JPS6084252A - Aminimide compound containing oligooxyalkylene group and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is group shown by the formula IV; Y is 1-5C polymethylene, (substituted) phenylene, aralkylene, or (substituted) naphthylene; R<2> is methyl, or ethyl; R<3> is H, or methyl]. EXAMPLE:N-Trimethylamino-14-hydroxy-3,6,9,12-tetraoxatetradecanimide. USE:Useful as a precursor for isocyanate. The precursor is prepared mildly and easily by the use of widely used reagents without using a dangerous azide compound. PREPARATION:An alkyl ester containing an oligooxyalkylene group shown by the formula II is reacted with a trialkyl hydrazinium salt shown by the formula III in a solvent such as ethanol, etc. in the presence of a base such as potassium alcoholate, etc. at room temperature -100 deg.C, to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel amine imide compound containing an oligooxyalkylene group having a hydroxyl group at the end of the molecule, represented by the following general formula (1), and a method for producing the same.

1 HO-R1-CN-N+(R2), (1) [In the above general formula, R1 is an oligooxyethylene group or an oligooxypropylene group having a linking group -Y-, which is represented by the formula, and the linking group - Y- is a polymethylene group having 1 to 5 carbon atoms, a 7-enylene group with or without a substituent, an aralkylene group, a naphthylene group with or without a substituent, R2 is a methyl group or an ethyl group, R3 is hydrogen representing an atom or methyl group] amineimide (representing an atom or methyl group)
) compound is a zwitterionic ion with an N''-N- bond, and the charge on the imine nitrogen is dispersed and stabilized by the adjacent acyl group 10(=O)-.Amine imide compounds are It is known that cleavage of the N''-N-bond occurs to give incyanate through rearrangement, and this property has been used as an adhesive for tire cords and the like.

On the other hand, polyether polyurethane polymers have recently attracted increasing interest as medical polymer implants for artificial organs and prosthetic implants, and as new model membrane materials for living organisms. The first issue to consider as a pharmaceutical preparation is biocompatibility, which is determined by various factors such as the interaction between the surface of the preparation and plasma proteins, the ability to adsorb platelets, and the ability to deform adsorbed platelets.
- It is evaluated at 0. Various factors related to biocompatibility have been examined for various polyether polyurethane polymers, but segmented polyether polyurethane polymers that contain polyoxyethylene groups and polyoxypropylene groups as soft segments as polyether components. has been reported to be a material with low platelet adsorption ability and excellent antithrombotic properties (for example, U, S, 4, 17
3.689 (CA92:28617e), C, P, 5h
ar+na et at, Polym, J.

Dan911 (1981), E.W., Merrill eL.
al.

Trans Am, Soc, Artif, Int
Ern, Organs, 27.

482 (1982), E. W. Merrili et.
aLAAdv.

Cbe+I1.5eryl 99+ 95-107(1
982)).

In addition, as a new model membrane material related to living organisms, it is required to have an appropriate xylephilicity-hydrophobicity balance and high mechanical strength, and segmented polyoxyethylene containing polyoxyethylene groups and polyoxypropylene groups as the parent xylem is required. Various film properties have been investigated for ether polyurethane polymers (for example, Ger, Offen 2,91
8+027 (CA94:1045851+), published patent 81 37.00? (CA95:98788x), L,
E6Matheson eLaltJ, PharIIl
, 5cit Yu (1,571 (1981), W.

A, Hunke eL al, J, Phar+n, Sc
i, 70+ 1313 (1981)).

As mentioned above, segmented polyether polyurethane polymers containing polyoxyalkylene groups are attracting much attention, but most of the materials reported to date are hydrophobic and hard. The urethane bond linking group as a segment is formed from existing limited incyanates (for example, 2°4 tolylene diisocyanate, diphenylmethane-4,4'-diisocyanate). Therefore, the development of new incyanate compounds is of great scientific and medical value in the future improvement of polyether polyurethane polymers with the aim of improving biocompatibility and membrane properties.

As mentioned above, the amine imide compound containing an oligooxyalkylene group is an incyanate precursor, and the urethane compound derived from the incyanate is of a type previously unknown and has an oligooxyalkylene group, and is a medicinal product. There is interest in the properties of Tsukiji and its properties as a model film.

The present invention provides a novel and useful amine imide compound containing an oligooxyalkylene group having a hydroxyl group at the molecular terminal, which is different from conventional incyanate precursors, and a method for producing the same. The purpose is

As an isocyanate precursor having a hydroxyl group at the molecular end, GI+atge et al.
Synthesis of hydroxyethoxybenzoyl anode (N,
D., GhaLge et al., J., Poly.
m, Sci, Polym.

Cbe+a, Ed., 21.1941 (1983)), the method for producing incyanate precursors according to the present invention has the advantage that it can be carried out mildly and easily using general-purpose reagents without handling dangerous acid compounds.

The amine imide compound of the present invention is synthesized by the following two methods (a) and (b).

1 (a) HO-R'-COR'+H2NNII, .l-1,01 [However, in the above general formulas (II)-(IV), R',
l? '1. is the same as the above definition, and R4 represents a methyl group or an ethyl group. 1 The first method is to react an alkyl ester (1) containing an oligooxyalkylene group with a trialkylhydrazinium salt in the presence of a solvent and a base, as shown in the above formula (A), and is a method using McKillip. The method of et al. (W, J,
MeKillip, R, C, S lagel, c+u+
, J.

Compliant with CI+en+, 45+2619 (19(i7)).

The alkyl ester (11) containing an oligooxyalkylene group used in the present invention is synthesized by a known method. In general formulas (1) and (II), when the linking group -Y- is a methylene group, oligooxyethylene (or propylene) glyfur methoxycarbonyl methyl ethers can be synthesized by the method of the present inventors (M, 0k
abara et al., 5 synthesis, 198
1.42). When the linking group -Y- is an ethylene group, it can be obtained by reacting the corresponding oxyethylene glycol and methyl acrylate in the presence of a solvent and a base. Furthermore, when the linking group is a 7-enylene group, W i l l i aIos
On's method ends with the corresponding oligoethylene glycols being obtained by reaction with 1)-bromo(or chloro)-phenylacetic acid.

In the present invention, an iodide salt was used as the hydrazinium salt, which can be obtained quantitatively by reacting as3'l11-tumethylhydrazine or aoym-diethylhydrazine with the corresponding alkyl iodide in ether. It will be done. Lower alcohols such as ethanol, propatool and butanol can be used as the solvent, but tert-butyl alcohol is preferably used, and the corresponding alcohol, sodium or potassium flucorate, is used as the base. Post-reaction treatment is easier when potassium is used than sodium. The reaction temperature is room temperature to 100°C, preferably 50 to 60°C, and the reaction time is sufficient to be 30 minutes to several hours.

After the reaction, the mixture is carefully neutralized with hydrochloric acid, and then as much as possible of by-produced salts such as KI and KCI are removed.

However, it is difficult to completely remove the salt from the crude product, and it is necessary to purify it by column chromatography as described below.

The second method is to react an alkyl ester (11) containing an oligooxyalkylene group with hydrazine hydrate as shown in the above formula (b) to obtain a hydrazide compound (IV),
The amine imide compound is synthesized by reacting it directly with an alkyl halide such as methyl iodide in a solvent in the presence of a base such as potassium carbonate or sodium carbonate. , Kuwamura, Oil Chemistry,
↓81897 (1969)) was used as a reference. The method according to the present invention differs from the report by Kameyama, Eika et al. in that the hydrazide produced in the first step of the reaction is used as a crude product without being purified, and in the second step, a base such as potassium carbonate is added. The hydrazinium salt used is not isolated and the amine imide compound is directly obtained. The production of hydranoid was confirmed by IR.

In the second step, it is preferable to use at least three times the theoretical amount of methyl iodide. Alcohols such as methanol and ethanol are suitable as the solvent. The reaction temperature is reflux and several hours are required.

The disadvantage of the second method is that it requires two steps compared to the first method, but hydrazine hydrate is much cheaper than the above-mentioned as51111-dimethylhydrazine, etc.
Superior in manufacturing cost.

Most of the crude amine imide products obtained by the above two methods are viscous liquids, and are purified using silica gel column chromatography in a hexane-acetone-methanol system. Potassium iodide elutes when acetone is 100%,
The target amine imide compound is eluted when the developing solution of acetone-methanol is 90:10 or more polar. The purification yields from the starting ester by the two methods are approximately the same.

Next, the present invention will be specifically explained using examples.

Example 1 N-)rifthylamino-1-hydroxy-3,6,
Synthesis of 9,12-tetraoxatetradecanimide [1] (Reaction formula (a)) [11] A 300+n14 round flask equipped with a simlow condenser, a thermometer, a dropping funnel, and a magnetic rotor was prepared. erl-
Add butanol 10 (', Ill1f) and stir at 60'C for potassium 0.94g (0,024m).
ol) was added in small pieces to form Alquat. 4.04 g of trimethylhydranonium iodide (0,021,1+1
101) and further methyl 14-hydroxy-3,
6,9゜]]2-tetraoxatetrazocaate 53
Add 3g (0.02, Omol) dropwise and allow to react at 50°C for 5 hours. After cooling to room temperature, the mixture was carefully neutralized with hydrochloric acid, the salt was removed by filtration, and the solvent was distilled off. Subsequently, methylene chloride was added to the residue, insoluble matter was filtered off, and the solvent was distilled off. Acetone was further added and the same procedure was repeated to obtain 8.91 g of a pale brown substance as a residue. Absorption of carbonyl group in IR is a characteristic of amine imide compounds 1 600 cm
' was shown. 11 yield 144%. This is because the potassium iodide produced by the reaction is ``solubilized''.

The crude product was purified using silica gel column chromatography using a hexane-7cetone-methane system to remove potassium iodide and some impurities, yielding 4.10 g of a pale yellow liquid. This was confirmed to be the target compound [1] from the spectral data. Yield 67%.

n ''' 1 r 4700 1 R (neat, cnn-' ) 3340.2860,1600,1480.14'50
,1395,1350゜1305.1240,1110
,985,94ONMR (CDCl2.δ) 3.40 (s, 9H), 3.67 (m, 16+IH:I
)20 disappeared for 18 minutes), 3.90 (s, 21-
1) MS (m/e) 309 (M”+11A11111), 307 (M+1+
A+opL101(37), 100(19), 89(3
3), 88(17), 75(14).

70 (19) + 59 (100), 58 (95), 56 (
47), 45(67) Example 2 N-, trimethylamino-14-hydroxy-3,6,
Synthesis of 9,12-tetraoxateratecanimide [11 (reaction formula (b)) [11 5.63 g (0,09
methyl 14-hydroxy- at room temperature.
3,6,9,12-tetraoxatetradeca/ate 7
．． 99 g (0,030 mol) was added dropwise.

After that, the reaction was carried out at 60°C for 2 hours, and the temperature was returned to room temperature. Excess hydrazine hydrate was distilled off, and hydrazide 8 was obtained as a translucent liquid.
．． Obtained 30B (IR: c-o 1670 c
nn-'). Rough uniform rate: 104%. Next, the above crude product was dissolved in 100ml of methanol and added to three similarly equipped 300ml flasks, 13.828 g of potassium carbonate (0,10+nol) was added, and 41,46 g of methyl iodide was added. (0.3 Omol> was added dropwise at room temperature. After that, the reaction was carried out under reflux for 12 hours, and the temperature was returned to room temperature.
The salt is filtered off, excess methyl iodide and methanol are distilled off, methylene chloride is added to the residue, the salt is further precipitated and filtered off, and the methylene chloride is distilled off from the filtrate to form a translucent liquid.14.
98 g as crude product (also (IR Niji c=ol 6
00cm force. Rough clothing rate 162%. Column purification in the same manner as in Example 1 was performed to obtain 6.45 g of a pale yellow liquid. This showed the same spectrum as the previous compound [11] and was confirmed to be the target compound. Yield 70%.

(Spectral data are the same as Example 1) Example 3 N-trimethylamino-11-hydroxy-5°8.1
1-) Synthesis of remethyl-3,6,9-1-lioxaundecanimide [2] (reaction formula (a)) 2J Using the same reaction equipment as in Example 1, 15 terl-butanol (15 potassium in lol) .41B (0,036mo
1), dissolved at 60°C, and crushed at 50°C. 6.06 g (0.03
0 mol) was added, and further 7.93 g (0,0 mol) of the above trioxypropylene monomethoxycarbonyl methyl ether was added.
030+nol) was added dropwise thereto, and the mixture was reacted at 50°C for 5 hours. After cooling to room temperature, the same operation as in Example 1 was performed to obtain 13.32 g of a crude amine imide product. Rough clothing rate 145
%. Furthermore, purification was performed in the same manner by silica gel column chromatography using a hexane-7cetone-methanol system to obtain 7.39 g of purified product. It was confirmed to be compound [21] from the spectral data. Yield 8o%.

11゜1, 4920 I R (neat can-1) 3350.2970, 2900, 2600.1450.
1380.1310°1270.1110,990,9
50. ．． 860,79ONMR (CDC1,, δ) 1.05-1.27 (+a, 9H), 3.00-4.0
0 (+Il, 9H + IH-, IH disappeared by addition of D20), 3.40 (s.

9H) MS (Chin/e) 306 (M+ publication, A Chin p), 304 (M+ 11A10
p)+172(3), 117(6), 103(8)
, 101(24), 100(2).

75(2), 73(4), 59(100), 58(45
), 45(7) Example 4 N-)tumethylamino-12-hydroxy-4,7,1
0-) Synthesis of rioxadodecaneimide 131 (reaction formula (
b)) t -D uOK rv] DIf --1 b! '1io1'-110000 (CI+1.)
2 CN-N+(C11)-[31 Using the same reaction apparatus as in Example 1, 1.4.1 B(0, (
, 13, 6roof) and dissolved at 60°C.
Trimethylhydrazinium iodide G, ground at °C, 11. Gg (0,030 mol) was added, and further the above ethyl 12-hydroxy-4,7,10-)rioxadodec-7e-? , 5 og (o, o 30 import o1)
was added dropwise and reacted at 50°C for 5 hours. After cooling to room temperature, the same operation as in Example 1 was carried out to obtain 9.90 g of a crude amine imide product. Rough uniform rate 119%. Furthermore, by silica gel column chromatography, hexane-7
Purification was carried out using a seven-ton methanol system, resulting in a purified product of 5.4
2g was obtained. It was confirmed from the spectrum data that it was compound [3]. Yield 65%.

02° 1, 4685 I R (++eat, c+n-”) 3300.2890.1600.1480.1450.
1390.1335°1300.1240,1110,
990.94ONMR (CDCl2.δ) 3.40(s, 91(), 3.70(m, 141-1
+11-1; 18 minutes disappeared by addition of D20), 3.90
(st2H) MS (+n/e) 279 (M”+1.A), 277 (M”-LAml)
)+115(12), 101(25), 100(11)
, 89(35), 88(5).

75 (10), 73 (6), 59 (100), 58 (8
2), 56(31).

45(75) Example 5 N-)limethylamino p-(8-hydroxy-3,6
Synthesis of -dioxo)octyloxybenzoic acid nofamide [4] (reaction formula (b)) Capacity 1 (,1(,'l
III Hydrazine hydrate (8 (1%)
), 1.3i; ε(0,031) mol) and ethyl, (3-hydroxy-3,6-dioxo) at room temperature.
Octyloxybenzony) 2.98g (0,010m
ol) was added dropwise.

Thereafter, the reaction was carried out at 60°C for 2 hours, and the temperature was returned to room temperature. Excess hydrazine hydrate was distilled off to obtain 3.2 og of hydrazide as a flaky solid (IR Nizi c-ol 671) aIl.
l-'). Ill yield 113%. Next, into 13 Lof flasks with a capacity of 300 m equipped in the same manner, dissolve the above crude product in 100 nl of ethanol, add 4.15 g (0,030 mol) of potassium carbonate, and add 14 g of methyl iodide.
0.00 g (0.10 mol) was added dropwise at room temperature. Thereafter, the reaction was carried out under reflux for 10 hours, the temperature was returned to room temperature, the salt was filtered off, and excess methyl iodide and ethanol were distilled off from the filtrate.
The same operation as in Example 2 was carried out, and a pale yellow viscous liquid 3.
57 g was obtained as a crude product (R: νc=0160
0cn+-ri. Rough clothing rate 110%. Purified by silica gel galam chromatography, pale yellow liquid 2.28
I got g. It was confirmed from the spectrum data that it was compound [4]. Yield 70%.

+1゜1.5301 1 R (neat, Cm-') 3350.2900,1600,1590,1540*
1440,1340°1240.1120.1050
,940,840,77ONMR (CDC1,,δ) 2.36 2.78 (br, disappeared by adding IHtD20)
3.43 (s, 9H), 3.56-3.90 (m, l
0H).

4.15(t, 2H)', 6', 85(d, 2H), 7
．． 88. (d, 21-121-1)/e) 327 (M++1.Amp), 325 (M''-1, A Town)).

296(10), 267(16), 239(7), 20
7(5), 194(5).

162(7), 133(17), 89(31), 59(
50), 58(69).

45(100) Example 6 N-)limethylamino-4-(8-hydroxy-3,6
-dioxo)octyloxyphenylacetimide [5]
Reaction IIt (reaction formula (b)) [5] Same as Example 5, 1°88 g of hydrazine hydrate (80%)
(0,030 mol) and methyl 4-(8-hydroxy-
3,6-dioxo)octyloxybenzene acetylate (3.12 g (0.010 kg) was reacted to obtain hydrazide, which was then mixed with 4.15 g (0.030 kg) of potassium carbonate.
+ool) in 100 ml of ethanol under reflux with 14.00 g of methyl iodide (0,10+aol) and treated in the same manner to obtain 4.00 g of a crude product. Rough clothing rate 123%. Purified product 2.21 was purified using the same column.
I got g. It was confirmed from the spectrum data that it was compound [5]. Yield 68%.

n": L5235 IR (neatIcn+ -", )3350.29
60,2860,1600,1540,1420.13
50°1230, 1110.1070.970,850
,78ONMR(CDCI,,δ) 3.40(s, 91(+2l-1), 3.70(t
o.
．． 98 (d, 2H) MS (m/e) 341 (M”+1. AAl611) 1339 (”-1
, Atop)+195(5), 115(7), 101
(1,6), 89(35), 73(9).

59 (40), 58 (52), 45 (100).

Patent applicant: Ajinomoto Co., Inc.

Claims (3)

[Claims] (1) General formula (1) % formula % (1) [In the above general formula, R1 is an oligooxyethylene group or an oligooxypropylene group having a linking group -Y-, which is represented by the formula, and the linking group -Y - is a polymethylene group having 1 to 5 carbon atoms, a 7-enylene group with or without a substituent, an aralkylene group, a 7-tyrene group with or without a substituent, R2 is a methyl group or an ethyl group, R3 is An amine imide compound containing an oligooxyalkylene group represented by J representing a hydrogen atom or a methyl group. (2) General formula (II) II HO-R1-COR' (II) [In the above general formula, R1 is an oligooxyethylene group or an oligooxypropylene group having a linking group -Y-, which is represented by the formula, Linking group -Y- is a polymethylene group having 1 to 5 carbon atoms, a phenylene group with or without a substituent, an aralkylene group, a tyrene group with or without a substituent, R3 is a hydrogen atom or a methyl group, R4 is an alkyl ester containing an oligooxyalkylene group represented by 1 representing a methyl group or an ethyl group, and the general formula (III) 82NN+(R2), I (III) [In the above general formula, R2 represents a methyl group or an ethyl group] General formula (1) characterized in that a trialkylhydrazinium salt represented by 1 is subjected to a combustion reaction in the presence of a solvent and a base. [In the above general formula, Rl and R2 are A method for producing an amine imide compound containing an oligooxyalkylene represented by the following definition. (3) General formula (II) 1 HO-R1-COR' (II) [In the above general formula, R1 is an oligooxyethylene group or an oligooxypropylene group having a linking group -Y-, which is represented by the formula, Linking group -Y- is a polymethylene group having 1 to 5 carbon atoms, a phenylene group with or without a substituent, an aralkylene group, a tyrene group with or without a substituent, R3 is a hydrogen atom or a methyl group, R4 represents a methyl group or an ethyl group] and hydrazine hydrate. General formula (1) characterized in that a hydrazide compound containing an oligooxyalkylene group represented by the above general formula, R1 is the same as the previous definition] is reacted with an alkyl halide in the presence of a solvent and a base. (1) A method for producing an amine imide compound containing an oligooxyalkylene group represented by the general formula 1, in which R1 is the same as defined above and R2 represents a methyl group or an ethyl group.