JPS6034961A - Synthetic intermediate for labeled mevalonic acid and production of labeled mevalonic acid - Google Patents

Abstract

NEW MATERIAL:A synthetic intermediate of labeled mevalonic acid of formula I (R<1> is H, ethoxymethyl, methoxyethoxymethyl, benzyl or benzyloxymethyl; R<2> is hydroxymethyl or 1-4C lower alkoxycarbonyl). EXAMPLE:z-2,3-Epoxy-3-methyl-5-ethoxyethyloxypentanol. USE:Intermediate for the preparation of mevalonic acid labeled at 2- or 4-position. PREPARATION:The alcohol group of 3-butyn-1-o1 is protected with e.g. ethoxyethyl group, and the alcohol is treated with a chlorocarbonic acid ester in the presence of a strong base to obtain a compound having protected 5-alcohol group. The product is made to react with copper ioxide and methyl lithium, and epoxidized to obtain one of the compound of formula I . The obtained compound is reduced to the 1,3-diol compound of formula II (X is deuterium, etc.), and then subjected to the oxidization and deprotecting to afford labeled mevalonic acid of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to compounds of the general formula (1) (wherein R1 is a hydrogen atom, a methoxyethogine methyl group,
(represents an ethoxyethyl group, a hensyl group, or a -, ndyloxymethyl group, etc., and R2 represents a hydroxymethyl group, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, a carboxylic acid group, or an alkali diabetic base of a carboxylic acid). The mevalonic acid synthesis intermediate represented, as well as the general formula (wherein R represents a hydroxyl protecting group selected from ethoxyethyl group, methoxyethoxymethyl group, hensyl group, hensyloxymethyl group, etc., R2 is a hydrogen atom, A lower alkyl group having 1 to 4 carbon atoms or an alkali metal is reduced to form a compound represented by the general formula (2a) II (wherein R1 is as defined above, and X represents a positive hydrogen atom or a tritium atom). ) The present invention relates to a method for producing 2-position-labeled Mevalon M (3a), which is characterized in that it is prepared as a 1,3-diol compound represented by the following formula, and then subjected to oxidation and deprotection.

The present invention also relates to the general formula (lb) (wherein R' represents a protecting group for the hydroxyl group selected from an ethoxyethyl group, a 1-oxyethyl group, a hensyl group, a benzyloxymethyl group, etc.) The epoxy alcohol compound represented by is reduced to produce a 1,3-diol compound represented by the general formula (2b) (wherein R1 is as defined above and X represents a deuterium atom or a tritium atom). , and further this 1,3-diol compound (2
b) was esterified to obtain a hydroxyester compound (3b) represented by the general formula (3b) (wherein R1 is as defined above, R2 is an acyl group, and X represents a deuterium atom or a tritium atom). Thereafter, it was deprotected and oxidized to form a carboxylic acid compound represented by the general formula (4a) (wherein R2 and X are as defined above), and then hydrolyzed to form the general formula (4) (wherein This invention relates to a method for producing 4-position-labeled mevalonic acid, which has the same meaning as .

Prior Art Mevalonic acid, also known as 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 isoprenoids.Acetyl-CoA and acetoacetyl-Co
3-hydroxy-3-methyl-glucryl-Co from A
It is created 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 D1, vitamin A, steroid hormones, etc.
Many biological substances such as carotene are produced.

Mevalonic acid plays an important role in plants as well as in animals. This is an important issue in fields such as medicine and food, where the metabolic pathways of organisms are clarified and adjustments are made based on them. In particular, in the study of stereochemistry in enzyme reaction systems, which has become increasingly important in recent years, it can be said that the use of labeled mevalonic acid is the most efficient method.

However, until now Cornforth
b.

Metl+ods in Enzymology, IJ
, p. 369) has been synthesized and used. In this Cornforth method, mevalonic acid deuterated at the 4-position is obtained from the starting material at 3.
Only low yields of 2% and 6.9% (4-position stereoisomer) were obtained.

Purpose and structure of Komei The present inventor has diligently investigated an efficient production method for labeled mevalonic acid; The present invention was completed by successfully producing mevalonic acid.

That is, according to the present invention, there are provided a mevalonic acid synthetic intermediate represented by general formula (1) and a method for producing mevalonic acid labeled at the 2- or 4-position from the compound of formula (1).

Summary of the Invention The present invention relates to a compound represented by the above formula (1), which is a novel intermediate for the synthesis of rahelated mevalonic acid, and a method for producing 2- or 4-position labeled mevalonic acid. .

+11 Method for producing compound of formula (la) Alcohol xyethyl group of 3-phytin-1-ol,
2-Pentyn-1-one-2-pentyne-1-one-2-pentyl-1-oxymethyl, which is protected with a methoxymethyl group, hensyl group, or henzyl-oxymethyl group, is then treated with chlorocarbonate in the presence of a strong base to protect the 5-position alcohol group. 1-(51) The strong base used here is preferably an organic lithium compound.

When this 2-pentyne-1-oate (5) is reacted with copper iodide and methyllithium, 3-methyl-pent-2-noate (6) in which the alcohol group at the 5-position is protected can be obtained.

This 3-methyl-pente-2-noate (6) is dissolved in an organic solvent such as a chlorine thread, a hydrocarbon type, or an ether type, and m
- The compound (1a) of the present invention can be obtained by treatment with an epoxidizing agent such as chloroperbenzoic acid, perbenzoic acid, peracetic acid, perphthalic acid, etc.

(2) Process for producing the compound of the formula (1b) When the compound (6) in which the 5-position alcohol is protected is treated with lithium aluminum hydride, lithium hydrogen borohydride or lithium aluminum trialkoxy hydride, it becomes a reduced product 1 , 3-
It is converted to a bentanediol derivative (7). This compound (7) is dissolved in a la solvent, preferably a chlorine-based, ether-based, or hydrocarbon-based solvent, and treated with an epoxidizing agent such as m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perphthalic acid, etc. Compound (1b) of the present invention can be obtained by the following steps.

(3) Method for producing 2-position labeled mevalonic acid By reducing the compound (la) described above with a reducing agent such as lithium aluminum deuteride, lithium borodeuteride, lithium aluminum tritium, etc., the 2-position is labeled. A bentanediol derivative (8) can be obtained.

This bentanediol derivative (8) is oxidized using an oxidizing agent such as potassium permanganate, silver oxide, or chromic anhydride, and then with a strong acid such as p-1-luenesulfonic acid, hydrofluoric acid, or Hensensulfonic acid. Ether-based protecting groups can be deprotected, and Hensyl-based protecting groups can be deprotected by catalytic reduction using palladium on carbon, platinum, and palladium as catalysts.
(M can be done.

(4) Method for producing 4-position labeled mevalonic acid The above-mentioned compound (1b) is treated with a Rahelization reducing agent in the same manner as in the above-mentioned method for producing compound (8), and 1,3-bentanediol derivative (2b) is obtained. do.

Ester form (3b) can be obtained by reacting this compound (2b) with acetyl chloride, acetic anhydride, hendiyl chloride, propionyl chloride, hendiyl chloride, etc. in the presence of a base such as pyridine or trialkylamine. This compound (3b) can be deprotected to obtain an alcohol by catalytic reduction in the presence of a weak acid such as acetic acid or boric acid, or a catalyst such as palladium on carbon, palladium or platinum. This allows the oxidizing agent, without isolation, to
For example, the desired 4-position labeled mevalonic acid (4b) can be obtained by treatment with chromic anhydride, Jones reagent, potassium permanganate, silver oxide, etc., and then acid hydrolysis. Preferred acids used in acid hydrolysis include hydrochloric acid and p-toluenesulfonic acid.

The above steps are illustrated as follows.

Below margin 3-butyn-1-ol (5) ↓ (6) ↓ (1a) ↓ (7) ↓ (8) (38) (4a) R1, protecting group, R2=, acyl group, X: deuterium atom ,
Tritium Atom Examples Production examples and examples of the compounds of the present invention will be explained below.
It goes without saying that the technical scope of the present invention is not limited to these examples.

Preparation Example 1 Preparation of 3-butynyl-ethoxyethyl ether 7 g of 3-butyn-1-ol (0
, 1 mol) was added at 0° C. and further stirred for 20 minutes. The reaction solution was warmed to room temperature, diluted with 100 ml of hexane, and passed through an alumina column to remove impurities.
g of a colorless oil was obtained.

Yield: 97% Properties: Colorless oil IR spectrum (film, 1/cm): 3300
．． 2130.1390.1320.1120.1100
．． 1060,950'HNMR Subek 1-Jlz (CD
CA3, δppm): 4.70 (LH, q,, J-6
Hz), 3.211-3.80 (4H, revised +), 2
．． 42 (I H, d t, J=7.2Hz), 1.
94 (IHX L, J”7Hz), 1.29 (3
H,,d,J=(ilJz),1.17 (3H,t,
J=7Hz) Production Example 2 Ethyl-5-ethoxyethyloxy-2-pentyne-1
- Preparation of oeate 6.11 [(43
, 0 mmol) of 3-butynyl ethoxoethyl ether is melted and cooled to -78°C. 43 to this i;Ik
．． 0 mmol of n-phyllithium was added and after 10 minutes a solution of 43 g (50 my')-vinyl) rDx methyl chloroformate in 25 ml of dry tetrahydrofuran was added followed by 25 ml of tetrahydrofuran amine (6.7 ml). ) was added.

After the addition was complete, the reaction solution was stirred for 15 minutes, allowed to return to room temperature, and filtered through Florisil.

The soybean liquid was concentrated and distilled under reduced pressure (1 + ml Hg).

Yield: 8.19g (91%) Properties: Colorless oil mass spectrum (70 e/V) m/z: 2 1 4, 199, 169, 139IR
(Film, i/cm) 2240, III0'H-NMR (CDC I3, δppm): 4, 6
3 (q, I H), 4.1 0 (q, 2H)
, 3, 6 5 to 3.3 0 (rn, 4H), 2.
4 8 (t.

21(), 1.20 (d, 3H), 1.1'8
(t.

3H), 1.09 (t, 3H) Production Example 3 Production method of Z-ethyl-3-methyl-5-ethyl-xyethyloxypent-2-noate 2.10 g (11.3H), 1.09 (t, 3H) 0 mmol) was added to 50 ml (ID4, S) of dry ether (U), and 14.0 ml of methyllithium (21.1 mmol) was added under water cooling. -78℃
2.10 g (9.77 mmol) of ethyl-5-ethoxyethyloxo 2-pentyne-1-oate was added to 50 m
1 of the solution in ether was quickly added. under stirring, 5
After a few minutes, 3 ml of deuterated water was added. Filter the reaction solution through Florisil and get 150ml! ．． The Florisil was washed with ether. When the filtrate is concentrated, 2.23g (
Z-ethyl-3-methyl-5-ethoxyethyloxypente-2-noe 1~ was obtained with a yield of 99%).

MS spectrum (70 e/v) m/z: 2
00, 141113 IR spectrum (film, 17 cm) 1715, 16
45'I(-NMR (CDC I3, δppm): 5, 7
1 (bs, IH), 4.67 (q, III), 4,
12(q, 2H), 3. 7 5 ~3. 4 0
<m, 4H) , 2.8 7 (t, 2H) , 1
．． 9 3 (d, 3 H), 1.2 7 (d, 3
H), 12 5 mouths to 3H), 1.1 7 <L
, 311) Production Example 4 Production of Z , -5-ethoxyethylxy-3-methyl-2-pent-1-ol Z-ethyl-3-methyl-5-ethoxyethyloxypent-2-phate 230 mg (1 mmol ) 2ml
of dry ether, add 40 mg (0.95 mmol) of lithium aluminum hydride suspended in 5 ml of ether at 0°C, let stand at room temperature for 20 minutes, then add 1 ml of water. Then, the white colloid produced was removed by filtration, and the residue was prepared using hexane:ethyl acetate-2:
Washed with 1.

The first few layers were concentrated to give 171 mg of colorless oil.

Yield: 91% IR spectrum (film, 1/cm): 3430.1
460.1390.1320.1130.1100.1
080.1010 5O spectrum (m/z): 188 (Ivy
”), 173, 169, 143, 125.99.82.
73'tI-NMR spectrum (CDCff3.6 p
pm): 1.16 (3H x 5 J = 6 Hz)
, 1.28 ('3H, d, J=6Hz) , 1.74
(311,br,S),2.34(2H=t,,J
=GIlz), 3.24~3.76 (483m)
, 3.98 (2H8br, t, J-6Hz), 4.
66 (21-1, q, J=6Hz), 5.66 (LH
lbr.

Example I Z-2,3-epoxy-3-methyl-5-ethoxyethyloxypentanol dissolved in 5 ml of methylene chloride. 2-pent-1-ol 170mg
(0.9 mmol) to 270 μm of m-chloroperbenzoic acid (
70%, 1.1 mmol) was added and stirred for 20 minutes. Excess oxidizing agent was decomposed by blowing in phtadiene gas, and hexanoyl and then an aqueous solution of sodium bicarbonate were added to the reaction lfk to separate the layers.

The solvent was removed under reduced pressure and passed through a short silica gel column.
Elution was carried out with hexane:ethyl acetate-2:1.

Yield: 172cm (yield 92%) Properties: Colorless oil IR Spec 1H (film, 1/cm): 3400.
1390.1040. 1080.1130 MS spectrum (70e/v, m/z): 156.13
9.115.85.73'11-N MR spectrum (CD(1!3, δpp
m): 1.20 (3H, t, J=6Hz), 1.31
(31-IX d, J=6Hz), 1.36 (3■
(,S), 1.72'-2,04(2H,m), 2.
9 7 (11-L dd , J=8.5Hz),
3.30-4. OO(6H,, m> , 4.68 (1
1-1, q, J = 61-] z) Example 2 Production of 2-shoutero-3-methyl-5-1-xyethyloxy-1,3-bentanediol Lithium aluminum deuteride 175 mg (4 mmol) was suspended in 10 ml of dry ether and Z-2,3-epoxy-3-methyl-5-ethoxyethyloxy-1-pentanol 1
A t8 solution prepared by dissolving (IO + Tsu (0.7 d mmol)) in a small amount of dry ether was added and stirred for 30 minutes. One drop of water was added to the reaction solution, the white colloid formed was filtered using Florisil, and the filtrate was concentrated. .

Yield: 153 [IIg (yield 94%) IR spectrum (film, 1/cm): 3390.2
170.1390. 1140.1I00.1010 8O spectrum (m/z): 188 (M+-Ho
D), 162.146.143. 118.116.115, Ioo, 73'H-N M
R spectrum (CDCff3, δppm): 1.20
(3H, t, J=7Hz), 1.28 (3H, S),
1.30 (3H, d.

J=7Hz), 1.48-2.10 <3H1m>
, 3.30-4.00 (6H, rn), 4, 66 (
i I-1, q,, J = 7 Hz) Example 3 Preparation of 2-schoutero-5-ethoxyethyloxy-3-methyl-3-hydroxy-pentylacetate 2-schoutero-5-ethoxyethyloxy-3 -Methyl-1,3-bentanediol 145+■ (0.7 mmol) is dissolved in 2 ml of methylene chloride, 1 ml of triethylamine is added, and while stirring, 1 ml of anhydrous t!
i1: Acid was added. After standing at room temperature for 1 hour, it was directly subjected to silica gel column chromatography and eluted with ethyl acetate:hexane-1:1.

Yield: 173 mg (yield: 99%) Properties: Colorless oily compound IR spectrum (film, 1/cm): 3500.2
190.1740. 1390.1240.1140.1100.1060.
1010 4O Spec I-R (70e/v, rn/z): 204.
188.160.115.73:'H-N MR spectrum (CDC/23.δppm): 1.22 (3H
,t,,J=6Hz),1.24(3I],S),
1.30 (3Hldl, 1-6Hz), 1.68
~1.90 (311, m), 2゜05 (31 (, S)
, 3.38-3.96 (411, m) , 4.23
(2H3d, J=7tlZ) , 4.69(i)I, q
l J = 6 Hz) Example 4 Preparation of 4-schutelo-mevalonic acid 120 mg of 2-schutelo-5-ethoxyethyloxy-3-methyl-3-hydroxy-pentyl acetate (
0.5 mmol) in 5 ml of methanol, 50
% aqueous acetic acid was added and stirred for 1 hour. After removing the generated ethanol and acetaldehyde together with methanol, the residue was dissolved in 5 ml of acetone.

Three equivalents of Jones' reagent were added to the acetone solution and stirred for 1 hour, then ethanol was added to decompose the oxidizing agent. The reaction solution was filtered using Florisil, and the Florisil was further washed with methanol. Add 2 ml of 1N hydrochloric acid to the organic layer,
Stirred for 2 hours. ? , llμ reduction residue with 5ml of acetone
5 mg of p-toluenesulfonic acid was added thereto, and the mixture was stirred for 5 hours. After concentration, it was purified using silica gel column chromatography. Ethyl acetate was used as the elution solvent.

Yield: 52 mg (yield 80%) IR spectrum (film, 1/cm): 3430.2
190.1710, 1400.1240.1130.1
090.10106O spectrum (rn'/z):
132 (M+ 1), 114.100.72'H-NMR spectrum l-/[/ (CDC/23, δp
pm): 1.40 (3H1S), 1.86 (I H
lm.

%l/! 4=10Hz> , 2.46 (LH, d, J
=17Hz), 2.70 (IH, ddX J-17
, 2Hz) , 4.30 (LHldd, , J=11.
3.5Hz), 4.58 (IH,, dat, J-1
1,4,1,5Hz) Example 5 Production of Z-ethyl-2,3-epoxy-3-methyl-5-ethyloxypentanoate-1.Z-ethyl-3-methyl-5-ethoxyethylpentane 2.15 g (9.35 mmol) of -2-phate was added to 15+ methylene chloride.
4.10 g of m-chloroperbenzoic acid (70
%, 16.6 mmol) was added. Then, at room temperature for 20
After stirring for an hour, butadiene gas was passed through O'C to decompose the reagents.

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

Yield: 2.07 g (yield 90%) Properties: Colorless oil IR spectrum (film, 1/cm) Near 45 M5 spectrum (70e/V, rn/z): 231 (
M-CH,), 201,157°29'H-NMR spectrum (CDC C/3, δppm
): 4.65 (m, IH), 4.10-4.32 (
m, 2 H), 3.29 (S, L H).

3.70-3.40 (m, 4H), 2.05-1.
84 (m, 2H), 1.42 (5,311), 1
．． 33-1.22 (m, 6H), 1.18 (t.

3H) Example 6 LL, 2-) Preparation of rejuutero 5-ethoxyethyloxy-1,3-pencundiol Dry ether 25m
480 mg of lithium aluminum deuteride suspended in
Z-ethyl-2,3-epoxy-3-methyl-5- was dissolved in 5 ml of dry ether under water cooling.
Ethoxyethyloxypentanoate 2.07g (8,
4 mmol) was added. After the reaction was completed, 0.6 ml of 15% sodium hydroxide solution and 1.5 ml of water were further added, and the mixture was filtered through Celite. The Celite used was extracted with 100 ml of ethyl acetate, and the filtrate was combined to obtain '145. The -a condensate was subjected to silica gel column chromatography and eluted with ethyl acetate.

Yield: 1.53g (yield 87%) Properties: Colorless oil IR spectrum (film, 1/cm): 3400.2
200.2100 M5 spectrum (70e/V, rrt/z): 164
(M-QC2H5), 120. 118゜15 'H-NMR spectrum JL' (CDCl2, δppm)
:4.6 B (q, l H), 3.95-3.58
(m, 4 H+OH), 3.26 (bs, L H
).

1.94 (m, IH), 1.66 (m, III).

1.64 (bs, LH), 1.30 (d, 311
).

1.26 (S, 3H), 1.1 9 (t, 3H) Example 7 Preparation of Z-shutelo-mevalonic acid lactone 1.98 g (9.47 mmol) of diol was added to 16 ml of water and 4.0 ml of 15% thorium hydroxide.
2.20 g of potassium permanganate dissolved in Oml and cooled with water.
was added over 30 minutes.

After about 1 hour, 15% sodium hydroxide solution 2, 1
ml and 1.3 g of potassium permanganate were added. Excess oxidizing agent was decomposed by adding methanol and condensed. The pox residue was mixed with 50 ml of chilled water and ice-methanol (1:1
) was extracted.

The extract was brought to pH 8 with IN hydrochloric acid, concentrated under reduced pressure to 3-5 ml, brought to pH 2 with concentrated hydrochloric acid under cooling, and left at room temperature for 3 hours. After 3 hours, the mixture was concentrated to dryness using 15% sodium hydroxide to a pl+ of 4.

The resulting residue was extracted with acetone, and if the ethoxyethyl group, which is a protective group for the hydroxyl group, was not removed, +50'mg of p-)luenesulfonic acid was added. 0.1+nl of triethylamine was added to the reaction solution, concentrated, and purified using a silica gel column. Chroma 1 to graph were eluted with ethyl acetate:n-hexane=1:1 to 10:1.

Yield: 1.01g (yield 81%) Properties: Colorless oil IR spectrum (film, l/cm): 3420.1
720 M5 spectrum (70e/V, m/z): 132 (
M+1), 131 (M).

116, i13,104,7↓ 'H-N MR spectrum (CD (1!3, δppm
): 4.65 (IH, m), 4.30 (LH, d
t).

3.35 (LH, br, S), 2.60 (III.

b r, S) , 1.87 (211, m) , 1.3
8 (3H, S) Patent Applicant Suntory Limited Patent Attorney Akira Aoki Patent Attorney Kazuyuki Nishidate Patent Attorney Ishi 1) Honorable Patent Attorney Akira Yamaguchi Patent Attorney Masaya Nishiyama

Claims (1)

[Scope of Claims] 1. General formula (wherein R represents a hydrogen atom, an ethoxyethyl group, a methoxyethoxymethyl group, a benzyl group, or a hensyloxymethyl group, and R2 represents a hydroxymethyl group or a carbon (representing a lower alkoxycarbonyl group of numbers 1 to 4) A synthetic intermediate for rahelated mevalonic acid. 2. General formula (wherein R1 represents a protective bracket for a hydroxyl group selected from ethoxyethyl group, methoxyethoxymethyl group, Hensyl group, and Hensyl oxymethyl group, R2 is a lower alkoxycarbonyl group having 1 to 4 carbon atoms, (representing a carboxylic acid group, an alkali metal base of carboxylic acid) is reduced to form a compound represented by the general formula (in the formula, R1 is as defined above, and X represents a deuterium atom or a tritium atom). , a 3-diol compound, followed by oxidation and deprotection. 3. Epoxy alcohol having the general formula (in the formula, R represents a hydroxyl protecting group selected from ethoxyethyl group, methoxyethoxymethyl group, hensyl group, and hensyloxymethyl group) is reduced to form the general formula (in the formula, R is as defined above, and X represents a deuterium atom or tritium atom. That's right, I
2 represents an acyl group), which is further deprotected by weak acid or catalytic reduction, followed by oxidation and hydrolysis. A force method for molding lactonized mebaron represented by the general formula (wherein X is as defined above), which is characterized by lactonization.