JPS5959651A - Optically active n-substituted phenylalaninol - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is isopropyl, cyclopentyl, cycloheptyl, etc.) and its salt. EXAMPLE:N-Isopropyl-L-phenylalaninol. USE:An amine-type optical resolving agent. It can be prepared from an easily available raw material by simple reaction. It exhibits excellent resolving effect, and can be recovered easily and in high efficiency from the reaction liquid after the completion of the resolution operation. PROCESS:The compound of formula I can be prepared either by reacting L- or D-phenylalaninol with the compound of formula II (R1 is methyl, etc.) or formula III (R2 is 4-fluorophenyl, etc.) in a solvent such as methanol in the presence of a reducing agent such as sodium borohydride, or by reducing the raw material catalytically using a platinum catalyst, etc. The reaction temperature is usually 0-50 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel optically active N-substituted phenylalaninol useful as an amino-based optical resolution agent. More specifically, the general formula (I) (wherein R is an isobutyl group,
■-Ethylpropyl group, cyclopentyl group, Schiff [1 hexyl group, Schiff J heptyl group, 4-fluoro[benzyl group, 4-chlorobearazyl group, 4-bromobenzyl group, 4
~Methylbenzyl group.

4-meth; tosibenzyl group, 3,4-dimethoxybenzylnoiu, 3,4-methylenedioxybenzyl J1 (,
Optical activity (1, - or l) -> N = substituted phenylalaninol and its salts IV, I.

The compound represented by formula (I) is, for example, f, - or 1)-
F, 1-nylalaninol and -.Q'J Formula (II)
or (III) (R1) 2C=0 (formerly R2-C110(,III) (wherein, 1 is methylno, I, or
0 taste, or R1 and the other R1 become ・sll to form j trametylef group, pentamer/−1/7], (or ＼ki suzimedielene group, and 1 and 2 become 4-sol-o). I'')]-Nirno, (,4-Chlo'1)yNilno, 1
．． ．． 4-B'Imoff,'-Nyl left, 4-Methyl, 1-diphenyl, 3,4-Metho, 1-Diphenyl, 3,4-Metho, 53. By reductively reacting with the compound that is used as J゛niruno^, α-livbutino, (or β-lynchyl prefecture, (',:L))
-I can see what I can do.

This reaction is generally carried out in a suitable solvent, and is carried out by adding a reducing agent to a solution containing phenylalaninol and the compound of formula (11) or formula (III), or by increasing the contact speed. It will be done. Specific examples of the solvent include methanol, 1. Evening/-ru.

Al:1-ls such as isopropyl al:1-l, ethers such as Tetschich F-furan, diote phosphorus, acetonitrile, dimethyl, 1. A suitable solvent is selected depending on the reducing agent or reducing means used. Specific examples of the 2 reducing agent include borohydride triuno 1. Sodium borohydride, hydrogenated bis(2-methoxyethoxy)aluminum Uno 1
Examples include sodium, diborane, aluminum hydride, and the like. Catalysts for catalytic reduction include, for example, platinum and Raneynitrile, and are suitable for use under r;: tr or pressure. Reaction 11! Ha is 0 to 50°C. Note that this reaction may be carried out with a fine 17
11 may be present in the presence of glacial acetic acid of j.

The compound of formula (1) is separated and purified by conventional methods. The compound of formula (I) thus obtained is '+l'+'
Various inorganic acids (e.g. hydrochloric acid) according to the law.

Simple water: acid, sulfuric acid, phosphoric acid) or 41 organic acid (example: acid, sulfuric acid, phosphoric acid)
By treatment with acid, maleic acid, fumaric acid),
It can lead to acid addition.

Base 1:1 Compound 2- or D-F,1-nylalaninol is, for example, C11 (!II1. I'harI1.
l1u11. I:l, 9! +5 It can be produced from L- or l)-phenylalanine Nisdel by the method described in (19[;5).

The compound of formula (1) can be easily obtained from the raw material f[compound j11. It is extremely effective as an amine-based optical resolving agent because it exhibits an excellent resolving effect and can be recovered in a good yield from reaction 11k after the resolving operation line R. It is for 1.

For example, as shown in Examples below, by using the compound of formula (1) l) L-3-acetyldyl J-2-
Medilp 1) -3-acedyldio2-medilp 11-pionic acid can be obtained in a good yield. The acid of the l) body obtained here is combined with 1 U of antihypertensive agent and I-(+)-3 for (7)
-Merno J Boudo 2-Methylzo II Pyrinyl) -1,
-PIII phosphorus (-・Ship name Tsunobutozolyl) or I-(+)-3-acetylthio-2-medylprr1 pionyl) = L-zo [I-Lilu I.

-Phenylalanine (e.g. JP-A If/l 55-41
Reference No. 058 (1f<f) is the own vehicle as a raw material compound. As an optical resolving agent for obtaining this 0-body acid, a compound of formula (1) with 17 bodies is preferable. I-'
I has an isopropyl group, 4-methylbe/zirno, (
.

Compounds in which R is a 4-methoxybenzyl group or a 3,4-methylenedioxybenzyl group are preferred, and compounds in which R is an inpropyl group are also preferred. In addition, the compound of formula (1) and its salts can be used as auxiliary agents for asymmetric synthesis or as medical crystals.

It is also useful as an intermediate for the synthesis of agricultural leaves, etc.

The present invention will be further explained in detail with reference to Examples below, but the present invention is not limited to these Examples.

Note that the optical rotation is measured at 24 to 2 unless otherwise specified.
A column f'l of C=10 was carried out in 6°C 1 ethanol.

The compound's homogenization (h value, mass spectrum,
The measurement was carried out using IR spectroscopy and NMR spectroscopy.

The solvent in the cup 71 after the melting point represents the C crystal solvent.

Example I N-Isopro[! Manufacture of Piru L-phenylafinol
a) Dissolve 9.07 Jr of L-phenylalaninol in 10 ml of -1-tanol, add 7 ml of acetone and 1'i of water.
First add 0.3 ml of 1-acid and reflux for 45 minutes. The reaction i1i was cooled with water, and 2.5 g of 2 Litriuno was added little by little with stirring (1. hydrogenated, 1. . . .). After the addition, the mixture was heated to room 11.1 for 10 minutes.
7-Knol was distilled to 1: + 11; l, after adding hydrochloric acid to make M↑'1, make it alnolytic with aqueous sodium hydroxide solution to 1: + 11; After drying the rut layer over anhydrous sodium sulfate, the solvent 6 was distilled off, the remaining th was dissolved in coatanol, and 5.5 ml of (5%) tanolic hydrochloric acid was added.

+Ii': lJ The crystal is lJ・ζIrz Ll,
1. From the tanol, 111 products were recovered to obtain 11.7 g of 11 products in hydrochloric acid. Melting point 208-210"C(a)D
= 3.3° (c=1.0.methanol)bH,-
phenylalanyl/-31, I Sr):
/2: 1 ml, 120 ml of ethanol is added and dissolved, then 0.1 g of platinum oxide is added and catalytic reduction is carried out under normal pressure. Theory] 11. After absorbing the hydrogen gas, the catalyst is filtered off. Reduce σ・a liquid and make it dark blue] 1 item 40
I got g. Melting point 65~G (i ”C(α)1.)=
-5,4゜Example 2 (1), - or I) Using a getone derivative corresponding to -phenylalaninol, Example 1. The reaction and treatment were carried out in the same manner as in b), and if necessary, the following compound was obtained by adding 1/1 of acidic acid to 4i.

N-(1-1-Chilb 1 Bill)-L-F: I, Nil Asini/-Le Fist! 1-Urate Melting point 12f;~1;(0°
C(isopropylal; 2-l) [α)l, = −11
,0"N-Schiff 111 Pendel-Shiichi Soko, Niluanoninol'I'lltleaノ+': : m point 49-5
2°C (Hekilyne) [α) D = -8,7° Hydrochloride: Melting point 211~2+3''C (-'+-tanol) [α) D = -〇?, 3°N- Schiff II Hebjiru L-Noninol Free Salt No+, Melting Point 77-80°C (Rig 11in)
[α]D=-15,8゜Gyric acid salt゛Melting point 157-I60°C (isopropyl)' alcohol) [α]Cony-≦1.4'1) N-Isop[1-Pyl-I)-Phenylalani Nord hydrochloride Melting point 200-205°C Examples? 3. Preparation of N-Schiffjl/\-Tosyl-L-no,1-nyl)'laninol 1 Using -phenylalaninol and Schiff[I-tozano/, Example 1. The reaction and treatment were carried out in the same manner as in a) to obtain the hydrochloride of product 1-1. Points 211 to 21 on i and jl:
Example 4 Preparation of N-(4-methylbenzyl)-I, -ph, 1. Nylalaninol ■, -phenylalaninol c1.oil, 1, tanol 401 M PI' Add l'L, 4-methylbenzaldehyde 5: l5; and stir at room temperature for 30 minutes (1°). Next, hydrogenate using a water cooler while stirring;
1-Add 2.0 g of sodium uron little by little. After the addition is complete, the mixture is stirred at room temperature for 1.5 hours. After distilling the ethanol and adding dilute hydrochloric acid to the remaining th to make it acidic,
Make it alkaline with an aqueous solution of hydroxide ['
Extract with l'lform. ri'+mouth, 1, Runo・
After drying the layer with anhydrous sodium sulfate, the solvent was removed and
The residue was recrystallized from ethanol to obtain 8.9 g of compound II. Melting point 125-127°C [α]. ”” (i, 7
゜Example 5 ■, Using -phenylalanyl/- and the corresponding Al i' human derivative, react and treat it in the same manner as in Example 4 (■:, and if necessary add acid 1 and J≦A. Ushinari was Uota.

In addition, i1f! The solvent for the l+' product was ethanol in all cases except for compound No. 1 and No. 11.

N-(4-fur-11-1benzyl)-1,-fuco,nyl)'laninol hydrochloride Melting point 15: (~155°C (
isozo l-1 pyl alcohol) [α) 1+= −1≦1
．． "N-(4-p[Imobenzyl)-1,-f:[-nilf'sinyl/-l] Melting point 121-12:1℃ [α)l
-1= -,5,7" N-(4-methoxybenzyl)-■,-fi-di-alani/-ru Melting point 89 to old °C [α)1) = G, 4°N-(d3, 4-dimethoxybenzyl) -■, -so' Nylalaninol hydrochloride 1, Germany 184-187°C [α) p = -
20,+H.

x-<r3.4-nojirenshi 1st dibenzyl)-■,
-So2τ-Nilalaninol melt! ,'(127~+20''C(α)1)=
li, li”N-(α-li”Fujilmedil)-
I, -7, [, Nylalaninol Melting point 86-88.
5°C [α) D= -17,4°N -, (β-ri'butylmethyl) -1,,-phenylalanil 7-ol Melting point 100-103°C [α),]
=,, -13,8゜Example 6 N-Isozininobi-L-FJ-Nylacinyl/-L60
Dissolve 0g in vinegar r@:rchill 411 and add this to old.

-3-acetylthi-t-2-methylp-11-pinoic acid 1
20sr dissolved in 2.91 ml of ethyl acetate was added to ])-]3-acedel-f-o-2-methylzo-1picaric acid N-isoprop1! Inoculate 100 mg of Biru-I,-F:I-nylalaninol salt and store in the refrigerator overnight. Ccr], = -28,
1" crude salt 484+r was obtained. This was acid-resistant, ] Del 3
．． Recrystallize from 32 [α]D--1)-3- of Moon 5°
Acetylthi A-2-methylpyric acid N-isobu "1 pyru-■, -71 nylacininol salt 42 (ig) was obtained. Melting point 10: (~104°)
Dissolve 2(i)H in water 4201, 10% sulfuric acid 1.1!
was added, and extracted with acetic acid.The extract 11k was dried over anhydrous sulfuric acid and distilled off to remove 71 del of acetic acid. ] - and 3-acetylthio-2-methylbu++pinic acid 1! +01r was obtained.

Example 7 N-(di), 4-methylenedi”! Toshibenzyl)-■7
-Phenylalanyl 7-2.1) r and I) L -3-
After heating and dissolving 1.4 g of acetylthio-2-methoxylic acid in 1 chloride of acetic acid, the solution was slowly cooled to room fA, and further left in a refrigerator for 1 hour.

The precipitated crystals were collected by filtration and [α)1] = −1(i,
2° crude salt 2.5H was obtained. This was recrystallized twice from 1 times the amount of ethyl acetate to obtain [α]D-2(1 of i, o'=3-)'cetylthio-2-methylb[1binic acid/N- (3,4-methylene dioxy/pencil) -■.

-Phenylalaninol salt 1, 11r was obtained.

Melting point 98-10 pC Example 8 N-(4-metho-1-dibenzyl)-■, ~fuconylacininol 2. olr and l) 1. -3-A1=-) 1.4jr of Lunao 2-methylbutionic acid was dissolved in acid-resistant Cordyl 251 by heating, then slowly cooled to 5°Cyl, and left at the same temperature for several hours. The crystals were subjected to σ211y to obtain 1.8 g of crude salt. This was recrystallized from 1.tyl acetate 131 to give [α]I)"' -27
, 1) -3-aceidildio 2-medilp 1 pinic acid N-(4-methoxybenzyl)-1,-phenylalaninol salt 1. (Obtained Dr. Melting point 8r:) ~ 87
°C Example N-(4-Methylbenzyl)-■, -f;rnylacininol I, fj jr and l) 1. -a-a・1!
Dilute 1.4 g of tilthio-2-methylpionic acid with acetic acid
After heating and dissolving in Chill 251, the mixture was slowly cooled to 5°C and left at the same temperature for several hours. JR+Ht, Tamu 1'l
1.9 l'l was taken to obtain 2.1 g of crude salt. Add this to 1. Recrystallized from Dell 151 [α”I) = −25
,:l''1)=3-acetylthi-t-2-methylzo[Ipionic acid-di'J-(4-methylenebenzyl)-1
, -1.7 g of phenylalaninol salt was obtained. melting point 10
7-11 PiC Example 1O N-isozojJ Piru L-phenylalanyl 7-ol 1.9
g and l) I, 2.2 g of -3-acetylthi'A-2-medilp++bio/acid was dissolved in 20++1 acetone by heating, and then slowly cooled to 5°C and left at the same temperature for several hours. Filter out the precipitated crystals [α].

= -211,1]) -3-acediylthyl A 2-methylzolopionic acid/N-isobutylpyru-L-phenylalanyl salt 1, C1gwo1'-11r:.

Melting point 10! 〜102°C Example 11
-R 1.9g and 1)■, -33-A-
Hib Lub “: 4-5 C - Methylp l+
After heating and dissolving 2.7 g of Bi-A-noic acid in 22 ml of niger acetate, the solution was slowly cooled to 5°C and left at 11°C for several hours. Collect the precipitated crystals [α]+3”+
27.8'''!, -3-A・1! Chill f・;t −2
-Megroup "1 Pionic Acid N-Isopropyl-1)-
1.4 g of phenylalaninol salt was obtained.

Melting point: 101-102°C The mother liquor was washed with 3% sulfuric acid and then with water, dried over anhydrous (C acid chloride), concentrated to a yield h1, and 2.1 g of N-isopropyl-L-phenylacinyl/- In addition, leave it in the refrigerator for a while.Filter out the precipitated crystals [α],
= -30,1'''1) -3-Aceti Lunao 2
-Methylzo1pionlm-N-isobutyl°1pyruL-
2.2 g of phenylacininol salt was obtained.

Example 12 1) I, -3-acetylthio-2-methylzo-l-picalic acid and about 0.6 times molar fil of N-substituted-L-so,].

Example 8. ! ] The following 1- was obtained by the same reaction and treatment.

1,) -3-Acedylg-o-2-methylzolopionic acid N (4-fur-1-benzyl)-L-phenylalaninol salt ((1)), = -1!1.1"1)
-3-acedelthio-2-methylzo[lpionic acid-N
-<4-bromobenzyl)-L-f;T.

Nilalaninol salt [α)1)=-H;, 1”1)
-3-acetylthio-2-, l-tylzo1.1 bionoic acid.
N-(3,,4-cymetho-1-dibenzyl)-■.

-So, '1. Nilalaninol salt (α)1) = 2
1.5"D-33-acetylthio-2-methylbu1"
1 p'/acid-N-benzyl-17-ph: I-nylalaninol 1 hll[α)1) = -21,1@1)-3-
Acetylthio-2-medilzo II pyric acid N~(α-
naphdylmethyl)-L-hue ink

Claims (1)

[Scope of Claims] General formula (wherein r is an isopropyl group;
1 Pill), (, Cyclopentyl J, I:, Shikto\; 1-Sil Jk, Schiff 11 Heptyl, Shi 4-
Nluo 11 benzilno, (,4-kuro'1 benzil J1
';, 4'-bu11 mobe/zyl group, 4-methylbenozyl j, I:,. 〕〕1-Metho 1. Dibenzyl group, 3/l-cybenzyl, (,3,4-methy1/-'di;1-tocybenzyl group, α-naphthylmethyl J, (or β-naphthylmethyl, (meaning)) Optically active N −+7/PA phenyl azonol and its salts.