JPS58103365A - M-hydroxyphenyl substituted compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to m-hydroxyphenyl substituted compounds, methods for their preparation, and intermediates used in their preparation.

Many m-hydroxyphenyl substituted compounds are known and are particularly useful as pharmaceuticals. Meptazinol (me
3-Hydroxyphenyl-hexahydroazepine analgesics such as PTAZILEOL") are disclosed, for example, in British Patent Specification No. 1285025. Profadol and its related pyrrolidines are described in J. Med. , Chew, vol. 948, p. 316 (
1965) and Belgian patent specification IJ850777
On the other hand, myfade
l) and its related piperidines in J. Med.

Chem, Vol. 8, p. 313 (1965). The present inventors have now discovered a new method for producing m-hydroxyphenyl substituted compounds. This production method can be used to produce pharmacologically active compounds such as those described above.

According to the present invention, a compound represented by the general formula (■): [In the formula, k is an organic group, k is hydrogen or an organic group, and X means chlorine or bromine] in the presence of a strong nucleophilic acid catalyst. Perform dehydrohalogenation 1. Accordingly, a method for producing a m-hydroxyphenyl substituted compound represented by the general formula (1): [wherein k means an organic group and R1 means hydrogen or an organic group] is provided.

When R1 is an organic group, both the organic group and 1 may be an aliphatic, aromatic or heterocyclic group.

The group may be a substituent containing a functional group. Since certain substituents can change under the reaction conditions, k or R1 in the starting material may be different from the organic group k or R1 in the product.

Preferably k is hydrogen. When it is a heterocyclic group,
For example, it may be a monocyclic or bicyclic heterocyclic group containing one or more heteroatoms. The heteroatom or atoms may be, for example, oxygen, sulfur or nitrogen. Examples of heterocyclic groups include pyrrolidine, piperidine and hihexahydroazebin groups, in particular formula (Ill)
:3 [In the formula, n is 2, 3 or Ha4 (preferably tL<Ha4), R
2 means hydrogen or lower alkyl, R3 means hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl (lower) alkyl or aryl (lower) alkyl. "lower" used here
means that the group contains 1 to 6 carbon atoms. The group preferably contains 1 to 4 carbon atoms.

For example, lower alkyl groups are preferably methyl, ethyl, pro(yl or butyl). Examples of lower alkenyl and lower alkynyl groups include allyl, propargyl, 3,
Mention may be made of 3-dimethylallyl and 1-methyl-2-propyl. An example of cycloalkyl(lower)alkyl is cyclopropylmethyl. Examples of aryl(lower)alkyl include phenethyl or benzyl. Here, the phenyl group may be substituted with one or more substituents such as halogen, alkoxy, trifluoromethyl, and other substituents known in medicinal chemistry.

X has the above meaning, R1 has the above meaning (preferably water lA), and k is the formula (I[),
) is a novel compound and provided by the present invention.

A compound of formula CI in which kl is hydrogen and k is formula (■) (wherein R2 is lower alkyl and K and n are the same as above) is a hydrogen transfer agent such as lithium aluminum hydride. may be reduced using the formula % to form a compound represented by the formula % [wherein R4 is lower alkyl, and n and 13 are the same as above]. Compounds of general formula (IV) are useful, for example, as analgesics or intermediates thereof, as explained in the above-mentioned literature. R3 is methyl, n is 4
, R4 is ethyl, the compound of general formula (IV) is mepdazinol, which has analgesic properties.

Compounds of formula (I) where R2 is hydrogen can be C-alkylated to give the corresponding compounds where R2 is lower alkyl. Compounds of formula (I), i.e. compounds of formula (■) where 3 is hydrogen, are N-
Alkylated, R3 is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl (lower) alkyl,
or aryl(lower)alkyl. Furthermore, the reduction, C-alkylation and N-alkylation steps are described, for example, in GB 1285025 and EP 0003253.

The method of the present invention is characterized in that, for example, k is a carboxymethyl group or a derivative thereof such as -CH2COO (lower) alkyl, kl is (lower) alkyl, phenylmata is a substituted phenyl such as chlorophenyl (1 in the substituent is (located meta to both k and hydroxy) can also be used in the preparation of compounds of formula (I). The compound has an anti-inflammatory effect or
et al., JlMed.

It is useful as an intermediate for the anti-inflammatory compounds disclosed in Chem, Vol. J420, pp. 709-714 (1977).

The method of the invention provides a method in which k is hydrogen and R is of the formula M:(CI(
2) It can also be used to produce compounds represented by formula (I), such as m-hydroxyphenyl-substituted compounds represented by 2C[(3 (0'l2)2CH3). :() (Q'l2)2cH3 [In the formula, X means chlorine or bromine (preferably bromine)] It is produced by dehydrohalogenating a compound represented by the following formula by the method of the present invention.

The product of general formula (VI) is reduced, for example using a hydrogen transfer agent (preferably a borane-tetrahydrofuran complex), to form a 3-(1- propyl-3-piperidinyl)phenol.

The compound of general formula (■) and its pharmaceutically acceptable acid addition salts are known and are said to be selective dopamine autoreceptor agonists, and are used to treat, for example, diseases accompanied by disorders of the central dopamine autoreceptor transmission system. It can be used to treat.

The process of the invention can be carried out in a solvent such as methylene chloride, chloroform or acetic acid, for example under substantially anhydrous conditions. The reaction may proceed at room temperature. Strong nucleophilic acid catalysts may be, for example, hydrogen bromide or hydrogen chloride. The method of the invention has advantages over conventional aromatization methods. That is, the starting materials of the present invention are usually easily separated;
The process uses mild conditions and avoids the use of bromine, which is difficult to handle on a large scale and tends to give multibrominated products.

The starting material, the substance of formula (II), has the general formula (For example, trimethyl
siloxy)] can be produced by reacting a 2-halocyclohexanone derivative represented by the following with a nucleophile and then hydrolyzing the product. For example, k in the formula (■) is the formula (I[
I), the nucleophile has the general formula (X): R5(X) [where n and R2 are the same as above, and k5 is hydrogen, lower alkyl, aryl (lower) alkyl or trialkyl] -, triaryl- or triallkyl-silyl] may be an anion or dianion of a lactam.

The preparation and reaction of anions or dianions of formula (Vl) are described, for example, in European Patent Specification No. 0003253.
Disclosed in the issue. When k in formula (CTI) is of formula (V), the nucleophile may be an anion of a lactam (preferably sodium, potassium, lithium or Mg) of general formula (XI): . The lactam anion can be prepared by reacting the lactam with, for example, lithium diisopropylamide.

2-halocyclohexanone derivatives represented by general formula (IX) are known. Alternatively, it can be produced by the method below.

The halogenation step (XI) is carried out by known methods (e.g. with N-bromosuccinimide or N-chlorosuccinimide in a solvent such as carbon tetrachloride, or with sulfuryl chloride in a solvent such as chloroform, or with chlorine or However, to obtain high yields, bromination can be carried out using aqueous potassium bromide in aqueous hydrobromic acid, or by reaction with Chloramine T (N-chloro Preference is given to chlorination with an aqueous solution of -4-methylbenzenesulfonamide sodium salt).

The halogenation step (XII[)-(IX) may also proceed according to known methods1, in which X is preferably bromine, the bromination using bromine, e.g. in sodium acetate/acetic acid, or It can be carried out using N-bromosuccinimide, for example in carbon tetrachloride. However, it is convenient to carry out the bromination using N-bromosuccinimide in a more polar solvent such as dichloroethane or acetonitrile.

Step (XI)=(Xlll)OJ:bi(Xll)-(I
X) may proceed according to known methods, for example (XT) or CM) may be carried out by reaction with an alcohol in the presence of an acid in a solvent such as toluene and azeotropic removal of water. Other methods of alkylation are described in the applicant's pending UK application filed concurrently with this application. The application is based on British Patent Application Nos. 8136364 and 8211.
The patent claims priority based on No. 201, and the title of the invention is [3-alkoxycycloalk-2-eneto monones]. Reaction of compound (X[) or (XI) with a silylating agent (such as trimethylsilyl chloride in the presence of an organic base) provides compounds in which Q is trialkyl-, triaryl- or trialkyl-silyloxy.

The present invention will be explained in more detail below with reference to Examples.

Example 1 3-(210rho-3-t-1-fucyclohex-1-enyl)-hexahydro-1-methylazepine-2-one lithium diisopropylamide to n-butyllithium 6
．． 45 m/(1.55 M in hexane) and 1.4 ml of diisopropylamine in 1 ornl of tetrahydrofuran
Get more. l-Methylcabralactam 1 at 0°C.
．． 279 and then 2-chloro-3 in THF5-
- treated with 1.61 p of methoxycyclohexenon. The reaction mixture is stirred for 5 minutes and then poured into cold 2N hydrochloric acid.

After 0.5 hours toluene is added and the layers separate. The organic layer is washed with aqueous NaOH and water, dried and then evaporated to give crystalline product 1.9f. Melting point 118-120℃
.

Elemental analysis value, Cl5I''I□8CjNo2 actual measured value C%): C, 61,4; H, 7,3; N, 5.3 Calculated value C%): C, 61,1; H, 7,1 :N, 5.5 Example 2 3-(2-butyl 3-oxocyclohex-1-enylhexahydro-1-methylazepin-2-one amino in hexane with 12.9 rnl of n-butyllithium (1, 55 M) and 2.8 m of diisopropylamine in THF.
2. Then treated with 4.1 g of 2-bromo-3-methoxycyclohexenon in 15 ml of THF. After 1 minute, the reaction mixture is poured into 8 ml of 5N HCl and 100 ml of cold water. After 0.5 hours ether is added and the organic layer is separated, dried and evaporated. The residue is recrystallized from ethyl acetate to obtain the title compound 4.91. Melting point 112-115°C (decomposition elemental analysis value, C□3H□s BrN02 actual value (%): C, 51,7:H, 6,2:N, 4.7 calculated value C%): C , 52,0:H, 6,0:N, 4.7 Example 3 3-ethyl-1
The following compounds were prepared using the appropriate halomagnesium anion of -methylhexahydroazepin-2-one.

(a) 3-(2-bromo-3-oxocyclohexy-1
(enyl)-3-ethyl-hexahydro-1-methylazepin-2-one, mp 106-107°C.

Elemental analysis value, actual value C% as C□5H22BrNO2
): C, 54,7; H, 6,8; N, 4.2 Calculated value C%
) :C,54,9;t(,6,8;N,4.3(b)
3-(2-chloro-3-oxocyclohex-1-enyl)-3-ethylhexahydro-1-methylazepine-
2-one, melting point 115-116°C.

Elemental analysis value, Cs 5H22Cj Actual value C% as N02): C, 63,7; H, 7,9; N, 4.85
Calculated value C%): C, 63,5; H, 7,8: N, 4.9
Example 4 Hexahydro-3-(3-hydroxyphenyl)-1-
Methyl-2H-azepin-2-one (al) 1.4 Jl of 3-(2-bromo-3-oxocyclohex-1-enyl)-hexahydro-1-methylazepin-2-one in 10-methylene chloride Treat with 48% HBr in acetic acid. After 3 hours, add water and remove the organic solvent under reduced pressure. Recrystallization from the aqueous solution gives the product 844 ml. Melting point 19
0-192℃. This was the same as the standard product.

(bl 3-(2-bromo-3 in chloroform 60-
A solution of 62 -oxohex-1-enyl)-hexahydro-1-methylazepin-2-one in 1 tnl of acetic acid
Treat with 8% HBr. After 4 hours, NMR showed the reaction was complete. Aqueous ammonia is added and the organic solvent is removed under reduced pressure to yield the title compound as a crystalline solid. Melting point 19
2-193°C (EtOAc).

Example 5 Hexahydro-3-(3-hydroxyphenyl)-1-
Methyl-2H-azepin-2-one (a) Using chloroform as the solvent 3-(2-
Chloro-3-oxocyclohex-1-enyl)-hexahydro-1-methylazepin-2-one 5.12S'
A solution of is treated with 48% HBr in 2-acetic acid. After 12 hours, the organic solvent is removed under reduced pressure and the resulting residue is triturated with aqueous ammonia to yield the title compound. Melting point 192-193°C (EtOAc).

(bl Using acetic acid as the solvent. A solution of 5.12 P of 3-(2-chloro-3-oxocycloh-1-cy-1-enyl)-hexahydro-1-methylazepin-2-one in 50 i of glacial acetic acid. Treat with 48% HBr in 2rnl. After 12 hours, the reaction mixture is poured into water and the resulting residue is evaporated to give the title compound, mp 192-193°C (EtOAc).

Example 6 Hexahydro 3-ethyl-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one dichloromethane 3-(2-bromo-3-oxocyclohex-1-enyl )-3-Ethylhexahydro-1-methylazepin-2-one 6.579 is treated with 48% HBr in acetic acid 1-. After 3 hours, NMR
indicated the completion of the reaction.

The solvent is removed under reduced pressure and the residue is triturated with aqueous ammonia to give the title compound as a white crystalline solid.

Melting point 178-180 (EtOA).

Example 7 Hexahydro 3-ethyl-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one 3-(2-chloro-3-oxocyclohex-1-enyl)- in 60 m/dichloromethane A solution of 5.68 g of 3-ethylhexahydro-1-methylazepin-2-one is treated with 48% HBr in acetic acid. After 12 hours, the mixture is treated with excess aqueous ammonia, the organic solvent is removed under reduced pressure, and the resulting solid is then removed to give the title compound.

Melting point 178-180°C (EIOAc).

Example 8 3-(2-bromo-3-oxocyclohex-1-enyl)-1-propyl-2-piperidoneben 40m/
A solution of 50 aM of 1-propyl-2-piperidone in a solution of lithium diisopropylamide (e.g. 32 aM of hexane)
．． 3 m/(5(haM), diisopropylamine 7
m/(50mM) and n-butyllithium in THF33).

T) 2-bromo-3-methoxycyclohex-2-en-1-one in lF4Q-10.259 (507FLM
) and after 5 minutes the mixture is quenched by pouring it into excess aqueous hydrochloric acid. The ether extract was passed through a silica packed bed using ethyl acetate as the eluent to obtain the title compound 10.7.
5F is obtained as a colorless oil.

Example 9 3-(3-hydroxyphenyl)-1-furopyru2
-Piperidone dichloromethane 70-Product of Example 8 10°551
(33.4 mM) is treated with 48% hydrogen bromide in approximately 0.51 nl acetic acid. After 16 hours, the solvent is evaporated under reduced pressure and the residue is then partitioned between chloroform and water. The organic layer was dried, evaporated and the residue was dissolved in Otaroroform.
Chromatography on alumina (neutral, grade 3) with % methanol as eluent. The appropriate fractions were evaporated and then recrystallized from ether to yield the title compound 6.
Get 8 no. Melting point 61-63°C.

Elemental analysis value, actual value (%) as C□4H19”02:
C, 71,9; H, 7,8: N, 5.6 Calculated value (%)
:C,? 2.1;H, 8,2;N, 6.0Example 10 3-(1-propyl-3-pipe IJ cinyl)phenolProduct of Example 9 in THF50-4.879C21m
M) is treated with borane-THF 63m/(63mM). After 3 hours, the mixture is poured with water and the THF is evaporated under reduced pressure. The residue is acidified with 2N hydrochloric acid and the resulting solid is then removed. The P solution is made alkaline (pH 10), extracted with chloroform, and the organic layer is then dried and evaporated. The oil obtained is converted into 3.01 hydrobromide salts. Melting point 144-145°C.

Elemental analysis value, actual value (%) as C14H2□No.1/4 H2O: C, 55, 1:H,? , 3:N, 4.6
Calculated value (%): C, 55, 2: H, 7, 3: N, 4.6
Agent Masukonshi Aoyama and 2 others

Claims (1)

[Claims] A compound represented by formula (1): [wherein k is an organic group, R1 is hydrogen or an organic group, and X means chlorine or bromine] is decomposed in the presence of a strong nucleophilic acid catalyst. By performing halogenated water, the formula=C, k and R
1 is the same as above] A method for producing the m-hydroxyphenyl substituted compound shown below. (2) The method according to item (1) above, wherein R'' is hydrogen.
) or method (2). (4) k is the formula: [where n is 2, 3 or 4, k2 is hydrogen or lower alkyl, R3 is hydrogen, lower alkyl, lower alkenyl,
lower alkynyl, cycloalkyl C means lower) alkyl or aryl(lower) alkyl] The method according to the above item (1) or (2). (5) The method according to paragraph 47, where n is 4. (6) The method according to paragraph (2), where k is represented by the formula: (CI(2)2CH3). (7) The nucleophilic acid catalyst is a bromide The method according to any one of the above items (1) to (6), wherein hydrogen or hydrogen chloride is hydrogen or hydrogen chloride.Formula (8): [wherein R1 is hydrogen or an organic group, X is chlorine or bromine, n is 2.3 or 4, R2 is hydrogen or lower alkyl, R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl (lower) alkyl or aryl (lower) alkyl. (9) )3-(2-chloro-3-oxocyclohexy-1
-enyl)-hexahydro-1-methylazepine-2-
on, 3-(2-bromo-3-oxocyclohexy-1
-enyl)-hexahydro-1-methylazepine-2-
one, 3-(2-bromo-3-oxocyclohexyl-1-enyl)-3-ethyl-hexahydro-1-methylazepin-2-one or 3-(2-chloro-3-oxocyclohexy-1- (8) which is 1-methylazepin-2-one
compound of term. Q10-(2-bromo-3-oxocyclohexy-1-
The compound of item (8) above, which is (enyl)-1-propyl-2-piperidone. Formula 01: [wherein, X is chlorine or bromine, k is hydrogen or an organic group,
Q means a hydrolyzable protecting group] 2-
The halocyclohexanone derivative has the formula: [where n is 2.3
or 4, R2 is hydrogen or lower alkyl, K is hydrogen,
lower alkyl, aryl(lower)alkyl or trialkyl-, doaryl- or trialkyl-silyl) and then hydrolyzing the product to produce a compound of the formula : [wherein, X, n, R and R are the same as above, k is hydrogen,
means lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl (lower) alkyl or aryl (lower) alkyl].