JPH04270272A - Production of aminoalkylmorpholine derivative - Google Patents

Abstract

PURPOSE:To obtain the title compound as an intermediate for medicines safely and in high yield by Hoffmann reaction with a readily available and novel carbamoylmorpholine derivative. CONSTITUTION:A compound of formula I (R is alkyl, aralkyl, acyl, etc.; (n) is 1-3) is put to Hoffmann reaction and, if needed, to deprotecting reaction into the objective compound of formula II[R' is H, alkyl, aralkyl, etc.; R<1> is H or COOR<2> (R<2> is alkyl or aralkyl)]. The Hoffmann reaction can be performed in the presence of e.g. sodium hypochlorite in a solvent such as water or an alcohol (e.g. methanol, ethanol) at -30 to 200 (pref. 0-100) deg.C.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing aminoalkylmorpholine derivatives useful as synthetic intermediates for pharmaceuticals.

0002

[Prior Art] JP-A No. 2-138278 discloses that it has enhanced efficacy and broad antibacterial activity against Gram-positive bacteria in vitro and in vivo compared to conventional pyridonecarboxylic acid antibacterial agents, and that it has a broad antibacterial effect on experimental animals. 1-Cyclopropyl-6,8 exhibits superior absorption, almost no problematic side effects, and low toxicity when administered orally.
-difluoro-1,4-dihydro-7-[2-(aminomethyl)morpholino]-4-oxo-3-quinolinecarboxylic acid is disclosed, and this compound is expected to have better clinical utility. There is. 2-aminomethylmorpholine and its derivatives are useful as intermediates for their synthesis, and it is desired to establish an industrial synthesis method for this intermediate. Conventionally, as a method for synthesizing aminoalkylmorpholine derivatives, for example, 2-
(N-Methyl-N-benzylaminomethyl)-4-ethylmorpholin-5-one was reduced with lithium aluminum hydride to produce 2-(N-methyl-N-benzylaminomethyl)-4-ethylmorpholine. It is stated that you can get JP-A-62-228082 discloses 4-
By reacting benzyl-2-chloromethylmorpholine with potassium phthalimide and treating the obtained phthalimide with hydrazine etc., 2-aminomethyl-4
- A method for producing benzylmorpholine is described. In addition, JP-A No. 63-264467 describes the method using phthalimide as well as 4-benzyl-2-
Discloses a method for producing 2-aminomethyl-4-benzylmorpholine by reacting chloromethylmorpholine with sodium azide and reducing the resulting azide with sodium bis(2-methoxyethoxy)aluminum hydride. has been done. Furthermore, in European Patent Publication No. 311948, there is a general formula for active esters such as 4-benzyl-2-chloromethylmorpholine.

(In the formula, R3 and R4 represent hydrogen, lower alkyl, or benzyl, or R3 and R4 represent a group bonding to each other to form a heterocycle with the adjacent nitrogen atom.) A method for producing an aminoalkylmorpholine derivative is described, which comprises amination with a converting agent and then subjecting it to a debenzylation reaction.

0003

[Problem to be solved by the invention] The above-mentioned Japanese Patent Application Laid-open No. 53-9
No. 0275, No. 62-28082 and No. 63-26
When the method of Publication No. 4467 is used industrially, lithium aluminum hydride, which has a risk of ignition, potassium azide and sodium azide, which have a risk of explosion, or azide compounds obtained by reaction with them, etc. must be used. In addition, it is necessary to use expensive raw materials and intermediates such as potassium phthalimide. In addition, all of them also had drawbacks such as a long number of synthesis steps. Furthermore, the method using an aminating agent disclosed in European Patent Publication No. 311,948 requires conditions of high temperature and high pressure in the amination reaction, which is disadvantageous in terms of industrial economy.

0004

[Means for Solving the Problems] As a result of intensive research into industrial synthesis methods for aminoalkylmorpholine derivatives, the present inventors have found that by subjecting readily available carbamoylmorpholine derivatives to the Hoffmann reaction, high yield and The present inventors have discovered that aminoalkylmorpholine derivatives can be produced safely and have completed the present invention. That is, the present invention has the following general formula:

embedded image (wherein R represents alkyl, aralkyl, acyl, alkoxycarbonyl, aralkyloxycarbonyl, or phenyl which may have a substituent, and n represents an integer of 1 to 3) Subjecting the compound to a Hoffmann reaction,
characterized by subjecting it to a deprotection reaction if necessary,
general formula

[In the formula, R' is hydrogen, alkyl, aralkyl, acyl,
alkoxycarbonyl, aralkyloxycarbonyl or phenyl which may have a substituent, R1 represents hydrogen or -COOR2 (here, R2 represents alkyl or aralkyl), and n has the same meaning as above. An aminoalkylmorpholine compound represented by the following formula can be produced.

In this specification, alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl,
1 to 18 carbon atoms such as decyl, dodecyl, octadecyl, etc.
Aralkyl is a substituent on an aromatic ring selected from halogens such as fluorine, chlorine, bromine, and iodine, alkyls, alkoxys such as methoxy, ethoxy, and propoxy, trifluoromethyl, hydroxyl groups, nitro, and amino. Acyl refers to benzyl, phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, etc., which may have 1 to 3 carbon atoms, and acyl refers to formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, etc., which may have 1 to 3 carbon atoms.
5 acyl, alkoxycarbonyl has 1 to 1 carbon atoms
Those having four alkoxy moieties, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, etc., and aralkyloxycarbonyl include halogens such as fluorine, chlorine, bromine, and iodine, alkyl, methoxy, ethoxy, propoxy, etc. on the aromatic ring. benzyloxycarbonyl, phenylethoxycarbonyl, phenylpropoxycarbonyl, phenylbutoxycarbonyl, naphthylmethyloxycarbonyl, etc., which may have 1 to 3 substituents selected from alkoxy, trifluoromethyl, hydroxyl, nitro, and amino; show. Furthermore, examples of the substituent of phenyl which may have a substituent include halogen, alkyl, alkoxy, trifluoromethyl, hydroxyl, nitro, and amino.

In the method of the present invention, the Hofmann reaction is carried out in the presence of a reagent such as sodium hypochlorite, sodium hypobromite or a mixture of bromine and sodium hydroxide.
Appropriate solvents (including water, alcohols (methanol, ethanol, propyl alcohol, butyl alcohol, tertiary butyl alcohol, benzyl alcohol, etc.), tetrahydrofuran, dioxane, diglyme, dimethyl sulfoxide, etc. alone or in combination) can be used] at a temperature of -30 to 200°C, preferably 0 to 100°C, for 1 to 48 hours. In addition, compounds of [Chemical formula 2] in which R' is hydrogen can be obtained by hydrolyzing the compounds of [Chemical formula 2] in which R' is other than hydrogen under acidic or alkaline conditions or by catalytic reduction. You can get it.

The compound of formula 2 thus obtained can be separated and purified from the reaction mixture by methods known per se such as recrystallization and chromatography. Moreover, in the compound of [Chemical formula 2], since an asymmetric carbon exists, optical isomers based on the asymmetric carbon exist. Therefore, when the compound of [Chemical formula 2] is a racemate, tartaric acid, malic acid, N-acetyltryptophan, 10-
It can be resolved into corresponding optical isomers by using an acidic optical resolving agent such as camphorsulfonic acid, mandelic acid, dibenzoyltartaric acid, etc. Furthermore, these optical isomers can also be produced by using corresponding optically active raw material compounds, and individual optical isomers can be produced by recrystallization,
It can be purified by methods known per se, such as chromatography.

[0008] The compound of [Chemical formula 2] thus obtained can be converted into a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, methanesulfonic acid, para-toluenesulfonic acid, etc., according to a conventional method. , salts with organic acids such as lactic acid, acetic acid, maleic acid, citric acid, and tartaric acid.

[0009] The compound [Formula 1] used as a starting material for the present invention is a new substance, and for example, the compound of the general formula

[In the formula, R5 is a hydroxyl group, halogen (chlorine, bromine, iodine, fluorine), alkoxy (methoxy, ethoxy, propoxy, butoxy, etc.), or -OR6 (where R
6 represents acyl, alkoxycarbonyl or aralkyloxycarbonyl. ), and R and n have the same meanings as above. ] and its reactive derivatives (esters, acid chlorides, acid anhydrides, etc.) can be produced by reacting them with ammonia. (However, compounds in which R5 of [Chemical formula 6] is ethoxy are referred to in Synthetic Commun., No. 10
Vol. 59, 1980. ) These reactions involve adding 1 to 5 ammonia to the compound of [Chemical formula 6].
Using 0 times the mole, without solvent or in the presence of an appropriate solvent,
1 to 4 at a temperature of 0 to 200°C, preferably 0 to 100°C
It takes 8 hours. Water, alcohols, tetrahydrofuran, etc. can be used as suitable solvents. Moreover, the compound of [Chemical formula 1] has the general formula

A compound represented by (wherein each symbol has the same meaning as above) (J. Med. Chem., Vol. 33,
1406 (1990)).

0010

EXAMPLES The present invention will be specifically explained below with reference to Reference Examples and Examples, but the present invention is not limited by these in any way.

Reference Example 1 4-benzylmorpholine-2-acetic acid ethyl ester 13
．． 2g, potassium hydroxide 5g and 70% aqueous methanol 1
Leave 50 ml of the solution overnight. After neutralizing with dilute hydrochloric acid, concentrate to dryness and add ethanol. Insoluble materials were removed and concentrated to obtain 11 g of 4-benzylmorpholine-2-acetic acid. NMR (CDCl3), δ (ppm): 1.7
~2.9 (6H, m), 3.47 (2H, s), 3.
4-4.1 (3H, m), 7.26 (5H, s)

0
Reference Example 2 A solution of 10 g of 4-benzylmorpholine-2-acetic acid and 30 ml of methylene chloride was added dropwise to a mixture of 9.6 g of phosphorus pentachloride and 80 ml of methylene chloride under ice cooling. After stirring at 10° C. for 3 hours, it is concentrated under reduced pressure to obtain 4-benzylmorpholine-2-acetic acid chloride. The obtained acid chloride was added to 28% aqueous ammonia and stirred at room temperature for 1 hour. Extracted with chloroform, washed with water, dried, and concentrated under reduced pressure to obtain 4.0 g of 4-benzylmorpholine-2-acetamide.
get. Melting point 97-100℃

Reference Example 3 100 ml of ethanol was saturated with ammonia, and 5.27 g of 4-benzylmorpholine-2-acetic acid ethyl ester was added.
Add. The mixture is left in a sealed tube at room temperature for 3 days, and the solvent is concentrated to obtain 4-benzylmorpholine-2-acetamide. The melting point was consistent with that obtained in Reference Example 2.

Reference Example 4 4-benzylmorpholine-2-acetonitrile 8.65
11 ml of concentrated sulfuric acid was added to the mixture, and the mixture was stirred at 40°C for 4 hours. Pour into ice water, neutralize, extract with acetic acid ethyl ester-tetrahydrofuran mixed solvent, wash with water, dry, and concentrate under reduced pressure to obtain 4-benzylmorpholine-2-acetamide 8.
．． Obtain 0g. The melting point was consistent with that obtained in Reference Example 2.

Example 1 To a solution of 5.0 g of 4-benzylmorpholine-2-acetamide and 120 ml of ethanol, 28 ml of a 12% aqueous sodium hypochlorite solution was added under ice cooling, and the mixture was heated at the same temperature for 1 hour.
Further, the mixture was stirred at 60°C for 1.5 hours. The organic layer was poured into water, extracted with chloroform, washed with water, dried, and concentrated under reduced pressure to obtain 4-benzyl-2-ethoxycarbonylaminomethylmorpholine as an oil. NMR (CDC
l3 ), δ (ppm): 1.24 (3H, t, J=
7), 1.76 ~ 2.36 (2H, m), 2.5
~2.8 (2H, m), 2.9 ~ 3.35 (2H,
m), 3.51 (2H, s), 3.5 ~ 3.9 (
3H, m), 4.10 (2H, q, J=7), 4.
9 (1H, bs), 7.31 (5H, s)

Example 2 55.7 g of 4-benzyl-2-ethoxycarbonylaminomethylmorpholine and 300 m of isopropyl alcohol
10 g of 10% palladium-carbon and then 12 g of hydrazine monohydrate are added to the solution of 1 ml of the mixture, and the mixture is refluxed for 1.5 hours. The catalyst is removed and concentrated under reduced pressure to obtain 2-ethoxycarbonylaminomethylmorpholine. Melting point 97-98℃

[
Example 3 4-Benzylmorpholine-2-acetamide was added to water in the same manner as in Example 1 to obtain 2-aminomethyl-4-benzylmorpholine. Boiling point 150-160℃/0.5m
mHg

Example 4 4-Benzyl-2-methoxycarbonylaminomethylmorpholine was obtained from 4-benzylmorpholine-2-acetamide and methanol in the same manner as in Example 1. NMR
(CDCl3), δ (ppm): 1.75 to 2.3
5 (2H, m), 2.5 ~ 2.8 (2H, m),
2.9-3.35 (2H, m), 3.49 (2H, s
), 3.5 to 3.9 (3H, m), 3.68 (3
H, s), 5.1 (1H, bs), 7.30 (5H
,s)

Example 5 2-methoxycarbonylaminomethylmorpholine was obtained from 4-benzyl-2-methoxycarbonylaminomethylmorpholine in the same manner as in Example 2. NMR (CD
Cl3), δ (ppm): 2.2 (1H, bs),
2.4 ~ 4.0 (9H, m), 3.70 (3H,
s), 5.1 (1H, bs)

Example 6 From 4-benzylmorpholine-2-acetamide and benzyl alcohol, 4-benzyl-
2-benzyloxycarbonylaminomethylmorpholine was obtained. NMR (CDCl3), δ (ppm): 1
．． 74 ~ 2.34 (2H, m), 2.5 ~ 2.8 (
2H, m), 2.9-3.35 (2H, m), 3.
49 (2H, s), 3.5 ~ 3.9 (3H, m),
5.02 (2H, s), 5.5 (1H, bs),
7.30 (10H, s)

Example 7 4-Benzylmorpholine-2-acetamide and tertiary butanol were prepared in the same manner as in Example 1.
-(tert-butoxycarbonylaminomethyl)morpholine was obtained. NMR (CDCl3), δ (ppm):
1.48 (9H, s), 1.75-2.35 (2H,
m), 2.5 to 2.8 (2H, m), 2.9 to 3
．． 35 (2H, m), 3.49 (2H, s), 3.
5 ~ 3.9 (3H, m), 5.3 (1H, bs),
7.30 (5H, s)

[0022]

[Effects of the Invention] The compound of formula 2, which can be obtained economically by the method of the present invention, is useful as an intermediate for pharmaceuticals. For example, 2-ethoxycarbonylaminomethylmorpholine obtained in Example 2 and 1-cyclopropyl-6,7,8-
By condensing trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and further removing the ethoxycarbonyl group, 1-cyclopropyl-6,8-difluoro-1,4-dihydro -7- [2-
(aminomethyl)morpholino]-4-oxo-3-quinolinecarboxylic acid (hereinafter referred to as compound A), melting point 18
3-185°C. Compound A obtained in this way maintains antibacterial activity against Gram-negative bacteria, and has significantly stronger antibacterial activity against Gram-positive bacteria than conventional pyridonecarboxylic acid compounds, and can be administered orally to experimental animals. It exhibits extremely good absorption when administered, and as a result, it directly reflects its in vitro antibacterial activity, and shows sufficient infection-protective effects when administered orally in systemic infection experiments such as in mice. It is an extremely useful drug that does not exhibit any problematic side effects during administration.

Claims (1)

[Claims] Claim 1: General formula [Formula 1] (wherein R is alkyl, aralkyl, acyl, alkoxycarbonyl, aralkyloxycarbonyl, or phenyl which may have a substituent, and n is an integer of 1 to 3. ) is subjected to a Hoffmann reaction and, if necessary, a deprotection reaction,
General formula [Formula 2] [In the formula, R' is hydrogen, alkyl, aralkyl, acyl,
alkoxycarbonyl, aralkyloxycarbonyl or phenyl which may have a substituent, R1 represents hydrogen or -COOR2 (herein, R2 represents alkyl or aralkyl), and n has the same meaning as above. ] A method for producing an aminoalkylmorpholine derivative represented by