JPS59186972A - Octahydronaphthalene derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1 is H; R2 is lower alkyl; R3 is H, tert-butyldimethylsilyl, triethylsilyl or benzyl; R4 is lower alkyl). USE:An intermediate for mevinolin, mevinolinic acid, etc. The mevinolin is a remedy for hyperlipemia and a preventing agent for arteriosclerosis. PREPARATION:A compound of formula II is oxidized with chromic acid or dimethyl sulfoxide (DMSO), and the resultant oxidation product is then treated with an acid to give the aimed compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel compound represented by general formula (1) and a method for producing the same.

(3) (In the formula, RI is a hydrogen atom, Rt is methyl, ethyl, pro,
Lower alkyl such as pyru, butyl, isopropyl, 5et-butyl, R3 is a hydrogen atom, t-butyldimethylsilyl, triethylglyl, benzyl, R4 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
(represents a lower alkyl group such as 5ec-butyl) Mevinolin (monacolin K), which is a competitive inhibitor of HMG-CoA reductase and has a remarkable effect of lowering blood cholesterol, is a compound having the structure of the formula: This substance is being developed as a treatment for hyperlipidemia and a preventive agent for arteriosclerosis.

However, the synthesis of this compound has not yet been successful.

(4) There is thus much literature on mevinolin (monacolin K) due to its interesting activities.

For example, Endo, A. J., Antibiot,, 82
, 852 (1979), A.W., Albttrts et al.
roc, Hat l, Acad, Sci, U,
S.A.

77.8957 (1980), JP-A-56-14228
6゜Thus, the present inventors conducted intensive research on a method for synthesizing mevinolin; a new synthesis method was developed in which mevinolin was synthesized via an octahydronaphthalene derivative having the general formula (1), which is a new compound unknown in the literature. found the law.

The compound having the general formula (1) is not only useful as an intermediate for mevinolin synthesis as described above, but also
We discovered that this compound is an extremely important compound as an intermediate for mevinolic acid, which has the same skeleton as mevinolin, and completed the present invention.

The present invention provides novel compounds having the general formula (1) as well as general formulas (2) (5) (wherein R1 is a hydrogen atom, R1 is a lower alkyl group).

R3 is a hydrogen atom, t-butyldimethylsilyl, triethylsilyl, benzyl, and R4 is lower alkyl. This is the manufacturing method of 1).

δR3 (6) In the general formula (1), R represents H, and R7 is methyl, ethyl, propyl,
Represents isopropyl, n-propyl, n-butyl, and 5ee-butyl. R3 represents a hydrogen atom, -butyldimethylsilyl, triethylsilyl, or benzyl, and R4 represents methyl, ethyl, n-propyl, inopropyl, n-butyl, or 5eC-butyl.

As a compound having formula (2), R8 is a hydrogen atom, R
2 is methyl, ethyl, n-propyl, isopropyl, n
-butyl, 5ec-butyl. R3 is a hydrogen atom,
Represents t-butyldimethylsilyl, triethylsilyl, benzyl, and % R< represents haemyl, ethyl, n-propyl, isopropyl, n-butyl, and 5ec-butyl.

Collins oxidation of general formula (2), pyridinium dichromate, pyridinium chlorochromate, dimethyl sulfoxide-trifluoroacetic anhydride, dimethyl sulfoxide-
The compound represented by general formula (1) can be obtained by treating with oxalyl chloride etc. to convert the primary alcohol into a carboxylic acid, and then treating with fluorinated water ('7) acid, p'-)luenesulfonic acid, hydrochloric acid etc. can get.

The compound of general formula (1) obtained by the method shown above can be easily converted into a derivative by treatment with benzyl chloride, benzyl bromide, t-butyldimethylsilyl chloride, triethylsilyl chloride, etc.

The method of the present invention is a combination! Pl! Specifically shown in the process diagram below for producing mevinolin salt from I(6), it corresponds to the process from (12) to (18).

(6) (8) Ptl(OAc)t (10) (11) (↓t) O (18) (15) (14) R in the process diagram above! , Ra and R are lower alkyl groups.

Compound (6) phenylselenyl chloride is subjected to phenylselenylation by treatment with lithium dialkylamide,
Next, enone (7) is obtained by oxidation with sodium metaperiodate, hydrogen peroxide, etc., but after generating 1 lithium erot from compound (8) using lithium dialkylamide, etc., trimethylsilyl chloride, triethylsilyl It can be obtained by treatment with chloride or the like to form silyl erulate, which can be obtained by oxidation with a weak oxidizing agent such as palladium acetate.

The enone (7) is treated with lithium di-lower alkyl steel to form a compound (8) into which a lower alkyl group is stereoselectively introduced, and then an excess of potassium t')-sec-butylhydroborate or tri-5ec-butyl Reduction of the ketone using lithium hydroborate stereoselectively gives alcohol (9). Other reducing agents, such as lithium aluminum hydride, result in poor stereoselectivity, but the desired product can be obtained.

Alcohol (9) Dissolve in Ranithil-based solvent and add to liquid ammonia-lithium solution. Diol (10) is similarly obtained by using sodium instead of lithium.

Excess (more than 2 times) Ra CO with respect to diol (10)
CE or CRaC0)t C in the formula 84 is lower alkyl), for example 5-2-methylbutyric anhydride, father is 2
S-methylbutyric acid chloride is treated in the presence of pyridine, dimethylpyridine, etc. to give diester (11), which is then treated with an alkali,
It is preferably treated with caustic soda or caustic potash to form the monoester (12).

Monoester (12) is converted into chromium Ffi (Collins oxidation) and then treated with acid to form hydroxylactone (12).
3) K becomes. For oxidation, Collins's reagent, pyridinium dichromate, pyridinium chlorochromate, dimethylsulfoxide-trifluoroacetic anhydride, dimethylsulfoxide-oxalyl chloride, etc. are preferable, and the acid used for acid treatment is preferably hydrogen fluoride water.

Hydroxylactone (18) is treated with trialkylsilyl chloride, preferably t-butyldimethylsilylchloride, in the presence of imidazole to form monosilyl ether (14).
).

monosilyl ether (14) with a base, e.g. pyridine,
Treatment with a dehydrating agent such as thionyl chloride or phosphorus oxychloride in the presence of dimethylpyridine or the like gives diene (15).

Diene (15) is treated with acid, preferably with aqueous hydrogen fluoride or tetraalkylammonium fluoridonate, to give mevinolin (monacolin K).

The synthetic products obtained here are natural mevinolin and 'H-NM.
R, 1, R,, mass 4 kutor, etc. were in perfect agreement.

(17) The present invention will be specifically explained with reference to the following examples, and the usefulness of the compound of the present invention as an intermediate for mevinolin synthesis will be demonstrated by the following reference examples.

(10) (11) (18
) 11.1rn9 (0,022 mmol) of diol (1
0) in Q, 3rrl of anhydrous pyridine 0.8d,
120 μ# (0.6 mmol) of S'-2-methylbutyric anhydride and 4-N,N'-dimethylaminopyridine
and stirred at room temperature for 20 hours. After distilling off pyridine and butyric anhydride under reduced pressure, the product was purified using silica gel column chromatography. 11.2 Da (76 Ti) of diester (11) was obtained.

(11): Colorless oil [α)”4+ 55.6° (C1,1, CHCl,) δ
(CDC3s, 860 MHz) 5.70 (I
II, ddd, J=9.8, 5,8, 2.8
), 5.88 (IH, width d, J=9.8), 5
．． 15 (IH2'rrL), 4.16 (2H, m),
8.91 (IH, m), 8.71 (IH, m), 8.
65 (IH9 width 8), 2.54 (14, width d, J=
11), 1.39.1.34 (8H, s each), 1.14
(8H, d, J=6.5), 1.12 (8H
.

d, J=6.5), 1.04 (BH, d, J=7
．． 8), 0.90 (811,t, J=7), 0
．． 89 (8H.

t, J=7), 0.85 (9Jf, s),
0.82 (8H, d, J=6.8), 0.0
1 (6H,s).

ν (film) 2960.2985, 2880.1737.1260.
1187.840C1n-' Mass spectrometry: Calculated value (as CsJ7nsOySs(A/CHs)) 649.4497 Actual value 649.4467 Diester of 111119 (0,0165 mmol) (
11) in 0.51 ethanol and 0.4-l
Add N-NaOH dropwise and stir at room temperature. 17 hours later,
Ethanol is distilled off under reduced pressure, and ether and saturated water are added for extraction. After washing the ether layer and saturated ammonium chloride water, it was dried and purified by CMISO<> and silica gel column chromatography.

8.611!9 (90%) of monoester (12) was obtained.

(12): Colorless oil [α)''; +64.7χCO, 86, CHCl5
) δ (CDC1,, 860MHz) 5.70CIH, ddd, J=10.0, 5.1°2.
8), 5.88 (width d, J=10.0),
5.15 (IH9 width s, W'y; = 7 Hz)
, 4.08 (IH.

m), 8.75 (8H, m), 8.65 (14, width 8), 2.54 (14, width d, J = 11), 2.81
(IH, 5ezt,, J=7), 2.27 (IH
, m), 1.9'7cddd, J=15.6.3.2
), 1.98 (IH,td, ,7=11.2.4
), 1.83 (14, regular), 1.44.1.86 (8H each).

8), 1.12 (8H, d, J='l), 1.03 (8
H1d, J=7.5), 0.90 (8H,t
.

J=7.4), 0.85 (9H, s), 0.82 (
8H,d, J=7), 0.01 (6H,s).

ν (film) 3450.2950.2980.2860.1734.
1257.1200.885.776-1 Mass spectrometry: Calculated value (Cs3H6゜o6siut+) 58
0.4156 Actual value 580.4090 (21) Example 1 (12) Anhydrous pyridine 48 in anhydrous dichloromethane 11117
μm 0.59 μm IJ mol) was added, followed by 80 η chromic anhydride (0.80 μm 1 mol) and stirred at room temperature for 15 minutes. To this orange-red chromic acid-pyridine solution (22) was added 8.6 m9 (0,015 mmol) of a solution of alcohol (12) in dichloromethane (1d), and the solution was heated to 1 d at room temperature.
Stir for 5 minutes. Dilute with ether (151d) and add Celite. Stir for a while until a clear solution forms.

It was filtered through a column of 2 cIn Celite and the filtrate was concentrated to give 8.5 ml of residue. Dissolve it in 5 ml of anhydrous MF, add 561 Hg (0.15 mmol) of PDC and stir at room temperature for 16 hours. Add 20 tablespoons of ether, add Celite and stir until a clear solution is obtained. Filter through a Celite column (2 crn) and wash the Celite well with ether. The residue was dissolved in 47% hydrogen fluoride water/acetonitrile (1-) and stirred at room temperature for 2 hours.

After concentrating under reduced pressure to 0.5 ml or less, add ether,
Wash with saturated soap water. Wash the ether layer with saturated ammonium chloride water. After distilling off the solvent, it was purified by silica gel column chromatography. 8.5m9 lactone (13)
(56%).

(18): Colorless oil [α]”+98.7°(CO,85,CHCl3)δ(
CDClls -360MHz )5.91 (14,
ddd, J=9.8.5.2, 2.9Hz), 5.4
5 (14, width d, J=9.8), 5.20 (IH, width S), 4.61 (IH, ?FL), 4.87 (IH
, m), 8.78 (lH, width 8), 2.78 (IH,
dd,, 7=17.5, 5.1), 2.66 (width d
, J=11.5), 2.61 (IH.

ddd, J=IT,5. 8.8, 1.5), 2.3
5 (IH, ser, t, J=6.9), 2.82
(IH, m), 1.14 (8H, d, J=7), 1,0
9 (3H.

d, J-4,5), 0.91 (8H,t, J=7
．． 4), 0.88 (8H, d, J=1) ν (film) 3480.2960.2930.2875.1725.
1260,1072α-1 H (13) 8.5■ (0,0088 mmol) of diol (13)
was dissolved in 0.2 rnA anhydrous DMF and 12#(0,
176 mmol) of imidazole and 10W9 (0,06
6 mmol) of t-butyldimethylsilyl chloride is added and stirred at room temperature for 8 hours. After concentrating under reduced pressure, it was purified by silica gel column chromatography to obtain (25) 3.9 monosilyl ether (I) (88%)
.

(14): Colorless oil [α]” +59°CC0,89,CHC8,)δ(C
DC7? s, 100MH2) 5.90 (IH, d
dd, J=10.5.2.5), 5.48 (IH, width d, J=10), 5.16 (IH9 width 8),
4.58 (IH, @), 4.24 (IH, ya), 8
．． 72 (I H, width 8), 0.88 (9H, s
), 0.07 (6H,a).

ν (film) 3490.2960.2940.2880.2870.
1739.1260.1087.841crn-' Mass spectrometry: Calculated value (as C5nHnO6S i (M+))
586.8580 Actual value 586.8520 Calculated value (as CvHsoOsS i CM H2O) 518.8424 Actual value 518.8417 (26) 2.9# (0,0054 mmol) of alcohol (14
) in 0.2 m of anhydrous dichloromethane,
mA of anhydrous pyridine is added, then cooled to 0° C. and one drop of the distilled thionyl chloride is added. After stirring at 0° C. for 10 minutes, the mixture was stirred at room temperature for 1 hour and 10 minutes. After adding a small amount of water, extract and wash with dichloromethane and IN-Shiomine. The organic layer was further treated with IN-hydrochloric acid, 5 tNαH.
Wash with CO3 then saturated NHa CI water and dry with #/So. The solvent was distilled off and separated by preparative TLC (SiOx, hexane/ether). 0.9■ diene (15)
(49%') was obtained. In addition, 1.0 ml of raw material was recovered.

9 Physical properties (CNMR, IR, MS, TLC) completely matched the physical properties of the standard product derived from natural monacolin K (the unrecovered rate took into account the recovered raw material).

(15): Colorless oil [α period + 197' (CO, 1, CHCAs) standard material: [α period + 218 @ (Ct, 7, CHCl5) δ (
CDCI! s, 860 MHz) 5.99 (IH
9d, J=9.6), 5.79 (IH.

d d , J=9.6.6.2), 5.52 (14,
Width 8), 5.86 (LH, narrow), 458 (In
2), 4.26 (IH, q, J=8.5),
2.60 (LH, dd, J=17.5, 43
), 2.56 (IH, ddd, J=17.5.3
．． 5.1.8), 1,10 (8H,d, J='1
．． 0), 1.07 (8H, d, , 7=7.4)
, 0.89 (8H1d.

J=7), 0.88 (9H, 19), 0.87 (8H
.

t, J='1.4), 0.08. (8H,s)
, 0.07 (8H1I!I) ν (film) 2960.2980.2860.1787.1260.
1185.1084.840.782In-1 Mass spectrometry: Calculated CC5o island. o, s■1>closed) 518.8
118 Da (0,082 mmol) of 425 monacolin was dissolved in 0.81 DMF anhydrous and the excess t-butyl di(2
9) Add methylsilyl chloride and imidazole and stir at room temperature for 8 hours. It was directly subjected to silica gel column chromatography to obtain silyl ether (15) 16.8# (10
0%) was obtained. The physical constants are the same as the composite product on the previous page.

6.7η (0,018 mmol) of (15) is 0.5-
of CH, CM, 47% HF/CH3CN (
Add 1N of the solution and stir at 0°C for 5 hours. After making alkaline by adding saturated soda water, extract with ether.

Separate and purify using preparative TLC (SiO, ether). 4.
A monacolin K of 0.0 mm was obtained (771°).The physical properties completely matched those of natural monacolin K.

Patent applicant Sun) L-Co., Ltd. (4 others) (30) Procedural amendment 1. Display of the case Patent Application No. 58796 of 1982 2, Name of the invention Octahydronaphthalene derivatives and their manufacturing method 3, Person making the amendment Relationship to the case Patent applicant address name (190) Suntory Ltd. 4, Agent 5 , Column 6 of [Claims] and [Detailed Description of the Invention] of the specification to be amended, contents of the amendment C) IlaC/r) 2zh (Attachment) (1) The scope of claims should be as follows: Correct.

"(1) has the general formula (wherein R1 represents a hydrogen atom, R2 represents a lower alkyl group, R3 represents a hydrogen atom, a t-butyldimethylsilyl group, a triethylsilyl group, a honeydyl group, and R4 represents a lower alkyl group)" Compound.

(2) General formula % Formula % In the formula C, R1 is a hydrogen atom, R2 is a lower alkyl, is a hydrogen atom, t-butyldimethylsilyl, triethylsilyl,
indyl, R4 represents lower alkyl) is oxidized and then treated with an acid, having the general formula (1) (wherein R1, R2, R3, and R4 have the same meanings as above) Method of manufacturing compounds. (2) The description is amended as follows.

Page Line Before correction After correction 12
Lower 2 Chromic acid oxidation (3) Specification No. 1
"Monoester (12)...is oxidized" from the second line from the bottom on page 6 to the first line on page 17 is corrected as follows.

``The monoester (12) is oxidized with chromic acid or dimethyl sulfoxide to convert the primary alcohol into an aldehyde, and then treated with chromic acid such as pyridinium dichromate or silver oxide, and then treated with acid to convert the monoester (12) into an aldehyde. It becomes roxylactone (13).The oxidation of alcohol to aldehyde is 620-

Claims (2)

[Claims] (1) General formula (in the formula, R1 is a hydrogen atom, JI Rt is a lower alkyl group,
R3 represents a hydrogen atom, a t-butyldimethylsilyl group, a triethylsilyl group, a benzyl group, and R4 represents a lower alkyl group). (2) General formula (in the formula, R1 is a hydrogen atom, R3 is , 1 lower alkyl, R1 is a hydrogen atom, t-butyldimethylsilyl, triethylsilyl,
After oxidizing a compound having benzyl (R4 represents lower alkyl) with chromic acid or dimethyl sulfoxide,
A method for producing a compound having the general formula (1) (wherein R1, R8, R3, and R4 have the same meanings as above), which is treated with an acid.