JPH02235872A - 2-oxazoline derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The 2-oxazoline derivative of formula I (R<1> is H or 1-10C alkyl; R<2> is 1-16C alkyl, substituted alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl when R<1> is alkyl and R<2> is 5-16C alkyl, substituted alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl when R<1> is H; R<3> is 1-10C alkyl, substituted alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl). EXAMPLE:(+)-2-Methyl-4-decyl-2-oxazoline. USE:A raw material for pharmaceuticals, agricultural chemicals, functional organic materials, etc. PREPARATION:The compound of formula I, especially the optically active compound of formula III (C* is optically active asymmetric carbon; R<1> is not R<2>) is produced in high purity at a low cost by reacting a compound of formula II (especially an optically active compound having R or S absolute configuration of C bonded with R<1>) with a peroxide.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel 2-oxazoline derivative useful as an intermediate for producing medicines, agricultural chemicals, or functional organic materials, and a method for producing the same. In particular, the present invention relates to an optically active 2-oxazoline derivative useful as an intermediate for optically active 2-aminoalkanol or α-amino acid synthesis, and a method for producing the same.

[Prior Art] Unnatural amino acids, especially optically active unnatural amino acids, are important compounds as intermediates in pharmaceutical synthesis.
In many cases, they must be synthesized by a method that uses an expensive asymmetric source (for example, Iwao Ojima, Proceedings of the 56th Spring Annual Meeting of the Chemical Society of Japan, Special Edition 2404) or manufactured using costly optical resolution. A cheap and simple synthesis method was desired.

On the other hand, 2-oxazoline compounds are extremely useful compounds as synthetic intermediates for carboxylic acids, aldehydes, ketones, lactones, amino acids, thiirane, etc., and various synthesis methods and usage methods have been investigated [JA Trump
, A. Trump), Chemical Review (Che
m, Rev, ), 71, p483 (1971) or A.I. Meyers et al., Angew.
gl. ), Dan, 270 (1976)). As one of the synthetic methods, a method has recently been disclosed in which 1-hexene is reacted with acetonitrile to produce 2-methyl-4-butyl-2-oxazoline [Nan
X, Yu) and others, Tetrahedron Letters (Tetr
ahedron Letters) Average, p1049-1
052 (1988)). However, the following general formula (1) (wherein R'' is hydrogen or an alkyl group having 1 to 10 carbon atoms, R' is an alkyl group having 1 to 16 carbon atoms when R'' is an alkyl group, a substituted alkyl group, Phenyl group, substituted phenyl group, benzyl group or substituted benzyl group, R'' is R'
is hydrogen, an alkyl group having 5 to 16 carbon atoms, a substituted alkyl group, a phenyl group, a substituted phenyl group, a benzyl group or a substituted benzyl group, R゜ is an alkyl group having 1 to 10 carbon atoms, a substituted alkyl group, phenyl Of course, the 2-oxazoline derivatives represented by the following general formula (
I') (wherein R'' is hydrogen or an alkyl group having 1 to 10 carbon atoms, R1 is an alkyl group having 1 to 16 carbon atoms, a substituted alkyl group, a phenyl group, a substituted phenyl group, a benzyl group, or a substituted benzyl group , R゜ is an alkyl group having 1 to 10 carbon atoms, a substituted alkyl group, a phenyl group, a substituted phenyl group,
Optically active 2-oxazoline derivatives represented by a benzyl group or a substituted benzyl group, Cx represents an asymmetric carbon imparted with optical activity, and R゜ and R8 are not the same) have not yet been synthesized. There is no such thing, and it is completely unknown.

[Problems to be Solved by the Invention] In view of the above-mentioned current situation, the present inventor has conducted intensive research and found that when a specific selenium compound is treated with a peroxide, a corresponding 2-oxazoline derivative is obtained, and furthermore, this We have found that when an optically active form of a specific selenium compound is used, an optically active form of the corresponding 2-oxazoline derivative can be obtained. The present invention has been made based on this knowledge, and the object of the present invention is to provide novel 2-oxazoline derivatives useful as raw materials for medicines, agricultural chemicals, functional organic materials, etc., as well as optically active forms thereof and their optically active forms. The object of the present invention is to provide a new method for producing compounds.

[Means for Solving the Problems] The present invention provides a novel 2-oxazoline derivative represented by the above general formula (I), an optically active substance represented by the above general formula (I'), and the following general formula ( II) NHCOR"R'-C-CH, -S eA r (II
) R1 (wherein R゜ is hydrogen or an alkyl group having 1 to 10 carbon atoms, R' is an alkyl group having 1 to 16 carbon atoms, a substituted alkyl group, a phenyl group, a substituted phenyl group, a benzyl group, or a substituted benzyl group , R゜ is an alkyl group having 1 to 10 carbon atoms, a substituted alkyl group, a phenyl group, a substituted phenyl group,
A selenium compound represented by a benzyl group or a substituted benzyl group, Ar represents a phenyl group or a biridyl group), especially a compound in which the absolute configuration of the carbon atom to which R' is bonded exceeds either R or S. This method consists of a method for producing a 2-oxazoline compound, which comprises reacting it with an oxide.

Substituents included in the substituted alkyl group and substituted phenyl group in the above general formulas (I), (bi), and (n) of the present invention are not particularly limited, but include hydroxy, methoxy, merkabuto, methylmerkabuto, amino , halogeno, carboxyl, carboxamide, phenyl, hydroxyphenyl,
Examples include guanyl and cyano.

The compound represented by the above general formula (1) of the present invention includes 2-methyl-4-pentyl-2-oxazoline, 2-methyl-
4-hexyl-2-oxazoline, 2-methyl-4-hebutyl-2-oxazoline, 2-methyl-4-octyl-2-oxazoline, 2-methyl-4-nonyl-2-oxazoline, 2-methyl-4-decyl-2 -oxazoline, 2-methyl-4-undecyl-2-oxazoline,
2-Methyl-4-dodecyl-2-oxazoline, 2-methyl-4-tridecyl-2-oxazoline, 2-methyl-4-tetradecyl-2-oxazoline, 2-methyl-
4-pentadecyl-2-oxazoline, 2-methyl-4
-hexadecyl-2-oxazoline, 2-ethyl-4-
Benthyl-2-oxazoline, 2-ethyl-4-hexyl-2-oxazoline, 2-ethyl-4-heptyl-2
-oxazoline, 2-ethyl-4-octyl-2-oxazoline, 2-ethyl-4-nonyl-2-oxazoline, 2-ethyl-4-decyl-2-oxazoline, 2-ethyl-4-undecyl-2-oxazoline, 2- Ethyl-4-dodecyl-2-oxazoline, 2-ethyl-4-
Tridecyl-2-oxazoline, 2-ethyl-4-tetradecyl-2-oxazoline, 2-ethyl-4-pentadecyl-2-oxazoline, 2-ethyl-4-hexadecyl-2-oxazoline, 2-propyl-4-pentyl-2-oxazoline , 2-proyl-4-hexyl-2
-oxazoline, 2-propyl-4-heptyl-2-oxazoline, 2-propyl-4-octyl-2-oxazoline, 2-propyl-4-nonyl-2-oxazoline, 2-propyl-4-decyl-2-oxazoline, 2-
Propyl-4-undecyl-2-oxazoline, 2-propyl-4-dodecyl-2-oxazoline, 2-propyl-4-tridecyl-2-oxazoline, 2-propyl-4-tetradecyl-2-oxazoline, 2-propyl-4- Pentadecyl-2-oxazoline, 2-propyl-4-hexadecyl-2-oxazoline, 2-isobrobyl-4-hexy-2-oxazoline, 2-isopropyl-4-octyl-2-oxazoline, 2-methyl-
4-Methyl-4-propyl-2-oxazoline, 2-methyl-4-methyl-4-butyl-2-oxazoline, 2
-Methyl-4-methyl-4-pentyl-2-oxazoline, 2-phenyl-4-hexyl-2-oxazoline,
Examples include 2-methyl-4-phenyl-2-oxazoline, 2-isobrobyl-4-phenyl-2-oxazoline, 2-penzyl-4-hexyl-2-oxazoline, 2-methyl-4-benzyl-2-oxazoline, etc. .

Further, as the compound represented by the general formula (I'), in addition to the above (+) or (-) compound, (+) or (-) 2-methyl-4-methyl-2-oxazoline,
2-Methyl-4-ethyl-2-oxazoline, 2-methyl-4-propyl-2-oxazoline, 2-methyl-4
-Butyl-2-oxazoline, 2-ethyl-4-methyl-2-oxazoline, 2-ethyl-4-ethyl-2-oxazoline, 2-ethyl-4-propyl-2-oxazoline, 2-ethyl-4-butyl-2 -oxazoline, 2
Examples include -propyl-4-propyl-2-oxazoline and 2-propyl-4-butyl-2-oxazoline.

Next, the physical and chemical properties of representative compounds among these will be shown.

2-phenyl-4-hesil-2-o sazoline■IR
(Thin film, cm''): 2930, 1650, 69
6■'H NMR (200MHz, δ): 0,87 (3
H, t, J=6.5Hz), 1.2-1-9 (
I O H tra ) y 4 - 0 1 (
f H − t, J = 7 − 8Hz) t
4-1 5-4. 3 5 (Summer H, m), 4.
46 (!H, del, J=9.2 and 7.8
Hz), 7.3-7.5 (3}1, m), 7.9-8.
0(2H, m) ■Elemental analysis value: C, 7B. 11. H,
9,43. N, 5.71 calculated value (C,, .H,, No
): C, 77,88; H, 9, 15; N, 6,052
- Chiru-4-phenyl-2-O IR (thin film, cm-'): 1673, 1250, 98
4, 760, 700■'HNAR (200MHz,
δ): 2.08 (3H, d, J=1.4Hz), 4.0
7 (IH, L, J-8.4Hz), 4.58 (IH, d
d, J=8.4 and 10.2Hz), 5.15(
IH, ddq, . J'IO, 2, 8.4 and 1.
4), 7.2-7.4 (5H, m) ■MS: M”, 161.0833 ((1:,
,H,,calculated value as No., 161.0840) 2-Methyl-4-hesil-2-oxazoline■IR(
Thin film, cm-'): 2930, 1680, 123
0,988■'H NMR (200M1{z, δ): 0
, 83 (3H, t, J4.5Hz), 1. 1-1.7
(10H, +++), 1.91 (3H, d, J=1.
2Hz), 3.76 (LH, t, J-7.8Hz), 3
．． 85-4. 10(IH, m), 4.24(IF{,
dd, J=9.2 and 7.8Hz) 2-Sobrovir-4-phenyl-2-osazoline ■IR (thin film, c+++-'): 2970, 166
0,700■'H NMR (200MHz, δ): 1,
268 (3H, d, J = 7.0), 1,272 (3Hy
d t J4, O Hz) + 2 - 69
(I Hyd of septe t * J
=1 ,O and 7.0)4.05(11{,t,
J=10, lHz), 4.57(IH, dd, J=10
．． 2 and 8.4Hz), 5.14 (IH, ddd
, J=IO. 0.8.4 and 1.0Hz), 7.
15-7.40 (5H, a) 10 -2- Roux 4--
Shiru 2- Sazori? ■rR (thin film, am-'): 2930, 1680
, 1228■'H NMR (200MHz, δ): 0
．． 82 (31{, t, J=6.5Hz), 1.1-1.
6(181{,it), 1.90(31{,d,J=
1.4Hz), 3.74 (IH, t, J=7.8Hz
), 3.85-4.05 (LH, m), 4.23 (IH
, dd, J=9.2, 7.8 Hz) ■MS: (M+1)” , 226.2176 (C, 48
■NO+} {Calculated value after closing, 226.2170) The compound represented by the above general formula (I) or (VI) is obtained by starting from the corresponding selenium compounds represented by the above general formula (ff). It can be synthesized as a substance. The selenium compounds in this case are, for example, trifluorinated β-hydroxyselenide obtained by ring-opening 1,2-epoxyalkane as a starting material and 2,2'-dibyridyldiselenide and sodium borohydride. It can be obtained by reacting rostane sulfonic acid with a nitrile compound in the presence of water (Akio Toshimitsu, Masaaki Ito, Proceedings of the 57th Autumn Annual Meeting of the Chemical Society of Japan, 2C101). In this case, if an optically active substance obtained by oxidizing an α-olefin with a microorganism (see Japanese Patent Publication No. 56-40) is used as the starting material 1,2-epoxyalkane, the above general formula (r1) can be obtained. The selenium compound shown has the absolute configuration of the carbon atom to which R" is bonded to either R or S. By using this selenium compound, an optically active 2-oxazoline derivative can be obtained. .

That is, the 2-oxazoline derivative represented by the above general formula (I) or (VI) can be obtained by reacting the starting material represented by the above general formula (I[) with a peroxide. As the oxide, methacroperbenzoic acid, peracetic acid, butyl hydroperoxide, hydrogen peroxide, sodium periodate, ozone, or the like can be used. Although this reaction can be carried out without a solvent, methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, etc. It is preferable to carry out the reaction in an organic solvent. In this case, the organic solvent may be used alone or in a mixture of two or more.

The reaction temperature ranges widely from -20°C to 150°C, but preferably ranges from 10°C to 40°C, and may be determined depending on the solvent and type of selenium compound used. Also,
The reaction time is appropriately determined in the range of 1 minute to 10 hours depending on the reaction temperature.

The amount of peroxide used for the selenium compound is 0.5 to 1
Although 0 equivalents are used, preferably 1 to 3 equivalents are used.

Additionally, by adding an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, or sodium carbonate, or an organic base such as triethylamine, tributylamine, diisobutylamine, or pyridine during the reaction, the reaction can be accelerated and the yield can be increased. can be improved. After carrying out the reaction as described above, regarding the reaction product,
The 2-oxazoline derivative is separated and recovered using known techniques such as phase separation, extraction, filtration, distillation, and column chromatography.

The present invention will be specifically explained below using Examples.

[Example] 1.
=+ 1 0. 2” (neat))
-(1-(2-Biridylseleno)methyl]undecylacetamide 0.767 g (2, Ommol) and 0.475 g (7.0 mmol) of 85% strength potassium hydroxide.
80% pure methachloroperbenzoic acid (0.2+umol) in 30n+1 methanol solution. 8 6 3g (4mm
ol) and 10 ml of methanol were added, and the colorless homogeneous solution was stirred for 1 hour at room temperature.

The reaction solution was added to 100 ml of saturated aqueous sodium hydrogen carbonate solution, extracted with methylene chloride, washed with saturated brine, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, column chromatography (activated alumina (activity ■); developing solution, hexane: ethyl acetate = 10:1)
(+)-2-Methyl-4-1-decyl-2-oxazoline 0.00% having the above-mentioned physicochemical properties. 3 9 7g
[1. 7 6 mmol, yield 88.1%, [α]
,=+55.9±0.1″(c O.87+, etha
nol)) was obtained.

(+)-2-Methyl-4-1-decyl-2-oxazoline 0
．． 1.25 ml of 4N hydrochloric acid aqueous solution to 2.5 ml of methanol solution of 173 g (0.76 8 mmol)
was added and stirred at reflux temperature for 2 hours. After cooling, the solvent was distilled off under reduced pressure to obtain 0.183 g of 2-amino-1-dodecanol hydrochloride.

0.1 83g of the above hydrochloride Ether solution 12.511
triethylamine 0.7 5 under nitrogen atmosphere and water cooling.
ml (5.37+ uol) and acetyl chloride 0.27 ml (3.84 m+aol) were added sequentially, and the resulting yellow-white suspension was stirred at room temperature for 3 hours. The reaction mixture was added to 40 ml of water and extracted with methylene chloride.

The organic layer was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, 2-(N,
N-diacetyl) aminododecyl acetate 0. 0
30g (0.092mmol, yield 12%),
and 2-(N-acetyl)aminododecyl acetate 0. 126 g (0.599 mmol, 78% yield) was isolated.

The physicochemical properties of 2-(N,N-diacetyl)aminododecyl acetate were as follows.

■IR(#g,cm-t:1740, 1696■'H
NMR (200M}1z, δ): 0,83 (3H, t
, J=6.5Hz), 1.1-1.3(16H, a)
, 1.55-2.0 (2H, m), 2.00 (3H,
s),2,? 2 (6H, s), 3.97 (IH, tt,
J=8.6 and 5.4Hz), 4.21 (114
, dd, J! 10.4 and 5.2Hz), 4.4
9(l}!, dd, J=10.4 and 8.6Hz
) ■Elemental analysis value: C, 66.46; H, 10.38; N
,4.63 Calculated value (C,,H,,No.):C,66.
02. H, 10, 16. N, 4, 28 ■ [α Sakura = 1'y
．． s±0.4° (c O.271, ethanol.)
The physicochemical properties of 2-(N-acetyl)aminododecyl acetate were as follows.7■IR (KBr tablets,
c+a-'): 3280, 1733, 1648■
'H NMR (200MHz, δ): 0,84 (3H,
t, J'6.5Hz), 1.1-1.6 (18H, m)
, 1.95 (3H, s), 2.04 (31{, s),
3.95-4.2 (3H, m), 5.61 (IH, d,
J=8.4Hz) ■Elemental analysis value: C, 67,07; H,
11,00:N, 4.84 calculated value (C,,H■No,
): C, 67.33; H, lo. 95;N,4,91
■tat=+1 6.0±0.2'' (c O.5
24, ethanol) 2-(N-acetyl)aminododecyl acetate 0.1 1 9g (0.3 9mm
Add 0.0% potassium carbonate to 5ml of methanol solution of ol). 2
7 6 g (2 mmo"t) was added, and the pale yellow suspension was stirred at room temperature for 15 hours. The reaction mixture was added to 50 ml of an aqueous solution of sodium hydrogen carbonate, extracted with methylene chloride, and the organic layer was washed with saturated brine. After that, it was dried over magnesium sulfate.The solvent was distilled off under reduced pressure to obtain 0.95 g (0.39 m
mol, yield 100%).

The physicochemical properties of 2-(N-acetyl)aminododecanol were as follows.

■IR (KBr tablet, cyr-'): 3295, 32
30(sh), 1652, 1560■'H NMR(2
00MHz, δ): 0, 87 (3f{,t
t J:6-5Hz) tl-E1,
6 (18Htm) - 2. 01 (3
H t s ), 2. 6 8 (IH t t
- J = 5. 6 Hz)3. 55 (d
t t IHy J-1 1 , l and 5
．． 61-1z)3. 69 (IH, ddd-, I
'll, 1, 5.6 and 3.5Hz), 3.85
-4.00 (11-1, m), 5.60 (IH, br.
d, J = 6.6Hz) The optical purity of the above 2-(N-acetyl)aminododecanol was determined by the following method6 2-(N-acetyl)aminododecanol 0.047
(0.2 mmol) and 0.122 g (lmmol) of N,N-dimethylaminopyridine in 0.5 ml of methylene chloride solution under a nitrogen atmosphere (R)-α-methoxy-α-trifluoromethyl-α-phenyl. Acetic acid (
MTPA) chloride in a 1.0 molar solution of methylene chloride.
2 ml was added and stirred at room temperature for 48 hours. After treatment by adding 0.2 N aqueous hydrochloric acid solution, column chromatography (silica gel; developing solution, hexane: ethyl acetate = 2
:1) gives 2-(N-acetyl)aminodode f3)-
At(1) MTPk Engineering7. Tel 0.0 7 8g (0,
170 mmol, yield 85%) was obtained. From the integral ratio of the acetyl group signal (1.90 Major, 1.87 Minor) of this product, d, e, 2-(N-
acetyl)aminododecanol e. e. was determined to be 82%.

11■1 1 mmol of various selenium compounds listed in Table 1 was added to N
-[1-(2-Biridylseleno)methyl]undecylacetamide, used in place of 3.6 mmol of various bases. The 2-oxazoline derivative was synthesized by the method described in Example 1, except that the reaction was carried out using 2 mmol of methacroperbenzoic acid in 20 ml of methanol, and the results shown in Table 1 were obtained.

[Effects of the Invention] The 2-oxazoline derivatives and optically active substances thereof of the present invention are novel compounds that are important as intermediates for various useful substances as described above, and according to the production method of the present invention, specific selenium By using a compound or its optically active form as a starting material and reacting it with a peroxide, it has the special effect of being able to produce highly purified 2-oxazoline derivatives or their optically active forms at low cost. play.

Claims (4)

[Claims] (1) The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 is hydrogen or an alkyl group having 1 to 10 carbon atoms, and R^2 is R^1 is an alkyl group. When a group, an alkyl group having 1 to 16 carbon atoms, a substituted alkyl group, a phenyl group, a substituted phenyl group, a benzyl group or a substituted benzyl group, R^
2 is an alkyl group having 5 to 16 carbon atoms, substituted alkyl group, phenyl group, substituted phenyl group, benzyl group or substituted benzyl group when R^1 is hydrogen; R^3 is an alkyl group having 1 to 10 carbon atoms; , a substituted alkyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group). (2) The following general formula (I') ▲Mathematical formulas, chemical formulas, tables, etc. are available▼(I') (In the formula, R^1 is hydrogen or an alkyl group having 1 to 10 carbon atoms, and R^2 is a carbon number of 1 to 16 alkyl groups, substituted alkyl groups, phenyl groups, substituted phenyl groups, benzyl groups, substituted benzyl groups, R^3 is an alkyl group having 1 to 10 carbon atoms, substituted alkyl groups, phenyl groups, substituted phenyl groups, A benzyl group or a substituted benzyl group, C^* represents an asymmetric carbon imparted with optical activity, and R^1 and R^2
An optically active 2-oxazoline derivative represented by (3) General formula (II) below ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (II) (In the formula, R^1 is hydrogen or an alkyl group having 1 to 10 carbon atoms, and R^2 is a carbon number of 1 to 16 alkyl group, substituted alkyl group, phenyl group, substituted phenyl group, benzyl group or substituted benzyl group, R^3 is an alkyl group having 1 to 10 carbon atoms, substituted alkyl group, phenyl group, substituted phenyl group, benzyl group A method for producing a 2-oxazoline derivative, which comprises reacting a selenium compound represented by a substituted benzyl group (Ar represents a phenyl group or a pyridyl group) with a peroxide. (4) In claim (3), the optical activity characterized in that the absolute configuration of the carbon atom to which R^1 of the selenium compound represented by general formula (II) is either R or S. A method for producing a 2-oxazoline derivative.