JPH06157505A - 1,6,7-triacylforskolin derivative - Google Patents

Abstract

PURPOSE:To obtain a new 1,6,7-triacyl-7-deacetylforskolin derivative useful as an intermediate for producing forskolin derivatives expected as medicines. CONSTITUTION:A 1,6,7-triacyl-7-deacetylforskolin derivative of formula I (R<1> and R<2> are acyl; R<3> is 2-3C hydrocarbon, e.g. 1-formyl-6-dimethylaminoacetyl-7- deacetyl-7-formyl-forskolin. The compound of formula I is obtained by reacting a 6-acyl-7-deacetylforskolin derivative of formula II with an acylating agent and acylating hydroxyl groups at 1 position and 7 position thereof. A 6,7- diacyl-7-deacetylforskolin derivative of formula III (R<1> is acyl) useful as a medicine is obtained by subjecting 1,6,7-triacyl-7-deacetylforskolinj derivative of formula I to solvolysis to selectively remove the acyl group at 1 position.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an intermediate useful for producing a forskolin derivative represented by the following formula (1) expected as a medicine.

[0002]

2. Description of the Related Art As a method for producing a 6,7-diacyl-7-deacetylphoruscholine derivative, for example, a method of directly acylating the 7-position of a derivative of the following formula (2) is known.
(E.P222413A).

[0003]

[Problems to be Solved by the Invention]
The -position acylation method has a drawback that the selectivity with respect to the 1-position hydroxyl group is poor.

[0004]

Therefore, the inventors of the present invention have made various investigations as a result of the expression (2).

[0005]

[Chemical 2]

[In the formula, R ² is an acyl group and R ³ is C ₂
To C ₃ hydrocarbon group]
An acylating agent is allowed to act on the 7-deacetylfluoroskolin derivative to acylate the hydroxyl groups at the 1-position and the 7-position to give the following formula (3).

[0007]

[Chemical 3]

A 1,6,7-triacyl-7-deacetylforskolin derivative represented by the formula [wherein R ¹ is an acyl group and R ² and R ³ are the same as above] is obtained, and the compound is then solvolyzed. Then, surprisingly, the acyl group at the 1-position is selectively removed, and the formula (1)

[0009]

[Chemical 4]

It has been found that a 6,7-diacyl-7-deacetylphoruscholine derivative represented by the formula [wherein R ¹ , R ² and R ³ are the same as above] can be obtained in good quality and in high yield. The present invention has been completed based on the above findings.

Examples of R ¹ in the above general formulas (1) and (3) include formyl group, acetyl group, propionyl group, butyryl group, pentanoyl group, hexanoyl group, glycyl group, dimethylamioacetyl group, piperidinoacetyl group. , T-butoxycarbonylaminoacetyl group, glycoloyl group, 2-morpholinopropionyl group, 2-
Aminopropionyl group, 3-dimethylaminopropionyl group, 3-benzyloxycarbonylaminopropionyl group, 2,3-dihydroxypropionyl group, 2-pyrrolidinobutyryl group, 3-thiomorpholinobutyryl group, 4
-Dimethylaminobutyryl group, 5-methylaminopentanoyl group, 6-dimethylaminohexanoyl group, tyrosyl group, hemisuccinyl group, thienoyl group, prolyl group,
Examples thereof include histidyl group, lysyl group, ornithyl group, 2-dimethylaminopropionyl group, 3-dimethylamino-2-methylpropionyl group, 4-dimethylamino-2-methylbutyryl group.

Further, R in the general formulas (1), (2) and (3)
Examples of ² include alkyl (C ₁ -C ₆ ) carbonyl groups such as formyl group, acetyl group, propionyl group, butyryl group, pentanoyl group, hexanoyl group, glycyl group, dimethylaminoacetyl group, piperidinoacetyl group, t- Butoxycarbonylaminoacetyl group, glycoloyl group, 2-morpholinopropionyl group, 2-aminopropionyl group, 3-dimethylaminopropionyl group, 2-dimethylaminopropionyl group, 3-dimethylamino-2-methylpropionyl group, 4- Aminoalkyl (C ₁ -C ₆ such as dimethylamino-2-methylbutyryl group, 4-dimethylaminobutyryl group, 5-methylaminopentanoyl group, 6-dimethylaminohexanoyl group, 3-benzyloxycarbonylaminopropionyl group. )
Carbonyl group, 2,3-dihydroxypropionyl group,
2-pyrrolidinobutyryl group, 3-thiomorpholinobutyryl group, hemisuccinyl group, thienoyl group, prolyl group, histidyl group, lysyl group, tyrosyl group, ornityl group, 2,2-dimethyl-1,3- Examples thereof include dioxolane-4-carbonyl group.

Examples of R ³ include vinyl group, ethyl group,
Examples thereof include C _{2 to} C ₃ hydrocarbon groups such as cyclopropyl group.

As the compound of the general formula (2), for example, 7
-Deacetyl-6-dimethylaminoacetylforskolin, 7-deacetyl-6-glycylforskolin,
7-deacetyl-6-piperidinoacetylforuscholine, 7-deacetyl-6- (2-dimethylaminopropionyl) foruscholine, 7-deacetyl-6- (3-
Dimethylaminopropionyl) forskolin, 7-deacetyl-6- (2-morpholinopropionyl) forskolin, 7-deacetyl-6-alanylforskolin, 7-deacetyl-6- (2-aminobutyryl) forskolin, 7 -Deacetyl-6- (4-dimethylaminobutyryl) forskolin, 7-deacetyl-6-
(2,3-dihydroxybropionyl) forskolin, 7-deacetyl-6-hemisuccinylforskolin, 7-deacetyl-6-histidylforskolin,
7-deacetyl-6-prolylforskolin, 7-deacetyl-6-lysylforskolin, 7-deacetyl-6-glycoloylforskolin, 7-deacetyl-
14,15-Dihydro-6-dimethylaminoacetylforskolin, 7-deacetyl-14,15-dihydro-6- (3-dimethylaminopropionyl) forskolin, 7-deacetyl 14,15-dihydro-6- (4
-Dimethylaminobutyryl) forskolin, 13-cyclopropyl-7-deacetyl-6- (3-dimethylaminopropionyl) -14,15-dinorforskolin, 13-cyclopropyl-7-deacetyl-6- (4
-Dimethylaminobutyryl) -14,15-dinorforskolin, 7-deacetyl-14,15-dihydro-
6-Piperidinoacetylforskolin, 7-deacetyl-14,15-dihydro-6- (2-morpholinopropionyl) forskolin, 7-deacetyl-6-
(T-Butoxycarbonylaminoacetyl) forskolin, 7-deacetyl-6- (2-benzyloxycarbonylaminopropionyl) forskolin, 7-deacetyl-6- (2-t-butoxycarbonylaminobutyryl) forskolin, 7 -Deacetylforskolin-
6- (2,2-dimethyl-1,3-dioxolane-4-
Carboxylate), 7-deacetyl-6- (3-methoxycarbonylpropionyl) forskolin, 7-deacetyl-6- (3-dimethylamino-2-methylpropionyl) forskolin, 7-deacetyl-14,1
5-dihydro-6- (3-dimethylamino-2-methylpropionyl) forskolin, 7-deacetyl-6-
(4-Dimethylamino-2-methylbutyryl) forskolin, 7-deacetyl-14,15-dihydro-6-
(4-Dimethylamino-2-methylbutyryl) forskolin, 13-cyclopropyl-7-deacetyl-6-
(3-Dimethylamino-2-methylpropionyl) -1
4,15-Dinorforskolin, 13-cyclopropyl-7-deacetyl-6- (4-dimethylamino-2-
Methyl butyryl) -14,15-dinorforskolin and the like.

Examples of the compound of the general formula (3) include 1-
Formyl-6-dimethylaminoacetyl-7-deacetyl-7-formylforskolin, 1-acetyl-
6-Dimethylaminoacetylforskolin, 1-propionyl-6-dimethylaminoacetyl-7-deacetyl-7-propionylforskolin, 1-acetyl-
6-piperidinoacetylforskolin, 1-butyryl-6-piperidinoacetyl-7-deacetyl-7-butyrylforskolin, 1-acetyl-6- (2-dimethylaminoprodionyl) forskolin, 1 -Pentanoyl-6- (2-dimethylaminopropionyl) -7-
Deacetyl-7-pentanoylforskolin, 1-acetyl-6- (3-dimethylaminopropionyl) forskolin, 1-hexanoyl-6- (3-dimethylaminopropionyl) -7-deacetyl-7-hexanoylforskolin, 1-dimethylaminoacetyl-6-
(3-dimethylaminopropionyl) -7-deacetyl-7-dimethylaminoacetylforskolin, 1-piperidinoacetyl-6- (3-dimethylaminopropionyl) -7-deacetyl-7-piperidinoacetylforskolin, 1- (t-butoxycarbonylaminoacetyl) -6- (3-dimethylaminopropionyl) -7
-Deacetyl-7- (t-butoxycarbonylaminoacetyl) forskolin, 1-acetyl-6- (2-morpholinopropionyl) forskolin, 1- (2-
Morpholinopropionyl) -6- (2-morpholinopropionyl) -7-deacetyl-7- (2-morpholinopropionyl) forskolin, 1-acetyl-6
-(4-Dimethylaminobutyryl) forskolin, 1
-(3-Dimethylaminopropionyl) -6- (4-dimethylaminobutyryl) -7-deacetyl-7- (3-
Dimethylaminopropionyl) forskolin, 1-
(3-Benzyloxycarbonylaminopropionyl)-
6- (4-Dimethylaminobutyryl) -7-deacetyl-7- (3-benzyloxycarbonylaminopropionyl) phoruscholine, 1- (2-pyrrolidinobutyryl)
-6- (4-dimethylaminobutyryl) -7-deacetyl-7- (2-pyrrolidinobutyryl) forskolin,
1-acetyl-6-hemisuccinylforskolin, 1
-(3-Thiomorpholinobutyryl) -6-hemisuccinyl-7-deacetyl-7- (3-thiomorpholinobutyryl) forskolin, 1-acetyl-14,15-
Dihydro-6-dimethylaminoacetylforskolin, 1- (4-dimethylaminobutyryl) -14,15
-Dihydro-6-dimethylaminoacetyl-7-deacetyl-7- (4-dimethylaminobutyryl) forskolin, 1-acetyl-14,15-dihydro-6- (3
-Dimethylaminopropionyl) forskolin, 1-
(6-Dimethylaminohexanoyl) -14,15-dihydro-6- (3-dimethylaminopropionyl) -7
-Deacetyl-7- (6-dimethylaminohexanoyl) forskolin, 1-acetyl-14,15-dihydro-6- (4-dimethylaminobutyryl) forskolin, 1-propionyl-14,15-dihydro-6 −
(4-Dimethylaminobutyryl) -7-deacetyl-7
-Propionylforskolin, 1-acetyl-13-
Cyclopropyl-6- (3-dimethylaminopropionyl) -14,15-dinorforskolin, 1-acetyl-13-cyclopropyl-6- (4-dimethylaminobutyryl) -14,15-dinorforskolin , 1-
Acetyl-14,15-dihydro-6-piperidino acetylphoruscholine, 1-acetyl-14,15-dihydro-6- (2-morpholinopropionyl) forskolin, 1-acetyl-6- (3-dimethyl Amino-2
-Methylpropionyl) forskolin, 1-acetyl-14,15-dihydro-6- (3-dimethylamino-
2-methylpropionyl) forskolin, 1-acetyl-13-cyclopropyl-6- (3-dimethylamino-2-methylpropionyl) -14,15-dinorforskolin, 1-acetyl-6- (4-dimethyl) Amino-2-methylbutyryl) forskolin, 1-acetyl-14,15-dihydro-6- (4-dimethylamino-
2-methylbutyryl) forskolin, 1-acetyl-
13-cyclopropyl-6- (4-dimethylamino-2
-Methylbutyryl) -14,15-dinorforskolin and the like.

Examples of the acylating agent used in the present invention include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, glycine, N, N-dimethylglycine, piperidinoacetic acid, Nt-butoxycarbonylglycine and glycol. Acid, 2-morpholinopropionic acid, alanine, 3-
Dimethylaminopropionic acid, 3-benzyloxycarbonylaminopropionic acid, 2,3-dihydroxypropionic acid, 2-pyrrolidinobutyric acid, 3-thiomorpholine butyric acid, 4-dimethylaminobutyric acid, 5-methylaminovaleric acid, 6-dimethylaminocaproic acid , Tyrosine, succinic acid, proline, histidine, lysine, ornithine, thiehuenecarboxylic acid, 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid, 3-dimethylamino-2-methylpropionic acid, 4-dimethyl Examples thereof include carboxylic acids such as amino-2-methylbutyric acid and reactive derivatives thereof.

Examples of the reactive derivative include acid halides, acid anhydrides, mixed acid anhydrides, and Leuhi anhydride.

The acylation reaction is carried out by using the above-mentioned acylating agent in the formula (2).
To about 2 to 50 times mol, preferably about 2 to 4 times
The reaction may be carried out at a temperature of about 0 ° C to the boiling point of the solvent, preferably about 0 ° C to room temperature, for about several minutes to 24 hours, preferably for about several minutes to 2 hours, using a double mole. Here, examples of the solvent include benzene, chloroform, ether, dichloromethane, 1,1,1-trichloroethane, 1,2-dichloroethane, carbon tetrachloride, ethyl acetate and the like. Selective removal of the acyl group at the 1-position of the compound of formula (3) obtained by this acylation reaction is carried out by alcoholysis,
It is carried out by a method such as amine-decomposition or hydrolysis, preferably hydrolysis. The hydrolysis is carried out in a solvent in the presence of a base or a acid at about 0 ° C. to the boiling point of the solvent, preferably about 0 ° C. to room temperature for about 1 minute to 12 hours, preferably about 5 minutes to 3 minutes.
It is carried out by reacting for about a time. The reaction time is preferably short when the temperature is high and long when the temperature is low. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, dimethylsulfoxide, N, N-dimethylformamide, acetone, tetrahydrofuran and a mixed solvent thereof with water. . The mixed solvent preferably has a water content of 50 v / v% or less, preferably a water-containing C ₁ -C ₄ alcohol having a water content of about 0.5 to about 20 v / v%.

As the base, for example, alkali hydroxide such as sodium hydroxide and potassium hydroxide, alkali carbonate such as potassium carbonate, alkali hydrogen carbonate such as sodium hydrogen carbonate, ammonia, amines such as triethylamine, Examples of the acid include mineral acids such as sulfuric acid and hydrochloric acid, and organic acids such as acetic acid, and the concentration thereof in the solvent is about 0.01 to about 50%, preferably about 0.05 to about 10%.

When R ¹ or R ² has an amine component bonded to the β-position of a propionyl group such as a dimethylaminopropionyl group, after completion of acylation or after completion of selective deacylation, It is preferable to treat the reaction product with an amine corresponding to the amine component in a solvent at 0 ° C. to room temperature for about 1 minute to 12 hours because generation of by-products can be suppressed. Examples of the solvent include benzene, carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane, ether, diisopropyl ether, ethyl acetate, acetone, propanol, ethanol and methanol. The amount of amine used is preferably about 0.1 to 3 times the molar ratio.

After the selective deacetylation reaction is completed, the excess reaction can be avoided by neutralizing the reaction. 6,7-diacyl-7-obtained by the above method
To isolate the deacetylforskolin derivative, after the reaction is complete, the reaction solution is concentrated, the resulting residue is diluted with water or saline if necessary, extracted with an organic solvent, and then the organic layer is washed and dried. After that, the residue obtained by concentration can be recrystallized, and can be easily purified without using a purification method such as chromatography.

[0022]

The yields obtained by the method of the present invention (Examples 1 and 2) and the method described in Japanese Patent Application No. 61-255941 are summarized as follows.

[0023]

[Table 1]

As is apparent from this table, 6,7-diacyl-7-deacetylforskolin can be obtained in good yield by the method of the present invention. In addition, Japanese Patent Application No. 61-25
The manufacturing method described in 5941 is as follows. Acetyl chloride is allowed to act on a dichloromethane solution of 6-acyl-7-deacetylforskolin in the presence of pyridine, and after completion of the reaction, the reaction product is purified by silica gel column chromatography.

Example 1 6- (4-Dimethylaminobutyryl) forskolin 7-deacetyl-6- (4-dimethylaminobutyryl)
Acetic anhydride (30 ml) was added to a mixed solution of forskolin (31.7 g), 4-dimethylaminopyridine (0.5 g) and pyridine (120 ml) under ice cooling. Stir at room temperature for two nights, and after the reaction is complete, concentrate the reaction mixture. The concentrate obtained is dissolved in methanol (600 ml), 1N sodium hydroxide (250 ml) is added, and the mixture is stirred at room temperature for 35 minutes. The reaction solution was filtered off and the obtained elementary crystals (31.2 g) were recrystallized from acetone to give 6- (4-dimethylaminobutyryl) forskolin 28.7 g, 7-deacetyl-6- (4-dimethylamino). 83% from butyryl) forskolin. IR (KBr) ν: 3450, 1730, 1710 cm
^-1 By separating the reaction product before hydrolysis with sodium hydroxide by silica gel column chromatography, 1
-Acetyl-6- (4-dimethylaminobutyryl) forskolin is obtained.

¹ H-NMR (CDCl ₃ ) δ: 5.84 (1H, t, J = 3.5Hz),
5.57 (1H, brs), 5.56 (1H, d, J = 4.8Hz), 2.41 (6H, s), 2.03 (6
H, s), 1.64 (3H, s), 1.52 (3H, s), 1.34 (3H, s), 1.04 (3H, s),
0.97 (3H, s).

Example 2 6- (3-Dimethylaminopropionyl) forskolin 7-deacetyl-6- (3-dimethylaminopropionyl) forskolin (12 g), 4-dimethylaminopyridine (35 mg), anhydrous pyridine (48 ml) A mixture of acetic anhydride (5.9 ml) was stirred at room temperature for 2 hours.
4-Dimethylaminopyridine (35 mg) is added, and the mixture is further stirred at room temperature for 3 hours. After completion of the reaction, methanol (5m
1) is added and the reaction solution is concentrated. The concentrated solution obtained was diluted with methanol (120 ml) and water (25 ml), and diluted with 1N.
Add sodium hydroxide (40 ml) and stir at room temperature for 30 minutes. The reaction is stopped with 1N hydrochloric acid (50 ml), and the reaction solution is concentrated. The concentrate is diluted with water, made basic with concentrated aqueous ammonia, and then extracted with diisopropyl ether.
The organic layer is dried over anhydrous magnesium sulfate and the desiccant is filtered off. The filtrate is concentrated, the resulting residue (13.4 g) is dissolved in dichloromethane and dimethylamine is introduced. The mixture is stirred at room temperature for 1 hour, and after the reaction is completed, the reaction solution is concentrated. The residue obtained was first recrystallized from ethanol and then 6 from cyclohexane-dichloromethane.
-(3-Dimethylaminopropionyl) forskolin (7.04 g, 54% from 7-deacetyl-6- (3-dimethylaminopropionyl) forskolin) is obtained. IR (KBr) ν: 3200, 1735, 1710 cm
^-1 1-Acetyl-6- (3-dimethylaminopropionyl) was obtained by separating the reaction product before hydrolysis with sodium hydroxide in the synthetic process of 6- (3-dimethylaminopropionyl) forskolin by silica gel column chromatography. ) Get Forskolin.

IR (nujol) ν: 3500,173
^{5,1710cm -1 1 H-NMR (CDCl} 3) δ: 5.85 (. 1H, q J = 4.8Hz J = 2.9Hz), 5.
57 (1H, br s), 5.55 (1H, d, J = 4.8Hz), 2.32 (6H, s), 2.02
3 (3H, S), 2.020 (3H, s), 1.65 (3G, s), 1.53 (3H, s), 1.34
(3H s), 1.04 (3H, s), 0.98 (3H, s). MS (hydrochloride) m / z (relative intensity): 552 (M ⁺ , 18 in free base), 160 (22), 118 ( 7
0), 116 (33), 59 (39), 58 (10
0).

Example 3 1-Acetyl-6- (2-morpholinopropionyl)
Fluorskolin (1) 7-deacetyl-6- (2-morpholinopropionyl) phorskolin (700 mg), pyridine (1
Acetyl chloride (945 mg) was dissolved in dichloromethane in a mixture of g) and dichloromethane (30 ml), and the mixture was stirred at room temperature for 9 hours.
Add 6 times during the time. After completion of the reaction, water is added to the reaction solution, which is made basic with 20% sodium hydroxide and extracted with dichloromethane. The organic layer is dried over anhydrous magnesium sulfate and the desiccant is filtered off. The filtrate was concentrated and the residue was recrystallized from hexane-toluene to give 1-acetyl-6- (2-morpholinopropionyl) forskolin (606 m as a colorless solid diastereomer mixture).
g, 75%).

IR (nudjiol) ν: 3490,175
0,1715,1230 cm ^-1 MS m / z (relative intensity): 593 (M ⁺ , 0.0
3), 549 (0.7), 518 (0.5), 410
(0.7), 228 (0.9), 191 (12), 16
0 (8), 115 (23), 114 (100), 70
(9).

(2) 6- (2-morpholinopropionyl) forskolin 1-acetyl-6- (2-morpholinopropionyl)
Forskolin (372 mg) and methanol (20 m
1N sodium hydroxide (0.75 ml) in the mixture of l)
And stir at room temperature for 30 minutes. After the reaction is completed, the reaction solution is concentrated. The concentrate is diluted with saturated brine and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and the desiccant is filtered off. The filtrate was concentrated and the resulting solid residue (3
88 mg) was recrystallized from hexane-ethyl acetate to give 6- (2-morpholinopropionyl) forskolin (214 mg, 62%).

IR (nujor) ν: 3170,173
5,1710 cm ^-1 MS m / z (relative intensity): 551 (M ⁺ , 0.2),
518 (2), 158 (20), 115 (100), 1
14 (100), 70 (47).

Example 4.6 6-Piperidinoacetyl fluoscholine 7-deacetyl-6-piperidino acetylphoruscholine (188 mg), 4-dimethylaminopyridine (10
mg) and pyridine (4 ml) under ice cooling, acetic anhydride (520 mg) is added, and the mixture is stirred at room temperature for 3.5 hours.
After completion of the reaction, methanol is added under ice cooling and concentrated. Saturated saline is added to the obtained oily residue, which is made basic with concentrated aqueous ammonia and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and the desiccant is filtered off. The filtrate is concentrated to give a solid product (224 mg). This product (120 mg) was dissolved in methanol (5 ml) and
Sodium hydroxide (0.20 ml) was added, and the mixture was stirred at room temperature for 25
Stir for a minute. After the reaction is completed, the reaction solution is concentrated. The concentrate is diluted with saturated brine and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and the desiccant is filtered off. The filtrate was concentrated, and the resulting residue (113 mg) was added to hexane-
By recrystallizing from ethyl acetate, 59 mg of 6-piperidinoacetylforskolin, (7-deacetyl-6
-54%) from piperidino acetylforskolin.

IR (nujol) ν: 3180, 174
5,1710 cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 5.85 (1H, q, J = 4.2Hz _, J = 2.7Hz),
5.55 (1H, d. J = 4.4Hz) 4.61 (1H, br s), 3.18 and 3.1
4 (respectively 1H, d, J = 16Hz), 2.5 (4H, m), 2.0 3 (H,
s), 1.66 (3H, s), 1.44 (3H, s), 1.35 (3H, s), 1.03 (3H,
MS, m / z: 535 (M ⁺ ), 1-acetyl-6-pyrene by separating the reaction product before selective hydrolysis with sodium hydroxide by silica gel chromatography. Obtain peridinoacetylfluorosulcholine. MS m / z: 577 (M ⁺ ).

Example 5 6- (3-Dimethylaminopropionyl) -14,15-dihydroforsucholine hydrochloride 7-Deacetyl-6- (3-dimethylaminopropionyl) -14,15-14,15-dihydroforsu A mixed solution of choline, 4-dimethylaminopyridine (7 mg), pyridine (2 ml) and acetic anhydride (0.4 ml) is stirred at room temperature for 3 hours. After completion of the reaction, methanol (1 ml) is added with stirring under ice cooling, and the reaction solution is concentrated. The concentrate is diluted with saturated brine, made basic with concentrated aqueous ammonia, and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and the desiccant is filtered off. The filtrate was concentrated to give 1-acetyl-6.
-(3-Dimethylaminopropionyl) -14,15-
Dihydroforskolin (231 mg) is obtained. This residue was diluted with methanol (2 ml) and cooled to 0.25N under ice cooling.
Aqueous sodium hydroxide solution (0.4 ml) is added, and the reaction solution is stirred under ice-cooling for another 1.5 hours. 1N hydrochloric acid (0.6m
l) is added to stop the reaction and the reaction solution is concentrated. The concentrate is diluted with water, made basic with concentrated aqueous ammonia and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and the desiccant is filtered off. The filtrate is concentrated to give a residue (202 mg). Dissolve this residue in dichloromethane (2 ml) and
Hydrochloric acid is added in dioxane solution (0.15 ml). The mixture was concentrated and the resulting solid residue (210 mg) was recrystallized from methanol-ethyl acetate (2: 3) to give 6- (3-dimethylaminopropionyl) -1.
4,15-Dihydroforskolin hydrochloride (112m
g, 7-deacetyl-6- (3-dimethylaminopropionyl) -14,15-dihydroforskolin yield 48%).

Reference Example 7-Deacetyl-6- (3-dimethylaminopropionyl) -14,15-dihydroforskolin 7-deacetyl-6- (3-dimethylaminopropionyl) forskolin (703 mg), 5% palladium carbon catalyst A mixture of (23 mg) and methanol (20 ml) was stirred under a hydrogen atmosphere at room temperature for 1 hour and 40 minutes. After completion of the reaction, the reaction solution is filtered to remove the catalyst. The filtrate was concentrated, and the resulting solid residue (689 mg) was recrystallized from chloroform-isopropyl ether (1: 5) to give 7-deacetyl-6- (3-dimethylaminopropionyl) -14,15-dihydrofluorescein. Rukon (541m
g, yield 70%).

Mp 163-165 ° C. IR (nujol) ν: 3200, 1735, 1705
^{cm -1 1 H-NMR (CDCl} 3) δ: 5.94 (. 1H, t J = 4H z), 4.50 (1H, br
s), 4.18 (1H, d, J = 5Hz), 2.26 (6H, s), 1.53 (3H, s), 1.42 (3
H, s), 1.31 (3H, s). 1.10 (3H, s), 0.97 (3H, tJ = 7Hz), 0.9
5 (3H, s). MS m / z (relative intensity): 469 (M ⁺ , 5), 159)
13), 118 (48), 116 (12), 91 (3
0), 69 (13), 59 (10), 58 (100),
57 (11), 55 (13).

Claims (2)

[Claims] 1. A formula (3): [Wherein R ¹ and R ² are each an acyl group, and R ³ is C _{2 to} C
₃ represents a hydrocarbon group]], a 1,6,7-triacyl-7-deacetylforskolin derivative. 2. The 1,6,7-triacyl-7-deacetylforskolin derivative according to claim 1, wherein R ¹ is an acetyl group, R ² is a 3-dimethylaminopropionyl group, and R ³ is a vinyl group.