JPH03291274A - Preparation of aminoalkylmorpholine derivative - Google Patents

Abstract

PURPOSE:To safely prepare a compound useful as a synthetic intermediate for drugs in a good yield under a mild condition by reducing a morpholine derivative with a boron compound. CONSTITUTION:A compound of formula I [R is H, alkyl, aralkyl, substitutable phenyl; R<1> is nitrile, -CH2NR<2>R<3>, -CONR<2>R<3> (R<2>, R<3> are H, alkyl, aralkyl, heterocyclic ring together with N); A is O, H2; n is 0-3; but when A is H2, R<1> is not -CH2NR<2>R<3>] is reduced with a reducing agent such as a boron compound (e.g. sodium borohydride) in a solvent such as dimethyl sulfoxide at 0-200 deg.C to prepare a compound of formula II. The boron compound as the reducing agent is preferably combined with a Lewis acid or a sulfonic acid compound.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to compounds of general formula (1) useful as synthetic intermediates for pharmaceuticals (wherein R is hydrogen, alkyl, aralkyl, or optionally substituted phenyl). , R1, R3 represent hydrogen, alkyl, aralkyl, or R1, R3 represent a group bonding to each other to form a heterocycle with adjacent nitrogen atoms,
n represents an integer of 0 to 3) The present invention relates to a method for producing an aminoalkylmorpholine derivative represented by:

[Conventional technology]

For example, 2-(N
-Methyl-N-benzylaminomethyl)=4-ethylmorpholin-3-one is reduced with lithium alkalihydride to produce 2-(N-methyl-N-benzylaminomethyl)-4-ethylmorpholine. It is stated that you can get JP-A-62-228082 discloses that 2-aminomethyl-4-benzylmorpholine is produced by reacting 4-benzyl-2-chloromethylmorpholine with potassium phthalimide and treating the obtained phthalimide with hydrazine or the like. A method for manufacturing is described. In addition, in JP-A-63-264467, in addition to the above-mentioned method using phthalide, 4-benzyl-2-chloromethylmorpholine is reacted with sodium azide, and the resulting azide is hydrogenated bis( 2-methoxyethoxy)
By reducing with aluminum sodium etc., 2
-A method for producing methyl-4-benzylmorpholine is disclosed. In addition, European published patent number 3
No. 11948 discloses that active esters of the general formula (II) such as 4-pen';
I) (In the formula, R4 and RS represent hydrogen, lower alkyl, and benzyl, or R4 and R5 represent a group that is bonded to each other to form a heterocycle with the adjacent nitrogen atom.) A method for producing aminoalkylmorpholine derivatives is described, which is characterized by amination and subsequent debenzylation.

[Problem to be solved by the invention]

JP-A-53-90275 and JP-A-62-22808 mentioned above
When the methods of No. 2 and No. 63-264467 are used industrially, lithium aldanium hydride, which has a risk of ignition, potassium azide and sodium azide, which have a risk of explosion, or reactions with them, must be used. It is necessary to handle the azide compound obtained by the method, and it is also necessary to use expensive raw materials or 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.

[Means to solve the problem]

As a result of intensive research on industrial synthesis methods for aminoalkylmorpholine derivatives, the present inventors have discovered that readily available morpholine nitrile derivatives, morpholine carbamoyl derivatives, or amino T-alkylmorpholin-3-one derivatives can be synthesized under mild conditions. The present invention was completed based on the discovery that methylkylmorpholine derivatives can be produced safely in high yield by reduction.

The following margins, that is, the present invention is (11-form (n) [wherein R is hydrogen, alkyl, aralkyl or optionally substituted phenyl, R1 is nitrile, CHz
NR"R" or -CONR"R3 (where RtR3
represents hydrogen, alkyl, aralkyl, or represents a group in which R1 and R2 are bonded to each other to form a heterocycle with adjacent nitrogen atoms. ), A represents oxygen or H□, and n represents an integer of 0 to 3.

(However, when A is R2, R1 is -C1(, NR"R'
Not. )] A method for producing an aminoalkylmorpholine derivative represented by the -format (I), characterized by reducing a compound represented by the formula (I) with a boron compound, (2) in the reduction reaction, using a boron compound as a reducing agent; The present invention relates to a method for producing an aminoalkylmorpholine derivative as described in 1 above, characterized in that a Lewis acid or a sulfonic acid compound is used in combination.

In this specification, alkyl means methyl, ethyl, propyl,
Isopropyl, butyl, iso*butyl, tertiary butyl,
Aralkyl refers to alkyl having 1 to 18 carbon atoms such as pentyl, hexyl, heptyl, octyl, decyl, dodecyl, octadecyl, etc., and aralkyl refers to alkyl containing fluorine, chlorine, bromine,
Halogens such as iodine, alkyls such as methoxy, ethoxy, propoxy, trifluoromethyl,
Benzyl, phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, etc., which may have 1 to 3 substituents selected from hydroxyl group, nitro, amino,
Optionally substituted phenyl means halogen,
Alkyl, alkoxy, trifluoromethyl, hydroxyl group,
A heterocycle formed by phenyl, which may have 1 to 3 substituents selected from nitro and amino, together with adjacent nitrogen atoms by bonding Rz and Rs to each other, refers to a heterocycle containing at least one nitrogen atom. pyrrolidine, piperidine, morpholine, thiomorpholine,
Examples include piperazine and 4-methylpiperazine.

[For production]

In the present invention, by using a boron compound as a reducing agent, the reduction reaction can proceed safely in high yield and under mild conditions, and furthermore, during the reaction, the reducing agent of the present invention and a Lewis acid or a sulfonic acid By combining compounds, the reduction reaction can be carried out under more suitable conditions.

In the present invention, the boron compounds used as reducing agents include diborane, tetraborane, pentaborane, dihydroborane, hexaborane, decaborane, methyldiborane,
These include boranes such as dimethyldiborane, trimethyldiborane, and tetramethyldiborane, and borohydride complex compounds such as lithium borohydride, sodium borohydride, and sodium cyanoborohydride.

Further, Lewis acids that can be combined with the reducing agent of the present invention in the reduction reaction include argonium chloride, cobalt chloride, palladium chloride, rhodium chloride, tin chloride, nickel chloride, osmium chloride, iridium chloride, gallium chloride, Examples of the sulfonic acid compound include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

Further, as suitable solvents, ether, tetrahydrofuran, dioxane, diglyme, dimethyl sulfoxide, dimethyl sulfide, etc. can be used.

The reaction is carried out in the above-mentioned solvent at a temperature ranging from 0 to 200°C, preferably from room temperature to the boiling point of the solvent used, over a period of 1 to 48 hours.

Further, in compound (1), a compound in which R is hydrogen can also be obtained by subjecting a compound in which R is benzyl to debenzylation by subjecting it to catalytic reduction. This reaction can be used regardless of R1 and R3 of compound (r).

This reaction is usually carried out at room temperature to 150°C and at normal pressure to 100 atmospheres. As the solvent, water, alcohols, acetic acid, or a mixed solvent thereof is used, and as the catalyst, palladium carbon, platinum oxide, Raney nickel, etc. are used.

Compound (1) obtained in this manner may be prepared as necessary by conventional methods such as salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, para-toluenesulfonic acid, lactic acid, acetic acid, etc. , and salts with organic acids such as maleic acid, citric acid, and tartaric acid.

Furthermore, since the compound (1) of the present invention has an asymmetric carbon number, optical isomers and stereoisomers based thereon exist. Therefore, when compound (1) is a habit compound, it can be treated by using an acidic optical resolving agent such as tartaric acid, malic acid, N-acetyltryptophan, lO-camphorsulfonic acid, mandelic acid, dibenzoyltartaric acid, etc. It can be separated into optical isomers.

Compound (II) used as a starting material is disclosed in, for example, JP-A-62-30785, JP-A-53-90275, Tetrahedron Letters (Tetra-hedr).
on Lett,) Vol. 22, p. 141 (1981)
, Journal of Medicinal Chemistry (J
, Med, Che+w, ) No. 21 @, page 785 (
1978) or by the method described in German Patent No. 2,520,872.

In addition, the compound (U) in which R1 is -CONR"R' and A is R2 is a new compound, for example, the corresponding ester described in JP-A-62-30785, or if necessary, This is converted into carboxylic acid derivatives such as acid chlorides and acid anhydrides, and then reacted with the corresponding amine, or the compound (■) in which R1 is nitrile and A is R2 is treated with sulfuric acid or hydrochloric acid, etc. It can also be produced by hydrolysis.

The following margins [Examples] The present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 20.2 g of 4-benzylmorpholine-2carbonitrile was added to 27 ml of concentrated sulfuric acid, and the mixture was stirred at 60°C for 4 hours. The reaction was poured into ice water, neutralized with sodium hydroxide, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled under reduced pressure to obtain 4-benzylmorpholine-2 calfogisamide. Melting point 109-1
11°C Example 1 Sodium borohydride 2.36 g diglyme 40
20.2 g of 4-benzylmorpholine-2-carbonitrile was added to the m11 compound, and then 20.2 g of 4-benzylmorpholine-2-carbonitrile was added.
．． 8 g of diglyme 20ml solution was added dropwise at room temperature.

After stirring at 90°C for 1 hour, pour into 220ml of 1N hydrochloric acid,
- I installed it at night. After neutralizing with a sodium hydroxide solution and removing generated insoluble materials, the mixture was made alkaline with aqueous ammonia and extracted with chloroform. The extract was concentrated and then distilled under reduced pressure to obtain 2-aminomethyl-4-benzylmorpholine. Boiling point 125-130°C 10.25 mmHg Example 2 Methanesulfonic acid was added to a mixture of 15 ml of dimethyl sulfoxide containing 1.10 g of 4-benzylmorpholine-2-carboxamide obtained in the reference example and 0.47 g of sodium borohydride. A solution of 1111 in 10 ml of dimethyl sulfoxide was added dropwise. The mixture was stirred at 70°C for 7 hours, neutralized, and then extracted with chloroform.

The extract was concentrated and then distilled to obtain 2-aminomethyl-4-benzylmorpholine.

Example 3 4-benzylmorpholine-2-carbonitrile 2,02
Diporan was introduced into a tetrahydrofuran 20111 solution of g at room temperature and refluxed for 3 hours. Excess diborane and boron complex were decomposed with hydrochloric acid, neutralized, and extracted with chloroform. After concentrating the extract, it was distilled to give 2-aminomethyl-4-
Benzylmorpholine was obtained.

Example 4 11.7 g of 4-benzyl-5-oxomorpholine-2-carboxamide and 9.5 g of sodium borohydride
dimethyl sulfoxide-100+1 mixture, add 10 ml of dimethyl sulfoxide of methane sulfoxide #22 mt.
The solution was added dropwise. The mixture was stirred at 70°C for 7 hours, neutralized, and then extracted with chloroform. The extract was concentrated and then distilled to obtain 2-aminomethyl-4-benzylmorpholine. boiling point 15
0-160°C 10.5 mm Hg* [Effects of the Invention] The compound of general formula (r) economically obtained by the method of the present invention is useful as an intermediate for pharmaceuticals. For example, 2-(aminomethyl>morpholine contained in -form (1))
1-Cyclopropyl-6,8-difluoro- 1,4-dihydro-7-[2
-(aminomethyl)morpholino]-4-oxoquinoline-3-carboxylic acid (hereinafter referred to as compound A), melting point 1
A pyridonecarboxylic acid compound having a temperature of 83 to 185°C can be obtained.

Compound A obtained in this way maintains strong antibacterial activity against Durham-negative bacteria, and has significantly stronger antibacterial activity against Durham-positive bacteria than conventional pyridonecarboxylic acid compounds. As a result, the antibacterial activity in vitro is directly reflected, and it has been shown to have sufficient infection protective effects when administered orally in systemic infection experiments such as mice. It is an extremely useful drug that does not exhibit any problematic side effects when administered to patients.

Procedural record (spontaneous) 3. Relationship with the case of the person making the amendment Patent applicant address 2-6-9 Hirano-cho, Chuo-ku, Osaka-shi, Osaka Prefecture Name Yoshitomi Pharmaceutical Co., Ltd. (672) Representative Tadashi Taiya 4,
Agent Address: 2-6-9 Hirano-cho, Chuo-ku, Osaka-shi, Osaka Prefecture Claims and Detailed Description of the Invention Column 6 of the Specification
, the statement of contents of the amendment shall be amended as follows.

(1) The scope of claims is amended as shown in the attached sheet.

(2) Correct "0 to 3" in line 5 of page 3 of the specification to "0 to 3" and correct "-3-on" to "-5-on" in line 12 of the specification.

(3) Correct "-3-on" in line 4 of page 6 of the same book to "-3 (or 5)-on."

(4) Change “0 to 3” from the bottom 7 lines of page 7 of the same book to “0 to 3”
” is corrected.

Claims (11-Form (n) [In the formula, R is hydrogen, alkyl, aralkyl, or optionally substituted phenyl, R1 is nitrile, CHt
NR"R" or -CONR"R' (where R8
R3 represents hydrogen, alkyl, aralkyl, or R1゜,
R3 represents a group that combines with each other to form a heterocycle with adjacent nitrogen atoms), A represents oxygen or Hz, and n represents L21α (however, when A is R2,
R1 is -CH! is not NR寞R3, )] is reduced with a boron compound,
- A method for producing an agomethylkylmorpholine derivative represented by format (1) (in the formula, each symbol has the same meaning as above).

(2) In the reduction reaction, using a boron compound as a reducing agent,
2. The manufacturing method according to claim 1, characterized in that this is used in combination with a Lewis acid or a sulfonic acid compound.

-8(

Claims (2)

[Claims] (1) General formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R is hydrogen, alkyl, aralkyl, or optionally substituted phenyl, R^1 is nitrile, -CH
_2NR^2R^3 or -CONR^2R^3 (where R^2, R^3 represent hydrogen, alkyl, aralkyl, or R^2, R^3 are bonded to each other and together with adjacent nitrogen atoms represents a group forming a heterocycle), A represents oxygen or H_2, and n represents an integer of 0 to 3. (However, when A is H_2, R^1 is -CH_2NR^2R
It's not ^3. )], which is characterized by reducing the compound represented by boron compound (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, each symbol has the same meaning as above.) A method for producing an aminoalkylmorpholine derivative represented by (2) In the reduction reaction, using a boron compound as a reducing agent,
2. The manufacturing method according to claim 1, characterized in that this is used in combination with a Lewis acid or a sulfonic acid compound.