JPS58183660A - Polyprenyl nitrile - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (formula II is the trans-type isoprene unit; formula III is the cis-type isoprene units; n is an integer 11-19). USE:Useful as a raw material for medicines, cosmetics, etc., particularly a synthetic intermediate for dolichol present in mammals. PROCESS:A polyprenyl halide of formula IV (X is halogen) is reacted with a cyanomethylcopper in a solvent, e.g. tetrahydrofuran (THF), at -60-0 deg.C to give the compound of formula I . Preferably, the fully dried solvent is used for advancing smoothly the aimed reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to polyprenylnitrile. More specifically, the present invention is based on the general formula % formula % (1) □O, wa 1, -OH Section 6□2-177.

It represents a unit, and n is an integer from 11 to 19. ) is related to a novel polyprenyl nitrile.

The polyprenyl nitrile represented by the general formula (1) provided by the present invention is a substance useful as a raw material for medicines, cosmetics, etc., and is particularly useful as a synthetic intermediate for mammalian dolichols.

To IJ co-/l/class was established in 1960 as J', F,
It was first isolated from pig liver by Pennock et al. [Nature (London), 186
, 470 (1960)], and this was later changed to the general formula (A) 2- -C) 1 combination H s H H s + - OH (A) 1 Keo Ka 1,
(□2-UJ-3□2-1. Representing a 2-1. type ippun unit; the same shall apply hereinafter in this specification)], wherein the mixture has the formula (A)
The number of cis isoprene units in the j is generally 12.
to 18, and j=x 4 , l 5 and 1
It was revealed that the homologs of 6038 were the main components (g, w.

Keenan et al., Biochemica
Journal, 165, 505 (1977)
Reference] 0 dolicholes Not only the liver of pigs but also suckling lol
It is known that it is widely distributed within objects and plays an extremely important function in sustaining the life of living organisms. For example, J. B. Hardford et al. used the white medulla of calves and pigs in vitro.

Tests revealed that exogenous dolichol promotes the incorporation of sugar components such as mannose into lipids, and as a result, has the effect of increasing the formation of glycoproteins, which are important for sustaining the life of living organisms. (Biochemical
and Biophysical Research
Communication, 76, 1036
(1977)].

The effect of dolichols on promoting the incorporation of sugar components into lipids is remarkable both in growing organisms and in already mature animals, so the role of dolichols in preventing aging is attracting attention. . Also, R, W, K
Eenan et al. state that it is important for living organisms that continue to grow rapidly, such as during childhood, to ingest dolichol from outside and supplement the dolichol obtained by biosynthesis within the body [Archives of Bioc]
hemistry and biophysics.

Furthermore, Akamatsu et al. quantified dolichol phosphate ester in the regenerated livers of rats, and found that the levels of dolichol phosphate in the offspring, which were normal, decreased significantly, indicating that the amount of dolichol phosphate in the liver tissue was significantly reduced. We found that the glycoprotein synthesis function was significantly reduced4- and that adding dolichol phosphate from the outside improved axillary function [54th Annual Meeting of the Japanese Biochemical Society (1981>VC Announcement]

As mentioned above, dolichols are substances that control extremely important functions for living organisms, and are useful as pharmaceuticals or their intermediates. Yatsuto 0.6
Dolicall of f is obtained, Ic is too fz I [F, W
, Burgoa at al., Biochemi
calJournal, 88. 470 (1963)
reference]. Total synthesis of dolichols is extremely difficult using current organic synthesis techniques, as is clear from their complex and unique molecular structures. It would be advantageous if dolichols could be obtained by relying on natural products as synthetic intermediates and simply adding gold to them through simple synthetic chemical treatment, but such convenient substances have not been found so far. Conventionally, polyprenols (these are called betumbrenols) represented by the following general formula (B) 5- [however, k-4 to 6] have been used. However, it is difficult to synthesize dolichols, which mainly contain 14.15 and 16 cis-isoprene units, using current organic synthesis technology. It's impossible.K again.

Hannus et al.
A polyprenyl component was isolated at a yield of 1% based on the amount of dry N from the leaves of Japan (Japan), and this component contained 10 to 19 isoprene units.
It has been reported that it is a polyprenylacetate mixture having a cis configuration with Phytoche as king.
mistry, s 3, 2563 (1974)
], their report states that the polyprenylacetate f-)+4
'l)) The details of the lance and cis configurations have not been elucidated. Furthermore, s D, F, Zsnck
el et al. strobe pine (Pinus 5trobus)
reported the presence of Coo's polyprenols with 18 isoprene units or an average value of 18 isoprene units in leaf extracts of Phytoch.
emistry, 11.

6-3387 (1972)], this report does not provide a detailed analysis of the trans and cis configurations of the polyprenol.

In the present invention, some of the authors and their co-researchers first hydrolyzed the extracts extracted from ginkgo biloba and Himalayan cedar using organic solvents, as necessary, and then applied various methods such as chromatography, fractional dissolution, and other methods. 14-22 isopre-7 units can be converted into 114
A polyprenyl fraction consisting of a polyprenol and/or a mixture of its acetate homologs having exactly the same trans and cis configuration as mammalian dolichols is obtained, and the polyprenyl fraction has an α
- exhibiting a distribution of polyprenyl congeners very similar to that in the mammalian dolichols, only in the absence of terminal saturated isobray units, of which the polyprenyl fraction is optionally a constituent; It can be relatively easily separated into individual (uniform isoprene number) polyprenyl congeners, and therefore the polyprenyl fraction and each polyprenyl congener separated therefrom are all mammalian dolichols. It was found that it is very suitable as a synthetic intermediate.

In order to efficiently produce peephole dolichols using the above-mentioned polyprenyl compounds, the Ministry of the Invention and others conducted intensive studies on a method of introducing a saturated inprene unit into the α-terminus of the polyprenyl chain of the polyprenyl compound. The present invention was completed by creating a polyprenyl nitrile represented by the general formula (1) that is useful as an intermediate in such a method.

The polyprenyl nitrile of the present invention represented by general formula (1) [hereinafter referred to as polyprenyl nitrile (1)]. ] is a polyprenyl halide [hereinafter referred to as polyprenyl halide (If)] represented by the general formula (in the formula, X represents a halogen atom, and n is the same as in the previous Hpi foot table). ) can be produced by reacting with cyan methyl steel 8-.

As mentioned above, polyprenyl halide (II) is a polyprenol represented by the general formula (wherein n is as defined above) that can be obtained from extracts of ginkgo biloba or Himalayan cedar through @ contact or hydrolysis. or a mixture thereof with a halogenating agent such as FCIs, phosphorus trihalide b 80 (1'2.5OBr2) such as PBr3
It can be easily obtained by halogenation with thionyl halide, etc. This halogenation reaction is usually
For example, the polyprenol is dissolved in a suitable solvent such as hexane or diethyl ether, and a halogenating agent is added to the solution at a temperature of about -20°C to +50°C in the presence or absence of a base such as triethylamine or pyridine. This is done by adding .

The reaction between polyprenyl halide (U) and cyan methyl steel is preferably carried out in a solvent. Preferably, the solvent used is an ether solvent such as diethyl ether, tetrahydrofuran, or 1,2-dimethoxyethane. 2-10 against
0 times (1 sub), preferably 5 to 50 times (vehicle volume).

It is preferable to use a sufficiently dried solvent to allow the intended reaction to proceed smoothly.

Cyan methyl steel is usually heated in the above solvent under an inert gas atmosphere such as nitrogen or argon at -100°C to -5°C.
Cyanomethyllithium to be cleaved by adding an alkyllithium such as n-butyllithium or methyllithium to acetonitrile while cooling to 0°C, preferably -78°C, can be heated to 0°C to -2°C. . The stool amount of cyan methyl steel is generally 0.5 to 10.0 mol, preferably 1.0 to 5.0 mol, per 1 mol of polyprenyl halide (■), with the use lid of 1 ha alkyl lithium. v@ clause 10- can be done. At this time, acetonitrile is alkyl lithium 1
It is generally preferable to use 1 to 2 moles. Polyprenyl halide (11) is added to the solution of the cyanomethyl steel subjected to MW in this manner and reacted. Depending on the reaction conditions used, the reaction may be able to proceed smoothly by adding polyprenyl-ride (It) in small portions or in a dropwise manner rather than adding the entire amount at once. Although the temperature during the addition of polyprenyl halide (II) and thereafter until the reaction is completed is not critical, it is preferably within the range of 0°C to θ°C. If the reaction temperature is too low, the reaction progresses slowly and it takes too much time to complete the reaction. On the other hand, if the reaction temperature is too high, it will be necessary to continue stirring the reaction mixture at the above reaction temperature in order to complete the reaction after adding the undesirable secondary polyprenyl halide (If), and the time required for this will be Although it varies depending on the reaction temperature, it is usually about 30 minutes to 2 o'clock. In order to confirm the progress of the reaction, it is convenient and preferable to monitor the amount of raw material polydalenyl halide (II) by thin layer chromatography.

After the reaction, polyprenylnitrile (1) from the reaction mixture
Isolation of σ can be easily achieved by applying separation and purification techniques known per se. Chromatography is particularly conveniently used. Adsorbents that can be used in this chromatography include silica gel, alumina, activated carbon, and cellulose.

Among them, silica gel is particularly suitable for OMrA.
M medium,! : Hexane, Benkun, petroleum ether,
It is preferable to use a mixture of a small amount of a polar solvent such as diethyl ether, chloroform, ethyl acetate, or ethyl alcohol in a carbonized water/wood bath medium such as benzene.

Polyprenyl nitrile synthesized by the above method (
From 1), mammalian dolichols can be synthesized, for example, by the synthetic route shown below.

(1) (mV) (■) (■) However, in the above formula, the radical represents a group represented by the formula (in the formula, n is as defined above).

Reaction (2) is the reduction of polyprenylnitrile (1), usually by adding diisobutylaluminum hydride and reacting in the coexistence of a base such as raldehyde (IV), Winchch toxoxide, or potassium t-butoxide. It is. For reaction ■, after adding methyllithium, e
This is done by treatment with a weak acid such as rf:y. The obtained oxazoline (Vl) is usually used in the hydrolysis reaction (2) without isolation. This hydrolysis reaction is carried out by heating using a mineral acid such as hydrochloric acid or sulfuric acid. By reducing the polyprenylcarboxylic acid (■) thus obtained using, for example, lithium aluminum hydride, p alcohol (4) is produced.
That is, mammalian dolichol can be synthesized.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples. In addition, IR analysis in Examples and Reference Example 14 was performed using a liquid film, and NMkt analysis was performed using TMS as an internal standard. FD-MASS analysis value is “H”
, 12C, "N, 160, 79Br.

Diameter example 1 Separation of polyprenol Ichok leaves 1'J1 (undried 1'J1) collected in Kurashiki City at the end of October were dried with hot air at about 40℃ for 24 hours and then kept in room m (about 15℃) for 1 week. It was extracted by immersion in chloroform SOt. The insoluble components were separated by adding 5 tons of petroleum ether to the concentrate obtained by distilling off chloroform from this extract, and after concentrating the liquid f, it was separated by silica gel column using chloroform as a developing agent. 372 corrugations were obtained.

Approximately 400 d of acetone is added to this wavy material to dissolve the acetone-soluble components, the resulting mixture is treated with e-polymer, the P solution is S-condensed, and the wavy material obtained is mixed with 400 d of methanol, 40 d of water, and 20 ml of sodium hydroxide. After heating at 65°C for 2 hours, methanol was distilled off, and the residue was extracted with diethyl ether (500 d).
It was washed with JEl water for 5 months, dried with anhydrous sodium chloride, and the bath agent was distilled off to obtain a wavy material of 24.2 f.

Next, this corrugated material was treated with n-hexane/isopropyl ether = 90/10 (volume ratio) using silica gel of about 1 hour.
The mixture was separated to obtain a 21.8F corrugated material. This corrugated material is a polyprenol having a pure lacrimal content of 95 or more, and this material is a semi-preparative high performance liquid chromatography column manufactured by Merck & Co., Ltd. LiChrosorb RP18-10 (C1
acetone/methanol = 90710 (
High performance liquid chromatography analysis was performed using a mixed solvent (volume ratio) as the eluent and a differential refractometer as the detector.
The results of determining the area ratio of each peak in the obtained chromatogram were as follows.

Beak number Number of cis isoprene units (n) q
Product ratio (%) 1 11
0.32
12 1.13
13 5.94
14
25.65 15
39.46
16 19.27
17 5.98
18 1.8
9 19
0.8 Using this high-performance liquid chromatography, each component was fractionated from the above-mentioned wave-like substance, and mass spectrometry, infrared absorption spectrum, 'f(-NMR spectrum and 18 cmN
It was confirmed by MR spectrum that these components were polyprenol having a structure represented by general formula (II).

Field ionization mass spectrometry (FD-MASS) for each component
) results and IH-NMR δ values are shown in Table 1.
-NMR δ values are summarized in Table 2.

171 Reference Example 2 Synthesis of Polyprenyl Bromide Polybrenol 12.4r of general formula (Ill), which is n-15, and pyridine 11 were mixed at 200 MI! of Q-hexane, and the resulting solution was heated at room temperature (about 20°C) under a nitrogen gas atmosphere for 2 hours.
．． Of phosphorus tricarbide was added dropwise, and after the addition was completed, the mixture was stirred overnight at room temperature under a nitrogen gas atmosphere. Next, put the n-hexane solution into a separating funnel, wash it three times with about 50*l of water, dry it with anhydrous magnesium sulfate, and add n-hexane 7k.
By distilling off, a slightly yellow liquid substance12. I got of.

When NMR analysis was performed on this product, a signal (
d, δ = 4.08) disappears and becomes -CHzBrlC
An assigned signal (d, δ=3.91) appeared.

When this liquid material was analyzed by FD-MASS, it was found that m/e=t304. Based on these analysis results,
The above product has general formula (II) where n=15 and X=
It was confirmed that it was polyprenyl bromide, which is 13r.

Polyprenyl bromides with n other than 15 and polyprenyl bromide mixtures with n arbitrarily distributed between 11 and 19 were also synthesized by similar operations.

Example 1 Acetonitrile 1.29F and anhydrous tetrahydrofuran 50% under nitrogen gas atmosphere in a 20011L three-neck flask
*Pour rl, cool to -78℃ and stir.
Butyl lithium (1,6M hexane solution) 15.211
II! After stirring was continued for 030 minutes, 6.02 f of cupric iodide was added at once to warm the mixture to -25°C, and the mixture was stirred for 15 minutes. In the thus prepared solution of cyanomethyl steel, in the general formula (n), n=15, X=
Polyprenyl bromide with Br 12. Anhydrous tetrahydrofuran solution (30*/) of (1') was added dropwise. After stirring as it was for 1 hour, saturated ammonium chloride aqueous solution was added and stirred at room temperature for 30 minutes. After filtering through Celite-lined Nutsutsue, the liquids were separated. The water increase is 2 with diethyl ether.
Extracted twice. *mJ- were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off using a rotary evaporator to obtain a yellow liquid. This product was subjected to silica gel chromatography [hexane/ethyl acetate = 98/2 (volume ratio)]
was used as a developing solution] to obtain a 10.5F colorless liquid. This product was confirmed to be polyprenyl nitrile, which is n-15 in general formula (I), according to the following analysis results.

IR analysis +2250.1660,1440,1375,
830 cIn”pm 1H-NMR analysis: δ 1.53 (S, 9H), 1
．． 62 (S, 48H).

Cα4 1.7-2.5 (m, 72l-1), 5.05
(br, 18H) FD-MASS analysis: m/e=
1265 Examples 2 to 9 By the same operation as in Example 1, general formula (II) -C
X, -BY where n is 11.12, 13, 14, 16, 17
．． A pair was synthesized from each polyprenyl bromide, 18 and 19. Their yield is n in general formula (1)
It was almost the same as that when polyprenyl nitrile of -15 was synthesized. Moreover, the characteristic absorption of their infrared absorption spectrum and the characteristic signal of their IH-NMR spectrum substantially coincided with those of the polyprenyl nitrile in which n in the general formula (1) is 15 at that position.

Further, the results of FD-MASS analysis were as follows.

2 11 9933
12 10614 13
11295 14
11976 16 1333
7 17 14018
18 14699 19
1537 Patent Applicant RiRa Shi Co., Ltd. Agent Patent Attorney Ken Honda 23-

Claims (1)

[Claims] Represents a general formula position, -CHx-a=A-cout- represents a cis-type unit, and n represents an integer from 11 to 19. )
Polyprenyl nitrile represented by