JPH0242039A - Fluorophenoxyalkane derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R is lower alkyl; X is halogen or phthalimide). EXAMPLE:2-(2-Chloroethoxy)-4-fluoroanisole. USE:A synthetic intermediate for medicines. PREPARATION:An alcoholic derivative expressed by formula II is reacted with a halogenating agent (e.g., thionyl chloride or phosphorus pentabromide) in or without an organic solvent (e.g., chloroform or benzene) at a temperature within the range of cooling with ice to 200 deg.C to afford the compound expressed by formula I.

Description

Detailed Description of the Invention - No. 1 The present invention provides a compound of the following general formula (I) (wherein R represents a lower alkyl group and X represents a halogen atom or a phthalimide group) which is useful as a synthetic intermediate for pharmaceuticals. ) Many pharmaceutical drugs containing fluorine atoms are known, and their usefulness is also widely known. The present invention is based on the objective of synthesizing phenoxyalkane derivatives containing fluorine and providing new derivatives of conventional pharmaceuticals.

As a result of intensive studies to achieve the above object, the present inventors succeeded in synthesizing the fluorophenoxyalkane derivative represented by the general formula (I), and completed the present invention.

In the general formula (I) of the present invention, the lower alkyl group represented by R is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ee
Examples of the halogen atom represented by X in -butyl, tert-butyl, etc. include chlorine, bromine, and the like.

The novel fluorophenoxyalkane derivative represented by the general formula (I) of the present invention can be produced by various methods.

According to the first mode of the method for producing a compound according to the present invention,
Among the compounds represented by the above general formula (I), the compound in which X is a halogen atom is prepared by adding an alcohol derivative represented by the following general formula (wherein R represents the same meaning as above) without a solvent or in an organic solvent. It can be produced by treating it with a halogenating agent in a medium.

Examples of organic solvents used in the method of the present invention include chloroform and dichloromethane.

1.2-dichloroethane, pyridine, benzene.

Toluene, xylene, etc. are used as the halogenating agent, and examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride,
Examples include phosphorus pentachloride and phosphorus pentabromide, and the reaction is carried out at a temperature of 200° under water cooling.

In addition, the general formula (II) used in the method of the present invention
) is represented by the following general formula (III
) (wherein R represents the same meaning as above) and an organic solvent (N, N-dimethylformamide, dimethyl sulfoxide).

base as a deoxidizing agent (potassium carbonate,
It can be produced by reacting ethylene carbonate or ethylene chlorohydrin in the presence of sodium carbonate, sodium hydroxide, etc.).

According to the second mode of the method for producing a compound according to the present invention,
Among the compounds represented by the general formula (I), the compound in which X is a halogen atom is obtained by adding the phenol derivative represented by the general formula (III) in the absence of a solvent or in an organic solvent in the presence of a base as a deoxidizing agent. It can be produced by reacting with ethylene bromide or ethylene chlorobromide.

Examples of organic solvents used in the method of the invention include N,N-dimethylformamide.

Dimethyl sulfoxide, toluene, methanol.

Examples of the base as a deoxidizing agent include pyridine, triethylamine, potassium carbonate, sodium carbonate, etc., and the reaction is carried out at room temperature while heating the solvent to reflux.

According to the third mode of the method for producing a compound according to the present invention,
Among the compounds represented by the general formula CI), the compound in which X is a phthalimide group is a compound in which X is a halogen atom in the general formula (I) in the presence of a base as a deoxidizing agent in a battering solvent. It can be produced by reacting with phthalimide in the absence or presence of phthalimide.

Examples of organic solvents used in the method of the invention include N,N-dimethylformamide.

Examples of the base as a deoxidizing agent include dimethyl sulfoxide, toluene, etc., and potassium carbonate, for example.

Examples include sodium carbonate and triethylamine, and the reaction is carried out at room temperature while heating the solvent to reflux.

The fluorophenoxyalkane derivative represented by the general formula (I) produced in this manner is extremely useful as a synthetic intermediate for various pharmaceuticals, and has an α-receptor blocking effect as shown below. can lead to compound (IV) containing

(rV) (In the formula, R represents the same meaning as above.) EXAMPLE E Hereinafter, the present invention will be explained by reference examples and examples.
The invention is not limited to the specific details of these examples.

Reference Example 1 A suspension of 8.75 g of 2-(5-fluoro-2-methoxyphenoxy)ethanol 5-fluoro-2-methoxyphenyl, 10.9 g of ethylene carbonate, and 8.50 g of potassium carbonate in 121 toluene was 2. Heat to reflux for 5 hours. After washing the reaction solution with water and dehydrating it, the solvent is distilled off. Distill the residue under reduced pressure,
Colorless liquid with a boiling point of 138-140° (8 aunHg)9.
Obtain 15g.

Mass spectrum m/z: 18Ei (M”)NM
R spectrum δ (CDC13) ppm: 2
．． 9B (IH, S), 3.58-4.30 (4H, m
), 3.83 (3■, S).

6.48-6.92 (3H, m) Compounds of Reference Examples 2 to 4 are obtained according to the method of Reference Example 1.

Reference Example 2 2-(4-Fluoro-2-methoxyphenoxy)ethanol Properties Colorless liquid Boiling point 147-150° (9mmHg) Mass spectrum 1/z: 18G (NMR spectrum δ
(CDC13) ppm: 2.95 (IH, s)
, 3.83 (3■, s), 3.90 (211, t, J=
4Hz) +4.07 (2H, t, J: 4Hz), 6.4
5-6.94 (3H4) Reference Example 3 2-(3-fluoro-2-methoxyphenoxy)ethanol Properties Colorless liquid mass spectrum rs/z: 186 (M”)NM
R spectrum δ (CDCl2) pI)■ :2
．． 40 (II, s), 3.93 (3H, d, J: 1Hz
), 3.80-4.20 (4H, m), lli, GO-
7,08 (3H, ■) Reference Example 4 2-(2-Ethoxy-5-fluorophenoquine) Ethanol Properties Colorless liquid Fluorescence point 141-145° (I 1mlHg
) Mass spectrum ■/z: 200 (Mass NMR
Spectrum δ (CDCl31 l)pIl:
1.41(3)1. t, J near Hz), 3.00 (IH
, s), 3.85-4. IG(61(,m),G,52
4.89<3H,+m)(8n+mHg) professional liquid 8
．． Obtain 50g. The ice crystals crystallized and showed a melting point of 35-38''.

Mass spectrum IIHz: 204.20G (3
:1. M”) NMR spectrum δ (CDCl2)
I) l) II: 3.82 (2H, t, J: 6.5
Hz), 3.83 (3H, s), 4.24 (2H.

t, J=8.5Hz), 6.48-6.9Ei (3B,
m) Compounds of Examples 2 to 4 are obtained according to the method of Example 1.

Example 1 2-(2-chloroethoxy)-4-fluoroanisole 2-(5-fluoro-2-methoquinofenoquine)ethanol9. 3.9 ml of thionyl chloride was added dropwise to a solution of 4.51 OOg of pyridine under stirring under water cooling, and the mixture was heated at 80 to 90° for 2
Stir for an hour. After cooling, the reaction solution was poured into 10% hydrochloric acid 401 and extracted with chloroform. Wash the chloroform layer with water,
After dehydration, the solvent is distilled off. The residue was distilled under reduced pressure and the boiling point was 11
8-120' Example 2 2-(2-chloroethquine)-5-fluoroanisole Properties Colorless crystals Boiling point 120-125' (8 nuiHg) Melting point 30
~34° mass spectrum i/z: 204.2011i (3
:I, M+) NMR spectrum δ (CDCl2)
pp-:3.79(2)1. t, J:H2), 3.
85 (3■, s), 4.23 (2H, t.

J=6Hz), 6.45-11i, 95 (3H, m) Example 3 2-(2-70 ethoxy)-6-fluoroanisole Properties Colorless liquid mass spectrum Sono/z: 204,20G (3:
I, M+) NMR spectrum δ (CDCl2)
ppll: 3.84 (2H, t, J: 1iHz) +
3.94 (3H, d, J: 0.5Hz).

4.28 (2H, t, J: GHz), 8.59-7.
10 (3H, m) Example 4 2-(2-chloroethquine)-1-ethoxy-4-fluorobenzene Properties Pale yellow liquid Boiling point 120-122° (7 mmHg) Mass spectrum rg/z: 218,220 (3:1 .M+)N
MR spectrum δ (CDC13) I)l)■
: 1.41 (3H, t, J near Hz), 3.82 (20
, t, J=8Hz).

4.04 (2H, q, J=7Hz), 4.24 (2H,
t, J=IliHz).

8.54-fi, 93 (3B, m) Example 5 2-(2-bromoethoxy)-4-fluoroanisole 5-fluoro-2-methoxyphenol 10°0g+
52.9 g of ethylene bromide and 14.9 g of potassium carbonate.
6 g of N,N-dimethylformamide 501 suspension was added to 8
Stir at 0° for 11 hours. After cooling, pour the reaction solution into water.
Extract with ethyl acetate.

After washing the ethyl acetate layer with water and dehydrating it, the solvent was distilled off.

The residue was subjected to column chromatography [silica gel.

Elution was performed with a mixture of chloroform and n-hexane (1:1) to obtain 11.6 g of a colorless liquid.

Mass spectrum s/z: 248,250 (setting:
I, M+) NMR spectrum δ (CDC13)
ppm '3.65 (2H, t-d, J:8.5,0
．． 5Hz), 3.84 (3[1,s).

4.30 (2H, t-d, J:G, 5.0.5H2)
, 6.48-f;, 9fi (3H, m) Example 6 N-[2-(5-fluoro-2-methquinphenoxy)
Ethylkottalimide 2-(2-chloroethoxy)-4-fluoroanisole8. OOg, phthalimide 5.75g and potassium carbonate 3.24g N,N-dimethylformamide 15
Heat the m1 suspension at 120-130' for 2 hours. After cooling, the reaction solution was poured into water, the precipitated crystals were collected by filtration, and colorless crystals 1
Obtain 0.4 g. Recrystallized from ethanol, melting point 13
Colorless needle crystals of 4.5-136° are obtained.

Elemental analysis value CFH14FNO4 Theoretical value C, 64,78; H, 4,48; N, 4
．． 44 Experimental value C, fi4.88; H, 4,72;
N, 4.39 Based on the method of Example 6, Examples 7-
Compound 9 is obtained.

Example 7 N-C2-(4-fluoro-2-methoxyphenoxy)
Ethyl Kottalimide Properties Colorless needle crystals (EtO former melting point 102-104° Elemental analysis value C1□H14FN04 Theoretical value C, 64,7B; H, 4,48; N,
4.44 Experimental value C, 64,88; H, 4,80:
N, 4.31 Example 8 N-[2-(3-fluoro-2-methoxyphenoquine)
Ethyl] phthalimide Properties Colorless scale-like product (EtOH) Melting point 112-113° Elemental analysis value C□7H, FNO4 Theoretical value C, 84, 7G; H, 4, 48; N,
4.44 Experimental value C, B4.57; H, 4,48;
N, 4.42 Example 9 N-[2-(2-ethoxy-5-fluorophenoxy)
Ethyl Kottalimide Properties: Colorless needle crystals (EtOH) Melting point: 119-121° Elemental analysis: C grade, H grade. FNO4 theoretical value C, G5. G5; H, 4,90; N.

4.25 Experimental value C, 65, G9; H,4,9G; N.

4.25

Claims (1)

[Claims] A fluorophenoxyalkane derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a lower alkyl group, and X represents a halogen atom or a phthalimide group.)