KR890002103B1 - Substituted aromatic or heterocyclic ring compound - Google Patents

Abstract

The cpd. of formula (III) shows antihistamine and antiallergy activities. In formula, A is benzene, naphthalene or pyridine ring; Y is halogen, lower alkyl, lower alkoxy, NO2 or CF3; R is H, lower alky1, cycloalkyl or Ph-lower alky1(opt. substd. by 1 or 2 halogen, lower alky1, lower alkoxy, NO2 or CF3); n is 1 or 2; X is Cl, Br or F; E is 0 or S.

Description

Substituted aromatic or heterocyclic ring compound

The present invention shows an antihistamine action and an antiallergic action and contains an aromatic component fused to an oxazepine or thiazepine ring and is substituted with a short-chain aminoalkyl group at the 2-position and is an aromatic-2,3-dihydro-1,4-oxazepine Novel substituted aromatic or heterocyclic ring compounds for preparing -5 (4H) -one and sulfur homologues thereof.

3-aryl-1,4-benzoxazepin-5 (4H) -one substituted with an aminoalkyl group on oxazine nitrogen is K. It is described in Swiss Federal Patent Nos. 505, 850 (C. A. 75, 98600S) by K. Schenker.

The conversion of flavanones to benzoxazepinones 2-substituted by phenyl groups is described by A. Levi and R. Bognar, A Levai and R. Bognar, Top Flavanoid Chem. Biochem. Proc. Hung. Bioflavonoid Symp. 4th Ed. 1973 (Pub. 1975) 119-23 (C. A. 85, 79098n). Thion derivatives are obtained by treatment with phosphorus pentasulfide.

Chemical intermediates 1-methyl-3- (2-carbamoyl-phenoxy) pyrrolidine, 1-benzyl-3- (2-carbamoylphenoxy) -pyrrolidine and 1-methyl-3- (2- 1-Substituted-3-substituted phenoxypyrrolidines, such as carboxyphenoxy) pyrrolidine, are described in US Pat. No. 3, 577, 415.

Oxazepine and thiazepine derivatives exhibiting antihistamine activity, provided by the process of the present invention, are the compounds of formula (I) and pharmaceutically acceptable salts thereof.

Wherein A represents an aromatic ring selected from the group consisting of benzane, naphthalene and pyridine, which share two carbon atoms with the oxazepine or thiazepine moiety at any one of the four positions, any of which may optionally be halo , Substituted with one or two Y groups selected from the group consisting of lower alkyl, lower alkoxy, nitro and trifluoromethyl; B and E are oxygen or sulfur and may be the same or different; R is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl and phenyl-lower alkyl, wherein double phenyl may be optionally substituted with one or two groups selected from halo, lower alkyl, lower alkoxy, nitro and trifluoromethyl ; n is 1,2 or 3; Z is -NR ¹ R ² , 1H-pyrazol-1-yl or 1H-imidazol-1-yl; R ¹ and R ² may be optionally substituted with one or two groups selected from hydrogen, lower alkyl, cycloalkyl and phenyl-lower alkyl (double phenyl being halo, lower alkyl, lower alkoxy, nitro, trifluoromethyl and cyano) Or R ¹ and R ² together with the adjacent nitrogen atom are 1-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl , 1-piperidinyl, 4-substituted piperidin-1-yl, 4-morpholinyl, 1-piperazinyl, 4-substituted paprazin-1-yl and 1,2,3,6 -Heterocycle moiety selected from tetrahydropyridin-1-yl, provided that if R is hydrogen, Z cannot be a primary or secondary amine, and if n is 3, Z is 1H-pyrazole- 1-yl, 1H-imidazol-1-yl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl or 1,2,3,6-tetrahydropyridine-1 -It's not work.

The novel oxazepine and thiazepine precursors, which prepare compounds of formula (I), are of the following formula (II) and acid addition salts thereof:

Wherein A, B, E and Y are as defined in general formula (I) above; R is as defined in formula (I) above, but is not hydrogen; n is 1 or 2; X is chlorine, bromine or cyano.

Other chemical intermediates used in the preparation of compounds of formula (II) are novel and are compounds of formula (III).

Wherein A, E, R, n and Y are as defined in formula (II) above; X is chlorine or bromine.

Further, the chemical intermediate for preparing the compound of formula (IVb) described below is the following formula (IVa) compound.

, -CN 또는

(여기에서 R³는 수소, 알칼리 금속이온 또는 에스테르화기이다)이다. 일반식(IVa)의 화합물은 A가 페닐 또는 치환된 페닐이고 E가 산소인 경우를 제외하고는 신규이다.Wherein A, E, R, n and Y are as defined in formula (II); Q is

, -CN or

Wherein R ³ is hydrogen, an alkali metal ion or an esterification group. Compounds of formula (IVa) are novel except when A is phenyl or substituted phenyl and E is oxygen.

As used herein in the specification and claims, the definitions of the markers in the general formulas herein and the terms have the following meanings.

The term "lower alkyl" as used herein includes straight and branched chain groups of up to 8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, amyl, isoamyl, hexyl , Heptyl and octyl groups. "Lower alkoxy" means -0- lower alkyl.

The term "cycloalkyl" as used herein generally includes cyclic alkyl groups having 3 to 9 carbon atoms, such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl cyclohexyl, cycloheptyl, and the like. There is this.

The term "halo" or "halogen" includes fluorine, chlorine, bromine and iodine unless otherwise stated.

"Pharmaceutically acceptable salts" include acid addition salts, hydrates, alcoholates and quaternary salts of the general formula (I) compounds that are physiologically acceptable in warm blooded animals. Acid addition salts may be formed with strong or weak acids. Representative strong acids are hydrochloric acid, sulfuric acid and phosphoric acid, and weak acids include fumaric acid, maleic acid, succinic acid, oxalic acid, citric acid, tartaric acid and cyclohexamic acid.

Suitable quaternary salts include lower alkyl halides and lower alkyl sulfates.

"Sulfurizing agent means a reactant or mixture of reactants that converts ox- and thiazinone to ox- and thiazepine-thione, for example 2,4-bis (4-methoxyphenyl ) -1,3,2,4-dithiadiphosphetane-2,4-disulfide or mixtures of phosphorus pentasulfide and alkali metal sulfides or mixtures of phosphorus pentasulfide in pyridine.

Compounds of the present invention exhibit antihistamine activity in guinea pigs. The method of testing this activity is a variation of Tozzi et al. (Agents and Actions, Vol. 4/4, 264-270, 1974): guinea pigs in each cage 18 Fast for 24 hours. Water is optionally administered. On the day of testing, three groups of animals are injected intraperitoneally with a dose of 30 mg / kg of the compound prepared in the appropriate excipient. After 30 minutes, histamine is injected into the vein at the edge of the ear at a dose of 1.2 mg / kg (= 2 × LD ₅₀ ). Animals are alive for 24 hours and are determined to have positive antihistamine activity. If the excipient used in the test compound is not water, the effect of the excipient is evaluated by testing as a control using the same dose. Doses that protect 50% of the animals from death (ED ₅₀ ) are obtained from the dose-response curve.

The novel process of the present invention consists of the following steps:

Step 1) The compound of formula (IVb) is then halogenated to produce the compound of formula (III) or free base thereof.

Wherein A is an aromatic ring selected from benzene, naphthalene and pyridine optionally substituted by one or two Y-groups selected from halo, lower alkyl, lower alkoxy, nitro or trifluoromethyl at any one of four positions Represents; E is oxygen or sulfur; R is selected from the group consisting of lower alkyl, cycloalkyl and phenyl-lower alkyl, wherein phenyl may be optionally substituted with one or two groups selected from halo, lower alkyl, lower alkoxy, nitro and trifluoromethyl; ; R ³ is hydrogen or acid neutralized ion; n is 1 or 2; X is chlorine or bromine. Suitable halogenating agents include a) thionyl halide b) triphenylphosphine and carbon tetrahalogenated c) phosphorus pentasulphide d) phosphorus trihalide, and e) triphenylphosphine trihalide, of which thionyl halides are preferred. .

Step 2) If necessary, the carboxylic acid halide derivative produced in step 1 is neutralized, and then fused to produce oxazinone or thiazinone of the following general formula (IIa).

Wherein A, E, R, X, Y and n are as defined in step 1; A shares two carbon atoms with an oxazepine or thiazepine moiety.

Step 3) The compound produced in Step 2 is optionally reacted with a sulfiding agent to obtain the following oxazepinethione or thiazinethione of general formula (IIa).

Wherein A, E, R, X, Y and n are as defined in step 2 above.

Step 4) If desired, the compound produced in Step 2 is reacted with an alkali-metal cyanide to obtain a compound of the following general formula (IIc).

Wherein A, E, Y and R are as defined in step 2.

Step 5) The halogen compound obtained in step 2 or 3 is reacted with a compound of the general formula ZH, wherein Z is as defined below, to give a compound of the general formula (Ia).

Wherein Z is -NR ¹ R ² , 1H-pyrazol-1-yl or 1H-imidazol-1-yl; R ¹ and R ² may be optionally substituted with one or two groups selected from hydrogen, lower alkyl, cycloalkyl and phenyl-lower alkyl, wherein phenyl is halo, lower alkyl, lower alkoxy, nitro, trifluoromethyl and cyano Or R ¹ and R ² together with adjacent nitrogen atoms are 1-pyrrolidinyl, 2,5-dimethyl pyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1 -Piperidinyl, 4-substituted piperidin-1-yl, 4-morpholinyl, 1-piperazinyl, 4-substituted piperazin-1-yl and 1,2,3,6-tetrahydro May form a heterocycle moiety selected from the group consisting of pyridin-1-yl; B represents an oxygen or sulfur atom; A, E, R, n and Y are as defined in step 2 above.

Step 6) The compound of B which is generated in step 5 is an oxygen atom is optionally reacted with a sulfiding agent, preferably with phosphorus pentasulfide in pyridine to give a compound of formula (Ib).

Wherein A, E, R, n, Y and Z are as defined in step 5.

Step 7) The cyano compound prepared in Step 4 (formula (IIc)) is reduced to produce a primary amine of the following formula (Ic-1a).

Wherein A, E, Y and R are as defined in steps 2 and 4.

Step 8) Optionally, the primary amine produced in steps 5 or 7 and then reacted with a) formaldehyde and formic acid to form tertiary dimethylamine, or b) with dihalide Reacting to form a heterocyclic amine, or c) reacting with dialdehyde and sodium cyanoborohydride to form a heterocyclic amine, or d) an equivalent molar amount of aldehyde or ketone, Reacting sodium cyanoborohydride to produce a secondary amine, or e) reacting an equimolar amount of primary amine with sodium cyanoborohydride with at least two equivalents of aldehyde or ketone, or f) trifluoro Acetyl chloride, alkyl or phenyl-alkyl halides, potassium hydride and potassium hydroxide are reacted in order to obtain compounds of the following general formula (Id) in the above reactions and the resulting aze Optionally a non-sulphide or non-thiazol skin and produces a compound with the corresponding thione, which in step 6.

Wherein A, E, Y and R are as defined in step 2 provided that R is not hydrogen; Z is -NR ¹ R ² ; Wherein R ¹ and R ² are lower alkyl, cycloalkyl or phenyl-lower alkyl, wherein phenyl is optionally substituted with halo, lower alkyl, lower alkoxy, nitro, trifluoromethyl or cyano, or R ¹ and R together with the nitrogen atom to which ^two are adjacent to the 1-pyrrolidinyl, 1-piperidinyl, 4-substituted piperidin-1-yl, 4-morph morpholinyl, 1-piperazinyl-1-yl or 1, Heterocycle moieties such as 2,3,6-tetrahydro pyridin-1-yl.

Step 9) optionally Z is tertiary amino, pyrazolyl or imidazolyl, obtained in steps 5, 6 or 8, then benzyl or substituted benzyl compounds of formula (Ie) are reacted with sodium and ammonia to To yield a compound of formula (If).

Wherein A, E and Y are as defined in step 2; n is 1 to 3 and Z is as defined in formula (I) (including proviso provisions).

Step 10) The free base of the compound obtained in steps 5 to 9 is optionally reacted with a pharmaceutically acceptable acid or quaternary forming halide or sulfate to form a pharmaceutically acceptable salt thereof.

Compounds of formula (I) wherein n is 2 are preferred as antihistamines. Processes comprising steps 1 to 3,5,6 and 10, in which the prepared compound has methyl or ethyl side chains (ie n = 1 or 2), correspond to the continuous processes of steps A to F described below It is a process.

Compounds of formulas (Ia), (Ib), (Ic-1) to (Ic-7), (Ic-1a), (Id), (Ie) and (If) are all included in formula (I) And the compounds of formulas (IIa), (IIb), (IIc), (IId) and (IIe) are all included in formula (II).

Steps 1 to 4 also represent novel processes for preparing compounds of formula (IIa), (IIb), (IIc) which are all included in formula (II).

Therefore, an object of the present invention is a novel aromatic 2,3-dihydro-1,4-oxazepin-5 (4H) -one (and sulfur homologue thereof) which exhibits antihistamine activity and is substituted at the 2-position with a short-chain aminoalkyl group. To provide.

Another object of the invention is as a chemical intermediate, a novel aromatic 2,3-dihydro-1,4-oxazepin-5 (4H) -one (and sulfur thereof) substituted at the 2-position with an alkyl halo or alkyl cyano group. Homologs).

The object of the invention is also an aromatic 2,3-dihydro-1,4-oxazepin-5 (4H) -one (and sulfur homologue thereof) substituted in the 2-position with short-chain alkyl halo or alkyl cyano or alkyl amino groups. It is to provide a novel manufacturing method for manufacturing.

Additional objects and advantages of the invention will be apparent to those skilled in the art, and others will become apparent from the following detailed description of the best method for carrying out the invention and the appended claims.

The invention provides not only methods for preparing compounds of formula (I), (II) and (III), but also novel oxazepine and thiazepine derivatives of formula (I) and (II) and formulas (III) and (IVa) And novel compounds of (IVb).

Schemes I and II illustrate the preparation of all intermediates. Where R is not hydrogen.

Scheme III illustrates the reaction sequence for the preparation of the desired product where R is not hydrogen and n is 1 or 2.

Scheme IV illustrates the preparation of a compound having ethyl and propyl groups substituted omega with primary amine (-NH ₂ ) at the 2-position. Wherein R is not hydrogen.

Scheme V describes a method for converting omega-NH ₂ substituted ethyl and propyl compounds to secondary and tertiary amines. This method is a variant for preparing ethyl-secondary and tertiary amines. Wherein R is not hydrogen.

Scheme (VI) illustrates how to prepare compounds in which R is hydrogen.

Preparation Examples 1-23 illustrate the synthesis of compounds of Formulas (IVa) and (IVb) or provide their starting materials. Intermediates 1 to 36 (see Table 1) are aromatic 2,3-dihydro-1,4-oxazinpin-5 (4H) -ones (and their sulfur homologues) substituted with alkyl halo or alkyl cyano groups in the 2-position It demonstrates the manufacturing method of the compound contained in General formula (II) which is Compounds of formula (III) are generally formed in the reaction mixture without separation. Examples 1-71 (reference, Table 2) demonstrate the manufacturing method of the compound contained in general formula (I). However, the scope of the present invention is not limited to these preparations, intermediates and examples.

Scheme I

Preparation of Intermediate (a) (b)

Scheme II

Modification Method of Preparation of Pyridocyclic Halogenated Intermediate (a)

<Note>

X = Cl, Br, CN

E and R are as defined in formula (I).

a) n = 1 or 2

Scheme III

Preparation of the desired product

(n = 1 or 2; not R = H)

<Note>

Z is as defined when n is 1 or 2 in formula (I).

Scheme IV

Preparation of primary ethyl and propyl amino compounds in which R is not hydrogen from cyano intermediate

Scheme VI

Preparation of Compounds Containing Unsubstituted Azepine Nitrogen (R = H)

<Note>

^* Z cannot be a primary or secondary amine.

Scheme V

Process for preparing secondary and tertiary amino-alkyl compounds in which R is not H

<Note>

n = 1-3

^{* Method described by RF Borch, et} al.,

J., Amer. Chem. Boc. 93, 2897 (1971).

(Note ^* Continued reaction Scheme V)

Reaction of General Formula (Ic-1) Compounds in which Z is NH ₂ with Aldehydes and Ketones:

^** JENorlander et al., Tetrahedron Letters 1978 (50) pp 4987-4990.

The process and process steps of the present invention as outlined above, which are applied to the preparation of compounds of formula (I), (II) and (III), are explained in more detail as follows.

In step 1, it is in nearly pure form, or preferably produced by hydrolysis of a precursor containing carbamoyl, cyano or carboxylic ester functional groups in the ortho position without substantially separating the carboxylic acid (or salt) compound from the reaction mixture. Starting compounds of formula (IVb) containing acid neutralizing ions, such as carboxylic acids or alkali-metal salts on the orthoin A ring to ether bonds, derived from the reaction mixtures described above (see Scheme I) as described above Treatment with a suitable halogenating agent, preferably thionyl chloride or triphenylphosphine and carbon tetrachloride. Halogenation is carried out in a suitable organic solvent, preferably a reflux organic solvent or a reflux halogenating agent such as preferred thionyl chloride. A wide range of chlorination temperatures can be applied, for example it can be carried out at room temperature to 100 ° C. or higher but preferably from 50 to 80 ° C. and this temperature includes the temperature of reflux chloroform or thionyl chloride. If an excess halogenating agent such as thionyl chloride is used as the carrier, it is advantageously evaporated. If a solvent such as chloroform is used, it can be evaporated off but need not be. In any case, a solution consisting of a solvent and a compound of formula (III) or a residue consisting of a compound of formula (III), all of which are identified by infrared analysis, can be used in the next step.

In step 2, if the halogenated compound of general formula (III) prepared in step 1 is not already dissolved in the solvent, it is solubilized with an organic solvent, preferably with chloroform and generally, preferably with a tertiary amine such as triethyl amine. Neutralize or basify, then fuse with basic nitrogen and carbonyl and decompose the cyclic amine, for example in reflux triethylamine, to 2- (2-alkyl chloro or bromo) oxazine of general formula (IIa) Or heated to a sufficient temperature for a sufficient time to form a thiazine compound. If the tendency for fusion to occur is sufficiently large, neutralization or basicization can be omitted. Formula (IIa) compounds can be separated by conventional methods, for example, partitioning between a suitable organic solvent or mixture of solvents and an aqueous acid or base, drying and evaporating the organic phase to recrystallize the residue from a suitable solvent. To separate.

In step 3, the compound of formula (IIa) can be optionally converted to oxazeptinone or thiazepinthione of formula (IIb) by heating with a sulfiding agent in a suitable organic solvent such as toluene. Thion (IIb) can be separated by conventional methods, preferably by partitioning between an organic solvent and a dilute alkali-metal base and crystallizing with a suitable solvent such as ethanol.

In step 4, oxazepinone or thiazepinone of general formula (IIa) is reacted with potassium cyanide in a hot protonic solvent using a phase transfer catalyst such as tetrabutyl ammonium chloride. The resulting cyano compound is then extracted with a suitable solvent such as ethyl acetate and the solution is dried and evaporated. The residue is then recrystallized with a suitable solvent such as a mixture of ethyl acetate and isopropyl ether or a solvent of ethyl acetate only. As noted, the resulting compounds contain methyl and ethyl cyano side chains (n = 1 or 2) from which side chains can be extended to produce aminopropyl (n = 3), or amino of methyl side chains. It can be a starting material for extension to ethyl.

In step 5, oxazepinone and thiazepinone of general formula (IIa) obtained in step 2 or oxazepine thione and thiazepinthione of general formula (IIb) obtained in step 3 are pyrazole, imidazole or general formula Reaction with an amine of NHR ¹ R ² , wherein R ¹ and R ² have the meanings defined in formula (I), yields compounds of formulas (Ia) and (Ib), respectively. The latter reaction is preferably carried out in excess of amines such as volatile methylamines. The free bases of the formulas (Ia) and (Ib) products are separated by conventional methods to remove the volatiles and partition between the dilute aqueous alkali metal base and a solvent such as chloroform or methylene chloride and then evaporate. The free base can be recrystallized by conventional methods by conversion to the appropriate acid or, if a quaternary salt, a lower alkyl halide or sulfate to a pharmaceutically acceptable salt. The free base can be redistributed between the free base and a suitable solvent and evaporated to recover from acid addition salts, generally in a more pure form. As noted and shown in Scheme I, the side chains of the resulting intermediates are limited to amino methyl and aminoethyl (n = 2).

In step 6, if desired, the compound wherein B prepared in step 5 is oxygen is sulfided by refluxing for several hours with phosphorus penta sulfide, preferably in anhydrous pyridine. The resulting thions are separated by cooling the solution and partitioning between a suitable solvent such as chloroform and an aqueous base to evaporate the organic phase and separate it in a conventional manner.

In step 7, the cyano compound (IIc), oxazepinone and thiazinone prepared in step 4, is reduced to hydrogen using a Raney Nickel catalyst, preferably at about 60 ° C. The resulting primary aminoethyl or aminopropyl compound (n = 2 or 3) is preferably separated in the form of acid addition salts according to conventional methods, which acid salts are partitioned between a suitable solvent and an aqueous base and then the organic layer is separated. It can be converted back to an organic base by drying and evaporating.

In step 8 (see Scheme V), the primary amine is converted to a secondary or tertiary amine by selecting the appropriate reactant. This method is provided by a process for preparing secondary and tertiary amino compounds of formula (I) with n equal to 3, which is not produced in step 5, and is also a secondary of formula (I) with n equal to 1 or 2 And modified methods for preparing tertiary amino compounds. Processes for the preparation of dimethylamino derivatives by the reaction of primary amines with formaldehyde and formic acid are conventional methods for preparing tertiary dimethyl amines, which are also hetero, such as 1-pyrrolidino, piperidino or 4-morpholino. The same holds true for the reaction of dihalide to produce cyclic amines. Modification methods using sodium cyanoborohydride are in accordance with the process described by R. F. Borsch et al., J. Amer. Chem. Soc. 93, 2897 (1971). Processes using conversion to trifluoro acetamide have been described in J. E. Norlander et al., J. E. Norlander et al, Tetrahedron Letters, 1978 (50) pp 4987-4990.

In step 9, the 4-benzyloxazepineone or thiazinone derivative of formula (I), except for primary or secondary amines (R is benzyl) is reacted with sodium and ammonia to give the corresponding 4-unsubstituted (R Silver hydrogen) can be separated as described in Example 68 by conversion to oxazepinone or thiazinone.

Step 10 is optionally carried out depending on whether the compound of formula (I) is already in the form of a pharmaceutically acceptable salt, or wants to convert it to another salt or desires a free base. In order to obtain the free base from the addition salt of formula (I), the salt is partitioned between a suitable organic solvent such as chloroform and dilute aqueous base. The organic layer is dried and concentrated to give the free base and then optionally reacted with the above-mentioned acid to give the desired salt.

As mentioned above, preferred steps for preparing the preferred compounds having ethyl side chain at the 2-position include steps 1 to 3, 5, 6 and 10 in the general process for preparing all compounds of formula (I). Since compounds containing methyl side chains are prepared in the same process, compounds with n = 1 are included in the preferred process. Such preferred process steps are represented by A to F corresponding to the steps indicated by the numbers in the general process as follows, provided that n is 1 or 2 and R is not hydrogen.

Production Example 1

2- (1-benzyl-3-piperidinyloxy) benzamide

To a suspension of 4.3 g (0.11 mol) of sodium amide in 60 ml of dry toluene is added 19.3 g (0.11 mol) of 1-benzyl-3-pyrrolidinol at a rate such that the temperature is maintained at 35 ° C. Stirring is continued for 3 hours at room temperature. 19 g (0.1 mole) of p-toluenesulfonyl chloride is rapidly added dropwise to the mixture while cooling with an ice bath to maintain the temperature as 20 to 30 ° C. After stirring is continued for 2.5 hours at room temperature, the mixture is left overnight. Toluene was washed twice with water, dried over sodium sulfate and concentrated.

In another vessel, to a suspension of 5.4 g (0.1 mole) of sodium methoxide in 50 ml of dimethylformamide, 13.6 g (0.1 mul) of salicyamide in 75 ml of dimethylformamide are added at a rate such that the temperature is maintained at 50 ° C. After stirring for 15 minutes, the sulfonate prepared above in 25 ml of dimethylformamide is added dropwise and the solution is refluxed for 5 hours. The resulting material is partitioned between 500 ml of ethyl acetate and 500 ml of water. The ethyl acetate layer is extracted with dilute hydrochloric acid, the acid is made basic by adding dilute sodium hydroxide and extracted with ethyl acetate. The organic layer is dried and concentrated to crystallize the residue twice with isopropyl ether-ethyl acetate. The yield of the product is 12.5 g (42%) and the melting point is 120.5 to 122 ° C.

Elemental Analysis: C ₁₈ H ₂₀ H ₂ O ₂

Calculated Value: C; 72.95, H; 6.80, N; 9.46 (%)

Found: C; 73.23, H; 6.78, N; 9.56 (%)

Production Example 2

2- (1-methyl-3-pyrrolidinyloxy) benzamide

202 g (2 moles) of 1-methyl-3-pyrrolidinol are added to 85.6 g (2.2 moles) of sodium amide in 1.5 l of anhydrous toluene so as not to exceed a temperature of 50 ° C. The mixture is then heated to 70 ° C. for 4.5 h. The mixture is cooled and 381 g (2 moles) of o-toluenesulfonyl chloride are added dropwise rapidly while maintaining the temperature at 20-30 ° C. The mixture is stirred for 2.5 hours at room temperature and washed with water. The toluene solution is dried over sodium sulfate and concentrated. The residue dissolved in 500 ml of dimethyl formamide was added to a reaction mixture prepared by adding 119 g (2.2 mol) of dimethyl formamide 11 sodium methoxide and 274 g (2.0 mol) of salicyamide, and the mixture was treated as in Preparation Example 1 Complete. The yield of the product is 170 g (38%) and the melting point is 116 to 118 ° C.

Elemental Analysis: C ₁₂ H ₁₆ N ₂ O ₂

Calculated Value: C; 65.43, H; 7.32, N; 12.72 (%)

Found: C; 65.28, H; 7.28, N; 12.77 (%)

Preparation Example 3

2- [3- (1-benzyl) pyrrolidinyloxy] benzoic acid

To a solution of 20.3 g (0.52 mol) of sodium hydroxide in 600 ml of ethanol and 400 ml of water is added 150 g (0.51 mol) of 2- [3- (1-benzyl) pyrrolidinyloxy] benzamide and the mixture is stirred under reflux for 48 hours. . The mixture is concentrated to 1/2 volume on a rotary evaporator and the residue is extracted with ethyl acetate to remove unreacted amide. The aqueous layer is filtered and the pH of the filtrate is adjusted to 6.5 with hydrochloric acid. The filtrate is concentrated on a rotary evaporator. The residue is dissolved in isopropyl alcohol. The resulting mixture is filtered and the filtrate is concentrated. 85.7 g of residue consisted mostly of the title compound.

Production Example 4

3-[(1-methyl-3-pyrrolidinyl) oxy] -2-naphthalene carboxamide

74 g (0.63 mol) of methanesulfonyl chloride are added dropwise to a cooled solution of 68 g (0.67 mol) of 1-methyl-3-pyrrolidinone and 74 g (0.73 mol) of triethylamine in 700 ml of anhydrous benzene. After stirring at room temperature for 45 minutes, the mixture is filtered and the filtrate is concentrated under reduced pressure and dissolved in 100 ml of dimethylformamide.

In another vessel, 84 g (0.45 mol) of 3-hydroxy-2-naphthalene carboxamide dissolved in 400 ml of dimethylformamide are added dropwise to a cooled suspension of 10.8 g (0.45 mol) of sodium hydride in 75 ml of dimethylformamide. . The sulfonate solution prepared above is added dropwise and the reaction mixture is stirred and heated to reflux for 16 hours. The cooled solution is diluted with 1000 ml of water and extracted twice with 500 ml of chloroform. The chloroform is washed with water and extracted twice with 500 ml of 3N hydrochloric acid. 50% sodium hydroxide is added to the aqueous extract to make alkaline, and extracted three times with 500 ml of chloroform. After drying over magnesium sulfate, chloroform is evaporated under reduced pressure to give 27.4 g (22%) of a pale yellow solid. The product is recrystallized from ethyl acetate to give a product having a melting point of 128 to 130 ° C.

Elemental Analysis: C ₁₆ H ₁₈ N ₂ O ₂

Calculated Value: C; 71.09, H; 6.71, N; 10.36 (%)

Found: C; 70.88, H; 6.68, N; 10.37 (%)

Production Example 5

3-[(1-methyl-3-pyrrolidinyl) oxy] -2-naphthalene-carboxylic acid oxalate [2: 1]

74 g (0.27 mol) of 3-[(1-methyl-3-pyrrolidinyl) -oxy] -2-naphthalene carboxamide is added to a solution of 21.6 g (0.54 mol) of sodium hydroxide in 500 ml of water. The solution is heated to reflux for 10 hours and then cooled to adjust the pH to 6.8 with concentrated hydrochloric acid. The resulting solid is filtered off and the pH of the filtrate is adjusted to 6.02. The filtrate is concentrated under reduced pressure and the residue is filtered by boiling in 200 ml of isopropyl alcohol. The filtrate is concentrated again under reduced pressure to give 69 g (94%) of an amorphous solid. Aliquots are dissolved in isopropanol and treated with oxalic acid. The oxalate salt is recrystallized from ethanol / water to give a product having a melting point of 209 to 212 ° C.

Elemental Analysis: C ₁₇ H ₁₈ NO ₅

Calculated Value: C; 64.55, H; 5.74, N; 4.43 (%)

Found: C; 63,86, H; 5.68, N; 4.37 (%)

Production Example 6

Sodium 2-[(1-methyl-3-pyrrolidinyl) oxy] -3-pyridine carboxylate

To a stirred suspension of 6.4 g (0.13 mol) of 50% sodium hydride (mineral oil) in 50 ml of dimethylsulfoxide was added 6.4 g (0.063 mol) of 1-methyl-3-pyrrolidinol dropwise. During dropping, the temperature rises from 25 ° C to 31 ° C. After 10 minutes, a solution of 10 g (0.063 moles) of 2-chloronicotinic acid in 50 ml of dimethyl sulfoxide is added dropwise to cause a temperature rise. When the temperature reaches 55 ° C., the ice bath is used intermittently until the addition is complete to maintain the temperature. The mixture is then heated to 55-60 ° C. for 1.5 hours, cooled and filtered. The filter cake is suspended in 100 ml of ethyl acetate and filtered. The solid is recrystallized from ethyl acetate-methanol. The yield of the product is 5 g and decomposes at 240 ° C. NMR analysis confirmed that the resulting compound contained 1/3 mol of sodium acetate as an impurity.

Elemental analysis: C ₁₁ H ₁₃ N ₂ O ₃ Na · _1/3 C ₂ H ₃ O ₂ Na

Calculated Value: C; 51.62, H; 5.20, N; 10.32 (%)

Found: C; 51.81, H; 5.15, N; 10.39 (%)

Production Example 7

4-chloro-2-[(1-methyl-3-pyrrolidinyl) oxy] benzamide

50.5 g (0.50 mol) of 1-methyl-3-pyrrolidinol is added dropwise to a solution of 55.5 g (0.55 mol) of triethylamine in 500 ml of anhydrous benzene at a rate such that the temperature is maintained at 25 to 35 ° C. To the mixture maintained at 20-25 ° C., 57 g (0.50 mol) of methanesulfonyl chloride are added dropwise. After stirring for 1 hour at room temperature, the mixture is filtered and the precipitate is washed with 250 ml of hot benzene. The filtrate and washings are combined and concentrated under reduced pressure and the residue is dissolved in 200 ml of dimethyl formamide.

In another vessel, to a cooled suspension of 19.6 g (0.41 mol) of sodium hydride in 100 ml of dimethylformamide, 70 g (0.41 mol) of 4-chlorosalicylamide in 200 ml of dimethylformamide at a rate maintained at 20 ° C. The solution is added dropwise. The sulfonate salt prepared above is added dropwise to the resulting reaction mixture and the mixture is heated to reflux for 19 hours. Cool the reaction mixture and dilute with water 11. The diluted mixture is extracted three times with 300 ml each of chloroform. The chloroform extracts were combined and extracted twice with 500 ml of 3N hydrochloric acid. Combine the aqueous extracts, add 50% sodium hydroxide to make alkaline and extract three times with 500 ml of ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulfate and concentrated under reduced pressure to give 46.5 g (45%) of a beige solid. The solid is recrystallized from ethyl acetate to give a product having a melting point of 122 to 123 ° C.

Elemental Analysis: C ₁₂ H ₁₅ N ₂ ClO ₂

Calculated Value: C; 56.58, H; 5.94, N; 10.99 (%)

Found: C; 56.48, H; 5.96, N; 10.84 (%)

Preparation Example 8

5-bromo-2-[(1-methyl-3-pyrrolidinyl) oxy] benzamide

To a cooled solution of 101 g (10 mol) of 1-methyl-3-pyrrolidinol and 111 g (1.1 mol) of triethylamine in 1000 ml of anhydrous benzene, 114 g (1.0 mol) of methanesulfonyl chloride are added dropwise. The reaction mixture is stirred at rt for 1 h and filtered. The filtrate is concentrated under reduced pressure and dissolved in 100 ml of dimethylformamide.

In another vessel, 5-bromosalicylamide (137 g, 0.63 mol) dissolved in 750 ml of dimethylformamide is added dropwise to a cooled suspension of 30 g (0.63 mol) of sodium hydride in 100 ml of dimethyl formamide. The sulfonate prepared above is added dropwise and the reaction mixture is heated to reflux for 18 hours. The cooled solution is diluted with 1000 ml of water and extracted three times with 500 ml of chloroform. The chloroform extract is washed with water and extracted four times with 500 ml of 3N hydrochloric acid. The aqueous layer is made alkaline with 50% sodium hydroxide and extracted with chloroform. The chloroform extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give 52 g (28%) of a yellow solid. The solid is recrystallized from ethyl acetate / chloroform to give a product having a melting point of 160 to 162 ° C.

Elemental analysis: C ₁₂ H ₁₅ N ₂ BrO ₂

Calculated Value: C; 48.18, H; 5.05, N; 9.36 (%)

Found: C; 48.02, H; 5.01, N; 9.22 (%)

Preparation Example 9

5-chloro-2-[(1-methyl-3-pyrrolidinyl) oxy] benzamide hemihydrate

In a cooled suspension of 2.4 g (0.41 mol) of sodium hydride in 50 ml of dimethyl formamide, 17 g (0.1 mol) of 5-chlorosalicylamide dissolved in 50 ml of dimethyl formamide was added at a rate not exceeding 20 ° C. Add it down. After the addition of salicylate is complete, 16.7 g (0.1 mol) of 3-bromo-1-methyl pyrrolidine dissolved in 50 ml of dimethyl formamide is added dropwise. The reaction mixture is stirred and heated to reflux for 19 hours. The cooled solution is diluted with 250 ml of water and extracted twice with 250 ml of chloroform. Extract three times with 500 ml each of chloroform 3N hydrochloric acid. The aqueous extract is made alkaline by adding 50% sodium hydroxide and extracted with ethyl acetate. Dry over magnesium sulfate and evaporate ethyl acetate under reduced pressure to afford 6g (23%) of the product as a beige solid. The solid is recrystallized from ethyl acetate to give a product having a melting point of 126 to 128 ° C.

Elemental analysis: C ₂₄ H ₃₂ N ₄ Cl ₂ O ₅

Calculated Value: C; 54.65, H; 6.11, N; 10.62 (%)

Found: C; 54.87, H; 6.12, N; 10.69 (%)

Preparation Example 10

1-[(1-methyl-3-pyrrolidinyl) oxy] naphthalene carboxamide

A solution of 118 g (0.63 mol) of 1-hydroxy-2-naphthalenecarboxamide in 250 ml of dimethyl sulfoxide is added dropwise to a suspension of 27.6 g (0.69 mol) of 50% sodium hydride (mineral oil) in 250 ml of dimethyl sulfoxide. The reaction is exothermic and the temperature rises to 60 ° C.

In another vessel, 79 g (0.69 mol) of methanesulfonyl chloride was added dropwise to a solution of 69.7 g (0.69 mol) of 1-methyl-3-pyrrolidinol and 77 g (0.76 mol) of triethylamine in 500 ml of anhydrous benzene while cooling in an ice bath. do. The mixture is stirred for 15 minutes and filtered. The filter cake is washed with 500 ml of benzene and the benzene filtrates are combined and concentrated to about 200 ml on a rotary evaporator. The residue was added dropwise to the dimethyl sulfoxide solution containing the sodium salt of 1-hydroxy-2-naphthalene carboxamide prepared above with stirring at 75 ° C. The temperature is kept at 75 ° C. for 18 hours by external heating. The resulting solution is cooled and the same amount of water is added. The mixture is extracted three times with chloroform. Combine the washes and concentrate. The residue is partitioned between ethyl acetate and dilute hydrochloric acid. The acid layer is made basic with sodium hydroxide and extracted twice with ethyl acetate. Combine ethyl acetate washes, dry over sodium sulfate and concentrate. The residue is crystallized from ethyl acetate-isooctane. The yield of solids is 55 g (32%). Recrystallization of a portion twice with ethyl acetate-isooctane yields a product having a melting point of 122-120 ° C.

Elemental Analysis: C ₁₆ H ₁₈ N ₂ O ₂

Calculated Value: C; 71.11, H; 6.71, N; 10.36 (%)

Found: C; 70.96, H; 6.71, N; 10.31 (%)

Production Example 11

5-methoxy-2-[(1-methyl-3-pyrrolidinyl) oxy] -benzamide

171 g (1.5 mol) of methanesulfonyl chloride is added dropwise while cooling to a solution of 151 g (1.5 mol) of 1-methyl-3-pyrrolidinol and 166 g (1.6 mol) of triethylamine in 1500 ml of anhydrous benzene. The reaction mixture is stirred at rt for 1 h and filtered. The filtrate is concentrated under reduced pressure to give an orange oil.

In another vessel, 139 g of the sulfonate and 5-methoxy salacamide prepared above dissolved in 600 ml of dimethylformamide while cooling in a suspension of 50% sodium hydride / mineral oil (72 g, 1.5 mol) in 150 ml of dimethylformamide. (0.93 mol) is added dropwise. The reaction mixture is heated to reflux for 14 hours. After cooling, the reaction is diluted with 1000 ml of water and extracted three times with 700 ml of chloroform. The combined chloroform extracts were washed three times with water and extracted three times with 500 ml of 3N hydrochloric acid. The aqueous layer is made alkaline and extracted with chloroform. The chloroform extract is washed three times with water and dried over magnesium sulfate and then evaporated under reduced pressure to give a viscous brown oil. The material is distilled in the major to obtain a viscous orange oil which is dissolved in chloroform, extracted with acid, made alkaline and extracted with chloroform again. The solvent is evaporated to give a dark brown oil which solidifies under reduced pressure. Recrystallization three times with ethyl acetate gave 10 g (4%) of white crystals with a melting point of 85 to 87 ° C.

Elemental Analysis: C ₁₃ H ₁₈ N ₂ O ₃

Calculated Value: C; 62.38, H; 7.25, N; 11.19 (%)

Found: C; 62.47, H; 7.26, N; 11.20 (%)

Preparation Example 12

3-[(1-methyl-3-pyrrolidinyl) oxy] -4-pyridine-carbonitrile fumarate [1: 2]

A solution of 55 g (0.55 mol) of 1-methyl-3-pyrrolidinol in 55 ml of anhydrous dimethylformamide is added dropwise to a suspension of 22 g (0.58 mol) of 60% sodium hydride / 40% mineral oil in 300 ml of dimethylformamide. The mixture is stirred at room temperature for 1 hour, and gently cooled to add 73 g (0.53 mol) of 3-chloro-4-cyanopyridine in 200 ml of dimethylformamide while maintaining the temperature at 30 to 40 ° C. The solution is stirred for 3 hours and the same amount of water is added. The solution is acidified with dilute hydrochloric acid and extracted with isopropyl ether. The aqueous layer was made basic by adding sodium hydroxide and then extracted five times with chloroform. The extracts are combined, dried over sodium sulfate and concentrated. The residue is treated with 400 g of isopropyl alcohol and 50 g of fumaric acid in 40 ml of water. The resulting crystals (51 g, 21%) are collected and 2 g of the double sample is recrystallized from methyl isobutyl ketone. The yield of the product is 1.5 g and the melting point is 172 to 174 ° C.

Elemental analysis: C ₁₉ H ₂₁ N ₃ O ₉

Calculated Value: C; 52.42, H; 4.86, N; 9.65 (%)

Found: C; 52.40, H; 4.90, N; 9.68 (%)

Preparation Example 13

1-[(1-methyl-3-pyrrolidinyl) oxy] -2-naphthalene carbonitrile oxalate

A solution of 29 g (0.11 mol) of 1-[(1-methyl-pyrrolidinyl) oxy] -2-naphthalene-carboxamide and 38 g (0.32 mol) of thionyl chloride in 150 ml of chloroform was heated to reflux for 6 hours. The solution is poured on ice and made basic with sodium hydroxide. The chloroform layer is separated, dried over sodium sulfate and concentrated. The residue is dissolved in hot isooctane, the solution is treated with charcoal, filtered and concentrated. The residue is dissolved in isopropyl alcohol and oxalic acid is added. The precipitate is recrystallized from an isopropyl alcohol-water mixture. The yield of the product is 11.5 g (31%) and the melting point is 176 to 184 ° C.

Elemental Analysis C ₁₈ H ₁₈ N ₂ O ₅ :

Calculated Value: C; 63.15, H; 5.30, N; 8.18

Found: C; 63.00, H; 5.29, N; 8.15

Preparation Example 14

3,5-Diiodo-methylsalicylate

150 g (0.39 mol) of 3,5-diiosalicylic acid is added to 1 liter of anhydrous methanol. Hydrogen chloride is passed through the reaction mixture under stirring to foam and reflux for 3 hours. The reaction mixture turns cloudy and rapidly precipitates large amounts of white crystals. After the mixture is filtered and dried, 136 g (83%) of product at melting point 198-202 ° C. are obtained.

Preparation Example 15

2-hydroxy-3,5-diiodobenzamide

An excess of liquid ammonia, 3,5-diiodo methylsalicylate and a catalytic amount of sodium hydride are added to a stainless steel bomb cooled with dry ice acetone. Seal the bomb and shake for 16 hours at room temperature. Cool again and pour out the contents of the bomb to evaporate excess ammonia at room temperature. The product melts at 190 to 195 ° C. Mass spectrometry confirms the molecular weight of the title compound.

Preparation Example 16

3,5-Diiodo-2-[(1-methyl-3-pyrrolidinyl) oxy] -benzamide

According to the procedure of Preparation Example 2, the title compound is prepared using 2-hydroxy-3,5-diiodobenzamide instead of salicylicamide.

Preparation Example 17

Sodium-2-[(1-methyl-3-azetidinyl) oxy] -3-pyridinecarboxylate

The title compound is prepared according to the procedure of Preparation Example 6 using 1-methyl-3-azetidinol instead of 1-methyl-3-pyrrolidinol.

Production Example 18

4-[(1-methyl-3-pyrrolidinyl) oxy] -3-pyridine carboxylic acid sodium salt

4-chloropyridine is reacted with diisopropyl lithiumamide and carbon dioxide to obtain a lithium salt of 3-carboxy-4-chloropyridine, followed by 1-methyl-3-pyrrolidinol as in Preparation Example 6. .

Preparation Example 19

3-[(1-methyl-3-pyrrolidinyl) oxy] -2-pyridine carbonitrile fumarate

과 반응시켜 2-시아노-3-클로로 피리딘을 수득한 다음, 제조실시예 12에서와 같이 1-메틸-3-피롤리디놀과 반응시켜 표제 화합물을 수득한다.2-carboxamide-3-hydroxy pyridine

To give 2-cyano-3-chloro pyridine, followed by reaction with 1-methyl-3-pyrrolidinol as in Preparation Example 12 to give the title compound.

Production Example 20

1-methyl-3-pyrrolidine thiol acetate (ester) ethanedioate

To a solution of 101 g (1 mol) of 1-methyl-3-pyrrolidinol and 110 g (1.1 mol) of triethylamine in 700 ml of anhydrous benzene, 115 g (1 mol) of methanesulfonyl chloride were added dropwise while cooling and stirring in an ice bath. The resulting mixture is stirred for 0.5 h and filtered. The filtrate is concentrated to about 200 ml, taking care not to overheat on the rotary evaporator. The residue is dissolved in about 150 ml of ethanol.

In another vessel, 25.3 g (1.1 moles) of sodium are dissolved in 800 ml of 200 proof ethanol while flushed with nitrogen gas. After complete dissolution, 83.6 g (1.1 mol) of thiol acetic acid are slowly added and the resulting solution is stirred for an additional 10 minutes. The prepared ethanol solution of methanesulfonate is added and the resulting solution is heated to 60 ° C. for 20 hours. The mixture is cooled to 25 ° C. and filtered to concentrate the filtrate on a rotary evaporator. The residue is dissolved in isopropyl ether and the mixture is filtered to remove a small amount of solids. The filtrate is concentrated and the residue is distilled to give 70 g of the free base of the title ester having a boiling point of 95 to 105 ° C./15 mm. A 7 g portion of free base was treated with 4 g of oxalic acid in isopropyl alcohol and the obtained salt was recrystallized from isopropyl alcohol to give 8.4 g of the title compound (melting point: 108 to 111 ° C.).

Preparation Example 21

1-methyl-3-pyrrolidinethiol oxalate

A solution of 62 g (0.39 mol) of 1-methyl-3-pyrrolidinethiol acetate (ester) in 200 ml of anhydrous methanol was treated with 2 mm sodium, and the resulting solution was distilled at 1 atm under a pot temperature of 100 ° C. . Process under vacuum and slowly reduce the pressure to 100 mm. The residue is distilled at a pot temperature of 130 ° C. to give 25 g (56%) of free base of the title compound as a distillate having a boiling point of 95 to 100 ° C./mm. 4 g of sample is treated with oxalic acid in isopropyl alcohol to give 5.5 g of oxalate salt with a melting point of 80 to 82 ° C.

Preparation Example 22

2-[(1-Methyl-3-pyrrolidinyl) thio] -3-pyridine-carboxylic acid

300 ml of dimethylformamide at a rate of maintaining the temperature at 60 to 67 캜 in a stirred suspension of 80 g (2 mol) of 60% sodium hydride (in mineral oil) in 800 ml of anhydrous dimethylformamide, all heated to 60 캜 under nitrogen gas stream. A solution of 157.0 g (1 mol) of 2-chloro-nicotinic acid and 117 g (1 mol) of 1-methyl-3-pyrrolidinethiol in water was added dropwise. The mixture is heated to 65 ° C. for 6 hours and left at room temperature overnight, then filtered. The solids are collected and suspended in 1 l of isopropyl alcohol and hydrogen chloride is passed through the suspension until the pH of the suspension reaches 6.2. The mixture is boiled and filtered. The solid is dissolved in 2 l of water and extracted with isopropyl ether. The pH is adjusted to 6.0 and the solution is concentrated to 800 ml volume and placed in the freezer. The resulting solid (85 g), collected by filtration, is a mixture of about 85% of the title compound and 15% sodium chloride. A portion of the sample in the product is crystallized once with ethanol and 12 times with isopropyl alcohol-water. The recrystallized product decomposes at about 225 ° C.

Preparation Example 23

Sodium 2-[(1-cyclohexyl-3-azetidinyl) -oxy] -3-pyridine carboxylate

A solution of 105 g (0.68 mol) of 1-cyclohexyl-3-azetidinol and 106 g (0.68 mol) of 2-chloronicotinic acid in 400 ml of anhydrous dimethylformamide was suspended at 60 ° C. in 400 ml of anhydrous dimethylformamide at 60% sodium hydride. Rapidly dropwise to 52 g (1.35 moles) of mineral oil. Mild exothermic reactions occur. After stirring at 60 ° C. for 2 hours, the mixture is filtered. The filter cake is washed with ethyl acetate and dried at 80 ° C./2 mm to give 174 g (86%) of the crude title compound.

[Intermediate 1]

2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one

To 54 g (1.35 mol) of sodium hydroxide in 800 ml of water, 148 g (0.67 mol) of 2-[(1-methyl-3-pyrrolidinyl) oxy] -benzamide are added and the mixture is refluxed for 18 hours. The pH is adjusted to 7 with hydrochloric acid and the solution is concentrated by filtration. The residue is boiled with 400 ml of isopropanol and filtered. The filtrate is concentrated to reflux the residue (crystallized) with 300 ml of thionyl chloride for 0.5 h and concentrated in vacuo. The residue is dissolved in 300 ml of chloroform and the solvent is boiled off in vacuo. The residue is redissolved in chloroform and 150 ml of triethylamine is added to reflux the mixture for 1 hour. The solution is concentrated in vacuo and the residue is partitioned between 400 ml of ethyl acetate, 400 ml of isopropyl ether and 500 ml of dilute hydrochloric acid. The organic layer is washed twice with water, then washed once with diluted sodium hydroxide, dried over sodium sulfate and concentrated. The residue is crystallized from isopropanol-water. The yield of the product is 75 g (47%) and the melting point is 97-107 ° C.

Elemental Analysis C ₁₂ H ₁₄ NO ₂ Cl:

Calculated Value: C; 60.13, H; 6.89, N; 5.84

Found: C; 60.35, H; 5.91, N; 5.65

[Intermediate 2]

4-benzyl-2- (2-chloroethyl) -2,3-dihydro-1,4-benzoxazepin-5 (4H) -one

150 ml of thionyl chloride is added to 85.7 g (0.29 mol) of 2-[(1-benzyl-3-pyrrolidinyl) oxy] -benzoic acid. The solution is left for 15 minutes, then refluxed for 30 minutes and concentrated in vacuo. The residue is treated twice with 250 ml of chloroform and concentrated in vacuo. The residue was dissolved in 500 ml of chloroform and slowly added with stirring 101 g (1 mol) of triethylamine. The solution is refluxed for 1 hour and concentrated in vacuo. The residue is partitioned between 50% ethyl acetate-50% isopropyl ether and dilute hydrochloric acid. The organic layer is washed with dilute sodium hydroxide and concentrated. The residue is crystallized five times with isopropyl ether-ethyl acetate. The yield of the product is 23.8 g (26%) and the melting point is 145.0 to 147 ° C.

Elemental Analysis C ₁₈ H ₁₈ NO ₂ Cl:

Calculated Value: C; 68.46, H; 5.74, N; 4.44

Found: C; 68.47, H; 5.89, N; 4.32

[Intermediate 3]

2- (2-Chloroethyl) -2,3-dihydro-4-methylnaphth- [2,3-f] [1,4] -oxazepine-5 (4H) -one

To a solution of 21.6 g (0.54 mol) of sodium hydroxide in 500 ml of water, 74 g (0.27 mol) of 3-[(1-methyl-3-pyrrolidinyl) -oxy] -2-naphthalene carboxamide was added and the mixture was stirred for 16 hours. Reflux. Adjust the pH to 6.8 with concentrated hydrochloric acid and concentrate the solution by filtration. The residue is filtered by boiling with 200 ml of isopropyl alcohol. The filtrate is concentrated under reduced pressure to dissolve the residue in chloroform. Thionyl chloride (59 g, 0.50 mol) is added and the reaction mixture is heated to reflux for 4 hours. After cooling, 67 g (0.67 mole) of triethylamine was added dropwise. The mixture is washed twice with 3N hydrochloric acid, twice with water, twice with 10% sodium hydroxide, and twice with water and dried over magnesium sulfate. Evaporate chloroform under reduced pressure to give 44 g (58%) of a viscous dark brown oil. The resulting material is purified by high pressure liquid chromatography (50/50 ethyl acetate / hexane) and recrystallized with isopropyl alcohol to give brown crystals with a melting point of 101 to 102 ° C.

Elemental Analysis C ₁₆ H ₁₆ NClO ₂ :

Calculated Value: C; 66.32, H; 5.57, N; 4.83

Found: C; 66.19, H; 5.63, N; 4.77

[Intermediate 4]

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride

Hydrogen chloride is introduced into a suspension of 150 g (0.61 mol) of sodium 2-[(1-methyl-3-pyrrolidinyl) oxy] -3-pyridine carboxylate in 1 l of chloroform until the pH reaches 6. To the stirred mixture, 350 g (1.34 mole) of triphenylphosphine and 350 g (2.3 mole) of carbon tetrachloride are added, and the resulting cloudy solution is stirred under reflux for 1.5 h. About 100 ml of ethanol are added and heating is stopped. The solution is stirred for 1 hour while cooling and 200 ml of isooctane is added. The solution is extracted four times with a total of 800 ml of diluted hydrochloric acid. Combine the acid extracts, add sodium hydroxide to make basic and extract with chloroform. The chloroform layer is separated, dried over sodium sulfate and concentrated. The residue is dissolved in a mixture of 500 ml each of isopropyl alcohol and isopropyl ether and acidified by addition of ethereal hydrogen chloride. The resulting crystals weigh 82 g (49%), some of which are recrystallized from isopropyl alcohol to give products having a melting point of 149-153 ° C.

Elemental Analysis C ₁₁ H ₁₄ N ₂ O ₂ Cl ₂ :

Calculated Value: C; 47.67, H; 5.09, N; 10.11

Found: C; 47.57, H; 5.18, N; 10.00

[Intermediate 5]

8-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5- (4H) -one

To a solution of 10.4 g (0.25 mol) of sodium hydroxide in 150 ml of water, 32 g (0.13 mol) of 4-chloro-2-[(1-methyl-3-pyrrolidinyl) oxy] benzamide were added and the mixture was heated to reflux for 24 hours. do. The reaction mixture is added to concentrated hydrochloric acid to pH 6 and filtered to concentrate the filtrate. The residue is boiled with 100 ml of isopropyl alcohol and the mixture is filtered. The filtrate is concentrated and heated to reflux with 98 g (0.83 mol) of thionyl chloride for 1 hour. Excess thionyl chloride is evaporated under reduced pressure. The residue is dissolved in 70 ml of chloroform and the solvent is evaporated under reduced pressure. The residue is redissolved in 75 ml of chloroform and 40 ml of triethylamine are added slowly. The mixture is heated to reflux for 1 hour. The solvent is evaporated under reduced pressure to give a dark brown solid. The solid is dissolved in ethyl acetate and the resulting solution is washed twice with 200 ml of water and then twice with 250 ml of 20% sodium hydroxide. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure to yield 21 g (59%) of a dark brown solid. The solid is recrystallized from isopropyl alcohol to afford the title compound at melting point 85-87 ° C.

Elemental Analysis C ₁₂ H ₁₃ NCl ₂ O ₂ :

Calculated Value: C; 52.57, H; 4.78, N; 5.11

Found: C; 52.57, H; 4.77, N; 5.04

[Intermediate 6]

7-bromo-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one

To a solution of 9.6 g (0.24 mole) of sodium hydroxide in 200 ml of water was added 37 g (0.12 mole) of 5-bromo-2-[(1-methyl-3-pyrrolidinyl) oxy] -benzamide and the mixture was stirred for 18 hours. Heated to reflux. The pH of the mixture is adjusted to pH 6.7 with concentrated hydrochloric acid solution. The solution is concentrated under reduced pressure and the residue is boiled in 250 ml of isopropyl alcohol for 1 hour. The mixture is filtered and the filtrate is concentrated. The residue is dissolved in chloroform and 28.3 g (0.24 mol) of thionyl chloride is added to the solution. The mixture is heated to reflux for 0.5 h and cooled to 15 ° C. in an ice bath. 26.6 g (0.26 mol) of triethylamine are added dropwise to the mixture at a rate such that the temperature does not exceed 25 ° C. The reaction mixture is stirred at room temperature for 1 hour and then washed successively with 3N hydrochloric acid, 15% aqueous sodium hydroxide and water. The chloroform layer is dried over magnesium sulfate and concentrated under reduced pressure to give 23 g (60%) of a brown solid. Some of the resulting solid is recrystallized from ethyl acetate-isopropyl ether to give a product having a melting point of 92 to 94 ° C.

Elemental Analysis C ₁₂ H ₁₃ NBrClO ₂ :

Calculated Value: C; 45.24, H; 4.11, N; 4.40

Found: C; 45.61, H; 4.17, N; 4.42

[Intermediate 7]

7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one

Hydrogen chloride is introduced into a solution of 113 g (0.44 mole) of 5-chloro-2-[(1-methyl-3-pyrrolidinyl) oxy] benzamide dissolved in 500 ml of glacial acetic acid, whereupon the reaction is cooled in an ice bath. Butyl nitrite (142 g, 1.38 moles) was added all at once and the reaction stirred at room temperature for 16 hours and heated to reflux for a further 6 hours. Acetic acid is evaporated under reduced pressure and tetrachloroethane is added to the residue twice.

The residue is dissolved in chloroform and treated with 163 g (1.38 mol) of thionyl chloride and heated to reflux for 22 hours. The reaction mixture is cooled in an ice bath and 152 g (1.5 mole) of triethyl amine are added dropwise at a rate such that the temperature is maintained at 25-30 ° C. The reaction mixture is diluted with 200 ml of chloroform and washed successively with 3N hydrochloric acid, water, 10% sodium hydroxide and water. Chloroform was evaporated under reduced pressure to give 40 g (33%) of residue per black tar.

An aliquot of the resulting residue is purified on a silica gel column using ethyl acetate as eluent. Recrystallization with isopropyl alcohol gives beige crystals with a melting point of 101 to 103 캜.

Elemental Analysis C ₁₂ H ₁₃ NCl ₂ O ₂ :

Calculated Value: C; 52.57, H; 4.78, N; 5.11

Found: C; 52.63, H; 4.83, N; 5.05

[Intermediate 8]

2- (2-Chloroethyl) -2,3-dihydro-4-methylnaphth- [2,1-f] [1,4] -oxazepine-5 (4H) -one

Hydrogen chloride gas is introduced into the solution of 8 g (0.03 mol) of 1-[(1-methyl-3-pyrrolidinyl) oxy] -2-naphthalenecarboxamide in 40 ml of acetic acid for about 2 minutes. The solution is cooled in an ice bath and 6.1 g (0.06 mol) of n-butyl nitrite are slowly added below the surface of the liquid at 12-15 ° C. (approximately 10 minutes are taken). The solution is stirred at 25 ° C. for 18 hours and heated in a steam bath for 3 hours. The solution is concentrated on a rotary evaporator. After the residue was dissolved in 60 ml of 1,1,2,2-tatrachloroethane, the solvent was removed on a rotary evaporator under 0.5 mm / vapor temperature.

The residue is dissolved in 75 ml of chloroform and treated with 7 g (0.06 mol) of thionyl chloride and refluxed for 12 hours. The solution is extracted with water and then with dilute sodium hydroxide, dried over sodium sulfate and concentrated. The residue is recrystallized twice with isopropyl ether-ethyl acetate. The yield of the product is 3.2 g (37%) and the melting point is 109-111 ° C.

Elemental Analysis C ₁₆ H ₁₆ NO ₂ Cl:

Calculated Value: C; 66.32, H; 5.57, N; 4.84

Found: C; 66.15, H; 5.56, N; 4.76

[Intermediate 9]

2- (2-Chloromethyl) -2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5 (4H) -one

To a solution of 19.2 g (0.48 mol) of sodium hydroxide in 500 ml of water was added 60 g (0.24 mol) of 5-methoxy-2-[(1-methyl-3-pyrrolidinyl) oxy] -benzamide and the mixture was stirred for 24 hours. Heat to reflux. Cool the reaction mixture and adjust the pH to 6.8 with concentrated hydrochloric acid. The mixture is concentrated under reduced pressure and the residue is boiled in isopropyl alcohol for 1 hour. The mixture is filtered and the filtrate is concentrated. The residue is dissolved in 500 ml of chloroform and 114 g (0.96 mol) of thionyl chloride are added to this solution. The mixture is heated to reflux for 48 hours and then cooled in an ice / acetone bath. To the mixture, 97 g (0.96 mol) of triethylamine are added dropwise at a rate such that the temperature does not exceed 25 ° C. The reaction solution is washed successively with water, 3N hydrochloric acid solution, water, 15% aqueous sodium hydroxide and water and finally dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give a black solid. The solid is purified on a silica gel column using ethyl acetate as eluent to separate 15 g (25%) of beige product with a melting point of 98 to 100 ° C.

Elemental Analysis C ₁₃ H ₁₆ NClO ₃ :

Calculated Value: C; 57.89, H; 5.98, N; 5.19

Found: C; 57.53, H; 6.00, N; 5.16

[Intermediate 10]

2- (2-Chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione

A mixture of 18.5 g (0.0834 mole) of phosphorus sulphide and 18.5 g of potassium sulfide was ground together to form 2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxa in anhydrous toluene. To 100 g (0.417 mol) of zepin-5 (4H) -one is added and the mixture is refluxed for 24 hours and filtered. The filtrate is concentrated and partitioned over chloroform and dilute sodium hydroxide. The chloroform layer is concentrated to crystallize the residue several times with ethanol. The yield of the product is 55 g (52%) and the melting point is 105 to 108 ° C.

Elemental Analysis C ₁₂ H ₁₄ NSOCl:

Calculated Value: C; 56.35, H; 5.52, N; 5.48, S; 12.54

Found: C; 56.55, H; 5.47, N; 5.49, S; 12.55

[Intermediate 11]

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -thione

59 g of 2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] [1,4] -oxazin-5 (4H) -one hydrochloride in 1500 ml of chloroform 0.25 mol) of the solution is added 41.5 g (0.19 mol) of phosphorus sulfide and the mixture is heated to reflux for 18 hours. The mixture is filtered and the filtrate is extracted with dilute sodium hydroxide. The chloroform layer is concentrated and the residue is dissolved in 250 ml of boiling isopropyl alcohol. Upon cooling, 28 g (44%) of a yellow solid precipitates. Some of them are recrystallized from isopropyl alcohol to give a product having a melting point of 134 to 136 ° C.

Elemental Analysis C ₁₁ H ₁₃ N ₂ ClOS:

Calculated Value: C; 51.46, H; 5.10, N; 10.81

Found: C; 51.35, H; 5.21, N; 10.72

[Intermediate 12]

2- (2-Chloroethyl) -2,3-dihydro-4-methylnaphth- [2,3-f] [1,4] -oxazepine-5 (4H) -thione

16.6 g of 2- (2-chloroethyl) -2,3-dihydro-4-methyl naphth [2,3-f] [1,4] -oxazin-5 (4H) -one in 150 ml of anhydrous toluene ( 0.06 mole) of a solution is added with a mixture of 8.6 g (0.045 mole) of phosphorus sulphide and 8.6 g of potassium sulfide. The reaction mixture is stirred and heated to reflux for 24 hours. The mixture is filtered on hot and the filtrate is concentrated under reduced pressure. 6.5 g (35%) of a yellow solid are obtained and recrystallized from ethanol to give a product having a melting point of 166 to 168 ° C.

Elemental Analysis C ₁₆ H ₁₆ NClOS:

Calculated Value: C; 62.84, H; 5.27, N; 4.58

Found: C; 62.29, H; 5.48, N; 4.47

[Intermediate 13]

8-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione

To a solution of 43 g (0.16 mol) of 8-chloro-2- (2-chloromethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one in 400 ml of anhydrous toluene Then, a mixture of 23 g (0.12 mol) of phosphorus sulphide crushed together and 23 g of potassium sulfide is added. The reaction mixture is stirred and heated to reflux for 24 hours. The mixture is filtered on heat and the filtrate is concentrated under reduced pressure to give 25.5 g (55%) of an orange oil which solidifies upon standing at room temperature. The solid is recrystallized from ethanol to give a product having a melting point of 105 to 106 ° C.

Elemental Analysis: C ₁₂ H ₁₃ NCl ₂ OS:

Calculated Value: C; 49.66, H; 4.52, N; 4.83

Found: C; 49.63, H; 4.53, N; 4.75

[Intermediate 14]

7-bromo-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -thione

11.0 g (0.035 mol) of 7-bromo-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one in 150 ml of anhydrous toluene To the solution is added a mixture of 13.4 g (0.07 mole) of phosphorus pentasulphide and 13.4 g of potassium sulfide. The reaction mixture is heated to reflux for 5 hours under a nitrogen atmosphere. The mixture is filtered on hot and the filtrate is concentrated under reduced pressure. The residue is dissolved in chloroform. The chloroform solution is washed twice with dilute aqueous sodium hydroxide, dried over magnesium sulfate and concentrated under reduced pressure to give 8.5 g (72%) of a yellow solid. The solid is recrystallized from ethanol to give a product having a melting point of 118 to 120 ° C.

Elemental Analysis C ₁₂ H ₁₃ NBrClOS:

Calculated Value: C; 43.07, H; 3.09, N; 4.18

Found: C; 43.08 H; 3.88, N; 4.12

[Intermediate 15]

2- (2-Chloroethyl) -2,3-dihydro-4-methylnaphth- [2,1-f] [1,4] -oxazepine-5 (4H) -thione

A mixture of 9.55 g of phosphorus sulfide and 9.5 g of potassium sulfide was ground together to prepare 2- (2-chloroethyl) -2,3-dihydro-4-methylnaphth [2,1-f] [in 200 ml of anhydrous toluene. 1,4] to a solution of 20.2 g (0.07 mol) of oxazin-5 (4H) -one. The mixture is stirred and heated to reflux for 7 hours. The hot mixture is filtered and the product is crystallized from the cooled filtrate. Recrystallization from chloroform affords 18 g (84%) of yellow crystals having a melting point of 167 to 170 ° C.

Elemental Analysis C ₁₆ H ₁₆ NClOS:

Calculated Value: C; 62.84, H; 5.27, N; 4.58

Found: C; 62.85, H; 5.20, N; 4.55

[Intermediate 16]

2- (2-Chloroethyl) -2.3-dihydro-4-methylpyrido- [4,3-f] [1,4] -oxazepine-5 (4H) -one hydrochloride

49 g (0.11 mol) of a sample of 3-[(1-methyl-3-pyrrolidinyl) oxy] -4-pyridine carbonitrile fumarate [1: 2] were partitioned between chloroform and saturated potassium carbonate solution. The aqueous layer is extracted twice with chloroform. All chloroform extracts are combined, dried and concentrated. The residue is dissolved in 125 ml of tert-butanol and added to 34 g (0.6 mol) of potassium hydroxide pellets. The mixture is stirred at room temperature for 88 hours and then diluted with 150 ml of toluene. The mixture is filtered to concentrate the filtrate. After the residue was dissolved in chloroform while cooling, the pH was adjusted to 6.0 with hydrogen chloride gas. The resulting mixture was concentrated and 400 ml of anhydrous toluene was added to the residue. Remove toluene and water on a rotary evaporator (steam bath / decompression). The residue was dissolved in 400 ml of chloroform, 63 g of triphenylphosphene was added, followed by 70 g of carbon tetrachloride. The solution is stirred at reflux for 2 hours and additionally 30 g of triphenylphosphine is added. After refluxing for an additional hour, reflux is continued for 4 hours with addition of at least 70 g of carbon tetrachloride and at least 63 g of triphenylphosphine. The solution is extracted with dilute sodium hydroxide and then concentrated. The residue is partitioned between toluene and dilute hydrochloric acid. The toluene layer was extracted five times with dilute hydrochloric acid, the acid extracts were combined, made basic with sodium hydroxide and extracted with chloroform. The chloroform layer is dried over sodium sulfate and concentrated. The residue is chromatographed on a 7 × 25 Cm column of silica gel using acetone liquid phase. After evaporation 5.8 g (20%) of the free base of the title compound are separated. To some of the free base dissolved in isopropyl alcohol, ethereal hydrogen chloride and isopropyl ether are added. The resulting crystals are collected and dried to give a product having a melting point of 188 to 190 ° C.

Elemental Analysis C ₁₁ H ₁₄ N ₂ O ₂ Cl ₂ :

Calculated Value: C; 47.67, H; 5.09, N; 10.11

Found: C; 48.33, H; 5.22, N; 9.73

[Intermediate 17]

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido- [3,4-f] [1,4] -oxazepine-5 (4H) -one hydrochloride

Equimolar amount of sodium 4-[(1-methyl-3-pyrrolidinyl) -oxy]-in place of 2-[(1-methyl-3-pyrrolidinyl) oxy] -3-pyridinecarboxylic acid in the process of intermediate 4 3-pyridine carboxylate is used to yield the title compound.

[Intermediate 18]

2- (2-Chloroethyl) -2,3-dihydro-4-methyl-pyrido [2,3-f] [1,4] oxazepin-5 (4H) -one hydrochloride

3-[(1-methyl-3-pyrrolidinyl) -oxy]-in place of 3-[(1-methyl-3-pyrrolidinyl) oxy] -4-pyridine-carbonitrile fumarate in the process of intermediate 16 Using 2-pyridine carbonitrile fumarate, the title compound is obtained.

[Intermediate 19]

7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione

Together with a solution of 20 g (0.07 mol) of 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one in 200 ml of toluene A mixture of 9.55 g (0.05 mol) of pulverized phosphorus sulfide and 9.5 g of potassium sulfide is added. The reaction mixture is filtered and the filtrate is coaxially under reduced pressure to give a yellow solid. Recrystallization with anhydrous ethanol yields 12.5 g (68%) of product at melting point 102-104 ° C.

Elemental Analysis C ₁₂ H ₁₃ NCl ₂ OS:

Calculated Value: C; 49.66, H; 4.52, N; 4.83

Found: C; 49.62, H; .55, N; 4.76

[Intermediate 20]

2- (2-Chloroethyl) -7,9-diiode-2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one

3,5-Diiod-2-[(1-methyl-3-pyrrolidinyl) oxy] -benz instead of 2-[(1-methyl-3-pyrrolidinyl) oxy] benzamide in the process of intermediate 1 Using the amide, the title compound is prepared.

[Intermediate 21]

2-Chloromethyl-2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] oxazepine-5 (4H) -one hydrochloride

Equimolar amount of sodium 2-[(1-methyl-3-azetidinyl) oxy] instead of sodium 2-[(1-methyl-3-pyrrolidinyl) oxy] -3-pyridinecarboxylate in the process of intermediate 4 The title compound is prepared using 3-pyridine-carboxylate sodium acetate.

[Intermediate 22]

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [4,3-f] [1,4] oxazepine-5 (4H) -thione

5 g (0.021) of 2- (2-chloroethyl) -2,3-dihydro-4-methyl pyrido [4, 3-f] [1,4] -oxazepine-5 (4H) -one in 100 ml of anhydrous toluene Mole) and a solution of 5.1 g (0.0126 mole) of 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiodiphosphetane-2,4-disulfide are stirred under reflux for 2.5 hours. . Cool the solution and extract three times with sodium bicarbonate solution. The toluene layer is dried over sodium sulfate and concentrated. The residue is chromatographed (high pressure liquid chromatography) using ethyl acetate liquid and silica column. The product containing fractions are evaporated to concentration and the residue is crystallized from ethyl alcohol to give 0.6 g (11%) of the title compound.

[Intermediate 23]

2- (2-Chloroethyl) -2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepine-5 (4H) -thione

10.3 g (0.04 mol) of 2- (2-chloroethyl) -2,3-dihydro-7-methoxy-4-methyl-1,4-benz-oxazepine-5 (4H) -one in 200 ml of chloroform To the solution is added a mixture of 5.7 g (0.03 mol) of phosphorus pentasulphide and 5.7 g of potassium sulfide. The reaction mixture is stirred and heated under reflux for 5 hours under nitrogen atmosphere. The mixture is filtered on hot and the filtrate is concentrated under reduced pressure. The orange solid residue was recrystallized from ethanol to obtain 7.4 g (65%) of the product having a melting point of 98 to 100 ° C.

Elemental Analysis: C ₁₃ H ₁₆ NClO ₂ S

Calculated Value: C; 54.64, H; 5.65, N; 4.09

Found: C; 54.57, H; 5.67, N; 4.85

[Intermediate 24]

Compound (B) is obtained by using equimolar amounts of the following compound (A) instead of 2- (1-benzyl-3-pyrrolidinyloxy) benzoic acid in the process of intermediate 2.

Compound (A):

2-[(1-cyclohexyl-3-pyrrolidinyl) oxy] benzoic acid, 2-[(1-ethyl-3-pyrrolidinyl) oxy] benzoic acid, 2-[(1-isopropyl-3-pyrroli Diyl) oxy] benzoic acid, 2-[[(1- (4-chlorobenzyl) -3-pyrrolidinyl] oxy] benzoic acid, 2-[[1- (4-methoxybenzyl) -3-pyrrolidinyl] Oxy] bezoic acid, 2-[[1- (3,5-dimethoxybenzyl) -3-pyrrolidinyl] oxy] benzoic acid, 2-[[1- (trifluoromethylbenzyl) -3-pyrrolidinyl ] Oxy] bezoic acid and 2-[[1- (4-nitrobenzyl) -3-pyrrolidinyl] oxy] benzoic acid.

Compound (B):

a) 2- (2-chloroethyl) -4-cyclohexyl-2,3-dihydro-1,4-benzoxazepin-5 (4H) -one, b) 2- (2-chloroethyl)- 2,3-dihydro-4-ethyl-1,4-benzoxazepin-5 (4H) -one, c) 2- (2-chloroethyl) -2,3-dihydro-4-isopropyl-1 , 4-benzoxazepine-5 (4H) -one, d) 2- (2-chloroethyl) -4- (4-chlorobenzyl) -2,3-dihydro-1,4-benzoxazepine-5 (4H) -one, e) 2- (2-chloroethyl) -2,3-dihydro-4- (4-methylbenzyl) -1,4-benzoxazepin-5 (4H) -one, f) 2- (2-chloroethyl) -2,3-dihydro-4- (3,5-dimethoxybenzyl) -1,4-benzoxazepin-5 (4H) -one, g) 2- (2- Chloroethyl) -2,3-dihydro-4- (3-trifluoromethyl-benzyl) -1,4-benz-oxazinpin-5 (4H) -one, h) 2- (2-chloroethyl) -2,3-dihydro-4- (4-nitrobenzyl) -1,4-benzoxazepin-5 (4H) -one

[Intermediate 25]

Compound (B) is obtained by using the following compound (A) instead of sodium 2-[(1-methyl-3-pyrrolidinyl) oxy] -3-pyridine carboxylate in the process of intermediate 4, respectively.

Compound (A):

2-[(1-cyclohexyl-3-pyrrolidinyl) oxy] -3-pyridine carboxylate, 2-[(1-ethyl-3-pyrrolidinyl) oxy] -3-pyridine carboxylate, 2- [ (1-isopropyl-3-pyrrolidinyl) oxy] -3-pyridine carboxylate, 2-[[1- (4-chlorobenzyl) -3-pyrrolidinyl-oxy] -3-pyridine carboxylate, 2 -[[1- (4-methylbenzyl) -3-pyrrolidinyl] -oxy] -3-pyridine carboxylate, 2-[[1- (4-methoxybenzyl) -3-pyrrolidinyl] oxy] 3-pyridine carboxylate, 2-[[1- (3-trifluoromethylbenzyl) -3-pyrrolidinyl] oxy] -3-pyridine carboxylate, and 2-[[1- (4-nitrobenzyl ) -3-pyrrolidinyl] oxy] -3-pyridine carboxylate.

Compound (B):

a) 2- (2-chloroethyl) -4-cyclohexyl-2,3-dihydro-pyrido [3,2-f] [1,4] oxazepine-5 (4H) -one hydrochloride, b) 2- (2-chloroethyl) -2,3-dihydro-4-ethylpyrido [3,2-f] [1,4] -oxazin-5 (4H) -one hydrochloride, C) 2- ( 2-chloroethyl) -2,3-dihydro-4-isopropylpyrido [3,2-f] [1,4] -oxazin-5 (4H) -one hydrochloride, d) 2- (2- Chloroethyl) -4 (4-chlorobenzyl) -2,3-dihydro-pyrido [3,2-f] [1,4] -oxazin-5 (4H) one hydrochloride, e) 2- (2 -Chloroethyl) -2,3-dihydro-4- (4-methylbenzyl) -pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride, f) 2 -(2-chloroethyl) -2,3-dihydro-4- (4-methoxybenzyl) pyrido- [3,2-f] [1,4] -oxazin-5 (4H) one hydrochloride, g) 2- (2-chloroethyl) -2,3-dihydro-4- (3-trifluoromethylbenzyl) -pyrido [3,2-f] [1,4] -oxazepine-5 ( 4H) -one hydrochloride, and h) 2- (2-chloroethyl) -2,3-dihydro-4- (4-nitrobenzyl) -pyrido [3,2-f] [1,4] -oxa Zepin-5 (4H) -one hydrochloride.

[Intermediate 26]

2- (2-Chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] [1,4] -thiazepin-5 (4H) -one 2-[(1- A mixture of 80.75 g (0.34 mole) of methyl-3-pyrrolidinyl) thio] -3-pyridinecarboxylic acid, 500 ml of chloroform, 200 g of carbon tetrachloride and 178 g (0.68 mole) of triphenylphosphine is stirred under reflux for 2.5 hours. The resulting solution is extracted once with 500 ml of 1N hydrochloric acid and three times with 125 ml each. The acid extracts are combined and extracted with asopropyl ether. The aqueous layer is made basic with sodium hydroxide and extracted three times with chloroform. The chloroform extracts are combined, dried over sodium sulfate and concentrated. A portion of the residue is subjected to high pressure liquid chromatography using a silica column and ethyl acetate. The obtained compound is crystallized with isopropyl ether-isopropyl alcohol to give a product having a melting point of 97 to 100 ° C.

Elemental Analysis: c ₁₁ H ₁₃ N ₂ OSCl

Calculated Value: C; 51.46, H; 5.10, N; 10.91

Found: C; 51.63, H; 5.12, N; 10.85

[Intermediate 27]

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -thiazepine-5 (4H) -thione

4.3 g (0.017 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -thiazepin-5 (4H) -one, A mixture of 100 ml of toluene and 4.8 g (0.012 mol) of 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide was refluxed for 3 hours, Extract twice with diluted sodium hydroxide. The organic layer was concentrated and the residue was subjected to high pressure liquid chromatography using silica column, 50% ethyl acetate-50%, and hexane. 2 g of the title compound are obtained which have a melting point of 160 to 162 캜.

Elemental Analysis: C ₁₁ H ₁₃ N ₂ S ₂ Cl:

Calculated Value: C; 48.43, H; 4.80, N; 10.27

Found: C; 48.46, H; 4.81, N; 10.51

[Intermediate 28]

2- (2-Chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,4-f] [1,4] -oxazepin-5 (4H) -one

A solution of 78 g (0.5 mole) of 4-chloronicotinic acid and 52 g (0.52 mole) of 1-methylpyrrolidinol in 150 ml of dimethylformamide was maintained at a rate such that the temperature was maintained at 55 to 70 ° C. (preheated to 55 ° C.). To a suspension of 44 g (1.1 mol) of 60% sodium hydride / mineral oil in 800 ml of dimethyl formamide. The resulting mixture is heated to 60 ° C. for 4 hours and filtered on heat. The filtrate is concentrated on a rotary evaporator (5 mm / steam bath). The residue is dissolved in 600 ml of water and extracted with isopropyl ether. The pH of the aqueous layer is adjusted to 6 using hydrochloric acid and the solution is concentrated on a rotary evaporator (5 mm / steam bath). The residue was suspended in 800 ml of chloroform, 188 g (1.1 mol) of triphenylphosphine was added, followed by 250 ml of carbon tetrachloride. When the mixture is heated gently to 60 ° C., an exothermic reaction occurs and the temperature is maintained at 60 to 65 ° C. for about 20 minutes using an ice bath.

The ice bath is removed and the mixture is cooled by reflux heating for 3.5 hours. After extracting 600 ml of water, the solution was extracted twice with 200 ml of 1N hydrochloric acid. The acid layer is made basic with sodium hydroxide and extracted three times with chloroform. The chloroform extract is concentrated and the residue is subjected to high pressure liquid chromatography using silica gel and ethyl acetate eluent. The yield of the product is 30 g (25%). Mass spectrometry and NMR confirm the structure of the title compound.

[Intermediate 29]

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido- [3,4-f] [1,4] -oxazepine-5 (4H) -thione monohydrochloride

15 g (0.06 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] -oxazin-5 (4H) -one Dissolve in 200 ml of toluene and add 15 g (0.037 mol) of 2,4-bis- (4-methoxyphenyl) -1,3,2,4-dithiaphosphane-2,4-disulfide. The mixture is refluxed for 2.5 hours and the toluene solution is decanted. The residue is partitioned between dilute sodium hydroxide and chloroform to dry and concentrate the chloroform layer. The residue is subjected to high pressure liquid chromatography (Waters 500) using a silica column and ethyl acetate eluent. Fractions containing a substance having a molecular weight of 257 are concentrated. The residue in isopropyl alcohol is treated with hydrogen chloride and the resulting crystals are collected. 0.1 g (0.6%) of hydrochloride at a melting point of 168 to 171 ° C are obtained.

Elemental Analysis: C ₁₁ H ₁₄ N ₂ OSCl ₂ :

Calculated Value: C; 45.06, H; 4.81, N; 9.55

Found: C; 45.15, H; 4.98, N; 9.26

[Intermediate 30]

2,3,4,5-tetrahydro-4-methyl-5-oxopyrido- [3,2-f] [1,4] -oxazepine-2-propane nitrile

Dilute aqueous hydroxide of 100 g (0,415 moles) of 2- (2-chloroethyl) -dihydro-4-methylpyrido [3,2, -f] [1,4] -oxazepine-5 (4H) -one hydrochloride Distribute between sodium (200 ml) and chloroform (200 ml). The organic layer is separated separately and the aqueous layer is extracted with chloroform (3 x 50 ml). The combined organic layers are dried over sodium sulphate and concentrated on a rotary evaporator (70 ° C., water aspirator). 89 g (0.37 mol) of the free base of the starting hydrochloride are dissolved in 150 ml of toluene and 9 g (0.027 mol) of tetrabutyl ammonium bromide are added to the solution. Saturated aqueous potassium cyanide (100 ml) is added and the mixture is mechanically stirred under reflux. After 2 hours, additionally 3 g (0.009 mol) of tetrabutyl ammonium bromide and saturated aqueous potassium cyanide (20 ml) are added and the mixture is stirred at reflux for 0.75 h. Extract the contents of the reaction vessel with ethyl acetate (3 x 50 ml) (Note: Chloroform can be used instead). The organic layer is dried over sodium sulfate and concentrated to a third of the original volume with a rotary evaporator (70 ° C., water aspirator). Cooling causes the crystals to precipitate. The crystals are filtered off and washed several times with ethyl acetate and isopropylether. 30 g (35%) of off-white crystals having a melting point of 104 to 105 캜 are collected. The sample is recrystallized from ethyl acetate to give a product having a melting point of 104 to 105 캜.

Elemental Analysis: C ₁₂ H ₁₃ N ₃ O ₂

Calculated Value: C; 62.33, H; 5.67, N; 18.17

Found: C; 62.06, H; 5.65, N; 17.97

[Intermediate 31]

2- (2-Chloroethyl) -4-ethyl-2,3-dihydropyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride

A stirring suspension of sodium hydride / mineral oil (60% dispersion 81.45 g, 2.036 mol) in dimethyl sulfoxide (500 ml) heated to 50 ° C. at a rate where the temperature is maintained between 55 ° and 60 ° C. (sometimes cooling is required) , A solution of 2-chloronicotinic acid (142 g, 0.905 mol) and N-ethyl-2-pyrrolidinol (99 g, 0, 86 mol) in dimethyl sulfoxide (500 ml) was added dropwise. After the addition is complete, the mixture is stirred and cooled at 50 ° -60 ° C. for 1.5 h. The precipitated solid is filtered off, washed with ethyl acetate and dried.

Anhydrous sodium salt (172.53 g, 0.62 mol) is suspended in chloroform (11). Hydrogen chloride gas is introduced into the suspension until the pH reaches 5.76. Triphenylphosphine (365.5 g, 1, 395 moles) and CCl ₄ (365.5 g) are added and the solution is stirred for additional 45 minutes under reflux. Confirm that the reaction occurred> 99% by IR. After cooling, the solution is extracted several times with dilute hydrochloric acid (total 1.5 l). The aqueous layer is made basic with concentrated sodium hydroxide solution and extracted with chloroform (3 × 250 ml). The organic layer is dried over sodium sulfate and concentrated on a rotary evaporator (70 ° C., water aspirator). The bottom oil is dissolved in isopropyl alcohol (500 ml) and acidified with hydrogen chloride gas. Cooling produces oil and reduces the volume to one third of the original volume. Cool to collect 70 g (0.241 mol, 28%) of light brown crystals having a melting point of 153 to 155 캜.

Elemental analysis: C ₁₂ H ₁₆ N ₂ O ₂ Cl ₂

Calculated Value: C; 49.50, H; 5.53, N; 9.62

Found: C; 49.64, H; 5.62, N; 9.32

[Intermediate 32]

2- (2-Chloroethyl) -4-ethyl-2,3-dihydropyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -thione hydrochloride

Dilute aqueous solution of about 50 g of 2- (2-chloroethyl) -4-ethyl-2,3-dihydro-pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride. Partition between sodium hydroxide (50 ml) and chloroform (50 ml). The organic layer is separated separately and the aqueous layer is extracted with additional methylene chloride (2 x 50 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated on a rotary evaporator (70 ° C., water aspirator) to yield 39 g (0.153 mol) of free base. The free base thus obtained is dissolved in chloroform (1.2 l) and phosphorus sulphide (33.9 g, 0.153 mol) is added with stirring. The resulting mixture is heated to reflux for 16 hours. After cooling, the reaction mixture is filtered, washed with dilute aqueous sodium hydroxide (3 x 300 ml), dried over sodium sulphate and concentrated on a rotary evaporator (70 ° C., water aspirator) to give a yellow viscous oil. The resulting oil is dissolved in isopropyl alcohol (about 200 ml) and acidified with hydrogen chloride gas. Cool to give 20 g (43%) of crystals having a melting point of 133 to 135 ° C.

Elemental Analysis: C ₁₂ H ₁₆ N ₂ OSCl ₂

Calculated Value: C; 46.91, H; 5.25, N; 9.12

Found: C; 47.33, H; 5.38, N; 9.10

[Intermediate 33]

7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepin-5 (4H) -one

Sample of 2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] [1,4] -oxazin-5 (4H) -one hydrochloride (10 g, 136 mol) is dissolved in dimethylformamide (150 ml) and refluxed. Sulfuryl chloride (20 g, 0.148 mol) is then added dropwise over 40-50 minutes. The reaction mixture is stirred at reflux for 30 minutes and then SO ₂ Cl ₂ is added. After cooling, the contents of the flask are partitioned between water (150 ml) and benzene (150 ml). The benzene layer is separated separately and the aqueous layer is extracted with an additional amount of benzene (2 x 50 ml). The benzene extracts are combined and washed with dilute aqueous potassium hydroxide (2 x 50 ml) and then with dilute aqueous hydrochloric acid (2 x 50 ml). The benzene layer is dried over sodium sulfate and then concentrated on a rotary evaporator (about 70 ° C., water aspirator) to yield 2.61 g of crude material. The resulting crude was recrystallized from isopropyl ether to give 1.25 g (12.6%) of off-white crystals having a melting point of 78 to 79 ° C.

Elemental Analysis: C ₁₁ H ₁₂ N ₂ O ₂ Cl ₂

Calculated Value: C; 48.02, H; 4.40, N; 10.18

Found: C; 48.07, H; 4.53, N; 10.10

[Intermediate 34]

7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione

6.0 g of 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepine-5 (4H) -one ( 0.022 mole) is suspended in 20 ml of toluene. 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide is added to this suspension. The mixture is heated to reflux for 2 hours with vigorous stirring. Since the reaction was not completed, an additional amount (3.0 g) of 2,4-bis (4-methoxyphenyl) -1,3dithia-2,4-diphosphetane-2,4-disulfide was added and the mixture was added. Stir at reflux for 2 hours and allow to stand at room temperature for 56 hours. The toluene layer is decanted and washed with 50 ml of dilute aqueous sodium hydroxide and 50 ml of dilute hydrochloric acid. Toluene is removed by a rotary evaporator (about 80 ° C., water aspirator). The crude oil is recrystallized from isopropyl alcohol to give 3.5 g (54%) of pale yellow crystals having a melting point of 125 to 127 ° C.

Elemental Analysis: C ₁₁ H ₁₂ N ₂ OSCl ₂ :

Calculated Value: C; 45.37, H; 4.15, N; 9.62

Found: C; 45.40, H; 4.20, N; 9.71

[Intermediate 35]

2- (2-Chloroethyl) -4-cyclohexyl-2,3-dihydropyrido [3,2-f] [1,4] -oxazepin-5 (4H) -one

15 g (0.05 mol) of sodium 2-[(1-cyclohexyl-3-azetidinyl) -oxy] -3-pyridine carboxylate obtained in Preparation Example 23 were suspended in 100 ml of chloroform and chlorided until pH5.8. Pass hydrogen. 18 g thionyl chloride is added to the stirred mixture. The resulting solution is stirred at room temperature for 3 hours. The IR spectrum shows a peak at 1770 cm ⁻¹ that characterizes the acid chloride. 40 ml of triethylamine are added dropwise while cooling to about 25 ° C. in an ice bath. The chloroform solution is stirred for a further 0.5 h, extracted with water, dried over sodium sulfate and concentrated. The residue is chromatographed on a silica gel column (7 × 20 cm) using ethanol as eluent. The desired material is eluted primarily from the column. The ethanol solution is concentrated to crystallize the residue once with ethyl acetate-isopropyl ether and once with isopropyl alcohol. 1 g (7%) of the title compound at a melting point of 120 to 122 ° C. is obtained.

Elemental analysis: C ₁₅ H ₁₉ N ₂ O ₂ Cl:

Calculated Value: C; 61.12, H; 6.50, N; 9.50

Found: C; 61.11, H; 6.62, N; 9.32

[Intermediate 36]

2- (2-Chloroethyl) -2,3-dihydro-4- (phenylmethyl) pyrido [3,2-f] [1,4] -oxazepin-5 (4H) -one

The title compound is prepared in crude form in the first part of Example 67.

Example 1

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one hydrochloride

A solution of 9 g (0.2 moles) of dimethylamine in 250 ml of ethanol was added to 2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benxoxazepine-5 (4H)-in steel springs. It is added to 24g (0.1 mol) on. The mixture is heated at 100 ° C. for 18 hours. The solution is concentrated in vacuo and the residue is partitioned between ethyl acetate and dilute sodium hydroxide. The ethyl acetate layer is concentrated and the residue, consisting essentially of the free base of the title compound, is dissolved in a methyl isobutyl ketone-isopropanol mixture. The solution is acidified with hydrogen chloride gas to afford the title compound at melting point 188-197 ° C.

Example 2

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one

All of the hydrochloride obtained in Example 1 is partitioned between chloroform and dilute sodium hydroxide and the chloroform layer is concentrated. The residue is crystallized several times with isopropyl ether to give 6 g (21%) of free base with a melting point of 56 to 76 ° C.

Elemental Analysis: C ₁₄ H ₂₀ N ₂ O ₂

Calculated Value: C; 67.72, H; 8.12 N; 11.28

Found: C; 67.35, H; 8.16, N; 11.09

Example 3

2,3-dihydro-4-methyl-2- [2- (4-morpholino) -ethyl] -1,4-benzoxazepin-5 (4H) -one fumarate [1: 1]

To 50 ml of morpholine is added 20 g (0.084 mol) of 2- (2-chloroethyl) -2.3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one. The solution is refluxed for 5 hours and then concentrated in vacuo. The residue is dissolved in chloroform and the solution is washed with dilute sodium hydroxide, dried over sodium sulphate and concentrated in vacuo. The residue, consisting essentially of the organic base of the title compound, is reacted with 10.5 g (0.09 mol) of fumaric acid in isopropanol-water. The resulting solid is recrystallized from isopropanol-water to give 21.5 g (64%) of the product at a melting point of 199 to 201 ° C.

Elemental analysis: C ₂₀ H ₂₆ N ₂ O ₇

Calculated value; C; 59.10, H; 6.45, N; 6.89

Found: C; 58.95, H; 6.52, N; 6.88

Example 4

4-benzyl-2,3-dihydro-2- [2- (4-morpholino) ethyl] -1,4-benzooxazinpin-5 (4H) -one

To 200 ml of morpholine add 30 g (0.095 mol) of 4-benzyl-2 (2-chloroethyl) -2,3-dihydro-1,4-benzoxazepin-5 (4H) -one. The solution is refluxed for 3 hours and then concentrated in vacuo. The residue is partitioned between dilute sodium hydroxide and chloroform.

The solid obtained is recrystallized three times with isopropyl ether-ethyl acetate to give 15.2 g (43%) of Gote at a melting point of 97-99 ° C.

Elemental Analysis: C ₂₂ H ₂₆ N ₂ O ₃

Calculated Value: C; 72.10, H; 7.15, N; 7.64

Exact value; C; 72.25, H; 7.22, N; 7.64

Example 5

4-benzyl-2,3-dihydro-2- [2- (methylamino) -3-ethyl] -1,4-benzoxazepin-5 (4H) -one fumarate [1: 1]

5.95 g (019 mol) of monomethylamine in 200 ml of ethanol was added to the solution. The solution was placed in 4-benzyl-2- (chloroethyl) -2,3-dihydro-1,4-benzoxazepine-5 (4H)-in steel bomb. To 3 g (0.095 mol) on. The mixture is heated at 100 ° C. for 16 h. The solution is concentrated in vacuo to partition the residue between chloroform and dilute sodium hydroxide. The chloroform layer is concentrated to dissolve the residue, consisting essentially of the free base of the title compound, in isopropanol and react with fumaric acid to give fumarate. The resulting salt is dried in vacuo at 100 ° C. until the entrapped isopropyl alcohol is removed to give a product having a melting point of 178-181 ° C.

Elemental Analysis: C ₂₃ H ₂₆ N ₂ O ₆

Calculated Value: C; 64.77, H; 6.15, N6.57

Found: C; 64.87, H; 6.20, N; 6.62

Example 6

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione hydrochloride [1: 1]

To a solution of 7.2 g (0.16 mole) of dimethylamine in 350 ml of absolute ethanol, 2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione was added. Add. The solution is heated at 100 ° C. in a steel cylinder for 18 hours and then concentrated. The residue is partitioned between chloroform and dilute sodium hydroxide. The chloroform layer is dried over sodium sulfate and concentrated. The solid, which almost contains the free base of the title compound, is reacted with aq. Chloride gas in ethanol to give the hydrochloride. The salt is recrystallized from ethanol and dimethylmamide and then recrystallized three times from ethanol to yield 7.5 g (yield: 28%). (Melting point: 233 to 236 ° C)

Elemental Analysis: C ₁₄ H ₂₁ N ₂ SOCl

Calculated Value: C; 55.90, H; 7.04, N; 9.32

Found: C; 55.72, H; 7.26, N; 8.94

Example 7

4-benzyl-2- [2- (dimethylamino) ethyl] -2,3-dihydro-1,4-benzoxazepin-5 (4H) one monohydrate.

According to the process of Example 1, 4-Benzyl-2- (2-chloroethyl-2,3-dihydro-1,4-benzoxazepin-5 (4H) -one was reacted with dimethylamine and the concentrated residue To give the free base of the title compound in. Recrystallize from ethanol-water to give a fish product having a melting point of 75 to 77 ° C.

Elemental Analysis C ₂₀ H ₂₆ N ₂ O ₃ :

Calculated value; C; 70.13, H; 7.65, N; 8.21

Found: C; 70.02, H; 7.53, N; 8.25

Example 8

2,3-dihydro-4-methyl-2- [2- (4-morpholino) -ethyl] -1,4-benzoxazepine-5 (4H) -thione hydrochloride [1: 1] morpholine 60ml A solution of 20.4 g (0.08 mol) of 2,3-dihydro-4-methyl-2- (2-chloroethyl) -1,4-benzoxazepine-5 (4H) -thione in the mixture was refluxed for 5 hours. Concentrate. The residue is partitioned between dilute sodium hydroxide and chloroform. The chloroform layer is dried over sodium sulphate and concentrated to give a residue consisting almost of the free base of the title compound. Hydrochloride salt is prepared using hydrogen chloride gas in a methyl isobutyl ketone-dimethylformamide solution. The salt is recrystallized from ethanol-dimethylformamide to give 14 g (51%) of solids with melting points of 253 to 256 ° C.

Elemental Analysis C ₁₆ H ₂₃ N ₂ SO ₂ Cl

Calculated Value: C; 56.04, H; 6.76, N; 8.17

Found: C; 55.73, H; 6.63, N; 7.97

Example 9

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylnaphth [2,3-f] [1,4] -oxazepine-5 (4H) -one oxalate [1 : One]

5.0 g (0.017) of 2- (2-chloroethyl) -2,3-dihydro-4-methyl naphth- [2,3-f] [1,4] oxazepine-5 (4H) -one in a steel bomb Moles), 50 ml of absolute ethanol and 3,78 g (0.034 moles) of dimethylamine (in 40% aqueous solution). The bomb is heated at 100 ° C. for 16 hours. The volatiles are removed under reduced pressure and the residue is partitioned between chloroform and 15% aqueous sodium hydroxide. The chloroform layer is washed twice with water, dried over magnesium sulfate and concentrated under reduced pressure to give 2,7 g (54%) of a viscous yellow oil consisting almost of the free base of the title compound. The oil is dissolved in isopropyl alcohol and reacted with oxalic acid.

The oxalate salt is recrystallized from ethanol-mole to give a product having a boiling point of 192 to 194 ° C.

Elemental Analysis C ₂₀ H ₂₄ N ₂ O ₆

Calculated Value: C; 61.84, H; 6.23, N; 7.21

Found: C; 61.41, H; 6.27, N; 7.09

Example 10

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl pyrido [3,2-f] [1,4] oxyzepin-5 (4H) -one fumarate [2: 3]

90 g (0.8 mole) of 40% aqueous dimethylamine in steel bomb 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2f] [1,4] -oxazepine-5 25 g (0.09 mol) of (4H) -one hydrochloride are added. The mixture is heated to 100 ° C. for 15 hours with gentle stirring. The mixture is partitioned by extraction with dilute sodium hydroxide and extracted twice with chloroform. The chloroform layers are combined and concentrated. The residue, consisting essentially of the free base of the title compound, is dissolved in 200 ml of isopropyl alcohol and 9 g of oxalic acid are added. Recrystallize the oxalate salt with 95% ethanol to give 18 g. The oxalate salt is then partitioned between chloroform and dilute sodium hydroxide and the chloroform layer is evaporated to free base. The residue, the free base of the title compound, is dissolved in isopropyl alcohol and reacted with fumaric acid to yield 13 g (34%) of a white solid having a melting point of 146-148 ° C.

Elemental Analysis C ₁₉ H ₂₅ N ₃ O ₃

Calculated Value: C; 53.90, H; 5.90, N; 9.92

Found: C; 53.76, H; 6.02, N; 9.96

Example 11

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione fumarate [1: 1], ethanol [2: 1]

To a solution of 32.8 g (0.29 mol) of 40% aqueous dimethylamine and 100 mg of ethanol in a steel bomb, 2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] 15 g (0.058 mole) of [1,4] -oxazepine-5 (4H) -thione is added. The mixture is heated to 100 ° C. for 18 hours with gentle stirring. The solution is cooled and partitioned between chloroform and dilute sodium hydroxide. The chloroform layer is dried over sodium sulfate and concentrated. The residue, consisting essentially of the free base of the title compound, is dissolved in isopropyl alcohol and reacted with 7 g of fumaric acid. The fumarate salt is recrystallized with isopropyl alcohol to give 19 g (86%) of product at melting point 105 to 129 ° C. 14 g of the resulting salt was recrystallized from ethanol to give 10.5 g of a yellow solid at a melting point of 103 to 118 ° C. NMR spectrum shows that the crystal contains 1/2 mole of ethanol.

Elemental Analysis C ₃₆ H ₅₂ N ₆ O ₁₁ S ₂ :

Calculated Value: C; 53.45, H; 6.48, N; 10.39

Found: C; 53.07, H; 6.53, N; 10.23

Example 12

2- [2 (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione fumarate [1: 1 ]

To a solution of 113 ml (1.0 mol) of 40% aqueous dimethylamine and 326 ml of ethanol in a steel bomb, 2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] [ 1,4] 48.4 g (0.189 mole) of oxazinepin-5 (4H) -thione is added. The mixture is heated at 100 ° C. for 14 hours. Ethanol is removed on a rotary evaporator and some water in the residue is removed. The residue is dissolved in 200 ml of methylene chloride and washed three times with 100 ml of 20% aqueous potassium carbonate solution. The aqueous layers were combined and extracted three times with 150 ml each of methylene chloride. The methylene chloride solution is combined and treated with charcoal. Charcoal is filtered off and the filtrate is evaporated to give an oil. The resulting oil is dissolved in 215 ml of isopropyl alcohol and the solution is heated to boil slowly. A solution of 21.9 g (0.19 mol) of fumaric acid in 150 ml of boiling methanol is added to an isopropyl alcohol solution. 63.4 g (88%) of a crystalline solid are obtained. The solid is recrystallized from hot 200 proof ethyl alcohol. The crystals are filtered off, polished with isopropyl ether at room temperature and again separated by filtration. After drying overnight at 85 ° C. in a vacuum oven, 72.45 g (79%) of crystals having a melting point of 130 to 133 ° C. are obtained.

Elemental Analysis C ₁₇ H ₂₃ N ₃ O ₅ s:

Calculated Value: C; 53.53, H; 6.08, N; 11.02

Found: C; 53.23, H; 6.11, N; 10.64

Example 13

4-benzyl-2,3-dihydro-2- [2- (4-morpholino) ethyl] -1,4-benzoxazepin-5 (4H) -thione

4-benzyl-2,3-dihydro-2- [2- (4-morpholino) was added to a suspension of a finely divided pulverized mixture of 2.94 g (0.013 mol) of phosphorus penta sulfide and 2.0 g of potassium sulfide in 75 ml of mousse toluene. 12 g (0.033 mol) of ethyl] -1,4-benzoxazepin-5 (4H) -one are added. The mixture is stirred under reflux for 10 hours and filtered. The filtrate is concentrated to crystallize the residue with isopropyl ethane-toluene to give 2.5 g (20%) of product with a melting point of 236-238 ° C.

Elemental Analysis C ₂₂ H ₂₆ N ₂ O ₂ S:

Calculated Value: C; 69.08, H; 6.85, N; 7.32

Found: C; 69.60, H; 6.96, N; 7.15

Example 14

2,3-dihydro-4-methyl-2- [2- (methylamino) -ethyl] -1,4-benzoxazepin-5 (4H) -one fumarate [1: 1]

50 g (0.21 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one and monomethyl, according to the process of Example 5 13.0 g (0.42 mole) of amine (in 400 ml of ethanol) was reacted to obtain an organic base of the title compound, which was separated by reaction with fumaric acid and recrystallized with ethyl alcohol, followed by 17 g (23%) of the title compound having a melting point of 154 to 156 ° C. To obtain.

Elemental Analysis C ₁₇ H ₂₂ N ₂ O ₆

Calculated Value: C; 53.27, H; 6.33, N; 8.00

Found: C; 58.32, H; 6.52, N; 7.82

Example 15

2,3-dihydro-4-methyl-2- [2- (methylamino) -ethyl] -1,4-benzoxazepin-5 (4H) -one

2,3-dihydro-4-methyl-2- [2- (methylamino) -ethyl] -1,4-benzoxazepin-5 (4H) -one fumarate was partitioned between dilute sodium hydroxide and chloroform Convert to free base. The chloroform layer is evaporated and distilled at boiling point 182 ° / 0.2 mm to give 4.3 g of product.

Elemental Analysis C ₁₃ H ₁₈ N ₂ O ₂ :

Calculated Value: C; 66.64, H; 7.74, N; 11.96

Found: C; 66.48, H; 7.69, N; 11.88

Example 16

2,3-dihydro-2- [2- (4-hydroxy-4-phenyl) -piperidinylethyl] -4-methyl-1,4-benzoxazepin-5 (4H) -thione (and hydrochloride) )

10.7 g (0.078 mole) of potassium carbonate, 13.7 g (0.078 mole) of 4-hydroxy-4-phenyl piperidine and 2- (2-chloroethyl) -2,3-dihydro-4- in 200 ml of n-butanol A suspension of 19.8 g (0.078 mol) of methyl-1,4-benzoxazepine-5 (4H) -thione is refluxed overnight. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in ethanol-ligroin and reacted with hydrogen chloride gas to give the hydrochloride which is recrystallized from ethanol-dimethyl formamide. The hydrochloride is partitioned between chloroform and dilute sodium hydroxide and the chloroform is converted to the free base by evaporation. Recrystallization twice with isopropyl alcohol yields 9.27 g (30%) of free base product having a melting point of 142-148 ° C.

Elemental Analysis C ₂₃ H ₂₈ N ₂ O ₆ S:

Calculated Value: C; 69.66, H; 7.12, N; 7.07

Found: C; 69.78, H; 7.18, N; 7.00

Example 17

2,3-dihydro-4-methyl-2- [2- [1- (4-phenyl-1,2,3,6-tetrahydro) -pyridinyl] ethyl] -1,4-benzoxazepine- 5 (4H) -thione

24.3 g (0.176 mol) of potassium carbonate, 11.5 g (0.059 mol) of 4-phenyl-3,4-tetra hydropyridine and 2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4 -Reflux for 72 h with n-butanol sufficient to form a slurry with a suspension of 15 g (0.059 mol) of benzoxazepine-5 (4H) -thione. The reaction mixture is filtered on hot and the filtrate is cooled to room temperature and refiltered. The final filtrate is concentrated to dissolve the residue in ethyl acetate. The crystals obtained by cooling are recrystallized with ethyl acetate to give 7 g of a product having a melting point of 153 to 155 캜.

Elemental Analysis: C ₂₃ H ₂₆ N ₂ OS

Calculated Value: C; 72.98, H; 6.92, N; 7.40

Found: C; 73.36, H; 7.01, N; 7.47

Example 18

8-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione hydrochloride [1: 1]

A solution of 9.8 g (0.04 mol) of 8-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione in 50 ml of absolute ethanol And 10 ml of a 40% aqueous solution of dimethylamine are mixed and heated at 100 ° C. for 16 hours in a steel bomb. Ethanol is evaporated under reduced pressure and the residue is dissolved in chloroform and partitioned into 10% sodium hydroxide solution. The chloroform layer is evaporated under reduced pressure to give an amorphous solid. Solid to 6N; Dissolve in hydrochloric acid and wash the solution with ethyl acetate. The aqueous layer is made basic with 50% sodium hydroxide and extracted with ethyl acetate. The ethyl acetate layer is evaporated under reduced pressure to give a viscous oil consisting essentially of the organic base of the title compound, which is dissolved in anhydrous ethinol and reacted with ethereal hydrogen chloride. The hydrochloride is recrystallized from ethanol to give 30 g (25%) of product at melting point 196-199 ° C.

Elemental Analysis C ₁₄ H ₂₀ N ₂ OS:

Calculated Value: C; 50.15, H; 6.01, N; 8.35

Found: C; 50.15, H; 6.18, N; 8.07

Example 19

8-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one oxalate [1: 1]

10 g (0.037 mol) of a solution of 8-chloro-2- (2-chloroethyl-2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one in 50 ml of anhydrous ethanol and 40 10 ml of% aqueous dimethylamine solution is mixed and heated in a steel bomb for 16 hours at 100 ° C. The solution is concentrated under reduced pressure and the residue is dissolved in chloroform and partitioned with 15% sodium hydroxide (twice). The chloroform layer is magnesium sulfate Dry over phase and evaporate under reduced pressure to give an oil consisting of almost the free base of the title compound The oil is dissolved in anhydrous ethanol and reacted with oxalic acid The oxalate salt is recrystallized from ethanol to give 4 g of product at melting point 198 to 201 ° C. %) Is obtained.

Elemental Analysis C ₁₆ H ₂₁ N ₂ ClO ₆ :

Calculated Value: C; 51.55, H; 5.68, N; 7.51

Found: C; 51.07, H; 5.69, N; 7.43

Example 20

7-bromo-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one oxalate [1: 1]

3.0 g (0.01 mol) of 7-bromo-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one in 50 ml of absolute ethanol To the solution is added 2,2 ml of a 40% aqueous solution of dimethylamine. The reaction mixture is heated to 100 ° C. for 16 h in a stainless steel bomb and then concentrated under reduced pressure. The residue is partitioned between chloroform and 15% sodium hydroxide solution. Separating the chloroform layer into 3N; Extract with aqueous hydrochloric acid. The acid layer is basified with 50% aqueous sodium hydroxide and extracted with chloroform. Chloroform is evaporated under reduced pressure to give 2.4 g (73%) of a brown viscous oil which is the free base of the title compound. The oil is dissolved in isopropyl alcohol and reacted with oxalic acid. The oxalate salt is recrystallized from isopropyl alcohol / water to give the title salt with a melting point of 192 to 194 ° C.

Elemental Analysis C ₂₆ H ₂₁ N ₆ BrN ₆

Calculated Value: C; 46.06, H; 5.07, N; 6.71

Found: C; 46.00, H; 5.10, N; 6.68

Example 21

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylnaphth [2,1-f] [1,4] oxazepine-5 (4H) -silver oxalate [1: One],

8 g of 2- (2-chloroethyl) -2,3-dihydro-4-methylnaphth-2- [2,1-f] [1,4] oxazepine-5 (4H) -one in 100 ml of ethanol ( 0.028 mol) and 6.2 g (0.055 mol) of 40% dimethylamine are heated to 100 ° C. for 18 hours in a steel bomb. The resulting solution is partitioned between methylene chloride and dilute sodium hydroxide solution. The methylene chloride layer is dried over sodium sulfate and concentrated. The residue, consisting almost of the free base of the title compound, is dissolved in isopropyl alcohol and reacted with 2.6 g of oxalic acid. The obtained oxalate salt is recrystallized from isopropyl alcohol in water to give a product having a melting point of 206 to 209 ° C.

Elemental Analysis C ₂₀ H ₂₄ N ₂ O ₆

Calculated Value: C; 61.85, H; 6.23, N; 7.21

Found: C; 61.61, H; 6.26, N; 7.13

Example 22

In the process of Example 10,

Equimolar amounts of the following compounds instead of 2- [2 (chloroethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazinpin-5 (4H) -one hydrochloride Using (A), compound (B) is obtained respectively.

Compound (A):

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [4,3-f] [1,4] oxazepine-5 (4H) -one hydrochloride, 2- [2 (chloro Ethyl) -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepine-5 (4H) -one hydrochloride, and 2- (2-chloroethyl) -2, 3-dihydro-4-methylpyrido [2,3-f] [1,4] -oxazepine-5 (4H) -one hydrochloride.

Compound (B):

2- [2 (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [4,3-f] [1,4] oxazepine-5 (4H) -one fumarate, 2- [ 2 (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] -oxazepin-5 (4H) -one fumarate, and 2- [2 -(Dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [2,3-f] [1,4] -oxazepin-5 (4H) -one fumarate.

Example 23

2- [2 (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [4,3-f] [1,4] oxazepine-5 (4H) -thione hydrochloride [2: 3]

0.5 g of 2- [2- (chloroethyl) -2,3-dihydro-4-methylpyrido [4,3-f] [1,4] -oxazepine-5 (4H) -thione in 20 ml of ethyl alcohol To a solution of (0.002 moles) 2 ml of 40% aqueous dimethylamine is added. The mixture is heated to 100 ° C. for 14 hours in a steel bomb. The resulting solution is filtered and concentrated. The residue is dissolved in isopropyl alcohol and etheric hydrogen chloride drop is added. The salt crystals are recrystallized by dissolving in ethyl alcohol and boiling by replacing ethyl alcohol with isopropyl alcohol. 0.3 g (47%) of product having a melting point of 200 ° C. or more (decomposition) is obtained.

Elemental Analysis C ₂₆ H ₄₁ N ₆ O ₂ S ₂ Cl ₃ :

Calculated Value: C; 48.78, H; 6.46, N; 13.13

Found: C; 49.34, H; 6.47, N; 13.03

Example 24

2- [2 (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione

2- (2-Chloroethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione and diethyl amine in ethanol Heating together gives the title compound.

Example 25

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylnaphth [2,3-f] [1,4] oxazepine-5 (4H) -thione oxalate [1: 1] hemihydrate

15 g (0.05) 2- (2-chloroethyl) -2,3-dihydro-4-methylnaphth- [2,3-f] [1,4] oxazepine-5 (4H) -thione in 50 ml of absolute ethanol 10 ml of a 45% aqueous solution of dimethylamine is added to the solution. The solution is heated in a steel bomb for 16 hours. Ethanol is evaporated under reduced pressure and the residue is partitioned between chloroform and 15% aqueous sodium hydroxide. Separating off the chloroporium layer; Extract with aqueous hydrochloric acid. The acid layer is basified with 50% aqueous sodium hydroxide and extracted with chloroform. The chloroform solution is concentrated under reduced pressure and the residue is dissolved in isopropyl alcohol and reacted with oxalic acid. The salt is recrystallized from isopropyl alcohol and water to give the title compound having a melting point of 115 to 118 ° C.

Elemental Analysis C ₄₀ H ₅₀ N ₄ O ₁₁ S ₂ :

Calculated Value: C; 58.09, H; 6.09, N; 6.77

Found: C; 58.42, H; 5.85, N; 6.70

Example 26

2- [2 (dimethylamino) ethyl] -2,3-dihydro-7,9-diiodo-4-methyl-1,4-benzoxazepin-5 (4H) -one

2- (2-chloroethyl) instead of 2- (chloromethyl) -4-methyl-2,3-dihydro-1,4-benzoxazepin-5 (4H) -one in the processes of Examples 1 and 2 The title compound is obtained using -7,9-diiodo-4-methyl-2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one.

Example 27

7-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one oxalate [1: 1]

A solution of 9.0 g (0.033 mol) of 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one in 50 ml of anhydrous ethanol To 7 g (0.0066 mol) of 45% aqueous solution of dimethylamine is added. The solution is heated for 14 hours at 100 ° C. in stainless steel springs. The reaction mixture is concentrated under reduced pressure to partition the residue between chloroform and 15% aqueous sodium hydroxide. The chloroform layer is separated and evaporated under reduced pressure to give a brown viscous oil. The oil is dissolved in isopropyl alcohol and oxalic acid is added. Recrystallization with isopropyl alcohol / water affords 7.0 g (57%) of the oxalate salt with a melting point of 199 to 200 ° C.

Elemental Analysis C ₁₆ H ₂₁ N ₂ O ₆ Cl:

Calculated Value: C; 51.55, H; 5.68, N; 7.51

Found: C; 51.52, H; 5.72, N; 7.44

Example 28

2- (dimethylamino) ethyl-2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepin-5 (4H) -one

2- (2-Chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] [1,4] -oxazin-5 (4H) -one in the process of Example 10 Instead, 2-chloromethyl-2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazin-5 (4H) -one was used to prepare the title bud Optionally, separated into pharmaceutically acceptable salts.

Example 29

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione metiodide

2- [2 (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione fumarate [1: 3.8 g (0.01 mol) of ethanol [2: 1] are partitioned between chloroform and dilute sodium hydroxide.

The chloroform extract is dried over sodium sulfate and concentrated. The residue is dissolved in 15 ml of methyl isobutyl keron and added to a solution of 1.4 g (0.01 mol) of methyl iodide in 15 ml of isobutyl ketone. Recrystallization with 50% ethanol-50% methyl isobutyl ketone gave 2.5 g (78%) of product at melting point 221-225 ° C.

Elemental Analysis C ₁₄ H ₂₂ N ₃ OSI:

Calculated Value: C; 41.28, H; 5.44, N; 10.31

Found: C; 41.29, H; 5.51, N; 10.30

Example 30

7-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione oxalate [1: 1] hemihydrate

8.0 g (0.027 mol) of 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione in 50 ml of absolute ethanol To this was added 6 ml (0.054 mol) of 40% aqueous solution of dimethylamine. The solution is heated in a steel spring at 90 ° C. for 14 hours. Removed under reduced pressure with ethanol and the residue was partitioned between chloroform and aqueous sodium hydroxide. The chloroform layer is concentrated to give a yellow viscous oil. The oil is dissolved in isopropyl alcohol and reacted with oxalic acid. Oxalate salts precipitate immediately. The mixture is heated and a small amount of water is added to dissolve the salt. In this way, a white crystalline powder having a melting point of 150 to 151 캜 is obtained.

Elemental Analysis C ₃₂ H ₄₄ N ₄ O ₁₁ S ₂ :

Calculated Value: C; 48.30, H; 5.57, N; 7.04

Found: C; 48.74, H; 5.34, N; 6.95

Example 31

2- [2 (dimethylamino) ethyl] -2,3-dihydro-4-methylnaphth [2,1-f] [1,4] oxazepine-5 (4H) -thione hydrochloride [1: 1]

15.0 g (0.05) 2- (2-chloroethyl) -2,3-dihydro-4-methylnaphth [2,1-f] [1,4] oxazepine-5 (4H) -thione in 50 ml of absolute ethanol To 10 g of a 40% aqueous solution of dimethyl amine. The resulting solution is heated for 40 h at 100 ° C. in a steel bomb and concentrated under reduced pressure. The residue is partitioned between 15% aqueous sodium hydroxide and chloroform. The chloroform layer was evaporated to give 3N of the residue; Partition between hydrochloric acid and chloroform. The aqueous layer is made alkaline with 50% sodium hydroxide and extracted with chloroform. The chloroform extract is concentrated to dissolve the residue in isopropyl alcohol. The precipitate formed by adding etheric hydrogen chloride is recrystallized with isopropyl alcohol / water to give 3.0 g (20%) of product at melting point 238-240 ° C.

Elemental Analysis C ₁₈ H ₂₃ N ₂ ClOS:

Calculated Value: C; 61.61, H; 6.61, N; 7.98

Found: C; 61.80, H; 6.61, N; 7.91

Example 32

Instead of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione in the process of Example 11 Compound (B) is obtained, respectively, using an equimolar amount of the following compound (A).

Compound (A):

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido- [3,4-f] [1,4] -oxazepine-5 (4H) -thione and 2- (2- Chloroethyl) -2,3-dihydro-4-methylpyrido [2,3-f] [1,4] -oxazepine-5 (4H) -thione.

Compound (B):

a) 2- [2 (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido- [2,3-f] [1,4] oxazepine-5 (4H) -thione fumarate, And b) 2- [2 (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [2,3-f] [1,4] -oxazepine-5 (4H) -thione fumarate .

Example 33

2- [2- (dimethylamino) ethyl] -2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5 (4H) -one oxalate [1: 1] hemi Hydrate

3.0 g (0.011 mol) of 2- (2-chloroethyl) -2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5 (4H) -one in 50 ml of absolute ethanol To the solution is added 3.0 g of a 40% aqueous solution of dimethylamine. The reaction mixture is heated and cooled at 100 ° C. for 16 hours in stainless steel springs and evaporated under reduced pressure. The residue is partitioned between chloroform and 15% sodium hydride solution. The chloroform layer is concentrated to dissolve the free base residue in isopropyl alcohol and react with oxalic acid. The resulting oxalate salt is recrystallized from isopropyl alcohol / water to give 1.9 g (45%) of the title salt at melting point 176-178 ° C.

Elemental Analysis C ₃₄ H ₅₁ N ₄ O ₁₅

Calculated Value: C; 54.10, H; 6.67, N; 7.42

Found: C; 54.29, H; 6.59, N; 7.53

Example 34

7-bromo-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -thione oxalate [1: 1] yl Luggage.

A solution of 13 g (0.04 mol) of 7-bromo-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione in 50 ml of anhydrous ethanol To this was added 8 ml of a 45% aqueous solution of dimethylamine. The solution is heated for 16 h at 100 ° C. in a steel bomb. Ethanol is evaporated under reduced pressure and the residue is partitioned between ethyl acetate and 3N aqueous hydrochloric acid. The aqueous extract is basified with 50% aqueous sodium hydroxide and extracted with chloroform. Chloroform is concentrated under reduced pressure. The residue, the free base of the title compound, is dissolved in isopropyl alcohol and reacted with oxalic acid. The oxalate salt is recrystallized with 95% ethanol to give the title salt with a melting point of 155-157 ° C.

Elemental analysis: C ₃₂ H ₄₆ N ₄ Br ₂ O ₁₂ S ₂ :

Calculated Value: C; 42.58, H; 5.14, N; 6.12

Found: C; 42.93, H; 4.79, N; 6.19

[Examples 35a to h]

Equivalent molar amount instead of 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one in the process of Example 27 Compound (A) is used to obtain compound (B), respectively.

Compound (A):

2- (2-chloroethyl) -4-cyclohexyl-2,3-dihydro-1,4-benzoxazepin-5 (4H) -one, 2- (2-chloroethyl) -2,3-di Hydro-4-ethyl-1,4-benzoxazepine-5 (4H) -one, 2- (2-chloroethyl) -2,3-dihydro-4-isopropyl-1,4-benzoxazepine- 5 (4H) -one, 2- (2-chloroethyl) -4- (4-chlorobenzyl) -2,3-dihydro-1,4-benzoxazepin-5 (4H) -one, 2- ( 2-chloroethyl) -2,3-dihydro-4 (4-methylbenzyl) -1,4-benzoxazepin-5 (4H) -one, 2- (3-chloroethyl) -2,3-di Hydro-4- (3,5-dimethoxybenzyl) -1,4-benzoxazepin-5 (4H) -one, 2- (2-chloroethyl) -2,3-dihydro-4- (3- Trifluoro methylbenzyl) -1,4-benzoxazepin-5 (4H) -one and 2- (2-chloroethyl) -2,3-dihydro-4- (4-nitrobenzyl) -1, 4-benzoxazepin-5 (4H) -one.

Compound (B):

a) 4-cyclohexyl-2- [2- (dimethylamino) ethyl] -2,3-dihydro-1,4-benzoxazepin-5 (4H) -one oxalate, b) 2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-ethyl-1,4-benzoxazepine-5 (4H) -one oxalate, c) 2- [2- (dimethylamino) ethyl] -2 , 3-dihydro-4-isopropyl-1,4-benzoxazepin-5 (4H) -one oxalate, d) 4- (4-chlorobenzyl) -2- [2- (dimethylamino) ethyl] -2,3-dihydro-1,4-benzoxazepin-5 (4H) -one oxalate, e) 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4- (4 -Methylbenzyl) -1,4-benzoxazepin-5 (4H) -one oxalate, f) 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4- (3,5- Dimethoxybenzyl) -1,4-benzoxazepin-5 (4H) -one oxalate, g) 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-[(3-tri Fluoromethyl) benzyl] -1,4-benzoxazepin-5 (4H) -one oxalate, and h) 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4- (4 Nitrobenzyl) -1,4-benzoxazepin-5 (4H)- On oxalate.

[Examples 36a to h]

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazin-5 (4H) -one hydrochloride in the process of Example 10 Instead, using the same molar amount of the next compound (A), to obtain the next compound (B), respectively.

Compound (A):

2- (2-Chloroethyl) -4-cyclohexyl-2,3-dihydropyrido [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride, 2- (2 -Chloroethyl) -2,3-dihydro-4-ethyl-pyrido [3,2-f] [1,4] -oxazin-5 (4H) -one hydrochloride, 2- (2-chloroethyl) -2,3-dihydro-4-isopropyl-pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride, 2- (2-chloroethyl) -4- (4-chlorobenzoyl) -2,3-dihydropyrido [3,2-f] [1,4] -oxazin-5 (4H) -one hydrochloride, 2- (2-chloroethyl) -2, 3-dihydro-4- (4-methylbenzyl) -pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride, 2- (2-chloroethyl) -2 , 3-dihydro-4- (4-methoxybenzyl) -pyrido [3,2-f] [1,4] -oxazin-5 (4H) -one hydrochloride, 2- (2-chloroethyl) -2,3-dihydro-4- (3-trifluoromethylbenzyl) -pyrido [3,2-f] [1,4] -oxazin-5 (4H) -one hydrochloride, and 2- ( 2-Chloroethyl) -2,3-dihydro-4- (4-nitrobenzyl) -pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride.

Compound (B):

a) 4-cyclohexyl-2- [2- (dimethylamino) ethyl] -2,3-dihydro-pyrido [3,2-f] [1,4] oxazepine-5 (4H) -one fumar B) 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-ethyl pyrido- [3,2-f] [1,4] -oxazepine-5 (4H)- On fumarate, c) 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-isopropyl-pyrido [3,2-f] [1,4] -oxazepine-5 ( 4H) -one fumarate, d) 4- (4-chlorobenzyl) -2- [2- (dimethylamino) ethyl] -2,3-dihydro-pyrido [3,2-f] [1,4 ] -Oxazepine-5 (4H) -one fumarate, e) 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4- (4-methylbenzyl) pyrido [3,2- f] [1,4] -oxazepine-5 (4H) -one fumarate, f) 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4- (4-methoxybenzyl) -Pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -one fumarate, g) 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4 -(3-trifluoromethylbenzyl) -pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -one fumarate, and h) 2- [2- (dimethylamino) on Tyl] -2,3-dihydro-4- (4-nitrobenzyl) -pyrido [3,2-f] [1,4] -oxazepin-5 (4H) -one fumarate.

[Examples 37a to d]

In the process of Example 3 using equimolar amounts of pyrrolidine, piperidine, piperazine and 4-methylpiperazine in place of morpholine, the following compounds are obtained respectively: a) 2,3-dihydro-4 -Methyl-2- [2- (1-pyrrolidino) ethyl] -1,4-benzoxazepin-5 (4H) -one fumarate, b) 2,3-dihydro-4-methyl-2- [2- (1-piperidino) ethyl] -1,4-benzoxazepin-5 (4H) -one fumarate, c) 2,3-dihydro-4-methyl-2- [2- (1 -Piperazino) ethyl] -1,4-benzoxazepin-5 (4H) -one fumarate, and d) 2,3-dihydro-4-methyl-2- [2- (4-methylpiperazin -1-yl) ethyl] -1,4-benzoxazepin-5 (4H) -one fumarate.

Example 38

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-pyrido [3,2-f] [1,4] -thiazepin-5 (4H) -one dihydrochloride

1.5 g of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -thiazepin-5 (4H) -one in 20 ml of dimethylamine ( 0.0058 mole) of the solution is stirred in a sealed container at 25 ° C. for 72 hours. Excess dimethylamine is evaporated to partition the residue between chloroform and dilute sodium hydroxide. The chloroform layer is concentrated to dissolve the residue consisting of the free base of the title compound in isopropyl alcohol and react with hydrogen chloride. 1.5 g (77%) of hydrochloride at melting point >

Elemental Analysis: C ₁₃ H ₂₁ N ₃ OSCl ₂ :

Calculated Value: C; 46.16, H; 6.27, N; 12.42

Found: C; 45.68, H; 6.18, N; 12.35

Example 39

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-pyrido [3,2-f] [1,4] -thiazepine-5 (4H) -thione oxalate

1.5 g of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -thiazepine-5 (4H) -thione in 40 ml of dimethylamine ( 0.005 mol) of the solution is stirred in a sealed container at 25 ° C. for 96 hours. Dimethylamine is evaporated and the residue is partitioned between methylene chloride and dilute sodium hydroxide. The chloroform layer is concentrated and the free base residue of the title compound is reacted with 0.4 g of oxalic acid in a 30 ml solution of 90-100 isopropyl alcohol / water. The resulting crystals are recrystallized from the same solvent to obtain 1 g of a product having a melting point of 191 to 193 ° C.

Elemental analysis: C ₁₅ H ₂₁ N ₃ S ₂ O ₄ :

Calculated Value: C; 48.50, H; 5.70, N; 11.33

Found: C; 48.49, H; 5.84, N; 10.99

Example 40

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-pyrido [3,4-f] [1,4] oxazepin-5 (4H) -one oxalate (1 2) Hemihydrate

5 g (0.02 mol) of 2- (2-chloroethyl) -2.3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepine-5 (4H) -one in 25 ml of dimethylamine The solution is placed in a sealed container and stirred for 72 hours. Open the vessel and evaporate excess dimethylamine. The residue is dissolved in chloroform and the solvent is evaporated in vacuo to remove excess dimethylamine. The residue is partitioned between dilute sodium hydroxide and ethyl acetate. The ethyl acetate solution is concentrated and the residue is treated with boiling 50 ml of isopropyl alcohol and 3 g (0.033 mol) of oxalic acid in an amount sufficient to dissolve the salt. The resulting crystals are recrystallized from the same solvent to give 5.3 g (60%) of the product at 179 to 181 ° C.

Elemental analysis: C ₃₄ H ₄₈ N ₆ O ₂₁ :

Calculated Value: C; 46.48, H; 5.52, N; 9.58

Found: C; 46.58, H; 5.70, N; 9.61

Example 41

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-pyrido [3,4-f] [1,4] -oxazepine-5 (4H) -thione oxalate ( 1: 2)

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] -oxazepin-5 (4H) -one oxalate (1 2) Dispense 4 g (0.009 mol) of a sample of 1/2 hydrate between diluted sodium hydroxide and chloroform. The aqueous layer is extracted three times and the combined chloroform extracts are dried over sodium sulfate and concentrated. The residue is dissolved in 200 ml of anhydrous toluene and concentrated to dryness again in vacuo. The residue is dissolved in anhydrous pyridine (10 ml) and treated with 2.8 g (0.01 mol) of phosphorus sulphide. After the mixture is stirred at reflux for 20 hours, the cooled mixture is partitioned between dilute sodium hydroxide and chloroform. The aqueous layer is extracted three times with chloroform, the combined chloroform extracts are dried over sodium sulfate and concentrated. 1 g of residue is treated with 0.6 g of oxalic acid in isopropyl alcohol / 10% water. The resulting crystals were collected by filtration to obtain 0.37 g of an oxalate salt having a melting point of 111 to 114 ° C.

Elemental Analysis: C ₁₇ H ₂₃ N ₃ SO ₉ :

Calculated Value: C; 45.84, H; 5.20, N; 9.43

Found: C; 45.46, H; 5.38, N; 9.28

Example 42

2- (2-Aminopropyl) -2,3-dihydro-4-methyl-pyrido- [3,2-f] [1,4] -oxazin-5 (4H) -one oxalate [1: One]

Wet 5 g (0.22 mol) of 2,3-dihydro-4-methyl-5 (4H) -oxopyrido- [3,2-f] [1,4] -oxazepine-2-propanenitrile in 150 ml of ethanol Treat with about 1.5g of raninickel. The mixture is hydrogenated in a Parr apparatus at 60 ° C., 40 psi. The mixture is cooled and filtered to concentrate the filtrate. The residue is treated with 3.9 g of oxalic acid in 13 ml of boiling isopropyl alcohol containing 2 ml of water. The hot solution is filtered and cooled. The resulting solid is recrystallized from ethanol to give 3 g (43%) of oxalate 1/2 hydrate at melting point 126-134 ° C.

Elemental Analysis: C ₂₈ H ₄₀ N ₆ O ₇ :

Calculated Value: C; 50.30, H; 6.30, N; 12.57

Found: C; 50.46, H; 5.77, N; 12.21

Example 43

2,3-dihydro-4-methyl-2- [2- (4-morpholino) ethyl] -pyrido [3,2-f] [1,4] -oxazin-5 (4H) -one Maliate [1: 1]

16 g (0.058 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride Is dissolved in morpholine (30 ml) and stirred overnight at room temperature. Dilute sodium hydroxide solution (50 ml) is added to the solution, and the resulting mixture is extracted with chloroform (3 x 30 ml). Chloroform is aspirated off on a rotary evaporator. Residual morpholine is removed in vacuo at 50 ° C. (rotary evaporator). To the residual free base (15.5 g, 0.053 mole) isopropyl alcohol (11) and maleic acid (9.24 g, 0.080 mole) are added. The mixture is boiled and the clear solution is cooled at 20 ° C. for several hours. 16 g (68.1%) of the resulting crystals were recrystallized from isopropyl alcohol to obtain a product having a melting point of 163 to 165 캜.

Elemental analysis: C ₁₉ H ₂₅ N ₃ O ₇ :

Calculated Value: C; 56.01, H; 6.18, N; 10.31

Found: C; 55.71, H; 6.21, N; 10.18

Example 44

2,3-dihydro-4-methyl-2- [2- (1-pyrrolidinyl) ethyl] -pyrido- [3,2-f] [1,4] -oxazepine-5 (4H)- On fumarate [1: 1]

16 g (0.058) of a sample of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazin-5 (4H) -one hydrochloride Mole) is dissolved in 65 ml of pyrrolidine. The stirred solution is heated to 80 ° C. for 3 hours. The solution is cooled to room temperature and dilute sodium hydroxide solution (50 ml) is added. The resulting solution is extracted with chloroform (3 × 30 ml) and concentrated in vacuo. The residue is taken up in boiling isopropyl alcohol (500 ml) and fumaric acid (9.2 g, 0.079 mol) is added. The solution is filtered on hot and the filtrate is cooled to 20 ° C. for several hours. 14 g (47.8%) of the resulting crystals were collected and recrystallized from isopropyl alcohol to obtain a product having a melting point of 147 to 149 ° C.

Elemental Analysis: C ₂₃ O ₁₀ N ₃ H ₂₉ :

Calculated Value: C; 54.43, H; 5.76, N; 8.28

Found: C; 54.38, H; 5.83, N; 8.27

Example 45

2- [2- (dibutylamino) ethyl] -2,3-dihydro-4-methyl-pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -one maleate [1: 1]

16 g (0.058 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride Is dissolved in dimethyl formamide (30 ml) and di-n-butylamine (30 ml). The solution is stirred at 90 ° C. for 3 hours and at 100 ° C. for 2.5 hours. Cool the solution and add 50 ml of diluted sodium hydroxide solution. The resulting mixture is extracted with chloroform (3 x 50 ml). Chloroform is removed with suction at 50 ° C. on a rotary evaporator. Residual dimethyl formamide and di-n-butylamine are removed in low vacuum at 50 ° C. (on a rotary evaporator). To 13.8 g (0.041 mole) of the residual free base, isopropyl alcohol (900 ml) and 5.6 g (0.062 mole) of oxalic acid are added and the solution is heated to boiling. The clear solution was cooled overnight at 20 ° C. and filtered to yield 13.6 g (56.5%) of crystals, which were recrystallized from isopropyl alcohol to give a product having a melting point of 195-196 ° C.

Elemental Analysis: C ₂₁ H ₃₃ N ₃ O ₆ :

Calculated Value: C; 59.59, H; 7.85, N; 9.72

Found: C; 59.37, H; 7.91, N; 9.86

Example 46

2- [2- (diethylamino) ethyl] -2,3-dihydro-4-methyl-pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -one oxalate [1: 1]

16 g (0.058 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride It is suspended in diethylamine (30 ml). The suspension is stirred at rt for 72 h. The mass spectrum shows that the reaction proceeded 33% at this point. The mixture is then heated to reflux for 6 hours. Diethylamine is removed on a rotary evaporator (70 ° C., water aspirator). The residue is taken up in chloroform (100 ml) and washed with dilute aqueous sodium hydroxide (2 x 30 ml). The organic layer is concentrated with a rotary evaporator (70 ° C., water aspirator). The residue is dissolved in boiling isopropyl alcohol and treated with oxalic acid. Cool to collect 18.6 g (87,7%) of light brown crystals (melting point 150 ° -155 ° C.). The sample is recrystallized three times with isopropyl alcohol to give a product having a melting point of 156-157 ° C.

Elemental Analysis C ₁₇ H ₂₅ N ₃ O ₆ :

Calculated Value: C; 55.57, H; 6.86, N; 11.43

Found: C; 55.28, H; 6.85, N; 11.27

Example 47

2,3-dihydro-4-methyl-2- [2- (1-piperidinyl) ethyl] -pyrido [3,2-f] [1,4] oxazepin-5 (4H) -one oxal Rate [1: 1]

4 g (0.015 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazin-5 (4H) one hydrochloride Dissolve in piperidine (30 ml) and heat to 80 ° C. with stirring for 20 minutes. Piperidine is removed using a rotary evaporator (85 ° C., vacuum pump) and the residue is dissolved in chloroform (50 ml). The organic layer is washed with dilute aqueous sodium hydroxide (2 x 20 ml) and concentrated on a rotary evaporator (80 ° C, water aspirator). The resulting oil is taken up in hot isopropyl alcohol and treated with oxalic acid. Cool to collect oxalate salt crystals and recrystallize with isopropyl alcohol to yield 3.4 g (62%) of light brown crystals with melting points of 133 to 136 ° C.

Elemental Analysis C ₁₈ H ₂₅ N ₃ O ₆ :

Calculated Value: C; 56.98, H; 6.64, N; 11.07

Found: C; 56.95, H; 6.87, N; 10.79

Example 48

2,3-dihydro-4-methyl-2- [2- [methyl (phenylmethyl) -amino] ethyl] pyrido- [3,2-f] [1,4] oxazepine-5 (4H)- On Maliette [1: 1]

4 g (0.015 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methyl-rirido [3,2, -f] [1,4] -oxazin-5 (4H) -one hydrochloride ) Is dissolved in methyl benzylamine (30 ml) and heated to 80 ° C. with stirring. After 3 hours, excess amine is removed with a rotary evaporator (90 ° C., vacuum pump). The bottom oil is dissolved in chloroform (40 ml) and washed with dilute aqueous sodium hydroxide (30 ml). The chloroform layer is concentrated on a rotary evaporator (90 ° C., water aspirator). Residual oil is dissolved in hot isopropyl alcohol and treated with maleic acid. Cool to collect 4.23 g (66%) of light brown crystals with melting points of 167-169 ° C.

Elemental Analysis C ₂₃ H ₂₇ N ₃ O ₆ :

Calculated Value: C; 62.57, H; 6.16, N; 9.52

Found: C; 62.28, H; 6.16, N; 9.24

Example 49

2,3-dihydro-4-methyl-2- [2- (methylphenylamino) ethyl] -pyrido [3,2-f] [1,4] oxazepin-5 (4H) -one

4.00 g (0.015 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride ) Is dissolved in N-methylaniline (30 ml) and heated to 95 ° C. for 2 days with stirring. Excess N-methylaniline is removed using a rotary evaporator (95 ° C., vacuum pump), and the residue is dissolved in chloroform (80 ml) and washed with dilute aqueous sodium hydroxide (30 ml). The chloroform layer is decolorized with activated charcoal, dried over sodium sulfate, filtered and concentrated by rotary evaporator. The residue is dissolved in ethyl acetate (50 ml) and purified by high pressure liquid chromatography using silica gel column and ethyl acetate eluent. After purification, crystals are formed from ethyl acetate. The resulting crystals were recrystallized from ethyl acetate to give 1.40 g (31%) of light brown crystals.

Elemental Analysis C ₁₈ H ₂₁ N ₃ O ₂ :

Calculated Value: C; 69.43, H; 6.79, N; 13.49

Found: C; 69.31, H; 6.77, N; 13.54

Example 50

2- [2- (2,5-dimethyl-1-pyrrolidinyl) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 ( 4H) -on fumarate [1: 1]

2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -one 5.0 g (0.021 mol) Is dissolved in 25 ml of anhydrous ethanol and 3 g (0.03 mol) of 2,5-dimethylpyrrolidine is added. The solution is heated to 75 ° C. for 48 hours with stirring. Since the reaction is incomplete at this time, an additional amount of 2.5-dimethylpyrrolidine (1.00 g, 0.01 mol) is added to continue the reaction. After 5 days, an additional 2,5-dimethylpyrrolidine (1.00 g, 0.01 mol) is added, since it is still incomplete until this time. The reaction is confirmed to be complete after 2 days. The solvent is removed with a rotary evaporator (80 ° C., water aspirator). Excess 2,5-dimethylpyrrolidine is removed with a rotary evaporator (80 ° C, straight pump). The residue is taken up in chloroform (200 ml) and washed with dilute aqueous sodium hydroxide (2 × 75 ml). The organic layer is dried over sodium sulfate and filtered to concentrate the filtrate with a rotary evaporator (70 ° C., water aspirator). The resulting oil is dissolved in hot isopropyl alcohol and treated with fumaric acid. After cooling, 2.38 g (27.4%) of light brown crystals having a melting point of 161 to 162 ° C are collected.

Elemental Analysis C ₂₁ H ₂₉ N ₃ O ₆ :

Calculated Value: C; 60.13, H; 6.95, N; 10.02

Found: C; 59.79, H; 6.93, N; 9.76

Example 51

2,3-dihydro-4-methyl-2- [2- (2-methyl-1-pyrrolidinyl) ethyl] -pyrido [3,2-f] [1,4] oxazepine-5 (4H )-On

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazin-5 (4H) -one in ethanol (15 ml) 3.5 To methyl (0.0145 mol) solution of 2-methylpyrrolidine (5.0 g, 0.063 mol) is added. The solution is heated to reflux for 3 hours with stirring. Ethanol is removed by rotary evaporator (aspirator, 80 ° C.). The residual oil is partitioned between dilute aqueous sodium hydroxide (500 ml) and chloroform (50 ml). The organic layer is separated and the aqueous layer is extracted with chloroform (2 × 30 ml). Combine all chloroform layers, dry over anhydrous sodium sulfate and concentrate with rotary evaporator (aspirator, 70 ° C.) Residual oil is distilled under 200 ° C., low vacuum (vacuum pump) to give 1.5 g (35.7%) of a clear oil. do.

Elemental Analysis C ₁₆ H ₂₃ N ₃ O ₂ :

Calculated Value: C; 66.41, H; 8.01, N; 41.52

Found: C; 65.58, H; 8.06, N; 14.39

Example 52

2.3-dihydro-4-methyl-2- [2- (1H-pyrazol-1-yl) ethyl] pyrido- [3,2-f] [1,4] -oxazepine-5 (4H)- On

To a suspension of sodium hydride (1.2 g activity, 0.05 mole) in dimethylformamide (15 ml) was added dropwise a solution of pyrazole (3.10 g, 0.45 mole) in dimethylformamide (15 ml). The resulting solution was then added to 2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] [1,4] -oxazepine-5 in 30 ml of dimethylformamide. To a solution of (4H) -one (9.12 g, 0.38 mol). Seal the flask and stir overnight. At this point, pyrazole (3.12 g, 0.45 mol) is added to the reaction solution and the reaction is stirred overnight, since the reaction is not yet complete. Since the reaction is not completed by this time, an additional suspension of sodium hydride (0.5 g activity, 0.021 moles) and pyrazole (1.5 g, 0.022 moles) in dimethylformamide (10 ml) is added and the reaction mixture is stirred overnight. Upon completion of the reaction, remove with dimethylformamide rotary evaporator (80 ℃, vacuum pump), dissolve the residue in chloroform (100ml), wash with diluted aqueous sodium hydroxide (1x50ml), dry over anhydrous sodium sulfate, and rotary evaporator (70 ℃, Concentrator). The resulting material is purified by high pressure liquid chromatography on silica gel column using 95: 5 (volume ratio) ethanol: methanol. Fractions containing the desired product are concentrated using a rotary evaporator (70 ° C., water aspirator). Cooling causes crystallization, and the resulting crystals are collected and recrystallized with ethanol to obtain 1.5 g (14.5%) of the product having a melting point of 132 to 134 ° C.

Elemental Analysis C ₁₄ H ₁₆ N ₄ O ₂ :

Calculated Value: C; 61.75, H; 5.92, N; 20.58

Found: C; 61.35, H; 5.89, N; 20.67

Example 53

2.3-dihydro-2- [2- (1H-imidazol-2-yl) ethyl] -4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H)-in dimethylformamide (30 ml) 5.66 g (0.083 mole) of imidazole is added to a 9.12 g (0.0038 mole) solution. The solution is heated to 130 ° C. for 18 hours. Remove dimethylformamide with a rotary evaporator (80 ° C, vacuum pump) and dissolve the residue in chloroform (100 ml). Chloroform is washed with dilute aqueous sodium hydroxide (30 ml), dried over sodium sulfate and concentrated by rotary evaporator to give an oil. Crystallization with ethanol yields 1.5 g (14.5%) of white crystals having a melting point of 150 to 152 캜.

Elemental Analysis C ₁₄ H ₁₆ N ₄ O ₂ :

Calculated Value: C; 61.75, H; 5.92, N; 20.58

Found: C; 61.36, H; 5.92, N; 20.60

Example 54

2- [2- (dimethylamino) ethyl] -4-methyl-2,3-dihydropyrido [3,2-f] [1,4] oxazepin-5 (4H) -one oxalate [1: One]

To 30 ml of dimethylamine collected at 0 ° C., 2- (2-chloroethyl) -4-ethyl-2,3-dihydropyrido- [3,2-f] [1,4] -oxazepine-5 (4H 6 g (0.021 mol) of) -one hydrochloride are added. The flask is completely sealed and stirred for 70 hours at room temperature. The solution is then cooled to 0 ° C. and the stopper of the flask is removed. Dimethylamine is evaporated. The residue is taken up in chloroform (1 x 50 ml) and washed with dilute aqueous sodium hydroxide (1 x 50 ml). The organic layer is dried over sodium sulfate and filtered, and the filtrate is concentrated on a rotary evaporator (70 ° C., water aspirator). The residue is dissolved in hot isopropyl alcohol and treated with oxalic acid. Cool to give 4.5 g (61.5%) of product at melting point of 208 ° C.

Elemental Analysis C ₁₆ H ₂₃ N ₃ O ₆ :

Calculated Value: C; 54.38, H; 6.56, N; 11.89

Found: C; 54.26, H; 6.61, N; 11.81

Example 55

2,3-dihydro-4-methyl-2- [2- (1-pyrrolidinyl) ethyl] pyrido [3,2-f] [1,4] oxazepin-5 (4H) -one

3 g (0.01 mol) of 2- (2-chloroethyl) -4-ethyl-2,3-dihydropyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -one hydrochloride Is dissolved in pyrrolidine (30 ml) and heated to 70 ° C. for 30 minutes with stirring. After cooling, the contents of the reaction flask are diluted with dilute aqueous sodium hydroxide (40 ml) and extracted with chloroform (2 x 30 ml). The chloroform layer is dried over sodium sulfate and filtered to concentrate the filtrate with a rotary evaporator (70 ° C., water aspirator) to give a brown viscous oil. The oil is dissolved in hot isopropyl alcohol and treated with oxalic acid. The solid produced by cooling is recrystallized with isopropyl alcohol to give 1.80 g (45.4%) of light brown crystals having a melting point of 185-188 ° C.

Elemental Analysis C ₁₈ H ₂₅ N ₃ O ₆

Calculated Value: C; 56.98, H; 6.64, N; 11.07

Found: C; 56.90, H; 6.67, N; 10.90

Example 56

2,3-dihydro-4-methyl-2- [2- (4-morpholinyl) ethyl] pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione

4.5 g (0.018 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione Is dissolved in morpholine (30 ml). The solution is heated with stirring at 50 ° C. to 60 ° C. for 6 hours. Morpholine is removed with a rotary evaporator (90 ° C, vacuum pump), and the residue is dissolved in chloroform (100 ml) and washed with dilute aqueous sodium hydroxide (2 x 30 ml). The organic layer was concentrated with a rotary evaporator (60 ° C., water aspirator), and the residue was recrystallized from ethanol to give 3.26 g (60%) of pale yellow crystals having a melting point of 152 to 153 ° C.

Elemental Analysis C ₁₅ H ₂₁ N ₃ O ₂ S:

Calculated Value: C; 58.61, H; 6.89, N; 13.66

Found: C; 58.48, H; 6.92, N; 13.62

Example 57

2- [2- (dibutylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one oxalate [1 : One]

4 g (0.016 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -thione It is suspended in di-n-butylamine (30 ml). To dissolution, dimethylformamide (about 10 ml) is added to the stirred mixture. The solution is heated to 140 ° C. for 3-5 hours with stirring. Di-n-butylamine and dimethylformamide are removed with a rotary evaporator (80, vacuum pump). The residue is then diluted with dilute aqueous sodium hydroxide (50 ml) and extracted with chloroform (3 x 40 ml). Chloroform is removed with a rotary evaporator (70 ° C., water aspirator), and the residue is dissolved in boiling isopropyl alcohol and treated with oxalic acid. The oxalate salt formed by cooling was filtered and recrystallized with isopropyl alcohol to give 3.2 g (47%) of yellow crystals having a melting point of 208 ° C.

Elemental Analysis C ₂₁ H ₃ N ₃ O ₅ S:

Calculated Value: C; 57.38, H: 7.57, N: 9.56

Found: C; 57.04, H: 7.63, N: 9.31

Example 58

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione oxalate [1: One]

4 g (0.016 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -thione Suspension in diethylamine (30 ml). Dimethylformamide (10 ml) is added to the stirred suspension until dissolution occurs. The stirred solution is heated to 65 ° C. for 8 hours. Diethylamine is removed with a rotary evaporator (70 ° C., water aspirator) to remove residual dimethylformamide at 90 ° C. under low pressure (vacuum pump). The residue is taken up in chloroform (100 ml) and washed with dilute aqueous sodium hydroxide (2 x 30 ml). The organic layer is concentrated on a rotary evaporator (70 ° C., water aspirator) and the residue is dissolved in boiling isopropyl alcohol and treated with oxalic acid. It cools and obtains 1.7 g (28.5%) of oxalate salts of melting | fusing point 142-144 degreeC.

Elemental Analysis C ₁₇ H ₂₅ N ₃ O ₅ S:

Calculated Value: C; 53.25, H; 6.57, N; 10.95

Found: C; 53.14, H; 6.60, N; 10.72

Example 59

2,3-dihydro-4-methyl-2- [2- (1-pyrrolidinyl) ethyl] -pyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione oxal Rate [1: 1]

2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -thione 5 g (0.02 mol) Is dissolved in 30 ml of pyrrolidine. The solution is heated to 60 ° -80 ° C. for 35 minutes with stirring. After cooling to room temperature, the reaction mixture is diluted with dilute aqueous sodium hydroxide (50 ml) and extracted with chloroform (2 x 50 ml). The organic layer is concentrated with a rotary evaporator (70 ° C., water aspirator). Residual pyrrolidine is removed with a vacuum pump at 90 ° C. The residue is dissolved in hot ethanol and treated with oxalic acid. The resulting oxalate salt was collected by cooling and recrystallized twice with ethanol to yield 3.35 g (45%) of the product having a melting point of 141 ° C.

Elemental Analysis C ₁₇ H ₂₃ N ₂ O ₅ S:

Calculated Value: C; 53.53, H; 6.08, N; 11.02

Found: C; 53.39, H; 6.11, N; 10.91

Example 60

2,3-dihydro-2- [2- (1H-imidazol-1-yl) ethyl] -4-methylpyrido- [3,2-f] [1,4] oxazepine-5 (4H) -Thione oxalate [2: 3]

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione in dimethylformamide (35 ml) To 4.5 g (0.018 mole) of solution add imidazole (2.20 g, 0.038 mole). The resulting solution is heated to 130 ° C. for 15 hours. Dimethylformamide is removed with a rotary evaporator (80 ° C., vacuum pump) and the residue is diluted with dilute aqueous sodium hydroxide (50 ml). The aqueous solution is extracted with chloroform (1 × 50 ml), dried over anhydrous sodium sulfate and concentrated on a rotary evaporator (water aspirator, 70 ° C.). The resulting oil is treated with oxalic acid in ethanol. 4 g (54%) of pale yellow crystals were collected and recrystallized again with ethanol to obtain a product having a melting point of 163 to 167 ° C.

Elemental Analysis C ₁₇ H ₁₉ N ₇ O ₄ S:

Calculated Value: C; 48.22, H; 4.52, N; 13.23

Found: C; 48.04, H; 4.62, N; 13.18

Example 61

2- [2- (dimethylamino) ethyl] -4-ethyl-2,3-dihydro-pyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione

5.00 g (0.016 mol) of 2- (2-chloroethyl) -4-ethyl-2,3-dihydropyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -thione hydrochloride ) Is added to 20 ml of anhydrous dimethylamine. The reaction flask is completely sealed and stirred for 6 days at room temperature. After cooling to 0 ° C., the reaction flask is opened and the dimethylamine is evaporated at room temperature. The residue is taken up in chloroform (100 ml) and washed with dilute aqueous sodium hydroxide (1 x 30 ml). The chloroform layer is dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The bottom oil is dissolved in hot cyclohexane and cooled to yield 1.76 g (39.4%) of pale yellow crystals with a melting point of 73 ° C.

Elemental Analysis C ₁₄ H ₂₁ N ₃ OS:

Calculated Value: C; 60.18, H; 7.58, N; 15.03

Found: C; 60.32, H; 7.70, N; 15.13

Example 62

2,3-dihydro-4-methyl-2- [2-methyl (phenylmethyl) amino] ethyl] -pyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione oxal Rate [1: 1]

4-g (0.0155) 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -thione in 70 ml of chloroform 10.0 g (0.086 mol) of benzylmethylamine is added to the solution. The solution is stirred at reflux for 24 h. The reaction solution is washed with water (2 × 50 ml) and concentrated on a rotary evaporator (about 70 ° C., water aspirator). The residue is distilled by a molecular distillation apparatus at 165 ° C./0.1 mm. Cool to collect two fractions of crystals. The two fractions are combined and recrystallized together with hot isopropyl alcohol. Cooling affords 3.69 g (55%) of pale yellow crystals at melting points of 163 to 166 ° C.

Elemental Analysis C ₂₁ H ₂₅ N ₃ O ₅ S:

Calculated Value: C; 58.45, H; 5.84, N; 9.74

Found: C; 58.24, H; 5.92, N; 9.61

Example 63

2,3-dihydro-2- [2- (methylamino) ethyl] -4-methylpyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione oxalate [1 : One]

2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) -thione 4.0 g (0.016 mol) Is suspended in a 30% solution of methylamine in 70 ml of ethanol and suspended at room temperature for 56 hours. Since the reaction is not completed, the reaction solution is slowly heated to 55 ° C. over 2 hours and then stirred at that temperature for 24 hours. Methylamine is removed using a water suction group for less than 1.5 hours. The resulting solution is concentrated on a rotary evaporator (70 ° C., water aspirator), and the residual oil is dissolved in chloroform (150 ml) and washed with 2M aqueous sodium hydroxide (1 × 50 ml). The chloroform layer is dried over sodium sulfate and concentrated on a rotary evaporator (70 ° C., water aspirator). The residue is dissolved in hot ethanol and treated with oxalic acid. Cool to collect 20 g (37.5%) of yellow crystals having a melting point of 137 to 138 ° C.

Elemental Analysis C ₁₅ H ₂₀ N ₃ O ₇ S:

Calculated Value: C; 46.63, H; 5.22, N; 10.67

Found: C; 46.47, H; 5.35, N; 40.85

Example 64

7-chloro-2,3-dihydro-4-methyl-2- [2- (1-pyrrolidino) ethyl] -pyrido [3,2-f] [1,4] oxazepine-5 (4H ) -On fumarate [1: 2.5]

7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazepin-5 (4H) -one (2.5 g, 0.009 mol) is dissolved in 50 ml of pyrrolidine and the solution is heated to 80 ° C. for 1 hour. Pyrrolidine is removed with a rotary evaporator (80 ° C., water aspirator) and the residue is dissolved in 100 ml of chloroform. The organic layer is washed with water (2 x 50 ml), dried over sodium sulphate and concentrated on a rotary evaporator (about 80 ° C., water aspirator). The residue is treated with fumaric acid and left overnight. 1.25 g (23.2%) of the resulting crystals were collected at a melting point of 164 to 166 ° C.

Elemental Analysis C ₂₅ H ₃₀ N ₃ O ₁₂ Cl:

Calculated Value: C; 50.05, H; 5.04, N; 7.00

Found: C; 50.22, H; 5.14, N; 7.02

Example 65

7-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -one oxal Rate [1: 1]

2.8 g (0.01) of 7-chloro-2- (2-chloroethyl) -2.3-dihydro-4-methylpyrido- [3,2-f] [1,4] -oxazin-5 (4H) -one Mole) is added to 25 ml of dimethylamine and stirred in a sealed flask for 96 hours. Excess amine is evaporated and the residue is dried over chloroform and dilute sodium sulfate and concentrated. The residue is treated with 0.7 g of oxalic acid in isopropyl alcohol. The resulting crystals are recrystallized from the same solvent to obtain 1.5 g (40%) of an oxalate salt having a melting point of 150 to 156 캜.

Elemental Analysis C ₁₄ H ₂₀ N ₃ O ₆ Cl:

Calculated Value: C; 48.20, H; 5.39, N; 11.24

Found: C; 48.09, H; 5.47, N; 11.12

Example 66

4-cyclohexyl-2-[(dimethylamino) methyl] -2,3-dihydro-pyrido [3,2-f] [1,4] oxazepin-5 (4H) -one oxalate

2- (chloromethyl) -4-cyclohexyl-2,3-dihydropyrido- [3,2-f] [1,4] -oxazepine-5 (4H)-using the process of Example 10 Warm intermediate 35 is reacted with 40% aqueous dimethylamine and with oxalic acid in isopropyl alcohol.

Example 67

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-phenyl-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one oxalate [ 1: 1.5] hemi hydrate

A solution containing 94.2 g (0.06 mole) of 2-chloronitocotinic acid and 100 ml (0.54 mole) of 1-benzyl-3-pyrrolidinol in 800 ml of tetrahydrofuran anhydride at 60% sodium in 500 ml of anhydrous tetrahydrofuran at reflux temperature To a stirred suspension of 52 g (1.3 mole) of hydride / mineral oil is added dropwise rapidly (addition time is about 1 hour). The mixture is further heated to reflux for 1.5 hours and then cooled to room temperature. About 1 l of ethyl acetate was added and no filtration. The mixture is left at room temperature overnight and then concentrated on a rotary evaporator under pressure of 100 ° C., 50 mm. The residue is dissolved in 1 l of chloroform and the pH of the solution is adjusted to 6.15 with hydrogen chloride gas. To the solution was added 383 g (1.0 mole) of triphenylphosphine and 383 g (2.48 mole) of carbon tetrachloride. The solution is cooled to room temperature and extracted three times with 400 ml each of diluted hydrochloric acid. The chloroform layer is extracted with dilute sodium hydroxide, dried over sodium sulfate and concentrated. 2- (2-Chloroethyl) -2,3-dihydro-4- (phenylmethyl) pyrido- [3,2-f] [1,4] -oxazin-5 (4H) -one by mass spectrum (Mass 316), the presence of triphenylphosphine (mass 262) and triphenylphosphine oxide (mass 278) are confirmed. One third of the residue was chromatographed with high pressure liquid chromatography but the compound was not purified. The remaining two thirds of the residue is dissolved in 30 ml of chloroform and added to a solution of 30 g of dimethylamine in ethanol. The solution is heated to reflux for 4 hours and concentrated on a rotary evaporator. The residue is partitioned between chloroform and 1N hydrochloric acid. The acid layer is made basic with sodium hydroxide and extracted with chloroform. The chloroform layer is dried over sodium sulfate and concentrated. The residue (10 g) is treated with an equivalent amount of oxalic acid in an isopropyl alcohol-ethanol-isopropyl ether mixture. 9 g (5%) of the resulting crystals were recrystallized from the same solvent to obtain a product having a melting point of 95 to 98 ° C.

Elemental Analysis C ₄₄ H ₅₄ N ₆ O ₁₇

Calculated Value: C; 56.28, H; 5.79, N; 8.95

Found: C; 56.61, H; 5.76, N; 8.77

Example 68

2- [2- (dimethylamino) ethyl] -2,3-dihydropyrido- [3,2-f] [1,4] oxazepin-5 (4H) -one

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-phenylmethylpyrido- [3,2-f] [1,4] -oxazepine-5 (4H) in about 50 ml of water A solution of 3.0 g (0.006 mol) of 1/2 hydrate [1: 1: 5] is made basic with diluted aqueous sodium hydroxide solution and extracted three times with 50 ml of benzene. The benzene extracts are combined, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator (steam bath / 50 mm). The residue is azeotropically distilled twice with about 50 ml of anhydrous benzene to further dry and evaporate firmly each time. The final residue is dissolved in 40 ml of liquid ammonia and stirred in the solution, adding sodium globules until the blue color lasts 20 minutes (addition time about 1 hour). Slowly add 3 g ammonium chloride and evaporate ammonia. The residue is suspended in chloroform and the mixture is filtered. The filtrate was concentrated and the residue was subjected to preparative high pressure liquid chromatography using a silica gel column and 75% ethyl acetate / 25% dimethylformamide as eluent. The yield of the product is 0.1 g (7%). Chemical ionization mass spectrometry shows a peak at 236 corresponding to a molecular weight of 235. The ¹ H NMR spectrum of the resulting compound is measured in CDCl ₃ containing 1% tetramethylsilane (TMS) to identify dimethylformamide (DMF) and mineral oil with the desired structure and minor impurities. Chemical shifts, multiplicity and corresponding sites are as follows.

Example 69

2- [3- (dimethylamino) propyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepin-5 (4H) -one fumarate [1 : 1.5] hemi hydrate

To 5.0 g (0.021 mol) of 2- (3-aminopropyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazin-5 (4H) -one 20 g (0.38 mol) of 88% aqueous formic acid is added while cooling in an ice bath. To the resulting solution is added 10.7 g (0.13 mol) of 37% aqueous formaldehyde (obstructed with 13% methanol). The resulting solution is heated in a steam bath for 5.5 hours.

Cool the mixture and add 100 ml of dilute aqueous hydrochloric acid. The solution is evaporated to dryness and the residue is dissolved in 50 ml of water. The solution is neutralized with dilute aqueous sodium hydroxide and extracted with 50 ml each of chloroform. The chloroform extracts are combined, dried over sodium sulfate and concentrated on a rotary evaporator.

The residue is reacted with fumaric acid in hot isopropyl alcohol. 3.0 g (31.8%) of the product were collected and recrystallized twice with isopropyl alcohol to obtain a product having a melting point of 108 to 110 ° C.

Elemental Analysis C ₄₀ H ₅₆ N ₆ O ₁₇ :

Calculated Value: C; 53.81, H; 6.32, N; 9.41

Found: C; 53.69, H; 6.33, N; 9.41

Example 70

2- [3- (dimethylamino] propyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione oxalate [1 : 2]

2- [3- (dimethylamino) -propyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazin-5 (4H) -one in 125 ml of pyridine To 11.0 g (0.042 mole) of solution is added 9.25 g (0.042 mole) of phosphorus sulphide. The mixture is heated to reflux for 3.5 hours with stirring. After cooling to room temperature, the reaction solution is added to a 2 molar potassium hydroxide equivalent capacity. The mixture is extracted several times with 800 ml of methylene chloride. The organic phase is washed three times with 100 ml of diluted potassium hydroxide, dried over sodium sulfate, filtered and concentrated using a rotary evaporator (water aspirator, 70 ° C.). The residual oil is placed under reduced pressure using a vacuum pump at 90 ° C. for 2 hours and then cooled to react with oxalic acid in isopropyl alcohol. 4.5 g and 3.1 g of two fractions are obtained and collected and recrystallized with isopropyl alcohol to give 6.5 g (34%) of yellow crystals having a melting point of 136 to 138 ° C.

Elemental Analysis C ₁₈ H ₂₅ N ₃ O ₉ S:

Calculated Value: C; 47.05, H; 5.42, N; 9.16

Found: C; 46.76, H; 5.75, N; 9.04

Example 71

7-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] -oxazepine-5 (4H) -thione Fumarate [1: 1] hemihydrate, hemiisopropyl alcoholate

To 55 ml of a methanolic solution containing 57% by volume of dimethylamine, 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] Add 2.50 g (0.009 mol) of oxazine-5 (4H) -thione. The reaction vessel is sealed and left for 16 hours. Thin layer chromatography confirmed that the reaction proceeded about 60%. The solution is slowly heated to 45 ° C. (heating time is about 5 hours). Methanol and unreacted dimethyl amine are removed by rotary evaporator (aspirator, 60 ° C).

The residue is taken up in 100 ml of chloroform and the solution is washed twice with 40 ml of water. The organic layer is dried over sodium sulfate and concentrated on a rotary evaporator. The residue is reacted with fumaric acid in isopropyl alcohol. 1.43 g (36.5%) of the resulting crystals are recrystallized from isopropyl alcohol and completely dried in a drying pistol to give a product having a melting point of 98 to 104 ° C.

Elemental Analysis C ₃₇ H ₅₄ N ₆ O ₁₂ Cl ₂ S ₂ :

Calculated Value: C; 48.84, H; 5.98, N; 9.23

Found: C; 48.82, H; 5.80, N; 9.37

TABLE 1

TABLE 2

The present invention also provides a pharmaceutical composition for administration to a living animal which contains, as an active ingredient, at least one of the compounds of formula (I) according to the invention in combination with a pharmaceutical carrier or excipient. The compound therefore forms a therapeutic composition suitable for oral, rectal, parenteral, subcutaneous, intramuscular, intraperitoneal, intravenous or intranasal administration. For example, the composition for oral administration may be in the form of elixirs, capsules, tablets or tablets containing a carrier commonly used in the pharmaceutical field. Suitable tableting excipients include lactose, potato and corn starch, talc, gelatin and stearic acid and silicic acid, magnesium stearate and polyvinyl pyrrolidone.

For parenteral administration, the carrier or excipient may consist of sterile liquids which are acceptable for parenteral use, such as water contained in ampoules or arachis oil.

The carrier in the rectal composition may consist of a suppository base such as cocoa butter or glycerides.

For the nose, throat or bronchial region, it is possible to use a gargle or aerosol spray containing fine particles of the active agent of general formula (I) in the form of a spray or dry powder.

Advantageously, the composition is reformulated in unit dosage form, each unit being formed to be suitable for administering an amount of the active ingredient. Examples of preferred dosage forms according to the invention include tablets, gels, capsules, ampoules and suppositories. These dosage forms should contain an effective amount of the active ingredient, with the dosage form used be consistent with a suitable effective amount. The exact individual dose and daily dose are, of course, determined in accordance with standard medication guidelines at the discretion of the physician or veterinarian. Generally, pharmacological tests on guinea pigs compared to other antihistamines show that the effective dose of the compounds of the present invention in the range of 2 to 8 mg for adults is more active.

Based on animal test data, unit dosage forms containing about 0.03 to 0.10 mg of active agent per kg of body weight are preferred. For humans a daily dosage form of about 0.2 to 0.6 mg / kg body weight is preferred, and several smaller unit dosage forms may also be administered at one time.

However, the scope of the present invention is not limited to this dosage form due to the uncertainty of applying animal test data to humans.

Examples of unit dosage forms are as follows:

Capsule

Tablet manufacturing process:

1. Mix components 1, 2, 3 and 4 in large quantities.

2. Add enough water little by little to the mixture of step 1 and mix with gentle stirring. This addition and stirring of water continues until the mass is combined to be suitable for conversion to wet granules.

3. The wet mass is passed through a vibrating granulator using an 8 mesh screen to form granules.

4. The wet granules are dried in an oven at 140 ° F.

5. Smooth dry granules with magnesium stearate.

6. Tablet the granules treated with the suspending agent with a suitable tableting machine.

Intramuscular injection

Content per ml

1.Active ingredient 10.0mg

2. Add 1.0 mg of isotonic buffer solution

Manufacture process

1. Dissolve the active ingredient in the buffer solution.

2. Filter the solution of step 1 aseptically.

3. Aseptically fill the sterile ampoules with sterile solution.

4. Seal the ampoule under aseptic conditions.

Suppository

Content per component suppository

1.Active ingredient 10.0mg

2. Polyethylene glycol 1000 1350.0mg

3. Polyethylene glycol 4000 450.0mg

Manufacture process :

1. Melt components 2 and 3 and stir until uniform.

2. Dissolve component 1 in the molten mass of step 1 and stir until uniform.

3. Pour the molten mass of step 2 into the suppository mold and cool.

4. Remove suppository from mold and pack. Therefore, the aspect of this invention contains the therapeutic composition of the unit dosage form which inhibits histamine which consists of an effective amount of general formula (I) compound or its pharmaceutically acceptable acid addition salt, and a pharmaceutical carrier.

Various modifications and equivalents to the methods of preparation, compounds, pharmaceutical compositions and methods of treatment of the invention, without departing from the scope and spirit of the invention, will be apparent to those of ordinary skill in the art and, therefore, the invention is defined in the appended claims It should be understood that it is limited only to.

Claims (8)

A compound selected from the group of formula (III)

Wherein A represents an aromatic or heterocyclic ring selected from the group consisting of benzene, naphthalene and pyridine in any of four positions, some of which are halo, lower alkyl, lower alkoxy, nitro and trifluoromethyl Optionally substituted with one or two Y groups selected from the group consisting of: R is selected from the group consisting of lower alkyl, cycloalkyl and phenyl-lower alkyl, wherein phenyl may be optionally substituted with one or two groups selected from halo, lower alkyl, lower alkoxy, nitro and trifluoromethyl ; n is 1 or 2; X is chlorine, bromine or fluorine; E is oxygen or sulfur. A compound selected from the group of formula (IVa)

Wherein A represents an aromatic or heterocyclic ring selected from the group consisting of naphthalene and pyridine at any of the four positions, wherein any of the rings is optionally halo, lower alkyl, lower alkoxy, nitro and trifluoromethyl Optionally substituted with one or two Y groups selected from the group consisting of: R is selected from the group consisting of lower alkyl, cycloalkyl and phenyl-lower alkyl, wherein phenyl may be optionally substituted with one or two groups selected from halo, lower alkyl, lower alkoxy, nitro and trifluoromethyl ; n is 1 or 2; Q is

Cyano, or

Wherein R ³ is H, an acid neutralized ion or an esterified group; E is oxygen or sulfur. The compound of claim 2, which is 3-[(1-methyl-3-pyrrolidinyl) -oxy] -2-naphthalenecarboxamide. The compound according to claim 2, which is 3-[(1-methyl-3-pyrrolidinyl) -oxy] -2-naphthalenecarboxylic acid or an oxalate salt thereof. The compound according to claim 2, which is sodium 2-[(1-methyl-3-pyrrolidinyl) -oxy] -3-pyridinecarboxylate or a free base thereof. The compound of claim 2, which is 1-[(1-methyl-3-pyrrolidinyl) -oxy] -2-naphthalenecarboxamide. The compound according to claim 2, which is 3-[(1-methyl-3-pyrrolidinyl) -oxy] -4-pyridinecarbonitrile or a fumarate salt thereof. The compound according to claim 2, which is 1-[(1-methyl-3-pyrrolidinyl) -oxy] -2-naphthalenecarbonitrile or an oxalate salt thereof.