JPH0533713B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Field of Application: The present invention relates to novel compounds with antihyperlipidemic activity. More specifically, the present invention provides an α-alkylcinnamic acid having 1 to 4 carbon atoms, which has excellent antihyperlipidemic activity and low toxicity, i.e., is safe and has a triterpene alcohol mono- or di-substituted group attached to the benzene nucleus. Ester, or an alkoxy group having 1 to 4 carbon atoms and a nitro group, an alkoxy group having 1 to 4 carbon atoms and an amino group, or an alkoxy group having 1 to 4 carbon atoms and a nitro group having 2 to 4 carbon atoms
The present invention relates to a benzoic acid or cinnamic acid ester having a disubstituted acylamino group of No. 5 attached to a benzene nucleus. BACKGROUND OF THE INVENTION Hyperlipidemia is well known to be an important risk factor for arteriosclerosis, especially coronary arteriosclerosis.
1975, Miller and Miller [GJ Miller, NE
Miller; Lancet: Jan. 4, p. 16 (1975)] is a high-density lipoprotein cholesterol (HDL) in plasma.
It is called C. ) and the cholesterol pool in the body, and no correlation was observed between blood total cholesterol (hereinafter referred to as TC) and other lipoprotein concentrations. During ~
He proposed the idea that a decrease in HDL-C concentration leads to a decrease in the clearance of cholesterol from the arterial wall, which promotes arteriosclerosis. Since this report, numerous epidemiological studies [e.g. T. Gordon
et al.: Am.J.Med., vol. 62, p. 707 (1977)] demonstrated that there is an inverse correlation between the occurrence of ischemic heart disease and HDL-C concentration. It was confirmed that hypolipidemia is one of the major risk factors for the development of ischemic heart disease, regardless of the presence or absence of antihyperlipidemic agents. It has long been known that plant sterols lower serum cholesterol. For example, a mixture of β-sitosterol and dihydro-β-sitosterol (trade name: Cytellin, manufactured by Lilly, USA); a mixture of soysterol, plant sterol, and tocopherol (trade name: Moristerol, manufactured by Morishita Pharmaceutical, Japan)
etc. are commercially available as therapeutic agents for hyperlipidemia. On the other hand, the following literature has been published regarding triterpene alcohols. JP-A No. 57-18617 states that when 1 part of plant sterol is combined with 0.01 to 0.1 part of cycloartenol or 24-methylenecycloartanol, a synergistic effect results in a stronger serum cholesterol lowering effect than when plant sterol is used alone. It is being JP-A-58-116415 discloses that plant sterols
When combined with 1 to 20 parts (especially around 5 parts) of cycloartenol, 24-methylenecycloartanol or cyclolaudenol per 100 parts, the synergistic effect lowers serum cholesterol much more strongly than when using plant sterol alone. It is stated that the effect was observed. In particular, cycloartenol shows a synergistic effect on the serum cholesterol-lowering effect of plant sterols, while 24-methylenecycloartanol and cyclolaudenol show a less synergistic effect than cycloartenol. Japanese Patent Application Laid-Open No. 59-27824 discloses that cholesterol
For 0.5% additive food, cycloartenol or 24
- When 1% methylenecycloartanol was added, compared to the control of high cholesterol intake
The rate of decrease in TC is reported to be 13.7% for the former and 10.2% for the latter (calculated by the inventors based on the results in Table 2 of the same publication). However, although the above three publications report the effect of lowering serum TC, serum triglycerides (hereinafter referred to as TG), total phospholipids (hereinafter referred to as PL), HDL-C, Atherogenic
Index [calculated by TC-HDL-C/HDL-C, below
It is called AI. Among medical scientists in our country, this AI
Some people refer to this as the cholesterol ratio or arteriosclerosis index. ] and lipid peroxide (hereinafter referred to as LPO)
There is no mention of anything regarding it. Although cycloartenol, 24-methylenecycloartanol, and cyclolaudenol reduced serum TC either alone or in the coexistence with plant sterols, they are still important in determining the treatment of hyperlipidemia. It also has a lowering effect on the serum lipids TG, PL, and LPO, and also has the effect of increasing HDL-C, which has recently been particularly important in the treatment of hyperlipidemia, and further lowering AI. It is unknown whether or not it has. or,
Such general pharmacological activity is inconceivable. Furthermore, γ-oryzanol, which is currently marketed in Japan as a head and neck injury therapeutic agent, is not a single product, but a mixture of various plant sterols and ferulic acid esters of triterpene alcohols. An example of this component ratio is 14% campesterol, 1% stigmasterol, 4% β-sitosterol, 2% cycloartanol, 35% cycloartenol, 44% 24-methylenecycloartanol, and each ferulic acid. It consists of an ester composition and contains almost no cyclobranol ferulate ester. Recently, the following report has been made regarding the effect of γ-oryzanol on cholesterol metabolism in hyperlipidemic rats. Fumio Kuzutani, Noriyoshi Yoshimine, Shoji Kato, Katsunari Fujita, Hiroyo Ushigome et al. [Geriatric Medicine Vol. 18, 519
~524 (1980)] used rats fed a high-cholesterol diet, and using this as a control, the TC of rats fed a high-cholesterol diet supplemented with 0.1, 0.5, and 1% γ-oryzanol was clearly decreased, and this decrease was caused by administration. It was quantity dependent. The rate of decrease in TC is greater than the rate of decrease in PL, and the rate of decrease in TC is higher than that of HDL.
The rate of decrease was the same as that of -C, and no effect was observed on AI. They reported that TG showed an increasing trend, and LPO clearly showed a decreasing effect. Kouga Mitani, Yasuhiro Kido, Seiichi Shimizu, Seiji Morita et al. [Arteriosclerosis Vol. 11, No. 2, June 411-416 (1983)] found that γ-oryzanol increased by 0.5% compared to rats fed a high-cholesterol diet. In rats fed high-cholesterol diets supplemented with 1.0% and 2.0%, serum TC values decreased by 8.1%, 23.4%, and 30.9%, respectively. On the other hand, no significant decrease was observed in serum TG and serum PL values. Shuji Inoue, Masato Egawa, Shinobu Sato et al. [Arteriosclerosis 11
Vol., No. 2, June 417-428 (1983)] investigated the effect of γ-oryzanol on hyperlipidemia in hypothalamically obese rats. No significant decrease was observed in middle TG. They also reported that it had no effect on blood PL and HDL-C. On the other hand, for organic acids, RDSharma
[Atherosclerosis Vol. 37, pp. 463-468 (1980)]
Compared to rats ingesting a high-cholesterol diet, in rats ingesting a high-cholesterol diet supplemented with 0.2% organic acid, the rate of decrease in TC for ferulic acid and p-Coumaric acid was 10.8 for the former.
%, the latter significantly decreased by 9.4%. The decrease in TG was 18.7% for ferulic acid and 19.8% for p-coumaric acid, but the decrease was not significant. Almost no decrease in PL was observed in both cases. Vanillic acid, Caffeic acid, and Cinnamic acid include TC, TG, and LP.
They reported that no decrease was observed in either case. Although not an organic acid alone, the following report has been published regarding the antihyperlipidemic effect of α-methylcinnamic acid derivatives. Hiroki Takashima et al. [Biochemical Pharmacology 27
Vol., p. 2631 (1978)] reported on the antihyperlipidemic effect of α-mono-p-myristyloxy-α'-methylcinnamoylglycerol in rats. Toshiro Watanabe et al. [Journal of Medicinal
Chemistry Vol. 23, p. 50 (1980)] are p-alkoxycinnamic acid and p-alkoxy-α-methylcinnamic acid (however, the alkyl group of alkoxy is methylene, vinyl, and _C8 - _C18 ; phenyl group); o- , p
- or m-myristyloxycinnamic acid; m-methoxy-p-alkoxy-α-methylcinnamic acid (however, the alkyl groups of alkoxy are C ₁₂ and C ₁₄ ); p-
Ester derivatives of alkoxycinnamic acid and p-alkoxy-α-methylcinnamic acid [the alkyl group of alkoxy is methylene, vinyl, methyl, butyl,
_C8 to _C18 ; ester groups include chloroethyl, methacryloxyethyl, monoglyceride, diglyceride, etc.] and their antihyperlipidemic activities were reported in detail. Furthermore, Toshiro Watanabe et al. (Special Publication No. 51-45582) reported that p-alkoxy-α-methylcinnamic acid (however, the alkyl group of alkoxy
A method for producing C ₈ -C ₁₆ ) was reported. Tomio Ota et al. (Japanese Unexamined Patent Publication No. 57-80370) disclosed that α-methyl-p-[pyridyl (or pyridyl alkyl)oxy]-cinnamic acid (or C ₁ -C ₃ alkyl ester of cinnamic acid)
This article reports on the method for producing the same, and antihyperlipidemic agents containing the same. Recently, Helmiyut Grill et al.
25953) is N-carboxymethyl-4-(2
-Hydroxy-4-phenylbutoxy)benzamide, 4-[4(4'-t-butylphenyl)-2-
We reported on p-oxybenzoic acid derivatives such as oxobutoxy]benzoic acid, their production methods, and antihyperlipidemic agents. Problems to be Solved by the Invention: The present inventors conducted additional tests on the antihyperlipidemic effects of known compounds such as cycloartenol, 24-methylenecycloartanol, and cyclobranol. The pharmacological test method for antihyperlipidemia is described in B below.
(hereinafter referred to as method B) was conducted in which male Wistar rats, initially weighing 100±1 g, were reared for 4 weeks with free access to food and water. For reference, method A of the pharmacological test method for antihyperlipidemia (feed intake was limited to 10 g/day for one Wistar male rat with an initial body weight of 100 ± 1 g. However, Water is available ad libitum and the breeding period is 2 weeks - below A
It's called law. ) is the method adopted in the earlier application (Patent Application No. 59-115306 (Japanese Unexamined Patent Publication No. 60-258198), filing date: June 4, 1982), and to distinguish it from this, in the present invention, B It's called law. The method for measuring each lipid component in serum will be described later. The antihyperlipidemia test results of known triterpene alcohols by method B are shown in Tables 1 and 2. As can be seen from Tables 1 and 2, the cycloartenol and cyclobranol administration group significantly (P<0.01) lowered serum TC compared to the control group administered hyperlipidemic feed. Admitted.
In addition, a significant (P<0.05) decrease in TC was also observed in the 24-methylenecycloartanol administration group. HDL-C
Cycloartenol was significant (P<
0.01), and the decrease in 24-methylenecycloartanol was slight and not significant. On the other hand, cyclobranol showed a slight increasing tendency, but the increase was not significant. It is desirable that this HDL-C increases significantly as shown in the above-mentioned literature. One of the objectives of creating an antihyperlipidemic agent using the compound of the present invention is to significantly lower serum TC and significantly increase HDL-C.
As shown above, in line with previous literature results, it was confirmed that single doses of known triterpene alcohols such as cycloartenol, cyclobranol, and 24-methylenecycloartanol significantly lowered serum TC. did. However, regarding HDL-C, A (patent application filed in 1983) conducted by the present inventors
-115306) and Method B, no significant increase was confirmed by the antihyperlipidemia test method in which the rearing conditions were different. Regarding AI, all three types of triterpene alcohols showed a decreasing trend. For TG, PL and LPO, the three triterpene alcohols showed no significant variation. However, when comparing these three types of triterpene alcohols, cyclobranol has TC, AI,
While TG, PL, and LPO showed a decreasing trend, HDL−
C and showed a different action behavior from cycloartenol and 24-methylenecycloartanol. That is, cyclobranol was found to have a better antihyperlipidemic effect than cycloartenol and 24-methylenecycloartanol. As a result of detailed studies to improve the antihyperlipidemic effect of triterpene alcohols, the present inventors discovered the existence of a number of novel triterpene alcohol organic acid ester compounds that have excellent antihyperlipidemic activity. discovered. That is, the present inventors found that serum
HDL-C while decreasing TC, PL, TG content
The ideal goal of our research was to create an antihyperlipidemic agent that increases LPO content, simultaneously lowers AI, and also lowers serum LPO content. Next, we will discuss the creation of an antihyperlipidemic agent that shows clear improvement in antihyperlipidemic effects compared to the known starting materials triterpene alcohol and γ-oryzanol in 2 to 3 or more of the 6 measurement items. I considered it carefully. As a result, it has been found that the organic acid ester of triterpene alcohol according to the present invention has excellent antihyperlipidemic effects. This fact is difficult to imagine from the conventionally known properties of triterpene alcohols and organic acids alone or of γ-oryzanol. Means for solving the problems: The novel triterpene alcohol organic acid esters of the present invention include cycloartenol, cyclobranol, 24-methylenecycloartanol, lanosterol, lanosterol, agnosterol,
It is an organic acid ester of cyclosadol, dihydroagnosterol, cyclolaudenol, cycloartanol, cycloeucalenol, euphol, butyrospermol, tircalol, euphorbol or damaradienol. Among these,
Preferred are organic acid esters of cycloartenol, cyclobranol, and 24-methylenecycloartanol. Preferred organic acids are amino groups, nitro groups, hydroxy groups, acylamino groups having 2 to 5 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, or alkylcarboxy groups having 2 to 6 carbon atoms as a substituent in benzene. α-carbon number 1 in the nucleus
-4 alkylcinnamic acid; hydroxy group and alkoxy group having 1 to 4 carbon atoms, hydroxy group and 2 carbon atoms
~6 alkylcarboxy groups, alkoxy groups having 1 to 4 carbon atoms and alkylcarboxy groups having 2 to 6 carbon atoms, alkoxy groups having 1 to 4 carbon atoms and nitro groups, alkoxy groups having 1 to 4 carbon atoms and amino groups, Carbon number 1
~4 alkoxy groups and acylamino groups having 2 to 5 carbon atoms, 2 alkoxy groups having 1 to 4 carbon atoms, 2 alkylcarboxy groups having 2 to 6 carbon atoms, or 2 disubstituted hydroxy groups. α-alkylcinnamic acid having 1 to 4 carbon atoms; alkoxy group having 1 to 4 carbon atoms, nitro group, 1 to 4 carbon atoms;
Cinnamic acid or benzoic acid having a disubstituted group of an alkoxy group and an amino group having 4 or an alkoxy group having 1 to 4 carbon atoms and an acylamino group having 2 to 5 carbon atoms attached to a benzene nucleus; a saturated fatty acid having 4 to 20 carbon atoms; be. The compounds of the present invention are stable compounds. As is clear from the production method shown in Examples, it is a stable compound that does not undergo any hydrolysis even when heated and stirred at 60 to 70°C for 3 hours in a strongly acidic aqueous solution with a pH of 0.5 to 1.5. The structural formulas of three preferred organic acid esters of triterpene alcohols in the compounds of the present invention are shown below. When R is H in general formulas Ia, Ib, and Ic, formula Ia
is cycloartenol, formula Ib is 24-methylenecycloartanol, and formula Ic is cyclobranol. These three types of triterpene alcohols are known. In the present invention, R in Ia, Ib and Ic represents a residue of the various monobasic organic acids shown above. Among these organic acid residues, _C4 to _C20 , preferably _C6 to _C16
The compounds of the present invention consisting of organic acid residues other than saturated monobasic fatty acid residues are represented by the general formulas a to d and e.
Shown below. general formula However, R ₁ represents an α-C ₁ to C ₄ alkyl-α,β-unsaturated carbonyl group [-CH=C(R ₃ )-CO-], and R ₂ represents an amino group (-NH ₂ ), an acylamino group ( _-NHCOR3 ), nitro group ( _-N02 ), hydroxy group (-OH), alkoxy group having 1 to 4 carbon atoms ( _-OR3 ), or alkylcarboxy group having 2 to 6 carbon atoms ( _-OCOR4 ) is shown. R ₃ is an alkyl group having 1 to 4 carbon atoms, i.e. methyl, ethyl, propyl,
iso-propyl, butyl, iso-butyl, s-butyl or t-butyl. R ₄ is an alkyl group having 1 to 5 carbon atoms, that is, pentyl, iso-pentyl, s-pentyl, 3-pentyl or t-pentyl in addition to the above-mentioned alkyl group having 1 to 4 carbon atoms.
That is, the general formula [] is a triterpene alcohol ester of α-alkylcinnamic acid having 1 to 4 carbon atoms, in which one substituent of R ₂ is bonded to the ortho, meta, or para position of the benzene nucleus. general formula However, R ₁ and R ₃ in general formulas a to d have the same meanings as above. general formula However, R ₅ of e represents an α,β-unsaturated carbonyl group (-CH=CH-CO-) or a carbonyl group (-CO-), and R ₃ represents the same meaning as above. The compound of general formula a has an OH group on the benzene nucleus.
Different disubstituents of ₃ OR groups or OH groups and ₄ OCOR groups,
The compound of general formula b has _three OR groups on the benzene nucleus.
It is a triterpene alcohol ester of α-C _1-4 alkylcinnamic acid bound to different disubstituents of OCOR ₄ , NO ₂ , NH ₂ or NHCOR ₃ groups. Below a
The compounds of and b will be explained in detail. That is, in the compound represented by general formula a, OH
When the group is attached to the ortho position (position 2) of the benzene nucleus, the OR ₃ or OCOR ₄ group is 3, 4, 5 or 6
It is a compound that is bonded at each position. Similarly OH
When the group is bonded to the meta-position (3-position) of the benzene nucleus, the OR ₃ group or the OCOR ₄ group is attached to the 2,
These are compounds bonded at the 4, 5, or 6 positions, respectively. Similarly, the OH group is located at the para position (4) of the benzene nucleus.
When bonded to the 2nd or 3rd position of the benzene nucleus, the _OR3 group or the _OCOR4 group is a compound bonded to the 2nd or 3rd position of the benzene nucleus, respectively. (Hereinafter, these will be abbreviated as compounds of general formula a). The individual bonding modes of these compound groups a are shown in the following general formulas a ₁ to a ₁₀ . general formula However, in general formulas _a1 to _a10 , _R1 and _R3 have the same meanings as above. The bonding mode for the compound group of general formula b is:
The OH group of the compound group of general formula a is replaced by an OR ₃ group, and the benzene nucleus has an OR ₃ group and an OCOR _{4 group} ,
It is a triterpene alcohol ester of α-C _1-4 alkylcinnamic acid that binds a heterogeneous disubstituent of NO ₂ , NH ₂ or NHCOR ₃ groups. Therefore b ₁ is a ₁
OR ₃ group in place of the OH group in the compound of , and OCOR ₄ in place of the OR ₃ group or OCOR ₄ group in the compound of a ₁ ,
It is a compound in which _three NO ₂ , NH ₂ or NHCOR groups are alternatively bonded. The following b ₂ to _{b 10} are the same, and these b ₁ to
The general formula of _b10 is shown below. _{OCOR 4 ,} NO ₂ , _{NH 2 or}
The _three NHCOR groups are collectively designated as "X". general formula However, in general formulas _b1 to _b10 , _R1 and _R3 have the same meanings as above. The compound of general formula c is a triterpene alcohol ester of α-C _1-4 alkylcinnamic acid having two OH groups on the benzene nucleus, and the compound of general formula d has two OR ₃ groups on the benzene nucleus. That is, the compound of general formula c has the 2nd and 3rd positions, the 2nd and 4th positions, the 2nd and 5th positions, the 2nd and 6th positions, the 3rd and 4th positions, or the 3rd and 5th positions of the benzene nucleus.
It has two OH groups at each position and consists of the six types of bonds shown below. general formula In addition, the bonding mode of the compound group of general formula d is that two OR ₃ groups are substituted for the two OH groups of the compound of general formula c, and d ₁ to _{c 6} as well as c 1 to _{c 6} There are six compounds with d ₆ . In the compound group of general formula e, when NO ₂ , NH ₂ or NHCOR ₃ groups are collectively designated as "Y", the bonding mode is R ₁ in the general formula of b ₁ to b ₁₀ above.
There are 10 types of compounds which are the same as b ₁ to b ₁₀ , in which R ₅ group is substituted in place of the group, and Y group is substituted in place of the X group. The method for producing the compound of the present invention will be explained below. The above-mentioned γ-oryzanol is a preferred source of cycloartenol, 24-methylenecycloartanol and cyclobranol. In other words, γ, which is currently commercially available in Japan as a treatment for head and neck injuries.
-Oryzanol is not a single product, but a mixture of various sterols and ferulic acid esters of triterpene alcohols. An example of this ingredient ratio is 14% campesterol and 1% stigmasterol.
%, β-sitosterol 4%, cycloartanol 2%, cycloartenol 35%, and 24-methylenecycloartanol 44%. Isolation method of cycloartenol: That is, γ-oryzanol was isolated using acetone-methanol, acetone, and ethyl acetate, with reference to the method of Endo, Misu, Inaba et al. Repeated recrystallization to obtain cycloartenol ferulic acid ester, which was then saponified and decomposed to give cycloartenol with a melting point of 101~
102°C, specific optical rotation [α] ^21.5 _D + ^49.7 ° (C1.01, CHCl ₃ )
I got it. This product showed a single peak in gas chromatography. Isolation method of 24-methylene cycloartanol: Followed the method of Endo et al. (Oil Kagaku Vol. 18, pp. 63-67 (1969)). That is, 24-methylenecycloartanol was isolated from the mother liquor from which cycloartenol was separated from γ-oryzanol. The crystals were acetylated with pyridine-acetic anhydride, and this acetylated product was repeatedly recrystallized using chloroform-ethyl acetate-ethanol (4:3:2).
Deacetylation and recrystallization with acetone-methanol mixed solvent give 24-methylenecycloartanol ferulic acid ester, which is saponified and decomposed to obtain 24-methylenecycloartanol melting point.
123-124℃, specific optical rotation [α] ²⁴ _D +48.1゜(C1.00,
CHCl ₃ ) was obtained. This product showed a single peak in gas chromatography. Isolation method of cyclobranol: 1.1 kg of γ-oryzanol (cyclobranol content 0%) was dissolved in acetone 8, 40 g of iodine was added, and the solution was heated under reflux for 1.5 hours. After cooling, 10%
After adding 500 ml of sodium thiosulfate aqueous solution and stirring for 30 minutes, 550 ml of water was further added and the precipitated crystals were filtered off. Add this to a 2% sodium thiosulfate aqueous solution.
Washed with 700 ml followed by 4 ml of water and dried. This γ
-As a result of gas chromatography analysis of oryzanol, γ- contains approximately 23% cyclobranol.
1 kg of oryzanol was obtained. 1 kg of this crystal was suspended in 4% caustic potash-ethanol solution 8 and heated under reflux for 3 hours. After cooling, the precipitated potassium salt of γ-oryzanol was collected by filtration, and then methanol 8
The suspension was suspended in water and heated under reflux for 2 hours. After cooling, the precipitated yellow crystals were collected by filtration and dried to obtain 260 g of potassium salt of γ-oryzanol. The crystals were treated as described above with caustic potash-ethanol solutions at alkali concentrations of 3% and 2% to obtain 130 g of yellow crystals. This contained 88% cyclobranol. Next, add 130g of yellow crystals to a 2N caustic potash-ethanol solution.
After saponification and decomposition in step 2.6, the residue was dissolved in chloroform.
Extracted with 1.2. After drying the chloroform layer, it was distilled off under reduced pressure to obtain 80 g of crude cyclobranol (purity 88
%) was obtained. 80 g of this crude crystal was recrystallized 3 times with 1.6 acetone to crystallize cyclobranol 28
I got g. Melting point 165-166℃, specific rotation [α] ²⁵ _D +
47.0° (C1.00, chloroform). This showed a single peak in gas chromatography. The triterpene alcohol organic acid ester of the compound of the present invention can be easily obtained by utilizing a known esterification reaction between a general alcohol and an organic acid. Namely, the esterification reaction of an organic acid and a triterpene alcohol by dehydration using a catalyst such as sulfuric acid, P-toluenesulfonic acid, or boron triboide (BF ₃ ); Reaction between organic acid halide and triterpene alcohol; Reaction between organic acid halide (also referred to as organic acid halide, hereinafter the same meaning) and triterpene alcohol, etc. are used. Among these, the most preferred is a method based on a reaction between an organic acid halide and a triterpene alcohol. That is, C ₆ to ₁₆
monobasic acid of saturated fatty acid; in the organic acid of the general formula of the compound of the present invention, substituent R ₂ is NO ₂ groups, OR ₃ groups,
α-C _1-4 alkylcinnamic acid having one substituent of OCOR ₄ group or NHCOR ₃ group; an organic acid of the compound of the above general formula b with OR ₃ group and OCOR ₄ , NO ₂ , NH ₂
or NHCOR ₃ groups, a total of 2; OR ₃ groups and NO ₂ , NH ₂ or NHCOR ₃ groups in the organic acid of the compound in e above, or 2 OR ₃ groups as in the organic acid of the compound in d. When using cinnamic acid, benzoic acid, or α-C _1-4 alkylcinnamic acid as a starting material, the COOH group of these organic acids is converted into an acid halide using a halogenating reagent. , this acid halide was treated with a triterpene alcohol in a solvent in the presence of a dehydrohalogenating agent at a temperature of 10
By carrying out the esterification reaction at ~100°C, a triterpene alcohol organic acid ester having the desired structure could be obtained easily and in high yield. Preferred halogenating reagents include thionyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus oxychloride, benzoyl chloride, phthaloyl chloride, hydrogen chloride, and hydrogen bromide. Examples of dehydrohalogenation agents include pyridine, quinoline, trimethylamine, triethylamine, tripropylamine, tributylamine,
Magnesium, dimethylaniline, etc. are used. Among the organic acids of the present compound of the general formula,
α- in which R ₂ has a monosubstituent of OH group or NH ₂ group
Alkylcinnamic acid having 1 to 4 carbon atoms; OH group and ₃ OR groups as in the organic acid of the compound of the present invention in a.
Different disubstituted groups of OH group and ₃ OCOR groups; When starting material is α-alkylcinnamic acid having 1 to 4 carbon atoms, which has a disubstituted group of OH group attached to the benzene nucleus, as in the organic acid of the compound c. , using an organic acid with acylated OH groups or NH ₂ groups as a raw material and converting it into acid halide by the above method,
The organic acid ester of triterpene alcohol having the desired structure can be obtained easily and in high yield by the same operation method as described above. Thereafter, a deacylation reaction, that is, a heating treatment with a concentrated aqueous solution of ammonia, caustic alkali (caustic soda, caustic potash) or inorganic acid (hydrochloric acid, sulfuric acid, phosphoric acid),
A compound of the general formula a or c of the present invention compound having an OH group or NH ₂ group attached to a benzene nucleus can be easily synthesized. The acylation shown above is acetic acid, propionic acid,
The purpose can be easily achieved by using an acylating agent such as an acid anhydride of a lower fatty acid such as butyric acid or caproic acid, or an acid halide. In addition, among the general formulas b and e of the compounds of the present invention, a group of compounds of the present invention having one NH ₂ group; NH ₂ and OR ₃ groups, or NH ₂ and OCOR ₄ groups are:
Triterpene alcohol esters of cinnamic acid, benzoic acid or α-C _{1 to} C ₄ alkyl cinnamic acids, each with the corresponding NO ₂ group attached to the benzene nucleus, are combined with iron or zinc and an acid (hydrochloric acid, sulfuric acid, acetic acid), tin or chloride. Only NO ₂ groups are selectively reduced to NH ₂ groups using reduction methods such as tin and concentrated sulfuric acid. This reduction method of metal and acid is the best reduction method because the unsaturated groups present in the triterpene alcohol group are not reduced. Next, when the above amino compounds are acylated by the usual method, the corresponding
1 of ₃ NHCOR; ₃ NHCOR and ₃ OR
A compound of the present invention having two groups, ₃ NHCOR groups and ₄ OCOR groups, can be easily obtained. Effect: The toxicity and antihyperlipidemic pharmacological test results of the compound of the present invention will be explained in detail below. Acute toxicity test: DDY male mice weighing 30±2g and mice weighing 100±
An acute toxicity test by oral administration was conducted using 2 g Wistar male rats in each group of 5 rats. For example, compounds of the present invention for which acute toxicity tests were conducted are shown below. Example 2 (cycloartenol-4-hydroxy-3
-methoxy-α-methyl cinnamic acid ester), Example 4 (cyclobranol-4-hydroxy-3-methoxy-α-methyl cinnamic acid ester), Example 6 (24-methylenecycloartanol-4-hydroxy-3- methoxy-α-methylcinnamic acid ester), Example 8 (cycloartenol-4-hydroxy-3-
methoxy-α-ethylcinnamate), Example 28 (cyclobranol-3-ethoxy-4-hydroxy-α-methylcinnamate), Example 18 (cycloartenol-4-hydroxy-α-
ethylcinnamic acid ester), Example 34 (cycloartenol-4-hydroxy-3
-propoxy-α-methylcinnamic acid ester), Example 55 (cycloartenol-4-amino-3-methoxybenzoic acid ester), Example 61 (cyclobranol-5-amino-2-methoxybenzoic acid ester), Example 77 (cycloartenol-4-amino-3-methoxy-α-methyl cinnamic acid ester), Example 65 (cycloartenol-4-amino-3-methoxycinnamic acid ester), Example 93 (cycloartenol -p-amino-α-methyl cinnamic acid ester), Example 71 (cycloartenol-5-amino-2-ethoxycinnamic acid ester), Example 100 (cyclobranol-m-amino-α-methyl cinnamic acid ester) , Example 79 (24-methylenecycloartanol-4-amino-3-methoxy-α-methylcinnamic acid ester), Example 85 (24-methylenecycloartanol-5-amino-2-propoxy-α-methylcinnamic acid ester) ester), Example 59 (cycloartenol-5-amino-2-methoxybenzoic acid ester), Example 58 (cycloartenol-2-methoxy-5-
nitrobenzoic acid ester), Example 66 (cyclobranol-4-amino-3-methoxycinnamic acid ester), Example 83 (cycloartenol-5-amino-2-propoxy-α-methyl cinnamic acid ester), Implementation Example 101 (24-methylenecycloartanol-m-amino-α-methylcinnamic acid ester), Example 1 (cycloartenol-3-methoxy-4-
Propionyloxy-α-methylcinnamic acid ester), Example 5 (24-methylenecycloartanol-3-methoxy-4-propionyloxy-α-methylcinnamic acid ester), and the control drug cycloartenol, 24- Dosage of methylenecycloartanol, cyclobranol and γ-oryzanol from 0.1g/Kg to 6
g/Kg (0.1 to 5 g/Kg).
(2 to 6 g/Kg) and rats (2 to 6 g/Kg) were dosed individually by gavage with a throat prod. Animals were maintained at an animal room temperature of 22-23 °C during the study period and 14 days after dosing.
Observed for days. No deaths were observed at the doses administered. Toxicity and behavior after administration were observed over time, but no differences were observed from the normal animal group. Furthermore, there was no difference in weight gain from the normal animal group. A post-test necropsy did not reveal any macroscopic damage to any part of the major organs. Therefore, it was not possible to determine an LD ₅₀ value for the compounds of the invention due to their very low toxicity. Method B of antihyperlipidemic pharmacology test: (1) Animal: Wistar male rats weighing 100±1 g were used. (2) Feed: Ordinary food is powdered feed (CE-2) manufactured by Clea Japan Co., Ltd.
The hyperlipidemic diet was a normal diet supplemented with 1% cholesterol and 0.5% cholic acid. The drugs were added to this hyperlipidemic diet at 1% each and administered to rats. (3) Rearing conditions: Groups of 8 animals (16 animals per group only in the hyperlipidemic diet control group) were raised on each diet for 4 weeks. Two rats were placed in each cage, and food and water were available ad libitum. Temperature 23±1℃ and humidity 55±
The animals were raised for 4 weeks at a constant temperature and humidity of 5%. After starting the experiment
On the 29th day (the rats were fasted for 16 hours from 4:00 p.m. on the 28th day to 8:00 a.m. on the 29th day), rats were treated with pentobarbital sodium [trade name:
Blood was collected from the abdominal descending aorta under anesthesia using Nembutal, and TC in serum,
HDL-C, TG, PL, and LPO were measured by the following methods. Measuring method of serum TC value: Using TC Kit-K (Manufacturer: Nippon Shoji Co., Ltd.). The principle of this measurement is that ester cholesterol in serum is hydrolyzed into free cholesterol and fatty acids by cholesterol ester hydrolase, and all of the free cholesterol is oxidized by cholesterol oxidase to produce Δ ⁴ -cholestenone and hydrogen peroxide. In this method, phenol and 4-aminoantipyrine are oxidatively condensed using the generated hydrogen peroxide and peroxidase, and the generated red quinone dye is colorimetrically determined using a spectrophotometer at 500 nm to determine the absorbance and the TC value. Preparation of color reagent used: Color reagent: 1 vial (Ingredients: 25000 u of cholesterol esterase, 25 u of cholesterol oxidase, 3554 u of peroxidase, 20 mg of 4-aminoantipyrine) Buffer: 33.3 mg of phenol, 33.3 mg of dihydrogen phosphate in 100 ml of ingredients Dissolve 489.9 mg of potassium and 908.5 mg of anhydrous sodium monohydrogen phosphate in purified water. Standard solution: Contains 300mg of cholesterol in 100ml of ingredients. One vial of the above coloring reagent dissolved in 160 ml of buffer is called the coloring reagent used. Add 3.0ml of coloring reagent to 0.02ml of sample serum,
Mix well and heat at 37°C for 15 minutes, then analyze with a spectrophotometer.
The value of absorbance measured at 500 nm is defined as EA. Separately, add 3.0 ml of the coloring test solution to 0.02 ml of the standard solution, mix well, heat at 37°C for 15 minutes, and then measure the spectrophotometer.
The value of absorbance measured at 500 nm is defined as ES. this
Both EA and ES are measured using a blind test of 3.0 ml of the coloring test solution used as a control. TC value mg/dl = EA/ES x 300 mg/dl Method for measuring serum HDL-C value: Measured by HDL-C Kit-N (manufacturer: Nippon Shoji Co., Ltd.). i.e. very low density lipoprotein (VLDL), low density lipoprotein (LDL) in serum
A precipitate is formed by the action of heparin in the presence of calcium ions, and the precipitate is centrifuged to dissolve high-density lipoprotein (HDL) in the supernatant. The ester cholesterol in this fraction is hydrolyzed to free cholesterol and fatty acids by cholesterol ester hydrolase, and all free cholesterol is oxidized by cholesterol oxidase to produce Δ ⁴ -cholestenone and hydrogen peroxide. The red quinone pigment produced by oxidative bonding of phenol and 4-aminoantipyrine with the produced hydrogen peroxide and peroxidase was measured using a spectrophotometer.
By measuring the absorbance at 500nm
The content of HDL-C was determined. Measuring method of serum PL value: Measured using PL Kit-K (manufacturer: Nippon Shoji Co., Ltd.). Lecithin, sphingomyelin, and lysolecithin in serum are phospholipase D
It is decomposed into choline, phosphatidic acid, N-acylsphingosyl phosphate and lysophosphatidic acid, respectively. The produced choline is oxidized by choline oxidase to quantitatively produce hydrogen peroxide and betaine. This hydrogen peroxide was produced by oxidative condensation of phenol and 4-aminoantipyrine using peroxidase, and the PL content was determined by measuring the absorbance at 500 nm using a spectrophotometer. Method for measuring serum TG level: TG in serum was measured using a triglyceride test kit (manufacturer: Wako Pure Chemical Industries, Ltd.) using acetylacetone. That is, when isopropyl alcohol is added to serum and mixed, proteins are precipitated, lipids and sugars in the serum are transferred to isopropyl alcohol, an adsorbent is added, substances that interfere with coloration are adsorbed, and after centrifugation, the supernatant is When potassium hydroxide is added to a portion, the triglyceride is saponified and glycerin is liberated. Next, a buffer solution is added to adjust the pH to 6, and a sodium metaperiodate solution is added to oxidize the glycerin into one molecule of formic acid and two molecules of formaldehyde. The formed formaldehyde reacts with acetylacetone and ammonia in the buffer to form a cyclic compound, 3,5-diacetyl-1,4-dihydrortidine (3,5-diacetyl-1,4-dihydrortidine).
diacetyl-1,4-dihydrolutidine) was produced, and the triglyceride content was determined by measuring the absorbance of this yellow pigment at 410 nm using a spectrophotometer. Measuring method of serum LPO level: Yagi thiobarbituric acid method [Kunio Yagi
Biochem.Med. vol. 15, p. 212 (1976), Kunio Yagi
Lipoperoxide in Vitamin Vol. 49, p. 403 (1975)
Measurement was performed using a test kit (manufacturer: Wako Pure Chemical Industries, Ltd.). i.e. 1.0ml of physiological saline
Add 0.05 ml of serum to the solution, stir gently, centrifuge (3000 rpm, 10 minutes), and add N/12 to 0.5 ml of supernatant.
Add 4.0 ml of sulfuric acid and mix well. Add 0.5 ml of 10% phosphotungstic acid aqueous solution to this, stir well, leave at room temperature for 5 minutes, and then centrifuge (3000 rpm, 10 minutes). The obtained precipitate is N/12
2.0ml of sulfuric acid and 0.3ml of 10% phosphotungstic acid aqueous solution
Add and suspend the precipitate well with a mixer. Next, centrifuge (3000 rpm, 10 minutes), add 4.0 ml of distilled water to the precipitate, and suspend well with a mixer. Next, add 1.0 ml of TBA reagent (50% acetic acid solution, containing 2-thiobarbituric acid) and mix well.
Place a glass ball at the top of the centrifuge tube, heat it in a boiling water bath for 60 minutes, and then cool it in running water for 5 minutes. Next, add 5.0 ml of n-butanol, attach a stopper, mix well with a mixer for 20 seconds, extract and centrifuge (3000 rpm, 10 minutes), and perform fluorescence measurements on the upper n-butanol layer. After adjusting the zero point of fluorescence measurement using a reagent blind test, the standard solution (1, 1,
3,3-tetraethoxypropane 5nmol/ml)
The fluorescence intensity (F) of 0.1 ml and the fluorescence intensity (f) of the sample were measured using a fluorometer with an excitation wavelength of 515 nm and a fluorescence wavelength of 553 nm. That is, in this method, the reaction product between LPO and thiobarbituric acid is the same as the reaction product between malondialdehyde and thiobarbituric acid. Therefore, the concentration of LPO was determined as the amount of malondialdehyde in 1 ml of serum. The standard solution quantitatively gives malondialdehyde 1,1,
It is an aqueous solution of 5 nmol/ml of 3,3-tetraethoxypropane, and 0.1 ml of the standard solution is used for measurement, so 1,1,3,3-tetraethoxypropane is
Since 0.5 nmol was used, the LPO content is calculated using the following formula. LPO content (nmol/ml serum) = 0.5 × f / F × 1.0 / 0.05 × 1.05 / 0.5 = f / F × 21 Antihyperlipidemic pharmacological test results: Using rats loaded with high cholesterol diet or normal diet, serum We report on the active effects of representative compounds of the present invention on lipids and serum lipid peroxides, ie, the same compounds as acute toxicity. Cycloartenol, 24−, used as a control drug
The results of the antihyperlipidemia test of methylenecycloartanol and cyclobranol are shown in Tables 1 and 2. These effects have been explained above. Furthermore, the antihyperlipidemic effects of the compounds of the present invention and control drugs cycloartenol, cyclobranol, 24-methylenecycloartanol, and γ-oryzanol according to method B are shown in Tables 3 to 8. The control group given a normal diet had lower TC and PL than the control group given a hyperlipidemic diet.
and LPO showed a significant (P<0.001) decrease without exception, while HDL-C showed a significant (P<0.001) decrease.
0.001). However, although TG showed a decreasing trend, no significant difference was observed. In the group to which the compound of the present invention or the control drug was added to the hyperlipidemic feed, a clear improvement in serum lipid components was observed compared to the control group to which the hyperlipidemic feed was administered. In particular, the compound group of the present invention showed significantly lower levels of serum lipids such as TC, HDL-C, PL, and LPO than the control drug group.
The above ingredients have been improved. That is, regarding TC, the control drugs triterpene alcohol and γ-oryzanol had a significant effect (P<
A decrease of 0.01) was observed. In contrast, Examples 2, 4, 6, 77, 93, 100, 79, 85,
59, 66, 83 and 101 showed a significant (P<0.001) decrease, and Examples 8, 28, 18, 34, 55, 61,
Compounds 65, 71, 58, 1 and 5 were significant (P<
A decrease of 0.01) was observed. Regarding HDL-C, the control drug cycloartenol showed a significant (P<0.01) decrease, but cyclobranol, 24-methylenecycloartanol, and γ-oryzanol showed a slight tendency to increase or decrease. However, no significant difference was observed. In contrast, Examples 2, 4, 6, 28 of the compounds of the present invention,
34, 55, 61, 77, 65, 93, 100 and 101 are significant (P
<0.001) was observed in Examples 8, 18, 71, 79,
Compounds 85, 59, 66, 83, 1 and 5 were significant (P<
0.01), and the compound of Example 58 showed a significant (P<0.05) increase. What is particularly noteworthy is that the compounds of Examples 4, 6, 28, 55, 61, 58, 66, 83, and 101 showed a more significant increase than in the normal food administration group. Regarding AI, both the control drug and the compound of the present invention showed a decreasing tendency, but the compound of the present invention showed a particularly remarkable decrease. Regarding TG, both the control drug and the compound of the present invention showed a tendency to decrease slightly to some extent, but no significant difference was observed. Regarding PL, the control drug showed a slight tendency to decrease, but the decrease was not significant. In contrast,
Examples 2, 4, 6, 28, 34, 59 of the compounds of the present invention,
Compounds 83 and 101 showed a significant (P<0.001) decrease, and Examples 8, 18, 77, 93, 100, 79, 85, 58,
The compounds of Examples 66, 1 and 5 showed a significant (P<0.01) decrease, and the compounds of Examples 55, 61, 65 and 71 showed a significant (P<0.05) decrease. Regarding LPO, the control drug γ-oryzanol showed a significant decrease (P<0.01), and the three triterpene alcohols showed a clear tendency to decrease, although the decrease was not significant. In contrast, Examples 2, 4, 6, 8, 28, 18, 34, 77,
93, 100, 71, 79, 85, 59, 66, 83 and 101 showed a significant decrease (P<0.001), Examples 55, 61, 65,
Compounds 58, 1 and 5 showed a significant (P<0.01) decrease. As shown above, while the compounds of the present invention clearly increase HDL-C in many cases, TC,
A clear downward trend was observed for AI, PL, and LPO. That is, it is clear that the antihyperlipidemic activity of the compound of the present invention is synergistic compared to administration of free triterpene alcohol alone. Examples of weight gain in rats in this antihyperlipidemia test are shown in Tables 9 and 10. The weight gain of the normal diet administration group showed a significant (P<0.001) increase compared to the control group administered the hyperlipidemic diet. The group in which the control drug and the compound of the present invention were added to the hyperlipidemic diet showed a slightly smaller increasing tendency than the group administered with the hyperlipidemic diet, but no significant difference was observed.

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[Table] Approximately calculated from the consumption amount of feed supplemented with the compound of the present invention, the maximum amount of the compound of the present invention per rat is
This means that 210mg was administered. For example, cycloartenol-4-hydroxy-3-methoxy-α-
Methylcinnamic acid ester (Example 2), cyclobranol-3-ethoxy-4-hydroxy-α-
Methylcinnamic acid ester (Example 28), cyclobranol-5-amino-2-methoxybenzoic acid ester (Example 61), cycloartenol-p-
Amino-α-methyl cinnamic acid ester (Example
93) and cyclobranol-m-amino-α-methylcinnamic acid ester (Example 100), 70.8 mg of free 4-hydroxy-3-methoxy-α-methylcinnamic acid, 3-ethoxy -4-hydroxy-α-methylcinnamic acid is 72.5
mg, 5-amino-2-methoxybenzoic acid is 59.4
mg, p-amino-α-methylcinnamic acid is 63.4 mg,
m-amino-α-methylcinnamic acid is 62.0 mg. Feed containing each of these free organic acids added to the hyperlipidemia feed was administered in the same manner as in this antihyperlipidemia test method B, and the effects were examined.
No antihyperlipidemic effect was observed at a dose of 72.5 mg. That is, it was proved that the effect of the compound of the present invention is not due to the organic acid liberated by hydrolysis of the triterpene alcohol organic acid ester. Among the compounds of the present invention, the most preferred antihyperlipidemic agents are α-cinnamic acid having 1 to 4 carbon atoms; alkoxylic acid having 1 to 4 carbon atoms; It is an ester of a triterpene alcohol of cinnamic acid, cinnamic acid, or benzoic acid having 1 to 4 carbon atoms, in which two groups, a hydroxy group or an alkoxy group having 1 to 4 carbon atoms and an amino group, are attached to a benzene nucleus. The compounds of the present invention may be administered in the form of oral or parenteral administration for clinical treatment, but oral administration is particularly preferred. Oral dosage forms of the compound of the present invention include tablets, granules, powders, coatings, etc. by mixing with a suitable pharmaceutical carrier.
Preparations such as sugar-coated tablets, capsules, and emulsions are used. Examples of pharmaceutical carriers include excipients such as lactose, sucrose, mannitol, glucose, starch, sorbitol, glycine, potassium phosphate, and microcrystalline cellulose; binders such as starch, gelatin,
Gum arabic, glucose, white sugar, sorbitol,
Mannitol, tragacanth, hydroxypropylcellulose, hydroxypropoxymethylcellulose, carboxymethylcellulose, 2-methyl-
5-vinylpyridine-methacrylic acid-acrylic acid methyl ester copolymer, polyvinylpyrrolidone, sodium alginate, etc.; As a lubricant, stearic acid, hydrogenated oil, magnesium stearate, calcium stearate, polyoxyethylene monostearate, talc, Silicon oxide, polyethylene glycol, etc.; Starch containing potato starch powder, surfactant, etc. as a disintegrant; Sodium lauryl sulfate, etc. as a wetting agent.
Furthermore, when administered parenterally, intramuscular injection drugs,
It can also be used as a suppository. In particular, as a base for suppositories, cocoa butter, Witepsol, Subanal, polyethylene glycol, polypropylene glycol, glycerogelatin, gelatin capsules, etc. are used. In addition, known safe preservatives such as methyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, butyl hydroxyanisole, and other safe dyes are used. Although the dosage of the compound of the present invention varies depending on the method of administration, age, weight, condition, and type of disease of the patient, it is generally preferred to be about 0.01 g to 5 g per day for humans. Most preferred is 0.02g to 1.5g
It is. The novel triterpene alcohol organic acid ester shown in the present invention uses cycloartenol, cyclobranol, and 24-methylenecycloartanol organic acid ester described above as representative examples of preferred triterpene alcohol organic acid esters, and uses other than these. Lanosterol, lanosterol, agnosterol, cyclosadol (3β-hydroxy-24-methylene-9,19-cyclo-9β-lanost-23-ene), dihydroagnosterol, cyclolaudenol, cycloartanol, cycloeucalenol It also includes organic acid esters of triterpene alcohols having the structure shown in the present invention, such as , euphol, butyrospermol, tircalol, euphorbol, and damaradienol. These are preferred as antihyperlipidemic agents. Also, sterols with similar structures to triterpene alcohols, such as dihydro-β-sitosterol, dihydro-γ-sitosterol, campesterol,
β-sitosterol, γ-sitosterol, stigmasterol, 24-methylene cholesterol,
The esters of organic acids shown in the present invention, such as episterol and 22-dihydroergosterol, can be expected to exhibit the same effects as antihyperlipidemic agents.
The compounds of the present invention are most preferably used alone, and can also be used as a mixture of two or more. Example 1 Process for producing cycloartenol-3-methoxy-4-propionyloxy-α-methylcinnamic acid ester 3-methoxy-4-propionyloxy-α-
Toluene to 72.0g (0.272mol) of methylcinnamic acid
400 ml, 40.0 ml (2 equivalents) of thionyl chloride, and 0.5 ml of dimethylformamide were added and reacted at 60°C for 1.5 hours. After concentrating the reaction solution under reduced pressure, 100 ml of dioxane was added and stirred at 0°C. Thereto was added 80.0 g (0.187 mol) of cycloartenol dissolved in 300 ml of pyridine, and the mixture was further heated and stirred at 60°C for 3 hours. After the reaction, the solvent was distilled off under reduced pressure and the resulting residue was
After dissolving in 1 ml of chloroform, the solution was washed with 500 ml of saturated sodium bicarbonate solution. The aqueous layer was further extracted twice using 500 ml of chloroform each time, and the entire chloroform layer obtained was dried, concentrated under reduced pressure, and subjected to silica gel column chromatography [solvent: hexane-methylene chloride,
(5:1)] to obtain 110 g of cycloartenol-3-methoxy-4-propionyloxy-α-methylcinnamic acid ester. Yield 87.1%, melting point 130-131°C Specific optical rotation [α] ¹⁹ _D +41.1° (C1.00, CHCl ₃ ) Elemental analysis result C ₄₄ H ₆₄ O ₅ Assuming molecular weight 672.95 Calculated value (%): C 78.53 H 9.59 Actual value (%): C 78.59 H 9.52 IRν, KBr (cm ^-1 ): 2920, 2850, 1765, 1710,
1630, 1600, 1510, 1240, 1140, 1110. PMR (CDCl ₃ ) δ: 0.39 (1H, 1/2ABq, 4.2Hz),
0.60 (1H, 1/2ABq, 4.2Hz), 0.60~2.20 (27H,
m), 0.90 (9H, s), 0.98 (6H, s), 1.27 (3H,
t, 7.2Hz, 1.58 (3H, bs), 1.68 (3H, bs),
2.12 (3H, d, 1.2Hz), 2.62 (2H, q, 7.2Hz),
3.80 (3H, s), 4.50~5.30 (2H, m), 6.80~
7.70 (4H, m). Example 2 Cycloartenol-4-hydroxy-3-methoxy-α-methylcinnamic acid ester (also known as:
Cycloartenol-3-methoxy-4-propionyloxy-α-obtained by the method of Example 1
Methylcinnamic acid ester 84.0g (0.125mol)
After dissolving in 1000ml dioxane, 25% ammonia water
200 ml was added and the mixture was heated and stirred at 50°C for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was diluted with 500 ml.
of chloroform and washed with 500 ml of saturated saline. The aqueous layer was further extracted twice with 300 ml of chloroform, and all the chloroform layers were collected and dried.
Cycloartenol-4-hydroxy-3-methoxy-α- was obtained by concentrating under reduced pressure and recrystallizing the residue with methylene chloride-methanol (1:4).
Methyl cinnamic acid ester (cycloartenol)
73.0g of α-methylferulic acid ester) was obtained. Yield 94.8%, melting point 143-144°C Specific rotation [α] ¹⁹ _D +44.1° (C1.00, CHCl ₃ ) Elemental analysis result C ₄₁ H ₆₀ O ₄ Assuming molecular weight 616.93 Calculated value (%): C 79.82 H 9.80 Actual value (%): C 79.88 H 9.81 IRν, KBr (cm ^-1 ): 3400, 2900, 2850, 1695,
1690, 1625, 1600, 1510, 1250, 1110. PMR (CDCl ₃ ) δ: 0.38 (1H, 1/2ABq, 4.2Hz),
0.59 (1H, 1/2ABq, 4.2Hz), 0.60~2.30 (27H,
m), 0.88 (6H, s), 0.97 (6H, s), 1.60 (3H,
bs), 1.66 (3H, bs), 2.12 (3H, d, 1.2Hz),
3.88 (3H, s), 4.50~5.30 (2H, m) 5.80 (1H,
bs), 6.70-7.70 (4H, m). Example 3 Process for producing cyclobranol-3-methoxy-4-propionyloxy-α-methylcinnamic acid ester 3-methoxy-4-propionyloxy-α-
15.59g (0.59mol) of methylcinnamic acid in toluene
20 ml (4.6 equivalents) of thionyl chloride and 5 drops of dimethylformamide were added, and the mixture was stirred at 60°C for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was suspended again in 150 ml of toluene and 30 ml of anhydrous pyridine, 20 g (0.045 mol) of cyclobranol was added, and the mixture was stirred at 60°C for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was extracted with 300 ml of chloroform. The chloroform layer was washed with water, dried and evaporated under reduced pressure. The residue was washed with 50 ml of ethanol and then recrystallized from acetone-water (19:1) to obtain 24.69 g of cyclobranol-3-methoxy-4-propionyloxy-α-methylcinnamate. Yield 79.2%, melting point 146-147°C Specific rotation [α] ¹⁹ _D +39.2° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₅ H ₆₆ O ₅ Assuming molecular weight 686.98 Calculated value (%): C 78.67 H 9.68 Actual value (%): C 78.75 H 9.62 IRν, KBr (cm ^-1 ): 3400, 2590, 2850, 1760,
1710, 1630, 1600, 1240, 1150, 1120. PMR (CDCl ₃ ) δ: 0.37 (1H, 1/2ABq, 4.8Hz),
0.62 (1H, 1/2ABq, 4.8Hz), 0.70~2.22 (27H,
m), 0.92 (6H, s), 0.99 (6H, s), 1.29 (3H,
t, 7.2Hz), 1.64 (9H, s), 2.14 (3H, d, 1.2
Hz), 2.63 (2H, q, 7.2Hz), 3.84 (3H, s),
4.48~4.88 (1H, m), 6.80~7.08 (3H, m),
7.59 (1H, q, 1.2Hz). Example 4 Process for producing cyclobranol-4-hydroxy-3-methoxy-α-methylcinnamic acid ester Cyclobranol-3 obtained by the method of Example 3
-Methoxy-4-propionyl-α-methylcinnamic acid ester 24.69g (0.036mol) was added to dioxane.
After dissolving in 400ml and dropping 40ml of 25% ammonia water,
Stirred at 50°C for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, the residue was washed with ethanol, and then recrystallized from acetone-water (19:1) to give cyclobranol-4-hydroxy-3-methoxy-α-
21.72 g of methylcinnamic acid ester was obtained. Yield 95.8%, melting point 185-186°C Specific rotation [α] ²⁰ _D +43.7° (C1.00, CHCl ₃ ) Elemental analysis result C ₄₂ H ₆₂ O ₄ Assuming molecular weight 630.92 Calculated value (%): C 79.95 H 9.91 Actual value (%): C 79.96 H 9.98 IRν, KBr (cm ^-1 ): 3380, 2920, 2850, 1693,
1600, 1510, 1285, 1250, 1120, PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.8Hz),
0.61 (1H, 1/2ABq, 4.8Hz), 0.76~2.30 (27H,
m), 0.91 (6H, s), 0.99 (6H, s), 1.63 (9H,
s), 2.14 (3H, d, 1.2Hz), 3.90 (3H, s),
4.48~4.84 (1H, m), 5.84 (1H, bs), 6.80~
6.98 (3H, m), 7.55 (1H, q, 1.2Hz). Example 5 Process for producing 24-methylenecycloartanol-3-methoxy-4-propionyloxy-α-methylcinnamic acid 3-methoxy-4-propionyloxy-α-
0.8 g (0.003 mol) of methylcinnamic acid to 2 toluene
ml, 0.5 ml (2.2 equivalents) of thionyl chloride and 2 drops of dimethylformamide were added, and the mixture was stirred at 60°C for 2 hours. After the reaction, the solvent was distilled off under reduced pressure and the residue was suspended again in 2 ml of toluene and 1 ml of anhydrous pyridine.
1 g (0.0023 mol) of 24-methylenecycloartanol was added and stirred at 60°C for 2 hours. After the reaction, the solvent was distilled off under reduced pressure and the residue was dissolved in chloroform 20
Extracted in ml. The chloroform layer was washed, dried, and evaporated under reduced pressure. After washing the residue with 5 ml of ethanol, it was recrystallized from acetone-methanol (1:1) to give 24-methinerecycloartanol-3-
1.35 g of methoxy-4-propionyloxy-α-methylcinnamic acid ester was obtained. Yield 86.1%, melting point 134-135°C Specific optical rotation [α] ¹⁹ _D +41.2° (C1.00, CHCl ₃ ) Elemental analysis value C ₄₅ H ₆₆ O ₅ (as molecular weight 686.98) Calculated value (%): C 78.67 H 9.68 Actual value (%): C 78.75 H 9.62 IRν, KBr (cm ^-1 ): 3400, 2920, 2850, 1760,
1700, 1240, 1115. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.2Hz),
0.61 (1/2ABq, 4.2Hz), 0.70~2.22 (34H, m),
0.88 (6H, s), 0.96 (6H, s), 1.26 (3H, t,
7.2Hz), 2.11 (3H, d, 1.2Hz), 2.60 (2H, d,
7.2Hz), 3.80 (3H, s), 4.44-4.86 (1H, m),
4.86-5.26 (2H, m), 6.76-7.08 (3H, m),
7.55 (1H, q, 1.2Hz). Example 6 Process for producing 24-methylenecycloartanol-4-hydroxy-3-methoxy-α-methylcinnamic acid ester 24-methylenecycloartanol-3-methoxy-4-propionyloxy-α obtained by the method of Example 5 -Methylcinnamic acid ester 1.35g (0.002
mol) was dissolved in 20 ml of dioxane, 2 ml of 25% aqueous ammonia was added dropwise, and the mixture was stirred at 50°C for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was washed with ethanol, and then recrystallized from ethanol.
-methylenecycloartanol-4-hydroxy-3-methoxy-α-methylcinnamate ester
1.02g was obtained. Yield 82.2%, melting point 144-145°C Specific optical rotation [α] ²⁰ _D +44.8° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₃ H ₆₂ O ₄ (as molecular weight 630.92) Calculated value (%): C 79.95 H 9.91 Actual value (%): C 79.99 H 9.84 IRν, KBr (cm ^-1 ): 3400, 2900, 2850, 1690,
1600, 1510, 1250, 1110. PMR (CDCl ₃ ) δ: 0.37 (1H, 1/2ABq, 4.2Hz),
0.61 (1H, 1/2ABq, 4.2Hz), 0.70~2.21 (34H,
m), 0.89 (6H, s), 0.98 (6H, s), 2.14 (3H,
d, 1.2Hz), 3.88 (3H, s), 4.50~4.88 (1H,
m), 4.88-5.28 (2H, m), 5.80 (1H, bs),
6.82-7.10 (3H, m), 7.59 (1H, q, 1.2Hz). Example 7 Cycloartenol-4-butyryloxy-3
-Production method of methoxy-α-ethylcinnamic acid ester 4-butyryloxy-3-methoxy-α-ethylcinnamic acid 18.0g (0.062 mol) in benzene 40ml
Cool the solution to 0°C and add 15.0 ml (3.3
equivalent amount) was added dropwise. This mixture was heated at 60°C for 2 hours. After the reaction, excess thionyl chloride and the solvent were distilled off under reduced pressure, and 10 ml of pyridine and 40 ml of dioxane were added.
ml, and 30 ml of pyridine solution containing 17.5 g (0.041 mol) of cycloartenol was added dropwise while cooling to 0°C. This mixture was stirred at 20°C overnight. After the reaction, the solvent was distilled off under reduced pressure, the residue was extracted with 200 ml of chloroform, the chloroform layer was concentrated under reduced pressure, and the resulting crude crystals were recrystallized from acetone-methanol (1:1) to extract cycloartenol. -4-Butyryloxy-3-methoxy-α-ethylcinnamic acid ester was obtained in a yield of 22.4 g. Yield 77.9%, melting point 118.5-119.5°C Specific rotation [α] ²⁰ _D +35.7° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₆ H ₆₈ O ₅ (assuming molecular weight 701.00) Calculated value (%): C 78.81 H 9.78 Actual value (%): C 78.72 H 9.86 IRν, KBr (cm ^-1 ): 3400, 2920, 2800, 1700,
1600, 1510, 1230, 1120. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.2Hz),
0.52-2.26 (29H, m), 0.61 (1H, 1/2ABq, 4.2
Hz), 0.90 (6H, s), 0.96 (6H, s), 1.04 (3H,
t, 7.2Hz), 1.18 (3H, t, 7.2Hz), 1.60 (3H,
s), 1.66 (3H, s), 2.26-2.82 (4H, m),
3.79 (3H, s), 4.50~4.88 (1H, m), 4.88~
5.28 (1H, m), 6.70~7.12 (3H, m), 7.48~
7.68 (1H, m). Example 8 Process for producing cycloartenol-4-hydroxy-3-methoxy-α-ethylcinnamate cycloartenol-obtained by the method of Example 7
Dissolve 22.0 g (0.0314 mol) of 4-butyryloxy-3-methoxy-α-ethylcinnamate in 200 ml of dioxane, and add 20 ml of 25% concentrated ammonia water.
was dripped. This mixture was heated at 50°C for 5 hours. After the reaction, the solvent was distilled off under reduced pressure, the residue was extracted with 200 ml of chloroform, the chloroform layer was concentrated under reduced pressure, the obtained crude crystals were recrystallized from acetone-methanol (1:1), and cycloalkaline Tenol-4-hydroxy-3-methoxy-α-ethylcinnamic acid ester was obtained in a yield of 17.2 g. Yield 86.8%, melting point 136-137°C Specific rotation [α] ²⁰ _D +41.5° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₂ H ₆₂ O ₄ (as molecular weight 630.92) Calculated value (%): C 79.95 H 9.96 Actual value (%): C 79.90 H 9.83 IRν, KBr (cm ^-1 ): 3400, 2830, 1700, 1595,
1510, 1240, 1120. PMR (CDCl ₃ ) δ: 0.35 (1H, 1/2ABq, 4.2Hz),
0.50~2.18 (27H, m), 0.60 (1H, 1/2ABq, 4.2
Hz), 0.89 (6H, s), 0.95 (6H, s), 1.19 (3H,
t, 7.2Hz), 1.57 (3H, s), 1.65 (3H, s),
2.56 (2H, bq, 7.2Hz), 3.87 (3H, s), 4.47~
4.85 (1H, m), 4.85-5.24 (1H, m), 5.76
(1H, bs), 6.96-7.09 (3H, m), 7.24-7.64
(1H, m). Example 9 Cyclobranol-4-butyryloxy-3-
Method for producing methoxy-α-ethylcinnamic acid ester 18.0g (0.062 mol) of 4-butyryloxy-3-methoxy-α-ethylcinnamic acid was added to 40ml of benzene.
Cool the solution dissolved in thionyl chloride to 0℃,
15.0 ml (3.3 equivalents) was added dropwise. Add this mixture to 60
After heating and stirring at 0.degree. C. for 2 hours, excess thionyl chloride and the solvent were distilled off under reduced pressure, 40 ml of pyridine and 40 ml of dioxane were added, and 18.1 g (0.041 mol) of cyclobranol was added while cooling to 0.degree. This mixture was stirred at 20°C overnight. After the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with 200 ml of chloroform.
The chloroform layer was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from acetone-ethanol (1:1) to give cyclobranol-4-butyryloxy-3.
-Yield of methoxy-α-ethylcinnamate ester
Obtained in 22.3g. Yield 76.0%, melting point 138-139°C Specific optical rotation [α] ²⁰ _D +33.7° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₇ H ₇₀ O ₅ (as molecular weight 715.03) Calculated value (%): C 78.94 H 9.87 Actual value (%): C 78.89 H 9.88 IRν, KBr (cm ^-1 ): 3400, 2920, 2850, 1760,
1710, 1625, 1510, 1230, 1120. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.8Hz),
0.52-2.22 (29, m), 0.61 (1H, 1/2ABq, 4.8
Hz), 0.92 (6H, s), 0.97 (6H, s), 1.03 (3H,
t, 7.2Hz), 1.18 (3H, t, 7.2Hz), 1.60 (9H,
s), 2.22-2.82 (4H, m), 3.81 (3H, s), 4.48
~4.90 (1H, m), 6.70 ~ 7.18 (3H, m), 7.40 ~
7.64 (1H, m). Example 10 Process for producing cyclobranol-4-hydroxy-3-methoxy-α-ethylcinnamic acid ester Cyclobranol-4 obtained by the method of Example 9
21.3 g (0.0298 mol) of -butyryloxy-3-methoxy-α-ethylcinnamic acid ester was dissolved in 200 ml of dioxane, and 20 ml of 25% concentrated aqueous ammonia was added dropwise. After heating and stirring this mixture at 50 °C for 5 hours,
The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform 200
Extracted in ml. The chloroform layer was concentrated under reduced pressure, and the resulting crude crystals were recrystallized from ethanol.
Cyclobranol-4-hydroxy-3-methoxy-α-ethylcinnamic acid ester was obtained in a yield of 17.1 g. Yield 88.9%, melting point 156-157°C Specific optical rotation [α] ²⁰ _D +37.7° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₃ H ₆₄ O ₄ (as molecular weight 644.94) Calculated value (%): C 80.07 H 10.00 Actual value (%): C 80.13 H 10.12 IRν, KBr (cm ^-1 ): 3400, 2930, 1696, 1235,
1130. PMR (CDCl ₃ ) δ: 0.38 (1H, 1/2ABq, 4.8Hz),
0.52-2.22 (27H, m), 0.62 (1H, 1/2ABq, 4.8
Hz), 0.91 (6H, s), 0.97 (6H, s), 1.21 (3H,
t, 7.2Hz), 1.62 (9H, s), 2.57 (2H, bq, 7.2
Hz), 3.98 (3H, s), 4.48-4.86 (1H, m),
5.78 (1H, bs), 6.70-7.00 (3H, m), 7.53
(1H, m). Example 11 Process for producing cycloartenol-4-propionyloxy-α-methylcinnamic acid ester 4-propionyloxy-α-methylcinnamic acid
A solution of 17.6 g (0.075 mol) dissolved in 40 ml of benzene was cooled to 0°C, and 18.1 ml of thionyl chloride was added to it.
(3.3 equivalents) and dimethyl formaldehyde 0.5 ml
was dripped. After heating and stirring this mixture at 60°C for 2 hours, excess thionyl chloride and the solvent were distilled off under reduced pressure, and 40 ml of dioxane and 10 ml of pyridine were added.
21.3g of cycloartenol while cooling to 0℃
A 40 ml solution of pyridine (0.050 mol) was added dropwise. This mixture was stirred at 20°C overnight. After the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform.
After extraction with 200 ml, the chloroform layer was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from acetone-ethanol (1:2) to give cycloartenol-
4-propionyloxy-α-methylcinnamic acid ester was obtained in a yield of 27.0 g. Yield 83.9%, melting point 87-88°C Specific rotation [α] ¹⁹ _D +45.9° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₃ H ₆₂ O ₄ (as molecular weight 642.93) Calculated value (%): C 80.33 H 9.72 Actual value (%): C 80.31 H 9.79 IRν, KBr (cm ^-1 ): 3400, 2920, 2850, 1760,
1700, 1260, 1215, 1115. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.2Hz),
0.52-2.20 (27H, m), 0.61 (1H, 1/2ABq, 4.2
Hz), 0.89 (6H, s), 0.97 (6H, s), 1.25 (3H,
t, 7.2Hz), 1.57 (3H, s), 1.65 (3H, s),
2.10 (3H, d, 1.2Hz), 2.58 (2H, q, 7.2Hz),
4.28-4.84 (1H, m), 4.92-5.24 (1H, m),
6.92-7.09 (2H, m), 7.11-7.50 (2H, m),
7.50-7.70 (1H, m). Example 12 Process for producing cycloartenol-4-hydroxy-α-methylcinnamic acid ester Cycloartenol-4 obtained by the method of Example 11
27.0 g (0.042 mol) of -propionyloxy-α-methylcinnamic acid ester was dissolved in 200 ml of dioxane, and 20 ml of 25% aqueous ammonia was added dropwise. This mixture was heated at 50°C for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, the residue was extracted with 200 ml of chloroform, the chloroform layer was concentrated under reduced pressure, the obtained crude crystals were recrystallized from ethanol, and cycloartenol-4-hydroxy-α -Methylcinnamic acid ester was obtained in a yield of 20.5 g. Yield 83.1%, melting point 190-191°C Specific rotation [α] ¹⁹ _D +45.8° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₀ H ₅₈ O ₃ (as molecular weight 586.86) Calculated value (%): C 81.86 H 9.96 Actual value (%): C 81.77 H 9.99 IRν, KBr (cm ^-1 ): 3400, 2992, 2985, 1700,
1675, 1600, 1510, 1260, 1200, 1170, 1120. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.2Hz),
0.52-2.24 (27H, m), 0.61 (1H, 1/2ABq, 4.2
Hz), 0.90 (6H, s), 0.98 (6H, s), 1.61 (3H,
s), 1.64 (3H, s), 2.13 (3H, d, 1.2Hz),
4.50~4.88 (1H, m), 4.88~5.24 (1H, m),
5.88-6.60 (1H, m), 6.68-7.12 (2H, m),
7.12-7.50 (1H, m), 7.50-7.68 (1H, m). Example 13 Cyclobranol-4-propionyloxy-
Production method of α-methylcinnamic acid ester 4-propionyloxy-α-methylcinnamic acid
Dissolve 17.6g (0.075mol) in 40ml of benzene,
While cooling the solution to 0°C, thionyl chloride
18.1 ml (3.3 equivalents) and 0.5 ml of dimethyl formaldehyde were added dropwise. After heating and stirring this mixture at 60°C for 2 hours, excess thionyl chloride and the solvent were distilled off under reduced pressure, followed by 20 ml of dioxane and 40 ml of pyridine.
Add cyclobranol while cooling to 0℃.
22.0 g (0.050 mol) was added. Add this mixture to 20
Stir overnight at °C. After the reaction, the solvent was distilled off under reduced pressure, extracted with 200 ml of chloroform, the chloroform layer was concentrated under reduced pressure, the obtained crude crystals were recrystallized from acetone-methanol (1:1), and cyclobranol-4 -Propionyloxy-α-methylcinnamic acid ester was obtained in a yield of 26.3 g. Yield 80.0%, melting point 107-108°C Specific optical rotation [α] ¹⁹ _D +34.7° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₄ H ₆₄ O ₄ (assuming molecular weight 656.95) Calculated value (%): C 80.44 H 9.82 Actual value (%): C 80.39 H 9.77 IRν, KBr (cm ^-1 ): 3400, 2920, 2850, 1860,
1710, 1630, 1260, 1200, 1165, 1120. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.8Hz),
0.61 (1H, 1/2ABq, 4.8Hz), 0.74~2.32 (27H,
m), 0.89 (6H, s), 0.96 (6H, s), 1.26 (3H,
t, 7.2Hz), 1.61 (9H, s), 2.10 (3H, d, 1.2
Hz), 2.58 (2H, q, 7.2Hz), 4.46~4.86 (1H,
m), 6.90-7.52 (4H, m), 7.52-7.70 (1H,
m). Example 14 Process for producing cyclobranol-4-hydroxy-α-methylcinnamic acid ester Cyclobranol-4- obtained by the method of Example 13
26.3 g (0.040 mol) of propionyloxy-α-methylcinnamic acid ester was dissolved in 200 ml of dioxane, and 20 ml of 25% aqueous ammonia was added dropwise. After heating and stirring this mixture at 50° C. for 2 hours, the solvent was distilled off under reduced pressure. Extract the residue with 200ml of chloroform,
The chloroform layer was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from acetone-methanol (1:1) to obtain cyclobranol-4-hydroxy-α-methylcinnamate in a yield of 20.7 g. Yield 83.1%, melting point 203-204°C Specific optical rotation [α] ¹⁹ _D +46.0° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₁ H ₆₀ O ₃ (assuming molecular weight 600.89) Calculated value (%): C 81.95 H 10.07 Actual value (%): C 81.99 H 10.07 IRν, KBr (cm ^-1 ): 3400, 2920, 2850, 1780,
1605, 1510, 1265, 1265, 1170, 1125. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.8Hz),
0.61 (1H, 1/2ABq, 4.8Hz), 0.80~2.33 (27H,
m), 0.90 (6H, s), 0.98 (6H, s), 1.60 (9H,
s), 2.12 (3H, d, 1.2Hz), 4.08~4.88 (1H,
m), 5.56-5.80 (1H, m), 6.70-6.92 (2H,
m), 7.12-7.44 (2H, m), 7.58 (1H, q, 1.2
Hz). Example 15 Method for producing 24-methylenecycloartanol-4-propionyloxy-α-methylcinnamic acid ester Using the method of Example 13 instead of cyclobranol
25.8 g of 24-methylenecycloartanol-α-methylcinnamic acid ester was obtained by the same procedure except that 24-methylenecycloartanol was used. Yield 78.5%, melting point 94-95°C Specific rotation [α] ¹⁹ _D +44.2° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₄ H ₆₄ O ₄ (assuming molecular weight 656.95) Calculated value (%): C 80.44 H 9.82 Actual value (%): C 80.48 H 9.78 Example 16 Process for producing 24-methylenecycloartanol-4-hydroxy-α-methylcinnamic acid ester 24-methylenecycloartanol- obtained by the method of Example 15 24.0 g (0.036 mol) of 4-propionyloxy-α-methylcinnamic acid ester was dissolved in 200 ml of dioxane, and 20 ml of 25% aqueous ammonia was added dropwise. After heating and stirring this mixture at 50°C for 2 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform.
Extract with 200 ml, concentrate the chloroform layer under reduced pressure, and recrystallize the obtained crude crystals from acetone-methanol (1:1) to yield 24-methylenecycloartanol-4-hydroxy-α-methylcinnamate ester. Obtained in 19.4g. Yield 89.6%, melting point 195-196°C Specific optical rotation [α] ¹⁹ _D +43.8° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₁ H ₆₀ O ₃ (as molecular weight 600.89) Calculated value (%): C 81.95 H 10.07 Actual value (%): C 81.90 H 10.14 Example 17 Cycloartenol-4-butyryloxy-α
-Production method of ethylcinnamic acid ester 4-butyryloxy-α-ethylcinnamic acid 3.50
A solution of 4.0 g (0.0133 mol) dissolved in 7 ml of benzene was cooled to 0°C, and 4.8 ml (5 ml) of thionyl chloride was added to this solution.
equivalent amount) was added dropwise. After heating and stirring this mixture at 60°C for 2 hours, excess thionyl chloride and the solvent were distilled off under reduced pressure, 10ml of pyridine was added, and while cooling to 0°C, 2.85g (0.0067 mol) of cycloartenol was added.
A 10 ml solution of pyridine was added dropwise. This mixture was stirred at 20°C overnight. After the reaction, the solvent was distilled off under reduced pressure, the residue was extracted with 40 ml of chloroform, the chloroform layer was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from acetone-ethanol (1:1),
Cycloartenol-4-butyryloxy-α-
Ethylcinnamic acid ester was obtained in a yield of 3.63 g. Yield 80.7%, melting point 88-89°C Specific rotation [α] ²⁰ _D +41.2° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₅ H ₆₆ O ₄ (as molecular weight 670.98) Calculated value (%): C 80.55 H 9.92 Actual value (%): C 80.64 H 9.84 IRν, KBr (cm ^-1 ): 3400, 2940, 2860, 1760,
1710, 1240, 1200, 1170, 1125. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.2Hz),
0.52-2.22 (29H, m), 0.61 (1H, 1/2ABq, 4.2
Hz), 0.90 (6H, s), 0.96 (6H, s), 1.03 (3H,
t, 7.2Hz), 1.18 (3H, t, 7.2Hz), 1.58 (3H,
s), 1.66 (3H, s), 2.22-2.80 (4H, m),
4.42-4.88 (1H, m), 4.88-5.24 (1H, m),
6.89-7.18 (2H, m), 7.18-7.46 (2H, m),
7.46-7.64 (1H, m). Example 18 Process for producing cycloartenol-4-hydroxy-α-ethylcinnamate Cycloartenol-4 obtained by the method of Example 17
-Butyryloxy-α-ethylcinnamate ester
2.00 g (0.003 mol) was dissolved in 20 ml of dioxane, and 2 ml of 25% aqueous ammonia was added dropwise. This mixture was heated at 50°C for 5 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with 20 ml of chloroform.
The chloroform layer was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from acetone to obtain cycloartenol-4-hydroxy-α-ethylcinnamate in a yield of 1.68 g. Yield 93.2%, melting point 162.5-163°C Specific optical rotation [α] ²⁰ _D +46.1° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₁ H ₆₀ O ₃ (assuming molecular weight 600.89) Calculated value (%): C 81.95 H 10.07 Actual value (%): C 81.88 H 10.12 IRν, KBr (cm ^-1 ): 3300, 2920, 2800, 1760,
1710, 1625, 1500, 1280, 1240, 1200, 1165,
1120. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.2Hz),
0.52-2.22 (27H, m), 0.61 (1H, 1/2ABq, 4.2
Hz), 0.90 (6H, s), 0.96 (6H, s), 1.19 (3H,
t, 7.2Hz), 1.60 (3H, s), 1.67 (3H, s),
2.57 (2H, bq, 7.2Hz), 4.47~4.88 (1H, m),
4.92~5.32 (1H, m), 6.43~6.67 (1H, m),
6.68~7.04 (2H, m), 7.12~7.48 (2H, m),
7.52-7.69 (1H, m). Example 19 Cyclobranol-4-butyryloxy-α-
Production method of ethylcinnamic acid ester 4-butyryloxy-α-ethylcinnamic acid 5.25
Dissolve g (0.02 mol) in 10 ml of benzene, and while cooling the solution to 0°C, add 7.3 ml of thionyl chloride.
(5 equivalents) was added dropwise. This mixture was heated at 60℃ for 2 hours.
After heating and stirring for an hour, excess thionyl chloride and the solvent were distilled off under reduced pressure, and 40 ml of pyridine was added to the residue.
4.41 g of cyclobranol while cooling to °C.
(0.001 mol) was added. This mixture was stirred at 20°C overnight. After the reaction, the solvent was distilled off under reduced pressure, the residue was extracted with 60 ml of chloroform, the chloroform layer was concentrated under reduced pressure, the obtained crude crystals were recrystallized from acetone-ethanol (1:1), and cyclobranol -4-Butyryloxy-α-ethylcinnamic acid ester was obtained in a yield of 4.80 g. Yield 70.1%, melting point 117.5-118°C Specific optical rotation [α] ²⁰ _D +38.6° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₆ H ₆₈ O ₄ (assuming molecular weight 685.00) Calculated value (%): C 80.65 H 10.01 Actual value (%): C 80.59 H 10.06 IRν, KBr (cm ^-1 ): 3400, 2900, 2850, 1770,
1710, 1625, 1510, 1230, 1120. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.8Hz),
0.52-2.24 (29H, m), 0.61 (1H, 1/2ABq, 4.8
Hz), 0.90 (6H, s), 0.96 (6H, s), 1.03 (3H,
t, 7.2Hz), 1.18 (3H, t, 7.2Hz), 1.59 (9H,
s), 2.24-2.82 (4H, m), 4.48-4.84 (1H,
m), 6.90-7.18 (2H, m), 7.18-7.48 (2H,
m), 7.48-7.68 (1H, m). Example 20 Process for producing cyclobranol-4-hydroxy-α-ethylcinnamic acid ester Cyclobranol-4 obtained by the method of Example 19
-Butyryloxy-α-ethylcinnamate ester
4.11 g (0.0060 mol) was dissolved in 30 ml of dioxane, and 3 ml of 25% concentrated ammonia water was added dropwise. This mixture was heated at 50°C for 5 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with 40 ml of chloroform.
The chloroform layer was concentrated under reduced pressure, the obtained crude crystals were recrystallized from acetone, and cyclobranol-
4-Hydroxy-α-ethylcinnamic acid ester was obtained in a yield of 3.39 g. Yield 91.9%, melting point 202-203°C Specific optical rotation [α] ²⁰ _D +44.0° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₂ H ₆₂ O ₃ (as molecular weight 614.92) Calculated value (%): C 82.03 H 10.16 Actual value (%): C 81.97 H 10.18 IRν, KBr (cm ^-1 ): 3350, 2920, 2860, 1680,
1600, 1510, 1275, 1245, 1200, 1170, 1130. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.8Hz),
0.59-2.24 (27H, m), 0.61 (1H, 1/2ABq, 4.8
Hz), 0.90 (6H, s), 0.97 (6H, s), 1.19 (3H,
t, 7.2Hz), 1.61 (9H, s), 2.57 (2H, bq, 7.2
Hz), 4.52-4.84 (1H, m), 6.43-6.64 (1H,
m), 6.64-7.02 (2H, m), 7.12-7.48 (2H,
m), 7.48-7.67 (1H, m). Example 21 Process for producing cycloartenol-3-methoxy-4-valeryloxy-α-propylcinnamic acid ester Same procedure except that 17.9 g (0.056 mol) of 3-methoxy-4-valeryloxy-α-propylcinnamic acid was used as the raw material. Yield 23.2g of cycloartenol-3-methoxy-4-valeryloxy-α-propylcinnamic acid ester using the same procedure as in Example 7.
I got it from Yield 77.6%, melting point 113-114°C Specific optical rotation [α] ²⁰ _D +34.2° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₈ H ₇₂ O ₅ (as molecular weight 729.06) Calculated value (%): C 79.07 H 9.95 Actual value (%): C 79.13 H 9.88 Example 22 Process for producing cycloartenol-4-hydroxy-3-methoxy-α-propylcinnamic acid ester Cycloartenol obtained by the method of Example 21 as a raw material -3-methoxy-4-valeryloxy-α
-Propylcinnamic acid ester 23.3g (0.032mol)
Cycloartenol-4-hydroxy-4-methoxy-α-propylcinnamic acid ester was obtained in a yield of 18.1 g by the same procedure as in Example 8, except that . Yield 87.6%, melting point 122-123°C Specific optical rotation [α] ²⁰ _D +41.2° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₃ H ₆₄ O ₄ (as molecular weight 644.94) Calculated value (%): C 80.07 H 10.00 Actual value (%): C 80.14 H 9.97 Example 23 Cycloartenol-4-capryloxy-3
-Production method of methoxy-α-butylcinnamic acid ester Cycloartenol-4- Capryloxy-3-methoxy-α-butylcinnamic acid ester was obtained in a yield of 22.7 g. Yield 54.4%, melting point 100-101°C Specific optical rotation [α] ²⁰ _D +33.5° (C1.00, CHCl ₃ ) Elemental analysis results C ₅₀ H ₇₆ O ₅ (as molecular weight 757.11) Calculated value (%): C 79.31 H 10.12 Actual value (%): C 79.38 H 10.05 Example 24 Process for producing cycloartenol-4-hydroxy-3-methoxy-α-butylcinnamic acid ester Cycloartenol-4-capryloxy-3-methoxy as a raw material -α-Butylcinnamic acid 24.4
Cycloartenol-4-hydroxy-3-methoxy-α-butylcinnamic acid ester was obtained in a yield of 17.8 g by the same procedure as in Example 8, except that 0.032 g (0.032 mol) was used. Yield 84.4%, melting point 110-111°C Specific optical rotation [α] ²⁰ _D +40.6° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₄ H ₆₆ O ₄ (assuming molecular weight 672.99) Calculated value (%): C 80.19 H 10.10 Actual value (%): C 80.24 H 10.05 Example 25 Process for producing cyclobranol-4-hydroxy-3-methoxy-α-butylcinnamic acid ester Cyclobranol-4-capryloxy-3-methoxy as raw material -α-Butylcinnamic acid 26.2g
Cyclobranol-4-hydroxy-3 was prepared using the same procedure as in Example 8 except that (0.034 mol)
-Yield of methoxy-α-butylcinnamate ester
Obtained in 18.4g. Yield 80.4%, melting point 132-133°C Specific optical rotation [α] ²⁰ _D +37.0° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₅ H ₆₈ O ₄ (as molecular weight 672.99) Calculated value (%): C 80.31 H 10.18 Actual value (%): C 80.39 H 10.04 Example 26 Process for producing 24-methylenecycloartanol-4-hydroxy-3-methoxy-α-butylcinnamate ester 24-methylenecycloartanol- as a raw material
24-methylenecycloartanol-4-hydroxy-3-methoxy-α was prepared by the same procedure as in Example 8 except that 26.2 g (0.034 mol) of 4-capryloxy-3-methoxy-α-butylcinnamic acid was used.
-Butylcinnamic acid ester was obtained in a yield of 18.1 g. Yield 79.1%, melting point 124-125°C Specific optical rotation [α] ²⁰ _D +39.8° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₅ H ₆₈ O ₄ (assuming molecular weight 672.99) Calculated value (%): C 80.31 H 10.18 Actual value (%): C 80.25 H 10.22 Example 27 Process for producing cycloartenol-3-ethoxy-4-hydroxy-α-methylcinnamic acid ester Cycloartenol-3-ethoxy-4-propionyloxy as a raw material -Cycloartenol-
A yield of 15.8 g of 3-ethoxy-4-hydroxy-α-methyl cinnamic acid ester was obtained. Yield 78.2%, melting point 132-133°C Specific optical rotation [α] ²⁰ _D +43.9° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₂ H ₆₂ O ₄ (as molecular weight 630.92) Calculated value (%): C 79.95 H 9.91 Actual value (%): C 79.90 H 9.99 Example 28 Process for producing cyclobranol-3-ethoxy-4-hydroxy-α-methylcinnamic acid ester Cyclobranol-3-ethoxy- as a raw material
Cyclobranol-3-
Ethoxy-4-hydroxy-α-methylcinnamic acid ester was obtained in a yield of 16.1 g. Yield 80.5%, melting point 174-175°C Specific optical rotation [α] ²⁰ _D +42.4° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₃ H ₆₄ O ₄ (as molecular weight 644.94) Calculated value (%): C 80.07 H 10.00 Actual value (%): C 80.18 H 10.05 Example 29 Method for producing 24-methylenecycloartanol-3-ethoxy-4-hydroxy-α-methylcinnamate ester 24-methylenecycloartanol- as a raw material
24-Methylenecycloartanol-3-ethoxy-4-hydroxy-α- Yield methylcinnamate ester
Obtained in 16.7g. Yield 81.6%, melting point 134-135°C Specific optical rotation [α] ²⁰ _D +40.2° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₃ H ₆₄ O ₄ (as molecular weight 644.94) Calculated value (%): C 80.07 H 10.00 Actual value (%): C 80.13 H 9.92 Example 30 Process for producing cycloartenol-3-ethoxy-4-hydroxy-α-ethylcinnamic acid ester Cycloartenol-4-butyryloxy-3-ethoxy- as a raw material Cycloartenol-3-
Ethoxy-4-hydroxy-α-ethylcinnamic acid ester was obtained in a yield of 15.4 g. Yield 79.6%, melting point 124-125°C Specific rotation [α] ²⁰ _D +41.2° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₃ H ₆₄ O ₄ (as molecular weight 644.94) Calculated value (%): C 80.07 H 10.00 Actual value (%): C 80.04 H 10.08 Example 31 Process for producing cycloartenol-3-ethoxy-4-hydroxy-α-propylcinnamic acid ester Cycloartenol-3-ethoxy-4-valeryloxy as a raw material -Cycloartenol-3 was prepared by the same procedure as in Example 8 except that 26.0 g (0.035 mol) of α-propylcinnamic acid ester was used.
-Ethoxy-4-hydroxy-α-propylcinnamic acid ester (16.8 g) was obtained. Yield 72.8%, melting point 111-112°C Specific optical rotation [α] ²⁰ _D +40.7° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₄ H ₆₆ O ₄ (as molecular weight 658.97) Calculated value (%): C 80.19 H 10.10 Actual value (%): C 80.26 H 10.02 Example 32 Process for producing cyclobranol-3-ethoxy-4-hydroxy-α-propylcinnamic acid ester Cyclobranol-3-ethoxy- as a raw material
16.7 g of cyclobranol-3-ethoxy-4-hydroxy-α-propyl cinnamic acid ester was prepared by the same procedure as in Example 8 except that 24.2 g (0.032 mol) of 4-valeryloxy-α-propyl cinnamic acid ester was used. Obtained. Yield 72.8%, melting point 134-135°C Specific optical rotation [α] ²⁰ _D +37.1° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₄ H ₆₈ O ₄ (as molecular weight 672.99) Calculated value (%): C 80.31 H 10.18 Actual value (%): C 80.25 H 10.24 Example 33 Process for producing cycloartenol-3-ethoxy-4-hydroxy-α-butylcinnamic acid ester Cycloartenol-4-capryloxy-3-ethoxy as a raw material Cycloartenol-3-
16.2 g of ethoxy-4-hydroxy-α-butylcinnamate was obtained. Yield 80.2%, melting point 99-100°C Specific rotation [α] ²⁰ _D +40.0° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₅ H ₆₈ O ₄ (as molecular weight 672.99) Calculated value (%): C 80.31 H 10.18 Actual value (%): C 80.21 H 10.22 Example 34 Process for producing cycloartenol-4-hydroxy-3-propoxy-α-methylcinnamic acid ester Cycloartenol-4-propionyloxy-3-propoxy as a raw material 17.2 g of cycloartenol-4-hydroxy-3-propoxy-α-methyl cinnamic acid ester was obtained by the same procedure as in Example 8 except that 23.1 g (0.033 mol) of -α-methyl cinnamic acid ester was used. Yield 80.8%, melting point 138-139°C Specific rotation [α] ²⁰ _D +43.7° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₃ H ₆₄ O ₄ (as molecular weight 644.94) Calculated value (%): C 80.07 H 10.00 Actual value (%): C 80.19 H 10.04 Example 35 Process for producing cycloartenol-4-hydroxy-3-butoxy-α-methylcinnamic acid ester Cycloartenol-4-propionyloxy-3-butoxy as a raw material -Cycloartenol-
16.5 g of 4-hydroxy-3-butoxy-α-methylcinnamic acid ester was obtained. Yield 78.2%, melting point 126-127°C Specific rotation [α] ²⁹ _D +39.7° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₄ H ₆₆ O ₄ (as molecular weight 658.97) Calculated value (%): C 80.19 H 10.10 Actual value (%): C 80.24 H 10.03 Example 36 Process for producing 24-methylenecycloartanol-4-butyryloxy-3-methoxy-α-ethylcinnamate ester 24-methylenecycloartanol as raw material
22.8 g of 24-methylenecycloartanol-4-butyryloxy-3-methoxy-α-ethylcinnamate was obtained by the same procedure as in Example 9, except that 18.1 g (0.041 mol) was used. Yield 77.8%, melting point 127-128°C Specific optical rotation [α] ²⁰ _D +35.1° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₇ H ₇₀ O ₅ (as molecular weight 715.03) Calculated value (%): C 78.94 H 9.87 Actual value (%): C 78.90 H 9.79 Example 37 Process for producing 24-methylenecycloartanol-4-hydroxy-3-methoxy-α-ethylcinnamate ester 24-methylenecycloartanol- as a raw material
24-methylenecycloartanol-4-hydroxy-3-methoxy-α-ethylcinnamate was prepared by the same procedure as in Example 10 except that 21.5 g (0.0301 mol) of 4-butyryloxy-3-methoxy-α-ethylcinnamate was used. 17.3 g of acid ester was obtained. Yield 89.1%, melting point 137-138°C Specific rotation [α] ²⁰ _D +40.7° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₃ H ₆₄ O ₄ (as molecular weight 644.94) Calculated value (%): C 80.07 H 10.00 Actual value (%): C 80.11 H 9.93 Example 38 Process for producing cyclobranol-4-hydroxy-3-propoxy-α-ethylcinnamic acid ester Cyclobranol-4-butyryloxy-3-propoxy- as a raw material 17.8 g of cyclobranol-4-hydroxy-3-propoxy-α-ethyl cinnamic acid ester was obtained by the same procedure as in Example 8 except that 22.1 g (0.0297 mol) of α-ethyl cinnamic acid ester was used. Yield 89.1%, melting point 140-141°C Specific optical rotation [α] ²⁰ _D +36.8° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₅ H ₆₈ O ₄ (as molecular weight 672.99) Calculated value (%): C 80.31 H 10.18 Actual value (%): C 80.36 H 10.12 Example 39 Process for producing 24-methylenecycloartanol-4-hydroxy-3-propoxy-α-propylcinnamate ester 24-methylenecycloartanol- as a raw material
24-methylenecycloartanol-4-hydroxy-3-
Propoxy-alpha-propylcinnamate ester 17.2
I got g. Yield 82.1%, melting point 120-121°C Specific optical rotation [α] ²⁰ _D +39.1° (C1.00, CHCl ₃ ) Elemental analysis results C ₄₆ H ₇₀ O ₄ (as molecular weight 687.02) Calculated value (%): C 80.41 H 10.27 Actual value (%): C 80.32 H 10.34 Examples 40 to 42 Cycloartenol, cyclobranol or 24
-Production of methylenecycloartanol-3-propionyloxy-α-methylcinnamic acid ester 0.050 mol each of cycloartenol (21.3g), cyclobranol (22.0g) or 24-methylenecycloartanol (22.0g) and 3 -Propionyloxy-α-methylcinnamic acid 17.6 g (0.075 mol) was used, but the same procedure as in Example 11 was used to obtain the target compounds described. Their yield (%), melting point (℃), specific optical rotation {[α] ²⁰ _D
(C1.00, CHCl ₃ )} was as follows.

[Table] Examples 43-45 cycloartenol, cyclobranol or 24
-Production method of methylenecycloartanol-3-hydroxy-α-methylcinnamic acid ester Using 0.042 mol of each of the compounds of Examples 40 to 42 and following the same procedure as in Example 12, the target compound described above was obtained. The yield (%), melting point (°C), and specific optical rotation {[α] ²⁰ _D (C1.00, CHCl ₃ )} of these were as follows.

[Table] Examples 46-48 Cycloartenol, cyclobranol or 24
-Methylenecycloartanol-3-butyryloxy-α-methylcinnamic acid ester production method 3-butyryloxy-α-ethylcinnamic acid 3.50
g (0.0135 mol) and cycloartenol 2.85 g,
The desired compounds were obtained by the same procedure as in Example 17, except that 0.0067 mol of each of 2.95 g of cyclobranol and 2.95 g of 24-methylenecycloartanol was used. The yield (%), melting point (°C), and specific optical rotation {[α] ²⁴ _D (C1.00, CHCl ₃ )} of these were as follows.

[Table] Examples 49-51 cycloartenol, cyclobranol or 24
-Production method of methylenecycloartanol-3-hydroxy-α-ethylcinnamic acid ester By the same procedure as in Example 18 except that 0.003 mol of each of the compounds of Examples 46 to 48 was used,
The indicated target compound was obtained. These yields (%),
Melting point (℃), specific optical rotation {[α] ²⁰ _D (C1.00, CHCl ₃ )}
is as follows.

[Table] Examples 52-53 Cycloartenol or cyclobranol-2
-Production of hydroxy-α-methylcinnamic acid ester Example 11 except that 0.050 mol each of 21.3 g of cycloartenol or 22.0 g of cyclobranol and 17.6 g (0.075 mol) of 2-propionyloxy-α-methylcinnamic acid were used. By the same procedure as above, 27.5 g (yield 85.5%) and 27.5 g (yield 82.8%) of cycloartenol or cyclobranol-2-propionyloxy-α-methylcinnamic acid ester were obtained, respectively. Example using 24.5g each of these
Cycloartenol or cyclobranol-2-hydroxy-α-methylcinnamic acid ester was obtained by the same procedure as in 12. Their yield (%), melting point (°C), and specific optical rotation {[α] ²⁰ _D (1.00, CHCl ₃ )} are as follows.

[Table] Example 54 Process for producing cycloartenol-3-methoxy-4-nitrobenzoic acid ester 15.0 g of 3-methoxy-4-nitrobenzoic acid
(0.076 mol) were added with 34 ml (6 equivalents) of thionyl chloride and 0.5 ml of dimethylformamide, and the mixture was heated and stirred at 60°C for 2 hours. After concentrating the reaction solution under reduced pressure, dioxane
Add 75ml, stir at 0℃, and add 110ml of pyridine.
25.0 g of cycloartenol (0.059
mol) and stirred at 70°C for 20 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in chloroform, washed with saturated aqueous sodium bicarbonate, and then dried. The chloroform layer was concentrated under reduced pressure, and the residue was recrystallized from methylene chloride-methanol (1:2) to give cycloartenol-3-methoxy-4-.
30.5 g of nitrobenzoic acid ester was obtained. Yield 85.3%, melting point 182-183°C Specific optical rotation [α] ^25.5 _D + ^57.7 ° (C1.00, CHCl ₃ ) Elemental analysis results C ₃₈ H ₅₅ NO ₅ (as molecular weight 605.82) Calculated value (%) ): C 75.33 H 9.15 N 2.31 Actual value (%): C 75.42 H 9.07 N 2.36 IRν, KBr (cm ^-1 ): 2940, 1720, 1610, 1530,
1410, 1350, 1310, 1290, 1245. PMR (CDCl ₃ ) δ: 0.38 (1H, 1/2ABq, 4.2Hz),
0.62 (1H, 1/2ABq, 4.2Hz), 0.50~2.36 (27H,
m), 0.95 (6H, s), 0.97 (3H, s), 1.04 (3H,
s), 1.60 (3H, s), 1.69 (3H, s), 4.00 (3H,
s), 4.50-5.32 (2H, m), 7.42-8.01 (3H,
m). Example 55 Process for producing cycloartenol-4-amino-3-methoxybenzoic acid ester 40.0 g of cycloartenol-3-methoxy-4-nitrobenzoic acid ester obtained in Example 54
(0.066 mol) was added with 400 ml of acetic acid and 400 ml of dioxane, and while stirring at 0°C, 22 ml (2 equivalents) of 6N-hydrochloric dioxane and 40 g of zinc powder were added thereto, and stirring was continued at 25°C for 2 hours. After the reaction, the zinc powder is filtered off, the filtrate is concentrated under reduced pressure, the resulting residue is extracted with chloroform, the chloroform layer is washed with water, then saturated sodium bicarbonate solution, dried and concentrated, and the residue is chlorinated. By recrystallizing with methylene-methanol (1:2), 32.0 g of cycloartenol-4-amino-3-methoxybenzoic acid ester was obtained. Yield 84.1%, melting point 186-188°C Specific optical rotation [α] ^26.5 _D + ^64.3 ° (C1.00, CHCl ₃ ) Elemental analysis results C ₃₈ H ₅₇ NO ₃ (as molecular weight 575.83) Calculated value (%) ): C 79.26 H 9.98 N 2.43 Actual value (%): C 79.32 H 9.99 N 2.39 IRν, KBr (cm ^-1 ): 3450, 3350, 2930, 1700,
1620, 1520, 1460, 1305, 1285, 1260, 1220,
1180, 1105. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.2Hz),
0.61 (1H, 1/2ABq, 4.2Hz), 0.48~2.39 (27H,
m), 1.61 (3H, s), 1.67 (3H, s), 3.88 (3H,
s), 4.20 (2H, bs), 4.51-5.31 (2H, m),
6.46-6.77 (1H, m), 7.30-7.71 (2H, m). Example 56 Process for producing cyclobranol-3-methoxy-4-nitrobenzoic acid ester 50.0 g of 3-methoxy-4-nitrobenzoic acid
(0.254 mol) were added with 60 ml (3.2 equivalents) of thionyl chloride and 0.5 ml of dimethylformamide, and the mixture was heated and stirred at 60°C for 2 hours. After concentrating the reaction solution under reduced pressure, 100 ml of dioxane was added and stirred at 0°C, and 93.0 g of cyclobranol dissolved in 150 ml of pyridine was added thereto.
(0.211 mol) was added and stirred at 70°C for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in chloroform, washed with saturated aqueous sodium bicarbonate, and then dried. The chloroform layer was concentrated under reduced pressure and the residue was recrystallized from chloroform-ethanol (1:3) to obtain 94.4 g of cyclobranol-3-methoxy-4-nitrobenzoic acid ester. Yield 72.1%, melting point 213-214°C Specific optical rotation [α] ^25.5 _D + ^53.9 ° (C1.00, CHCl ₃ ) Elemental analysis results C ₃₉ H ₅₇ NO ₅ (as molecular weight 619.85) Calculated value (%) ): C 75.57 H 9.27 N 2.26 Actual value (%): C 75.63 H 9.22 N 2.33 IRν, KBr (cm ^-1 ): 2930, 1715, 1610, 1530,
1410, 1360, 1310, 1285, 1240. PMR (CDCl ₃ ) δ: 0.39 (1H, 1/2ABq, 4.8Hz),
0.62 (1H, 1/2ABq, 4.8Hz), 0.50~2.28 (27H,
m), 0.92 (6H, s), 0.99 (3H, s), 1.05 (3H,
s), 1.63 (9H, s), 4.01 (3H, s), 4.62~
5.03 (1H, m), 7.48-7.96 (3H, m). Example 57 Process for producing cyclobranol-4-amino-3-methoxybenzoic acid ester Cyclobranol-3 obtained by the method of Example 56
-Methoxy-4-nitrobenzoic acid ester 94.3g
(0.152 mol) acetic acid 1.2 and tetrahydrofuran
1.2 and add 6N-hydrochloric acid-dioxane thereto.
100 ml and 94 g of zinc powder were added and stirred at 25°C for 2 hours. After the reaction was completed, the zinc dust was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was extracted with chloroform.
The chloroform layer was washed with water and then with saturated sodium bicarbonate solution, dried and concentrated, and the residue was recrystallized from chloroform-ethanol (1:4) to obtain cyclobranol-4-amino-3-methoxybenzoic acid ester 64.2 I got g. Yield 71.5%, melting point 235-236°C Specific optical rotation [α] ²⁵ _D +60.8° (C1.00, CHCl ₃ ) Elemental analysis results C ₃₉ H ₅₉ NO ₃ (as molecular weight 589.86) Calculated value (%): C 79.41 H 10.08 N 2.37 Actual value (%): C 79.49 H 10.12 N 2.42 IRν, KBr (cm ^-1 ): 3450, 3350, 2900, 1680,
1620, 1310, 1280, 1260, 1110. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.8Hz),
0.61 (1H, 1/2ABq, 4.8Hz), 0.50~2.20 (27H,
m), 0.89 (6H, s), 0.96 (3H, s), 1.01 (3H,
s), 3.85 (3H, s), 3.92-4.36 (2H, bs),
4.51-4.91 (1H, m), 6.42-6.72 (1H, m),
7.26-7.72 (2H, m). Example 58 Process for producing cycloartenol-2-methoxy-5-nitrobenzoic acid ester 17.3 g of 2-methoxy-5-nitrobenzoic acid
(0.088 mol) were added with 65 ml (10 equivalents) of thionyl chloride and 0.3 ml of dimethylformamide, and the mixture was stirred at 50°C for 1.5 hours. After concentrating the reaction solution under reduced pressure, dioxane
Add 125ml of pyridine, stir at 0℃, and add 125ml of pyridine.
25.0 g of cycloartenol (0.059
mol) was added dropwise, and the mixture was stirred at 60°C for 1.5 hours. After the reaction, the solvent was distilled off under reduced pressure, the residue was extracted with chloroform, the chloroform layer was washed with water, then with saturated sodium bicarbonate solution, dried and concentrated, and the residue was dissolved in methylene chloride-hexane (1:3). Recrystallization was performed to obtain 31.5 g of cycloartenol-2-methoxy-5-nitrobenzoic acid ester. Yield 88.7%, melting point 186-187℃ Specific rotation [α] ²⁵ _D +43.9゜ (C1.00, CHCl ₃ ) Elemental analysis results C ₃₈ H ₅₅ NO ₅ (as molecular weight 605.82) Calculated value (%): C 75.33 H 9.15 N 2.31 Actual value (%): C 75.30 H 9.22 N 2.29 IRν, KBr (cm ^-1 ): 2930, 1695, 1610, 1520,
1340, 1280, 1135. PMR (CDCl ₃ ) δ: 0.39 (1H, 1/2ABq, 4.2Hz),
0.62 (1H, 1/2ABq, 4.2Hz), 0.50~2.40 (27H,
m), 0.90 (3H, s), 0.96 (6H, s), 1.01 (3H,
s), 2.60 (3H, bs), 2.68 (3H, bs), 4.00 (3H,
s), 4.65-5.30 (2H, m), 7.08 (1H, d, 9.4
Hz), 8.34 (1H, dd, 3.0Hz, 9.4Hz), 8.64 (1H,
d, 3.0Hz). Example 59 Process for producing cycloartenol-5-amino-2-methoxybenzoic acid ester 34.0 g of cycloartenol-2-methoxy-5-nitrobenzoic acid ester obtained in Example 58
(0.056 mol) was suspended in 1.2 mol of acetic acid at 20°C,
19 ml (2 equivalents) of 6N hydrochloric acid-dioxane and 68 g of zinc powder were added thereto, and the mixture was stirred at 30°C for 1 hour. After the reaction was completed, the zinc dust was filtered off, the filtrate was concentrated under reduced pressure, and then extracted with chloroform. Add the chloroform layer to water,
Subsequently, after washing with saturated sodium bicarbonate solution, drying and concentration, the residue was recrystallized from methylene chloride-hexane (1:4) to obtain 27.2 g of cycloartenol-5-amino-2-methoxybenzoic acid ester. . Yield 84.4%, melting point 180-182°C Specific optical rotation [α] ^26.5 _D + ^47.8 ° (C1.00, CHCl ₃ ) Elemental analysis results C ₃₈ H ₅₇ NO ₃ (as molecular weight 575.83) Calculated value (%) ): C 79.26 H 9.98 N 2.43 Actual value (%): C 79.32 H 9.94 N 2.41 IRν, KBr (cm ^-1 ): 3450, 3350, 2900, 2860,
1690, 1630, 1500, 1440, 1300, 1270, 1245. PMR (CDCl ₃ ) δ: 0.38 (1H, 1/2ABq, 4.2Hz),
0.59 (1H, 1/2ABq, 4.2Hz), 0.50~2.30 (27H,
m), 0.90 (6H, s), 0.93 (6H, s), 1.59 (3H,
bs), 1.67 (3H, bs), 3.55 (2H, bs), 3.88 (3H,
s), 4.50-5.30 (2H, m), 6.68-7.24 (3H,
m). Example 60 Preparation of cyclobranol-2-methoxy-5-nitrobenzoic acid ester 11.6 g of 2-methoxy-5-nitrobenzoic acid
(0.059 mol) were added with 20 ml of thionyl chloride and 0.2 ml of dimethylformamide, and the mixture was stirred at 50°C for 2 hours.
After concentrating the reaction solution under reduced pressure, add 150ml of toluene and pyridine.
Add 30ml and then 20g of cyclobranol
(0.045 mol) was added and stirred at 60°C for 2 hours.
After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The chloroform layer was washed with water and then with saturated saline, and after drying and concentration, the residue was recrystallized from chloroform-ethanol (1:3) to obtain 25.9 g of cyclobranol-2-methoxy-5-nitrobenzoic acid ester. I got it. Yield 92.0%, melting point 207-208°C Specific optical rotation [α] ²⁵ _D +32.5° (C1.00, CHCl ₃ ) Elemental analysis results C ₃₉ H ₅₇ NO ₅ (as molecular weight 619.85) Calculated value (%): C 75.57 H 9.27 N 2.26 Actual value (%): C 75.52 H 9.34 N 2.30 IRν, KBr (cm ^-1 ): 2930, 1700, 1610, 1520,
1345, 1280, 1130. PMR (CDCl ₃ ) δ: 0.39 (1H, 1/2ABq, 4.8Hz),
0.62 (1H, 1/2ABq, 4.8Hz), 0.76~2.24 (27H,
m), 0.91 (3H, s), 0.96 (6H, s), 1.01 (3H,
s), 1.63 (9H, s), 4.01 (3H, s), 4.64~
5.02 (1H, m), 7.06 (1H, d, 9.6Hz), 8.34
(1H, dd, 9.6Hz, 3.6Hz), 8.67 (1H, d, 3.6
Hz). Example 61 Process for producing cyclobranol-5-amino-2-methoxybenzoate 25.0 g (0.040
mol) was suspended in 1 acetic acid, 21 ml of 6N-hydrochloric acid-dioxane and 25.0 g of subsalt powder were added thereto, and the mixture was stirred at 30°C for 2 hours. After the reaction is complete, filter out the zinc powder,
The filtrate was concentrated under reduced pressure, and then extracted with chloroform. The chloroform layer was washed with water and then with saturated sodium bicarbonate solution, dried and concentrated, and the residue was recrystallized with chloroform-ethanol (1:2) to obtain 13.7 g of cyclobranol-5-amino-2-methoxybenzoic acid ester. I got it. Yield 57.5%, melting point 193-195°C Specific optical rotation [α] ^{26.5 °} _D +41.5° (C1.00, CHCl ₃ ) Elemental analysis results C ₃₉ H ₅₉ NO ₃ (as molecular weight 589.86) Calculated value ( %): C 79.41 H 10.08 N 2.37 Actual value (%): C 79.35 H 10.15 N 2.35 IRν, KBr (cm ^-1 ): 3430, 3350, 2930, 1690,
1500, 1460, 1430, 1310, 1270, 1245. PMR (CDCl ₃ ) δ: 0.36 (1H, 1/2ABq, 4.8Hz),
0.61 (1H, 1/2ABq, 4.8Hz), 0.50~2.28 (27H,
m), 0.92 (3H, s), 0.96 (6H, s), 1.00 (3H,
s), 1.64 (9H, s), 2.88-3.26 (2H, m),
3.81 (3H, s), 4.52~5.02 (1H, m), 6.74~
6.90 (1H, m), 7.08-7.22 (2H, m). Examples 62-64 cycloartenol, cyclobranol or 24
-Production method of methylenecycloartanol-3-methoxy-4-nitrocinnamic acid ester 17.0 g of 3-methoxy-4-nitrocinnamic acid
(0.076 mol) and 0.059 mol each of 25.0 g of cycloartenol, 26.0 g of cyclobranol, or 26.0 g of 24-methylenecycloartanol were used.
The title compound was obtained by the same operation as in Example 54. The yield (%), melting point (°C), and specific optical rotation {[α] ²⁵ _D (C1.00, CHCl ₃ ) of these were as follows.

[Table] Examples 65-67 cycloartenol, cyclobranol or 24
-methylenecycloartanol-4-amino-
Method for producing 3-methoxycinnamic acid ester Cycloartenol obtained in Examples 62 to 64 above,
Using 0.066 mol each of 41.7 g, 42.6 g, or 42.6 g of cyclobranol or 24-methylenecycloartanol-3-methoxy-4-nitrocinnamic acid ester, the title compound was obtained in the same manner as in Example 55. . The yield (%), melting point (°C), and specific optical rotation {[α] ²⁵ _D (C1.00, CHCl ₃ )} of these were as follows.

[Table] Examples 68-70 Cycloartenol, cyclobranol or 24
-Production method of methylenecycloartanol-2-ethoxy-5-nitrocinnamic acid ester 19.5 g of 2-ethoxy-5-nitrocinnamic acid
(0.082 mol) and 0.059 mol each of 25.0 g of cycloartenol, 26.0 g of cyclobranol, or 26.0 g of 24-methylenecycloartanol were used.
The title compound was obtained by the same operation as in Example 58. The yield (%), melting point (°C), and specific optical rotation {[α] ²⁵ _D (C1.00, CHCl ₃ )} of these were as follows.

[Table] Examples 71-73 cycloartenol, cyclobranol or 24
-methylenecycloartanol-5-amino-
Method for producing 2-methoxycinnamic acid ester 36.2g, 37.0g or 37.0g of cycloartenol, cyclobranol or 24-methylenecycloartanol-2-ethoxy-5-nitrocinnamic acid ester obtained in Examples 68 to 70 The title compound was obtained by the same operation as in Example 59 using 0.056 mol of each. The yield (%), melting point (°C), and specific optical rotation {[α] ²⁵ _D (C1.00, CHCl ₃ )} of these were as follows.

[Table] Examples 74 to 76 cycloartenol, cyclobranol or 24
-Production method of methylenecycloartanol-3-methoxy-4-nitro-α-methylcinnamic acid ester 17.3 g (0.073 mol) of 3-methoxy-4-nitro-α-methylcinnamic acid and 25.0 mol of cycloartenol
The title compound was obtained by the same procedure as in Example 54, except that 0.059 mol of each of g, 26.0 g of cyclobranol, or 26.0 g of 24-methylenecycloartanol was used. These yields (%), melting points (℃)
and the specific optical rotation {[α] ²⁵ _D (C1.00, CHCl ₃ )} were as follows.

[Table] Examples 77-79 cycloartenol, cyclobranol or 24
-methylenecycloartanol-4-amino-
43.6 g of cycloartenol, cyclobranol or 24-methylenecycloartanol-3-methoxy-4-nitro-α-methylcinnamic acid ester obtained in Examples 74 to 76 , 44.5g or 44.5g each
The title compound was obtained by the same operation as in Example 55, except that 0.066 mol was used. Their yield (%), melting point (℃), specific optical rotation {[α] ²⁵ _D (C.100,
CHCl ₃ )} was as follows.

[Table] Examples 80-82 cycloartenol, cyclobranol or 24
-methylenecycloartanol-5-nitro-
Method for producing 2-propoxy-α-methylcinnamic acid ester 21.2 g (0.080 mol) of 5-nitro-2-propoxy-α-methylcinnamic acid and cycloartenol
The title compound was obtained by the same operation as in Example 58, except that 0.059 mol of each of 25.0 g, 26.0 g of cyclobranol, and 26.0 g of 24-methylenecycloartanol was used. Their yield (%), melting point (℃) and specific optical rotation {[α] ²⁵ _D (C1.00, CHCl ₃ )}
was as follows.

[Table] Examples 83-85 cycloartenol, cyclobranol or 24
-methylenecycloartanol-5-amino-
37.7 g of cycloartenol, cyclobranol or 24-methylenecycloartanol-5-nitro-2-propoxy-α-methylcinnamic acid ester obtained in Examples 80 to 82. , 38.5g or 38.5g each
The title compound was obtained by the same operation as in Example 59, except that 0.056 mol was used. Their yield (%), melting point (℃), specific optical rotation {[α] ²⁵ _D (C1.00,
CHCl ₃ )} was as follows.

[Table] Examples 86-87 Cycloartenol or cyclobranol-3
-Production method of methoxy-4-nitro-α-iso-propylcinnamic acid ester 19.1 g (0.072 mol) of 3-methoxy-4-nitro-α-iso-propylcinnamic acid and 25.0 g of cycloartenol or 26.0 g of cyclobranol each of
The title compound was obtained by the same operation as in Example 54, except that 0.059 mol was used. Their yield (%), melting point (℃) and specific optical rotation {[α] ²⁵ _D (C1.00,
CHCl ₃ )} was as follows.

[Table] Examples 88-89 Cycloartenol or cyclobranol-4
-Production method of amino-3-methoxy-α-iso-propylcinnamic acid ester Cycloartenol or cyclobranol-3-methoxy-4-nitro-α obtained in Examples 86 to 87
-iso-propylcinnamic acid ester 44.5g, 45.4
The title compound was obtained by the same procedure as in Example 55, except that 0.066 mol of each of g and 45.4 g was used. The yield (%), melting point (°C), and specific optical rotation {[α] ²⁵ _D (C1.00, CHCl ₃ )} of these were as follows.

[Table] Examples 90-92 cycloartenol, cyclobranol or 24
-methylenecycloartanol-p-nitro-
Production method of α-methylcinnamic acid ester p-nitro-α-methylcinnamic acid 78.3g
(0.378 mol) were added with 112 ml (4.0 equivalents) of thionyl chloride and 1 ml of dimethylformamide, and the mixture was stirred at 60°C for 2 hours. After concentrating the reaction solution under reduced pressure, dioxane
Add 250 ml and 250 ml of pyridine, followed by 125.0 g of cycloartenol, 129.1 g of cyclobranol or
24-methylenecycloartanol 129.1g each
0.293 mol was added and stirred at 60°C for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was extracted with chloroform. The chloroform layer was washed with water and then with saturated aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The residue was recrystallized from chloroform-ethanol (1:3) to obtain the desired compounds. Their yield (%), melting point (℃), specific optical rotation {[α] ²⁵ _D (C1.00,
CHCl ₃ )} was as follows.

[Table] Examples 93-95 cycloartenol, cyclobranol or 24
-methylenecycloartanol-p-amino-
Production method of α-methylcinnamate ester Cycloartenol, cyclobranol or 24-methylenecycloartanol-p-nitro-α-methylcinnamic acid ester obtained in Examples 90 to 92.
Acetic acid
The suspension was suspended in a mixture of 150 ml and dioxane, 9.5 ml of 6N-hydrochloric acid-dioxane and 8 g of zinc powder were added thereto, and the mixture was stirred at 4°C for 3 hours. After the reaction was completed, the zinc dust was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was extracted with chloroform. The chloroform layer was washed with water and then with saturated aqueous sodium bicarbonate, dried, and concentrated, and the residue was recrystallized from chloroform-ethanol (1:3) to obtain the desired compounds. Their yield (%), melting point (℃), specific optical rotation {[α] ²⁵ _D (C1.00,
CHCl ₃ )} was as follows.

[Table] Examples 96-98 cycloartenol, cyclobranol or 24
-methylenecycloartanol-m-nitro-
Production method of α-methylcinnamic acid ester m-nitro-α-methylcinnamic acid 80.4g
(0.388 mol) were added with 60 ml (2.1 equivalents) of thionyl chloride and 1 ml of dimethylformamide, and the mixture was stirred at 60°C for 2 hours. After concentrating the reaction solution under reduced pressure, dioxane 300
ml and 200 ml of pyridine, followed by 125.9 g of cycloartenol, 130.0 g of cyclobranol or 24
- 0.295 each of 130.0 g of methylene cycloartanol
mol was added and stirred at 60°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was extracted with chloroform. The chloroform layer was washed with water and then with saturated aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The residue was recrystallized from chloroform-ethanol (1:4) to obtain the desired compounds. These yields (%),
Melting point (℃), specific optical rotation {[α] ²⁵ _D (C1.00, CHCl ₃ )}
was as follows.

[Table] Examples 99-101 cycloartenol, cyclobranol or 24
-methylenecycloartanol-m-amino-
Process for producing α-methyl cinnamic acid ester Cycloartenol, cyclobranol or 24-methylenecycloartanol-m-nitro-α-methyl cinnamic acid ester obtained in Examples 96 to 98
0.027 mol each of 16.6g, 17.0g or 17.0g is
The suspension was suspended in a mixture of 150 ml and 200 ml of tetrahydrofuran, 12.5 ml of 6N-hydrochloric acid-dioxane and 16.5 g of zinc powder were added thereto, and the mixture was stirred at 20°C for 2 hours. After the reaction was completed, the zinc dust was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was extracted with chloroform. The chloroform layer was washed with water, then with saturated sodium bicarbonate solution, and after drying,
Concentrate and dissolve the residue in chloroform-ethanol (1:
2) to obtain the desired compounds. The yield (%), melting point (°C), and specific optical rotation {[α] ²⁵ _D (C1.00, CHCl ₃ )} of these were as follows.

[Table] Examples 102-103 Cycloartenol or cyclobranol-p
-Production method of nitro-α-ethylcinnamic acid ester p-nitro-α-ethylcinnamic acid 8.9g (0.040
mol), dioxane 30ml, thionyl chloride 6ml
(2.0 equivalents) and 0.1 ml of dimethylformamide,
The mixture was stirred at 60°C for 2 hours. After concentrating the reaction solution under reduced pressure, 30 ml of dioxane and 20 ml of pyridine were added, followed by 12.8 g of cycloartenol or 13.2 g of cyclobranol.
0.030 mol of each were added and stirred at 60°C for 2 hours.
After the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was extracted with chloroform. The chloroform layer was washed with water and then with saturated aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The residue was recrystallized from chloroform-ethanol (1:3) to obtain the desired compounds. Their yield (%), melting point (℃), specific optical rotation {[α] ²⁵ _D (C1.00,
CHCl ₃ )} was as follows.

[Table] Examples 104-105 Cycloartenol or cyclobranol-p
-Production method of amino-α-ethylcinnamic acid ester 0.027 mol each of 17.0 g or 17.4 g of cycloartenol or cyclobranol-p-nitro-α-ethyl cinnamic acid ester obtained in Examples 102 to 103 was added to 150 ml of acetic acid and tetrahydrofuran. The suspension was suspended in 200 ml of a mixed solution, 12.5 ml of 6N-hydrochloric acid-dioxane and 16.5 g of zinc powder were added thereto, and the mixture was stirred at 22°C for 2 hours. After the reaction, the bad lead powder was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was extracted with chloroform. The chloroform layer was washed with water followed by saturated sodium bicarbonate solution, dried,
After concentration under reduced pressure, the residue was recrystallized from chloroform-ethanol (1:3) to obtain the desired target compounds. The yield (%), melting point (°C), and specific optical rotation {[α] ²⁵ _D (C1.00, CHCl ₃ )} of these were as follows.

[Table] Example 106 Process for producing 24-methylenecycloartanol-3-methoxy-4-nitrobenzoic acid ester 24-methylenecycloartanol 93.0g
24-methylenecycloartanol-3 was prepared using the same procedure as in Example 56 except that 24-methylenecycloartanol
-Methoxy-4-nitrobenzoic acid ester 93.7g
I got it. Yield 71.6%, melting point 205-206°C Specific optical rotation [α] ^25.5 _D + ^56.5 ° (C1.00, CHCl ₃ ) Elemental analysis results C ₃₉ H ₅₇ NO ₅ (as molecular weight 619.85) Calculated value (%) ): C 75.57 H 9.27 N 2.26 Actual value (%): C 75.51 H 9.38 N 2.28 Example 107 Process for producing 24-methylenecycloartanol-4-amino-3-methoxybenzoic acid ester Obtained by the method of Example 106 except that 92.2 g (0.149 mol) of 24-methylenecycloartanol-3-methoxy-4-nitrobenzoic acid ester was used.
By the same procedure as in Example 57, 62.8 g of 24-methylenecycloartanol-4-amino-3-methoxybenzoic acid ester was obtained. Yield 71.5%, melting point 222-223°C Specific optical rotation [α] ²⁵ _D +63.2° (C1.00, CHCl ₃ ) Elemental analysis results C ₃₉ H ₅₉ NO ₃ (as molecular weight 859.86) Calculated value (%): C 79.41 H 10.08 N 2.37 Actual value (%): C 79.38 H 10.14 N 2.35 Example 108 Process for producing cycloartenol-4-amino-3-methoxybenzoic acid ester 4-acetamido-3-methoxybenzoic acid 6.5 g
(0.031 mol) was dissolved in 110 ml of dioxane. This solution was stirred at 20°C and thionyl chloride 21.0
ml dropwise, then add 0.5 ml of pyridine at 50°C.
The mixture was allowed to react for 5 minutes. After concentrating the reaction solution under reduced pressure to remove thionyl chloride, add 50 ml of dioxane and 50 ml of benzene.
10.0g of cycloartenol dissolved in a mixture of
(0.023 mol) at 20℃, and then add 20 ml of pyridine.
added. After reacting this at 70°C for 3 hours, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in chloroform.
After dissolving in 100 ml, the solution was washed with saturated sodium bicarbonate solution. Furthermore, the saturated sodium bicarbonate solution was extracted five times with 100 ml of chloroform.
The chloroform layers were combined and dried, concentrated under reduced pressure, and purified by silica gel column chromatography [solvent chloroform-ethyl acetate (1:6)] to obtain cycloartenol-4-acetamido-3-methoxybenzoic acid ester 10.8 I got g. Yield 76.5%, melting point 224-225°C Specific rotation [α] ²⁵ _D +61.5° (C1.00, CHCl ₃ ) 10.0 g of cycloartenol-4-acetamido-3-methoxybenzoic acid ester obtained above
(0.016 mol) to 200 ml of tetrahydrofuran and 30%
20 ml of hydrochloric acid was added and heated under reflux for 2 hours. After the reaction, the solvent was distilled off under reduced pressure and 300ml of chloroform was added.
Dissolve the chloroform layer in 1N caustic soda water
It was washed with 200 ml and then with saturated saline. The saturated saline solution was then extracted three times with chloroform. The chloroform layers were combined, dried, concentrated under reduced pressure, and subjected to silica gel column chromatography [solvent: ethyl acetate]
Hexane (1:6)] to obtain 5.4 g of cycloartenol-4-amino-3-methoxybenzoic acid ester. Yield 58.7%, melting point 186-187°C Specific rotation [α] ²⁶ _D +64.4° (C1.00, CHCl ₃ ) Example 109 Cyclobranol-4-amino-3-methoxy-α-methylcinnamic acid Production method 21.93g (0.088mol) of 4-acetamido-3-methoxy-α-methylcinnamic acid was added to 150ml of dioxane.
and add 25.7 ml of thionyl chloride to make 60
The mixture was heated and stirred at ℃ for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. This residue is again dioxane 150
ml, then dissolved in 50 ml of pyridine, added 30 g (0.068 mol) of cyclobranol, and stirred at 60℃ for 2 hours.
Stir for hours. After the reaction was completed, the solvent was concentrated under reduced pressure, 300 ml of ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration. The crystals were subjected to silica gel chromatography [solvent chloroform-ethyl acetate, (1:
6)] to obtain 38.5 g of cyclobranol-4-acetamido-3-methoxy-α-methylcinnamic acid ester. Yield 84.2%, melting point 248-249°C Specific rotation [α] ²⁶ _D +38.2° (C1.00, CHCl ₃ ) The above cyclobranol-4-acetamide-3
-Methoxy-α-methylcinnamate ester 34.4g
(0.051 mol) was dissolved in 300 ml of tetrahydrofuran, 60 ml of 30% hydrochloric acid was added, and the mixture was stirred at 70°C for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified twice by silica gel chromatography [solvent: chloroform-ethyl acetate, (1:6]) to obtain cyclobranol-4-amino-3-methoxy-
18.9 g of α-methylcinnamic acid ester was obtained. Yield 58.8%, melting point 225-226°C Specific rotation [α] ²⁵ _D +42.0° (C1.00, CHCl ₃ ) Example 110 24-methylenecycloartanol-4-amino-3-methoxycinnamic acid ester In the method of Example 109, 4-acetamide-3
-21.93 g of 4-propioamido-3-methoxy-cinnamic acid instead of methoxy-α-methylcinnamic acid
(0.088 mol), 38.4 g of 24-methylene dichloroartanol-4-propioamide-3-methoxy-cinnamate ester using the same procedure except that 30 g (0.068 mol) of 24-methylenecycloartanol was used instead of cyclobranol. I got it. Yield 83.8%, melting point 210-211°C Specific rotation [α] ²⁶ _D +39.4° (C1.00, CHCl ₃ ) Also, cyclobranol-4-acetamide-3-
24-methylenecycloartanol-4-propioamide instead of methoxy-α-methylcinnamic acid
18.7 g of 24-methylenecycloartanol-4-amino-3-methoxycinnamic acid ester was obtained by the same procedure as in Example 109, except that 35.2 g (0.052 mol) of 3-methoxycinnamic acid ester was used. Yield 57.1%, melting point 227-228°C Specific rotation [α] ²⁵ _D +41.8° (C1.00, CHCl ₃ )

Claims (1)

[Claims] 1 The following chemical formula [a], [b] or [c]
Triterpene alcohol organic acid ester represented by [However, R is or (R ₂ represents an amino group, a nitro group, a hydroxy group, or an alkylcarboxy group having 2 to 6 carbon atoms, R ₃ and R ₄ represent an alkyl group having 1 to 4 carbon atoms, and R ₅ represents an amino group or a nitro group. ).