JPH03106891A - Phosphatidylcholine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (n is 8-22; R and R1 are alkoxy or H). USE:Useful in assembling a light-responsive liposome system for medicine or agricultural chemical. The compound expressed by formula I is a compound containing a m-methoxybenzyl group which is a highly efficient light accepting group in the end of hydrophobic part and can be synthesized in good efficiency. PREPARATION:An acid chloride expressed by formula II is reacted with m- methoxybenzyl alcohol (derivative) expressed by formula III in a polar aprotic solvent and then the reaction product is subjected to after-treatment with water to afford a compound expressed by formula IV. Then the compound expressed by formula IV is condensed with phosphatidylglycerol expressed by formula V, e.g. by a method dissolving the compound expressed by formula IV, 4- dimethylaminopyridine and dicyclohexylcarbodiimide which is a condensing agent in chloroform, adding CdCl2 salt of compound expressed by formula V thereto and stirring the mixture.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of the Invention) The present invention relates to a phosphatidylcholine derivative having a photoaccepting group at the end of the hydrophobic portion, which is useful for constructing a photoresponsive ribbon-like system.

(Prior Art) As an example of introducing a photoaccepting group into phos-7-acylcholine, an example of using an O-nitrobenzyl group as a photoaccepting group is described in Chemistry Letters, page aSS, 2010. ing. However, this compound has poor photoreactivity, and the 0-nitrobenzyl group that is cleaved and released by light irradiation converts into 0-nitrobenzaldehyde, an extremely dangerous substance suspected of being carcinogenic. This fatal drawback has been pointed out, and the development of highly efficient and safe photoreceptive groups has been desired.

(Object of the Invention) Therefore, the object of the present invention is to provide m-
An object of the present invention is to provide a phos-7 atidylcholine derivative having a methoxybenzyl group at the end of the hydrophobic part.

(Collection of invention) Phos-7-acydylco of the present invention It is a compound represented by

Formula 1 The phosphorus derivative is the following formula 1 O In Formula 1, n represents an integer of r-22.

In formula 1, R and R. represents an alkoxy group or a hydrogen atom,
The alkoxy group mentioned above is particularly a lower alkoxy group (such as a methoxy group). Preferred specific examples of the present invention are listed below along with physical property values.

Compound A6 R H H H O C H s H OCH3 H OCR. H OCH3 H thing to 0c - 7 °C //'C I? '''C az'c da1C t4A 'c zt 0c 44L 'C 67 °C bu7 °C [α]25 D [α)25 D [α]25 D [α]25 D [α]25 D [α ]25 D [α]25 D [α]25 D [α]25 D [α)25 D [α)25 D Sex value +0.02 +0.02 +o. or +0.02 +0.02 +0./ 10o .otr +0./ +0./ +0.01 +0.2 (CHCt3 (CHcts (CHα3 (CHα3 (CHα3 (7.j) 0.j) O.! ) 0.2ㆫ0.7j) (7.j) Q.!》 O.!} O.!》 o.r冫O.!) Next, outline and actual method for synthesizing the compound of the present invention. An example of the method for combining the compounds of the present invention is shown below, but the method for combining the compounds of the present invention is not limited to this route.

Synthetic Route Outline The acid chloride represented by A is reacted with m-methoxybenzyl alcohol or its derivative represented by B in a polar aprotic solvent such as THF to form l ester moieties, and then the mixture is reacted with water. The treatment leads to compound C.

Next, compound C and commercially available phosphatidylglycerol Di
By condensing using a condensing agent such as dicyclohexylcarbodiimide, the target compound can be efficiently synthesized.

The compound of the present invention (formula 1) is useful as a phospholipid containing a photoreceptor group when forming photoresponsive liposomes for pharmaceuticals, agricultural chemicals, cosmetics, and the like.

The response mechanism is as shown in the equation below.

Mysterious Formula 1 The target compound, ie, 1, is irradiated with light, the hydrophobic end is cleaved, and Vc2 and 3 are obtained as a result. 2 is liposome (bilayer membrane)
The balance between hydrophilicity and hydrophobicity sufficient to maintain 't- is lost, the membrane structure is disturbed, and the inclusions are released.

As is clear from the model experiment in the solution system shown below, m-
Methoxybenzyl photoreceptor group D7g63,4,7)0
- It was confirmed that the reaction rate was more than 0 times higher than that of the nitrobenzyl type (/i68), and that it became a safe nabezyl alcohol after trench cleavage.

Reference example (disaster of substituent effect in solution system) Compound used Light source! W low pressure mercury lamp (zz4cnm) quartz cell; substrate JmM acetonitrile/phosphate buffer room temperature
pH=7゜Relative reaction efficiency of Q photoreaction " 16 R2 R3 R4 R5 R6
Decomposition (1) Raw lol! i. (n) mln X/(7
mtnX#71. OCH30CH3H
H H2. H OCHa 00{a H
H3. H α field 3 H OCH3
H4. H OCHa H H OCHa
5. H OC'Ha CI H H6.
H OCH3 H H (?/!7.
H (X,'H3 H H Hs.N
O2 H H H H7. / /4t. ! /03 37.6 t. l /7.4I Tei6. j44. / 6.6 lλ. 6 62.2 3j. 3 6. Q/0. / l7.7 3.0 / R4 R4 However, O. D. is the absorbance of 2j←nm Example l Compound 41 (n=r%R=R1=H)
) Synthesis of compound A (n=r) Decanni rR/009f thionyl chloride lOOn!
, toluene ioow and heated under reflux for /0 hour. I
After confirming that the absorption of carboxylic acid disappeared and the absorption of acid chloride was completed in R, the reaction solution was concentrated under reduced pressure.
Compound A (n=r)//ry<quantitative) was obtained.

I R (-Coα)/I00cm-" (2) Synthesis of compound C (n=r) (R=R1=H) m-methoxy7benzyl alcohol/j.If/and triethylamine/0./9 A solution of gold, compound A (n=r).2J.2g dissolved in THF so od was dissolved in THF.
Add dropwise to a solution dissolved in p200yd at room temperature! Stir for hours. 200 ml of saturated sodium bicarbonate water was added to the reaction mixture, stirred for 20 minutes, and extracted with 200 ml of ethyl acetate. Furthermore, remove the aqueous layer with ethyl acetate! After extraction with OQ1, the organic layer was collected and dried over sodium sulfate. Sodium sulfate fc! After separation, liquid a was vacuum-tlmL to obtain a brown oily substance.

? The reaction mixture was purified by silica gel column chromatography (eluent: hexane/ethyl acetate 3//(v/v)) to obtain an oily compound C (n=t)tsg<yield 4
cts>'t got.

The physical property values are shown below.

IR (neatL' (ester)/74AOcm-
"ν(carboxylic acid)/700cm-" (3) Methanol solution of condensation reaction compound D (Nippon Fine Chemicals product) 6θ-(.
27 w/v excellent) was concentrated under reduced pressure to obtain 7001 df of ethanol.
Add (ta. tjK power}'Mi17 A (Cdct2 -
J. jH20)J■Ji'eFj＊ethamol
．． It was dissolved in 2FORl and added dropwise to the ethanol solution of Compound D. After standing at 10C for 12 hours, the white precipitate was filtered off and washed twice with ethanol and twice with ether. After drying, white powder (compound D) 2 (Cdα2》3
of. 2.2. I got Oji.

Compound C(ner)tx. 2g, φ-dimethylaminopyridine x. pg, zinclohekiclcarbodiimide t.
Dissolve zy in chloroform/00ml and add C of compound D.
d Cl 2 salt da. 6 g was added and stirred at room temperature for 3 days. This reaction mixture is an? -Light/R-l, 2Q
B (eluent chloroform/methanol/water = U/!/
/) and further κ silica gel chromatography (eluent: CIICI form/methanol/water =
6! /coz7a). Concentrate the eluent under reduced pressure,
/00ml of chloroform was added and washed with water. After drying with sodium sulfate, it was concentrated under reduced pressure to obtain an oily compound A 1
1. t. 09 (yield 70%) was obtained.

The physical property values are shown below.

I R (neat); W (ester) / 7-tei Ocm
-”' H NMR (CDc7!s) δ;/
．． JQ(brs,/AH,CH2),/. 44A (m%
rH, CH2CH2CO), J. 3 7 (m,tH
%CH2CO), J. 4Z/ (br s.PH,N
(CHa)s), j. r/ (s, AH, OCRs)
, i. rr-a. uz(m, rH%CH20 and
CH2N)j. Oj(s, $8%CH2φ)%
j. /j' (m, /H, CHO), 4. III-7
．． j4A (m, tH, φ)? AB-MS; I 4
4 (M+H) Example 2 Synthesis of Compound 45 (n=/J, RggR1-H) Compound/l65i was synthesized according to the method described in Example 1 by changing the starting materials. The physical property values are described below. I R (KBr); y (K x Ter)
i7uocm-””H NMR (CDα3}δ;/.
Jr (br s, IJH%CH2), t. tz<m
, rH. CH2 CH2 Co., J. l
6 (m, !rH%CHzCO), 1. lr
(s, taH,N(CHs)s), i. to( s.
AH, OCH3), 3. r day $. $J(m1rH,C
H20 and CH2N),! ．． 07(s%4c
H%CH2φ),z. / I (m, /H, CHO)
, t. rj-7. l4L(rn.IH, φ》FAB
-M8; f'yr<M+H)" Example 3 Compound A? (nm/u, R=R1-H) Compound/l67t according to the method described in Example 1, changing the starting material -The properties were described below.

IR (KBr); y (ester)/7 4A
O cm-''H NMR (CDcJ3)δ
;/． Jr(br s, uoH, CH2), / −
4 3 (ms r H, CH2CH2CO),
Ko. 3r (m, IH, CH2CO), 3. jA(s%
51'H%N(CHs)s), J. to(S,
6H, OCH3) 7. 90-II. 4(t(m
, rH, CH20 and CH2N), 1.01
<s,! H, C}12φ》, r. / t (m% /
H, CHO), 6. 12-7. 744 (m%rH
, φ》FAB-MS; tos←(M+H
) +Example 4 Compound 41 1 (n=/f, R=H, Rl=OC
Synthesis of H3) According to the method described in Example 1, the starting materials were changed and the compound/Mll was synthesized.

Physical property value IR (KBr): y (ester)/74cOcm-''
H NMR (CDα3)δ', i. sr(br s
4AIH, CH2)/. t7 (m%fH%CH2C
H2CO), J. Jj (m, rH.CH2CO)
J. #Q(s,?H%N(CHa)a), i. r co(
S%/2H, OCH3)! ．． Ta λ-44. u7(m%t
H, CH20 and CH2N), t. /O(s
, $HFAB-MS; t t J t (M+H
)"Example 5 Compound/I68 (n=/#, R=OCHa, Rs
According to the method described in Example 1, the starting material was modified and Compound 4 8 t-merized.

starting material This is a known compound that is easily generated by NaBH4 treatment.

Physical property value IR (KBr); ν<ester)/7uOcm-
''H NMR (CDα3)δ; t. 3r(br
s, uOH CH2)/ ,44A(m, rH, CH
2c}{2co), J. l F (m% I H,
CH2CO)J. JP(S,PH%N(CH3)a)
, 3. r/<s,/JH%OCHs) s. yt-a
．． to(m, rH, CH20 and CH2N)
j. /

[Brief explanation of drawings]

Figures 1 to 3 are 1H NMR of the compounds of the present invention.
This is a chart showing the spectrum, and Figure 1 is a chart showing the spectrum of compound/1.
61, Figure 2 is Compound Hawk 5, Figure 3 is Compound/#6
7 is a 1H NMR spectrum.

Claims (1)

[Claims] A phosphatidylcholine derivative represented by the following formula 1. Formula 1 ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, n represents an integer of 8 to 22. In the formula, R and R_1 represent an alkoxy group or a hydrogen atom.