JPS59186973A - Octahydronaphthalene derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1' is benzyl, tert-butyldimethylsilyl or triethylsilyl; R2 is lower alkyl; R3 is H, tert-butyldimethylsilyl, triethylsilyl or benzyl; R4 is lower alkyl). USE:An intermediate for mevinolin and mevinolinic acid. 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 oxdiation product is then treated with an acid to give a compound of formula I (R1' is H), which is then reacted with a compound of the formula R1'X (X is halogen) to afford the aimed compound of formula I .

Description

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

(3) (In the formula, Bl is benzyl, t-butyldimethylsilyl,
triethylsilyl, R3 is methyl, ethyl, propyl,
Lower alkyl such as butyl, isopropyl, 5et-butyl, R1 is a hydrogen atom, t-butyldimethylsilyl, triethylsilyl, benzyl, R4 is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, -'#'$
(represents a lower alkyl group such as 6-butyl) Mevinolin (monacolin K), which is a competitive inhibitor of the HMG-Co14 enzyme and has a remarkable effect of lowering blood cholesterol, is a compound having the formula (4). It is a substance that 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.

There is thus much literature regarding mevinolin (senacolin K) due to its interesting activities.

For example, Exdo, A.J., Antibiot,
, 82, 852 (1979), A.W., Alber.
ta et al. Proc, Natl.

AcadJci, U, S, A,, T'l, 8957 (
1980), Japanese Unexamined Patent Publication No. 56-142286 Therefore, the present inventors conducted intensive research on a method for synthesizing mevinolin. We have discovered a new synthetic method for synthesizing mevinolin via .

The compound having the general formula (1) is not only useful as an intermediate for mevinolin synthesis as described above, but also
We have 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 formula (2) (wherein 81 is a hydrogen atom; R1 is a lower alkyl group, R3 is a hydrogen atom, t-butyldimethylsilyl, triethylsilyl, benzyl, A compound having the formula (1) 6R3 is produced by oxidizing the compound with chromic acid or dimethyl sulfoxide with chromic acid or dimethyl sulfoxide, followed by acid treatment, to form a compound having the general formula (1)6R3.

is benzyl, t-butyldimethylsilyl or triethylsilyl, and X is a halogen.

(1') R3 In the general formula (1), (7) H/ represents benzyl, t-butyldimethylsilyl, triethylsilyl, and R8 represents methyl, ethyl, propyl, isopropyl, n-propyl, n-butyl, 5ee-
Represents butyl. R3 represents a hydrogen atom, t-butyldimethylsilyl, triethylsilyl, or benzyl, and R4 represents methyl, ethyl, 7-propyl, isopropyl, n-butyl, or 5ec-butyl.

In the compound having formula (2), R1 represents a hydrogen atom, and R3 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, agC-butyl. R3 represents a hydrogen atom, t-butyldimethylsilyl, triethylsilyl, or benzyl, and R4 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, or 886-butyl.

General formula (2) is subjected to Collins oxidation, and pyridinium di(8)
) Treat with romate, pyridinium chlorochromate, dimethyl sulfoxide-trifluoroacetic anhydride, dimethyl sulfoxide-oxalyl chloride, etc. to convert primary alcohol to carboxylic acid, and then treat with hydrofluoric acid, p-toluenesulfonic acid, hydrochloric acid, etc. In particular, compounds of the general formula (1) are obtained.

The compound of the general formula (1) obtained by the method shown above is a compound of the formula (2R', XC, where B and I represent benzyl, t-butyldimethylsilyl, or triethylsilyl, and , such as benzyl chloride, benzyl bromide, t-butyldimethylsilyl chloride,
The compound of general formula (1') of the present invention can be easily obtained by treatment with triethylsilyl chloride or the like.

The method of the present invention is specifically shown in the process diagram below for producing mevinolin salt from compound (6) (12) → (18) → (14)
This process corresponds to

(9) (10) (10) b-8-+ 1 121 (11) (5~) (18) HO , /\, Mevinolin (ゐ=CH8, &=\) R in the above process diagram
2, R4 and R are lower alkyl groups.

Compound (6) is phenylzelenylated by treatment with phenylzelenyl chloride lithium sialkylamide,
Next, enone (7) is obtained by oxidation with sodium metaperiohydrocyanate, hydrogen peroxide, etc., but after generating lithium erulate from compound (3) using lithium dialkylamide, etc., trimethylsilyl chloride, triethylsilyl chloride, etc. Silyl erlate can be obtained by treating with K and oxidizing with a weak oxidizing agent such as palladium acetate.

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

Alcohol (9) is dissolved in an ethereal solvent and added to the liquid ammonia-lithium solution. Diol (10) is similarly obtained by using sodium instead of lithium.

R<C0C in excess (more than 2 times) relative to diol (10) K
IJ or (R4Co)tOC (in the formula R4 is lower alkyl), for example, S'-2-methylbutyric anhydride, 2S-methylbutyric acid chloride is treated in the presence of pyridine, dimethylpyridine, etc. to form a diester ( 11) and treated with an alkali, preferably caustic soda or caustic potash, to form a monoester (12).

Chromic acid oxidation (Collins oxidation) of monoester (12)
After that, when acid treatment is performed, hydroxylactone (18
)become. 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.

Hydroxyl lactone (13) is treated with trialkylsilyl chloride, preferably t-butydimethylsilyl chloride in the presence of imidazole to obtain monosilyl ether (14).
Make it.

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

(1)) When diene (15) is treated with an acid, preferably with hydrogen fluoride water or tetraalkylammonium fluoride, it becomes mevinolin (monacolin K).

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

The present invention will be specifically illustrated by the following examples, and the usefulness of the compounds of the present invention as intermediates for the synthesis of mevinolin will be demonstrated by the following reference examples.

(18) 11.1 Mg (0,022 mmol) of diol (10
) in 0.8 d of anhydrous pyridine, 120
μ# (0.6 mlJ mol) of 5-2-methylbutyric anhydride and 4-N,N'-dimethylaminopyridine were added 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. 11.21v (76%) of diester (1
1) was obtained.

(11): Colorless oil [α)''; + 55.6'' (C1,1, CHCl
5) δ (CDC's, 860 MHz) 5.70
(IH, ddd, J=9.8.5.8, Otsu 8), 5.8
8 (IB, width d, J=9.8), 5.15 (IH,'
m), 4.16 (2H, m, ), 3.91 (IH,
m), 8.71 (IH, m), 3.65 (IH1 width 8), 2.54CIH, width d, J=11), 1.8
9.1.84 (8H, s each), 1.14 (8H, d
, J=6.5), 1.12 (8H.

d, J=6.5), 1.04 (8H, d,
J=7.8), 0.90C8H,t, J='l), 0.
89 (8H.

t, J=1), 0.85 (9H, s), 0.82 (8H
, d, J=6.8), 0.01 (6H,s)
.

ν (film) 2960.2985.2880.1787.1260.
1187.840 side-1 Mass spectrometry: Calculated value C, 昌sotstcM CHs), 649.
4497 Actual value 649.4467 11Mg (0,0165 mmol) of diester (11
) in 0.5111/ (7) x-ta/-yv, add 0.411#)1#-NaOH dropwise and stir at room temperature. After 17 hours, ethanol is distilled off under reduced pressure, and ether and saturated brine are added for extraction. After washing the ether layer and saturated ammonium chloride water, drying (CMIISO4)
, purified by silica gel column chromatography.

8.69 (90%) of monoester (12) was obtained.

(12): Colorless oil [α3” +64.7° (CO, 86, CHCl,) δ
(CDCJIs, 860 MHz)5.70 (
IH, ddd, J=10.0.5.1.2.8),
5.88 (width d, J=10.0), 5.
15 (IH9 width s, WK = 7 Hz),
408 (IH.

m), 8.75 (8H, m), &65 (IH, width S
), 2.54 (14, width d, 7=11), 2.81
(I H, 5ezt0.J = 7), 2.27 (
IH.

m), 1.97 (ddd,, 7=15.6.8.2),
1.98 (IH, td, J=11.2.4), 18
8 (IH, m), 1.44.1.86 (8H, s each)
, 1.12 (8H, d, J=7), 1.08 (8H.

d, J='1.5), 0.90 (8H,t, ,7
=7.4), 0.85 (9H,s), 0.82C8
H, d, J = 7), 0.01 (6H, s).

(21) ν (film) 3450.2950, 2980.2860.1784.
1257.1200.885.776-1 Mass spectrometry: Calculated value Cs5H6oOeSiC,AI”), 5
80.4156 Actual value 580.4090 (22) 48μ# of anhydrous pyridine in 1d of anhydrous dichloromethane (
0.59 mmol) and then 80 μm of chromic anhydride.
(0.80 mmol) and stirred at room temperature for 15 minutes.

To this orange-red chromic acid-pyridine solution, 8.61v (
A solution of alcohol (12) (0,015 mmol) in dichloromethane (1d) was added and stirred at room temperature for 15 minutes. Dilute with ether (15117) and add Celite. Stir for a while until a clear solution forms. Filter through a column of 2c+++ Celite, concentrate the filtrate,
A residue was obtained.

Dissolve it in 0.5d of anhydrous DMF and
Add 5 mmol of PDC and stir at room temperature for 16 hours. Add 2011tj ether, add celite and stir until a clear solution. Celite column (2c1
Filter through 11) and wash the Celite thoroughly with ether. The residue was dissolved in 47% hydrogen fluoride/acetonitrile (We).
I Dissolve in III and stir at room temperature for 2 hours.

After concentrating to 0.5M under reduced pressure, ether was added, and the mixture was washed with saturated sodium chloride water. Wash the ether layer with saturated ammonium chloride water. After distilling off the solvent, it was purified by silica gel column chromatography. 3.5■ lactone (18) was obtained (5
6chi).

(18): Anhydrous oil [α)'; +98.7° (CO185, ClIC8
g) δ (CDCI!s, 860 MHz)5.
91 (IH, ddd, J=9.8, 5.2,
2.9Hz), 5.45 (14, width d, J=9.8
), 5.20 (IH, width 8), 4.61 (IH, m)
, 4.87 (IH, inertia), 8,78 (14, width 8),
2.78 (IH, dd, J=17.5, 5.1
), 2.66 (width d, 7=11.5), 2.6
1 (IH.

ddd, J=17.5, 8.8, 1.5),
2.35 (I H, 5ezt, J = 6.9),
2.82 (IH, m), 1.14 (8ff, d, J=
7), 1.09 (8H.

d, J=7.5), 0.91 (8H,t, J=7
．． 4), 0.88C8H, d, J=7).

ν (film) 8480.2960, 2980, 2875.1725,
1260. Diol (18
) in Q, 2r11 anhydrous DMFK, 1211+9
(0,1 fluorimole) of imidazole and 10 ri(0,
066 mmol) of t-butyldimethylsilyl methane is added and stirred at room temperature for 8 hours. After condensing 11Ca under reduced pressure, it was purified by silica gel column chromatography, and 8
, 9 m9 of monosilyl ether (14) was obtained. (8
8ch) (14): Colorless oil [α]z +596(c O,89, cHces>δ(
CDCI! 8.100MHg) 5.90 (IH, ddd, J=10, 5.2.5)
, 5.48'CIH, width d, J=10), 5-16(
IH0 width 8), 4.58 (IH, m), 4.24 (
IH, m),' 8. '72 (1//, Towahiro Jl),
0.88C9H,s), 0.07(6H,a).
.

ν (film) 8490.2960,2940,2880°2870.
1739.1260, 1087.841c+++-” Mass spectrometry: Calculated value (C5oHn (as ksi (A/+)) 58
6.8580 Actual value 586.8520 Calculated value (C-trHso o5 Si, (as JI Ht) 518.1424 Actual value 518.8417
.

Reference Example 2 Synthesis of Monacolin K (Mevinolin) from Compound (14) 2.9 Da (0,0054 mmol) of alcohol (14
) in 0.21 dichloromethane, 0.2R
1 of anhydrous pyridine is added, then after cooling to 0° C., 1 drop of the distilled thionyl chloride is added. 1 at 0℃
After stirring for 0 minutes, stir at room temperature for 1 hour and 10 minutes. After drinking a small amount of water, extract with dichloromethane and 1#-4 acid.
Perform cleaning. Add organic layer to KIN-hydrochloric acid, 5'JN
aHCOs then washed with saturated NH < CE water, M
9 Dry with S04. The solvent was distilled off and preparative TLC (
Ss Ox, hexane/ether CNMR, JR, M
S, TLC) completely matched the physical properties of the standard product derived from natural monacolin K.

(15): Colorless clear autumn product [α)” + 197° (C0,1, CHCljs) Standard material: CCl3” + 218” (C1,7, C
HCll5) δ (CDCll5-860 MHz)5
．． 99 (IH, d, J=9.6), 5.79
(IH.

dd, J=9.6.6.2), 5.52 (IH, width g
), 5.86 (IH, narrow? 7L), 4.58CIH
, m), 4.26 (IH, q, J=8.5)
, 2.60 (IH, d , , 7=17.5.4
．． 8), 2.56 (IH, ddd, J-17, 5, 8,
5,1,8), 1.10 (8H,d, J=1.0
), 1.07 (8H, d, J=7.4), 0
．． 89C8H,d.

J=7), 0.88 (!ll#, 8), 0.87 (8H
.

t, J=1.4), 0.08 (8H9s), 0.
07 (8#, a) ν (film) 2960.2930.2860.1787.1260.
1185.1084.840.782In-1 Mass spectrometry: Calculated value (as C5oH5o 05 Si (1))
518.8425 Monacoli/to, 18rng(0
, 082 mmol) was dissolved in 0.8 d of anhydrous DMF, excess t-butyldimethylsilyl chloride and imidazole were added, and the mixture was stirred at room temperature for 3 hours. The silyl ether (15) was directly subjected to silica gel column chromatography.
16.8 (100%) was obtained. The physical constants are the same as the composite product on the previous page.

Dissolve in CH, CN, add 47% HF/CH, CN (Toni) solution for 11 hours, and stir at 0°C for 5 hours. After making alkaline by adding saturated soda water, extract with ether. Separate and purify by preparative TLC (5ift, ether).

4.0 ■ of monacolin K was obtained (77%).

The physical properties completely matched those of natural monacolin.

Patent Applicant San) l- Co., Ltd. (4 others) Procedural Amendment 1975 Prefecture 1st, - + Ear / Commissioner of the Patent Office Kazuo Wakasugi 1, Indication of Case 1982 Patent Application No. 38797 6. Relationship with the case of the person making the amendment Address and name of the patent applicant (190) Suntory Ltd. 5. Column 6 of [Claims] and [Detailed Description of the Invention] of the specification to be amended, Contents of the amendment (05) (Attachment) (1) The scope of claims is amended as follows.

(1) In the general formula c, ' is a silyl group, t-butyldimethylsilyl group, triethylsilyl group, R2 is a lower alkyl group, R3 is a hydrogen atom, t-butyldimethylsilyl group, triethylsilyl group, benzyl group, R4 represents a lower alkyl group).

(2) A compound having the general formula (as shown in the attached sheet) R3 (in the formula R1 is a hydrogen atom, R2 is a lower alkyl, R3 is a hydrogen atom, t-butyldimethylsilyl, triethylsilyl, silyl, and R4 is a lower alkyl). After oxidation, the obtained compound is treated with an acid to produce a compound having the general formula (I) (in the formula, R1, R2, R3, and R4 have the same meanings as above), and this compound is (In the formula, R and / represent silyl, t-butyldimethylsilyl, or triethylsilyl, and X is) XQgen. "(2) Specification page 6 Page 7, line 1 from the last line [delete chromic acid or dimethyl sulfoxy y4].

(3) Correct "General formula (2)...Fluoride" from the last line of page 8 to the fourth line of page 9 of the specification as follows. After oxidation or dimethyl sulfoxide oxidation to convert the primary alcohol into an artehyde, the carboxylic acid is obtained by treatment with pyridinium dichromate or silver oxide.

For the oxidation of alcohol to aldehyde, it is preferred to use Collins' reagent, pyridinium chlorochromate, pyridinium dichromate, dimethyl sulfoxide, trifluoroacetic anhydride or oxalyl chloride. The carboxylic acid is then fluorinated.'' (4) Page 13 of the specification, bottom line 2, ``
Correct "chromic acid" to "oxidation".

(5) “Item x,” written in lines 5 to 7 on page 17 of the specification
, <Full (12) tt...oxidation" is corrected as follows.

"The monoester (12) is oxidized with chromic acid or dimethyl sulfoxide to convert the primary alcohol into an aldehyde, then treated with chromic acid such as pyridinium dichromate or silver oxide, and then treated with acid to produce hydroxylactone. Becomes (13). - Oxidation of alcoholic springs to aldehydes.”

Claims (1)

[Claims] (1) General formula (in the formula, 8 is a benzyl group, t-butyldimethylsilyl group, triethylsilyl group, R2 is a lower alkyl group, R1 is a hydrogen atom, t-butyldimethylsilyl) 1 ethylsilyl group, Hensyl group, R4G': lk represents a lower alkyl group). (2) General formula (1) (In the formula, R1 is a hydrogen atom, R, -lower alkyl, R8 is a hydrogen atom, t-butyldimethylsilyl), I! After oxidizing a compound having the general formulas (1) (2) (in which R1, R1 , R1 and R4 have the same meanings as above), and this compound is converted to 2R,'X (where Rζ represents benzyl, t-butyldimethylsilyl, triethylsilyl, and X is halogen) A method for producing a compound having the general formula (1u δR3 (in the formula, H, I, R2b RB % R4 have the same meanings as above), characterized by reacting with a compound of the following.