 60 ml of ethyl ether, the mixture was washed three times with a saturated saline solution and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to column chromatography using 15 g of silica gel, and 362 mg (yield) of a colorless oily compound (16) was obtained from a stream of ethyl ether: hexane = 1: 9 (volume). 93%).

▲ [α] ²⁴ _D ▼ -3.35 ゜ (c = 1.014, CHCl ₃ ) Elemental analysis C ₁₉ H ₂₆ O ₂ CH Theoretical value (%) 79.68 9.15 Analytical value (%) 79.61 9.10 IR νmax (neat) 1670 cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 0.95 (2H, d, J = 6.4 Hz) 1.59 (3H, s) 1.84 to 2.11 (2H, m) 2.13 to 2.40 (2H, m) 2.47 (1H, dd, J = 2.7Hz, 5.1Hz) 2.70 (1H, t, J = 4.9Hz) 2.90 (1H, m) 3.96 (2H, d, J = 4.9Hz) 4.48 (2H, s) 5.15 (1H, t, J = 7.1) Hz) 5.48~5.67 (2H, m) 7.32 (5H, s) MS m / e: 285 (M + -1), 91 (100%) C 19 H 25 O 2 theory 285.1855 (M ⁺ -1) analysis Value 285.1894 (M ⁺ -1) <Synthesis of compound (17)> Sodium hydride (60%) in 30 ml of dimethyl sulfoxide
789 mg (19.7 mmol) in oil (at room temperature) were added in a stream of argon at room temperature and heated to 70 ° C. until hydrogen evolution ceased (about 50 minutes). After the obtained green transparent solution was returned to room temperature, concentrated sulfuric acid and acetylene gas passed through a silica gel washing bottle were introduced for 40 minutes. To this, 1.41 g (4.9 g) of the compound (16) obtained above was obtained.
3 mmol) of dimethyl sulfoxide in 10 ml at room temperature
Stir for 4.5 hours. Under ice cooling, 50 ml of water was added dropwise to the reaction solution, and the mixture was extracted with ethyl ether. The ether layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography using 70 g of silica gel to obtain 1.23 g (yield: 80%) of a pale yellow oily compound (17) from a stream of ethyl ether: hexane = 1: 4 (volume). Was.

bp 196 ° C (0.5mmHg, Kugelrohr) ▲ [α] ²⁶ _D ▼ + 7.55 ゜ (c = 1.032, CHCl ₃ ) Elemental analysis C ₂₁ H ₂₈ O ₂ CH Theoretical value (%) 80.73 9.03 Analytical value (%) 80.70 9.22 IR νmax (neat) 1670,3310,3460cm -1 1 H-NMR (CDCl 3) δ: 0.97 (3H, d, J = 6.6Hz) 1.61 (3H, brs) 1.77~2.10 (3H, m) 2.17 (1H, d, J = 5.1Hz, exchangeable with D ₂
O) 2.23 to 2.50 (5H, m) 3.75 (1H, m) 3.95 (2H, m) 4.50 (2H, s) 5.15 (1H, t, J = 7.1Hz) 5.46 to 5.65 (2H, m) 7.33 (5H , s) MS m / e: 313 (M + -1), 91 (100%) C 21 H 28 O 2 theory 313.2167 (M ⁺ +1) analysis 313.2182 (M ⁺ +1) thus obtained Optically active (4R, 9R) compound (17) and the optically active (4S, 5R) compound (A)-
1 uses these as a starting material, according to the above-mentioned synthetic route III, via compound (18) and compound (19), to obtain milbemycin β.
₂ , compound (B), which is the northern hemisphere part.

Optically active compounds of the present invention (Effect of the Invention) are important as intermediates which can milbemycin beta ₂ naturally occurring synthetic mass production.

Claims (1)

(57) [Claims] 1. A trans-form (4S, 5R) optically active compound among the compounds represented by the following formula (A). In the above formula (A), the symbol * represents an asymmetric carbon atom.