JPS63303978A - Novel brassinosteroid derivative and its production - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R is acyl; Y is COCH2, COOCH2; X is formula II-III; R<1> is 1-2C alkyl; * shows the position in which the com pound bonds to steroid; where the case where Y is COOCH2, and R is acetyl in the formula II is excluded). EXAMPLE:( 22S,23S,24S )-2alpha,3alpha-Diacetoxy-22,23-isopropylidenedioxy-5alpha-stigmastan- 6-one. USE:Plant growth regulator. PREPARATION:The compound of formula IV is oxidized into the compound of formula V, which is isomerized into the compound of formula VI. The prod uct is allowed to react with a compound of R2<1>C(OR<2>)2 (R<2> is 1-2C alkyl) or R2<1>CO to give the compound of formula VII, which is oxidized into the compound of formula VIII. The compound is acylated, lactonized, when needed, and hydrolyzed at the acetalated part with an acid to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel method for producing brassinosteroid derivatives useful as plant growth regulators.

[Conventional technology]

Japanese Patent Publication No. 7195/1983 discloses (228.238)-28-homobrassinolide, which is a compound analogous to brassinolide, and its 2,3-diacetate derivative.

[Problem that the invention seeks to solve]

In Special Publication No. 62-7195, (22S, 23S)-2
8-Homobrassinolide 2.3-diacetate showed (228°23S)-2 in the second internode elongation test of hanging legumes.
8-Homobrassinolide is known to have a significant elongation-promoting effect.

However, the synthesis method in this patent can be obtained from stigmasterol in 8 steps with a total yield of 20% (228,
238)-28-Homobrassinolide was obtained by acetylation with acetic anhydride in pyridine at low temperature, but the yield was as low as 27% (therefore, the total yield was 5.4%), and at the same time (228° 238)-28-Homobrassinolide 2.2
As much as 46% of 2-diacetate is produced as a by-product, and it is extremely difficult to separate the two, a better synthesis method is desired.

[Means for solving problems]

The present invention proposes various synthetic methods to solve the above problems. Upon investigation, (22B, 248)-3α is readily obtained from stigmasterol.

5-fukuro-5α-stigmas)-22-ene-6-
It is represented by the following formula using 1 or (22g, 24S)-2α,3α-diacyloxy-stigmast-22-en-6-one as a starting material.

The formula do.

shows. R1 represents a C1-C2 alkyl group, and * represents the bonding site of group X to the steroid ring. )(223,2
38) - A novel method for synthesizing homobrassinolide derivatives is provided.

The brassinosteroid derivative of formula (1) of the present invention can be produced by the following methods (1) and (11).

A compound represented by the formula is oxidized to produce a compound represented by the formula, then this compound is isomerized to produce a compound represented by the formula, and then this compound is converted to a compound represented by the formula (wherein, al, R2 is a C1-C2 alkyl A compound represented by the formula (in the formula, R1 means the same as above) is produced by reacting with a compound represented by the formula A compound represented by the formula (in which R represents an acyl group and W has the same meaning as above) is prepared by producing a compound represented by the formula (meaning the same as above), and then acylating this compound to obtain a compound represented by the formula and then lactonizing this compound to produce a compound represented by the formula (wherein R and R' have the same meanings as above), and then removing the acetonide group of this compound by acid treatment. A method for producing a compound represented by a characteristic formula (wherein R has the same meaning as above).

(11) A compound represented by the formula (in the formula, R represents an acyl group) is oxidized to produce a compound represented by the formula (in the formula, R means the same as above), and this compound and the formula This compound is reacted with a compound represented by the formula (in the formula, R1 means the same as above), and then this compound is lactonized to form a compound represented by the formula (in the formula, R, R' means the same thing as above], and then the acetonide group of this compound is removed by acid treatment (wherein R means the same thing as above). Methods for making the compounds shown.

In the method of (1), formula (2) (8, Takatsu
to andN, Ikekawa, Chem, P
harm, Bull, 30.4181 (1982
) The compound of formula (3) can be produced by oxidizing the compound of formula (3) as follows.

That is, the compound of formula (2) is mixed with ether, pyridine, benzene, t-butanol, impropatol, tetrahydrofuran, dioxane, water, or a mixed solvent of two or more of these in any proportion; The compound of formula (3) can be obtained by reacting it with an oxidizing agent in a solvent that can sufficiently dissolve the compound, for example, in a tetrahydrofuran-water system, preferably at 0°C to room temperature, preferably using 0sO= as a catalyst. As the oxidizing agent, for example, NMO (N-methylmorpholine-N-oxide) is preferable. (Oxidation using NMO is performed by e.g. V, Van Rheenen, R
, C, Kelly, and D, Y, Cha T.
etra-hedron Left,, 1976e
1973 method.

Also, an oxidation method using 8e% t-BuOOH etc. (K.

B,5harplesJ,Am,Chem,Soc,,
98.1986 (1976)) is also a preferred method.

Next, in order to produce a compound of formula (4) by isomerizing the compound of formula (3), the reaction can be carried out in an aprotic polar solvent in the presence of an acid as described below. That is, heating with p-toluenesulfonic acid in sulfolane, reacting with hydrochloric acid in acetic acid and then heating with Li Br in DMF, heating in DMF in the presence of an acid, an inorganic halide, or In sulfolane, this can be carried out by heating with sulfuric acid or hydrobromide of pyridine, or with a compound having both a sulfonic acid group and an amino group in the same molecule, such as sulfamino acid, in sulfolane. .

Alternatively, a method of heating 10-camphorsulfonic acid and an alkali metal halide in an amide aprotic polar solvent is also preferred. However, the isomerization method is not limited to the above method. The reaction temperature for isomerization is 80°
A range of ~200°C is preferred.

The compound of formula (4) is reacted with the compound of formula (5) to form the compound of formula (
Preferably, acetone, 2
．． The reaction can be carried out in a solvent such as 2-dimethoxypropane, tetrahydrofuran, diethyl ether, or dioxane in the presence of an organic acid such as p-toluenesulfonic acid, preferably at 0° C. to room temperature.

Next, in order to produce the compound of formula (7) by oxidizing the compound of formula (6), the compound of formula (2) described above is oxidized to produce the compound of formula (3).
) can be carried out in substantially the same manner as the method for producing the compound.

Next, the compound of formula (8) can be acylated to produce a compound of formula (8) by reacting a suitable acylating agent in an inert solvent in the presence of a base as follows. reactor.

Examples of inert solvents include aromatic hydrocarbons such as benzene, toluene, xylene, and monochlorobenzene, n-
Examples include aliphatic hydrocarbons such as hexane, cyclohexane, carbon tetrachloride, chloroform, dichloromethane, and 1,2-dichloroethane, ketones such as acetone and methyl ethyl ketone, and ethers such as dioxane and tetrahydrofuran.

Examples of the base include tertiary amines such as pyridine, picoline, triethylamine, and trimethylamine, and inorganic and organic bases such as sodium acetate, potassium acetate, soda carbonate, potassium carbonate, caustic soda, and caustic potash. In addition, in the present invention, acylation can also be carried out using a base such as pyridine as a solvent without using an inert organic solvent.

Examples of acylating agents include acetic anhydride, acetyl chloride, propionic anhydride, propionyl chloride, propionyl bromide, butyryl chloride, valeryl chloride, benzoyl chloride, benzoyl bromide, and benzoic anhydride. The oxidizing agent is used in an amount of 2 to 4 per mol of the compound of formula (6).
Mol can be used.

The acylation reaction temperature can be carried out, for example, from 08 to 150°C, but preferably from room temperature to 100°C.

Next, the compound of formula (8) can be lactonized to produce the compound of formula (9), for example, as follows.

The compound of formula (8) is optionally mixed with an organic peracid (e.g., trifluoroperacetic acid, monoperoxyphthalic acid, metachloroperbenzoic acid (mcPBA)) in an oxidation-stable organic solvent.
The compound of formula (9) can be obtained by the so-called Bayer-Villiger reaction. In this case, for example, m-CPBA is used in a solvent such as dichloromethane or perchlorethylene at a low temperature (preferably -5°C to room temperature).
A method of oxidizing with is preferred.

Next, in order to produce a compound of formula (10) by hydrolyzing the compound of formula (9), the compound of formula (9) is mixed with a weak acid (for example, 3
(0 to 80% aqueous acetic acid solution) or a solution of p-toluenesulfonic acid, concentrated sulfuric acid or HCl03 acid in methanol-water-tetrahydrofuran (or dioxane, ether, etc.), preferably at 50-80°C. The acetonide group [protecting group] can be removed.

Next, method (11) will be explained.

Compound (S, Takatsuto an
dN, Ikckawa.

Chem, Pharm, Bull,, 30.4181
(1982)] to produce the compound of formula (12), the compound of formula (2) described above is oxidized to produce the compound of formula (12).
It can be carried out in the same manner as for producing the compound 3).

The compound of formula (8) is produced by reacting the compound of formula (I2) with the compound of formula (5) to produce the compound of formula (6) from the compound of formula (4) and the compound of formula (5). This can be done in a similar way to manufacturing.

Lactonization of the compound of formula (8) to produce the compound of formula (9) L-1 Furthermore, the compound of formula (10) can be produced by the method described in method (1).

The novel brassinosteroid derivative of formula (1) of the present invention exhibits a favorable effect on plant growth.

To use the compound of formula (1), one or two of them may be used.
Mix seeds or more and use by diluting with water to a low concentration, or mix with commonly used pesticide adjuvants, and form into preparations such as powders, granules, granules, irrigation agents, flowable agents, or emulsions. It can be used.

The steroid of the present invention is expected to be applied to agriculture and horticulture as a plant growth regulator. For example, grass crops (rice, wheat, corn, etc.), vegetables (tomatoes, cabbage, cauliflower, cucumbers, etc.), and fruit trees (grapes, apples, etc.)
It can be used as a growth regulator for legumes (soybeans, kidney beans, etc.), coffee, cocoa, etc.

〔Effect of the invention〕

By the method of the present invention, (228,238)-28-homobrassinolide 2,3-diacetate can be produced in high yield (total yield 30-35%) by a simple method.

〔Example〕

The present invention will be explained below with reference to Examples.

Example 1. (228,23S,24S)-3α,5
-Production of Fukuro-22,23-dihydroxy-5α-stigmast/-6-one: (22E,24S)-3α,5-Fukuro-22,23-dihydroxy-5α-stigmast-22-en-6-one 2.2 g (5, 37
mmol) in THF (15 ml) and water (1 m
1), and then add osmium tetroxide (50111g) and NMO (5.0g, 37.0mm) at room temperature.
ol) was added and allowed to react in the dark for 7 days. The reaction mixture was poured into water, extracted with methylene chloride, and the extract was washed and dried (
The crude product obtained by distilling off the solvent was purified by silica gel column chromatography (i. benzene-ethyl acetate = 5:1) to obtain the desired (
22S, 238.248)-3α, 5-cyclo-22,
1.72 g (yield 72%) of 23-dihydroxy-5α-stigmastan-6-one was obtained. Recrystallized from methanol and obtained mp156-158°C 'HNMR (CDCh); δ 0.75 (3H,
s, 18-CH5).

1.01 (3H,s, 19 CH3), 3.
58 (2H, m.

22-H and 23-H) BI-MS: m/z 444 (M) Example 2.
Preparation of (22S, 238.248)-22,23-dihydroxy-5α-stigmast-2-en-6-one: (228.238)-diol prepared in Example 1 1.
70 g (3,83 mmol) and sulfamic acid 5
60 mg (5.77 mmol) of sulfolane 20
ml and reacted at 160°C for 6 hours. After that, it was poured into water and extracted with ethyl acetate. The extract was washed with water and dried (Mg 804). =20:1) to obtain the desired (22
8,238,248)-22゜23-dihydroxy-5
α-stigmast-2-en-6-one with t4tg (
Yield: 83%). Recrystallize from methanol (ml) 1
69-170℃.

'HNMR (CDCl5); δ 0.71 (314
, s, 19 CHa).

0.75 (3H,s, 18 CH3), 3.
58 (2H, m.

22-H and 23-H), 5.63 (L H,m,
2-H).

5.68 (IH,m, 3-H)EI-MS
: m/z 444 (M) Example 3. (228
, 238, 248) Production of -22,23-isopropylidenedioxy-5α-stigmast-2-en-6-one: (228.23S, 248)-22 produced in Example 2
, 1.35 g (3.04 mmol) of 23-dihydroxy-5α-stigmast-2-en-6-one was dissolved in 50 ml of acetone, 50 rrIg of p-toluenesulfonic acid was added thereto, and the mixture was reacted at room temperature for 1 hour. I let it happen. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried (Mg SO4). The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (eluent benzene-ethyl acetate = 50:
1) to obtain the desired (228,23S,248)-
1.45 g of 22,23-isopropylidenedioxy-5α-stigmast-2-en-6-one (yield: 99
%) Got. Recrystallize from methanol to obtain mp163-16
6℃.

'HNMR (CDCl3); δ0.70 (3H,s,
18 CH3).

0.71 (3H,s, 19-CH5), 1.37
(6H,s, acetonide), 3.91 (IH
, dd, J=2.9 and 8.3Hz, 22-H),
4.00 (LH, dd, J=2.0 and 8.3H
z, 23-H), 5.60 (IH, m, 2-H
).

5.68 (LH, m, 3-H).

EI-MS: m/z 484 (M) Example 4.
(228,238,248)-2α,3α-dihydroxy-22,23-isopropylidenedioxy-5α
-Production of stigmastan-6-one: (228.238.248)-22 produced in Example 3
, 23-impropylidenedioxy-5α-stigmus)-2-en-6-one 750 μ (1,55 mmol
) in 30 ml of THF and 1.5 ml of water, and add 30 ml of osmium tetroxide and 7 ml of NMo.
00 mg (5.19 mmol) was added thereto, and the mixture was reacted in the dark at room temperature for 5 hours. The reaction mixture was poured into water, extracted with methylene chloride, and the extract was washed with water and dried (Mg S 04
) Shita. The solvent was distilled off under reduced pressure to obtain the desired (22S,
238.24S)-2α,3α-dihydroxy-22,
800 μl of 23-impropylidenedioxy-5α-stigmastan-6-one (yield 99%) was obtained.

Example 5. (228,23S,248)-2α,3
Production of α-diacetoxy-22,23-impropylidenedioxy-5α-stigmastan-6-one: Dissolve 800 μl of the 2α,3α-diol produced in Example 4 in 1Qml of pyridine, and add 5ml of acetic anhydride thereto. , and reacted overnight at 60°C. After that, it was poured into water, extracted with ethyl acetate, and the extract was washed with water and dried with MgSO4. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent Benzene-
Purify with ethyl acetate = 20:1 to 5:1) to obtain the desired (2
23,238,248)-2α,3α-diacetoxy-
728 μm (yield 78%) of 22,23-isopropylidenedioxy-5α-stigma stan-6-one was obtained.

Recrystallized from methanol to yield mp2L3-215°C.

'HNNI 几(CDCl5) tδ 0.70 (3H
, 5, 18-Cf-13).

0.83(3H,s, 19-CH5), 1.03(
3H, d.

J = 5.8H2, 21CH3), 1.37 (6H
, S, acetonide)+ 2.00 (3H+
s+ acetyl group), 2.08 (3H, 5, acetyl group), 2.34 (IH, dd, J = 1.32 and 4
．． 4Hz, 7β-H), 2.57 CIH, dd.

J=5.4 and 10.3Hz, 5α-H), 3
．． 91 (tH.

dd, J=2.9 and 8.3Hz, 22-H),
4.00 (IH.

dd, J=2.0 and 8.3Hz, 23-H),
4.95 (LH.

m, 2β-H), 5.38 (IH, m, 3β-
H).

FJI-MS: m/z 602 (M) Example 6
．． (22S, 23S, 243)-2α,3α-diacetoxy-22,23-ingropylidenedioxy7-B
-Production of homo-7-oxa-5α-stigmastan-6-one: (228,238,248)-2α produced in Example 5
, 3α-diacetoxy-22,23-impropylideneoxy-5α-stigmastan-6-one 850■ (
1,41 mmol) was dissolved in 15 ml of methylene chloride (1K), and mcPBA 800 rr@(4,62
mmol) and allowed to react at room temperature in the dark for 15 days. Afterwards, 2 g of calcium hydroxide was added to the reaction mixture, and 3
Stirred for 0 minutes. The precipitate was filtered off, the filtrate was concentrated, and the resulting crude product was subjected to silica gel column chromatography (
Eluent benzene-ethyl acetate = 20:1-5:1
) ”c-n made for the purpose (228, 238, 248)
-2α,3α-diacetoxy-22,23-inglobylidenedioxy-B-homo-7-oxa-5α-stigmastan-6-one was obtained in an amount of 610 μm (yield 70%). Recrystallized from methanol, mp 180-182°C'HNMR (CDCl5); δ0.73 (3H, s
, 18 CH3).

1.37 (6H,s, acetonide), 2.
00 (3H, s acetyl group), 2.11 (3H,
s, acetyl group).

3.00 (LH, dd, J = 4.4 and 12.
5Hz, 5α-H).

3.89 (LH, dd, J=2.9 and 8.3H
z, 22-H).

3.98 (IH, dd, J=2.0 and 8.3H
z, 23-H).

4.10 (2H, m, 7-CH2), 4.87
(IH, m, 2β-H), 5.37 (I
H, m, 3β-H).

EI-MS: m/z 618 (M) Example 7. (22S, 23S, 24S)-2α,3α-diacetoxy-22,23-dihydroxy-B-homo-7
-Production of oxa-5α-stigmastan-6-one: (22S, 238,248)-2α produced in Example 6
, 3α-diacetoxy-22,23-ingropyritenedioxy-B-homo-7-oxa-5α-stigmastan-6-one 300 μ (0,485 mmol) was added to 7
After reacting for 1.5 hours under boiling reflux in 3Qml of 0% acetic acid, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (eluent: benzene-
Purify with ethyl acetate = 1:1) to obtain the desired product (228゜23
8.248)-2α,3α-diacetoxy-22゜23
-Dihydroxy-B-homo-7-oxa-5α-stigmastan-6-one was obtained in 237 μm (yield: 85%).

Recrystallized from a mixed solvent of acetone and hexane to pH 9.
-121°C (Literature value, mp 120°C) 'HNMR (CDCl2); δ0.75 (3H, s,
18-CH5).

0.99 (3H,s, 19 CH3), 2.0
0 (3H, s.

acetyl group), 2.11 (3H,s, acetyl group).

3.00 (IH, dd, J=4.4 and 12.5
Hz, 5α-H).

3.58 (2H,m, 22-H and 23-H),
4.10 (2H, m, 7-CHz), 4.8
7 (IH,m, 2β-H).

5.37 (IH, m, 3β-H).

BI-MS: m/z 578 (M)l) Special Publication No. 1987-7195 Example 8. (228,238,24S)-2α,3
α-Diacetoxy-22,23-dihydroxy-5α-
Preparation of stigmastan-6-one: (22E, 248)-2α,3α-diacetoxy-5α
-Stigmas)-22-en-6-one 250■(0
, 473 mmol) in THF 5 ml and water Q,
Dissolve in 5 ml and add 1 ml of osmium tetroxide.
0ryg and NMO650III (4,81mmo
l)' and allowed to react in the dark at room temperature for 6 days. The reaction mixture was poured into water, extracted with methylene chloride, and the extract was thoroughly washed with water and dried (Mg 804). The solvent is distilled off under reduced pressure to obtain the desired (228,23S,248)-2α
, 3α-diacetoxy-22,23-dihydroxy-5
α-stigma stan-6-one 240 μ (yield 90%)
) got it.

Example 9. (22S, 23S, 24S)-2α, 3
Production of α-diacetoxy-22,23-inpropylidenedioxy-5α-stigmastan-6-one:

Claims (3)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (1) (In the formula, R represents an acyl group, Y is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ indicates that ▲ there is a mathematical formula, chemical formula, table, etc. ▼ group is bonded to the A ring. Yes▼ indicates.R^1 indicates an alkyl group of C_1 to C_2,
* indicates the bonding site of group X to the steroid ring. However, this does not apply when Y is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and X is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and R is an acetyl group. ) steroid derivatives. (2) A compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (2) is oxidized to produce a compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (3), and then this compound isomerize to produce a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (4), and then this compound is converted to the formula ▲There are mathematical formulas, chemical formulas, tables, etc. There is ▼ (5) (In the formula, R^1 and R^2 represent C_1 to C_2 alkyl groups) By reacting with a compound represented by the formula ▲ mathematical formula, chemical formula, table, etc. ▼ (6) (In the formula, R ^1 means the same as above) A compound represented by the following is produced, and then this compound is acylated to form the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (8) (In the formula, R represents an acylated group. , R^1 means the same thing as above) By producing a compound represented by and then lactonizing this compound, the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (9) (In the formula, R, There are formulas, chemical formulas, tables, etc. that are characterized by producing a compound represented by (R^1 means the same as above) and then removing and hydrolyzing the acetonide group of this compound by acid treatment. ▼(10) A method for producing a compound represented by (wherein R means the same as above). (3) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (11) (In the formula, R represents an acyl group) A compound represented by the formula is oxidized to form the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (12) (R means the same as above) A compound shown by is manufactured, and then this compound and the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (5) (Formula In the formula, R^1 and R^2 represent C_1 to C_2 alkyl groups). means the same as above), and then lactonizes this compound to form the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (9) (In the formula, R and R^1 are as above) There are formulas, chemical formulas, tables, etc. that are characterized by producing a compound represented by (meaning the same thing) and then removing the acetonide group of this compound by acid treatment. means the same as above)