JPH013179A - Bornene compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] [Field of invention] The present invention relates to novel bornene compounds.

[Background of the Invention] Depending on their structure, alkaloid compounds have antihypertensive effects,
It exhibits specific pharmacological effects such as sedative and tranquilizer effects, and is widely used as a medicine.

Conventionally, such alkaloid compounds have been produced by extraction from plants and the like. However, since the content of alkaloid compounds in plants is very low or common, it is reported that extraction methods cannot meet the demand.Currently, many alkaloid compounds are
It is produced using organic chemical synthesis methods.

However, alkaloid compounds have very complex structures, and their pharmacological effects vary depending on their optical activity. Therefore, when synthesizing alkaloid compounds, selectivity is required from an optical point of view as well.

For example, alkaloid compounds such as reserpine and acimaricin can be synthesized via loganine and secologanin, but these compounds have multichiral centers, and conventional methods cannot synthesize compounds with such multichiral centers. The synthesis of secologanin is extremely difficult, and secologanin in particular could not be produced using organic chemical synthesis methods.

[Object of the Invention] An object of the present invention is to provide a bornene compound that can be effectively utilized for the construction of alkaloid compounds via compounds having multichiral centers such as loganin and secologanin.

[Means for achieving the above object] The configuration of the present invention for achieving the above object is expressed by the following formula [II
This is a bornene compound characterized by the following:

(Hereinafter, blank space) In the above formula [II, R1 and R2 each represent a hydrogen atom or jointly represent a - oxygen atom. Further, R3 represents a hydrogen atom, and R4 represents a hydrogen atom or -CH20H1 or R3 and R4
or jointly represents an oxygen atom. However, R1 and R2 and R3 and R4 do not represent oxygen atoms at the same time.

Hereinafter, the bornene compound of the present invention will be explained along with a manufacturing method according to the following reaction formula.

(Hereinafter, blank space) To explain the above reaction in detail, the dihydrofuran derivative used as a raw material is represented by the following formula [11].

In the above formula [■], R1 and R2 each represent a hydrogen atom or jointly represent a - oxygen atom.

R3 represents a hydrogen atom, and R4 represents a hydrogen atom or -CH20H1, or R3 and R4 jointly represent an oxygen atom. Tatami, R' and R2 and R'' and R
4 does not represent an oxygen atom at the same time.

In the present invention, the dihydrofuran derivative includes R1
and R2 is a - oxygen atom, RlN is a hydrogen atom, and R4 is -CH20H, the following formula [11-A
Compounds represented by 1 are preferred.

...[II-A]'' Bipedal dihydrofuran derivative [11] or [■-A
] and cyclopentadiene is carried out in the absence of oxygen, and usually both are sealed in a sealed tube and heated.

In this case, cyclopentadiene is used in excess with respect to the dihydrofuran derivative [■] ([II-Al in the above reaction formula).

Further, the temperature during the reaction is usually 80°C or higher (preferably within the range of 100 to 180°C), and the reaction time is usually 1 to 50 hours (preferably 10 to 30 hours).
within the range.

The above reaction is usually carried out without using a solvent.

After the reaction is completed, the produced bornene compound can be separated and produced using chromatography. The developing solvent used in this case is usually a mixed solvent of hexane and ethyl acetate.

” Bipedal cyclopentadiene and dihydrofuran derivative [
(2) (In the above reaction formula, the reaction with [ll-Al) is a Diels-Alder reaction.

That is, for example, dihydrofuran derivative [II]
By the reaction of cyclopentadiene and cyclopentadiene, a bornene compound represented by the formula [1] is obtained.

Specifically, as the dihydrofuran derivative [11], [
Using the compound shown in II-Al, the following formula [I
It is possible to obtain a bornene compound represented by -Al.

(Hereinafter, blank space) Furthermore, the bornene compound represented by the formula [I-Al obtained in this way is heated with sodium borohydride (usually at the boiling point of an aliphatic alcohol such as isopropyl alcohol used as a reaction solvent). An oil is obtained by treatment with an aqueous solution of sodium metaperiodate at low temperature (usually below 5° C.), and this oil is heated with silver carbonate-celite (
Usually, by refluxing at the boiling point of an aromatic solvent such as benzene used as a solvent, the [α] back becomes +147.
52° of the following formula [(2S,3R)-3- expressed in ml
Colorless crystals of hydroxymethyl-5-norbornene-2-carboxylic acid lactone can be obtained.

・・・・・・・・・[ml On the other hand, the obtained bornene compound represented by the formula [I-Al] is hydrolyzed at room temperature using an alkali such as potassium hydroxide, and after cooling, carbon dioxide is added. After preparing the solution to a weak alkaline using a method such as introducing
By treating with periodate and sodium borohydride at a temperature usually below 5°C, and then making this solution slightly acidic, the following formula for [α] -148,20° is obtained: (2R,3S)-3-hydroxymethyl-5-norbornene-2-carboxylic acid lactone represented by [IV] can be obtained.

(Hereinafter, blank spaces) ・・・・・・・・・[IV] In addition, as a method for purifying the compounds represented by the above formulas [III] and [IV], it is advantageous to use chromatography, and the development in this case is as follows. As the solvent, it is preferable to use a mixed developing solvent of hexane/ether.

[Effects of the Invention] The bornene compound of the present invention thus obtained can be effectively used as an intermediate in the synthesis of alkaloid compounds via loganin, secologanin, and the like.

Moreover, the yield is very high and separation and purification is easy.
The reaction operation is not complicated, and intermediates for the synthesis of alkaloid compounds can be industrially produced very advantageously.

[Example] Next, examples of the present invention will be shown.

(Example 1) 1.0 g (8.77 mmol) of (
S)-5-hydroxy-2-penten-4-olito and 4
．． A mixture of 4 ml (52.6 mmol) of cyclopentadiene was heated in a sealed tube at 140° C. for 20 hours to react.

After cooling, the mixture was separated and purified by column chromatography packed with 45 g of silica gel using a hexane/ethyl acetate mixed solvent (mixing volume - 2 = 1) as a developing solvent.
A crystalline solid was obtained.

Recrystallize from this solid hexane/benzene mixed solvent,
Colorless foliar crystals of (2R,3S)-3-[(S)-1,2-dihydroxyethyl]-5-norbornene-2-carboxylic acid lactone were obtained.

・Yield; ], 114 g Yield near 2% ・Melting point; 96-97°C ・[Ct] ”f ;-49,77° (c=1.
CHCJJ3) Elemental analysis results; C! . H□203 Carbon m Hydrogen (z) Calculated value 66.65 6.71 Measured value 66.37 6.68 ・IR (Nuchillor method) y=3350c+a-', 1 7 2 0 cm-'
・'H-NMR (CDC statement, /TMS) δ = 1.4
5 (d, 11LJ=9.0 Hz), 1.63 (dt,
J = 9.0 and 1.0 Hz), 2.16 (br, t
, ill, J=7.0 Hz, compatible), 2.85
~3.22 (■, 211), 3.27~3.34 (
m, 2H), 3.45-1.75 (■, 28), 3.
80 ~4', 08 (shoulder, 111), 6.29 (s, 2
11)・Masspertle m/e=181. (M”+]), 180 (+M), 66
(100%) (Example 2) (2R,33)-3-[(S)-1 obtained in Example 1
,2-dihydroxyethyl]-5-norbornene-2-
Carboxylic acid lactone 120mg (0
, loamimole) and 25 mg of sodium borohydride.
(0,0 mmol) was poured into 1 rnJl of isopropyl alcohol, and the solution was refluxed for 1 hour.

After the reaction was completed, the solvent (isopropyl alcohol) was removed under reduced pressure and the resulting residue was poured into 1mM water.

This aqueous solution was dissolved in 2 ml of water and treated with 156 mg of sodium metaperiodate (1,68 mmol) at 0° C. with stirring.

After 2 hours, the above mixed solution was extracted three times with 2 mM dichloromethane, the extracts were combined, and the extracts were washed with 5 ml of a 5% aqueous sodium bicarbonate solution and 5 ml of brine. After washing, extraction was carried out using magnesium sulfate, and then the extraction solvent (dichloromethane) was removed under reduced pressure.

The obtained oily residue was poured into 6 ml of benzene,
Silver carbonate (F) supported on diatomaceous earth (product name: Celite)
etizon reagent, 680 mg, approximately 1.2 mmol) for 1 hour.

The reaction solution was filtered to remove silver carbonate supported on diatomaceous earth, and then benzene in the filtrate was removed under reduced pressure.

The obtained oily residue was subjected to column chromatography packed with 2.5 g of silica gel, and hexane/
The above formula [
[III] Colorless columnar crystals of (2S, 3R)-3-hydroxymethyl-5-norbornene-2-carboxylic acid lactone were obtained.

・Yield: 62 mg ・Yield: 62% ・Melting point: 65-67°C ・[α]v: +147.52° (c=0.52, CHC
l 3) Elemental analysis results; C9H. 02 Carbon (%) Hydrogen (z) Calculation step 7], 98 6.71 Measured value 72
．． 03 6.7:1・IR (film) C=1745c+m-'・'H-NMR (CDC reference 3/TMS) δ=1.4
5 (d, ill, J=9.0 Hz), 1.65 (d,
IH, J=9.0Hz), 3.07~:1.3:l(m
, 411), 3.79 (dd, Ill, J = 10 and 3 Hz), 4.29 (ddJ) + 1, J = IO and 8H7,), 5-29 (s, 2H)' ・Mass spelt m/e =150 (M”), 65 (100%) (Example 3) (2R,3S)-1-[(S)-1 obtained in Example 1
,2-dihydroxyethyl]-5-norbornene-2-
Carboxylic acid lactone 132mg (
0.73 mmol) in 20% potassium hydroxide aqueous solution 1
ml for 10 minutes at room temperature.

After cooling, carbon dioxide was blown into the solution while stirring to adjust the solution to weak alkalinity (pH 8 to 9).

It was then treated with 235 mg of sodium metaperiodate (1.1 mmol) and 81 mg of sodium borohydride (2.2 mmol) dispersed in 1 mM water at a temperature of 0.degree. C. with stirring.

After making the reaction solution acidic by adding 10% hydrochloric acid,
The extracts were extracted three times with 5 ml of dichloromethane, and the extracts were combined and washed with 5 ml of brine. After washing, the extract was dried using magnesium sulfate, and then the extraction solvent (dichloromethane) was removed under reduced pressure.

The obtained oily residue was separated and purified by column chromatography packed with 5 g of silica gel using hexane/ether (1:2) as a developing solvent to obtain the above-mentioned formula [IV
] (2R,3S)-3-hydroxymethyl-5-
Colorless columnar crystals of norbornene-2-carboxylic acid lactone were obtained.

・Yield: 60 mg ・Yield: 55% ・Melting point: 65-67°C −[α] Y ;-148,20° (c=0.52,
Cl-1cJL:l)・Elemental analysis result; C9H□. 0
2 Carbon (z) Hydrogen (X) Calculated value 71.98 6.71 Measured value 7], 98 6.67 ・IRl 'H-NMR and mass spectrometry data are similar to the compound prepared in Example 2.

Claims (1)

[Claims] (1) Bornene compound characterized by being represented by the following formula [I]; ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・[I] (However, in the above formula [I], R^1 and R^
2 each represents a hydrogen atom or both together represent one oxygen atom, R^3 represents a hydrogen atom, and R^4
represents a hydrogen atom or -CH_2OH, or R^3 and R^4 jointly represent one oxygen atom, and R^
1 and R^2, R^3 and R^4 do not represent an oxygen atom at the same time. ).