JP3453188B2 - Method for producing oleanolic acid derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to the formula (I):

[Chemical 4] (In the formula, X and Y are either one of hydrogen and the other of which is optionally protected hydroxy, or together form an optionally protected carbonyl, and R ¹
Represents a hydroxy or amino) and relates to a novel method for producing an oleanolic acid derivative (hereinafter referred to as compound (I)).

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION Compound (I) is
Useful as an intermediate in the synthesis of various compounds, including pharmaceuticals for humans or animals, for example known for their usefulness as endothelin receptor antagonists,
The following formula (III):

[Chemical 5] [In the formula, R ⁴ represents hydrogen or a metabolizable ester residue, and R ⁵ represents hydrogen or -R ⁶ -R ⁷ . However, R ⁶ is SO ₃ , CH ₂
COO, COCOO or COR ⁸ COO (R ⁸ is lower alkylene or lower alkenylene), R ⁷ represents hydrogen or a metabolizable ester residue. ] It is a manufacturing intermediate of the triterpene derivative shown by these. This triterpene derivative (III) is a receptor antagonist of endothelin, which is a peptide derived from endothelial cells having a vasoconstrictor action, and thus is particularly effective for treating or preventing various diseases caused by hypersecretion of endothelin. [PCT / JP91 / 01707 (International Publication Number WO9
2/12991) and Japanese Patent Application No. 5-140416
issue]. Examples of such diseases include hypertension, ischemic heart disease, cerebral circulation disorder, renal disorder, circulatory failure of various organs, asthma and the like.

This triterpene derivative (III) has heretofore been referred to as myriceron or myricelol (in the present specification, compounds of the formula (I), respectively, in which X and Y together represent carbonyl and R ¹ is hydroxy, And one of X and Y is hydroxy and the other is hydrogen,
Shall mean a compound in which R ¹ is hydroxy)
Can be produced by a known method (WO92 / 12991 and Japanese Patent Application No. 5-140416). For example, myriceron is reacted with dimethylphosphonoacetic acid to give formula (IV):

[Chemical 6] And a compound of the formula (V):

[Chemical 7] (In the formula, R ⁵ has the same meaning as above, and R ⁹ represents a phenol protecting group such as Boc (t-butoxycarbonyl group) or a hydrogen atom), and the aldehyde is condensed under the reaction conditions of the Horner-Emmons reaction. And deprotection and / or chemical modification.

Conventionally, the compounds of the formula such as Miriseron (I) is obtained by extracting from Shirokoyamamomo (Myricacerifera), it has been prepared by chemically modifying the derivative of Miriseron or Miriseroru. That is, the branches of white peaches were extracted with a polar solvent such as methanol for several days, and the extract was extracted with an organic solvent such as chloroform immiscible with water, and the obtained extract was separated by silica gel column chromatography. Then, the compound of formula (I) was produced by further chemically modifying the obtained substance. Thus, the conventional method requires extremely complicated steps, and thus the yield of the target substance was extremely low. Therefore,
It has been strongly desired to develop a method for efficiently producing a compound represented by the formula (I) such as myriceron and myricerol from a commercially available product or an easily available starting material.

[0005]

The present inventors have found that by reducing certain lactones under the conditions of the Birch reaction,
It was found that the desired compound (I) can be easily produced efficiently, and the present invention has been completed.

That is, the present invention is a novel process for producing compound (I), which comprises the formula (II):

[Chemical 8] (In the formula, X and Y are either hydroxy which may be hydrogen and the other may be protected, or they may together form oxo which may be protected, R ² is oxygen, A compound represented by optionally protected hydroxyimino or optionally protected imino, R ³ represents an ester type hydroxy protecting group is reduced in an amine solution using an alkali metal or an alkaline earth metal. The present invention provides a method characterized by the above. The protecting group used in the method of the present invention will be described.

The hydroxy-protecting group for X or Y may be one that is deprotected during the reduction as long as it does not adversely affect the reduction reaction, and known hydroxy-protecting groups can be widely used. Methoxybenzyl, nitrobenzyl, 2,4-dimethoxybenzyl,
Trityl, etc.), alkylcarbonyl (acetyl, acetyl halide, pivaloyl, formyl, cyclohexylacetyl, etc.), arylcarbonyl (benzoyl, toluoyl, xylyl, indanyl, etc.), alkoxycarbonyl (methoxycarbonyl, hebutoxycarbonyl, etc.)
Cyclopropoxycarbonyl etc.), alkenyloxycarbonyl (propenyloxycarbonyl etc.), aryloxycarbonyl (phenoxycarbonyl etc.), aralkyloxycarbonyl (nitrobenzyloxycarbonyl etc.), silyl type (trimethylsilyl, t-butyldimethylsilyl, dimethylphenylsilyl) , Tobutoxydiphenylsilyl, etc.) and ether type (alkyl ether, aryl ether, aralkyl ether, methoxymethyl, tetrahydrofuranyl, etc.) and the like. Preferred is alkanoyl such as acetyl. It should be noted that there is no inconvenience in carrying out the present reduction reaction even if the hydroxy moiety is not protected.

As the protecting group for oxo which may be protected in X and Y, any known carbonyl protecting group can be widely used as long as it does not adversely affect the reduction reaction, but preferably during the reduction reaction. It is not deprotected and is easily deprotected by a known method after the reaction, and is a dialkyl acetal type (dimethyl acetal,
Examples thereof include diethyl acetal), alkylenedioxy type (ethylenedioxy, propylenedioxy, etc.) and alkylenedithio type (ethylenedithio, propylenedithio, etc.), and the like, and alkylenedioxy type is particularly preferable. When X and Y are unprotected oxo, the 3-position hydroxy form of compound (I) reduced to hydroxy may be obtained as the main product by this reaction. For example, Japanese Patent Application No. 5-1
It can be easily converted into the 3-position oxo form by the method described in No. 40416. The hydroxyimino protecting group for R ² may be one that is deprotected during reduction as long as it does not adversely affect the reduction reaction, and among the above hydroxy protecting groups, alkylcarbonyl, alkoxycarbonyl, ether There are types. There is no problem even if the hydroxy moiety is not protected in carrying out the present reduction reaction.

The imino protecting group for R ² may be one that is deprotected during the reduction as long as it does not adversely affect the reduction reaction, and known imino protecting groups can be widely used, but are preferred. Is alkyl (ethyl, t-
Butyl etc.). The ester-type hydroxy protecting group for R ³ must be one that can be easily removed by a reduction reaction and does not adversely affect the reaction, and among the above-mentioned hydroxy protecting groups, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxy. Carbonyl. After the reduction reaction, the compound (I)
If any of the above protecting groups remains, it can be deprotected by a method well known to those skilled in the art, if desired. The compounds (I) and (II) involved in the present reduction reaction have a β-amyrin type skeleton among triterpenes.
In this reaction, by utilizing the Birch reaction condition, the 27-position side chain of compound (II) and the 12-position and 13-position
The position moiety can be reduced in one step, and compound (I) can be obtained in high yield.

The Birch reaction is a reduction reaction usually carried out with an alkali metal or alkaline earth metal in an amine solution, the reaction conditions of which are known to those skilled in the art and described in many literatures [eg. , New Experimental Chemistry Course 15 "Oxidation and Reduction II", Chapter 1, 165 (1976), and Tebiki [3] Synthetic Reaction of Organic Chemistry (I) Tokyo Kagaku Dojin (1990), pp. 40-42. ]. That is, examples of the alkali metal or alkaline earth metal used for the Birch reduction include lithium, potassium, sodium, calcium and magnesium, and lithium, sodium and calcium are preferable in the method of the present invention. As the amine solution, liquid ammonia or mono- or di-lower alkylamine such as methylamine, ethylamine, ethylenediamine, dimethylamine and diethylamine can be used, and liquid ammonia is particularly preferable in the method of the present invention.

Usually, in the presence of 2 equivalents or more of an alkali metal or an alkaline earth metal, if desired, in the presence of a proton donor (anion scavenger) such as methanol, ethanol, isopropanol or t-butanol, preferably anhydrous. React under conditions. In the method of the present invention, anhydrous ethanol is particularly preferable as the proton donor.
The reaction solvent may be an amine solution alone, but if desired, an auxiliary solvent such as ether, tetrahydrofuran or dimethoxyethane may be used in combination. The reaction temperature is generally under ice cooling to -100 ° C, preferably -50 to -80 ° C.
Is. After the reaction, concentration under reduced pressure, neutralization, extraction with an organic solvent, drying, concentration, and purification by column chromatography on silica gel, alumina, etc., the target compound (I) can be obtained.

The lactone represented by the formula (II) can be obtained by, for example, using oleanolic acid or the like as a starting material by a method known to those skilled in the art [eg, DHR Barton et al., Tetrahedron, Supplemen.
t No. 7, pp. 57-67 (1965)]. In formula (II), one of X and Y is hydrogen and the other is optionally protected hydroxy, and R ² is oxo, optionally protected hydroxyimino or protected. Good imino, R
^The compound in which ³ is hydrogen or an ester-type hydroxy protecting group is novel and is a useful intermediate in the production method of the present invention. According to the method of the present invention, the amount of the solvent used is significantly smaller than that of the conventional method, and the process is simple.
Since labor can be saved and the compound (I) can be obtained in high yield, the production efficiency of the final target substance can be dramatically improved. Accordingly, the method of the present invention comprises the formula (I)
It is widely useful for improving the efficiency of the production process using any compound represented by.

[0013]

The present invention will be described in detail below with reference to examples, but these examples do not limit the present invention. Example 1 Production of myriceron

[Chemical 9]

[Chemical 10]

1) Synthesis of Compound 2 Oleanolic acid 1 (10.0 g, 21.9 mmol) was dissolved in a mixed solution of chloroform (150 ml) -acetone (500 ml) and cooled under ice-cold Jones reagent ((CrO ₃ / acetone / H. ₂ SO ₄ ) 1
6 ml, 42.7 mmol) are added and stirred for 30 minutes. After adding 2-propanol (2.0 ml) to decompose excess reagent,
Water (50 ml) is added and the mixture is concentrated under reduced pressure. The residue is ethyl acetate
It was extracted with (200 ml × 2), washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crystalline crude product 2 . Yield 9.95 g (21.9 mmol), 100% yield. Compound 2 : TLC Rf = 0.43 (hexane / ethyl acetate = 2/1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.81 (3H, s), 0.9
1 (3H, s), 0.93 (3H, s), 1.03 (3H, s), 1.05
(3H, s), 1.08 (3H, s), 1.14 (3H, s), 2.84
(1H, dd, J = 13.0,4.0Hz), 5.30 (1H, dd, J
= 3.5,3.5Hz)

2) Synthesis of compound 3 Crude product 2 (9.95 g, 21.9 mmol) was converted to methylene chloride (3
(00 ml) -dissolved in methanol (30 ml) mixture, -60 ° C
Cool to: Ozone gas is introduced until the solution turns purple. Then, nitrogen gas was bubbled to remove excess ozone, dimethyl sulfide (2.0 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was treated with 2-
Crystallization from propanol gave compound 3 . Yield 9.
24 g (19.7 mmol), yield 90%. Compound 3 : TLC Rf = 0.42 (methylene chloride / ethyl acetate = 9
/ 1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.91 (3H, s), 0.9
9 (6H, s), 1.05 (3H, s), 1.10 (3H, s), 1.19
(3H, s), 1.32 (3H, s), 3.91 (1H, br s)

3) Synthesis of Compound 4 Compound 3 (3.24 g, 6.9 mmol) was dried with pyridine (50 m).
Dissolve in l) and cool to -40 ° C. Nitrosyl chloride (1.81 g, 27.6 mmol) was introduced with nitrogen gas,
The mixture was stirred at the same temperature for 30 minutes. Add ice water (100 ml),
The precipitated crystals were collected by suction filtration, washed with water (40 ml × 2), and dried under reduced pressure to obtain powdery compound 4 . Yield 3.40g
(3.40 mmol), yield 99%. Compound 4 : TLC Rf = 0.76 (methylene chloride / ethyl acetate = 9
/ 1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.77 (3H, s), 0.9
5 (3H, s), 1.01 (3H, s), 1.06 (3H, s), 1.11
(3H, s), 1.17 (3H, s), 1.28 (3H, s), 5.64
(1H, dd, J = 3.5,2.0Hz)

4) Synthesis of Compound 5 Compound 4 (20.0 g, 40.1 mmol) in dry methylene chloride
After bubbling nitrogen gas into the (1.00 L) solution for 10 minutes, the solution was cooled with ice. At the same temperature, a high pressure mercury lamp (450 W) was irradiated for 1 hour and 20 minutes under nitrogen bubbling. The reaction mixture was evaporated under reduced pressure to remove the solvent, and 1,2-dichloroethane was added to the residue.
(200 ml) was added and the mixture was heated under reflux for 1.5 hours. After cooling to room temperature, the precipitated crystals were collected by suction filtration to obtain a crude product (10.6 g). This product was suspended in 1,2-dichloroethane (80 ml), heated and allowed to cool to room temperature. The precipitated crystals were collected by filtration to obtain compound 5 as an amorphous powder. Yield 9.41g (18.
8 mmol), yield 47%. Compound 5 : TLC Rf = 0.11 (methylene chloride / ethyl acetate = 9
/ 1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.90 (3H, s), 0.9
5 (3H, s), 0.98 (3H, s), 1.03 (3H, s), 1.07
(3H, s), 1.26 (3H, s), 3.88 (1H, br d, J = 6.
0Hz) 4.20 (1H, br d, J = 6.0Hz), 7.60 (1
H, s), 8.12 (1H, s)

4) Synthesis of Compound 6 Compound 5 (20.0 g, 40 mmol) in dioxane (300 ml)
Ammonium acetate (40.0 g, 519 mmol), 50 in solution
% Acetic acid aqueous solution (60 ml) is added, and an aqueous titanium trichloride solution (96 ml) is added dropwise under ice cooling. After stirring at room temperature for 2 hours, ice water
The mixture was poured into a mixed solution of (500 ml) -ethyl acetate (800 ml) and neutralized with sodium hydrogen carbonate (270 g). The organic layer was separated, the aqueous layer was re-extracted with ethyl acetate (600 ml), each organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate to obtain powdery compound 6 . Yield 16.1g (3
3 mmol), yield 83%. Compound 6 : TLC Rf = 0.20 (n-hexane / ethyl acetate = 1 /
1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.89 (3H, s), 0.9
2 (3H, s), 0.99 (3H, s), 1.02 (3H, s), 1.05
(3H, s), 1.30 (3H, s), 3.76 (1H, br d, J = 1
0.3Hz), 6.99 (1H, br d, J = 10.0Hz), 8.1
1 (1H, br d, J = 14.8Hz)

5) Synthesis of Compound 8 Compound 6 (25.37 g, 53 mmol) was added to 1,4-dioxane.
Suspended in (500 ml) and sodium nitrite (36.2 g, 5
25 mmol) and sodium acetate (36.2 g, 441 mmol) were added, and 50% acetic acid aqueous solution (150 ml) was added to the mixture at 15 ° C. under stirring to 2 times.
It was dripped in 0 minutes. After stirring at room temperature for 40 minutes, the reaction solution was concentrated under reduced pressure, and ethyl acetate (260 ml) and water (300 ml) were added to the residue.
Was added and then neutralized with sodium carbonate (67 g).
The mixture was extracted with ethyl acetate (400 ml x 2), the ethyl acetate layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give compound 7 (by-product) and the novel compound.
A mixture with 8 (28.2 g) was obtained. This mixture was dissolved by heating in a tetrahydrofuran-methanol mixture (3: 2, 280 ml), and at room temperature, 2N aqueous potassium hydroxide solution (20 ml) was added.
Was added and stirred for 40 minutes. The reaction solution was a 2N aqueous hydrochloric acid solution (10 m
It was neutralized with l) and concentrated under reduced pressure. The residue was diluted with methylene chloride (20
It was extracted with 0 ml and 100 ml). The organic layer was washed with brine, dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was crystallized from 2-propanol to obtain compound 8 .
Yield 22.9 g (47 mmol), yield 90%. Compound 7 : TLC Rf = 0.53 (n-hexane / ethyl acetate = 1 /
1) Compound 8 : TLC Rf = 0.40 (n-hexane / ethyl acetate = 1 /
1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.90 (3H, s), 0.9
4 (3H, s), 0.98 (3H, s), 1.02 (3H, s), 1.06
(3H, s), 1.26 (3H, s), 3.55 (1H, d, J = 8.5
Hz), 3.94 (1H, br d, J = 8.5Hz), 10.01 (1
H, s)

6) Synthesis of compound 9 A suspension of compound 8 (25.0 g, 52 mmol) in toluene (500 ml) was added to ethylene glycol (29 ml, 520 mmol) and pyridinium-p-toluenesulfonic acid (650 mg, 2.6 mmol).
Was added and the mixture was heated under reflux for 1 hour with a dehydrator filled with molecular sieves. After cooling the reaction solution, toluene (25
0 ml), diluted with water (250 ml) and saline (200 ml)
After that, it was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain a crystalline crude product 9 . Yield 27.1
3 g (51 mmol), yield 99%. Compound 9 : TLC Rf = 0.38 (methylene chloride / ethyl acetate = 9
/ 1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.79 (3H, s), 0.8
9 (3H, s), 0.90 (3H, s), 0.94 (6H, s), 1.21
(3H, s), 3.26 (1H, d, J = 7.5Hz), 3.94 (5
H, m), 10.03 (1H, s)

7) Synthesis of compound 10 Compound 9 (25.4 g, 48 mmol) in dry pyridine (80 ml)
Acetic anhydride (20 ml, 200 mmol) and 4-dimethylaminopyridine (290 mg, 2.4 mmol) were added to the solution, and the mixture was stirred at 60 ° C for 30 minutes. After cooling the reaction solution, ice water (500 ml) was added, and the precipitated crystals were collected by suction filtration, washed with water (100 ml × 3), and then air-dried. The crude product was suspended in methanol (100 ml), heated at 60 ° C. for 5 minutes and allowed to cool to room temperature. The precipitated crystals were collected by suction filtration to obtain powdery novel compound 10 . Yield 25.9
3 g (45.5 mmol), yield 95%. Compound 10 : TLC Rf = 0.46 (methylene chloride / ethyl acetate = 1
9/1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.80 (6H, s), 0.9
0 (3H, s), 0.92 (3H, s), 0.94 (3H, s), 1.21
(3H, s), 2.12 (3H, s), 3.95 (4H, m), 5.26
(1H, dd, J = 2.8,2.8Hz), 10.23 (1H, s)

8) Synthesis of compound 11 Lithium metal (1.84 g, 263 mmol) was added to liquid ammonia (300 ml) cooled to −78 ° C. and dissolved with stirring for 30 minutes. A solution of compound 10 (30 g, 53 mmol) in anhydrous tetrahydrofuran (300 ml) was added dropwise thereto over 45 minutes, and the mixture was stirred at the same temperature for 1 hour. Then absolute ethanol (15m
l) is added dropwise, the mixture is left at room temperature to remove ammonia, and then concentrated under reduced pressure. Water (150 ml) and methylene chloride on the residue
(400 ml) was added, and the mixture was stirred vigorously with 2N aqueous hydrochloric acid to p
Adjust to H4. The organic layer is separated and the aqueous layer is methylene chloride.
Re-extract with (200 ml). Each organic layer was washed successively with water and brine, dried over magnesium sulfate,
Concentrate under reduced pressure. The oily residue was crystallized from ethyl acetate-n-hexane to give compound 11 . Yield 23.2 g (45 mmol), yield 86% Compound 11 : TLC Rf = 0.40 (methylene chloride / ethyl acetate = 9
/ 1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.70 (3H, s), 0.8
3 (3H, s), 0.90 (3H, s), 091 (3H, s), 0.92
(3H, s), 0.96 (3H, s), 2.92 (1H, dd, J = 13.
0,4.0Hz), 3.16 (1H, d, J = 11.8Hz), 3.7
8 (1H, d, J = 11.8Hz), 3.93 (4H, br s), 5.8
3 (1H, br s)

9) Synthesis of compound 12 (myriceron) Compound 11 (515 mg, 1 mmol) tetrahydrone (2.5
2N hydrochloric acid (0.5 ml) is added to the solution) and the mixture is heated under reflux for 1 hour. Water (5 ml) and methylene chloride (10 ml) were added to this reaction solution, the mixture was left standing with stirring, the organic layer was separated, and the aqueous layer was reextracted with methylene chloride. Each organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methylene chloride-methanol to obtain compound 12 . Yield 374 mg (0.79 mmol), yield 79%. Compound 12 : TLC Rf = 0.57 (n-hexane / ethyl acetate = 1 /
1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.79 (3H, s), 0.9
4 (3H, s), 0.98 (3H, s), 1.03 (6H, s), 1.11
(3H, s), 2.3 to 2.6 (2H, m), 2.96 (1H, dd, J =
13.2, 3.8 Hz), 3.26 (1 H, d, J = 11.8 Hz),
3.81 (1H, d, J = 11.8Hz), 5.89 (1H, br s)

Example 2 Production of millicerol

[Chemical 11]

[Chemical 12]

[0025] 1) Compound 2 oleanolic acid 1 starting materials for synthesis of '(32.42G, dissolved 71 mmol) in pyridine (260 ml), at room temperature, acetic anhydride (36.2
g, 355 mmol) is added dropwise. Then, 4-dimethylaminopyridine (867 mg, 7 mmol) is added, and the mixture is stirred at room temperature for 1 hour. Then, methanol (20 ml) was introduced under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water (400 ml) is added to form a slurry and filtration is performed. The crude crystals obtained were mixed with methylene chloride (3
Redissolved in 00 ml) and added to 1N hydrochloric acid (110 ml). The organic layer is separated and the aqueous layer is extracted with methylene chloride. Each organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product 2 '. Yield 3
5.93 g (72 mmol), yield 100% Compound 2 ′: TLC Rf = 0.64 (chloroform / ethyl acetate = 1
5/1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.74 (s, 3H), 0.8
5 (s, 3H), 0.86 (s, 3H), 0.90 (s, 3H), 0.93
(s, 3H), 0.94 (s, 3H), 1.13 (s, 3H), 1.0
2.0 (m, 22H), 2.05 (s, 3H), 2.82 (dd, J = 1
4.0, 4.0Hz, 1H), 4.50 (dd, J = 7.8, 7.8H
z, 1H), 5.27 (br s, 1H)

[0026] 2) Compound 3 'generating synthetic crude product 2' (35.93g, 72mmol) in methylene chloride
(360 ml) -dissolved in methanol (50 ml) mixed solution, -60
Cool to below ℃. Under cooling, ozone gas is introduced until the solution turns purple. Then, nitrogen gas is bubbled, excess ozone is removed (fading), and then concentrated. Capacity about 2
After concentrating to 00 ml, add isopropanol (300 ml) and reconcentrate. The slurry concentrated to a volume of about 200 ml was filtered, and the filtered crystals were isopropanol (100 ml).
After washing with, the product is dried under reduced pressure to obtain the target compound as a powder.
Yield 31.52 g (61.2 mmol), yield 85%. Compound 3 ′: TLC Rf = 0.50 (chloroform / ethyl acetate = 1
5/1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.86 (s, 3H), 0.8
7 (s, 3H), 0.91 (s, 6H), 0.99 (s, 3H), 1.15
(s, 3H), 1.31 (s, 3H), 2.05 (s, 3H), 1.0-
2.3 (m, 23H), 3.88 (br s, 1H), 4.49 (m, 1H) ¹³ CNMR (CDCl ₃ ) δ _ppm ; 16.4, 16.5, 17.
6,18.6,21.2,21.3,23.6,23.9,27.
5,27.9,28.0,28.7,31.6,33.3,33.
9,34.2,36.4,37.8,38.4,39.3,42.
0,42.3,44.5,44.7,51.1,55.3,76.
0,80.9,90.8,171.2,180.2

[0027] 3) in pyridine 'synthetic powder 3' Compound 4 (30.98g, 60.2mmol) (310
solution) is cooled to -30 to -40 ° C and nitrosyl chloride (23.7 g, 0.36 mol) is introduced. After stirring for 1 hour, ice water (310 ml) is added. The resulting slurry was filtered, the filter cake was washed with water (500 ml) and then washed with methylene chloride (2
Redissolve in 100 ml). N after drying over anhydrous magnesium sulfate
-Hexane (500 ml) is added and concentrated to a volume of about 100 ml. The resulting slurry was filtered and filtered using n-hexane.
After washing with (150 ml), it is dried under reduced pressure to obtain a powdery target compound. Yield 32.09 g (59.0 mmol), yield 98
%. Compound 4 ′: TLC Rf = 0.74 (chloroform / ethyl acetate = 1
5/1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.74 (s, 3H), 0.8
5 (s, 3H), 0.86 (s, 3H), 0.91 (s, 3H), 0.93
(s, 3H), 1.14 (s, 3H), 1.21 (s, 3H), 2.04
(s, 3H), 0.8 to 2.4 (m, 23H), 4.47 (dd, J = 8.
0,8.0Hz, 1H), 5.59 ((dd, J = 3.0,2.2Hz,
1H)

[0028] 4) 'Synthesis powder 4' compound 5 (4.0 g, after nitrogen gas was blown into circulation for 10 minutes in toluene (200ml) solution of 7.4 mmol),
Cool on ice. Nitrogen bubbling, under ice cooling, high pressure mercury lamp (4
50W) for 45 minutes. The green transparent reaction liquid from which the raw material 4 has disappeared is concentrated to a volume of about 50 ml, and then 80 ° C
Heat in the oil bath for 30 minutes. Then, it is re-concentrated and purified by column chromatography to obtain the target compound 5 . Chromatographic conditions: 100 g of SiO ₂ ,
Chloroform / ethyl acetate = 10/1 → 5/1 → ethyl acetate. Yield 2.31 g (4.2 mmol), yield 58%. Compound 5 ′: TLC Rf = 0.10 (chloroform / ethyl acetate = 1
5/1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.84 (s, 6H), 0.8
8 (s, 3H), 0.92 (s, 3H), 0.94 (s, 3H), 1.22
(s, 3H), 2.08 (s, 3H), 0.7 to 2.2 (m, 23H),
3.80 (d, 9.4Hz, 1H), 4.20 (d, 9.4Hz, 1H),
4.51 (dd, J = 11.2, 5.4 Hz, 1 H), 7.53 (s, 1
H), 8.16 (s, 1H)

[0029] 5) 'synthetic powder 5' (13.10 g Compound 6, 24 mmol) in dioxane (210 m
l) solution, ammonium acetate (24.9 g, 312 mmol),
50% Acetic acid water (39 ml) was added, and an aqueous titanium trichloride solution (55 ml) was added dropwise under ice cooling. After stirring at room temperature for 1.5 hours, ice-ethyl acetate (700 ml) -10% sodium carbonate (50
0 ml) Pour into the mixture. The organic layer is separated and the aqueous layer is extracted twice with ethyl acetate (300,100 ml). Each organic layer is washed with brine, dried over anhydrous magnesium sulfate, and concentrated. Dissolve the residue with methylene chloride, add n-hexane, and concentrate again. The precipitated solid is filtered to obtain the target novel compound 6 ′ as a powder. Yield 12.01g (23m
mol), yield 94%. Compound 6 ′: TLC Rf = 0.52 (n-hexane / ethyl acetate = 1 /
1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.81 (s, 3H), 0.8
3 (s, 3H), 0.89 (s, 3H), 0.92 (s, 6H), 1.26
(s, 3H), 2.04 (s, 3H), 0.6 to 2.3 (m, 23H),
3.74 (d, J = 9.4 Hz, 1 H), 4.48 (dd, J = 8.2,
8.2Hz, 1H), 6.90 (br s, 1H), 8.10 (br s, 1
H) ¹³ CNMR (CDCl ₃ ) δ _ppm ; 16.5, 16.7, 17.
5,18.7,21.2,21.3,23.5,24.0,25.
7,27.0,27.8,27.9,31.6,33.2,33.
8,35.7,36.5,37.8,38.2,40.6,43.
6,43.7,44.7,50.0,53.2,55.5,74.
6,80.5,89.1,171.0,179.3,182.7

[0030] 6) 'Synthesis powder 6' (50 mg compound 8, 0.095 mmol) in dioxane (15 m
l) Dissolve in 50% acetic acid water mixture and add sodium nitrite (1
60 mg, 2.375 mmol) was added to sodium acetate (160 mg,
1.951 mmol) is added. After stirring at room temperature for 30 minutes, the mixture was poured into a mixed solution of methylene chloride (40 ml) and water (10 ml). The organic layer is separated and the aqueous layer is extracted with methylene chloride. After each of the organic layers were washed with brine, dried over anhydrous magnesium sulfate, to obtain a mixed crude product is a concentrated residue was concentrated 7 'and 8' (62 mg). The concentrated residue is dissolved in benzene (5 ml) and neutral alumina (1 g) is added. After heating under reflux for 1.5 hours, the mixture was filtered, and the residue (alumina) was washed with methylene chloride (about 30 m
Wash with l). The benzene-methylene chloride solution is concentrated to obtain a crude product of the target compound 8 ′. Yield 40mg
(0.076 mmol), yield 80%. Compound 7 ′: TLC Rf = 0.55 (n-hexane / ethyl acetate = 2 /
1) Compound 8 ′: TLC Rf = 0.45 (n-hexane / ethyl acetate = 2 /
1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.83 (s, 6H), 0.8
9 (s, 3H), 0.94 (s, 6H), 1.22 (s, 3H), 2.05
(s, 3H), 0.6 to 2.4 (m, 23H), 3.57 (d, J = 7.
8Hz, 1H), 3.94 (brd, J = 7.4Hz, 1H), 4.4
5 (dd, J = 10.4, 5.8 Hz, 1 H), 10.05 (s, 1 H) ¹³ CNMR (CDCl ₃ ) δ _ppm ; 16.5, 17.2, 17.
5,18.6,20.9,21.2,21.3,23.5,24.
4,26.9,27.8,31.6,33.1,33.7,36.
3,36.9,37.6,37.8,38.3,43.4,44.
7,46.0,49.9,55.5,58.4,75.3,80.
5,871.1,171.1,179.1,210.0

7) Synthesis of compound 9 ′ Crude product 8 ′ (90 mg, 0.17 mmol) pyridine (1 ml)
Acetic anhydride (0.54 g, 5.3 mmol) and dimethylaminopyridine (9 mg, 0.07 mmol) were added to the solution, and heating was performed for 1.5 hours (oil bath 85 ° C.). Then methylene chloride (25 ml)
-Pour into a mixture of 2N hydrochloric acid (9 ml) and separate the organic layer. The aqueous layer is extracted with methylene chloride and each organic layer is washed with brine. The organic layer is dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography to obtain the desired product.
Get 9 '. Yield 78 mg (0.14 mmol), yield 80%. Compound 9 ′: TLC Rf = 0.58 (n-hexane / ethyl acetate = 2 /
1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.81 (s, 3H), 0.8
3 (s, 6H), 0.92 (s, 3H), 0.93 (s, 3H), 1.21
(s, 3H), 2.05 (s, 3H), 2.15 (s, 3H), 0.7 ~
2.4 (m, 23H), 4.42 (dd, J = 8.0,4.0Hz, 1
H), 5.25 (br s, 1H), 10.22 (s, 1H)

8) Synthesis of compound 10 '(millicerol) Lithium metal (45 mg, 6.5 mmol) was added to liquid ammonia (5 ml) cooled to -78 ° C., and dissolved by stirring for 30 minutes. Raw material 9 '(30 mg, 0.05 mmol) THF
The solution is flowed in and stirred at -78 ° C for 3 hours. afterwards,
Ammonium chloride (170 mg) is added, and it is confirmed that the reaction solution changes from purple to colorless. Furthermore, methylene chloride (2
(0 ml), the temperature was raised to room temperature, ammonia was removed as a gas, and 2N hydrochloric acid (10 ml) was added in the presence of ice. The organic layer is separated and the aqueous layer is extracted with methylene chloride. Each organic layer is washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue is purified by column chromatography to obtain the target compound 10 '. Yield 24mg (0.05mmo
l), yield 97%. Compound 10 ′: TLC Rf = 0.65 (n-hexane / ethyl acetate = 1 /
1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.70 (s, 3H), 0.7
5 (s, 3H), 0.88 (s, 3H), 0.91 (s, 3H), 0.96
(s, 3H), 0.98 (s, 3H), 1.0 to 2.0 (m, 22H),
2.91 (brd, J = 12.4Hz, 1H), 3.15 to 3.26
(m, 2H), 3.78 (d, J = 11.8Hz, 1H), 5.85 (br
s, 1H)

Example 3 Preparation of 27-Aminomyricerol

[Chemical 13]

9) Synthesis of compound 11 'Compound 5 ' (544 mg, 1 mmo prepared in 4) of Example 2
Acetic anhydride (509 mg, 5 mmol) in a solution of l) in pyridine (3 ml)
And dimethylaminopyridine (54 mg, 0.44 mmol) are added. After stirring at room temperature for 2 hours, ice-methylene chloride (20 ml)
Dip in a 6N hydrochloric acid (10 ml) mixture. The organic layer is separated and the aqueous layer is extracted with methylene chloride. Each organic layer is washed with brine, dried over anhydrous magnesium sulfate and concentrated.
The concentrated residue is purified by column chromatography to obtain the target novel compound 11 '. Yield 637mg (1.01mmo
l), 100% yield. Compound 11 ′: TLC Rf = 0.65 (methylene chloride / ethyl acetate = 1
0/1) ¹ H NMR (CDCl ₃ ) δ _ppm ; 0.80 (s, 3H), 0.8
4 (s, 3H), 0.85 (s, 3H), 0.90 (s, 3H), 0.92
(s, 3H), 1.25 (s, 3H), 2.06 (s, 3H), 2.17
(s, 3H), 2.25 (s, 3H), 0.7-2.4 (m, 23H),
4.48 (m, 1H), 5.16 (br s, 1H), 8.08 (s, 1H)

10) Synthesis of compound 12 '(27-aminomyricelol) powder 11 ' in liquid ammonia (6 ml) cooled to -78 ° C.
A solution of (15 mg, 0.24 mmol) in THF (2 ml) and ethanol (0.5 ml) are added. Lithium metal (91
mg, 13.1 mmol) was added and after stirring for 3 hours, ammonium chloride (0.3 g), methylene chloride (15 ml), methanol (1
5 ml) is added. After heating to remove ammonia as a gas, ice-methylene chloride (20 ml) -water (15 ml) -6N hydrochloric acid
(15 ml) Pour into the mixture. The aqueous layer was separated and washed with ethyl acetate (3
0 ml). The aqueous layer is extracted again with ethyl acetate, each ethyl acetate solution is washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The target compound 12 'is obtained as a crude product. Yield 52 mg (0.11 mmol), yield 46
%. Compound 12 ′: TLC Rf = 0.15 (ethyl acetate / acetic acid / water = 30 /
1/1) ¹ H NMR (CDCl ₃ + CD ₃ OD) δ _ppm ; 0.77 (s,
3H), 0.82 (s, 3H), 0.91 (s, 3H), 0.96 (s, 3)
H), 0.98 (s, 3H), 0.99 (s, 3H), 0.7 to 2.1
(m, 22H), 2.67 (d, J = 14.0Hz, 1H), 3.01
(br d, J = 14.0Hz, 1H), 3.26 (m, 2H), 5.92
(br s, 1H) Using the compounds produced in the above Examples, for example, the triterpene derivative (III) having anti-endothelin receptor activity can be produced by the method shown in the following Reference Example.

Reference Example 1 Synthesis of Horner-Emmons reagent (compound IV)

[Chemical 14]

Dimethylphosphonoacetic acid (7.07 g, 42.
To a solution of 1 mmol) in methylene chloride (100 ml) at room temperature under a nitrogen atmosphere is added thionyl chloride (9.21 ml, 126 mmol). After stirring at room temperature for 4 hours, the mixture was concentrated to give acid chloride (7.85 g). Compound 12 prepared in Example 1
A solution of (6.60 g, 14.0 mmol) in methylene chloride (70
ml) under a nitrogen atmosphere at −78 ° C. with pyridine (4.53).
(mL, 56 mmol) is added dropwise. At this time, the internal temperature is -73
It rose to ℃. Then the acid chloride (7.
85 g, 14.0 mmol) in methylene chloride solution (70 ml)
Is added dropwise over 25 minutes. The internal temperature at this time increased to -68 ° C. After stirring for 40 minutes at -75 ° C, the solvent is removed under reduced pressure. The residue was suspended in THF (84 ml), 0 ° C
After cooling to 2, 2N NaOH (14 ml, 28 mmol) is added and stirred at 0 ° C. for 1 hour. The reaction solution was iced-1N hydrochloric acid (5
0 ml) -ethyl acetate (200 ml) and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (150 ml x 2), and each organic layer is washed with brine (100 ml x 2).
The organic layers are combined, dried over anhydrous magnesium sulfate and concentrated. Purification by column chromatography gives the desired compound (IV). Chromatography conditions: SiO ₂
150 g, ethyl acetate / hexane = 1/1 → ethyl acetate → chloroform / methanol = 100/1 → 50/1
→ 20/1. Yield 7.43 g (11.97 mmol, 85
%). Mp. 110-113 ° C, [α] _D ²² : +83.9
° ( c 1.01 / CHCl ₃ ). Compound (IV) ¹ H NMR (CDCl ₃ ) δ ppm: 0.80 (s, 3H),
0.89 (s, 3H), 0.94 (s, 3H), 1.02
(S, 3H), 1.04 (s, 3H), 1.08 (s, 3
H), 1.0 to 2.0 (m, 20H), 2.3 to 2.7 (m,
2H), 2.8-3.0 (m, 1H), 2.95 (d, ² J _PH
= 22.0 Hz, 2H), 3.78 (s, 3H), 3.83
(S, 3H), 4.13 (ABq, Apart, J = 12.9)
Hz, 1H), 4.32 (ABq, Bpart, J = 12.9H
z, 1H), 5.60 (br s, 1H) IR (CHCl ₃ ): 2944, 1728, 1696, 1
263 cm ^{-1 13} C NMR (CDCl ₃ ) δppm: 15.3, 18.0, 1
9.5, 21.4, 22.7, 22.8, 23.5, 23.
7.26.5, 30.6, 32.2, 32.4, 32.8,
32.9, 33.6, 34.0, 34.9, 37.0, 39.
0, 39.9, 40.8, 45.3, 46.3, 46.4
(D, ¹ J _CP = 144 Hz), 47.4, 53.1 (d, ² J
_COP = 6.4 Hz), 53.2 (d, ² J _COP = 6.4 Hz),
66.8, 127.4, 137.0, 165.3 (d, ² J
_CCP = 6.4Hz), 183.2, 217.3

Reference Example 2 Production of aldehyde (V)

[Chemical 15]

Somei et al. (Chem. Pharm. Bull. 28 2
515 (1980)) was applied to synthesize an aldehyde. 2g of 1g hydroxynitrobenzaldehyde
It was dissolved in 0 ml of acetic acid-water (1: 1) mixture, and 25 ml of titanium trichloride aqueous solution was added. After stirring at room temperature for 10 minutes, the mixture was soaked in water-ethyl acetate. The aqueous layer is adjusted to pH 8 with aqueous sodium carbonate solution and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated to about 20 ml. 0.46 ml of pyridine was added to this solution under ice cooling, and 442 mg of 3-methoxycarbonylacrylic acid chloride was added thereto. 30 at 0 ° C
After stirring for a minute, extract with ethyl acetate. The extract was concentrated, the precipitated solid was filtered, and aldehyde (V) powder 432 mg
(29% yield). Compound (V) ¹ H NMR (CDCl ₃ + CD ₃ OD): 3.85 (s,
3H), 6.91 (d, 1H, J = 15.4Hz), 7.1
2 (d, 1H, J = 15.4Hz), 7.14 (d, 1H,
J = 2.8 Hz), 7.18 (dd, 1H, J = 8.8, 2.
8Hz), 8.58 (d, 1H, J = 8.8Hz), 9.86
(S, 1H)

Reference Example 3 Synthesis of triterpene (III)

[Chemical 16]

1) Condensation of compound (IV) with compound (V) 621 mg (1 mmol) of compound (IV) obtained in Reference Example 1 and 299 mg (1.2 mmo of aldehyde (V) obtained in Reference Example 2)
l) is dissolved in 6 ml DMF. DBU (diasabicycloundecene) 0.358 ml, lithium chloride 93 mg
Is added and stirring is continued at room temperature for 1.5 hours. The reaction solution was extracted with ethyl acetate and subjected to silica gel chromatography (chloroform / methanol) to give compound (IIIa) 670.
mg (90% yield) was obtained. Compound (IIIa) ¹ H NMR (CDCl ₃ ): 0.83 (s, 3H), 0.0.
84 (s, 3H), 0.93 (s, 3H), 1.03
(S, 3H), 1.04 (s, 3H), 1.07 (s, 3
H), 1.0-2.1 (m, 20H), 2.2-2.8 (m,
2H), 2.8-3.0 (m, 1H), 3.84 (s, 3
H), 4.16, 4.40 (ABq, 2H, J = 13.0H
z), 5.61 (br s, 1H), 6.27 (d, 1H, J =
16.0 Hz), 6.90 (dd, 1H, J = 8.8, 2.8)
Hz), 6.94 (d, 1H, J = 15.2Hz), 7.07
(D, 1H, J = 2.8Hz), 7.21 (d, 1H, J =
15.2Hz), 7.44 (d, 1H, J = 8.8Hz),
7.74 (d, 1H, J = 16.0Hz)

Then, 5 mg of compound (IIIa) (6.6)
(1 mol) in 300 μl methanol solution
Add 100 μl. After stirring at room temperature for 1.5 hours, the mixture is extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (ethyl acetate: acetic acid: water, 30-1-
Purified in 1), 3.5 mg of compound IIIb (yield 73
%)Obtained. Furthermore, this compound IIIb 21.9 mg (0.
(03 mmol) was suspended in 1.2 ml of water, and 0.1 N-NaOH was added.
Add 600 μl. The resulting solution was lyophilized to give the disodium salt (Compound IIIc) 21.5 mg (93% yield).

IIIb Rf: 0.65 (ethyl acetate: acetic acid: water; 30-1-
1) ¹ H NMR δppm (CD ₃ OD): 0.85 (s, 3
H), 0.87 (s, 3H), 0.94 (s, 3H),
1.03 (s, 6H), 1.05 (s, 3H), 1.1-
2.0 (m, 20H), 2.3-2.6 (m, 2H), 2.8
-3.0 (m, 1H), 4.11, 4.49 (ABq, 2
H, J = 12.6 Hz), 5.59 (br s, 1H), 6.3
6 (d, 1H, J = 16.0Hz), 6.84 (d, 1H,
J = 15.6Hz, 6.89 (dd, 1H, J = 8.6,
2.6 Hz), 7.12 (d, 1H, J = 2.6 Hz), 7.
14 (d, 1H, J = 8.6Hz), 7.20 (d, 1H,
J = 15.6Hz), 7.66 (d, 1H, J = 16.0H
z)

IIIc ¹ H NMR δppm (D ₂ O) DSS (Me ₃ SiCH
₂ CH ₂ CH ₂ SO ₃ Na) standard, 0.73 (s, 3
H), 0.80 (s, 3H), 0.87 (s, 3H),
0.97 (s, 3H), 1.00 (s, 6H), 1.1-
2.0 (m, 20H), 2.2-2.6 (m, 2H), 2.7
-3.0 (m, 1H), 4.05, 4.41 (ABq, 2
H, J = 12.4 Hz), 5.58 (br s, 1H), 6.3
4 (d, 1H, J = 16.0Hz), 6.87, 6.92
(ABq, 2H, J = 16.0Hz), 7.00 (dd, 1
H, J = 8.6, 2.0 Hz, 7.19 (d, 1H, J =
8.6 Hz), 7.21 (d, 1 H, J = 2.0 Hz), 7.
58 (d, 1H, J = 16.0 Hz) The compounds obtained in the above Reference Examples highly inhibit the binding of endothelin to the endrin receptor in vitro and in vivo, and specifically suppress the action of endothelin.

Reference Example 4 Photoreaction of Compound 4 in the presence of oxygen

[Chemical 17] 120 ml of acetone was added to the photoreactor, and the enzyme gas was bubbled for 5 minutes under ice cooling. Next, 1.0 g (2.0 mmol) of the raw material is added and dissolved with stirring by a rotor. High pressure mercury lamp (400W)
At 0.5 Hν. (Reaction temperature: 5-8 ° C). The reaction solution is concentrated under reduced pressure, and 2 ml of isopropanol is added to the residue for crystallization. 0.437 g (41.2%) of 27-nitrate having a dp221-222 ° C. was obtained. The mother liquor was purified by silica gel chromatography to give a further 96 mg (9.1%).
Total yield 50.3%. This compound 13 is a novel compound. Mp. 221-222 ° C (decomposition). Elemental analysis (as C ₃₀ H ₄₅ O ₇ N) Calculated: C, 67.77; H, 8.53 ; N, 2.63 Found: C, 67.29; H, 8.49 ; N, 2 .56 IRν _max (Nujol): 3410, 1749, 1701, 1625, 12
^{78 cm -1 1 H NMR (CDCl} 3) δ (200MHz): 0.92
(S, 3H), 0.98 (s, 3H), 0.99 (s, 3
H), 1.05 (s, 3H), 1.11 (s, 3H),
1.24 (s, 3H), 1.2-2.2 (m, 20H),
2.5 (m, 2H, J = 7.4Hz), 3.9 (t, 1H,
J = 2.6 Hz), 4.76 5.02 (ABq, 2H, J
= 13Hz)

[0046]

EFFECTS OF THE INVENTION According to the method of the present invention, a mycelone derivative which is highly useful as a synthetic intermediate for medicines and the like with high efficiency and high yield as compared with the conventional method of extraction from whiteberry and chemical modification. Can be obtained. Therefore, the method of the present invention greatly contributes to the mass production of the final target substance.

─────────────────────────────────────────────────── ─── Continued Front Page (56) References Tetrahedron, Supple element, (1966), No. 7, p. 57-67 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07J 63/00 C07J 53/00 C07J 75/00 CA (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. Formula (I): (In the formula, X and Y are hydroxy, in which one is hydrogen and the other is protected, or they together form an optionally protected oxo, and R ¹ is hydroxy or A compound represented by the formula (II): (Wherein, X and Y in accordance with the above definitions, R ² is oxygen, optionally protected hydroxyimino or optionally protected imino, R ³ represents an ester-type hydroxy protecting group) represented by A method comprising reducing a compound with an alkali metal or an alkaline earth metal in an amine solution. 2. The method according to claim 1, which further comprises a deprotection reaction. ^3. The method according to claim 1, wherein the ester-type hydroxy protecting group for R ³ is alkylcarbonyl or arylcarbonyl. 4. The alkali metal is lithium.
The method described. 5. The method of claim 1 wherein R ² is oxygen and X and Y are together protected oxo. 6. Formula (II): embedded image Wherein X and Y together form an optionally protected oxo, R ² is oxygen, optionally protected hydroxyimino or optionally protected imino, and R ³ is hydrogen. Or represents an ester type hydroxy protecting group). 7. Formula 11: embedded image The compound represented by.