JPS6034960A - Synthetic intermediate for mevalonic acid and production of labeled mevalonic acid therefrom - Google Patents

Abstract

NEW MATERIAL:The synthetic intermediate of mevalonic acid of formula I (R<1> is H, methoxyethoxymethyl, ethoxyethyl, benzyl of benzyloxymethyl; R<2> is H, 1-4C alkyl or alkali metal salt; X is deuterium or tritium). EXAMPLE:Z-Ethyl-2-deutero-2,3-epoxy-3-methyl-5-ethoxyethyloxypentanoate. USE:Intermediate for the production of labeled mevalonic acid. The acid can be produced from an inexpensive raw material in high yield, by the use of the novel intermediate. PREPARATION:For example, the alcohol group of 3-butyn-1-o1 is protected, and the alcohol is treated with a chlorocarbonic acid ester in the presence of a strong base. The treated product is made to react with copper iodide and methyl lithium, treated with labeling water, and epoxidized to obtain one of the compound of formula I . The obtained compound of formula I is reduced and converted to an alcohol to obtain the mevalonic acid derivative of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to an intermediate for the synthesis of lachelated mevalonic acid, which has become increasingly important in recent years, and a method for producing mevalonic acid therefrom.

Conventional technology Mevalonic acid, also called hiochi acid, is a compound that has been well known since ancient times, and is an early step in the biosynthesis process of steroids and imprenoids. Acetyl COA and acetoacetyl Co
3-hydroxy-3-methyl-glutaryl-Co from A
It is made through A.

In this way, mevalonic acid is a compound in the early stage of the metabolic pathway, and through this mevalonic acid, squalene, cholesterol, vitamin D and vitamin A are produced.

Many biological substances such as steroid hormones and carotene are produced.

Mevalonic acid plays an important role in plants as well as in animals. Clarifying the metabolic pathways of organisms and performing 81a adjustment based on them is a medical,
This is an important issue in fields such as pesticides and food. Particularly in the study of stereochemistry in enzymatic reaction systems, which has become increasingly important in recent years, it can be said that the most efficient method is to use rahelated mevalonic acid. However, until now, Cornforth, Metl+o
ds in Enzymology.

15, p. 369) has been synthesized and used. In this Cornforth method, mevalonic acid deuterated at the 4-position can only be obtained from the starting material in low yields of 3.2% and 6.9% (stereoisomer at the 4-position), respectively.

Purpose and Structure of the Invention In the process of investigating an efficient method for producing rahelized mevalonic acid, the present inventor came up with the idea of producing acid at a higher yield using a novel intermediate than from inexpensive raw materials. The invention was successfully completed.

That is, according to the present invention, general formula (1) (wherein R is a hydrogen atom, a methoxyethoxymethyl group, an ethoxyethyl group,
Represents a hensyl group or hensyloxymethyl group, R
2 represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, or an alkali metal, and X represents a deuterium atom or a tritium atom).

According to the present invention, the general formula (1a) (wherein R1 represents a hydroxyl protecting group such as an ethoxyethyl group or a methoxyethoxyethyl group, and R2 is a hydrogen atom and has a carbon number of 1
~4 lower argyl group or alkali metal, and X represents a hydrogen atom or a tritium atom) is reduced to form an epoxy compound represented by the general formula (2) (wherein R' and X are as defined above) It is then oxidized to form a diol represented by the general formula (3) (in which R,
is as defined above), or if necessary, the mevalonic acid derivative is treated with acid to produce a mevalonic acid derivative represented by general formula (4) (wherein X is as defined above). /'(A method for producing a rononic acid derivative is provided.

According to the present invention, the compound of the general formula (2) is further esterified to form a compound of the general formula (5) (wherein R1 and X are as defined above, and R has 1 to 1 carbon atoms.
4 lower alkyl acyl group or aromatic acyl group)
After forming the ester shown by, deprotecting group by acid treatment,
It is characterized by oxidation into a mevalonic acid derivative represented by the general formula (6) (in the formula, R and X is as defined above) A method for producing a mevalonic acid derivative is provided.

Summary of the Invention The present invention relates to a method for producing labeled mevalonic acid from the compound of formula (1) and the compound of formula (1a), which are new important intermediates for the synthesis of labeled mevalonic acid.

The compound represented by the formula (1d) can be easily synthesized using 3-butyn-1-ol as a raw material.

alcoholoxyethyl group of 3-phytin-1-ol,
Protected with methoxyethoxymethyl group, hensyl group, hensyloxymethyl group, etc., is treated with chlorocarbonate in the presence of a strong base to obtain 2-pentyne-1-oni-1-
(Set as 81. The base used here is preferably an organic lithium compound.

This 2-pentyne-1-oate (8) is reacted with copper iodide and methyllithium, and the reaction treatment is performed with Rahelized water, such as deuterium water or tritium water, so that the 2nd position is Rahelized and the 5th position is Z whose alcohol is protected by a protecting group
-3-Methyl-pente-2-noate (9) can be obtained.

This compound (9) was dissolved in a chlorine-based, hydrocarbon-based, or ether-based organic solvent, and m-chloroperbenzoic acid, perbenzoic acid,
Compound (1a) can be obtained by treatment with an epoxidizing agent such as peracetic acid or perphthalic acid. Also, the formula (1
The compound of the present invention represented by formula (1) can be obtained by treating the compound of a) with a general deprotecting agent such as acetic acid or palladium/carbon-hydrogen scum.

The compound (1a) is treated with a reducing agent such as lithium aluminum hydride or lithium borohydride to obtain a 1,3-bentanediol derivative (2) in which the 5-position alcohol group is protected and the 2-position is labeled. .

This compound (2) is treated with an oxidizing agent, such as potassium permanganate,
By oxidizing with silver oxide or the like, a mevalonic acid derivative represented by the general formula (3) can be obtained. For deprotection of hydroxyl groups, acetic acid, p-toluenesulfonic acid, Hensensulfonic acid,
Alkyl ether protecting groups can be deprotected with hydrochloric acid, hydrofluoric acid, etc., and palladium on carbon, palladium,
The hensyl ether-based protecting group can be deprotected by a catalytic source using platinum or the like as a catalyst.

By deprotecting in this way, mevalonic acid labeled at the 2-position represented by formula (4) can be produced.

Further, the 1,3-bentanediol derivative represented by the above formula (2) is treated in the presence of a base with an acylating agent such as acetyl chloride, acetic anhydride, probylchloride, etc. After treating with ester to give ester compound (5), the protecting group of allyl is deprotected in the same manner as in the synthesis of compound (4), and then an oxidizing agent such as potassium perganate, Mevalonic acid labeled at the 4-position represented by general formula (7) is produced by treating it with silver oxide, chromic anhydride, and Jones reagent to obtain a carboxylic acid, and then hydrolyzing it with an acid. can. Acid hydrolysis IW here refers to hydrolysis using a strong acid such as hydrochloric acid, p-1 toluenesulfonic acid, and Hensensulfonic acid.

The above steps are illustrated as follows.

Below margin 3-butyn-1-ol (8) (9) (la) 〆 \ (31(51 ↓ ↓ RI, protecting group, R2 di-lower alkyl group R3, acyl group, X: deuterium atom, tritium atom EXAMPLES The present invention will be described in detail below, but it goes without saying that the scope of the present invention is not limited to these Examples.

Production Example 1 Production of 3-butynyl-ethoxyethyl ether 30ml containing p-1-luenesulfonic acid of catalyst ffl
3-butyn-1-ol in ethyl vinyl ether of 7
g<0.1 mol) was added at 0° C. and stirred for an additional 20 minutes. The reaction solution was warmed to room temperature, diluted with 100mj2 of hexane, and passed through an alumina column to remove impurities. 13.
8 g of colorless oil was obtained.

Yield: 97% Properties: Colorless oil ＼ IIL spectrum (film, i/cm): 330
0゜2130.1390.1320.1120.1 1
00, 1060,950′ H-N MR spectrum (CDCA3, δppm
) 4.70 (IHlq, J=6H2), 3.28~3
．． 80 (4H8m) 2.42 (LHldt, J=7,
2Hz), 1.94 <LH,, t, J=7Hz)
, 1.29 (3H, d, J = 6Hz) , 1.17
(31-1, t, , J=7H2) Production Example 2 Ethyl-5-ethobyl diethyloxy 2-pentyne-1-
Preparation of oeate 6.11 g (4
3.0 mmol) of 3-butynyl-ethoxyethyl ether was dissolved and cooled to -78°C. 43 to this /g liquid
．． Add 0 mmol of n-butyllithium, and after 1° 5
．． Dissolve 43 g (50 mmol) of ethyl chloroform in 25 ml of dry tetrahydrofuran to give a total volume of 1 volume to 25 ml of tetrahydrofuran. ri! Tetramethylethylenediamine (6.7 ml) was added.

After the addition was completed, the reaction solution was stirred for 15 minutes to return to room temperature.
It was filtered using Florisil.

The filtrate was concentrated and distilled under reduced pressure (L mm > 11 g).

Yield: 8.19g (Yield: 91%) Properties: Colorless oil Mass spectrum (70e/V) mlz: 214.199.169.139IR (film, l/cm) 2240.1710'HNMR<CDC! 2a, δppm) 4.63
(q, L H), 4.10 (q, 211), 3.
65-3.30 (m, 4H), 2.48 (L,
2H), 1.2 0 (d, 3H), 1.1
8 (mu, 3H), 1.09 (t, 3l-1)
Preparation Example 3 Preparation of Z-Ethyl-2-Syutero-3-Methyl-5-ethoxyethyloxypent-2-noco-1.2, OOg copper iodide (10.5 mmol) in 50 ml of dry ether; Then, 13.5 ml of methyllithium (20.3 mmol) was added under ice-cooling. 2.01 g (9,3
5 mmol) of ethyl-5-ethoxyethyloxy 2-
Pentyne-1-oate in 50 ml of ether/8 solution was quickly added. After 5 minutes while stirring, 3 ml of deuterium water was added. The reaction solution was filtered through Florisil, and the Florisil was washed with 150 ml of ether. When the filtrate was concentrated, 2.061 (yield 96%)
Z-ethyl-2-shoutero-3-methyl-5-ethoxyethyloxypent-2-noate was obtained. Deuterium was present at the 2-position of the obtained 5-hydroxyethyloxypent-2-phate at a rate of 97%. Also Z
The ratio of Z and E was Z:E-≧50:1.

MS spectrum (70e/v) +r+/z: 201.142.114 IR spectrum (film, i/cm) 2240.1710.
1640′H-NMR (CDCff, δpptn >4.67
(q, L H), 4.12 (q, 2H), 3.75
~3.40 (m, 4H), 2.88 (t, 2H
) , 1.94 (S, 3H) , 1.27 (d, 3
H) , 1.25 (t, 3H) , 1.1 7 (t
, 3H) Example I Z-ethyl-2-schoutero-2,3-evogycy 3-
Preparation of methyl-5-ethyl oxyethyl oxypentanoate 1.95 g (8.47 mmol) of Z-ethyl-2
- Shutero-3-methyl-5-ethoxyethylpent-2-noe 1- is dissolved in 15 ml of methylene chloride,
3.70 g m-chloroperbenzoic acid (15 mmol, 7
0%) was added at 0°C. After stirring at room temperature for 20 hours, 0°C
The reagents were decomposed by passing butadiene gas through them.

The reaction solution was washed successively with 1.5N sodium hydroxide and saturated brine, and dried over anhydrous sodium sulfate.

Several times: 1.87g (yield 90%) Mass spectrum (70e/V) mlz: 232.202.15B, 130IR spectrum (film, I/cIIlin 2230.1745'H-NMR (CDCj23, δppm) 4, 65
<m, 11-1), 4. l O ~ 4.32 (m.

2H), 3.70-3.40 (m, 4H), 2.
05~i, 84 (rn, 2H), 1.42 (S
, 3I-1), 1.33-1.22 (m, 6H),
1.18 (t, 3H) Example 2 2R-2-Syutero-5-Ethoxyethyloxy-3
- Preparation of methyl-1,3-bentanediol 480 mg (11.4 mmol) of lithium aluminum hydride suspended in 25 ml of ether was dissolved in 5 ml of anhydrous ether under cooling with water.
Add 1,87 g (7,62 mmol) of 2,3-epoxy-3-methyl-5-coethoxy nityloxybentanoate, and after 20 minutes, add 0.5-i of water. Then 0.5-i 15% sodium hydroxide/8 solution, 1.5
ml water was added and filtered using Celite. 71 &: Excess residue is 100ml l! Extraction filtration was performed using 1il=acid ethyl ester. The filtrate was concentrated, subjected to silica gel column chromatography, and purified with ethyl acetate.

Yield: 1.44g (91% yield) Mass spectrum (70e/v) rn/z: 152.118.115 IR spectrum (film, 1/cm) 3400.
2170'H-NMR (CDC4, δppm) 4.68<q
, lH), 3.95-3.58 (Jn, 6H+
-0H), 3.29 (bs, -011), 1.94
(m, L H), 1.80 (nt, IH), 1.6
6 (m, I H), 1.30 (d, 311), 1
．． 26 (S, 3H), 1.19 (t, 311) Example 3 Preparation of 2-schutelo-mevalonic acid lactone 2-schutelo-5-lactone 1·±ethylmequin-1,3-bentanediol 2.11 g (10 , 19 mmol) in water 1
It was dissolved in 6 ml of 15% rhithrium hydroxide 4.1-i, and 2.25 g of potassium permanganate was added over 30 minutes while cooling with water. After about 1 hour, thorium hydroxide (15%)
2.1 ml of solution /8 and 1.3 g of potassium permanganate were added. Excess oxidizing agent was decomposed by adding methanol and filtered.

The filtration residue was mixed with 50 ml of cooled water and water-methanol (1:
1) Extracted at 50-i.

The extract was adjusted to pH 8 with IN hydrochloric acid, concentrated under reduced pressure to a volume of 3 to 5 ml, adjusted to pH 2 with concentrated hydrochloric acid under cooling, and left at room temperature for 3 hours.

After 3 hours, the pH was adjusted to 4 using 15% sodium hydroxide, and the mixture was concentrated to dryness.

The residue was extracted using acetylene, and if the ethoxyethyl group, which is a protective group for the hydroxyl group, was not removed, 50 mg of p-toluenesulfonic acid was added.

Triethylamine (0.1ml) was added to the reaction solution and concentrated.
Lamination was performed using a silica gel column. The chromatograph was run with ethyl acetate:n-hexane-1:1 to 10:1.

Yield: 1.12g (yield 85%) Mass spectrum (70e/v) m/z: 132.131.116.113.104,
7I IR spectrum (film, l/cm) 3420.
2080.1730'HNMR (CDC63, δppm) 4.56 <m
, I H), 4.30 (m, IN), 2.46 (
t, L H), 1.87 (m, 211), 1.37
(S, 3H) Example 4 Preparation of 5-ethoxyethyloxy-3-methyl-3-hydroxy-2-schoutero-pentyl acetate 2-schoutero-3-methyl-5-ethyloxyethyloxy-1,3 -bentanediol 83 mB (0,4
mmol) to 21Tll of methylene chloride? g M and
Triethylamine 1 to i was added thereto, 1 ml of acetic anhydride was added dropwise under stirring, and the mixture was further left at room temperature for 1 hour. The reaction mixture was directly adsorbed onto silica gel and then eluted with 1:1 ethyl acetate:hexane.

Yield: 9Hmg (yield 98%) Properties: Colorless oil IR spectrum (film, 1/cm): 3510
．． 1740.1390.1250.1130°1090
．． 1050.1010 3O spectrum (m/z) 2M+ was not observed.

232.204 (M"-QC, H5), 160.7
3'H-NMR spectrum (C, D(d!3, δp
pm >1.22 (3H, 5J=6Hz), 1.2
5(3I(,S), 1.32(3Hld, J=6Hz
), 1.68-1.96 (3H, m), 2.05
(3H1S), 3.96-4.00 (4H.

m) ,4.23 (2H,,d,,J=7Hz),4
．． 68 (LHlq-J=6Hz) Example 5 NL5-Ethoxyethyloxy-3-methyl-3-hydroxy-2-schutelo-pentyl acetate of 4-schutelo-mevalonic acid lactone 85 mg (0.34 mmol) was dissolved in 5 ml methanol. Comb, 50% vinegar M1ml
was added and stirred for 1 hour.

The generated methanol, acetaldehyde, etc. were removed together with methanol under reduced pressure, and the residue was dissolved in 4 ml of acetone. Next, 3 equivalents of Jones reagent was added and stirred for 1 hour. After the reaction was completed, excess reagent was decomposed with ethanol.
The mixture was filtered for 71 days using Florisil. Wash Florisil with a small amount of methanol, and add 2 ml of 1N hydrochloric acid to the combined filtrate.
was added, and the mixture was further stirred at room temperature for 2 hours. The organic solvent was removed under reduced pressure, the residue was dissolved in 5 ml of acetone, and 5 mg of p.
-Toluenesulfonic acid was added and stirred at room temperature for 5 hours. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using ethyl acetate as an elution solvent.

Yield: 37 mg (yield 82%) IR spectrum (film, 1/cm): 3470
．． 2190.1710.1460.1440.1300
．． 1240.1130.1050M5 spectrum (m/
z): l 32 (M+-+ 1), 114.
102.105.72'H-N MR spectrum (CDC/!3.δpp
m): 1.40 (3H, S), 1.97 (LH,
Ill, W'A-24Hz), 2.46 (LHld,
, J-48H2), 2.70 (IH, d, J=181
1z).

4.30 (IH, dd, J=ll, 6H2).

4.50 (IH, t, J=1 1 Hz> Patent applicant Suntory Ltd. Patent agent Akira Aoki Patent attorney Kazuyuki Nishidate Patent attorney Ishi 1) Honorable patent attorney Akira Yamaguchi Patent attorney Masaya Nishiyama

Claims (1)

[Claims] ■ General formula (wherein R1 represents a hydrogen atom, a methoxyethoxymethyl group, an ethoxyethyl group, a benzyl group, a benzyloxymethyl group, etc., and t is a hydrogen atom, a lower group having 1 to 4 carbon atoms) A synthetic intermediate for mevalonic acid, which represents an alkyl group or an alkali metal salt, and X represents a deuterium atom or a tritium atom. 2. General formula (in the formula, R' represents a hydroxyl protecting group such as an ethoxyethyl group or a methoxyethoxymethyl group, R1 represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, or an alkali metal, and X represents Representing a hydrogen atom or a lithium atom) is reduced to convert it into an alcohol of the general formula % (wherein R1 and X are as defined above), and then oxidized. Mevalonic acid derivatives represented by the general formula (wherein R' and A method for producing mevalonic acid derivatives. 3. Esterification of the alcohol derivative represented by the general formula (in the formula, R1 represents a hydroxyl protecting group such as an ethoxyethyl group or a methoxyethoxyethyl group, and X represents a hydrogen atom or a lithium atom) to produce a general Formula % Formula % (In the formula, R and X are as defined above, and R3 has 1 to 1 carbon atoms.
General jguX (in the formula, R3 and X are as defined above ) or, if necessary, further hydrolyzed to produce a mevalonic acid derivative represented by the general formula (wherein X is as defined above).