JPS59170088A - Production of steroid with plant growth regulating action - Google Patents

Abstract

PURPOSE:The deprotection in the 2,3-positions of a specific steroid protected with an acetonide in the 2,3-diol enables practically advantageous production of homodolicholide, a steroid having plant growth regulating action. CONSTITUTION:A readily available steroid, stigmasterol of formula I , is used as a starting material to synthesize an epoxidized steroid which is protected in the 2,3-diol with an acetonide group of formula II, then the epoxide is cleaved to a protected steroid of formulaIII. Then, the acetonide group is removed from the product to form the objective steroid of formula V, homodolicholide.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing steroids having plant growth regulating activity.

In recent years, a certain kind of steroid (Brassica napus L.) that shows a plant growth-promoting effect has been found in rapeseed (Brassica napus L.) pollen.
(named brassinolide) was isolated and the northern structure determined (
Chemical and Engineering
News.

Nov, 5. p, 20 (1979)], followed by the synthesis of stereoisomers of the above-mentioned brassinolide, the synthesis of authentic brassinolide, or the synthesis of analogues.

However, some brassinolides derived from other natural products have also been discovered, and one of them, the steroid compound represented by formula 1, is obtained from the seeds of Dolichos Iablab (Japanese name: Fujimame). It is named homotricholide and is known to have a strong plant growth regulating effect (T, Yokota J).

Baba and N, Taka<ashi, A
gric, Biol, Chem.

47 (1988)).

Previously, the present inventors found that as easily available starting materials,
2R,35,22 which has similar activity to brassinolide in a relatively short process using stigmasterol of formula 2
S, 23S-tetrahydroxy-24S-ethyl-B-
Homo-7-oxa-5α-cholestan-6-one (which was named ``22S, 28s-homobrassinolide-1'') was synthesized by Agric.

Biol, Chem, 44.1211 (1980)
In addition, various analogs were synthesized (Tetra+ed
Ron.

88, 2099 (1982), Heterocy
cles, 17.

801 (1982), Agric, Biol,
Chem,, 47.

(1988) +Agric, Bio1. Chem...
47, 688 (198B)).

Among them, we selected the stero-r-do compound 6, which is considered to be useful as a synthetic intermediate for the above homotricolide, and found that the homotricholide of formula I can be easily and inexpensively produced by the route shown below. I found it.

That is, the present invention uses the known compound represented by 28 announced by the present inventors, and reacts the ketone group of the B ring and the side chain double bond with an organic peracid to obtain the formula 4 and The epoxy lactone compound of formula 5 is prepared by opening the epoxy ring with a phenylselenyl anion to form a compound of formula 6,
Further, phenylselenyl is removed oxidatively to obtain a steroid compound having an allyl alcohol content in the side chain of formula 7, and the double bond portion is oxidized with an organic peracid.
The epoxy compound of formula 8 is subjected to an epoxy ring-opening a reaction to obtain the steroid compound of formula 9, and the acetonide group, which is the protective group for the diol at the 2 and 3 positions, is removed to obtain the desired homod of formula 1! The present invention provides a manufacturing method for obtaining nocolide.

Next, the present invention will be explained in detail.

First, in the first step, the reaction with an organic peracid (i), it is required to perform the Baeyer-Villigate reaction without opening the monopoxy ring of the side chain formed by the reaction, and we need a reaction that meets this requirement. A reaction with an organic peracid containing a buffer for the purpose of suppressing the acidity of the free organic acid, or a reaction which itself is said to be difficult to induce ring opening of the epoxy ring as a side reaction.
For example, metachloroperbenzoic acid and the like can be used.

In this reaction, what is obtained is as for the epoxy ring:
It is a mixture of a compound of formula 4 and its stereoisomer compound of formula 5.

In the second step, a reaction in which the epoxy ring is opened with a 1/nyl anion on phenyl, for example, B.

The method of Sharpless et al. CJ. Am. ('he
m. sOC. , 95.

2697 (197B)). The desired product in this case is the selenium compound No.26, but if the product of the first step is carried on to the next step as a mixture, it will naturally be obtained as a mixture with its isomer.

In the double bond formation reaction by oxidative deselenization in Step 3 (t), various oxidizing agents can be used, but the simplest method is a method using water peroxide.

In this case, in addition to the target compound of formula 7, an isomer of formula 7' is obtained, and the compound of formula 7 and the compound of formula 7' are further epoxidized in the reaction system. Epoxy bodies of formulas 8 and 8' that are considered to have undergone reaction are obtained.

The epoxidation reaction in the fourth step can be carried out in the same manner as in the first step, but the reaction is carried out more rapidly and with higher stereospecificity than in the first step due to the conjugate effect of the hydroxyl group. What is obtained here is that when the product of the previous step is subjected to this reaction as a mixture, the same epoxy products of formulas 8 and 8' as obtained in the previous step are obtained.

Next, the reaction of the epoxy ring in the fifth step is as follows:
It can be carried out according to the method of S. Terao et al. (Synthesis, 467 (1979)) using aluminum epoxide, and when the product of the previous step is subjected to this reaction as a mixture, as a mixture of formulas 9 and 9'. can get.

The final step, the reaction for removing the acetonide group of the protecting group of the 2.3-position diol, is carried out using hydrochloric acid, sulfuric acid, P-1-luenesulfone in water, alcohols such as methanol and ethanol, lower fatty acids such as acetic acid, or mixtures thereof. It can be carried out gently in the presence of an acidic catalyst such as an acid or acetic acid.

In the present invention, the products obtained in each step can be separated by chromatography or the like, or
It is also possible to proceed with the reaction in a mixture. The compounds of formulas 4 to 9 shown in the present invention are all new compounds that have not been described in any literature.

The present invention will be explained below with reference to examples, but the present invention is not limited to these examples.

Example 1 (2R, 85, 22R, 2BS, 24S)-22,2:
li-epoxy-24-ethyl-2,3-impropylide A special beef sea B-homo-7-oxa-5α-cholestan-6-one (2R,8S,24S)-24-ethyl-2,3-impropylide Dendioxy-5α-cholest-22-ene-
m-chloroperbenzoic acid (purity 85% or more, 10.
2F) was added and stirred at room temperature for 8 days. The resulting crystals were filtered and washed with methylene chloride. The P solution and the third washing solution were washed together with 1N NaOH (250-1) and water (250me) in that order, and dried with anhydrous magnesium sulfate.

After removing the desiccant, the P solution was concentrated under reduced pressure to 4.8
A syrupy concentrate of 2 was obtained. Silica gel (Merck
Knee, □Art, 7784, 70-230 Metsu'
Column (D 4cm j,
Isolated and purified by H42(7)) chromatography. Ethyl acetate-n-beef sanitation (15:85; l t;
), same (20:80.2e), same (22 near 8°11)
, (23 nia 7.1/) using an elution bath, the indicated chemical compound (1180+++p; 25.3% yield) was obtained from the fraction eluted with beef sanitation (20:80) to ethyl acetate-n-. rate) was obtained. ((+!) D+ 24.6° (co.

724, CH (J3) yarn seed solvent (ethanol, +
1-hexane-ether, methanol, n-hexane-
Crystallization from ethyl acetate) was attempted, but neither was successful.

&”mCam -1): 2960(s), 2875
(s), 1740(s).

ax 1462(s), 1400(m), 1; no(s), 1
370 (ml.

1380(wl, 1310(m), 1292(wL)
1279(w).

125'8 (sl, 1205(s), l 18
8(s), 1152 (ITI+.

1180(w), l L 15h), 1010
98(, 101075(.

1059(s),,101041(,101027(,
101010(.

987 (In), 962 (ml 920 (wL 9)
07 (m!, 877 (ml.

868(m), 888(w), 817(w3797(w)
), 765 (WL730(w), 702(w), P
MR (400MHz: CDCe3) 5: 071 (S,
3H), 0.88 (5,81), 0.93 (d, J=6
．． 8Hz, 6H), 0.96(t, J=7.4Hz, 3
H), 1.01 (d, J=6.8Hz, 3H).

1.10-2.05 (m), 1.82 (S, aH),
1.58 (S.

3H), 2.82(dd, J=3.5&15.5H
z, IH).

2.49 (m, 2H), 2.78 (dd
, J=2.2&7.1Hz, LH), 8.29(dd
, J”4.5&lO, OHz.

IH), 4. ll(m, 2H), 4. :118(br,
s, IH) MS (m/z): 516 (M+), 501 (
M"-Me) 498.487, 478, 441, 440
,481°408.887.3ri3°Example 2 (2R,3S,22R,28E)-24-ethyl-22
-Hydroxy-2,3-impropylidenedioxy-B
-Homo-7-oxa-5α-cholesto-J/f2B-en-6-one Sodium borohydride is added to a stirred solution of diphenyl diselenide (812q: 1 mmo+) in dry n-butanol (lQ+Re) under argon. (
77q: 2. '02 mmol) was added. After the reaction solution became colorless (2R, 8S, 22
R,23S,24S)-22,28-epoxy-24-
Ethyl-2,3-isopropylidenedioxy-B-homo-7-oxer 5α-cholestan-6-one (516+
v: 1 mmol) of dry n-butanol (4
me) solution was added. Stirred at reflux temperature for 117 hours. The reaction solution was dissolved in ether, washed twice with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an orange gummy substance of 887.

Tetrahydrofuran (1) of the above rubbery substance (880~)
5,/,) and ethanol (15me) were stirred at room temperature while 30% hydrogen peroxide (4,e) was added. After stirring for 1 hour and the reaction solution became colorless, it was diluted with water and extracted with ether. After extraction, the extract was washed twice with aqueous sodium bicarbonate solution and once with brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain a pale yellow rubbery substance (571~). Silica gel (M
Column chromatography was performed using Erck, Art, 77B4.70-230 mesh, 352). The raw material epoxy lactone (208
~; 40.3%) was recovered. Next, the indicated product and
Its positional isomer (2R,,8S,28R,24S
.

20E)-24-ethyl-23-hydroxy-2,3-
Impropylidenedioxy-B-homo-7-oxa-5
Both fractions containing a 65:35 mixture (167~; a2.4%) with α-cholest-20-en-6-one were obtained.

Next, a product that is considered to have undergone epoxidation by perselenic acid that may be generated during the reaction with the above mixture,
(2R285,22R,235,243)-28,24
-epoxy-24-ethyl-22-hydroxy-2,3
-Impropylidene 1, dioxy-B-homo-7-oxa-50-cholestan-6-one and (2R,8S,2O
8,2S,23R,24S)-20,22-epoxy-24-ethyl-23-hydroxy-2,3-isopropylidenedioxy-5α-cholestan-6-one (88my:17.1 %) were obtained. Finally, add the above epoxy alcohol mixture (L9 IIv: 7
．． A fraction containing 6%) was obtained. As the elution solvent, ethyl acetate-n-hexane (20:80 to 30:0) was used.

PMR of allyl alcohol fraction (400MHz, C
DCl3 ) + (described compound) a O,72(S
.

8X0.65H), 0.88(s, 8X0.65H),
1.02 (d, J=7Hz, 6X0.65H), 1
．． 32 (S', axO, 65H), 1.51 (s
, 8X0.65H), 2.26(septet
, J=7Hz, 0.65H), 8.30(dd
, J=4 4 10Hz, 0.65H), 4.11
(m, 2X0.65H), 4.37 (br, s, 2
X0.65H), 4.47(d, J=8Hz, 0.6
5H), 5.29(d, J=8Hz.

0.65H): (positional isomer): 0.58(s,
0. :(5H), 0.88 (s, 0.85H>
,, 1.00 (d, J=7Hz.

6X0.85H), IJ2(s, 8X0.85H),
1:58(s, 8X0.85H), 1.71(br
, s, 3X0.35H), 8.30(dd, J=4
& 6Hz, 0.35H).

4.11 (m, 2X0.85H), 4.37 (br
, s , 2XO, 35H), 4.49 (d , J=8H
z, 0.858).

5.88 (d, J=8Hz, 0.85H), MS(
m/z) (mixture): 498 (MHzO), 48
．． 3 (M+H20-Me), 455.440.408
．． 897.

(sh), 2920(s), 2850(s), 175
0(S).

1660(wJ, 1458(s), 1375(s)
, 1840 (wl.

1325('wl, 1808(w), 1800(wl,
1265 (sh).

1258(m), 1242(w), 1210(s), 1
170 (sh,).

1165 (sJ, 1122 (e), 1118 ((b)
, 101075(.

1050(sJ, 1005(wl), 997(w
l, 980(m), 962(w), 942(w
), 980(wL 918(wl, 870(m), 85
0(w), 825(wl, 820(w),'
802(w), 795(w), 777(w)
.

Example 3 (2R, 3S, 22R, 28S, 24S)-28°24
-epoxy-24-ethyl-22-hydroxy-2,3
-isopropylidenedioxysilohhomo-7-oxa-5α-cholestan-6-one<2R,8B,22R,28E)-24-ethyl-22
-Hydroxy-2,3-improvirideno, -B-
Oya 17-Oaa sir.

α-Cholest-23-en-6-one and (2R,33,
65:85 mixture of ~) of anhydrous methylene chloride (
m-chloroperbenzoic acid (170~) was added to the 1,0-) solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with IN NaO
It was washed once with H (25 ml) and twice with water (25, g), dried over Glauber's salt, and the solvent was distilled off under reduced pressure. A colorless gummy substance (170□) was obtained. Although it was not possible to isolate the title compound from the crude product, 400 MI (z PM
From the R spectrum, the crude product is the title compound and its positional isomer (2R, BS, 2O8, 22S, 23R,
24S)-20,22-epoxy-24-ethyl-23
-Hydroxy-2,8-inpropylidenedioxy-B
-homo-7-oxa-5α-cholestan-6-one was suggested to be a 65:35 mixture. PMR (4
00Δ (Hz; CD13): (described compound) δ2.88
(d, J=7Hz, 0.65H, 28-H).

B, 60 (br, s, Wy=12Hz, 0.65H, 2
2-H); (positional isomer) δ8.10 (d, J=7
H20, 35H, 22-H), 8.71 (br, d
, J=7Hz.

o, d 5 H+ 28 H) + M S (n
]/z) (Mixture) =517(M-R4e
), 514 (M - H2O), 512°498.41
7,404,408,389,848゜ufrmi::
m(m-1); B 470(sl, 2950(sl)
.

2870(s), 1738(sl, 1650(w), 1
460(s).

1400 (Inl, 1880 (F), 1370 (811
), 1850(v).

1880(w), 1810(ITll, 1290(wL)
1280(w).

12/f5(s), 1203(s), I 175(
s), l 152kl.

1125(w), l 113(Ill), 1065
(fil), l'157 (sl.

1042 (Xh), H) 30 (w, -, 101
010(,980(m).

960 (wl, 910 (m), 870 (ml)
, 835 (ml, 815 (wi.

76B(w), 700(wl.

Example 4 (2R, BS, 22R, 28R, 24 (28 h)-2
4-ethylidene-22,28-dihydroxy-21,3
-Impropylidenedioxy-B-homo-7-oxa-
50-cholestan-6-one (2R,8S, 22R,285,24S)-28,
24-epoxy-24-ethyl-22-hydroxy-2
,3-inpropylidenedioxy-B-homo-7-oxa-5α-cholestan-6-one and (2R,BS,20
5,22S.

28R,24S)-20,22-epoxy-24-ethyl-23-hydroxy-2,3-impropylidenedioxy-B-homo-7-oxa-5α-cholestane-6-
A 2:1 mixture (274 ~) of 100 ml of aluminum was dissolved in anhydrous toluene (80, e), aluminum isopropoxide (120 ml) was added, and the mixture was stirred for 1.5 hours at reflux temperature. After heating and cooling, 2N HCl was added, and the mixture was extracted with chloroform.

The extract was washed twice with water, dried over Glauber's salt, and the solvent was distilled off under reduced pressure to obtain a colorless gummy substance (28.7 l1v). Silica gel CMercka' Art, 778470-23
The desired product was isolated and purified using column chromatography (0 mesh, 16y). The elution solvent was n-
Hexane-ethyl acetate (3:2) was used. A mixture containing first the undesired regioisomer (78q: 29.7% yield) and then the geometric isomer of the desired product (18■; 6.
6% yield), and finally the title product (86mt', 82.7
% yield) was eluted. All attempts at crystallization from various solvents were unsuccessful.匝”,,”+19.0°(C1,
180, CHC13).

Le Pu-11): 8450(sl, 2970(
sJ, 2940(s).

2875(lnl, 1735(sL 1660(w)
), 1465 (ml.

1450 (sh), 1435 (sh), 140B (tn
), 1880! , 1875 (sh), 1325 (s
h), 1312 (tn), 1295 (wi, 128
0(w), 1260(s), 1205(sl, 1
180(s).

1175 (sb), 1157 (nc1132 (w), 1
117 (, v).

11l100f, 1080(sb), 1075(s
h), 1060 (sJ, 1040 (ni, 101030
(, 1010(wl, 985(ITI), 960
(e), 920 (ml), 875 (e), 88B (ml
, 830(wl, 820(W), PMR(400
MI (z, CDCI3) δ: 0. (37(s.

811), 0.88 Cs, 8H), 0.
92 (d, J = 6.6Hz, 8H), 1.06
(d, J=7.1Hz, 8H), 1.14 (d, J=7
．． 1Hz, 8H), 1.81(s, 8H).

1.51 (s, 8H), 1.72 (d, J=7.1Hz
, 8H).

1.05-2.00 (ni2.81(dd, J=8.5
& 15.7Hz, IH), 2.76(sep(et
, J=7.1. Hz, IH)+3.29(dd, J=
4.5 & 10.0Hz, IH), 8.68(c
l, J=8.5Hz, IH), 8.90(d, J=8,
5Hzl'H7,4,10(m-2H), 4.37(I
TI, 2H) + 5.51 (q, J = 7.1Hz, I
H), MS (m/z); 584 (M), 588 (M
->H), 517 (M -0+ 1 H), 499.419 (M -MezCHC (=CHC
H3) CHOH) 405,404,408,391
,361°848.881.255 Example 5 (2R, BS, 22R, 28R, 24(2B)E)-2
4-ethylidene-2,8,22,28-tetrahydroxy-B-homo-7-oxa-5α-cholestan-6-one (homotricolide) (2+<, 85,22R,28R,24(28)E )−
24-ethylidene-22,23-dihydroxy-2,3
-Impropylidenedioxy-B-homo-7-oxa-
5αcholestan-6-one (87 towns) in acetic acid-water (4:
1.2.5. e) The solution was stirred at 50°C for 1 hour. It was neutralized with soda carbonate (powder) and extracted five times with ethyl acetate.

Dry with Glauber's salt, remove the solvent under reduced pressure, and add 24-v (70
, 6%) of colorless crystals were obtained. Recrystallized from methanol,
Colorless microacicular crystals were obtained. mp, 209-212℃ (dec
, ) (t sintered at 94°C) 1 [(ll'l"+8
5.4゜(cO,480,CHC/3-MeOH(9
: 1. ))-7KB Brax (am): 8500(st, 3425(s)
l, 2980(s).

2900<m), 1740(s), 1705(s), 1
650(w).

1470 (ml, 1445 (In), 1410 (I),
131 (ml.

1'370 (sh), 1885 (sl, 128B (ml)
, 1285 (wl.

1225 (w+, 1182 (s), 1170 (sh),
1145 (wl.

1120(wl, 1090(w), 1070(w)
l, 1040(w).

101025(, 995(nC960(ml, 940
(w), 878(w).

840 ((b), 825(w), 775(w),
705(w), 670(w).

608hl; PMR (400MHz, 'CDCl3.5
0°C) J: 0.66 (s, 8H), 0.91 (s, 8H
), 0.98 (d, J=6.4Hz, 8H), 1.07
(d, J=7.1Hz.

8H), 1.14 (d, J=7.1Hz, 8H),
],,71(d,J=7.1Hz,;(H),1.16
-2.00 (m).

2.11(br,s,LH), 2]4(br
, s, H().

2.18 (br, s, IH), 2.27 (d, J=4.
8Hz.

IH), 2.76 (septet, J=7.
1Hz, 1l-1).

8.10 (dd, J=4.5 & 12.0Hz, LH
), 8.67 (ddd, J=1.0, 8.5 & 8.
8Hz, IH), 8.71 (m, IH), 8.
95 (dd, J=4.3 & 8.3Hz.

IH), 4.01 (br, s, LH), 4.07 ('m
, 2H) 5.51 (Q, , T=7.1Hz, IH)
:MS of bismethane boronate (m/z): 5
40.3836 (M) (540,8798C31H
500GB2) Procedural Amendment (Voluntary) Mr. Kazuo Wakasugi, Commissioner of the Patent Office■, Indication of Case 1982 Patent No. 450812, Name of Invention Process for Producing Steroids Having Plant Growth Regulating Effect 3, Relationship with the person making the amendment Patent applicant address 5-15 Kitahama, Higashi-ku, Osaka Name (20
9) Hijikata, Representative of Sumitomo Chemical Industries, Ltd.
Take 4, Agent Address: 5-15 Kitahama, Higashi-ku, Osaka, Detailed Description of the Invention /) Zo 9-6, Contents of Amendment (11 Specification, page 6, No. 1) Correct the ``'' in the first line to ``6''.

(2) IC0 in the 5th line to the 4th line from the bottom of page 11,
724j should be corrected to ``c O, 724J.''

(3) In the first line from the bottom of page 11, the word "effective" is corrected to "success."

(4) On page 12, line 10, “0.71 (5,3H)
, 0.88(s, 311)'' is changed to [0,71
(S, 3H), corrected as 0.88(5,3l-1)J.

(5) rl on page 12, lines 13 to 14,
82(S, 81()', 1.58(S, 3f-()) is rl, 32(S, 8H), 1.58(s,
3 tI ) Correct it as j.

■'' (8) On the 4th line from the bottom of page 18, l'-(:D I3
J is corrected to (” CDCl5J).

(9) r 4.10 (ITI
,2)()J is r4. I O(m, 2
H) Correct it as J.

(10) r540°883 on page 24, second line from the bottom
6J is corrected to r540.3886J.

(11) r (540°37
98 C31H5008B2)"
(540, 3798 (C3+' (as soOeB2)
)”” is corrected.

that's all

Claims (1)

[Claims] (1) A method for producing a steroid compound represented by the formula, which comprises removing the acetonide group that is the diol protecting group at the 2 and 8 positions of the steroid compound represented by the formula 0:2) Steroids represented by the formula 1. A method for producing a steroid compound, which comprises converting the epoxy ring into a steroid compound, and then removing an acetonide group, which is a diol protecting group at the 2 and 3 positions.