KR820000718B1 - Process for preparing hexahydroazepune piperidine and pyrrolidine derivatives - Google Patents

Abstract

2-oxo-Hexahydroazepine, -piperidine, -pyrrolidine, useful as analgesics, were prepared. Thus, N-methylcarprolactam reacted with 3-methoxy 2-cyclohexenone, (Me2CH)2, and B4HgLi in THF to yield I (n = 2, 3, 4; R = H, lower alkyl, arylalkyl R1 = H, lower alkyl).

Description

Method for preparing 2-oxo-hexahydro azepine, piperidine and pyrrolidine derivatives

The present invention relates to a process for the preparation of 2-oxo-hexahydro azepine, -piperidine and -pyrrolidine derivatives of general formula (I).

Above

n is 2, 3 or 4

R is hydrogen, lower alkyl or aryl (lower) alkyl

R ¹ is hydrogen or lower alkyl.

The invention also relates to 3,3-2 substituted-hexahydroazepine, -piperidine and pyrrolidine-derivatives. Various 3,3-2 substituted (disubstituted) -hexahydroazepines, -piperidine and pyrrolidine are known to have pharmaceutical and especially analgesic effects. Analgesic 2-unsubstituted-3,3-2 disubstituted-hexahydroazepines such as, for example, Peptazinol, are disclosed in British Patent No. 1,285,025. The 3,3-2 substituted -pyrrolidine associated with profadol is described in the following text by J. Med. Chem. It is stored in 1965,8,316. The 3,3-2 substituted -pyrrolidine associated with propadol is described in the following text by J. Med. Chem. 1965,8,316] Belgian Patent No. 850,777 and Myfadol and related 3,3-2 substituted-piperidine are listed in the following text. [Reference L J. Med. Chem. 1965. 8.313].

Since the preparation of the known 3,3-2 substituted -hexahydroazine, -piperidine and pyrrolidines is uneconomical, the object of the present invention can be easily prepared by a novel method from a readily available starting material. Cost to the entire process for preparing the final material by supplying an intermediate that can be converted to the desired 3,3-2 substituted -hexahydroazine, -piperidine and -pyrrolidine. Is generally much more economical than known methods.

The novel compounds prepared with the present invention are 2-oxo-hexahydroazepine, -piperidine and -pyrrolidine derivatives of the general formula (I).

Where n is 2, 3 or 4,

R is hydrogen, lower alkyl or aryl (lower) alkyl,

R ¹ is hydrogen or lower alkyl.

The term lower used herein means that the radical has 1 to 6 carbon atoms. The group preferably has 1 to 4 carbon atoms. For example, when R is lower alkyl, the group is methyl, ethyl, propyl or butyl. R ¹ is likewise methyl, ethyl, propyl or butyl. When R is aryl (lower) alkyl, the group is preferably phenyl (lower) alkyl, such as phenethyl or benzyl.

Phenyl may be substituted with one or more of halogen, alkoxy, trifluoromethyl or other substituents commonly used in medicinal chemistry.

It has been found by the present invention that compounds of general formula (I) can be prepared by novel methods from readily available starting materials. Also provided by the present invention is a method for preparing a compound of formula (I) by reacting a cyclohexene derivative of formula (IV) with an anion or di-anion of a lactam of formula (V) and hydrolyzing the product do.

Wherein Q is lower alkoxy (preferably methoxy, ethoxy or 0-propyloxy), benzyloxy, trialkyl-, triaryl- or tri-aralkylsiloxy (ie trimethyl siloxy) and n and R ¹ are As described above and R ⁴ is hydrogen, lower alkyl, aryl (lower) alkyl or trialkyl-, triaryl- or triarylalkylsilyl (ie trimethylsilyl) (R ¹ is lower alkyl, R ⁴ is other than hydrogen Condition).

Lactam of general formula (V) is when R ⁴ is hydrogen di-anion can form a one time be other than forming an anion, and R ⁴ is hydrogen. For example, when R ¹ is hydrogen and R ⁴ is other than hydrogen, the anionic lactam of the lactam of formula (V) is alkyllithium (ie tertiary butyllithium) or a compound of the general formula MA, wherein M is -MgX Is chlorine, bromine or iodine, sodium, potassium) and A is a secondary amine group]. When M is sodium, potassium, lithium, compound MA can be formed by reacting metal compound MR ⁵ , where M is sodium, potassium or lithium and R ⁵ is alkyl, aryl or aralkyl with secondary amines . Secondary amines include dialkylamines such as diethylamine, di-isopropylamine, di-tert-butylamine, di-n-decylamine, dicyclohexylamine, Nt-amyl-Nt-butylamine, N- Isopropyl-N-cyclohexylamine or N- (1′-ethylcyclohexyl) -1,1,3,3-tetramethyl butylamine or cyclic compound ie piperidine or 2,2,6,6-tetra Methylpiperidine. Preferred metalamides are lithium diisopropylamides.

When R ^{1 in} the lactam of general formula (V) is lower alkyl or hydrogen and R ⁴ is other than hydrogen, the anion forms the lactam as a Grignard reagent (preferably isopropyl magnesium bromide) or dialkyl. It can be prepared by reaction with aminomagnesium halide, ie bromomagnesium diisopropylamide. When R ⁴ is hydrogen and R ¹ is hydrogen, the di-anions of the lactams react with the lactams with alkyllithium (i.e. tertiary butyllithium or butyllithium) or alkali metal hydrides (i.e. sodium hydride) (i.e. And butyllithium).

The reaction product of one anion or di-anion of cyclotamene of formula (V) with cyclohexene (IV) is preferably not separated, but can be hydrolyzed to obtain a compound of formula (I). If R ⁴ in the compound of formula (V) is a tri-alkyl, tri-aryl-, or tri-aralkylsilyl group, this group is removed by hydrolysis to obtain a compound of formula (I) wherein R is hydrogen.

Example 1

Hexahydro-1-methyl-3- (3-oxocyclohexen-1-yl) -2H-azepin-2-one.

12.14 g of diisopropylamine, 17.0 ml, in dry tetrahydrofuran (THF 20 ml) are added dropwise to a stirred cold (-10 ° C.) solution of butyllithium (86 ml of 1.4 molar solution in hexane) under nitrogen. After 10 minutes, the Gilman test is negative. 3-methoxy-2-cyclohexenone (12.6 g, 0.1 mol) in THF (20 ml) is added. Treat the mixture to room temperature and add 1.5 to decompose. The mixture is stirred for 30 minutes at room temperature. The aqueous layer is separated and recrystallized from 60 ° C. to 80 ° C. extracted with dichloromethane to give the target compound having a melting point of 109 to 110C (18.99 g).

Example 2

1-methyl-3- (3-oxocyclohexen-1-yl) -2-piperidone.

n-butyllithium (1.4 m in hexane, 120 ml) is treated with diisopropylamine (27 ml, 19.2 g) in dry ether (25 ml) at 20 ° C. under dry nitrogen. After the addition is complete, the mixture is stirred at 20 ° C. for 10 minutes. Then 1-methyl-2-piperidone (20 g) in ether (25 ml) is added dropwise over 10 minutes.

The mixture is stirred for another 10 minutes and 3-isopropoxy-2-cyclohexenone (19.4 g) in ether (25 ml) is added dropwise over 10 minutes. The mixture is further stirred at 20 ° C. for 2 hours and hydrolyzed by the dropwise addition of a mixture of concentrated hydrochloric acid (50 ml) and water (50 ml). While the mixture is acidified, it is cooled in a water bath to moderate the reaction.

The mixture is cooled to room temperature (from 35 ° C.) and the organic layer is separated and dried (MgSO ₄ ). Removal of the solvent leaves a flowable yellow oil (0.63 g). The aqueous layer is completely extracted with chloroform (10 × 40 ml) and the combined extracts are washed with water (100 ml), washed with saturated aqueous NaCl solution (100 ml) and dried (MgSO ₄ ). Evaporate to give a pale green oil (25.97 g). The two fractions are collected and distilled to give a colorless liquid liquid, fraction A with a boiling point of 120 ° C./1 mm (4.6 g), and a fraction B with a boiling point of 150 C to 164 ° C./0.07 mm (14.64 g) yellow oil, solidifying to obtain a melting point of 41 to 62 ° C. You get a bright yellow substance. Fraction A is distinguished as 1-methyl-2-piperidone (25% recovery), slightly impurity mixed by 1R, and fraction B is separated into the title compound by IR and NMR.

Example 3

3-ethyl-hexahydro-1-methyl-3- (3-oxocyclohexen-1-yl) -2H-azin-2-one.

A 2M solution of isopropylmagnesium bromide in ether (70 ml) was added 3-ethyl-hexahydro-1-methyl-2H-azin-2-one (21.7 g, Aust. J. Chem. 1976, 29) in THF (20 ml). 2651) and the mixture is added dropwise to diisopropylamine (19.6 ml) (thermal dissipation). The reaction mixture is stirred for 2 hours and added dropwise to 3-methoxy-2-cyclohexenone (12.6 g) in THF (20 ml). After stirring for 2 hours the reaction mixture is poured into cold 2N HCl (250 ml). After 10 minutes the mixture is extracted with dichloromethane (2 x 300 ml) and the combined organic layers are washed with saturated aqueous NaHCO ₃ and dried (MgSO ₄ ). The solvent is removed under reduced pressure and distilled to give the title compound as a viscous oil (boiling point 155 to 160 ° C./0.1 mm) (13 g). Redistillation (154-158 ° C./0.77 mm) yields analytically pure material.

Example 4

Hexahydro-1-methyl-3- (3-oxocyclohexen-1-yl) -2H-azepin-2-one.

2-bromo propane (12.3 g) is added to the suspension of magnesium (2.43 g) in ether (50 ml) with slow reflux.

After the addition is complete the mixture is stirred for 30 minutes. Diisopropylamine (14 ml) is then added dropwise and the mixture is stirred until it is negative in the Gilman test (about 1 hour). N-methylcaprolactam (12.7 g) is added dropwise (thermal dissipation).

After adding N-methylcaprolactam and stirring, it becomes a sticky solid that is difficult to separate, which is dissolved again by adding THF (50 ml). After the addition was completed, the reaction mixture was stirred for 30 minutes, 3-isopropoxy-2-cyclohexenone (16.4 g) was added dropwise (heat dissipation) and stirred overnight. The reaction mixture is taken up in 2N aqueous hydrochloric acid (250 ml) and stirred for 30 minutes.

Dichloromethane (300 ml) is added and the layers are separated. The aqueous layer is extracted with dichloromethane (2 x 300 ml) and the combined organic layers are dried (MgSO ₄ ). The solvent is removed under reduced pressure and the residue is recrystallized from ethyl acetate to give the same compound as the product of Example 1 (13.2 g).

Example 5

1-methyl-3- (3-oxocyclohexen-1-yl) -2-pyrrolidine.

n-butyllithium (190 ml, 1.4 mol in hexane) was added dropwise over 10 minutes with diisopropylamine (30.3 g) in dry ether (50 ml) under dry nitrogen and water was poured into the outside to maintain the reaction temperature of 25 ° C. or lower. Be sure to After another 10 minutes of reaction, freshly distilled dry 1-methyl-2-pyrrolidine (27.72 g) in dry ether (25 ml) was added dropwise over 15 minutes and the suspension was further stirred at 20 ° C. for 20 minutes. 3-isopropoxy-2-cyclohexenone (31 g) in ether (25 ml) is added to the mixture over 15 minutes. The suspended solids melt during the addition. The mixture is stirred for 2 more hours at 20 ° C., cooled on ice and treated initially with a dropwise mixture of concentrated hydrochloric acid (100 ml) and water (100 ml). After 10 minutes of further reaction, the layers are separated and the organic layer sinks. The aqueous layer is extracted with chloroform (10 × 50 ml) and the combined extracts are washed with water (100 ml), washed with saturated aqueous NaCl solution (100 ml) and dried (MgSO ₄ ).

The solvent is evaporated to initially give a colorless oil that turns red in air (37.82 g). The oil is distilled off to obtain the target product as a pale yellow liquid and solidified to give a yellow product (32.75 g) having a boiling point of 161 ° C./0.035 mm to 165 ° C./0.07 mm and a melting point of 42 to 46 ° C.

Example 6

Hexahydro-3- (3-oxocyclohexen-1-yl) -2H-azepin-2-one.

Lithium diisopropylamide prepared by reacting diisopropylamine (45.3 ml) with 1.4 M butyllithium in hexane (231 ml) at -10 ° C. under nitrogen was subjected to 1-trimethylsilylhexahydro-2H- in dry THF (50 ml). Treatment with azepin-2-one (63.7 g) at -60 ° C. The white suspension is treated with 3-methoxy-2-cyclohexenone (40.8 g) solution in THF (50 ml) after 20 minutes. Treat the resulting solution to room temperature. After the reaction for 3 more hours, the cooling solution was treated with concentrated hydrochloric acid (120 ml) and stirred for 18 hours. The THF layer is mixed with several chloroform extracts from the aqueous layer. The solvent was evaporated to give a yellow solid which was recrystallized from ethyl acetate to give hexahydro 3- (3-oxocyclohexen-1-yl) -2H-azin-2-one as a white solid having a melting point of 159 to 165 ° C. (45.5 g).

Example 7

1-phenylmethyl-hexahydro-3- (3-oxocyclohexen-1-yl) -2-azin-2-one.

A solution of hexahydro-1-phenylmethyl-2H-azin-2-one (5.68 g) in dry THF was extracted from diisopropylamine (4.4 ml) and butyllithium (22.9 ml 1.4M solution in hexane) at -10 ° C. To lithium diisopropylamide (0.032 mol) prepared. The mixture is stirred for 30 minutes and treated with a solution of 3-methoxy-2-cyclohexenone (2.53 g) in THF. After 5 hours at room temperature the mixture is poured into ice-cold concentrated hydrochloric acid (100 ml). After vigorous stirring for 12 hours, the solution is shaken several times with chloroform. The combined layers of chloroform are evaporated to give an orange oil.

Example 8

Hexahydro-3- (3-oxocyclohexen-1-yl) -2H-azepin-2-one.

Butyllinium (143 ml of 1.4M solution in hexane) was added dropwise to a stirred solution of caprolactam (11.3 g) in dry tetrahydrofuran under nitrogen. After stirring at 0 ° C. for 50 minutes, 3-methoxy-2-cyclohexenone (12.6 g) in tetrahydrofuran is added.

After another 30 minutes, the reaction is poured into 5M hydrochloric acid. The organic layer is separated and the aqueous layer is extracted with chloroform. The combined organic layers are dried over magnesium sulfate. The solvent was removed under reduced pressure to give 15 g of a yellow solid. The product is recrystallized in ethyl acetate to give 2.5 g of the same compound as described in Example 17.

Claims (1)

Next, a method of preparing a compound of formula (I) by reacting a cyclohexene derivative of formula (IV) with an anion or di-anion of lactam of formula (V) and hydrolyzing the product.

Wherein n is 2,3 or 4, R is hydrogen, lower alkyl or aryl (lower) alkyl, R ¹ is hydrogen or lower alkyl, is a protecting group which can be hydrolyzed and R ⁴ is hydrogen, lower alkyl, aryl (Lower) alkyl or trialkyl-, triaryl or triarylalkylsilyl, provided that R ⁴ is other than hydrogen when R ¹ is lower alkyl.