CA1253145A - Fused aromatic oxazepinones, thiazepinones, diazepinones and sulfur analogs thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Disclosed are aromatic oxazepine, thiazepine or diazepine compounds of the formula:

(II) (wherein A is an aromatic ring, e.g., benzene, naphthalene, quinoline or pyridine, Y is halogen, alkyl, alkoxy, dialkylamino, nitro or trifluoromethyl, E is O, S or N-alkyl, B is O or S, R is alkyl, cycloalkyl or phenyl-alkyl in which phenyl may optionally be substituted, D is optionally alkyl-substituted alkylene, X is Cl,Br,CN or phthalimido) which are useful as intermediates for producing antihistamic and antiallergic compounds of the formula:

Description

~2~3~ 66197-169D

This is a Divisional Applica-tion of Serial No.
483,716 filed June 1~, 1985 and also is closely rela~ed to Serial No. 438,362, filed September 30, 1983.
The present invention provides an aromatic oxazepine, thiazepine or.diazepine of the formula:
~4 ~ E- ~ D - X

- ()0-2~ ~A ,~ N~ (II) B/ \ R

(wherein A represents an aromatic ring having two adjacent carbon atoms held mutually with the oxazepine, thiazepine or diazepine moiety, the aromatic ring being a benzene, naphthalene, quinoline or pyridine ring and being optionally substituted in any of the substitutable positions by one or two radicals Y selected from the group consisting of halogen, Cl 8~1kyl, Cl 8alkoxy, di(Cl 8alkyl)amino, nitro and trifluoromethyl:
-. E is oxygen, sulfur or N(Cl 8)alkyl;
B is oxygen or sulfur;
R is Cl 8alkyl, C3 gcycloalkyl or phenyl-(Cl 4)alkyl in which the phenyl radical may be substituted by one or two substituents selected from the group consisting of halogen, Cl 8 alkyl, Cl 8alkoxy, n~tro and trifluorome-thyl;

D is Cl 2alkylene which may be substituted by Cl 5 alkyl;

~53~
-la- 66197-169D

R is hydrogen or Cl 5alkyl; and X is chlorine, bromine, cyano or l-phthalimido) or an acid addition salt thereof, provided that a compound of formula (II) is excluded (in which:
A represents an aromatic ring having two adjacent carbon atoms mutually held with the oxazepine or thiazepine moiety, the aromatic ring being a benzene, naphthalene, or pyridine ring and being optionally substituted in any of the substitutable positions by one or two radicals Y selected from the group consist-ing of halogen, Cl 8alkyl, Cl 8alkoxy, di(Cl 8alkyl)amino, nitroand trifluoromethy;
E is oxygen or sulfur;
D is unsubstituted Cl 2alkylene;
R4 is hydrogen;
X is chlorine, bromine or cyano; and B and R are as defined above).
Another aspect of the invention provides a process for producing a compound of the formula (II) as defined above including the proviso or an acid addition salt thereof, which process comprises:
la] chlorinating or brominating a compound of the formula:

3~
-lb- 66197-169D

~_~ E- ~ D

~ ~ ~ C-oR3 1 ~ (IVb) O R

(wherein R is hydrogen or an acid neutralizing ion, and the other symbols are as defined above),and fusing the halogenation product to give a compound of formula (II) wherein s is oxygen and X is chlorine or bromine, [b] when required, reacting a product of step [a~
with a sulfurizing agent to give a compound of formula (II) where-in B is sulfur and X is chlorine or bromine, [c] when required, reacting a product of step [a~ or [b] with an alkali metal cyanide to give a compound of formula (II) wherein X is cyano, [d] when required, chlorinating a product of step [a] or [c] having the formula: R4 ~ r D - X

(wherein X is chlorine, bromine or cyano, and the other symbols are as defined above~,with sulfuryl chloride to give a compound ~2~
-lc- 661g7-169D
of the formula:
R
N ~ E ~ ~ - X

Cl/~
O R

(wherein X is as defined in [d], and the other symbols are as defined above),or [e] when required, reacting a product of step [a], [b] or [d] wherein X is chlorine or bromine, with an alkali metal salt of phthalimide to give a compound of formula (II) wherein X
is l-phthalimido, and if desired, converting a compound of formula (II) produced by any process above into an acid addition salt thereof.
Those compounds of the formula (II) excluded by the above proviso are disclosed in Application Serial No. 483,716.
Those compounds of the formula (II) are not excluded by the proviso:
(1) when A represents quinoline ring;

(2) when E is N(Cl 8)alkyl, namely, when the ring containing E is a diazepine moiety;

(3) when D is a Cl 5alkyl-substituted Cl 2alkylene;

(4) when R4 is Cl 5alkyl; or

(5) when X is l-phthalimido.

-ld- 66197-169D

BACKGROUND C)F THE INVENTION
1. Field of Invention The parent application relates to novel aromatic oxazepinones, thiazepinones and diazepinones and sulfur analogs thereof and is particularly concerned with aromatic l,~-oxazep-inones, thiazepinones, diazepinones and thi.ones, which have the aromatic componenk fused into the oxazepine, thiazepine or diazepine component, each component thereby having two commonly shared carbon atoms and the oxazepine, thiazepine or diazepine ring having an oxo (or thioxo) function on the carbon atom adjacent to one of the shared carbon atoms and a short chain aminoalkyl, alkylaminoalkyl or heterocyclicaminoalkyl radical attached to the carbon atom two positions away from the other shared carbon atom, the compounds having antihistaminic and anti-allergy utility. The present invention relates to the compounds of the formula (II) which are useful for producing those compounds of the parent application.
In the following descriptionl "the present invention"
broadly means the subject matters of the paren-t application, this application and another divisional application.
2. Information Disclosure Statement 3-Aryl-1,4-benzoxazepin-5(~H)-ones substituted on the oxazepine nitrogen by an aminoalkyl radical have been disclosed by Schenker, K. in Swiss Patent 505~850 (C.A. 75 98600s).

3~

Conversion of flavanones into benzoxazepinones substituted in the 2-position by a phenyl radical has been disclosed by Levai, A. and Bognar, R., Top. ~lavanoid Chem. Biochem. Proc. ~ung. Bioflavonoid Symp. 4th Ed. 197 (Pub. 1975) 119-23 (C.A. 8~ 79098n)0 Thione derivatives were obtained by treating with phosphorus pentasulfide.
- Certain chemical intermediates, the l-substituted-~-substituted phenoxypyrrolidines illustrated by ~ l-methyl-3-(2-carbamoylphenoxy)pyrrolidine, 1-benzyI-3 (2-carbamoylphenoxy)pyrrolidine, and l-methyl-3-(2-carboxyphenoxy)pyrrolidine, in an otherwise novel class are disclosed in U. S. Patent ~,~77~415.
OBJECTS A~D SUMM~RY OF TE~: I~JE~T ION
The oxazepine, thiazepine and diazepine derivatives of the present invention which exhibit antihistaminic activity have the formula:
R~
E ~. D - z , ~~` ~ ~

~ ~ B Formula I
wherein;
A represents an aromatic ring having two o~ its carbon atoms held mutually with the oxazepine, thiazepine or diazepine moiety ~elected from the group consisting of benzene, naphthalene, a quinoline, or a pyridine in any of its four positions, any of the rings optionally substituted by one or two Y radicals selected from the group consisting of halo, loweralkyl, loweralkoxy, diloweralkylamino, nitro or trifluoromethyl;
E is selected from oxygen, sulfur or loweralkyl ~ubstituted nitrogen, i~ selected from oxygen or ~ulfur;
R is selected from the group consisting of hydrogen, loweralkylJ cycloalkyl or phenyl-loweralkyl, of which phenyl may be optionally subs' tutcd by one or two radicals ~53~

selec~ed from halo, l~weralkyl, loweralkoxy, nitro or trifluoromethyl;
D is optionally Cl 5alkyl-substltuted Cl 3alkylene;
R is selected from hydrogen or loweralkyl (1-5 C);
Z is selected from the group consisting o -NRlR2, lH-pyrazol-l-yl, lH-imidazol-~-yl, l~-imidazol-2-yl, 4,5-dihydro-lH-imidazol-2-yl;
Rl and R2 axe selected from the group consisting of hydrogen, loweralkyl, cycloalkyl and phenyl-loweralkyl, of which phenyl may be otpionally 6ubstituted by 1 or 2 radicals ~elected from halo, l~weralkyl, loweralkoxy, nitro, trifluoromethyl or cyano, or Rl and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue sel~cted from the group consisting of l-azetidinyl9 l-pyrrolidinyl, 2~5-dimethylpyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, l-piperidinyl, 4-substituted piperidin-l-yl, 4-~bis(4-fluorophenyl)methylJ-piperidin-l-yl, 4-morpholinyl, l-piperazinyl, 4-~ubstituted piperazin-l-yl, lJ2,3,6-tetrahydropyridin-1-yl, l~-pyrr~l-l-yl or 2,5-dihydro-lH-pyrrol-l-yl, and the pharmaceutically acceptable salts thereo~ with the proviso that when R a H, Z is never a primary or secondary amine, and a further proviso that when n _ 3, Z is not pyrazolyl, or imidazolyl.

~s3~

c~emical intermediate~ in the preparation of compoun~s of Formula II are novel and ha~e the ~ormula:

~o~ X~
Formula III
wherein A, E, R, R*, D, and Y are as defined under Formula II above and X is chlorine or bromine.
Other chemical intermediates leading to compounds of Fo~mula III have the formula:

R~
E ~ D

Formula IY~

wherein A, E, R, R~ , D, and Y areOas de~ined und&r Formula II, and Q is selected ~rom C NH2 -CN or oR3 where R9 is H, alkali metal ion or an esterifying radical.
Compounds of Formula IVa are novel except wherein A i5 phenyl or substituted phenyl and E is oxygen.
Other chemical intermediates used in alternate procedures for preparing compounds of Formula I and which are not precursors of Formula III type compounds have the formula~ V and VI.

O-CH-D NRlR2 "` ~C H ~`R
o~ bR3 Formula V

3~

~ HO-~H- D-NR R
C ~R
O Formula VI

wherein A, Rl, R2, R4 and D have the values assigned under Formula I, and R3 is H or alkali metal ion. Compounds of Formulas V and VI are not part of the present invention but are intended to be the subject of a separate application.
In the further definition of symbols in the formulas hereof and where they appear elsewhere throughout this specification and the claims, the terms have the following significance.
The term "loweralkyl" as used herein, unless otherwise specified, includes straight and branched chain radicals of up to eight carbons inclusive and is exemplified by such 20 groups as methyl, ethyl, propyl, isopropyl, butyl, ~ec.
butyl, tert. butyl, amyl, isoamyl, hexyl, heptyl and octyl radicals and the like. The term "loweralXoxy" has the formula ~O-loweralkyl.
The term "cycloalkyl" as used herein includes primarily cyclic alkyl radicals containing 3-9 carbon atoms inclusive and includes such groups as cyclopropyl, cyclobutyl, cyclo-pentyl, cyclohexyl, methylcyclohexylJ cycloheptyl and the like.
~ he terms "halo" or "halogen" when referred to herein include fluorine, chlorine, bromine and iodine unless other-wise stated.
"Pharmaceutically acceptable salt~" include acid addition salts, hydrates, alcoholates and ~uaternary salts of the compounds of Formula I, which are physiologically ~5 compatible in warm-blooded animals. The acid addition ~alts may be formed by either strong or weak acids. ~epresentative of ~trong acids are hydrochloric, sulfuric and phosphoric acids. Representative of weak acid~ are fumaric, maleic, ~;~5~4~

6 66197-169D

succinic, oxalic~ citric, tarta_lc, hexamic, and the like.
Suita~le cuaternary salts include the loweralkyl haliaes and loweralkyl sulfates.
By "sulfurizing agent" is meant any agent or mixture of agents which will convert diazepinones, ox- and thiazepinones to diazepine-thiones, ox- and thiazepine-thiones, such as 2,4-bis(4-methoxyphenyl)-1,~,2,4-dithia-diphosphetane-2,4-disulfide (Lawesson) reagent or a mixture of phosphorus pentasulfide and alkalimetal ~ulfide o~
mixture of phosphorus pentasulfide in a suitable solvent such as acetonitrile, toluene or pyridine. By the use of !'sulfurizing agent" the azepinones are thereby "sulfurized"
to azepine-thiones.
The compounds of the present invention exhibit anti-15 histaminic activity in guinea pigs. The method of testingis a modification of the procedure of Tozzi et al (Agents and Actions, Vol. 4/4, 264-270, 1974) as follows: Guinea pigs are fasted 18-24 hrs in individual cages. Water is available ad libitum. On the test day, animals in groups of 3 are injected intraperitoneally with 30 mg ~g of the test compound prepared in an appropriate vehicle. Thirty minutes later histamine at a dosage level of 1.2 mg/kg (= 2 x the LD99) is injected into a marginal ear vein.
Survival of the guinea pigs for 24 hrs is positive evidence of antihistaminic activity. If the vehicle used for the test compound is other than water, its effect is established by testing an equal amount as a control. The dose protecting 50~ of the animals (PD50) from death may be established from dose-response curves. The non-sedative nature of the compounds is discusqed hereinbelow under "Additional ~harmacology."
A process for producing the compound (I) may comprise the following steps:
Step 1) Halogenating a compound of the formula E R (C~) ( ~ ) O -2 o ~

~419A-CIP-~
~253~

wherein;
A reprssents an aromatic ring selected from benz~ne, naphthalene, a quinoline, or a pyridine in any one of its ~our positions, any of the rings optionally substituted by one or two Y-radicals 6elected from halo, loweralkyl, loweralkoxy, diloweralkylamino, nitro, or trifluoromethyl;
E is oxygen, sulfur, or loweralkyl substituted nitrogen, R is selected from the group consisting of loweralkyl~
cycloalkyl or phenyl-loweralkyl, of which phenyl may be optionally substituted by one or two radicals ~elected from halo, loweralkyl, loweralkoxy, nitro or trifluoromethyl;
R3 is hydrogen or an acid neutralizing ion:
R4 and R5 are hydrogen or loweralkyl (1-5 C); and n is one or two, to give a compound of the formula ~ Y)0~ "C~x R ~ III

or its free base wherein X is chlorine or bromine and A, E, R, R~,.R5, Yland n are the ~ame as the starting values. Among suitable halogenating agents are a) thionyl halides b) triphenylphosphine and a carbon tetrahalide c) pho~phorus pentahalides d) phosphorus trihalides, and e) triphenylphosphine dihalide.

Step 2) Neutralizing, if necessary, and fusing the carboxylic acid halide derivative prepared in ~tep 1 to give an oxazepinone, thiazepinone or diazepinone of the formula `~ 41y~-CIP-2 ~:2S3~S

~ ~R5 ,~ E ~ (~H)n-X

(Y~ ~ N lIa wherein A, E, R, R4~ R5, XJ Y and n are as defined above in step 1, and A now has two of its carbon atoms held mutually with the oxazepineS thiazepine, or diazepine moiety;
Step ~) Optionally reacting the compound prepared in step 2 with a ~ulfurizing agent to obtain an oxazepine thione, thia~.epinethione, or diazepinethione of the formula R4 l5 ~ E ~ (~3n~X
; A ~ ) ~ ~ I IIb wherein A, E9 R, R4, R5, X, Y and n are as defined above in step 2.
Step 4) When reguired, reacting a compound prepared in step 2 with an alkali-metal cyanide to obtain a compound of the ~ormula R~ R5 E ~ ( )1.2 ~0 ~ A ¦
(Y~ 2`'`- " ~ I
O IIc wherein A, E, Y, R, R'~ and Rs are as de~ined in step 2, ~ 419A-CXP-2 ~:~5~

Step 5) Reacting a halogen compound prepared in step 2 or 3 with a compouna ~f the formula ZH
wherein z i5 ~elected from -NRlR2, lH-pyrazol-l-yl, lH-imidazol-l-yl, l~-imidazol-2-yl, or 4,5-dihydro-lH-imidazol-2-yl, and wherein R' and RZ are ~elected ~rom hydrogenJ loweralkyl, cycloalkyl and phenyl-loweralkyl, of which phenyl may be optionally substituted with 1 or 2 radi~als selected from halo, loweralkyl, loweralkoxy, nitro, trifluoromethyl or cyano, or Rl and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue ~elected from the group c~nsisting of l-azetidinyl, l-pyrrolidinyl~ 2,5-dimethylpyrrolidin-1-yl, 2-methyl-pyrrolidin l-yl, l-piperidinyl, 4-substituted-piperidine-l-yl, 4-~biR(4-fluorophenyl)methyl]piperidin-1-yl, 4-morpholinyl, l-piperazinyl, 4-substituted-piperazin-1-yl 1,2,3,6-tetrahydropyridine-1-yl, 2,5-dihydro-lH-pyrrol-1-yl, lH-pyrrol-1-yl, or l-phth~limidyl to give the compound of the formula 2 0 E~ 3 n-Z

(Y~ 2~ - "~
Ia wherein A, E, R, R4, R5, n and Y are a~ defined ~bove in step 2, Z is the same a9 in the ZH compound, and B is an oxygen or sulfur atom, Step 6) Optionally reacting a compound prepared in step 5 wherein B is an oxygen atom with a ~ul~uxizing agent, preferably phosphorus pentasul~ide in pyridine to obtain ~ compound of the formula R~ I
~5 "~ E ~ (CH)~_z 2 ~ R I~

~3~45 4-~A-CIP~2 wherein A, E, ~, R4, ~5, n, Y and z axe as defined in step 5.
Step 7) Reducing a cyano compound (Formula IIc) prepared in step 4, or reacting a phthalimido compound prepared in etep 4 with hydrazine-hydrate to give a primary amine of ~he formula R~
" ~ E_~(CH ) -~H2 ~ A ~ ) R Ic_la wherein A, ~J Y~ R, R4 and R5 are defined in steps ~ and 4.
Step 8) When required, reacting a primary amine prepared in steps 5 or 7 of the iormula ~ / E ~ (C~ ~H2 (Y ~ ~ C-1 wherein A, E, Y, R, R4 and R5 are as defined in step 2 25 with one of the following reactants or sets of reactants:
a) ~ormaldehyde and formic acid to give a tertiary dimethylamine, b) a dihalide or alkenedihalide to give a heterocyclic amine, c) a dialdehyde and ~odium cyanoborohydride to give a heterocyclic amine, d) equal molar amounts of aldehyde or ketone, ~odium cyanoborohydride with large exc~s~
of above primary amine to give a secondary amine, Jl9A-cIp-~253~

Q) e~ual molar amounts of ~he primary amine and sodium cyanoborohydride wi h at least two equivalent~ of aldehyde sr ketone, f) in seguence: triflu~roacetyl chl~ride, alkyl or phenyl-alkyl halide, potas~ium hydride and potassium hydroxide to give a ~econ~ary amine, all product~ being encompassed by the fonmula .. 4 l5 _~ ~ E ~ )1-9 A

R Id wherein A, E, Y, R, R~ and R5 are as d~fined in step 2 And Z i6 -NRlR2 wherein Rl and RZ
are loweralkyl, cycloalkyl and phenyl-loweralkyl with phenyl being optionally substituted by halo, loweralkyl, loweralkoxy, nitro, trifluoromethyl or cya~o or Rl and R2 taken together with the adjacent nitrogen may form a heterocyclic residue selected ~rom l-azetidinyl, l-pyrroli-dinyl, l-piperidinyl, 4-substituted-piperidin-l-yl, 4-tbis(4-flu~rophenyl)methyl~piperidin-l~yl, 4-morpholinyl, l-piperazinyl, 4-substituted-piperazin-l-yl, l,2,~,6-tetrahydropyridin-l-y~ pyrrol-l-yl ox 2-methylpyrrolidin-l-yl, and optionally sulfurizing the diazepinone, azepinone or thiaz~pinone to give the corresponding thione as in step 6.

Step 9) When required, reacting a benzyl or substituted benzyl compound obtained in steps 5, 6, or 8 wherein z is tertiary amino, or non-reactive heterocycle radical ~uch as pyrazolyl or lmidazolyl of the fonmula ,~ 3 ( ~ ~2 ~ CH2 Ie phenyl ~i3~

wherein A, E, Y, R4 and R5 are as defined in step 2, and z is a radical taken from the definition of Z under Formula I, subject to the same pr~visos given thereunder, with sodium and ammonia to give a compound of the formula R~ I
(CH) _z ~) O I I f wherein A, E, Y, R4 and R5 are as defined in step 2, n is 1 to 7 and Z i5 the same as the starting compound in this step, 5tep 10) Optionally reacting the free base of any compound prepared in steps 5 to 9 with a pharmaceutically acceptable acid or quaternary forming halide or sulfate to form a pharmaceutically acceptable salt thereof.
The compounds of Formula I wherein n is 2 are preferred ~or their antihistaminic activity. The process which includes steps 1 to 3, 5, 6 and 10 wherein compounds prepared have a methyl or ethyl side chain (n = 1 or 23 repsesents a preferred process corresponding to a succession of steps designated A to F a~ explained hereinbelow.
The compounds of Formulas Ia, Ib, Ic-l to IC_7, Ic~la.
Id, IeJ If are all encompassed by Formula I and the compounds of Formulas IIa, IIb, IIC, IId and IIe are all encompassed by Formula II.
Steps 1 to 4 also repre~ent a novel process for preparing compounds of Formula IIa, lIb, IIC, all encompassed by Formula II.
It is therefore an object of the present invention to provide certain novel aromatic 1,4-oxazepinones, thiazepinones and diazepinones and sul~ur analogs thereof as described hereinabove under "field of invention" and as defined by Formula I which have antihistaminic activity.

4l9A-cIp~2 ~ ~ 3 Another object is to provide certain novel aromatic 1,4-oxazepinones, thiazepinones and diazepinones (and sulfur analogs thereof) substituted with haloalkyl or cyanoalkyl and phthalimidoalky~ radicals which are chemical intermediates as defined by Formula I.
Still another object is to provide a novel route and process for preparation of aromatic l,4-oxazepinones, thiazepinones, diazepinones and sulfur analogs thereof substituted with short chain haloalkyl, cyanoalkyl or amino-alXyl radicals.
Additional objects and advantages of the presentinvention will be apparent to one skilled in the art and others will become apparent from the following descxiption of the best mode of carrying out the present invention and from the appended claims.
DETAILED DESCRIPTION OF THE I~VENTION
The present invention enoompasses the novel diazepine, oxazepine and thiazepine derivatives set forth in Formulas I and II and certain novel compounds of Formulas III, IVa and IVb as composition of matter and a process for the preparation of compounds of F~rmulas I, II and III.
Charts I and II illustrat~ the preparation of all intermediates. R is never hydrogen.
Chart III illustrates reaction se~uence for preparing end-products wherein R i8 other than hydrogen and n is 1 or 2.
Chart IV illustrates preparation of compounds having ethyl and propyl radicals-omega ~ubstituted by primary amine (-NH2). R is never hydrogen.
~ Chart V illustrates methods of converting the omega-~H~-substituted ethyl and propyl compounds to ~econdary and tertiary amines. This is an alternate method for pr~paring the ethyl-secondary and tertiary ami2~es. R is never hydroyen.
~5 Chart VI illustrates preparation o~ compounds wherein R is hydrogen.
Preparations 1--40 illustrate ~yntheses of compounds of Formulas IVa, IVb or provide certain starting materials ~ 419A-CIP-2 14 ~ ;3~5 therefor. Preparation 41 provides a starting material fox an alternate process. See Chart VIII, Formula VI. Inter-mediates 1-64 (see also Table 1) illustrate preparation of compounds encompassed by Formula II, which are chemical intermediates substituted with h~loalkyl, cyanoalkyl, or phthalimidoalkyl radicals. The compounds of Formula II are formed in the reaction mixture usually without isolation.
Charts VII and VIII illustrate the preparation of compounds of Formula I by novel alternate methods illustrated 10 further in Examples 68b, 90 and 107 to 109, which process methods thereof are not part of the present invention but which process methods are intended to be the subject of a separate application.
Examples 1-123 (see also Table 2) illustrate preparation of compounds encompassed by Formula I. The scope of the invention is not limited by the preparations, intermediates and examples, however.

1~

C ~ RT I
Preparation of Intermediates , A ~ + ~ ~ n A ~ t ~ ~CH)n See footnotes " ~~ ~ E ~ (~H)n c) ~nd d) for '~
10 ~ther E values (Y~-2 N
IVa *Hydrol yze ~t, ,~

( Y) 0-2 ~' ~oR9 ~ IVb R~ = H or M
Halogena~te ~ h~lo~

~ Heat and/or R4 R \neutralize when required ; A~ ~ ~tional , ~~
~ J Sulfurlzlng , A /
(y ~ `~' ~ I Agent ~ " ~ R IIa Optional to lengthen chain ~ ,KCN
E ~ (~H)n-C~

~ IIc ~5 (~ont.) ~ ~53~4,5; 66l97-l69D
Footnotes (Chart I):
a) R is never hydrogen.
b) n = 1 or 2.
X = Halogen (C1, Br) W = Aryl sulfonate, alkyl sulfonate or X.
M = Acid neutralizing ion, e.g. alkali-metal.
O O
Q is -C-NH2, -CN, -C-OR where R is H, M or esterifying radical.
O O
Il 11 *Hydrolyze when Q is other than -C-OH or C-OM.
**Diagram illustrating the suggested formation and cleavage of bonds to effect rearrangement.

tl loweralkyl R4 R5 c) Illustrates l When Z = loweralkyl ~ -~rNH Br- - (CH)n base R
and A = phenyl, naphthyl or 16a ~53~ 66197-169D

lowexalkyl E ¦ R R5 or ~ : ~ ,r ~/

n-butyl loweralkyl l.ithium R R
-A` ~] ~ t (CH) n -- ~0,~

d) Illustrates loweralkyl When E = loweralkyl ~~~ Cl ¦ R4 R
/N~ COOH + tN ~ n i and R

A = pyrido or loweralkyl or ~ ~ ~ ~n ~ )n '`

419A-CIP-~

~HaRT II
Alternate Method of Preparing Pyr$do Ring -R5Halogenated Ir~termediate~ a ) R5 [~ ( CH ) 1 2 -X ,[~( ~( CH) 1-2 -X

5R IId ~ So2cl2 ~ Cl " I IIe dimethylformamide R

Footnol:es:
X = Cl, Br, C~
E snd R are a~ defined in Formula I
a) n = 1 or 2 15CH~RT III
Preparation of End Products (n = 1 or 2; R = other than H) R4 R5 ~ R5 '~'` ~ (CH)~-halo " ~ ( ~ (CH)n-halo (Y)o 2 S' R IIb (Y)o-2 o R IIa ¦ZH I ZH
~ ~ I - E~ (CH)n-~

( Y) 0 2 (~ Agent ( YO~
Ib Ia ~ootnote -Z i~ as defined for n = 1 or 2 under Formula I.

~253~L45 419A-CIP-2 CH~RT IV
; .
Preparation of Primary Ethyl and Propyl Amino Comp~unds wherein R i~ other than ~ydrogen rt~m Cy~n~ Intermediate ~ ~(CH)1_2 CN ~ tCH )2~3-j/ "~ Reduc~

( Y) 0-2 I I~ ( Y 4-2 o R Ia CH~RT VI
Preparation of Compounds ~laving Unsubstituted Azepin~ ~itrogen (R=H) ~ 4 R5 R5 H ) l 3-Z , . ~ ( CH ) 1-3-Z

0-2g C~ NH3 ~Y~0-2 ~ H
Ce,H5 Ie If R = Benzyl R = H
F~otnote:
*Z ~ann~t be a primary or ~econdary amine.
3o 19 ~j3~
66197~169D
CHART V
Additional Preparations of Secondary and Tertiary Amino-alkyl Compounds ~herein R is other than H(a) ` ~ E~ ( CH 2 ) 1 3 -NH 2 ~ ( CH 2 ) nN ( CH 3 ) 2 ~ , ~ N HCOOH ~~~~ ~ Nl ( )0-2 o R HCOC (Y)0-2 o R

_l Ic_2 ~ria te ,_ E ~ (CH2)n-N Het HC-~CH2 ~ ~ ~ I
2 NaBH3CN (Y)0-2 o R
CH30H (pH 6-8) Ic_3 ~ E ~ (CH2)n-N-R

1 mole aldehyde or ketone ~ ~ ~ N
1 mole NaBH3CN ( )0-2 MeOH (pH 6-8) _l in excess Ic_4 1 mole same or different aldehyde or ketone;
1 mole NaBH3CN;
MeOH(pH 6-8~

~L~53~l45 66197-169D

, ~ ~ ~ (CH2)1-3 NH2 ,l ~ ~ ~ N
(Y)o-2 Ic-l * ,_~ ~E ~ (CH2)n~NR R2 2 mole aldehyde or ketone \~ ,~
2 mole NaBH3CN /~~ ~ N
MeOH (pH 6-8) (Y)0-2 R
Ic_5 ** H
React in sequence 1-4 13 Trifluoroacetyl chloride; E-~ (CH2) -N-R
2) Alkyl or phenylalkyl- I'A`I ~ \ n _ halide; ~ , ~ N
4) Metal hydroxide, suitable g solvent (Y)0-2 Ic-6 Rl = alkyl or 0-alkyl-_l) Optional to produce ,_~ ~ E ~ _(CH2)n-z to ) thione; - ~ / A I ) c 6) Sulurizing agent f ~ ~
(Y)0-2 R
Ic_7 (a3 Illustrated for R4 and R5 = H and is applicable for R and/or R = loweralkyl (1-5c).
n = 1-3 *Method described by R. F. Borch, et al,;
J. Amer. Chem. Soc. 93, 2897 (1971).

~S3~ i 66197-169D

Footnote Chart V continued under *.
Illustration of reaction of a compound of Formula Ic 1 wherein Z is NH2 with aldeh~des and ketones follows:
Reactant Z-Radlcal Produced 1) 1 mole acetaldehyde -NHC2H5 1 mole NaBH3CN
excess primary amine (Z=NH2) 2) 1 mole acetone -NHCH(CH3)2 1 mole NaBH3CN
3) 1 mole benzaldehyde -NHCH2C6H5 1 mole NaBH3CN
excess primary amine (Z=NH2) 4) 1 mole cyclohexanone -NHC6H
1 mole NaBH3CN
5) 2 mole acetaldehyde N(C2H5)2 2 mole NaBH3CN
6) 1 mole acetaldehyde 1 mole NaBH3CN
excess primary amine ) (Z=H) followed by 1 mole formaldehyde ) N(cH3)c2 5 1 mole NaBH3CN
**J. E. Norlander et al., Tetrahedron Letters 1978 (50) pp ~987-~990.

21a ~2S3~4~ 66197-169D

CHART_VII
Alterna-tive Method of Preparing Oxazepinones R R R R
~ C - (CH2)n-Z ~ KH ~ C - (1H2~n-Z

R R

Cl ~ ~ ~c oR3 o 1<
~ ~C N (CH) n Z

OR
Cyclize alkali-metal hydride - ~ ( ~ ( CH ) n ~3~ 419A-CIP-2 CH~RT VIII
Further Alternate Method of Preparing Oxazepinones R4 Rs ClHO-C -(CH)n-Z

ooR3 ~ CH2 lo Q~c=~D

or MeSO~Cl/Et3~

~ ~ (CH)n~Z X C-(CH)n Z

, N ~aH, KH, ` ,~ C I VI
~aNH2 or K-o-t-Bu *R3 = H, alkali-metal.

~ 419A-CIP-2 In reference to the processes and the pr~cess steps of the invention ~ummariæed above as they apply to the preparation of compounds of Formulas X, II and III, the following further description i6 applicable.
In step 1, starting compounds of Formula IVb (See Chart I) bearin~ a carboxylic acid or an acid neutralizing ion such as an alkali-metal salt thereof on the ~ ring ortho to the ether linkage as a substantially pure entity or preferably derived in a reaction mixture resulting ~rom hydrolysis of precursors bearing in the same ortho positivn, carbamoyl, cyano or carboxylic acid ester functions without ~ubstantial isolation of the carboxylic acid (or salt) compound from the xeaction mixture, are treated with any ~uitable halogenating agent such as are described above, preferably thionyl chloride or triphenyl phosphine and carbon tetrachloride. The halogenation is conducted in any ~uitable organic solvent, preferably a refluxing organic solvent or a re~luxing halogenating agent such as the preferred thicnyl chloride. Temperatures for the chlorinati~n over a wide range may be employed, for example, from room temperature to 100C. or above;
however, temperatures of 50-80C. are preferred, which temperatures encompass that of refluxing chloroform or thionyl chloride. When exce~s halogenating agent such as thionyl chloride has been used as carrier, it is advanta-geously evaporated. When solvent such as chloroform is used, it may, but not necessarily, be evaporated away. In any event a solution comprising a solvent and compounds of Formula III or a residue comprised of Formula III compounds~
all of which are confirmed by infra-red analysis is available for ufie in the next step.
In step 2, the halogenated com~ounds of Formula III~
prepared in ~tep 1, if not already in a aolvent, are ~olubilized with organic solvent, preferably chloroform and usually neutralized or basified preferably with a tertiary amine ~uch as triethyl amine, and then heated at a temperature and for a time au~ficient to effect ~ fusion ~ 2~ 419A-CIP-2 of the carbonyl with the basic nitrogen and cleavage of the cyclic amine and formation of the chloro or bromoalkyl-oxazepinone, thiazepinone or diazepinone compounds of Formula Ila. If the tendency to fuse i~ sufficiently great, the neutralization of basification may be eliminated. The Formula IIa compounds may be isolated by conventional means, for example, by partitioning between a suitable organic solvent or mixture ~f solvents and aqueous acid or base followed by drying and evaporating the organic layer and recrystallizing the residue from a suitable solvent.
In step 3, the compounds of Formula IIa may optionally be converted to the oxazepinethione, thiazepinethione or diazepinethione (IIb) by heating together with sulfurizing agent in a suitable organic solvent such as toluene acetonitrile. The thione (IIb) may be isolated by conven-tional means, preferably by partitioning between an organic solvent and dilute alkali metal base and cry~tallizing from a suitable solvent such as ethanol.
In step 4, an oxazepinone, thiazepinone or diazepinone (IIa) is reacted with potassium cyanide in a hot protic ~olvent u~ing a phase transfer catalyst such as tetrabutyl ammonium bromide. The resulting cyano compound is then extracted into a suitable solvent such as ethyl acetate, and the solution dried and evaporated. The residue i8 then recrystallized from suitable ~olvent such a~ a mixture of ethyl acetate and isopropyl ether or ethyl acetate alone.
As will be realized, the compounds produced have cyano-methyl and cyano-ethyl ~ide chains (n = 1 or 2) which lead to side chain lengthening to amino propyl n = 3 or as an alternate starting material for lengthening of a methyl chain to amino ethyl.
In step 5, the oxazepinone, thiazepinone (IIa) or diazepinone obtained in step 2 or the oxazepinethione and thiazepinethione (IIb) or diazepinethione obtained in step ~
~re reacted with pyrazole, imidazole or with an amine of the formula ~HRlR2 wherein Rl and R2 have the value given under ~ 3 Formula I above to give compounds of Formulas Ia and Ib, respectively. The latter reaction is preferably conducted in excess amine as in the instance of volatile methylamines.
The free bases of products of Formula Ia and Ib are isolated by conventional means by removing volatiles and partitioning between dilute aqueous alkali metal base and a ~olvent such as chloroform or methylen0 chloride followed by evaporation.
The free base may be converted to a pharmaceutically acceptable salt with an appropriate acid and in the case of a ~uaternary salt with a loweralkyl halide or ~ulfate and recrystallized by conventional means. The free bases may be recovered from the acid addition salts, usually in a purer form, by again partitioning the salt between aqueous base and a suitabl~ solvent followed by evaporation. As will be realized and as shown in Chart I, the side chain of the intermediate produced is l~mited to aminome hyl and aminoethyl (n = 2).
In step 6, when it is desirable, a compound prepared in step 5 wherein B is oxygen is sulfurized, preferably by refluxing in dry pyridine with phosphorus pentasulfide for several hours. ~he resulting thione is isolated by cooling the solution and partitionin~ between a suitable solvent such as chloroform and an aqueous base and evaporating the organic phase and isolating by conventional means.
In step 7J a cyano compound (IIc) prepared in step 4 which is a diazepinone, an oxazepinone or a thiazepinone is reduced, preferably with hydrogen using Raney nickel catalyst at about 60C. The primary aminoethyl or amino-propyl compound (n = 2 or 3) produced is isolated by conventional means, preferably as an acid addition ~alt which may be converted back to tha free base by partitioning between a suitable solvent and aqueous base and thereafter drying and evaporatiny the srganic layer.
In step 8 (~ee Chart V), a primary amine i8 converted 3~ to a secondary or tertiary amine by a choice of reactants.
The method provides a route to secondary and tertiary amino _ 419P~-CIP-2 ~ 2 compounds of Formula I having n = 3 not afforded by step 5 andJ in addition, provides an alternate route to seeondary and tertiary amino compound3 o~ F~rmula I wherein n = 1 or 2.
The preparati~n of dimethylamino derlvatives by reaction of primary amine with formaldehyde and formic acid is a conventional ~ethod for preparing tertiary dimethyl amines as is reaction of a dihalide to give a heterocyclic amine such as l-pyrrolidino, piperidino or 4-morpholino. The alternatives employing sodium cyanoborohydride follow the procedures described by R. F. Borch et al, J. Amer. Chem.
Soc. ~, 2897 (1971). The procedure which employs conversion to a trifluoroacetamide is described by J. E. ~orlander et al, Tetrahedron Letters, 1978 (50) pp 4987-4990.
In step 9, a 4-benzyloxazepinone, 4-benzyl-thiazepinone ox 4-benzyldiazepinone derivative (R = ~enzyl) under Formula I excluding primary or secondary amines is converted to the corresponding ~-unsubstituted (R = H) oxazepinone, thiazepinone or diazepinone by reaction with sodium and ammonia and may be isolated as illustrated in Example 68.
Step 10 is optional depending on whether the compound of Formula I is already in the form of a pharmaceutically acceptable salt or whether it is desirable to convert to another salt or whether the ~ree base is desired. To obtain ~he free base from any addition salt of Formula I, the salt is partitioned between a ~uitable organic solvent such as chloroform and a dilute aqueous base. The organic layer is dried and condensed to give the free base whi~h is then, if desired, reacted with an acid described above to give the desired salt.
As mentioned above, the preferred 6tep~ for reaching the preferred compounds having an ethyl side chain in the 2-position include steps 1 to 3, 5, 6 and 10 of the general process for preparing all the compounds of Formula I.
Inasmu~h a~ the compounds having a methyl ~ide chain can be made by the ~ame process, compounds wherein n = 1 are included in the preferred p~ocess. These steps of a 3 ~ ~
~ 27 preferred process are designa~ed A to F c~rresponding to the numbered steps of the general process with the limitation that n = 1 or 2 and R is other than hydrogen as follows:
Corresponding General Step Number with Preferred Process Description Pertaining SteP Desiqnation _ to n - 1 or 2 A

D

Compounds of Formula I wherein E is O or S are preferred because ~f their potency as antihistamines based ~n test comparisons made.

PreE~aration 1 2-(~=~nzyl-3-"~yr:rolidis~lc)xy~benzamlde .
To a su~p~nsion of 4.~ g (0.11 mole) of s~dium amide in 60 ml of dry toluene was added 19.3 g (0.11 mole) of l-benzyl-~-pyrrolidinol at a rate to maintain a temperature of ~5C. Stirring was continued at room temp~rature for 3 hour~. To the mixture was added at rapid drop 19 g (0.1 m~le) of o-toluenesulfonyl chl~ride with ice bath cooling to maintain a temperature of 20-30C. Stirring was ~ontinued at room temperature for 2.5 hours ~nd the mixture ~llow~d to stand ov~rnight. ~he toluene was wa~hed twice with water, dried with sodium sulfate and concentrated.
~o ~ ~uspension of 5.4 g (0.1 mole) Q~ sodium methoxide in 50 ml o~ dimethylformamide in another vessel was added 1~.6 g (0.1 mole) of ~alicylamide in 75 ml of dimethylformamide at a rate to maintain a temperature of 50C. After stirring 15 minutes, the above prepared ~ulfsnate in 25 ml of dimethylformamide wa~ ~dded drop-wise and the ~olution refluxed 5 hour~. The material was partitioned between 500 ml of ethyl acetate and 500 ml of water. The ethyl ~cetate was extrac~ed with dilute hydrochloric acid, the acid basi~ied with dilute ~od~um hydroxide and extracted with ethyl acetate. The organic layer was dried, concentr~ted, and the r~sidue crystal-lized twice from i80propyl ether-ethyl ~cetate. Yield of product was 12.5 g (42 0 , m.p. 120.5-122 C.
Analysis: Calculated for Cl~H20N202: C,72.95; ~,6.80;
N,9.46 Found : C,7~.23; R,6.78;
N,9.56 ~0 Pr~paration 2 2~ Methyl-3-pyrrolid~ylox~ benzamide.
To 85.6 g (2.2 mole~) of ~odium amide in 1.5 liter of dry toluene was added 202 g (2 moles) o~ 1-methyl-3-pyrrolidinol so as not to exceed a temperature of 50C.
The mixture wa~ then heated to 70C. ~or ~.5 hours. The ~ixture was ~0012d and ~81 g (2 moles) v~ o-tolu~ne-~ulfonylchloxide was ~dded at a rapid drop while maintaining ~ 4:L9A- CIP-2 ;3~4~i a temperature of 20-~0C. wit~ ~n ice bath. The mixture was stirred ~t room $emper~ture for 2.5 hours and washed with water. ~he toluene 801ution was dried with s~dium ~ulfate and concentrated. The residue, di~solved in 500 ml of dimethyl~ormamide, wa~ ~dded to a reaction mixture prepared by adding 119 g (2.2 moles) o ~dium meth~xide and 274 g (2.0 moles) of ~licylamide to one liter of dimethylformamide ~nd the mixture was worked up as in pr~paration 1. Yield of product wa~ 170 g (38%), m.p.
116-118C.
Analysis: Calculated for Cl2~l~N202: C,65.43: H,7.32;
N,12.72 Found : C,65.28: H,7.28 ~,12.77 Pre~aration 7 2 ~ (l-Benzyl)pyrrolid~nylsxy~benzoic acid.
To a ~olution of 200~ g (0.52 mole) of sodium hydroxide in 600 ml of ethano~ and 400 ml of water was added 150 g (0.51 mole) of 2-~3-(1-benzyl)pyrrolidinyloxy~
benzamide and the mixture was stirred at reflux ~or 48 hours. The mixture was ~oncentrated on the rotary evaporator to one-half volume ~nd the residue was extrac~ed with ethyl acetate to zemove unreacted amide. The water layer was filtered and the pH of the filtrate adjusted to 6.5 with hydrochloric acid. The filtrate was ~oncentrated on the rotary ev~porator. ~he re6idue was dissolved in i~opropyl alcohol. ~he resulting mixture was ~iltered and the ~iltrate concentrated. The residue 85.7 g waB comprised flubstantially of the title compound.
PreParation 4 ~-~(1-Methyl-~-pyrrolidinyl)oxy~-2-naphthalene-carboxamide.
To n cooled ~olut ion of 68 g ( O . 67 mole ) of l-methyl-3-pyrrolidinol and 74 9 (0.73 mole) triethylamine in 700 ml of dry benzene wa6 added dropwise 74 g (o.63 ~ole) of methane~lfonyl chloride. ~fter stirring ~t room temperature for 45 min, the mixture wa~ filtered ~nd the filtrate concentr~ted under reduced pressure and di~olved in 100 ml ~253 3o ~f dimethylf~rmamide.
To a cooled ~uspension o~ 10.8 9 (0.45 m~l~) of ~odium hydride in 75 ml of dimethylfDrmamide in another ve~sel, 84 g (0.45 mole) o~ 3-hydroxy-2-naphth~lene-carboxamide di~solved in 400 ml of dimethylformamide wasadded dropwise. The above prepared sulfonate solution was added dropwi~e and the reaction mLxture ~tirred and heated at reflux for 16 hr. The cooled solution was diluted with 1000 ml of water ~nd extracted twice with 500 ml p~rti~ns of chloro~rm. The chloroform was washed with water and extracted twice with 500 ml portions of ~N hydrochloric acid. The a~ueous extract~ were made alkaline with 50~ sodium hydroxide ~nd extracted thrice with 500 ml p~rtion~ of chloroform. After drying over magnesium sulfate, the chloroform was evaporated under reduced pressure affording 27.4 g (22%) ~f a pale yellow ~olid. Recrystallized ~rom ethyl ~cetate, m.p. =
128-1~0C.
Analysis: calculated for cle~lB~2oz: C,71.097 ~,6.71, ~,10.~6 Found : C,70.88; H,6.68, ~,10.37 Pre~aration ~
3~ Methyl-~-pyrrolidinyl)oxyl-2-naphthalene-L _ _ _ carboxylic acid oxalate r2:11.
..
To a ~olution of 21.6 g (0.54 mole) of sodium hydroxide in 500 ml of water was ~dded 74 g (0.27 mole) of 3-[l-methyl-3-pyrrolinyl)oxy]-2-naphthalenecarboxamide~
The solution was heated at reflux for 16 hr~ ~nd on cooling, the pH was adjusted to 6.8 with concentrated hydrochloric acid. The resultant ~olid wa~ sepaxated by ~iltration and the pH o~ the filtrate was adjusted to 6.02. The filtrate was concentrated under reduced pre~sure and the residue boiled in 200 ml of isopropyl ~lcohol and filtered. The filtrate was again concentrated under reduced pressure to give 69 g (94 0 of an amorphous ~olid. ~n ~ uot was ~ olved in i~opropanol and tre~ted with oxalic acid.
The oxal~te ~alt was recry~tallized from ethanol ~ater, J 419~CIP_2 m.p. 209-212C.
Analy~ Calculated for Cl7~laNOs: ~,64-55; H,5-74;
~,4.43 ~ound : C,63.~6; H,5.68 ~,4.37 Preparation 6 Sodium 2~ methyl-3-pyrrolidiny~) xy~-3-pYridine-carboxylate.
To a 6tirred ~uspen6ion of 6.4 g (0.13 mole) of 50%
~odium hydride (mineral oil) in 50 ml of dimethyl-sulfoxide was added dropwi~e o.4 ~ (o.o63 mole) ofl-methyl~3-pyrrolidinol. During addition, the temperature ro~e ~rom 25C. to 31C. After 10 minutes, a solution of 10 g (o.o6~ mole) o~ 2-chloronicotinic acid in 50 ml of dimethyl~ulfoxide was added dropwise causing the t~mperature to rise. When the tempçrature reached 55C., it was maintained there by the intermittent u~e of an ice bath until addition was complete, The mixture was then heated to 55-60C. for 1.5 hr., cooled and filtered. The filter cake was ~u~pended in 100 ml of athyl acetate and filtered. The 8~1id was xecrystallized from ethyl aeetate-methanol. Yield of product was 5 g., dec. 240C. The ~MR analysis showed that the c~mpound contained 1 h mole of ~odium ace ate as impurity.
Analy~ Calculated for CllH13N203Na-l ~C2~302Na:
C,51.62; H,5.20; ~,10.32 Found : C,51.81: El,5.15; N,10.39 Preparation 7 4-Chloro-2-C(l-methyl-~-pyrrolidinyl)oxylbenzamide.
~ o n ~olution of 55.5 g (0.55 mole) of triethyl~mine in 500 ml of dry benzene Wa8 added dropwi~e 50.5 g (9.50 30 mole) of 1-methyl-3-pyrrolidinol at ~uch a rate a~ to maintain a temperature of 25-35 C. To the mixture, m~intained ~t 20-50C., was added dropwi3e, 57 9 (0.50 mole) of methanesulfonyl chloride. After ~tirring for 1 hr nt xoom temperature, the mLxture wa6 ~iltered ~nA
the precipitate w~shed with 250 ml of hot benzene. The filtr~te ~nd wash were ~ombined nnd $on~entrute~ under J
419~-CIP-2 2~ 3 ~ ~

reduced pressure and ~he residue dissolved in 2~0 ml dimethyl~onmamide.
To a cooled su6pension of 19.6 g (0.41 mole) of sodi~n hydride in 100 ml of dimethylfonnamide in an~ther vessel was added dropwise a ~olution o~ 70 9 (0.41 mole) of 4-chlorosalicylamide in 200 ml dimethylormamide at a rate such as to maintain a temperature of 20C. ~o the resulting reaetion mixture was added dropwi~e the above-prepared ~ulfonate salt and the mixture was heated at reflux for 19 hrs. The reaction mixture was co~led and diluted with one liter of water. The diluted mixture was extracted three times with 300 ml p~rtions of chloroform.
The chloroform extracts were combined and extracted with two 500 ml portions of 3N hydrochloric acid. The combined aqueou~ extract was made alkaline with 50~ 60dium hydroxide and extracted three times with 500 ml portions of ethyl acetate. The combined ethyl acetate extract wa~ dried over magnesium sulfate and concentrated under reduced pressure to give 4605 g (45O beige 301id. The solid was recrystallized from ethyl acetate, m.p. 122-123C.
Analysis: Calculated for C~ Hl5~2Cl02: C,56.58; H,5,94;
N,10.99 ~ound : C,56.48; H,5.96, ~,10.84 PreParation 8 5-Bromo-2-r(l-methyl-~-pyrrolidinyl)oxylbenzamide.
To a cooled ~olution of 101 g (1.0 mole) 1-methyl~3-pyrrolidinol, 111 g (1.1 mole) triethylamine in 1000 ml of dry benzene was udded ~ropwise 114 g (1.0 mole) of methanesulfonyl chloride. The reaotion mixture wa~ stirred at room temperature for 1 hour and filtered. The ~iltr~te Wa8 concentrated under reduced pressure ~nd dissolved in 100 ml dimethylforrnamide.
To a cooled suRpen3ion of 30 g ~0.63 mole) sodium hydride in 100 ml dimethylformamide in another ves~el was 35 added dropwi~e 5-bromo~licylamide (137 g, 0.63 mole) ~ olved in 750 ml of dimethylformamide. The ~bove prep~red ~ulfonate was added dropwise ~nd the reaction ~S~

mixture heated at reflux for 18 hrs. The cooled ~lution was diluted with 1~00 ml of water and extracted thrice with 500 ml p~rtions of chloroform. The chloroform extr~ctfi were washed with water and extra~ted four times with 500 ml portions of ~ hyd~ochloric acid. ~he aque~uS
l~yer wa6 made alkaline with 50~ ~odium hydroxide ~nd extracted with chloroform. The chloroform extracts were washed with water, dried over magnesium ~ulfate and ev3porated under reduced pressure to give 52 g (28~) of a yellow ~olid. The solid was recry~tallized from ethyl acetate/chloroform, m.p. 160-162C.
Analy~is: Calculated ~or Cl2H15N2BrO2: C,48.18; H,5.05;
~,9-36 F~und : C,48.02; ~,5.01:
~,9.~2 5-Chloro-2~ methyl-3-pyrrolidinyl)oxy~benzamide hemihydrate.
To a cooled su~pension ~f 2.4 g (0.41 mole) sodium hydride in 50 ml of dimethylformamide wa~ added dropwise 17 g (0.1 mole) of 5-chlorosalicylamide dissolved in 50 ml of dimethylformamide at a rate ~uch that the temperature did not exceed 20C. A~ter addition of the salicylamide wa~ complete, 16.7 9 (0.1 mole) o~ 3-bromo-1-methyl-pyrrolidine dis~olved in 50 ml of d~methylformamide was ~dded dropwi~e. ~he re2ction mixture was ~tirred and heated at reflux for 19 hr. The cooled solution wa~
diluted with 250 ml of watex nnd extracted twice with 250 ml portion~ of chloroform. ~he chloroform was extracted thrice with 500 ml portions ~f 3N hydrochloric acid. The aqueou~ extract~ were made alkaline with 50~
~odium hydroxide ~nd extracted with ethyl acetate. Drying over magne~ium sulfate and evaporation of the ethyl acetate under reduced preQ~ure gave 6 g (23%) of product a~ a beige aolid. The solid was recry~tallized ~rom ethyl ~cetate9 m.p. 126-128C.
Analy~is: c~lculated for C2~H~z~4Cl205: C,54.65: H,6.11:
N,10 62 Found : C,54.87; HJ6.12;
~,10.69 -419~-C~P-~

~ ~ 5 3 Pre~aration 10 l~r (l-Methyl-3-pyrrolidinyl)oxyl-~-na~hthalene carb~xamide.
A solution o~ 118 g (o.63 mole) of 1-hydroxy-2-naphthalenecarboxamide in 250 ml of dimethylsulfoxide 5 was added dropwise 'co a suspension of 27.6 g (o.69 mole) of 50% ~odium hydride (mineral oil) in 250 ml of dimethyl-sulfoxide. The reaction wa~ exothermic ~nd the temperature ro~o to 60C.
In another vessel, 79 g (o.69 mole) of methane-sulfonylchloride WaB added dropwise to a solution of69.7 g (o.6g mole) of l-methyl-~-pyrrolidinol ~nd 77 g (0.76 mole) of triethylamine in 500 ml of dry benzene while cooling with an ice bath. The mixture was ~tirred 15 minutes ~nd filtered. The filter cake was wa~hed with 500 ml of benzene and the benzene filtrates were combined ~nd con~entrated on the rotary evaporator to about 200 ml.
The residue wa~ added dropwi~e to the a~ove prepared dimethylsulfoxide 301ution co~taining the sodium 6alt of l-hydroxy-2-naphthalenecarboxamide w~ile stirring at 75C.
20 ~he temperature was maintained at 75C. for 18 hr with external heat. The resulting Eolution was cooled ~nd an equal volume of water wa~ added. The mixture w~s extracted with three portions of chlorofonn. The washes were combined and concentrated. The residue was partitioned between ethyl acetat~ and dilute hydrochloric ~cid. The acid layer was made basic with ~odium hydroxid~ and extracted twice with ethyl acetate. The ethyl ~cetate washes were combined, dried over 00dium ~ulfnte ~nd concentrated. The residue was cry~tallized ~rom ~thyl ~c~tate-iaooctane. Yield of 30 ~olid was 55 g (32%). ~ portion w~ recry~tallized twice from ethyl acetate-isooctane~ m.p. 122-129C.
Analysis: Calcul~ted for CloH~N202: ,C,71.11; ~,6.71;
N, 10 .36 Found : c,70.g6; ~,6.71;
N, 10 .31 419~ CIP-2 . .

35 ~ i3~
~E~E~

To ~ solution of 151 g (1.5 mole) l-methyl-~-pyrrolidinol ~nd 166 g (1.6 mole) triethylamine in 1500 ml of dry benzene was ~dded dropwi6e 171 g (1.5 mole) of methane~ulfonyl chloride with cooling. The reactivn mixture wa~ ~tirred at room temperature for one hour and filtered. ~he ~iltrate was concentrated under reduced pressure to give an orange-colored oil.
In another vessel, to a ~uspension of 50~ ~odi~n hydride/
mineral oil (72 g; 1.5 mole3 in 1~0 ml dimethylformamide the sulfonate preparo~ ~bove and 139 g (0.93 mole) of 5-methoxy salicylamide dissolved in 600 ml dimethylformamlde were added dropwise with ct~oling . The react ion mixture was heated at reflux for 14 hr. A~ter cooling, the reaction was diluted with 1000 ml of water and extracted three times with 700 ml poxtion~ o~ chloroform. The combined chloroform extract~ were washed thri~e with water and extracted thrice with 500 ml portions of 3N hydrochl~ric acid. The ~ueous layer was made alkaline and extracted with chloroform. ~he chloroform extracts were washed thrice with water, dried over magnesium sulfate and evaporated under reduced pre~sure to give a vi~ous brown oil. Vacuum distillation o~ this material yielded a viscous orange oil w~ich wa~ dis~olved in chloroform, extracted in ~cid; made alkaline ana ~xtracted into chloro-~orm ~gain. Evaporation of the ~olvent gave n dark brown oil which s~lidified under reduced pres~ure. Three recrystallization~ from othyl acetate g~ve 10 g of white cry~tals (40 , m.p. 85-87C.
Analy~is: Calculated ~or Cl9Hle~209: C,62.~8; H,7.25;
~ 3, 11 . 19 Found : C,62.47; H,7.26;
N,11.20 ~, 419A-CIP-2 ~6 ~2~;3~45 Preparation 12 ~ -L( l-Methyl-3-pyrr~liainyl)oxy~-4-pyridine-carbonitrile fumarate r 1:2 ~ .
, A solution of 55 g (0.55 mole) of 1-methyl-3-pyrrolidinol in 55 ml of dry dimethylformamide was ~dded dropwise to a ~uspension of 22 g (0.58 mole) ~f 60~
~odium hydride/~0% mineral oil in 300 ml of dimethyl-~ormamide. The mixture was stirred ~t room temperature ~or one hour and 7~ 9 (0.53 mole) of 3-chloro~4-cyano-pyridine in 200 ml of dimethylformamide was added dropwise with mild cooling to maintain a temperature of 30-40 C.
The ~olution wa~ 6tirred 3 hours and an eaual volume of water added, The solution was made acidic with dilute hydrochloric acid and extracted with i~opropyl ether.
The z~ueous layer was made basic with odium hydroxide and extracted ~ tlme with chloro~onm. The extracts were combined, dried over ~odium ~ulfate and concentrated.
The residue was treated with 50 g of fumaric acid in 400 ml o isopropyl alcohol and 40 ml o~ water~ The resulting crystals (51 9; 21%) were collected. A 2 g ~ample was recrystallized from methyl i~obutyl ketone.
Yield of product was 1.5 g, m.p. 172-174C.
Analysis: calculated ~or Cl~HZ~309: C,52.42; H,4.86;
N,9-65 Found : C,52.40: H,4.90;
' N,9.68 Preparation 13 l-~(l-Methyl-3-pyrrolidinyl)oxy~-2-naphthalene-___ _ . _ carbonitrile oxalate.
A solution of 29 g (0.11 mole) of l-~(l-methyl-pyrrolidinyl)oxy-2-naphth~lenecarbox~mide nnd 38 g (0.32 mole) of thionyl chloride in 150 ml of chloroform was heated to re1ux for 6 hr. The ~olution was poured into ice ~nd made basic with ~odium hydroxide. The chloroform layer was ~eparated, dried over ~odium ~ulfate ~n~
concentr~ted. The residue w~s di~solved in hot i300Ctnne.
The solution was treated with charconl, filtered ~nd concentrated. Th~ residue was dis~olved in isopropyl --~i 1 9A-C I P-2 ~25;~

alcohol and oxalic acid was added. The precipitate was recrystallized ~rom isopropyl alcohol-water mixture.
Yield of product was 11.5 g (~1%), m.p. 176-184 C.
Analysis: Calculated for C~ N205: C,63.15, H,5.30;
N,8.18 Found C,63.00; H,5.29, ~,8.15 Preparation 14

7.5-Diiodo-methvlsalycilate.
To one liter of absolute methanol was add0d 150 g (0.39 mole) of 3,5-diiodosalicylic acid. Hydrogen chlo~ide was bubbled through the reaction mixture under agitation and refluxed for 3 hrs. The reaction mixture turned cloudy and suddenly a large volume of white crystals precipitated. The mixture was filtered to give, after drying, 136 g (8~%) of product, m.p. 198-202 C.
Preparation 15 2-Hydroxy-3,5-diiodobenzamide.
A stainless steel bomb, cooled with dry ice acetone, was charged with excess liquid ammonia, ~,5-diiodomethyl-salicylate and a catalytic ~mount ~f sodium hydride. The bomb was sealed and shaken at room t~mp~rature for 1~ hrs.
on cooling again, the contents o~ the bomb were poured out and excess ammonia allowed to evaporate at room temperature. The product melted 190-195Co with decomposition. ~ass spec analysis confirmed molecular weight of the title compound.
Preparation 16 ~,5-Diiodo-2-r(l-methyl-3-pyrrolidinyl)oxylbenzamide.
Following the procedure of preparation 1, ~ubstituting 2-hydroxy-3,5 diiodobenzamide Por salicylamide, the title compound is prepared.

J 41~A-CIP-2 ~8 PreParation 17 Sodium-2-e(1-methyl-3-azetidinyl?oxy~-3-pyridine-carboxylate.
The title compound i~ prepared by following the procedure o~ preparAtion 6 but ~ubstituting 1-methyl~3-szetidinol for l-methyl-3-pyrrolidinol.
Prepa rat ion 18 4-~ Methyl-3-pyrrolidinyl)oxy~-3-pyridine c~rboxylic acid 30dium 8al~-4-Chloropyridine i~ reacted with dii~cpropyl lithium amide and carbon dioxide to give the lithium salt of 3-carboxy-4-chloxopyridine which i~ then reacted with l-methyl-3-pyrrolidinol a-~ in Prepar~tion 6.
Preparation 19 15 fumarat e .
C1 2-Carboxamido-~-hydroxypyridine i~ reacte~ with 0 P=o to give 2-cyano-~-chloropyridine whi~h i8 then reacted with l-methyl-3-pyrrolidinol ~ in preparation 12 to give the title compound.
Pre~ration 20 l-MethYl-~-pyrrolidinethiol acet~te Laster~ h_ne-dioate.
.__ To a solution o~ 101 g (1 ~ole~ of 1-methyl-3-pyrrolidinol ~nd 110 g (1.1 mole) of triethylamine in 700 ml o~ dry benzene wa~ added dropwi~e 115 g (1 mole) of methanesulfonyl chloride while 3tirring and cooling with an ice bath. The re~ulting mixture was ~tirred for 0~5 hr.
and filtered. The ~ilt~ate was concentrated on the rot~ry evaporator to ~out 200 ml being careful not to overheat.
~0 The re~idue was di~olved in ~bout 150 ml of ethanol.
In a ~e~arate ve~el, 25.~ g (1.1 mole) of ~odium was dis~olve~ in 800 ml of 200 proof ethanol under nitrogen gas ~weep. After disBolution W~5 complete, 83.6 g (1.1 mole) of thiolacetic acid Wa8 ~ded ~lowly ~nd the re~ulting ~olution wa~ ~tirred ~n ~dition~l 19 min.

419A-cIP 2 ~;253 ~he Above prepared ethanolic s~luti~n of methanesulfonate wa~ ndded ~nd the re~ulting solution was heated to 60 C.
for 20 hrs. The mixture W~8 cooled to 25C. ~nd filtered ~nd the filtrate wa~ ~oncentr~ted on Æ rotary evaporator.
~he residue was di~solved in i~opropyl ether ~nd the mixture filtered to remove ~ ~mall amount of ~olid. The ~iltrate wa~ concentrated and the residue di~tilled to yield 70 g of the free base title ester, b.p. 95-105/15 mm.
A 7 g portion of the free base was treated with 4 g 1~ of oxalic acid in isopropyl alcohol and the salt obtained was xecrystallized from isopropyl alcohol to give 8.4 g of title product, m.p. 108-111C.
-eParation 21 l-Methyl~ vrrolidinethiol oxalate.
A solution of 62 9 (0.~9 mole) of 1-methyl-3-pyrrolidinethiol ~cetate (ester) in 200 ml of absolute methanol wa~ treated with a 2 mm ~phere of sodium and the resulting solution was distilled at 1 atm. preRsure to a pot temperature of 100C. Vacuum wa6 applied and 23 the pressure was slowly decreased to 100 mm. The residue was di~tilled to a pot temperature of 130~C., yielding 25 g (56%) of distillate with a boiling point of 95-100 C./
100 mm which was the free base of the title compound. A
4 g sample was treated with oxalic and in isopropyl alcohol to give 5.5 g of oxalate ~alt, m.p. 80-82C.
Preparation 22 2-rtl-Meth 1-~- rrolidinvl)thio~ pyridine--carboxylic acid.
To ~ atirred su~pension of 80 g (2 mole) of 60~ sodium hydride (in mineral oil) in 800 ml of dry dimethylformamide, ~11 heated to 60 C. ~nd u~ing nitroge~ g~ ~low wa~ ~dded dr~pwi~e, a 801utio~ o$ 157.0 g ( 1 mole) of 2-chloro-nicotinic acid ~nd 117 g ( 1 mole) o$ 1-methyl-3-pyrrolidinethiol in 300 ml of dimethylformamide ~t a rate ~5 which maintained a temper~ture of 60-67oC. ~he mixture wa~ heated to 65C. ~or 6 hr and allowed to ~tand cvernight ~t room temperature ~nd then ~iltered. ~he collected _ 4~A-CI~
i3~
~o ~lid was 6uspended in one liter of i~opropyl alcohol and hydrogen chloride was bubbled into the ~uspension until a pH of 6.2 was reached. The mixture was b~ought t~ a boil and filtered. ~he ~olid was dissolved in 2 liters 5 of water and extracted with isopropyl ether. The pH wa-adjusted to 6.o and the solution was c~ncentrated to a volume of 800 ml ~nd placed in a refrigerator. The resulting ~lid (85 g) collected by ~iltration, w~s a mixture consisting of about 85~ o~ the title compound and 15~ sodium chloride. A sample portion of thi~ was crystallized once from ethanol and twice from isopropyl alcohvl-water. The recrystallized product decomposed at ~bout 225C.
Preparation 23 S~dium 2~ Cyclohexyl-3-azetidinyl~oxy~-3-pyridine carboxylate.
A solution of 105 g (o.68 mole) of 1-cyclohexyl-3-a~etidinol and 106 g (o.68 mole) of 2-chloronic~tinic acid in 400 ml of dry dimethylformamide was added at a rapid drop to 52 g (1.35 m~le) of 60~ sodium hydride/mineral oil suspended in 400 ml of dry dimethylformamide at 60C.
Mild exothermic reaction was noted. After stirring for 2 hr at 60c.,the mixture was filtered. The filter cake was washed with ethylacetate and dried at 80C./2 mm to give 174 g (86O of crude title compound.
Pre~aration 24 ? I N-Methyl, N-(3-(l_ethylpyrrolidinyl)l-benzoic acid lithium salt.
A mixture of 1068 g (6 mole) of 3-bromo-1-ethyl-pyrrolidineJ ~28 g (6 mole) of pota~sium carbonate and 1700 ml of N-methylaniline was ~tirred at reflux for 2 hr, cooled and ~iltered. The filtrate was extracted with ~ilute aqueous sodium hydroxide~ dried over anhydrous ~odium 6ulfate and distilled. Yield of l-ethyi-3-(N-methyl, N-phenylamino)pyrrolidine was 452 g (~7.5%), b.p.
100-105/0.1 mm.
The above prepared compound, 20.5 g (0.1 mole) and 46.5 g of 15.1% butyllithium and 20 ml of diethyl ether were heated at reflux for 2 hr. The reaction mixture was _J
419A-CIP-~
~253~1l4~i then pou~ed onto a ~lurry of dry ice in diethyl ether. The excess carbon dioxide was allowed ~o evaporate over a period of time and the residue was stirxed in diethyl ether and filtered. The filter cake was dried in vacuo to give 15 g of the title product.
Preparation 25 2-Chloro-3-quinolinecarbox~lic acid.
To a solution of 21.3 ml (0.15 mole) of diisopropyl amine in ~00 ml o~ dry tetrahydrofuran under a continuous nitrogen blanket, at -70C., was added 61.6 ml of 2.7 M
n-butyllithium in hexane (0.165 mole) while maintaining the temperature at -60 to -70C. Subsequent to this addition, the temperature was maintained at -65C. for approximately 20 minutes. A solution of 20 g (0.12 mole) f 2-chloroquinoline in 60 ml of tetrahydrofuran was added dropwise while maintaining the temperature at -60 to -70C.
ACter holding the temperature at -65C. for 20 minutes subsequent to this addition, the entire reaction mixture was poured onto a large excess of dry ice. Most of the solvent was ~vaporated in a stream of air; the residual solvent was removed by rotary evaporation. The residue was taken up in 300 ml water, made basic with dil aq. sodium hydr~xide and washed with 3 x 50 ml of isopropyl ether. The aqueous layer was filtered and made acidic t 4 to 5 pH) with dilute aqueous hydrochloric acid. The precipitate was collected, washed with water, isopropyl alcohol, and isopropyl ether, and dried, giving 15.4 g (62%) of white crystals, m.p.
190-210C. (decomp.). A sample was recrystallized from isopropyl alcohol giving an analytical sample, m.p. 190-~0 210C. (decomp.).Analysis: calculated for CloH~02: C,57.85, H,~.91; ~,6.75 Found : C,57.80; H,2.96; ~,6.6 4~ i3~

Preparation 26 .
4-Chloro-7-(trifluoromethyl)~3-quinolineoarboxYlic acid.
.
To a cooled solution of 15.8 ml (0.11 mole) of diisopropyl amine in 250 ml of tetrahydrofuran under a blanket of dry nitrogen at -70C. was added 44 ml of 2.7 M
n-butyllithium in hexane at -60 to -70C. The ~olution was stirred for 20 minutes at -70C. and a solution/suspension of 25 g (0.11 mole) of 3-chloro-7-trifluoromethyl quinoline in 125 ml of tetrahydrofuran was added dropwise while maintaining the temperature between -60 and -70C. The temperature was held at -70C. for 20 minutes subsequent to the addition of the quinoline. ~he solution (deep red) was poured onto a large excess of dry ice and the solvent allowed to evaporate overnight at room temperature. The residual solvent was removed by rotary evaporation (60 C., 30 mm) and thP xesidue taken up in 800 ml of dil sodium hydroxide. An attempted wash with 75 ml of chloroform caused the sodium salt of the product acid to precipitate out. This precipitate was collected and washed with 1 liter of chloroform and suspended in 500 ml of watar. The ~uspension was stirred while acidifying with 6N hydro-chloric acid to pH 2. The solid was collected and washed with 500 ml of water. After drying, 16.2 g (53%) of white solid was collected, m.p. 310C.
Analysis: calculated for CllH~N02ClF3: C,47.94; H,1.83;
~,5 .o8 Found : C,47.56; H,1.79;
N,4.99 Preparation 27 ~,~,-Dichloro-4-D~ridinecarboxvlic acid.
To a solution of 4.96 ml (0.036 mole) of diisopropyl-amine in 200 ml of tetrahydrofuran at -65C. under a nitrogen blanket was added dropwi~e 14.9 ml of 2.5 M
n-butyllithium in hexane while maintaining the ~ove temperature. Twenty minutes subsequent to that ~ddition, a 301ution 5.0 g (00034 mole) of 3,5-dichloropyridine in ~0 ml tetrahydrofurcln at -60 to -70C. was added. The rea~tion mixture was ~tirred at -70C. for 1/2 hr, poured `J 4lgA-cIP~2 ~253gl~

onto a large excess of dry ice and allowed to evaporate overnight at room temperature. The residue was taken up in 100 ml of dilute aqueous sodium hydroxide, washed with ~ x 30 ml of methylenechloride and filtered. The filtrate was acidified to~ pH 2 with dilute hydrochloric acid to precipitate out the pxoduct. After cooling, the precipitate was collected and recrystallized from ethyl acetate~hex~ne giving 1.9 g ~290 of white analytically pure crystals, m.p. 2~ 5c.(decomp.).
lU Analysis: Calculated for C6H3~0zCl2: C,~7.53; ~,1.57;
N,7-30 Found : C,37.33; ~,1.56;
N,7.21 Preparation 28 5-Hydroxy-6-isoquinc~linecarboxamide .
5-Hydroxy-6 isoquinolinecarboxylic acid methyl ~ster as reported by Dyke, S. F. et al., in Tetrahedron 1973, 29(6), 857-62, is reacted with excess ammonia in a steel bomb for 12~18 hr. The excess ammonia is allowed to evapoxate and the residue is crystallized from a suitable solvent mix such as ethyl acetate-toluene to give the title compound.
PreParatin ?2 5~ Methy~ pyrrolidinyl)oxy~-6-isoquinoline carboxamide.
-Following the procedure of Preparation 10, but substituting 5-hydroxy-6-iso~uinolinecarboxamide ~or l-hydroxy-2-naphthalenecarboxamide, the title compound is prepared.
Preparation_~
7~Hydroxy-6-isoquinolinecarboxamide.
7-Hydroxy-5-isopuinolinecarboxylic acid methyl ester a~ reported by Dyke (see ref. given in Prep. 28) is reacted with exces ammonia in a ~teel bomb for 12-18 hx.
The excess ammonia iB allowed to evaporate and the residue ifi ~rystalliæed from a suitable solvent mix such a~ ethyl ncetate-toluene to give the title compound.

_~ 419A-CIP-2 ~25~ 5 Prep~_ation 31 7-r(l-Methyl-3-pyrrolidinyl)oxyl -6-isoau inol ine-L ~ ~ J _ _ _ carboxamide.
Followin~ the procedure of Prepara~ion 10, but su~stituting 5-hydroxy 6-i~oquinolinecarboxamide for 1-hydroxy-2-naphthalenecarboxamide, the title compound is prepared.
Preparation 32 5-Methyl-8- r (1-methyl-3-P~rrolidinyl)oxYl-7-quinoline-carboxamide.
Following the procedure of Preparation 10, but substituting 8-hydroxy-5-methyl-7-quinolinecarboxamide ras reported by V-Kapoor et al, Indian J. Chem. 4~10), 438-51 (1966): (C.A. 66, 75802p)] for 1 hydroxy-2-naphthalenecarboxamide, the title compound i~ prepared.
Preparation ~

8-HYdroxy~- _methyl-j~L~nolinecarboxylic acid methyl estQr .
8-~ydroxy-2-methyl-7-quinolinecarboxylic acid (as reported by Meek, W. H. et al., in J. Chem. EngO Data 1969, 14(~ 88-91) is reacted with methanolic boron trifluoride solution for ~everal hours. The resulting mixture is added to an aqueous solution of sodium bicarbonate to give finally a basic solution. The solution is extracted with chloro~orm. The chloroform extract is dried over anhydrous sodium ~ulfate and concentrated and the residue is crystal-lized from a suitable solvent such as isooctane to give the title compound.
Preparation ~4 8-Hydroxy-2-methYl-7-quinolinecarboxamide.
~0 8-Hydroxy-2-methyl-7-quinolinecarboxylic acid methyl ester is reacted with excess ammonia in a steel bomb for 12-18 hr. The excess ammonia is allowed to eva~orate and the residue i~ crystallized from a suitable golvent to give the title compound.

45 ~L ~5 Preparation ~i5 2-Methyl-8-~,(1-methyl-3-pyrrolidinyl)oxy~-7-quin~ïine~
carboxamide.
Following the procedure of Preparation 10, but substituting 8-hydroxy-2-methyl-7-quinc>linecarboxamide for 1-hydroxy-2-naphthalenecarboxamide, the title compound is prepared.
PreParation ~6 6-HvdroxY-5-quinolinecarboxylic acid methyl ester.
6-Hydroxy-5-quinolinecarboxylic acid ~as reported by Da Re, P. et al. in Ann. Chem. (Rome) 1970, 60(3), 215-24 (C.A. ~, 25338m)~ is reacted with methanolic boron trifluoride solution for several hours. The resulting mixture is added to an as~ueous solution of sodium bicarbon-ate to give finally a basic solution. The solution is extracted with chloroform. The chloroform ex'cract is dried over anhydrous sodium sulfate and concentrated and the residue is crystallized from a suitable solvent.
Preparation 37 6-EIydroxy-~-quinolinecarboxamide.
6-Hydroxy-5-quinolineoarboxylic acid methyl ester is reacted with excess ammonia in a steel bomb for 12-18 hr.
rhe excess ammon~ is allowed to evaporate and the residue i5 crystallized from a suitable solvent to give the title compound.
PreParation ~8 6i (1-MethYl-3-pyrrolidin ~ oxy~- ~ inolinecarobxamide.
Following the procedure of Preparation 10, but substituting 6-hydroxy-5-quinolinecarboxamide for l-hydroxy-2-naphthalenecarboxamide, the title compound is prepared.
Preparation ~
8-Hvdr~xv-7-qu inolinecarboxamide.
8-Hydroxy-7-quinolinecarboxylic acid methyl e~ter tas reported by Eckstein, Z. et al. in Pol. J Ch~m. 1979, 53(11), 2373-7 (C.A. 92, 215243s)] is reacted with excess ~5 ammonia in a steel bomb for 12-18 hr. The excess ammonia i~ allowed to evaporate nd the residue is crystallized from a suit~ble ~olvent to give the title compound.

~ 2~ 3~9 Pre~aration 40 8-[(1-Methyl-~-pyrrolid nyl~oxyl-7-quinolinecarboxamide.
Folling the procedure of Preparation 10, but substituting B-hydroxy-7-quinolinecarboxamide for l-hydroxy-2-naphthalenecarboxamide, the title compound is prepared.
Preparation 41 (Refer to chart VIII) 2-Chloro-N- r 4-(dimethylamino)-2~hydroxybutYl pyridinecarboxamide monohydrochloride.
To a uspension of 11.9 g (0.076 mole) of 2-chloro-nicotinic in 200 ml of methylene chloride was added 10.2 g (0.076 mole) of l-hydroxybenzotriazole, 10 g to-o76 mole) of l-amino-4-(dimethylamino)-2-butanol, and 15.6 g (0.076 mole) of dicyclohexylcarbodiimide. The resulting solution was stirred at room temperature for 6 hr and allowed to stand for 66 hr. The resulting mixture was filtered and the filtrate concentrated on the rotary evaporator. The residue was shaken with a mixture of dilute hudrochloric acid and isopropyl ether. The resulting ~ pha~e system ~1 solid, 2 liquid) was filtered and the solid discarded.
The aqueous layer was separated, made basic with ~odium hydroxide and extracted 3 times with chlsroform. The combined chloroform extracts were combined, dried over anhydrous sodium zulfate and concentrated. The residue was dissolved in isopropyl alcohol and acidified with ethereal hydroqen chloride. The resulting precipitate 2~ was dissolved by heating and adding methanol. The crystals obtained on cooling were recrystallized from ethanol to yive 9.6 g t41%), m.p. 182-192C.
Analysis: Calculated for ClzHl9N30zClz: C,46.77; H,6.21;
N,13.6 Found : C946.67; H,6.42;
N,1~.91 41y~-cIp-2 Intermediate_l 2-~2-chloroeth~ ?!3-dihydro-4-methyl-1,4-benzQx-azepin-5(4H~-~ne.
To 54 9 (1.35 mole) of sodium hydr~xide in 800 ml of w~ter was ~dded 148 g (o.67 mole) of 2-~(1-methyl-~-pyrrolidinyl)oxy]benzamide nnd the mixture ~rought ~oreflux ~or 18 hr. The pH was adju~ted to 7 with hydro-chloric acid and the ~olution filtered and concentrated.
~he re~idue was boiled with 400 ml of isopropan~l ~nd filtered. The filtrate wa3 concentrated and the residue (which crystallized) wa~ refluxed wit~ ~00 ml of thionyl chloride for 0.5 hr. and concentrated in vacuo. The residue was di6solved in ~00 ml of chloro~orm and the ~olvent boiled off in vacuo. The residue was redisRolved in chloroform, 150 ml of triethyl amine ~dded and the mixture refluxed 1 hr. The solution was concentrated in vacuo and the residue partitioned between 400 ml of ethyl a~etate J 400 ml of isopropyl ether and 500 ml of dilute hydrochloric acid. The organic layer was wa~hed twice with water ~nd once with dilute sodium hydroxide, dried with ~odium sulfate and concentrated. The re idue was cry.~tallized from i~opropanol-water. Yield of product wa 75 9 (47 0 , m.p. 97-107~C.
Analy~is: Calculated for Cl2~l4~0~Cl: C,60~13; H,5.89;
N,5.84 Found : C,60.35; H,5.91;
~5-65 Intenmediate 2 4-~enzyl-2-(2-chlrethv~1~4-benzox-azepin-5(4H)-one.
To 85.7 g (0.29 mole)of 2~ benzyl-~-pyrrolidinyl) ~0 oxy3-benzoic acid was added 150 ml ~f thionyl chloride.
~he ~olution sto~d for 15 min and Wa8 then refluxed 30 min.
~nd concentrated in v~cuo. The residue was twice treated with 250 ml of chloroform and concentrated in vzlcuo. The re~idue was di~olved in 500 ml o~ chloroform an~ 101 g (1 mol~) of triethylamine added ~lowly with ~tirring. The aolution was refluxed 1 hr. ~nd concentrated an vacuo.

~_ J
~ 419A-CIP-2 48 ~ ~ ~ 3 ~

The residue wa~ partitioned between 50% ethyl a~etate-50% is~pr~pyl ether ~nd dilute hydr~chl~rie acid. ~he organic layer was washed with dilute ~odium hydr~xide ~nd concentrated. The residue was cry6tallized 5 times from i~opropyl eth~r-ethyl acetate. ~iald of pr~duct was 23.8 g (26O , m.p. 145.0-147C.
Analysis: Calculated for Cl8Hl~NO2Cl: C,68.46; H,5.74;
~,4.44 Found : C,68.47; H,5.89;
~,4.32 Intermediate_~
? (2-~chloroethyl)-2~3-dihy~--4-methylnaphth~2~3-f]
~1,4~oxazepin-5(4H)-one.
. _ , . . . .
To a 301ution of 21.6 g (0.54 mole) ~odium hydroxide in 500 ml of water was added 74 g (0.27 mole) of 3-~1-methyl-3-pyrrolidinyl)oxy]-2 naphthalenecarboxamide and the mixture heated at re~lux for 16 hr. The pH was adjusted to 6.8 with con~entrated hydrochloric acid, the solution was filtered and c~ncentrated. The re~idue was boiled with 200 ml of isopropyl alcohol snd filtered. The filtrate was concentrated under reduced pressure and the residue di~solved in chlorofor~. Thionyl chloride ~59 g, 0.50 mole) was added and the reaction mixture heated at reflux for 4 hr. A~ter cooling (67 g, 0.67 mole) tri-ethylamine was added dropwi~e. The mixture was washed se~uentially: twice with ~ hydrochloric acid, twice with water, twice with 10~ ~odium hydroxide, twice with water ~nd dried over magnesium ~ulfate. Evaporation ~ the chloro~orm under reduced pressure gave 44 g (580 of a vi~cous dark brown oil. The m~terial was purified by ~0 high pre3~ure liquid chromatogr~phy (50/50 ethyl aeetate/
hexane) and recrystallized ~rom isopropyl ~lcohol to yield brown cry~tals, m.p. = 101-102C.
Analy~ Calculat0d for Cl~HloNCl02: C,66.32; H,5.57;
N,4.83 F~und : C,66.19; H,5.63;
~,4-77 ~19A_CIP-2 ; 3 3~5 ~=
2-(2-Chloroethyl)-2,3 dihydro-4-methylpyrido[3~2-f]
tl,4~-oxazepin-5(4H)-one hydrochloride.
~ ydrogen chloride ga~ was bubbled into a suspension of 150 g (0.61 mole) of sodium 2-t(l-methyl-~-pyrrolidinyl) oxy]-3-pyridinecarboxylate in 1 liter o c~loroform until ~ pH of 6 was reached. To the 6tirred mixture was added 350 g (1.~4 mole) of triphenylphosphine and 350 g (2.3 mole) of carbon tetrachloride and the resulting cloudy solution was stirred at reflux for 1.5 hr. A~out 100 ml of ethanol was added and the heat removed. The solution was stirrea ~or 1 hour while cooling and 200 ml of isooctane WaB added. The 601ution was extracted 4 times with a total of 800 ml of dilute hydrochloric acid. The acid extracts wer~ combinedl made basic with sodium hydroxide and extracted with chloroform. The chloroform layer was geparated and dried over sodium ~ulfate and concentrated. The residue was di~solv~d in a mixture of 500 ml each o isopropyl alcohol and isopropyl ether and acidified with ethereal hydrogen chlorid~. The resulting cry~tals weighed & g (49%). A portion was recrystallized ~rom isopropyl alcohol, m.p. 149 15~C.
Analy6is: Calculated ~Dr CllHl~N202Cl2: C,47.67; H,5.09;
N , 10 . 1 1 Found : C,47.57; H,5.18;
~, 10 .00 Intermediate S
8-Chloro-2-(2-chloroethyl)~2,3-dihydro-4-methyl-1 4-benzoxa~epin-~ 4H)-one.
To a ~olution o~ 10.4 g (0.26 mole) of ~odium hydroxide in 150 ml of water was added 32 g (0.13 mole) of 4-chloro-2-~ methyl-3-pyrrolidinyl)oxy~benzamide and the mixture wa5 heated at reflux ~or 24 hr. The reaction mixture was adju~ted to pH 6 with concentrated hydrochloric ~cid and filtered ~nd the filtrate concentrated. ~he r~idue was boiled with 100 ml of i~opropyl ~lcohol ~nd the mixture ~5 fil~ered. ~he filtrate w~ conc~ntrated ~nd heated at ~eflux with 98 y (o.83 mole) of thionyl chloride for 1 hr.

~ ~ 419A~CIP-2 S ~i3~

The excess thionyl rhloride was evaporated under reduced pressure. The residue w s dissolved in 70 ml of chl~ro-form ~nd the ~olvent evaporated under reduced pressure.
The re6idue was rediRsolved in 75 ral of chloroforrn and 5 40 ml of triethylamine wa~ ~dded gradually. The mixture waq heat~d at reflux for 1 hr. The ~olvent wa~ evaporated under reduced pressure to give a dark-brown ~olid. The solid was dissolved in ethyl acetate and the resulting solutiion wa~hed twice with 200 ml of water ~nd twice with 250 ml of 20% sodium hydroxide. The or~anic layer was dried over magnesium 3ulfate and concentrated under reduced pressure to give 21 g (59~) of dark-brown solid. The ~olid was recry6tallized from i~opropyl nlcohol to give the title compound, m.p. 85-B7 C.
Analysis: Calculated for Cl2Hl9~Clz02: C,52.57; ~,4.78;
N,5.11 Found : C,52.57; H,4.77, N,s.o4 Intermediate 6 2~ ~
To a solution of 9.6 g (o.24 mole) Df BodiUTn hydroxide in 200 ml of water wa~ added 37 g (0.12 mole) of 5-bromo-2-~(1-methyl-~-pyrrolidinyl)oxy]-benzamide and the mixture wa6 heated ~t reflux for 18 hr. The pH of the mixture wa~ adju~ted to 6.7 with concentrated hydrochloric acid solution~ The solution wa~ concentrated under reduced pre~sure and the residue w~s boiled in 250 ml of isopropyl alc~hol for 1 hr. The mixture was filtered and the ~iltrate wa0 concentrated. The residue wa~ di~solved in chloro~orm and to the ~olution wa6 added 28.3 g ~o.24 mole) of thionyl chloride. The mixture was heated at reflux for 0.5 hr and cooled to 15C. with an ice bath. To the mixture w~s added dropwi~e 26.6 9 (0.26 mole) of triethyl-amine nt ~uch a rate that the temperature did not ~xceed 25C. q~he reaction mixture wa~ 6tirred ~t room temperature f~r 1 hr~ then wa~hed con~ecutively with ~N hydrochloric ~cid, 15% ~UeOUB aodium hydroxide nnd water. ~he _ ! 419~CIP-2 51 ~L ~53~

chloroorm layer was dried ~vtr magnesium ~ulfate and concentrated under reduc~d press~re to give 23 g (60~) of brown ~olid. A portion of ~he solid was recryktallized from ethyl ~cetate-isopropyl ether, m.p. 92-94C.
Analysis: Calculated for Cl2~ BrClO2: C,45.24; HJ4.11 N,4 .40 Found : CJ45.61; HJ4.17;
N , 4 . 42 Intermediate 7 7-Chloro-2-(2-chloroethvl)-2.3-dihvdro-4-methYl-1,4=
benzoxazepin-~(4H~-one.
~ydrogen chloride wa~ bubbled through ~ solution of 11~ g (9.44 mole) 5-chloro-2-~(1-methyl-~-pyrrolidinyl)oxy]
benzamide dissolved in 500 ml of glacial acetic acid for 15 min while the reaction was cooled with an ice bath.
Butylnitrit.e ~142 g, 1.~8 mole) was then added in one portion; the reaction w~s ~tirr¢d at r~om temperature ~or 16 hr and heated at reflux for ~n ~dditional 6 hr. The ~cetic acid was evapor ted under reduced pre~sure, tetra-chloroethane was added twic~ to the residue and evapora~edO
The re~idue was di~solved in chloroform, treated with 163 g (1.38 mole) ~f thionyl chloride and heated at reflux for 22 hr. The reaction mixture was cooled with an ice bath and 152 g (1.5 mole) of triethylamine was added drop-wi~e at such a rate that the temperature was kept at 25-3QC. The reaction mixture wa~ diluted with 200 ml of chloro~orm and wa hed consecutively with ~N hydrochloric acid, water, 10% ~odium hydroxide and water. The chloro-form was evaporated under r~duced pre~ure to give 40 g of a black, tar-like residue (37%).
An aliquot ~f thi~ residue wa~ purified on a ~ilica gel column u~ing ethyl ~cetate a~ the eluting solvent.
Recryst~llization from i30propyl ~lcohol gave beige cry~tal~, m.p. 101-103C.
Analy~is: Calculated for C~2~l9NClz02: C,52.57; H,4.78;
~5 ~ound : C,52.6~; H,~ 83;
~,$ 5 41~ CIP-2 ~253 5~
Intermediæte 8 2-~(2-Chloroethyl)-?,3-d ydro~4-methylnaphth[2,1-f]
~ 41~azepin-5(4H)-one.
t, Hydrogen chloride ga3 was bubbled into 3 ~olution of ji~ g (o.o~ mole) of l-~(l-methyl-3-pyrr~lidinyl)oxy~-2-naphthalenecarboxamide in 40 ml o$ acetic acid for ~bout 2 min. The ~olution was cooled with ~n ice b~th and 6.1 g (o.06 mole) of n-butyl nitrite was added 810wly beneath the surface of the liquid at 12-15C. (about 10 minutes re~uired). The ~olution was ~tirred at ~5C. for lô hr and heated on the ~team bath for 3 hr. The ~olution was concentrated on the rotary evaporator. The residue was di~olved in 60 ml of 1,1~2,2-tetrachloroethane which was removed on the rotary evaporator at 0.5 mm/ateam tempera-ture.
~he xe~idue was dissolved in 75 ml of chloroform and treated with 7 g (o.o6 mole) of thionyl chloride and brought to reflux for 12 hr. The solution wa~ extracted with water (te~t2d acidic) ~ollowed by dilute sodium hydroxide, dried over ~odium ~ul~ate and concentrated.
The residue wac ~rystallized twice ~rom isopropyl ether-ethyl ~cetate. Yield of product was ~.2 g (37%), m.p.
l~9-111C .
Analysis: calculated for Cl~Hl~N02Cl: C,66.32: H,~.~7:
~,4.8~
~ound : C,66.15i H,5.56;
N,4.76 Intermediate 9 2-(2-Chloroethvl~-2~3-dihydro-7-methoxy-4-methYl-1,4-benzoxazepin-~(4H)-one.
To a ~olution of 19.2 g (o.48 mole) of sodium hydroxide in 500 ml o~ watex wa~ ~dded 60 y (0.24 mole) of 5-methoxy-2-t(l-methyl-3-pyrrolidinyl)oxy~-benz~mide ~nd the mixture was heated ~t reflux ~or 24 hr. The re~ction mixture was cooled and the pH ~djusted to 6.8 with ~oncentrated hydro-chloric acid. The mixtuxe wa~ concentr~ted under reduced pres~ure and the ro~idue W~B boiled in i~opropyl alcohol for 1 hour. The mixture was ~iltered and the filtrate was 4 l~A -C I P -2 ~53~5 ~3 c~ncentrated. The residue was diss~lved in 500 ml of chlorofo~m and to this ~olution w~s ~dded 114 g (o.96 mole) of thionyl chl~ride. The mixture was heated at reflux for 48 hr, then cooled with an ice/acetone bath. To the mixture was added dropwise 97 g (o.96 mole) of triethyl-amine at such a rate that the temper~ture did not exceed 25C. The reaction ~olution was washed in ~equence with water, 3N hydrochloric acid solution, water, 15~ a~ueous sodium hydroxide and water And finally dried over magnesium sulate. The solvent wa~ evaporated under reduced pressure to give a bl~ck solid. The solid was purified on n silica ~el column using ethyl acetate as the eluting solvent to give on isolation 15 g (23%) of beige colored product, m.p. 98-100C.
Analys i8: Calculated ~or C13~ NCl09: C,57,89; H,5.98;
N~5.l9 Found : C,57.53; H,6.oo:
N,5 .16 Intermediate 10 2-(?-Chloroethyl)-29~dihydro-4-mathvl-1,4-benzox-azePine-~(4H~-thione.
A mixtur~ of 18.5 g (0.0834 mole) of phosphorus pentasulfide and 18.5 g potassium sulfide was ground together and added to a solution of 100 g (0.417 mole) of 2-(2-chloroethyl)-2,3 dihydro-4-methyl-1,4-benzoxazepin-5(4~)-one in dry toluene, the mixture refluxed 24 hr. and filtered. The filtrate w~s concentrated and partitioned between chloroform and dilute sodium hydroxide. The chloroform layar was concentrated and the residue was crystallized several times from ethanol. Yield of product ~0 was 55 g (52%), m.pO 1~5-108C.
AnaluAis: calculated for C12Hl~NSOCl: C,56.~5; H,5.52;
N,5.48; S,12.54 Found : C,56.55; H,5.47;
~,5.~9: S,12.55 _ 419A-CIP-2 5~

Intermediate 11 2-(2-Chloroethyl)-2,~-dihydro-4-methylpyrldor3,2-f ~1,41-oxazepine 5(4H)-thione.
T~ a oluti~n of 59 9 (0.25 mole) ~f 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-$~1,4~ox~zepin-5(4H)one hydrochloride in 1500 ml of chloroform was added 41.5 g (0.19 mole) of phosphorus pentasulfide and the mixture was heated to reflux for lB hr. The mixture was filtered and the filtrate was extracted with dilute ~odium hydroxide.
The chloroorm layer was concentrated and the residue was dissolved in 250 ml of boiling isopropyl alcohol. On cooling, 28 g (44%) of yellow solid precipitated. A
portion was recrystallized from isopropyl alcohol, m.p.
134-1~6C.
Analysis: Calculated for Cl1H~3N2ClOS: C,51.46; ~,5.10, N,10.81 ~5 ~ound C,51.35; H,5.21;
~,10.72 Intermediate 12 2-(2-Chloroethyl)-2,~dihydro-4-methylnaphthr2,3-f~
~1,4~xa_ pi~e-5~4H)-thione.
To a ~olution of 16.6 g (o.o6 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-4-methylnaphth~2,~-f~1,4]oxazepin-5(4H)-one in 150 ml of dry toluene was added a mixture of 8.6 g (0.045 mole~ of phosphorus pentasulfide and 8.6 g of pot~sium ~ulfide which had been ground together. The reaction mixture was stirred ~nd heated at reflux for ?4 hr. The mixture was filtered hot and the filtrate concentrated under reduced preYsure. Yellow solid, 6.5 9 (~5%) was obtained which was recrystallized from ethanol, .p. 166-168C.
~0 ~nalysis: calcula~ed ~or Cl0H1~ClOS: C,62.84; ~,5 27;
Found : C,62.29; H,5. 8;
N,4.47 5~

Intermediate l~i 8-Chloro-2-(?-chloroethyl) -2 I~-dihy~ro-4-meth~ , 4-benzoxaze~?ine-5( 4H~ -thione .
To a solution of 4 5 g (0.16 mc:le) of 8-chloro-2-(2-chloroethyl)-2~3-dihydro-4-methy~ 4-benzox~zepin-5(4H) one in 400 ml of dry toluene wa_ added a mixture of 23 ~
(0.12 mole) of phosphorus penta~ulfide and 23 9 of potassium ~ulfide which had been ground together. The reaction mixture was stirred and heated at reflux for 24 hr. The mixture was filtered hot and the filtrate concentrated under reduced pressure to give 25.5 9 (55%) of or~nge oil which ~olidified on standing at room temperature. The solid wa~ recrystallized from ethanol, m.p. 105-106 C.
Analysi~: Calculated ~or C1æHl3~c120so C,49.66; ~,4.52;
~,4.83 Found : C,49.6~; H,4.5~;
~,4.75 Intermediate 14 . ~

To a ~olution o 11.0 g (0.0~5 mole) of 7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in 150 ml of dry tol~ene was added a mixture of 13 . 4 g (0.07 mole) of phosphorus pentaqulfide and 1~.4 9 of potassium ~ulfide which had been ground together. The r~action mixture was heated at reflux for 5 hr under a nitrogen atmosphere. The mixture was filtered hot and the filtrate concentrated under redu~ed pressure. The residue was di~solved in chloroform. The chloro~orm s~lution was washed twice with dilute ~oueou~ sodium hydroxide, dried over magne~ium sulfate and concentrAted u~der reduced pressure to giv~ 8.5 g (72%) of yellow ~olid. The solid was recryst~llized ~rom ethanol, m.p. 118-120C.
Analysi~: Calculated for Cl2Hl9NBrClOS: C,4~07; H,~.9e;
N,4.18 Found : C,43.08~ .88;
N,4.12 .; 419A-CIP-2 3 ~

Intermediate 1 2-(2-Chloroethyl)-2 ~ th~2,1-f~
1 4 oxaze ine-~(4H~-thi~ne.
A mixture of 9.55 9 of pho~phoru~ pentasulfide and

9.5 g of potassium ~ulfide were ground together ~nd added to a ~olution of 20.2 g (0.07 mole) of 2-(2-chloroethyl)-2~-dihydro-4-methylnaphth~2>l-f]~l~4~oxazepin-5(4H)-one -in 200 ml of dry toluene. The mixture was ~tirred and heated at r~1ux for 7 hr. ~he hot reaction mixture was filtered and the product crystallized from the cooled filtrate. Recry tallization from chloroform gave 18 9 (84~) o yellow crystal~, m.p. 167-170 C.
Analy~is: Cal~ulated ~or Cl8Hl~NClOS: C,62.84; H,5.27, N,4.58 Found - : C,62.85; H,5.20;
~.4-55 Intermediate 16 2-(2-chloroethyl)=2,~-dihydro-4-methylPyridoL4,~-f rl~41-~xazepin-5(4~)-one hydrochloride.
I . . ,1 . _ _ . _ A 49 g (0.11 mole) sample of 3~ methyl-~-pyrrolidinyl)oxy~-4-pyridinecarbonitrile fumarate ~1:2~
was partitioned between chloroform and a ffaturated solution of potassium carbonate. The aqueous layer was extracted twice with chloroform. All chloroform extracts were combined, dried and concentrated. The residue was dissolved in 125 ml of t-butanol and added to 34 g (o.6 mole) o~ potassium hydroxide pellets. The mixture was stirred at room temperature for 88 hr. and then diluted with 150 ml of toluene. This mixture was filtered and the filtrate concentrated. The residue was di~solved in . chloroform, wi~h cooling, and the pH sdjusted to 6.o with hydrogen chloride gas. The resulting mixture was concen-trated and 400 ml of dry toluene wa6 added to the re~idue.
The toluene was removed on the rotary evapor~tor (steam heat/reduced pressure) to remove ~ny water~ ~he residue W~8 di~olved in 400 ml of chloroform and 63 g of triphenyl-~5 phosphine wa~ ~dded followed by 70 g of carbon tetra-chloride. The ~olution was ~tirred at reflux ~or 2 hr and j ~ 4l9A-cIp-2 ~ ~ ~ 3 another 30 g of triphenylph~sphine added. Af~er an additional hour reflux, 70 9 more carbon ~etrachloride and 63 g more of triphenylphosphine were udded and reflux was continued for 4 hr. The 801ution was extracted with dilute ~odium hydroxide, then concentrated. The residue wa~ partitioned between toluene and dilute hydrochloric ~cid. The toluene layer was extracted ~ive time~ with dilute hydrochloric ~cid. The acid extracts were combined, basified with eodium hydroxide and extracted with chloro-form. The chloroform layer was dried over 60~ium sulfateand con~e~trated. The residue was chromatographed on a 7 x 25 cm column of silica gel with acetone liquid phase.
Free base of the title compound isolated after evaporation amounted to 5.8 9 (20%). To a portion of the free base dissolved in isopropyl alcohol was added ethereal hydrogen chloride and isopropyl ether. The resulting crystal~
were collected and dried, m.p. 188-190C.
Analy~ i5: Calculated for CllHl~202Clz: C,47.67; H,5.09;
N,10.11 Found : C,48.33; ~,5.22;
N,9.73 Intermediate 17 2-(2-chloroethyl)-?"3-dihydro-4-methylpyrido~3,4-f ~1,41oxazepin-5(llH)-one ydrochloride.
~n the procedure of Intermediate 4, equal molar amount~ ~f ~odium 4-[(1-methyl-3-pyrrolidinyl)oxy~-3-pyridin~carboxylateWas substituted for 2~ methyl~3-pyrrolidinyl)oxyJ-3-pyridinecarboxylic acid and the title cornpound was obtained.
Intermediate 18 3 2-(2-Chlor-ethyl)-2~3-dihydro-4-methylpyridor2~-f]
~1,4]oxazepin-5(4H)-one hydrochloride.
_ the procedure of Intermediate 16, ~-~(l-methyl-pyrrolidinyl)oxy~-2-pyridinecarbonitrile fumarate is subRtituted for 3-[(1-methyl-~-pyrrolidinyl)oxy]-4-~S5 pyridinec~rbonitrile fumar~te, "he title compound iB
obta ined .

I : ; 4l9A-cIp-2 58 ~53~45 Intermediate ~9 7-Chloro-?-(2-chloroethyl~-2 3-dlh~dro-4-methyl-1 4-To a solution ~f 20 g (0.07 mole) of 7-chloro-2-(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-benzoxazepin-5(~
Dne in 200 ml of toluene was added a mixture of 9.55 g (0.05 mole) of pho~phorus pentasulfide and 9.5 g of potassium ~ulfide which had been ground togetherD The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a yellow solid. Recrystal-lization from absolute ethanol gave 12.5 g (68%) of the product, m.p. 102-104C.
Analysis: Calculated for Cl2H19NC120S: ~,49.66; H,4.52;
~,4.83 Found . : C,49.62: H,4.55;
~,4.76 Intermediate ?
2-~_ Chloroethyl)~~ -diiodo-2~ ~-dihydro-4-methy~-~}~
When in ~he procedure of Intermediate 1, ~,5-diido-2-~(1 methyl-3-pyrrolidinyl)oxy~-benzamide i8 substituted ~or 2~ methyl-3-pyrrolidinyl)~xy~benzamide, the titl compound i6 prepared.

2-Chloromethyl-2,3-dihydro-4-methylpyrido~i,2-f~Ll,4 xazepin-5~4~)-hydro~hloride.
When in the procedure of Intermediate 4, an equal molar amount o~ ~odium 2~ methyl-3-azetidinyl)oxy~-~-pyridine-carboxyl~te sodium 3cetate i~ ~ubstituted ~or sodium 2-~ methyl-~-pyrrolidinyl)oxy~-3-pyridinec~rboxylate, the title compoun~ i5 prepared.
Intermediate 22 2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~4,3-f~
.
9 4~oxazepine-5(4~)-thione.
A solution of 5 g (0.021 mole) of 2-(2-chloroethyl)-29~s-dihydro-4-snethylpyrido~493-~]cl94~-oxazepin-5(4H)-one and 5.1 g (0.0126 mole) ~f 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiodipho~phet~ne-2,4-~isul~ide in 100 ml o dry - ~i 4l9A-clp -2 i A ~

toluene was ~tirr~d at reflux ~or 2.5 hr. The ~olution was ~ooled ~nd extr~c~ed three t~mes wi~h sodium bicarbonate s~lution. ~he toluene layer was dried ov~r sodium sulfate ~nd ~onc~ntrated. The residue was chromato-graphed (high pressur~ liquid chromatograph) u~ing a~ilica column and ethyl ~cetate liquid phas~. The fraction containing the product was concentrated by evaporati~n ~nd the residue was crystallized ~rom ethyl alcohol to give 0.6 g (11%) of the title compound.
Intermediate 23 ~ oroethyl)-2l~-dihydro-7-methoxy-4-methyl-1,4-be ~
To a solution of 10.3 g (0.04 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-7-methoxy-4-methyl-1,4-benz~xazepin-5~4H)-one in 200 ml o~ ~hloro~orm wa~ added a mixture of 5.7 g (0.0~ mole) of phosphorus pentasulfide and 5.7 g of pota~sium ~ulfide which had been ground tsgether. The reaction mixture was stirred ~nd he~ted ~t reflux under nitrogen ~tmosphere for 5 hr. The mixture wa~ filtered ho~ and the filtrate concentrated under reduced pressure.
The re~idue, an orange solid, waQ recrystallized from ethanol to give 7.4 g (65%) of product, m.p. 98-100 C.
Analysis: calculated ~or Cl3Hl~NClO2S: C,54.64; H,5.65, . go Found : C,54.57; H,5.67;
N,4.85 Interm-ediate 21~
When in the procedure of Intermediate 2, ~qual molar amounts of the following are ~ubstituted for ?-( l-benzyl-3-pyrrolidinyloxy)benzoic ~cid:
2-t~l-cyclohexyl-3-pyrrolidinyl)oxy]benzoic ~cid, 2~ ethyl-3-pyrrolidinyl)oxy~benzoic acid, 2-~(1-i~opropyl-3-pyrrolidinyl)oxy]benzoic acid, 2~ (4-chlorobenzyl)-3-pyrrolidinyl~oxyJbenzoic acid, 2-~1-(4-methylbenzyl)-3-~yrrolidinyl]oxy~benzoic acidJ
2-ttl-(3,5-dimethoxybenzyl)-3-pyrrolidinyl]oxy~benzoic acid, 2-~tl-ttrifluorom~thylb~nzyl)-3-pyrrolidinyl]oxy~
benzoic acid, and ~ ~ 3 ~ ~

2-t~1-(4-nitrobenzyl)-3-pyrro~idinylJoXy~benZoic acid, and there are o~tained:
~) 2-(2-chloroethyl)-4-cyclohexy~-2,3-dihydro-1,4-. benzoxa~epin-5(4H)-one, b) 2-(2-chloroethyl~-2J3-dihydro-4-ethyl-1,4-benzox-nzepin-5(4H)-one~
c) 2-(2-chloroethyl)-2,3-dihydro-4-i~opropyl-1,4-~enzoxazepin-5(4H)-one, d) 2-(2-chloroethyl)-4-(4-chlorobenzyl)-2,3-dihydro-1,4-b~nzoxazepin-5(4H)-one, e) 2-(2-chloroethyl)-2 ~-aihydro-4-( 4-methylbenzyl) -1,4-benzoxazepin-5(4H)-one, f) 2 (2-~hloroethyl)-2,3-dihydro-4-(3,5-dimethoxybenzyl)-1,4~benzoxazepin-5(4H)-one, g) 2-(2-chlor~ethyl)-2,3-dihydro-4~ trifluoromethyl-benzyl)-1,4-benzoxazepin-5( 4H)-one, h) 2-(2-ehloroethyl)-2, ~5-dihydro-4-(4-nitrobenzyl)-1,4-benzoxazepin-5(4H)~one.

Intenmediate 25 When in the procedure of Intermediate 4, equal molar ~mounts of the ~ollowing are ~ub~tituted for sodium 2-~(l-methyl-3-pyrrolidinyl)oxy~-3-pyridine carboxylate:
2-~ cyclohexyl-3-pyrrolidinyl)oxy~-3-pyridine carboxyl2te, 3~ 2~ -ethyl-3-pyrrolidinyl)oxy]-3-pyridine carboxylate, 2-~1-isopropyl-3-pyrrolidinyl)oxy~ -3-pyridine c~rboxylat e, 2-[~1-(4-chlorobenzyl)-3-pyrrolidinyl~oxy~-3-pyridine carboxylate, 2-~tl-(4-methylbenzyl)-3-pyrrolidinyl]oxy]-~ pyridine c~rboxylate, ~l9A-cIp-2 .

2~ (4-methoxybenzyl)-3-pyrrolidinyl~oxy] 3-pyridine c~rboxylate, 2-C[1-(5-trifluoromethylbenzyl)~ pyrrc)lidinyl]oxy]-3-pyridine carboxylate, and 2-[[1-(4-nitrobenzyl)-3-pyrrolidinyl]~xy]-3-pyridine carboxylate, there are obtained:

10a) 2-(2-chloroethyl)-4-cyclohexyl-2,3-dihydro-pyrido t~2-f~ 4]oxazepin-5(4~)-one hydrochloride, b) 2-(2-chloroethyl)-2,~-d~hydro-4-ethylpyrido~3,2-f~
~1,4] ox~zepin-5(4H)one hydrochloride, c) 2-(2-chloroethyl)-2,~-dihydro-4-isopr~pylpyrldo~3,2-f]
15~1,4]-oxazepin 5(4H)-one hydrochloride, d) 2-(2-chloroethyl);4-(4-chlorobenzyl)-2,3-dihydro-pyrido~3,2~ 1,4~-oxazepin-5(4H)-one hydrochloride, e) 2-(2-chloroethyl~-2,3-dihydro-4-~4-methylbenzyl) pyrido~3,2-f~ 4~-oxazepin-5(4H)-one hydrochloride, 20f) 2-t2-ehloroethyl)-2J3-dihydro-4-(4-methoxybenzyl) pyrido[~,2-f~1,4~-oxazepin-5(4H)-one hydrochloride, g) 2-(2-chloroethyl)-2,3-dihydro-4-(~-triflu~romethyl-benzyl)pyrido~,2-f]rl,4]-5(4H)-one hydrochloride,and h) 2-(2-chloroethyl)-2,3-dihydro-~-(4-nitrobenzyl)-25pyrido)t3,2-f~1,4~-oxazepin-5(4H)-oFie hydro-chloride.

Intermedi~te æ6 302-(2-Chloroethyl3-2,~-dihydro-4-methylpyridot3,2-f r lJ4l-thiazepin-5(4~)-one.
A mixtuxe of 80.75 9 (0.~4 mole) of 2-~(1-methyl-3-pyrrslidinyl)thio~-3-pyridinscarboxylic acid, 500 ml of chloro~or~, 200 g of c~rbon tetrachloride and 178 g (o.68 ~5 mole) of triphenylphosphine w~ stirred at re~lux ~or 2.5 hr.
The resulting ~olution Wa8 extr~cted with one 500 ml ~nd three 125 ml p~rtion~ of lN hydrochloric acid. The scid ~ -~ 419A-CIP-2 62 ~ L4~

extracts were combined and extracted with isopropyl ether.
The a~uesus layer was basified with s~dium hydroxide and extracted three times with chloroform. The combined chloro-form extract was dried over Rodium sulfate and concentrated.
A portion of the residue was chromatographed on the high pressure liquid chromatograph using a silica column and ethyl acetate. The compound obtained was crystallized from iRopropyl ether-isopropyl alc~hol, m.p. 97-100 C.
Analysis: Calculated for CllHl3NzOSCl: C,51.46, H,5.10;
N,10.91 Found : C,51.6~. H,5.12;
N,10.85 Intermediate 27 2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-fl A mixture of 4.3 g (00017 mole) ~f 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f]~1,4]thiazepin-5(4H~-one, 100 ml of toluene and 4.8 g (0.012 mole) of 2,4-bis~(4-methoxyphenyl)-1~3~2,4-dithiadiphosphetane-2,4-disulfide was refluxed for 3 hr and then extracted twice with dilute sodium hydroxide. Th~ organic layer was concentrated and the residu~ chromatographed on the high pressure liquid chromatograph u~ing a silica ~olumn and 50% ethyl acetate-50% hexane. The yield of title compound was 2 g, m.p.
1~0-162~.
Analysis: Calculated for CllRl3NzS2Cl: C,48.43; H,4.80;
N,10.27 Found : C,48.116; H,4.81;
N,10.51 Intermediate 28 2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f , _ ~1,4]oxazepin-5(4H)-one.
A solution of 78 g (0.5 mole) of 4-chloronicotinic a~id and 52 g (0.52 mole) of l-methylpyrrolidinol in 150 ml of dimethylformamide was added to a suspension of 44 g (1.1 mole) of 60% sodium hydride/mineral oil in 800 ml of dimethylformamide at a rate ~o as to maintain a ~emperature of 55-70 C. (preheated to 55C.). The re~ulting mixtur~ was heated to 60C. for 4 hr and filtered while hot. ~he filtrate was concentrated on the rotary evaporator (5 mm/steam - ` -bath). The re~idue W~6 ai~s~lved in 600 ml of water and extract~d with isopropyl ether. The p~ of the ~ueou~ layer wa~ adjusted to 6 with hydrochloric acid and the s~lution was concentrated on the rotary evaporator (5 mm/~team bath).
The r0sidue was ~u~pended ~n 800 ml of chloroform ~nd 188 g (1.1 mole) o~ triphenylphosphine added Pollowed by 250 ml ~f ca~bon tetrachloride. ~he mixture wa~ gently heated to 60C. whereupon the reaction became exothermic and an ice bath was used to mai~tain a temperature of 60-65C. for ~bout 20 minute The ice bath was removed and the mixture was heated to reflux ~or ~.5 hr ~nd cooled. The 301ution was extracted with 630 ml of water followed by two 200 ml portions o$ lN hydrochloric acid. The acid layer was made basic with ~odium hydroxide and extracted three times with chloroform. The chloroform was ~oncentrated ~nd the residue wa3 chrom~togr~phed by high pres~ure li~uid chrom~tography using ~ilica ~el and eluting with ethyl acetate. Yield of pr~duct wa~ 30 g (2~%~. ~he m~8~ spectr~ and ~MX are in agreement with the structur~ of the titl2 compound.
Inte 2-(2-Chloroeth ~ hy~r ~ rid~ fl~1,4 oxazepine-~ 4H) -th ione monoh~drochloride.
2-(2-Chloroethyl)-2, 3 -dihydro-4 -methylpyr i do ~ 3, 4 - f ]
~1,4]ox~zepin-5(4H)-one, 15 g ~o.o6 mole), was dissolved in 200 ml of dry toluene and 15 g (0.037 le~ of ~2,4-bis (4-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-di~ulfide wa~ added. The mixture wa~ refluxed for 2.5 hr and the toluene ~olution decanted~ The residue was partitioned between dilute ~oaium hydroxide ~nd chloroform. ~he chloro-form was dried ~nd concentrate~. The res~du~ was chroma-togr~phed on a high pre~sure li~uid chrom~tc-graph (Waters 500) using a ~ilica column and eluting with ethyl acetate. The ~raction containing material of molecul~r weight 257 w~s ~oncentrated. ~he re~idue ~n l~opropyl ~lco~ol was treated with hydrogen chlori~e a~ the re~ulting cry~tal~ were collected. Yield o~ hydxochloride ~21t w~s 0.1 g (o.6%), m.p. 168-171C.

64 ~ i3~

Analysis: Calculated for CllHl4~20SCl2: C,45.06; H,4.81;
N,9-55 Found : C,45.15; H,4.98 N,9.26 Intermediate ~0 2,3,4,5-Tetrahydro-4-methyl-5-oxopyrido[3,2-fl[19ll oxazepine-2-propanenitrile.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-~]
[1,4]oxazepin-5(4H)-one hydrochloride, 100 g (0.415 mole) was partitioned between dilute aqueous ~odium hydroxide

10 (200 ml) and chloroform (200 ml~. The organic layer was saved and the a~ueous layer extracted with chloroform (3 X 50 ml). The organic layer were combined, dried over sodium sulfate and concentrated by rotary evaporation (70 C., water aspirator). The residue, the free base of 15 the starting hydrochloride, 89 g (0.37 mole) was dissolved in 150 ml of toluene and to the solution wa~ added tetra-butyl ammonium bromide, 9 g (0.027 mole~; Saturated aaueous potassium cyanide (100 ml) was then add~d and the mixture stirred mechanically at refluxO After 2 hr, additional 20 tetrabutyl ammonium bromide, 3 g (0.009 mole) and saturated aqueous potassium cyanide ~20 ml) were added an~ the mixture ~tirred for 0.75 hr at reflux. ~he contents of the reaction vessel were extracted with ethyl acetate (3 X 50 ml). (Note:
chloroform ~hould be used instead). The organic layer dried over sodium 6ulfate and concentrated by rotary evaporation (70C., water aspirator) to 1 ~ the original volume. Upon cooling, crystallization ensued. The crystals were ~iltered and washed with several portions of ethyl acetate and i~opropyl ether. Thirty g (35%) of off-white crystals were collected, m.p. 104-105 C. A sample was recrystallized from ethyl acetate, m.p. 104-105 C.
Analysis: Calculated for C~2H13N302: C,62.33; H,5.67;
N,18.17 Found : C,62.06; ~,5.65 N,17.97 ~3~

I ermedlate 31 ? -~2-chloroethyl~-4-ethyl-2,3-dihY
Ll,4~ox~zepin-5( 4H) -one hydrochloride.
To a stirred suspension of sodium hydride mineral oil (81.45 g of 60% dispersion 2.036 mole) in dimethyl-~ulfoxide (500 ml) heated to 50C. was added dropwise a solution of 2-chloronicotinic acid (142 g, 0.905 mole) and N-ethyl-2-pyrrolidincl (99 g, o.86 mole) in dimethyl-sulfoxide (500 ml) at a rate to maintain 55-60c.
(occasional cooling was necessary). After the addition was complete, the mixture was stirred at 50-60c. for 1.5 hr and allowed to cool. The solid which precipitated was filtered, washed with ethyl acetate and dried.
The dry sodium salt (172.53 g, 0.62 mole) w2S
suspended in chloroform (1 liter)- Hydrogen chloride gas wa~
bubbled through the suspension until the pH meter read 5.76. Triphenylphosphine (365.5 g, 1~395 mole) and CCl4 ~365.5 g) were added and the mixture stirred at reflux.
After 45 minutesJ IR showed 95~ reartion. Additional triphenylphosphine (100 g, 0.38 mole) and CCl4 (100 g) were added and the solution ~tirred at raflux an additional 45 min. IR showed >99% reaction. After coolingJ the ~olution was extracted several times with dilut~ hydro-chloric acid (1.5 liter total) Ihe aqueous layer was then made ba~ic with concentrated sodium hydroxide colution and extracted into chloro~orm (3 x 250 ml). The organic layer was dried over sodium sulfate and concentrated by rotary evaporation (70 C, water aspirator). The residuel oil was dissolved in isopropyl alcohol (500 ml) and acidified with hydrogen chloride gas. Upon cooling, an oil was noted and the volume reduced to 1 ~ the original volume.
Upon cooling, 70 g (.241 mole, 28%) of pale brown crystals were collected, m.p. 153-155 c.
Analysis: Calculated for Cl2~leN202Cl2: c,49.50; H,5.53;
~,9.62 Found : C,49.64; ~,5.62;
~,9.32 Intermediate 32 2-(2-Chloroethyl)-4-ethyl-2,3-dihydropyridor3,2-f~
Ll,4~oxazepin-5(4H)-thio~e hydrochloride.
2-(2-chloroethyl)-4-ethyl-2,3-dihydropyrido~3,2-f]
~1,430xazepin-5(4H)-one hydrochloride, approximately 5 50 g, was partitioned between dilute aqueous sodium hydroxide (50 ml) and chloroform (50 ml). The organic layer was saved and the aqueous layer extracted with additional methylene chloride (2 x 50 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated by rotary evaporation (70C, water aspirator) yielding 39 g (0.153 mole) of the free base.
The free base thus obtained was dissolved in chloroform (1.2 1), and pho~phorus pe~tasulfide (33.9 g, 0.153 mole) was added while stirring. The resulting mixture was heated to reflux for 16 hr. After cooling, the reaction mixture was filtered, washed with dilute a~ueous sodium hydroxide (~ x 300 ml), dried over sodium sulfate and concentrated by rotary evaporation (70C, water aspirator) to a yellow viscous oil. The oil was taken up in isopropyl alcohol ~ 200 ml) and made acidic with hydrogen chloride gas. Upon cooling, 20 g (43%) of crystals were collected, m.p. 133-135C.
Analysis: calculated for C12HleN20SCl2: C,46.91, H,5.25;
N,9.12 Found : C,47.33; H,5.38;
N,9.10 Inter_ediate 33 7~Chloro-2-(2-chloroethY1)-2 3-dihydro-4-methylpyrido ~3~2-flrl~4]oxazepin-5(4H)~o-n-e.
A ~ample of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-pyrido~3,2-E~1,4~-oxazepin-5-(4H)-one hydrochloride (10 g, 136 mole) was dissolved in dimethylformamide (150 ml) and heated to reflux. Sulfuryl chloride (20 g, 0.148 mole) was then added dropwi-~e over a period of 40-50 minutes. The reaction was allowed to ~tir at reflux for 30 minutes following the addition of S02CL2. After cooling, the 419A-CIP-~

contents of the flask were partitioned between water (150 ml) and benzene (150 ml). The benzene layer was saved and the water lay~r extracted with an additional amount of benzene (2 X 50 ml). The benzene extracts were combined and washed with dilute aqueous potassium hydroxide (2 X 50 ml) ~ollowed by dilute aaueous hydrochloric acid (2 X 50 ml). The benzene layer was dried over sodium sulfate and concentrated by rotary evaporation (~70C., water aspirator) yielding 2.61 g of crude material. The crude material was recrystallized from isopropyl ether giving 1.25 g (12.6%) of off-white crystals, m.p. 78-79C.
Analysis: Calculated for CllHlzN202Cl2: CJ48.02; H,4.40;
NJ1O.18 Found : CJ48.07; H,4.53;
NJ1O.1O
Intermediate ~4 7-Chloro-?-(2-chloroethyl)-2,3-dihydro=4-methylpyrido r3 2-flrl~4loxazepine-5(4H)thione.
7-Chloro-2-~2-chloroethyl)-2,3-dihydro-4-methylpyrido ~,2-f]~1,4~oxazepine-5(4H)-one, 6.o g (0.022 mole) was ~spended in 200 ml of toluene. To this ~u pension was added 2,4-bis(4-methoxyphenyl)-19 3-dithia-2,4-diphosphetane-2,4-dilsulfide. The mixture wa~ heated to reflux with vigorous stirring for 2 hours. ~ecause the reaction was not complete, an additional amount (3.0 g) of 2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4 diphosphetane-2,4-disulfide was added and the mixture stirred at reflux for 2 hr and left standing for 56 hr at room temperature. The toluene layer was decan~ed and washed with 50 ml of dilute a~ueous sodium hydroxide and 50 ml of dilute hydrochloric acid. Toluene was removed by rotary evaporation (~80C., water aspirator).
The crude oil was recrystallized from isopropyl alcohol giving 3.5 g (54%) of pale yellow crystals, m.p. 125-127C.
Analysis: Calculated ~or CllHl2N2OSCl2: C,45.37; H,4.15;
~,9.62 Found : C,45.40; H,4.20;
~,9-71 - `~
4l9A-cIp-2 ~ ~ 3 Intermediate ~i~
2-(Chloromethyl)-4-cyclohexyl-2L3-dih~dropyrldor~?-f]
r 1~4loxaze~in-~4H)-one.
A 15 g (0.05 mole) sample of sodium 2-[(1-cyclohexyl-3-azetidinyl)oxy]-3-pyridine carboxylate obtained in Preparation 23 was suspended in 100 ml of chloroform and hydrogen chloride passed in until a pH of 5.8 remained steady. To the stirred mixture was added 18 9 of thionyl chloride. The resulting solution was stirred at room temperature for 3 hr. An l.R. spectrum showed a peak at 1770 cml which is characteristic of acid chloride.
Forty milliliters of triethylamine was added dropwise while cooling to about 25c. with an ice bath. The chloro-form solution was stirred an additional 0.5 hr and was extracted with water~ dried over sodium sulfate and concentrated. The residue was chromatographed on a 7 x 20 cm silica column using ethanol as the eluent. The desired material was the first to be removed from the column.
The ethanolic solution was concentrated and the residue crystallized onee from ethyl acetate-i~opropyl ether and once from isopropyl alcohol. Yield of title compound was 1 g (70 , m.p. 120-122C.
Analysis: Calculated for C1sH1~N202Cl: C,61.12; H,6.50, ~,9.50 Found : C,61.11; H,6.62;
N~9.32 Intermediate ~6 2-(2-chloroethyl)-2,3-dihydro-4-1phenylmethyl)pyrido r3,2-f~1,4~zepin-5(4H~one.
The title compound was prepared in crude form in the first part of Example 67.

419A-CIP-2 ~

6 3 2~3~

Intermediate ~1 2,3-Dihydro-2-rl,3-dihydro-1, ~-dioxo-2H-isoindc,1-2-yl) ethyl-4-methylpyrido~5,2-f~Ll,4~oxazepin-5~4H)-one.
To a s~luti~n of 4.92 g (0.02 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~3,2~f] -1,4-oxazepin-5-~4H)one in 35 ml of dimethylformamide was added 7.55 g (0.041 mole) of potassium phthalimide. The mixture was stirred for 5 hr at 100C. and left standing at room temperature overnight.
Dimethylformamide was removed by rotary evaporation (80 C.
vacuum pump). The residue was t~ken up in 100 ml of chloro-f~rm and washed with water (2 x ~0 ml) and 2M potassium hydroxide (2 x 3 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70 C.g water aspirator~. The 6.26 g of crude product was recrystallized from isopropyl alcohol to give 2.60 g (~6%) white cyrstalline powder, m.p. 146-47C.
Analysis: Calculated or Cl~Hl7~904: C,64.95; H~4.88; ~,11.95 Found : C,65.18; H,4.91; ~,12.09 Intermediate 38 2-r2-~2L7-Dih~dro-4-methyl-5~4H)-thioxopy~ oL32?-f ~1,4-oxazepin-2=yl)-ethyll-lH-isolndole-1,3t2H)-dione.
To a solution of 1.0 g (o.oo38 mole) of 2-(2-chloroethyl)-2,3-dihydro-4 methylpyrido~,2-f]-1,4-oxazepine-5(4H)-thione in 20 ml dimethylformamide was added 1.43 g (o.oo78 mole) of potassium phthal1mide. The mixture was heated to 100 C.
for 6 hr with stirring.
The dimethylformamide was removed by rotary evaporation (70, vacuum pump) and the residue taken up in chloroform (100 ml). The organic layer was washed with 2~ potassium hydroxide (2 x 30 ml), dried over anhydrous sodium sulfate, ~0 filtered, and concentrated by rotary evaporation (~70C., water aspirator). The crude oil (1.2 g) was recrystallized ~rom isopropyl ~lcohol giving 0.95 g (680 of pale white crystals, m.p. 172-73C.
Analysis: Calcul~ted for Cl~Hl7~303S: C,62.11; ~,4i66, ~5 Found : C,61.85; ~,4.70;
~,11.53 .J

~ ~ ~ 3 Int-r~ L ~
?,3,4,5-Tetrahydro-4-methyl-5-thioxopyrido~,2-f~1,4~-oxazepine-2 pro~anenitrile.
To a solution of 11.0 g (0.04 mole) of 2)~,4,5-tetrahydr~-4-methyl-5-ox~pyrido~3,2-f]~1,4~-oxazepine-2-propanenitrile in 175 ml toluene was added 10.5 g (o.026 mole) of 2,4-bis (4-methoxypher~yl)-1,3-dithia-2,4-diphosphetane-2,4-di~ulfideD
The reaction mixture was heated to reflux for 2 hr with vigorous mechanical stirring. Another 3.0 g (0.007 mole) of 2,4 bis (4-methoxyphenyl)-1,3-dithia-2,4-dipho~phetane 2,4-disul~ide was added and heating continued for 1 hr additional. The reaction mixture was allowed to cool and stand overnight at room temperature. Toluene was removed by rotary evaporation (90C., water aspira~or) and thé residue taXen up in 200 ml chloroform. This was washed with 2 x 50 ml 2M aque~us potassium hydroxide and concentrated by rotary evaporator (90C., water aspirator~. Crystallization en~ued upon cooling. Recrystallization from isopropyl alcohol afforded 1.60 g (13.8%) product, m.p. 155-56 C.
Analysis: Calculated ~or Cl2Hl~N30S: C,58.28; H,5 ~0.
Found : C, 58.00; H, 5 .26;
~I J 17 . 1 Intermediate 40 2-~2-Chloro-l-methYleth~l ~ .3-dihydro-4-met~ylpyrido r ~ ,2-f ~r 1J 4~-oxazepin-~ 4H)-one h~drochloride To a æuQpension of 59.6 g (60ST~) in oil, 1.49 mole) of sodium hydride in 400 ml of tetrahydrofuran heated to reflux wa~ added a solution of 110 g (0.71 mole) of 2-chloro-nicotinic acid ~nd 81.3 g (0.71 mole) of 1,4-dimethyl-3-pyrrolidinol in 400 ml o tetrahydro~uran at a rate such 30 that good reflux was maintained (20-35 minutes). Heating at re~lux was continued for 2 hr subsequent to the completion o~ the ~ddition. Because mas~ spectra showed 30~ ~tarting material at thi~ point, 25.0 g (o.63 mole) additional sodium hydride was added and reflux continued ~or 4 hr. The ~5 reaction mixture wa~ left ~tanding overnight.

~ 2 ~

The mixture was ouenohed with isopropyl alcohol and filtration attempted. ~owever, when filtration failed, the solvent was stripped off by rotary evaporation.
This crude ~alt was suspended in 1 liter of chloroform and hydrogen ch~oride gas was bubbled in until a pH of 6 was reached. To this suspension was added 372 g (1.42 mole) of triphenylphosphine and 372 g carbon tetrachloride and the ~ntire mixture heated at reflux for 1.5 hr. However, reaction was not complete as evidenced by I. R. An additional 100 g (0.38 mole) of triphenyl phosphine and 100 g of carbon tetrachloride was added and reflux continued overnight.
After cooling the reaction, 100 g of triethylamine was added.
The reaction mixture was extracted with 11 x 200 ml of dil aqueous hydrochloric acid. The hydrochloric acid extxacts were made basic with conc. sodium hydroxide and xtracted into a total of 1 liter of chloroform. The chloroform was removed by rotary evaporation (70 C; ~ mm) and the residue taken up in 300 ml toluene.
The toluene was extracted with 4 x 125 ml of dil aqueous hydrochloric acid. The hydrochloric acid ex~ract~
were combined and washed with 4 x 200 ml of methylene chloride. The hydrochloric acid layer was basified with conc. ~odium hydroxide and extracted with methylene chl~ride.
The organlc extracts were combined, dried over sodium sulfate, filtered and concentrated by rotary evaporation.
rrhe residue was taken up in isopropyl alcohol and treated with hydrogen chloride gas. Approximately 34 g (16~) of white crystals were collected. Recrystallization in isopropyl alcohol gave an analytical sample, m.p. 178-81 C.
Analysis: Calculated for ClzHleM~02Cl2: C, 49.50; H,5.54;
N,9.62 Found C, 49.46; H,5.54;
N J 9 . 50 3 ~

Intermediate 41 2-(2-Chl~roethyl)-2,3-dihydro-2,4-dimethylpyridoL3,2-fl-1~4-oxazepin-S(4H~-one hydrochloride.
To a suspension of 60 g (60~ in oil, 1.5 mole) of sodium hydride in 400 ml of tetrahydrofuran heated to reflux was added a solution of 110 9 (0.70 mole) of 2-chloronicotinic acid and 80 g (0.70 mole) of 1,3-dimethyl-3-pyrrolidinol s~
as to maintain good reflux. Heating at reflu~ was continued overnight. The mass spectra showed very little product at this point; therefore, 400 ml of dimethylformamide was added and heating at 77C. was continued overnight. Approximately 10% of the desired product was then observed by mass spectra.
The tetrahydrofuran was evaporated by passing nitrogen gas over the reaction mixture while at the same time being replaced with dimethylformamide. The temperature was concomitantly increased to 100C. The mixture was stirred overnight at 100 C. After cooling, no salt precipitated out; therefore, dimethylformamide was removed by ro~ary evaporation (90C.; 5 mm). Approximately 250 g of crude salt was collected.
Into a suspension of 2~0 g (~o.88 mole) of this crude salt in 1 liter of chloroform was bubbled hydrogen chloride gas to pH 6. To this suspension was added 46~ g (1.77 mole) of triphenyl phosphine and 463 g of carbon tetrachloride.
The mixture was then heated to reflux. After 8 minutes a vigorous exotherm ensued which subsided in 30 minutes.
Reflux was c~ntinued for 2.5 hr. According to infrared analysis, the reaction was near completion. Approximately 40 ml of triethylamine was added to drive the reaction to completion. The mixture was left standing overnight at room temperature.
The reaction mixture was extracted with 700 ml dil. ag.
hydrGchloric acid. The hydrochloric acid extracts were combined and washed with 4 x 100 ml of chloroform. The combined a~ueous hydrochloric acid extracts were then made basic with conc. sodium hydroxide and extracted with 5 x 200 ml of methylene chloride. The organic extracts were combined, dried over anhydrou~ sodium sulfate, filtered and concentrated by rotary evaporation ( 70~C .; ~0 mm). The J

residue was taken up in 600 ml of toluene and treated with activated charcoal 4 times. The toluene was then removed by rotary evaporation and the residue treated with hydrogen chloride in isopropyl alcohol which afforded 53 g (210 .
Recrystallization from isopropyl alcohol afforded an analytically pure sample, m.p. 155-158C.).
Analysis: Calculated for Cl2Hl8N202Cl2: C,49.50; ~,5.54;
N,9.62 Found : C,49.49, H,5.61 N,9-75 10Intermediate 42 2-(2-Chloroethyl)-2 7-dihy~ro-2.4-dimethvlpyridor3L2-f~
1,4-oxazepine-5(4H~-thione.
To a suspension of 4.6 g (0.04 mole) of p~osphorus pentasulfide in 50 ml of acetonitrile was added, all at 15once, a solution of 20 g (0.079 mole) of 2-(2-chloroethyl)-2,3-dihydro-2,4-dimethylpyrido~3,2-f]-1,4~oxazepin-5t4H)-one in 50 ml of acetonitrile. The mixture was heated to reflux for 4 hr with stirring, at which time the mass spectra showed no starting material. The reaction was left standing overnight at room temperature.
To the reaction mixture was added 100 ml of toluene followed by stirring for 15 minutes. Some tar-like material collected on the sides of the reaction vessel. The solution was filtered with much difficulty. The filtrate was saved and washed cautiously with 3 x 50 ml of saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, treated with activated charcoal, filtered, dried again over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation (80C.; 30 mm). The crude oil (9.2 g) was crystallized from isopropyl alcohol, giving 6.o g (28%) of yellow crystals, m.p. 119-121C.
Analysis: Calculated for Cl2Hl5~20SCl: C,53.23; H,5.58, N.10.35 Found : C,53.05; H,5.60, N,10.34 J

3~ 5 Intermediate 4~
2-(2 chloropropyl)-2J~-dihydro-4-methylpyrido[~2-f]
1,4-oxazepin-5(4H~-one hydrochloride.
-To a suspension of 36.1 g of 60% sodium hydride in oil (0.90 mole) in ~00 ml of tetrahydrofuran heated to reflux and under a nitrogen blanket was added a solution of 68.~ g(0.43 mole) o~ 2-chloronicotinic acid and 50 g (0.4~ mole) of 1,2-dimethyl-4-pyrrolidinol in ~00 ml of tetrahydrofuran at a rate such that good reflux was maintained (20 min).
Subsequent to this addition, heating at reflux was maintained for 2.5 hr at which time the reaction appeared to be complete (by mass spec.). The crude sodium salt was filtered and washed with ethyl acetate affording 135 g of the crude sodium salt.
To a suspension of 115 g (~0.44 mole) of the above sodium salt in 650 ml of chloroform was added hydrogen chloride to reach a pH of 6. To this mixture was added 2~1.8 g (o.88 mole) of triphenylp~osphine and 231.8 g of carbon tetrachloride and the entire reaction mixture heated to re~lux for 3 hr. After cooling, the reaction mixture was extracted wi~h 4 x 250 ml of di hydrochloric acid.
The aqueous layer was washed with 4 x 125 ml of chloroform and made basic with concentrated sodium hydroxide. The a~ueous layer was then extracted with 3 x 250 ml of chloroform. ThP organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evapoxation. To the residue was added 800 ml of toluene and th`e resulting solution dec410rized 3 times with activated charcoal. The solvent was remov~d by rotary evaporation (90C., ~0 mm). The residue was taken up in 300 ml of isopropyl alcohol and the solution was saturated with hydrogen chloride, ~eeded, and left standing overnight at room temperature. Approximately 30 g (~23%) of ~alt was colle~ted. An analytical sample was prepared by recrystal-lizating the salt 3 times from isopropyl alcohol, m.p.
143-49C.
Analysis: calculated ~or C~2Hl~2o2cl2: C,49.50; H,5.54 N,9.62 Found : C,49.85; H,5.62 ~,9.84 419A-cIP-?

~S3SL~

Intermediate 411 2-(2-Chloropropyl)-2,3-dihydro-3-methylpyrido~3,2-f~-1,4-oxazepine-5(4H)-thione.
-To a suspension of 4.90 g (0.022 mo~e) of phosphorus pentasulfide in 30 ml of acetonitrile was added a solution 5 of 10 9 (0.039 mole) of 2-(2-chloropropyl)-2,~-dihydro-4-methylpyrido~,2-f]-1,4-oxazepin-5(4H)-one in 25 ml of acetonitrile. The mixture was heated to reflux, with stirring, for 5.5 hours and left standing at room temperature overnight. To the reaction mixture was added 50 ml of toluene, followed by stirring for a few minutes. The mixture was filtered and the residue washed with 25 ml of toluene/
acetonitrile. The filtrate was washed cautiously with 3 x 75 ml of saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, treated with activated charcoal, filtered and ~oncentrated by rotary evaporation (90~C.; 30 mm). The crude syrup (10.0 g) was crystallized from isopropyl ether/isopropyl alcohol, giving 5 g of yellow csystalq, m.p. 95-97C. A second crop was collected, bringin~ the total to 6 g (57O .
Analysis: Calculated for Cl2Hl5~20SCl: C,53.28; H~5.58, N,10.35 Found : C,53.13; H,5.58;

Intermediate 4~
2-(2-Chloro-l-methylethyl)-2,3-dihydro-4-methylpyrido L3,2-f~ l-oxazepine-5(4H)-thione hydrochloride.
To a suspension of 5.35 g (o.024 mole) of phosphorus pentasulfide in 25 ml of acetonitrile was added a solution of 10.9 g (0.043 mole) of 2-(2-chloro-1-methylethyl)-2 r3~
dihydro-ll-methylpyrido~3,2-f~-1,4-oxazepin-5(4H)-one in 25 ml of acetonitrile. The mixture was heated to reflux for 2.75 hr and left standing at room temperature overnight.
To the cooled reaction mixture was added 50 ml of toluene, followed by filtration. The residue was washed with 45 ml o~ 3/1, V ~ toluene/acetonitrile. The filtrate wa~ washed cautiously with 3 x 75 ml of saturated sodium bicarbonate, dried over anhydrous ~odium ~ulfate, filtered, treated with activated chaxcoal, filtered,and concentrated by rotary ~ 419A-CIP-2 76 ~S3~4~

evaporation. The residue was treated with hydrogen chloride in isopropyl alcohol/isopropyl ether which yielded one crop of 4.5 g of yellow crystals, m.p. 148-51 C. [(Note: a second crop of 1.5 g was collected, bringing the total yield to 5 6.o g (45.4%)~.
Analysis: Calculated for Cl2Hl~NzOSClz: C,46.91; H,5.25, N,9.12 Found : C,48.86; H,5.34;
N,9.o5 Int~rmediate 46 2-~2-chloroethvl)-2 3-dihYdro-4-methy~-l 5 4-oxazePino r 6~7-b~-quinolin-5(4Hl-one.
To 21.3 ml (0.15 mole) of diisopropylamine in 300 ml of tetrahydrofuran at -70C. waq added dropwise, at a rate to keep the temperature between -70 and -60C.~ 61.1 ml of 15 2.7 M n-butyllithium (0.16 mole). The temperature was maintained at 70C. ~ 3C. for 20 minutesO A solution of 2-chloroquinoline in 60 ml of tetrahydrofuran was added dropwise at a rate such that temp~rature remained between -70 and -60C. After 20 minutes, the darkened reaction solution was poured onto a large excess of dry ice. The solvent was evaporated with a stream of air.
The residue was taken up in ~00 ml of water, made basic with dilute aqueous ~odium hydroxide and washed with 3 x 50 ml of isopropyl ether. The aqueous phase was filtered and treated with dilute hydrochloric acid to ~pH 4-5, ~t which time a copious precipitate formed. The precipitate was collected and the filtrate reacidified yielding more precipitate. The precipitates were combined and washed with water, isopropyl alcohol, and iaopropyl ether. Approximately 30 15.4 g (61.5%) of off-white crystals were collected.
To a suspension of 4.0 9 of 60% sodium hydrlde in oil (0.10 mole) in 100 ml tetrahydrofuran heated to reflux was added a solution of 5.5 9 (o.o48 mole) of N-methyl-3-pyrrolidinol and lo g (o.o48 mole) of the above prepared 2-chloro-3-~uinolinecarboxylic and in 50 ml of tetrahydrofuran at such rate as to maintain good reflux. Reflux was maintained ~or 1.5 hr and the reaction mixture cooled. The solvent was removed by rotary evapor~tion yielding 26 g crude pr~duct.
The entire crude pr~duct from above was suspended in 150 ml chl~roform and hydrogen chloride bubbled in until pH
of 5.76 was reached (note: after hydrogen chloride addition ceased, the pH continued to lower to 1.7). To this suspension was added 25.0 9 (o.og6 mole) of triphenylphosphine and 25 g of carbon tetrachloride. After 45 min, an additional 10 g (0.0~ mole) of triphenylphosphine and 10 g of carb~n tetrachloride was added. After 30 minutes, the heat was removed and the reaction driven to completion ~y dropwise addition of 20 ml of triethylamine.
The reaction mixture was extracted with 3 x 50 ml of ~ hydrochloric acid. The agueous extracts were combined, washed with 2 x so ml chloroform, made basic with concen-15 trated sodium hydroxide and extracted with 3 x 50 ml o~chloroform. The organi~ extracts were combined and concen-trated by rotary evaporation~ The syrupy residue was taken up in 100 ml of toluene and treated with activated charcoal.
The toluene was removed by rotary evaporation and the syrupy 2~ residNe crystallized from i30propyl alcohol, giving 1.5 g (11%) of white crystals, m.p. 133-134C.
Analysis: calculated for Cl5Hl5N202Cl: C,61.97; H,5.20 N,9.63 Found : C,61.73, H,5.18 N , 9 . 54 Intermedia ~
252-~2-Chloroethyl)-2,~ dihydro-4-methvl-1 4-oxazepino ~6,7-b1quinoline-~(4H)-thione.
To 3.0 g (0.0~ mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino~6,7-b]-quinolin-5(4H)-one in 30 ml of acetonitrile was added 1.3 g (o.oo6 mole) of phosphorus penta~ulfide. The mixture was stirred vigorously at reflux ~or 2 hr. After cooling, the reaction mixture was diluted with 60 ml of toluene and fil'ered. Tne residue on the filter papex was washed with 50 ml of additional toluene/
ac0tonitrile, ~/1, V ~ . The filtrate was washed with ~5 ~ x 50 ml 3a~urated codium carbonate (caution: gas evolved!, dried over anhy~rous sodium sulate, filtered, treated with activated charcoal, ~iltered again and concentrated by rotary evaporation (90 C., 30 mm). The residual syrup was ~ --'419A-CIP-2 cry~tallized from isopropyl alcohol, yielding 1.6 g (52 0 of yellow crystals, m.p. 1l4-ll6oc.
Analysis: calculated for Cl5Hls~20ClS: C,58.72; ~1,4.93;
~,9-13 Found : C,38.38; H,4.92;
N, 9 .07 Interm~dlat~ 8 2-(2-Chloroethyl)-2,~-dihYdro-4-methyl-~-(trifluoro-methYlLl~4-oxazepinor6l7-clqllininolin-5(4H)-one hYdro-chloride .
To a suspension o~ 3.16 g (60~ in oil, o~o8 mole) of sodium hydride in 250 ml o~ tetrahydrofuran under dry nitrogen atmosphere heated to reflux was added a solution of 10,42 g (o.o38 mole) of 4-chloro-7-(trifluoromethyl)-3-quinolinecarboxylic acid and 3.81 g (o~o~B mole) of N-methyl-3-pyrrolidinol in 50 ml of tetrahydrofuran at such a rate as ~o maintain good reflux, ~eating at reflux was continued for 3 hr. The solvsnt was removed by rotary evaporation (80 C., 30 mm), and the crude sodium salt (12 g) was dried overniqht.
The entire amount of crude odium ~alt was suqpended in 250 ml of methylene chloride. Hydrogen chloride was added to a pH of 2. To this suspension was added 19.4 g (0.074 mole) of triphenyl phosphine and 19.4 g of carbon tetrachloride. The extire mixture was heated to reflux for 3 hrs. IR indicated presence of acid chloride; therefore, the reaction was driven to completion by the addition of 15 ml of triethylamine. After cooling, the reaction mixture was extracted with 2 x 75 ml of 3~ hydrochloric acid. The acid waehings were combined and washed with 75 ml of methylene chloride. The water layer was made basic (after cooling with ice) and extracted with 3 x 75 ml methylene chloride. The methylene chloride was removed by rotary evaporation and the residue taken up in 100 ml of toluene.
The solution was treated with activated charcoal, filtered, ~nd concentrated by rotary evaporation (90C., ~0 mm~. The residue was dissolved in isopropyl alcohol and acidified with ethereal hydrogen chloride. Appruximately 1.1 g (7.3~) of white needles were collected, m.p. 172-174 C.

~%~i3~

Analysis: Calculated for Cl~Hl5N2O2Cl2F3: C,48.6~; ~,3.83:
N,7.09 Found : C,48.78, H,3.84;
N,7.04 Intermediate 4~
2-~2-chlorGethyL )-2,~-dihydro-4-methyl-~-(trifluoro-methY~ 4-oxazepino~6~7-c]quinoline-r~(4H)-t-hione.
~o a suspension of 0.85 g (.~04 mole) of phosphorus :-. .. . . .. . .
p~ntasulfide in 25 ml of acetonitrile was added to a solution of 2.3 g (o.0064 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-9-(trifluoromethyl)-1,4-oxazepino~6,7-c]guinolin-5(4H)-one and the mixture heated to reflux. TLC in ethyl acetate showed only 50% conversion; therefore, 0.5 g (0.0022 mole) of phosphoruspentasulfide was added. After an additional 2 hr, no change was seen in tarting material/
product. He~t was removed and the reaction mixture left standing overnight. The mixture was diluted with 75 ml of toluene and washed cautiously (gas evolved) with 3 x 50 ml of saturated sodium bicarbonate. The solvent was removed by rotary evaporation and the residue combined with a previous run of the same material. The combined products were purified by column chromatography over silica gel eluting with ethyl acetate. The solvent was removed from the fractions containing the product givin~ 0.9 g of yellow oil. The oil was recrystallized from isopropyl ether giving 0.55 g of yellow crystals, m-p. 135-37C
~nalysis: Calculated for Cl~Hl~N20SF3Cl: C,51.27; EI,3.77;
~,7.1~7 Found : C,51.41; H,3.8~;
N,7.42 Intermediate ~0 2-5hloromethYl-1l2~ 4-tetrah~dro-l-methyl-4-(l-methyl-eth~l)-5H-1,4-benzodiazepin-~-one.
To a ~tirring solution of 266 ml (o.64 mol0) of 2.4 m butyllithium solution in hexane, was filowly added 117.5 g (0.58 mole) of N-methyl-N-phenyl-l-(l-methylethyl)-3-azetidineamine. The temper~ture of the mixture rose to 55 C. which was then ~llow~d to reflux for 5.5 hours.
When cooled, the solution was poured slowly with vigorous ~ ~ 3 ~ ~ 419A-CIP-2 stirring onto a slurry of ~ry ice in hexane and allowed to stand overnight. The residue was dissolved in chl~roform and 117.0 g (1.16 mole) of phosphorous oxychloride was added dropwise while ~tirring. The solution was refluxed for two hours. Upon cooling, the solution was washed, ~irst with a dilute hydrochloric acid solutionJ then with a dilute sodium hydroxide solution. The hexane layer was dried over anhydrous sodium sulfate, filtered, and concentrated ln vacuo.
The residue was dissolved in hot isopropyl ether. The crystals obtained on cooling were recrystallized from the same solvent. The white solid weighed 45.0 g (29%). The solid was recrystallized twice more to give an analytical sample, m.p. 90-92C.
Analysis: Calculated ~or Cl4H~CllNzO: c,63.o3; H,7.18;
N,10.50 Found : C,62.59; H,7.09;
N,10.40 Intermediate ~1 2-(2-chloroethvl)-4-ethyl-1-methyl-112l7?4-tetrahydro-~H-1,4-benzodiazepin-~-one.
To 206 g (1 mole) of 1-ethyl-3-methylanilinopyrrolidine was added 660 ml (1.05 moles) of 14.98% butyllithium in hexane and the solution refluxed for 2 hours and poured on solid carbon dioxide. The carbon dioxide hexane mixture was allowed to evaporate overnight, leaving a dry yellow solid.
The solid was dissolved in chloroform. To this solution was added dropwise with stirring 1 mole of phosphorous tri-chloride. The temperature rose to xeflux during addition and remained there throughout most of the addition. When the addition was complete, the mixture was stirred one hour and watex was added cautiously. The resulting mixture was ma~e basic with sodium hydroxide. The chloroform layer was separated, dried over nnhydrous sodium sulfate and concen-trated. The residue WaR crystallized from isopropyl ether to yield 112 9 (42S~), m.p. 75-79 C. A 25 g sample was recrystallized from isopropyl ether to give 18 g of product, m.p. 78-80~c.
Analysis: Calculated for Cl4Hl~NzOlCl: c,63.o3: H,7.18;
~ , 10 . 50 Found : C,6~.27; H,7.22;

3~L~5 Intermediate 52 6-Chloro-2-(2-chloroethYl)-2~-dihydro-4-methylpyrido ~4,3-f~-1,4-oxazePin-~(4~-one.
To a suspension of 2.19 (60% in oil, 0.052 mole) of sodium hydride in 125 ml of dimethylformamide heated to 60 C.
under a nitrogen gas blanket was added a solution of 2.65 g (o.026 mole) of N-methyl-3-pyrrolidinol and 5.0 g (o.026 mole) of 3,5-dichloropyridine-4-carboxylic acid in 40 ml of dimethylformamide dropwise at such a rate as to maintain 60C. Subse~uent to this addition, the mixture was heated to 75C. for 3 hr. The solvent was then removed by rotary evaporation (60C., 5 mm). The entire solid residue was suspended in 150 ml methylene chloride and hydrogen chloride added until a pH of 3 was reached. To the resulting mixture was added 15 g (0.057 mole) of triphenylphosphine and 15 g carbon tetrachloride and the entire mixture heated to reflux.
After 1 hr, 7.5 g (0.029 mole) of triphenylphosphine and 7.5 g carbon tetrachloride were added, followPd by the same increments 1 hr later. The reaction was driven to completion by adding 20 ml of txiethyla~ine. The reaction mixture was washed with 6 x 50 ml of 3N hydrochloric acid, drie~ o~er sodium sulfate, filtered and concentrated by rotary evaporation. ~o the residue was added ethyl acetate, which caused much tarry material to fall out of solution, leaving the desired product and triphenylphosphine oxide in solution.
The mixture was chromatographe~ by column chromatoyraphy using silica gel as the ~tationary phase and ethyl acetate as eluent. Similar fractions were combined and ethyl acetate removed by rotary evaporation, yielding o.6 g (7%), of white cry~tals, m.p. 1~4-38C.
Analy~is: calculated for CllHl2W202Cl~: C,48.02; H,4.40 ~ ,10.18 Found : C,47.89; Hl4.38;
N,10.12 ~S3~L~5 Intermediate ~
2-( ? -Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino t7,6-f~isoquinolin-5(4H)-one.
Following the procedure of Intermediate 8, 5-~ methyl-3-pyrrolidinyl)oxy~-6-isoquinolinecarboxamide iE converted to the title compound.
Intermediate ~
2-(2-ChloroethYl)-2~3-dihydro-4-methyl-1,4-oxazepino r 7.6-flisoquinoline-5(4H)-thione.
Following the procedure of Intermediate 47, 2-(2-10 chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[7J6-f]
isoquinoline-5(4H)-one is sulfurized to give the title compound.
Intermediate ~
2~ 2-Chloroethyl)-2,~-dihydro-4-methyl-1,4-oxa~ino ~6 ! ?-q lisoquinolin~(4H)-one.
Following the procedure of Intermediate 8, 7-~
methyl-3-pyrrolidinyl)oxy]-6-isoauinolinecarboxamide is converted to the title compound.
Intermediate ~6 2-(2-Chloroethyl)-2~3-dihydro-4-meth~l-1 4-oxazepino ~6L~ isoguinoline-5(4H)-thione.
Following the procedure of Intermediate 47~ 2-(2-chloro-ethyl)-2,~-dihydro-4-methyl-1,4-oxazepino~6,7-g~isoauinolin-5(4H)-one is sulfurized to give the title compound.
Intermediate ~7 2-(2-ChloroethYl)-2.~-dih~dro-4,7-dimethyl-1,4-oxazepino r6~7-h~quin-ol~(4H)-one .
Following the procedure of Intermediate 8, 5-methyl-8-~1-methyl-~-pyrrolidinyl)vxy]-7-quinolinecarboxamide is converted to the title compound.
Intermediate S8 2-(2-Chloroethyl)-2 ~-dihYdro-4,7-dimethyl-l,4-oxaze~ino ~6,7-hlquinoline-5(4H)-thione.
Pollowing the procedure of Intermediate 47, 2-(2-chloro-35 ethyl)-2,3-dihydro-4,7-dimethyl-1,4-oxazepino~6,7-h~auinoline-5(4H)-one i~ ~ulfurized to give the title compound.

~~ J 4l9A-cIp-2 ~ ~ ~ 3 Intermediate 5~
2-(2-Chloroethyl)-2,~-dihydro-4.10-dimethyl-1~4-oxazepino[6 7-h~quinolin-~4H)-one.
Following the ~rocedure of Intermediate 8, 2-methyl-8[(1-methyl-3- pyrrolidinyl)oxy~-7-quinolinecarboxamide is ~onverted to the title compound.
Intermediate 60 ?-(2-Chioroethyl)-2.3-dihYdro-4,10-dimethyl-1,4-oxzaepino~6,7-hlquinoli.ne(5-4H)-thione.
Following the procedure of Intermediate 47, 2-(2-chloro-ethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxazepino~6~7-h]
quinoline-5(4H)-one is sulfurized to give the title compound.
Intermediate 61 2 -(? -chloroethyl)-3.4-dihvdro-2-meth~l 1 ~ -oxazepino r6,7-f1qUinolin-1(2H)-one.
Following the procedure of Intermediate 8, 6-~
methyl-3-pyrrolidinyl)-oxy~-5-quinolinecarboxamide is converted to the title compound.
Intermediate 62 4-~2-chloroethYl~-~ 4-dihydro-?-methYlrl,4-oxaze~ino ~6,7-flquinoline-1(2H)-thione.
Following the procedure of Intermediate 47~ 2-(2-chloroethyl)-3,4-dihydro-2-methyl~1,4]-oxazepino~6,7-f~
quinolin-1(2}I)one is sulfurized to give the title compound.
Intermediate 6~
2-(2-Chloroethyl)-2,3-dihydro-4-methyl-1l4-oxazepino ~6,7-hl~uinolin-5(4H~-one.
Following the procedure of Intermediate 8, 8-~(1-methyl-3-pyrrolidinyl)oxy~-7-quinolinecarboxamide is converted to the title compound.
Intermediate 64 ? -( 2-ChloroethYl)-2,~-dihydro-4-methyl 1,4-oxazepino ~6?7-h~guinollne-5(4H)-thione.
Following the procedure o~ Intermediate 47, 2-(2-chloro-ethyl)-2~3-dihydro-4-methyl-l~4-oxazepino~6J7-h]quinolin 5(4H)-one iB sulfurized to give the title compound.

~4 ~ ~53~D~5 Table 1 ~4 Rs ,...... , ~E ~ (CH)n-X

( Y ) ~` ~
L R

Inter-mea iD t ~ L R R~ E X ~(CH)n~ S31t 1 benz O -CH~ ~ O Cl ~ CH2 Z~
2 benz O -C~2-CoH~ H O Cl ~Hb 2-3 nDphth~2,3-f~ 0 ~CHa ~ Cl ~ CH2 2 -4 Pyr~dt3~2-f] 0 -CH9 H O Cl _ CH2~2- HCl B-cl-benz o -CH3 ~ O Cl _ cH2 ¦2 - ~
6 7-~r-benz 0 -CH9 .~ O Cl ~ CHz 2-7 7-C1-benz 0 -CH9 ~ O Cl ~ CUk Z~
8 n~phth~2~l-e~ O -C89 ~ O Cl C~2¦2 9 7-OC89-ben~ 0 -CH9 ~ O Cl _ CH~ 2-~enz S -CH9 ~ O Cl CH 2- -

11 pyrido[3,2-fJ S -CH9 H O Cl _ CH2 2-

12 n~phth[2,~-f~ S -CH3 ~ Cl ~ CH2 2-

13 8-Cl-benz S -CH3 ~ O Cl CH4 2-

14 7-Lr-benz S -CH~ H O Cl _ CHz 2- -1~ nnphth~2,1-f~ S -CH9 ~ Cl _ C~z 2 1~ pyrido[4 3-f~ 0 -CH3 ~ Cl CH2 Z~ ~Cl 17 pyrido~3 4-f~ 0 -CH~ ~ Cl _ CH2 2- HCl lB pyrido~2,3-f~ 0 -CH3 H O Cl ~ CH2 2- HCl 19 7 C1-benz S -C~3 H O Cl _ CH4 ~2-7,9-diiodo-benz 0 -CH3 ~ Cl _ CH4)2-21 pyridor~,2-f~ S -CH3 H O Cl _ H~- HCl 22 pyrido~4,3-f~ S -C~ H O Cl _ CH2 )2 -23 7~0CH~-bonz S -CH3 ~ O Cl _ CH2 2- ~
24a benz O -C~H,~ H O Cl ~ CH2 2- ~
b b~nz O ~C2Hs ~ O Cl _ CH2 z-c benz O -CH(CH~)z ~ O Cl _ CH2 2-d benz 0 4-Cl-CoH4~CH2~ ~ Cl _ CHz z-benz 0 4-CH -C~H4-CH~- ~ O Cl ~ CHz ~~ ~
f) b~nz 0 3,5-~OCH3)2- ~ O Cl _ CHz 2-CoB -CH2-g) behz O 3-CF~-C~H~-CH~- H O Cl -(C~2)2-h~ benz 0 4-~o~-C~-C~2- ~ O Cl -(CH2)2-~5~ pyrido~3,2-~ 0 -c~Hll H O Cl _ CH2~- HCl b pyridot3,2-~ 0 -C2~5 8 Cl _ CH2 z- HCL
c pyridot3,2-~ 0 -CH(CH~)2 ~ Cl _ CH2 2- HCl d pyrido[~J2-f~ 0 4-Cl-C~H~-C~2- ~ O Cl - CH2 z- BCl e pyrido[~,2-f~ 0 4-CH -C~H4-CH2- ~ O Cl _ CH2 2- HCl f pyrido[~2-~ 0 3,5-~OCH~)2- ~ Cl -~CHb 2- HCl CoH -CH2-g) pyrido~3,2-f~ 0 ~~CF9~CaH~~C~2~ ~ Sl -(CH2~z- HCl h3 py~ido[3,2-f] 0 4-~o~caH~ C~b- ~ o cl -~ci 2 )2 - HCl 26 pyri~o~3,2 i~ O -C~a ~ S Cl -~C~2~
27 py~i~ot3~2-f~ S -CHa S Cl -~CH2)2-( cont . ) 419~-CIP-2 Table 1 ~ cont . ) Inecr- RS
mediat~ ~
No. A(Y?Q? ~ R R4 E X ~(CH)n- salt 28 pyrido~3,4-f~ 0 -CH3 H O Cl _ CHz)2 29 pyrid5t3~4~f] 5 -CH3 H O Cl _ CH2)2- HCl pyrido~3,2-f~ 0 -CH3 H O -CN _ CEz)z-31 pyrido~3,2-f~ 0 -C2H5 H O Cl _ C~ )2- HCl 32 pyrido r 3,2-f~ S -C2Hs H O Cl _ CHz ? 2 - HCl 33 7-cl-pyrid3 0 -CH3 H O Cl - CH2 )2-34 7-Cl-pyrido S -CH3 H O Cl -(CH2)z-~3,2-f~
pyridor3,2-f~ 0 -C~H~ H O Cl -CH2-36 pyrido[3~2-f~ 0 -CH4CoHs H O Cl -(CH2)z-37 pyrido~3,2-f] 0 CH3 H O l-phtha-limido - CH2 ~2-38 pyridot3,2-f~ 5 -CH3 H O " _ CH2~z-39 pyrido~3~2-f] S -CH9 H O CN ~ ~H3 40 pyridor3,2-f~ 0 -CH3 H O Cl -C-CH2- HCl 41 pysido~3,2-f~ 0 -CH3 -CH3 0 Cl _ CH2)2- HCl 42 pyrido~3~2-f] 0 -CH3 -CH3 0 Cl _ CH2~H-43 pyrido~3,2-f~ 0 -CH3 H O Cl ~CHa-f-Cl HCl 44pyrido~3~2-f] S -CH3 H O Cl -CH2-C-Cl HCl 45pyrido[3~2-f~ 5 -CH3 H O Cl -C-C~2- HCl 46~ O -CH3 H O Cl -(C~2)z-47~ S -CH3 H O Cl _(CH2)2- ' ~

48~ O -CH3 H O Cl -(CHz)2- HCl 49~ S CH3 H O Cl -(CHz )2 CF3 N fH3 50 benz O -CH(CH3)2 H ~NC`H Cl _C~2_ 51 ben~ O -C2Hs H ~ Cl -(CHb)z-52 6-Cl-pyrido O -CH3 H O Cl -(CH2 )2-~4~3-f~E

53 ~ O -CH3 H O Cl -~CHk)~_ _ E

54 ~ ~ S -CH~ H O Cl -(CB2)z_ (cont.) 41g~-CIP-2 Table l~c~nt . ) Inter-mediate No. A(Y~O-~ B R R~ E X ~(CH)n~ 5alt ~ O -CH3 H O Cl -tcl~2 )z~

56 N~E E S -CH3 H O Cl -(CHz )2-57 [~ O -C~19 H 0 Cl -(CH2 )2 58 [~ S ~C}13 H 9 C1-(C~12 )z-CH~ O -CH3 H O Cl(CH2 )2-60 CH~_ S -CH3 H O Cl-(CH2 )2 ,N
61 ~_E O -CB3 H O Cl-(CH2 )2 62 ~ S -CH3 H O Cl-(CH2 )2 63 ~ O -CH3 H C) Cl -(CHz )2 64 ~ S -CH3 H O Cl-(CH2 )Z

~ ? -~19A-CI~

Example 1 2-r2-(Dimethylamino)ethyll-2~3-dihydro-4-methy~ 4 ben~4H~-~ne hydrochloride.
A solution of 9 9 (0.2 mole) of ~imethylamine in 250 ml of ethanol w~s added to 24 g (0.1 mole) o~ 2-(2-chloro-ethyl)-2,3~dihydro-4-methyl-1,4-benzoxazepin-5(4H)one in a ~teel bomb. ~he m~xture wa~ heated ~t lOO~C. for 18 hrs.
The solution was concentrated in vacuo and the re6idue ~artitioned between ethyl acetate and dilute sodium hydroxide. ~he ethyl ~cetate layer was concentrated and the r~sidue comprised ~ub~tantially of the free ba~e of the title compound was di~olved in methyl isobutyl ketone-isopropanol mLxture. The ~olution was acidified with hydrogen chloride gas to give the title compound, m.p.
188-197~C.
ExamE~
2-r2-(D~nethylamine)ethyll-2J3-dihydro-4-methy~ 4 benzoxaze ine-~(4H)-one.
_~ , . , _ All of the hydrochloride salt obt~ined in Ex~mple 1 was partitioned between chloro~orm and dilute ~odium hydroxide and ~he ~hloroform l~yer concentrated. The residue was crystallized several timeR from isopropyl ether to give 6 g (21%) of the free b~e, m.p. 56-76C.
Analysi~: Calcul~ted for Cl~H20~202: C,67.72; H,Bil2, Found : C,67.35; ~, B . i6, ~,11.~9 Example ~
?,~-Dihydro-4-methyl-~ L2-(4-morpholino)ethyl~-1,4-benzoxazepin-5(4H)-one fumarate C1:11~
To 50 ml of ~orpholine was ~dded 20 g (o.o&4 mole) of 30 2-~2-chloroethyl) -2 ,~5-dihydro-4-m~thyl-1 ,4-benzoxazepine-5(4H)-one. The ~olutic~n WF~B re~luxed ~or 5 hr6 and then concentrated in vacuo. The ro idue was dissolved in ~hloroform, and the ~olution was wa~hed with ~lilute ~odium hydroxide, tlri~d over ~odium ~ulfate and concentrated in 35 ~acuo. q~he residue cc~mpri~ed ~ubst~nti~lly oiE the Pree ~lgA -cIp-2 88 ~5~45i ~ase Gf the titl~ comp~und was reacted with 1005 9 (0.09 mole) o~ fumaric acid in i~opropa~ol-water. The resulting solid was recrystallized from i~opropanol-water to give 21.5 g (640 , m.p~ 199-201C.
An~lysi~: Calculated for CZOH2BN207: C,59.10; H,6 45;
Found : C,58.95; H,6.52, N,6. 8 Example 4 4-Benzyl-2,~-dihydro-2-r2-(4-morpholino)ethyll-1,4-benzoxazepin-5(4H)-one.
.
To 200 ml of morpholine was added 30 g to-og5 mole) of 4-benzyl-2 -( 2 -chloroethyl ) -2 ,3-dihydro-1, 4 -benzvxazepin-5-(4H)-one. The ~olution was refluxed for 3 hrs and then concentrated in vacuo. The residue wa~ partitioned between

15 dilute ~odium hydroxide and ~hlorofor~n. The chlorofonn layer was dxi~d over sodium sulfate and concentrated ln vacuo. The solid obtained was recrystallized from isopropyl ether-ethyl acetate three times to give 15.2 g of ~olid (4~%), m.p. 97-99 C.
20 Analygi~: Calcul~ted for C22H2~N2O~: C,72.10; H,7.15;
~,7.~4 Found : C,72.25; H,7.22;
~1,7 .64 Example 5 4-Benzyl-2 ,3 dihydro-2-r2-(methylamin ) -3-ethyll-1,4-benzoxazepin-5(4H)-one ~umarate ~
.., . . _ A ~olution of 5095 9 (0.19 mole) of monomethylamine in 200 ml of ethanol was added to ~0 g (0.095 mole) of 4-benzyl-2-(2-chloroethyl)-2,3-dihydro-1,4-benzoxazepin-5(4H)~one in a steel bomb. The mixture was heated at 100C. for 16 hr. The solution was concentrated in vacuo ~nd the re~idue partitioned between chloroform ~nd dilute ~odium hydroxide. The chloro~orm layer was concentrated and the re~idue compri~ed ~ubst~ntially of ~he free ba~e o~ the title compound was dissolved in isopropanol ~nd reacted with fumaric acid to give the fumarate~ ~he ~alt was ~ried under vacuum at 100C. until entrapped igopropyl 419~1'1p_~

8~

alcohol was removed, m.p. 178-Bl C.
Analysi 8: Calculated for CzgH2~N203: C,64.77; H,6.15, N,6.57 Found : C,64.87; ~,6.20;
N,6.62 Exam~le 6 2-r2-(Dimethylamino)ethyll-2,3-d~x~dro-4-methyl-1,4-b nzoxazepine-~(4H)thione h~drochl~ri_e rl ll.
To a ~olution of 7.2 g (0.16 mole) of dimethylamine in ~50 ml o~ abso~ute ethanol was add~d ~0.4 g (o.o8 mole) 10 ~f 2 (2-chloroethyl)-2~3-dihydro-4-methyl-1,4-benzoxazepine-5(4~)thione. The ~olution was hsated in a steel bomb for 18 hr at lOO~C. and then c~ncentratedO ~he re~idue was partitioned between chlorsform ~nd dilute sodium hydroxide.
The chloro~orm layer was dried over ~odium sulfate an~
~oncentratsd. ~he solid compri~ed ~ubstantially o~ the ~ree base o~ the title compound wa~ reacted with hydrogen ~hloride gas in eth~nol to give the hydrochl~ride salt.
The salt wa3 recryst~llized from etharlol and dimethyl-formamide followed by three recry~tallizations ~rom ethanol 20 to give 7.5 g (28%), m.p. 2~3-236~C.
Analysis: calculated for Cl~H21N2SOCl: C,55.90; H,7.o4, N,9-32 Found : C,55.72; H,7.26, N,8.94 Example 7 4-Benzyl -2-r2-(dimethylamino) ethyll-2~dihydro-1,4-benzoxazepin-~( 4H) -one monohydra te.
Following the procedure of Example 1, 4-benzyl-2-(2-chloroethyl)-2,3-dihydro-1,4-benzoxazepin-5(11H)-one ~nd dimethylamine were reacted and the free base of the title compound was obtained in the concentrated residue.
~ecrystallization ~rom ethanol-water gave the produc~, m.p.
75-77~C.
Analysis: Calcul~ted ~or CzoH23N20~: C,70.1~; ~,7.65, N,8.21 Found : C,70.02: ~,7.5~: N,8.25 . ) 419A-CI~2 ~2~3~.5 Examp~e 8 2,7-Dihydro-4-methy~ 2-(4-morp~olino~ethy~ -1,4-benzoxazepi~(4H)-thiOne hydrochloride rl.i1-A solutiQn of 20 .4 g (0 .o8 mole) of 2 ,3-dihydro-4-methyl-2 -(2 -chlorc~ethyl) -1, 4-benzoxazepin-5( 4H) -thione in 60 ml of morpholine was refluxed for 5 hr. then concentrated. The residue was partitioned b~tween dilute ~odium hydroxide and chloroform. The chloroform layer was dried over sodium ~ulfate and conce~trated to give a residue comprised substantially of the free base of the title csmpound. The hydrochloride salt was prepared in methyl isobutyl ketone-dimethylformamide ~olution with hydrogen chloride gas. The salt was recryst~llized from ethanol-dimethyl~ormamide to g~ve 14 9 solid (~1%), m.p. 253-256C.
Analysi~o calculated for Cl~H2g~2SO2Cl: C,56,04; H,6.76, N,8.17 Found : C,55.73; H,6.63, ~,7.97 Example ~
2 r2-(_ methylamino~et~yll-2,7-dihy~ro-4-meth lnaphth 2 3-flrlJ4l-oxazepin-5(4~)-one oxalate r ~
L ~ ~ L I ~
~ ~teel ~omb was charged with 5.0 g (0.017 mole) of 2-(2-chl~roethyl)-2,3-dihydro-4-methylnaphth~2,3-f]~1,4]
oxazçpin 5(4H)-one, 50 ml of ~bsolute ethanol aad 3.78 g (0.0~4 mole) of dimethyl~mine as 40~ aoueous 801ution. The bomb was heated ~t 100C. for 16 hr. Volatiles were removed under r~duced pre~sure and the residue partitioned between chloroform and 15~ aqueou~ sodium hydroxide. The chloro~orm layer was washed twice with water, dried over magnesium aulfate ~nd concentr~ted under reduced pres~ure to give 2.7 g (540 of viscou6 yellow oil comprised ~ubstantially o the free base of the title compound. The oil was dissolved in isopropyl alcohol and re~cted with oxalic acid. The oxal~te salt was recrystalli~ed ~rom ethanol-water, m.p.
192-194~C.
Analysi~: C~lculated for C2oH24~208: C,61.84; ~,6.2~; ~,7.21 Found : ~,61.417 ~,6.27; ~,7.09 ~ , 41~-C1P-2 91 ~L%5~
Example 10 2-r2-(Dimethylamino)ethyl~-2,3-dihydro-4-methylpyrido t~,2-f~[1,4~-oxazepin-5(4R)-one fumarate ~2:3~.
To 90 g to.8 mole) of 40% ~queous dimethylamine in a steel bomb was added 25 g (0.09 m~le) of 2-(2-chloroethyl~-2,3-dihydro-4-methylpyridot~,2-f~1,4~-oxazepin-5(4H)-one hydrochloride. The mixture was heated to 100C. for 15 hr under mild agitation. The mixture was partitioned using dilute sodium hydroxide and two chloroform extractions.
The chloroform layers were combined and concentrated. The residue comprised substantially of the free base of the titl~ compound was dissolved in 200 ml of i~opropyl alcohol and 9 g of oxalic acid added. ~he oxalate salt was recry~tallized from 95~ ethanol to give 18 g. The oxalate ~alt was then converted to the free base by partitioning between chloroform and dilute ~odium hydroxide and evaporating the chlorofonm layer. The re6idue, the free base of the title compound, was di~solved in i~opropyl alcohol ~nd reacted with fumaric acid to give 13 g of white ~olid (34%), m.p. 146-148 C. 0 Analysi~: Calculated for ClaH25N308: C,53.90; H,5.90, ~,9.92 ~ound : C,5~.76; H,6.02, -M,9.96 Example 11 2 -t? -~ Dimethylamino)ethyll-2,3-dihydro-4-methylpyrido 25 r~J2-flrl~4l-oxazepine-5(4H)-thion2 fumarate Compound with ethanol Ll5~:0.5]
To a aolution of 32.8 g (0.29 mole) of 40~ aqueou~
dimethylamine and 100 ml of ethanol in steel bomb was added 15 g (0.058 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~,2-f~tl,4~-~xnzepine-5(4H)-thione. The mixture wa~ heated to 100C. for 18 hr under mild agitation.
The ~olution wa~ cooled ~nd partitioned between c~loform and dilute ~odium hydroxide. The chlorof~rm layer w~s ~ried over ~odium ~ulfate and concentr~ted. The residue compri~ed sub3tan~ially of the free b~se of the title cDmpound wa~ di~olved in i~opropyl ~lcohol and reacted - ) 419A CIP-2 ~253 with 7 g of fumaric acid. ~he fumarate ~alt was recrystal-lized from is~pr~pyl alcohol to give 19 g (86%), m.p.
105-129C. A 14 g sample of the ~alt w~s recry tallized from ethanol to give 10.5 g yell~w solid, m.p. 10~-118c.
The NMR spectra indicates the crystals contain 1~ mole ethanol.
Analysis: Calculated ~or C9~5zNaOllS2: C,53.45; H,6.48;
N,10.39 Found : C,53.07; HJ 6.53;
N,10.23 Example 12 2-r2-(Dimethylamino)ethyll-2~3-dihydro-4-methylpyrido L _ _ _ _ __ _ _ r3~2-fl~lJ4l-oxazepine-5(4H)-thio~e fumarate rl:ll.
_. .. ,, _ To a solution of 113 ml (1.0 mole) of 40~ aqueous dimethylamine and 326 ml of ethanol in a steel bomb was added 48.4 g (00189 mole) o~ 2-(2-chlor~ethyl)-2,3-dihydro-4-methylpyridot3,2-f~1,4~-oxazepine-5(4H)-thione.
The mixture wa~ heated at 100s'C. for 14 hr. The ethanol wa~ removed in a rotary ev~porator leaving ~ome water in the residue. The residue was dissolved in 200 ml of 20 methylene chloride ~nd wa9hed with three 100 ml portions of 20% aqueous potassium carbonate solution. The combined aqueous layer6 were extracted with three 150 ml portions of methylene chloride . Methylene chloride solut io~s were combined ~nd treated wi~h ~harcoal. Charcoal was filtered 25 off and the filtrate wa~ evaporat~d to give an oil. The oil was di~olved in 215 ml i60propyl ~lcohol ~nd the ~olution was heated to a ~low boil. A eolution of 21.9 g (0.19 mole) of fumaric acid in 150 ml of boiling methanol was added to the isopropyl nlcohol ~olution. CryRtalline 30 solid was obtained weighing 63.4 g (88~). The ~olid was recrystallized from hot 200 proof ethyl alcohol. The crystals were filtered off ~nd triturated in isopropyl ether at room temperature and again ~eparated by filtering.
~ft~r drying in a vacuum oven overnight at ~C. ~ crystals in the amount of 72.45 g (790 , m.p. 130-133C.,were obtained.
~naly3i~: calculat~d or Cl7H2~NgO5S: C,53.53; H,6.o8; N~ll.o2 Found : C,53.23; H,6.11; N,10.64 ! 41~-C IP-2 93 ~ ~5 3 ~ 5 xam~le 1 benzoxaze~ne-5( 4H ) -th ione.
To a 0u~pension of a finely ground mixture of 2.9 g (0.01~ mole) of phosph~rus pentasulfide and 2.9 g of potas~ium ~ulfide in 75 ml of dry toluene was added 12 g (0.03~ mole) of 4-benzyl-2,3-dihydro-2-[2-(4-morpholino) e~hyl]-1,4-benzoxazepine-5(4H)-one. ~he mixture was ~tirred at reflux for 10 hr. and filtered. The filtrat~
was concentrated and the re~idue crystallized from isopropyl ether-toluene to give 2~549 (20%), m.p. 236-2~8~C.
AnalyRi~: Cal~ulated for C22H2e~20~S: c,6g.o8: ~,6.85;
N37-~2 Found : C,69.60; H,6.96;
N,7-15 ~
2,3-Dihydro-4-methyl-2-r2-(methylamino)ethyll~1,4-benzoxazepin-5(4H)-one fumarate rl 11.
___. _ Following the pr~cedure of Example 5, 50 9 (0.21 ~ole) of 2-(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one ~nd 13.0 g (0.42 mole) of monomethylamine (in 400 ml ethanol) were reacted to give the ~ree base of the title compound which wa~ reacted with fumaric acid to give, after i801~tion and recrystallization from ethyl alcohol, 17 g (23%) ~f the title compound, m.p. 154-156C.
Analysis: Calcul~ted for C17H22N20~: C,58.27; H,6.33;
N,8.oo Found : C,58.34: H,6.52;
N,7.82 Exam~
2,3-Dihydro-4-methyl-2-~ -(methylamino~ethyl1~1,4-benzox~zepin-5(4H)-one.
~0 2,~-Dihydro-4-methyl-2-~2-(methylamino)ethyl~-1,4-benzoxazepin-5(4~)-one fumarate w~s converted back to ~he free base by partitioning in dilute ~odium hydroxide and ~hloroform. Evaporation of the chloroform l~yer snd di~tiliing, b.p. 182/0.2 mm, gave 4.3 9 of the product.
Analysis: ~nlculated for Cl9Rl8N202: C,66064 :~,7.74; ~,11.96 Found : C,66.48; ~,7.69: ~,11.88 . . `J
4 l9A-C I P -2 ~i3 94.

EX amp L e 16 ethyl~-4 methyl-1,4-benzoxazepine-5(4~)-thione (and hydrochloride salt.) .

~ suspension of 10.7 g (0.078 mole) of potassium carbonate, 13.7 g (0.078 mole) of 4-hydroxy-4 phenyl-pipsridine and 19.8 g (o.078 mole) of 2-(2-chloroethyl)-293-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione in 200 ml of n-butanol was refluxed overnight. The mixture was filtered and the filtrate concentrated ln ~acuo.
The residue was d~solved in ethanol-ligroin and reacted with hydrogen chloride gas to give the hydrochloride ~alt which was recrystallized from ethanol-dimethyl-fo~mamide. The hydrnchloride salt wa~ converted back to the ~ree bsse by partitioning in chloroform and dilute ~odium hydroxide and evaporating the chlvroform. Recrystal-lization twice from isopropyl alcohol gave 9.27 g (30O
product free base, m.p. 142-148C.
~nalysis: calculated for C23N2~zO2S: 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-rl-(4-phenyl-1,2,3,6-tetrahydro)pyridinyl~ethyll-1,4-benzoxazepine-5(4H~thione.
A Ru~pension of 24.3 g (0.176 mole) of potassiu~
carbonate, 11.5 g (0.059 mole) of 4-phenyl-1,2,3,6-tetrahydro-pyridine nnd 15 g (0.059 mole) of 2-(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione ~nd enough n butanol to form a slurry were refluxed for 72 hr. The reaction mixture was filtered hot ~nd the filtrate cooled to room temperature and refiltered. The last filtrate was concentrated ~nd the re~idue di~olved in ethyl ~cetate.
The cry~tals obtained on cooling were recryst~llized from eShyl ~cetate to give 7 g of product (31%), m.p. 15~-155 C.
Analysi~: Calculated for C2sH~Nzos: C,72.98: ~,6092; ~,7.40 ~ound : C,73.~6; H,7.~1: N,7.47 ) ~19~-CI~-2 9~
Examp~

meth~l-1,4- ~ one hydroch A ~oluti~n of 9.8 g (0.04 mole) of 8-chloro-2~
(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-b~nzoxazepine-5 (4H)-thione in 50 ml of absolute ethanol ~nd 10 ml of a 40~ a~ueous ~olution of dimethylamine were mixed and heated in ~ steel bomb at 100C. for 16 hr. The ethanol was evaporated under reduced pressure and the residue dissolved in chloroform ~nd partitione~ with 10% sodium hydroxide solution. The chlorofor~ layer was evap~rated under reduced pressure to give an ~morphou~ solid. ~he solid wa~ dissolved in 6~ hydrochloric acid and the ~olution wa~hed with ethyl acetate. The zgueous layer was basified with 50% ~odium hydroxide and extracted with ethyl acetate.
15 The ethyl acetate layer was evaporated under reduced pre~ure to give ~ vi8cous oil comprised ~ubstantially of the free l:ase-o~ the title compound which was dissolved in absolute ethanol and reacted with ethereal hydrogen chlorideO The hydxochloride ~alt wa~ recrystallized from ethanol to give ~0 g (~5%) product, m.p. 196-199 C.
Analysi~: Calculated for C~4H20N2Cl20S: C,50.15: H,6.01:
N,8.35 Found : C,5U.15; ~,6.18;
N,8-o7 ExamPle ~
8-Chloro-2-r2-(dLmethylamino)ethyll-2,3-dihydro-4-""," _ _ methyl-1,4-benzoxazepin-5(4H~-one oxalate r~
A solution of 10 g (0.0~7 mole) of B-chloro-2-(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in 50 ml of absolute ethanol ~nd 10 ml of 40~ aqueDus 30 solution of dimethyl~mine were mixed and heated in a steel bomb ~t 100C~ ~or 16 hr. The ~olution was cvncentrated under reduced pro~sure and the residue dissolved in chloro-onm and partitioned with 15~ sodium hydroxide (2 w~shes).
The chloro~orm layer wa~ dried over magnesium ~ulf~te ~nd 35 evapQrated under reduced pres~ure to give an oil, comprised ~ub~antially o~ the ~r~e ba~e of the ti~le compound.

-J41~A-CIP-2 ; ' ) 96 ~ ~ 3 ~

The oil wa~ di~s~lved in ab~olute ethanol and reacted with oxalic acid. The oxalate salt was recrystallized from ethanol in the ~mount of 4 g (~8%), m.p. 198~201C.
Analysi~: calculated for Cl~2lN~Cl03: C,51.55; H,5.68;
N,7-51 Foun~ : C,51.07; ~,5.69;
~,7 43 Example_20 7-~romo-2-~2-(dimethylamino)ethylJ-2~-dihydro-4-methyl-1,4-benzoxazepin-5(4H~-one oxalate rl 1l.
To a ~olutiDn of 3.0 g (0.01 molejsf 7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-.
5(4~)-one in 50 ml o~ ab~olute ethanol wa~ add~d 2;2 ml of ~ 40~ aqueous solution of dimethylamine. The reaction mixture was heated i~ a stainle~s ~teel bomb at 1~0 C.
1~ ~or 16 hr and conc~ntrated under reduced pre~sure. The residue was partitioned betw~en chloroform and 15% ~odium hydroxide 801ution. Th~ chloro~orm layer was separated and ex~racted with ~N aqueous hydroehloric ~cid. The acid layer was basified with 50% aqueQus ~odium hydroxide and 29 extracted with chloroform. The chloroform wa~ evaporated under reduced pre~sure to give 2.4 g (7~) vi~cou~ brown oil, the ~ree base of the title compound. The oil was dissolved in isopropyl alcohol ~nd reacted with oxalic acid. The oxalate salt was recrystalli~ed from i60propyl ~lcohol/
water to ~ive the title ealt, m.p. 1s2-l94oc.
Analy~is: C~lculated for Cl6~2l0~BrN2: c,46~o6; H,5.07;
N,6.71 Found : c,46.oo; H,5.10;
~,6.68 Example 21 2-~2-(Dimethylamino)e hyll-2,~-dihydro-ll-methylnaphth ~2,1-~Jrl,41oxaz~pin-5(4H)-one oxal~te r ~
A solution of 8 9 (oOo28 mole) of 2-(2 chloroethyl)-2,3-dihydro-4-methylnaphthC2,1-f~1,4]oxazepin-5(4H)-one and 6.2 g of 40~ dim~thylamine (0.055 mol~) in 100 ml of 35 eth~nol was heated in ~ ~te~l bomb to 100C. for 18 hr.
The xe~ulting ~olution wa~ p~rtitioned between methylene chloride a~d dilute ~odium hydroxide ~olution. ~he methylene ~hloride lnyer wa~ ~ried over sodium ~ul~e and 419A,CIP-~

concentr~ted. The re~idue ~ompr~ed substantially of the ~ree ba~e ~f the title c~mp~und wa~ diq~olved in i~opr~pyl alcohol ~nd reacted with 2.6 g oxalic ~cid. The oxalate ~alt obtained wa~ recrystallized from i60propyl alcDhol in water, m.p. 206-209~C.
Analysis: Calculated for C20~2~N20B: C,61.85; ~,6.23:
N37.21 Found : C,61.61; ~,6.26;
. ~,7-13 Example 22 When in the procedure o~ Example 10 eaual molar amounts of the following are substituted for 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~3J2-f]~1,4~-oxazepin -5(4H)-one hydrochloride:
2~ hlaroethyl)-2,~-dihydro-4-methylpyrido~4,~-f]
~lJ4]-oxazepin-5(4H)-one hydrochloride, 2-(2-chlQroethyl)-2,3-dihydro-4-methylpyrido~3,4-f]
E 1,4]-oxazepin-5(4H)-one hydrochloride, and 2-(2-chlor~ethyl)-2,3-dihydro-4-methylpyrido~2,3-f~
tl,4]-~xazepin-5(4~ ne hydrochloride, there ~re obtained:
2-~2-(dimethylamino)ethyl~-2,3-dihydro-4-methylpyrido t4,3-f~1,4~-oxazepin-5(4H)-one fumarate, 2-~2-(dimethylamino)ethyl~-2,3-dihydro-4-methylpy~ido ~4-f~ 4]-oxazepin-5(4H)-one ~umarate, and 2-~2-(dLmethylamino)ethyl~-2,3-dihydro-4-methylpyrido t2,3-~1,41-oxazepin-5(4H)-one fumarate.
ExamPle 23 2-[2-(Dimethylamino)ethyll-2,3-dihydro-4-methylpyrido L4,3-f ~ 4~-oxazepine-5(4~-thione hydrochloride C2 3].
~0 To a solution of 0.5 g (0.002 mole) of 2-(2-chloro~
ethyl)-293-dihydro-4-methylpyrido~4,~i-$~1J4~-oxazepine-5(4H)-thione in 20 ml of ethyl alcohol was added ~ ml of 40~ ~aueou~ dimethylamine. The mixture was heated in a ~teel bomb to 100C. for 14 hr. The re~ulting solution was ~iltered and concentrated. The residue was di~olved in i~opropyl ~l~ohol and a f~w drops of ethereal hydrogen chloride wero ~dded. The hydrochloride salt crystals were _ ~ ! ~ 419A-CIP-2 98 ~ L7~rS

r~cry~talli~ed by di~301ving in ~thyl ~lcohol ~nd boiling while replacing the ethyl ~lcohol with i~opropyl ~lcohol.
The yield of product wa~ 0.3 g (~7%), m.p.- decom~. ab~ve 200C.
Analysi~: Calculated or C2eH4lN8O2S2Cl9: C,48.78; H,6.46;
~,13.13 Found : C,49.34; ~,6.47;
N,l~.0 ~3~
2-~2-(Diethylamino)ethyl~-2,~-dihydro-4-methylpyrido 10 ~2~ 1,4]oxazepine-5(4H)-thione.
-2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f]
~1,4~-oxazepine-5(4H) thiona and di~thylamine in ethanol are heated together to obtain the title compound.
Examele 2~
2~t2-(Dimethylamino~ethyll-2 3-dihydro-4 methylna~hth t2,~-f~194~oxazepine-5(4H)thione oxalate ~1:1] hemihydrate.
To a s~lutio~ of 15 g to-os m~le) of 2-(2-chloroethyl)-2~3-dihydro-4-methylnaphth~2~3-f]~lJ4~oxazepine-5(4~)-thione in 50 ml o~ absolute eth~nol was added 10 ml of a 20 45% ~queous 801ution of dim~thylamine. The ~olution was heated in a ~teel bomb for 16 hr. The ethanol was evaporated under reduced pressure and the residue par-titionad between chloro~orm and 15% a~ueou~ ~odium hydroxide.
The chloroform layer was separa'ced and extracted with 3N
a~ueou0 hydrochloric acid. The acid layer was basified with 50~ ~ueou~ sodium hydroxide and extracted with chloro~orm. Th~ chloroform solution wa~ concentrated under reduced pre~sure and the re~idue wa~ di3~01ved in i~opropyl alcohol and reacted with oxalic acid. The ~alt was recry~tallized ~rom i30propyl alcohol a~d water to give the title compound, m.p. 115-118C.
An~lysi~: Calculated ~or C~0~50N40llS2: C,58.09; H,6.o9;
~,6.77 Fou~d : C,58.42: ~,5.85;
~,6.70 `~19A_CIP_2 99 ~%~

? -~2 (DLmethylamino)ethyll-2,3-dihydro~7,9-~iiodo-4-methyl-1,4-benzoxazepin-5(4H)-~ne -Utilizing the procedures ~f Example 1 ~nd 2 and ~ub~tituting 2-(2-chloroethyl)-7,9-diiodo-4-methyl-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one ~or 2-(ehloro-ethyl)-4-methyl-2,3-dihydro-1,4-benzoxazepin-5(4~)-one, the title compound i~ obtained.
ExamPle 27 7-Chloro-2- ~ (dimethylamino)ethyll-2,3-dihydro-4-methyl-1,4-benzoxaxepin-5~4H)-one oxalate Ll~
To a solution of 9.0 g (0.033 mole) ~f 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-~enzoxazepin-5(4H~-one in 50 ml a~olute ethanol was sdded 7 g to-o66 mole) of a 45% ~ueous ~olution 9~ dimethyl~mine. The solution was heated in a 6tainless steel bomb at 100C. ~or 14 hr.
The reaction mixture w~s concentrated under reduced pres~ure and the residue wa6 partitioned between chloro-~orm and 15% a~ueou3 30dium hydroxide. The chloroform layer wa~ ~epar~ted and evaporated u~der reduced pre~sure to give a YiSCoU~ brown o~ he oil was dissolYed in i80propyl alcoh~l and oxalic acid addedO Recrystallization from isopropyl alcohol ~ater gave 7.0 g t57%) oxalate ~lt, m.p. 199-200C.
Analy~is: Calculat~d ~or Clo~2l~20OCl: C~51-55: ~5-68;
.~,7-51 Found s C,51.52; ~,5.72;
~.7.44 2-(Dimethylamino)methyl-2,3-dihydro~4-methylpyrido L~,2-f]rl~4~-oxazepin-5(4H)-one.
When in the procedure o~ Example 10, 2-chloromethyl-2,3-dihydro-4-methylpyrido~3,2-f~1,4~-oxazepin-5(4H)-one i~ ~ubstituted ~or 2-(2-chloroethyl)-2,3-dihydro-4-methyl-pyri~o~3,2-~1,4~-oxa~epin-5(4H)-~ne, the title compound i~ prep~red ~nd i8 i~lated if deaired a~ a pharmsceuti-~ally accept~ble s~lt.

~J
419A-CIP-~
3~

Examp~e ~
2-~2-(~imethylamino)ethyll-2,3-dihydro-4-methylpyridc) L3,2-f~1,4~ azepi~e-5(4~)-thione methiodide 2-~2-(Dimethylamino)ethyl~-2 ,3-dihydro-4-methylpyrido t3,2-$~[1,4~-oxazepine-5(4H)-thione fumarate ~
ethanol r2:1~, 3.8 9 (0.01 mole) was partitioned between chloroform and dilute ~odium hydroxide. The chloroform extract was dried over sodium ~ulfate ~nd concentrated.
The residue was dis~olved in 15 ml ~f methyl isobutyl ketone and added to a ~olution sf 1.4 g (0.01 mole) Df methyl iodide in 15 ml ~f i80~utyl ketone. Recrystal-lization from 50~ ethanol - 50~ methyl isobutyl ketone gave 2.5 g (78~;) of the product, m.p. 221-225C~C.
Analysis. Calculated for Cl~H22N30SI: C,41.28; ~,5.44;
N,10.31 Found : C,41.29; H,5.51;
~9 10 .30 methyl-1,4-benzoxazepine-5(4H)--thione oxalate tl~
hemihydxate.
To a ~olution of 8.o g (0.027 mole) of 7-chloro-2-(2-chloroethyl~2,3-dihydro-4-methyl-1,4-ben7Oxazepine-5(4H)-thione in 50 ml of absolute ethanol was added 6 ml (0.054 mole) o~ 40~ a~ueous ~olution o~ dimethylamine. ~he ~olution was heated in ~ ~teel bomb ~t 90C. for 14 hr.
The eth~nol wns removed under reduced pressure and the residue was partitioned between chloroform ~nd aqueous sodium hydroxide. The chloroform l~yer was concentr~ted to give a vi~cous yellow oil. The oil was dissolved in i~opropyl alcohol and reacted with oxalic acid. The oxalate ~0 ~alt immediat~ly precipit~ted. The mixture was heated and a ~mall amount of water W~8 ~dded to dis~olve the salt. A
white cry~talline powder wa~ ~bt~ined, m.p. 150-151 C.
Analysis: C~lcul~ted ~or C~2H~4N4C1201lS2: C,48.30; H,5,57;
~,7.04 Found : C~48.74; ~1,5.34;
~,6-95 ~ J
419~CIP- 2 .
~253~4~i ~1 ~Ll . 4~-oxazepine-5(4H)-thione hydrochlorlde ~o a solution of 15.0 g (0.05 mole) oX 2-~2-chloro-~thyl)-2,3-dihydro-4-methylnaphth~2,1-f]~1,4]-oxazepine-5(4H)-thione in 50 ml of absolute ~thanol W~8 added 10 g of a 40% aqueou~ solution of dimethylamine. The resulting eolution was heated in ~ et~el bomb 2t 100C. ~or 40 hr and ~oncentrated under reduced pressure. The xesidue was partitioned between 15~ aqueou6 sodium hydroxide a~d chloroform. The chloroform layer was e~aporated and the rasidue partitioned between 3~ hydrochloric acid and chloroform. The aqueou~ layer was made alkaline with 50 ~odium hydroxide and extracted with chlorofonm. The ehloroform extract wa~ coneentrated and the residu2 dis301ved in i~opropyl alcohol. Ethereal hydrogen chloride w~ added. Recry~tallization of the precipitate from isopropyl alcohol/water g~ve 3.0 g (20 0 of the product, m .p7 238-240C.
An~ly~is: Calculated for C~e~N2ClOS: ~,61.61; ~J6.61;
~,7.98 ~0 ~ound . C,61.&0; H,6.61;
N,7.91 Exam~le 32 When in the procedure o~ Example 11 e~ual molar ~mounts o~ the following are substituted for 2-(2-chloro-25 ethyl)-2,3-dihydro-4-methylpyrido~3,~-f~1,4]-oxazepine-5(4H)-thione:
2-(2-chloroethyl)-2,5-dihydro-4-methylpyridot3,4-f3 ~1,4]-ox~zepine-5(4H)-thione, and 2-(2-chlorGethyl-2,3-dihydro-4-methylpyridot2,3-f~
tl,4~-oxazepine-5(4H)-thione, t~ere are obtained:
~) 2-t2-(dimethylnmino)ethyl]-2,3-dihydro~4-methylpyrido C3,4-f~1,4~-oxazepine-5(4~)-thione fumarate, ~nd b) 2-t~-(dimethyl~mino)ethyl~-2,~-dihydro-4-methylpyrido ~2,~-f~tl,4~-~x~zepine-5(4H)-thione ~umar~te.

--~4 l9A_C IP-2 1~2 ~.2~

methyl-1,4-benzoxazepin-5(4H)-one oxalate hemihydrate.
To a ~olution of 3.0 g (~.011 mole) of 2-(2-chloro-5 e'chyl ) -2, ~-dihydro-7-methoxy-4 -methyl-l, 4 -benzoxazep in-5(4H)-one in 50 ml of absolute ethanol was ~dded 3.0 9 of a 40% ~queous ~olution of dimethylamine. The reaction mixture was heated ln ~ stainle~s steel bomb at 100C. for

16 hr, cooled and evaporated under reduced pressure. The residue was partitioned between chloro~orm and 15~ ~odium hydroxide solution. The chloro~orm layer was concentrated and the residue, the free base, was di~solved in isopropyl al~ohol and reacted with oxalic acid. The resulting ~xalate salt was recry3tallized from i~opropyl alcohol/H2o to give 1.9 g ~ 450 0$ the title salt, m.p . 176-178 C .
~nalys i ~ : Ca lculated for C3 ~I5 o~.0 l5: C , 54 . 10 ; H , 6 . 67 ;
N , 7 . 42 Found : C,54.29; ~,6.59, N,7-5 E~mple ~4 7-Bromo-2-r2-(dimethylamino) ethyl 1-2, 3-d ihydro-4 -methyl-1,4-benzoxaze monohydrate.
To a ~olution of 13 9 (0-04 mole) of 7-bromo-2-(2-chloroethyl)-2,~-d~hydro-4-methyl-1,~-benzoxazepine-5(4~)-thione in 50 ml o absolute etha~ol was added 8 ml of a 45~ aaueou~ solution of dimethylamine. Th~ solution was heated at 100C. in a ~teel bomb for 16 hr. The ethanol was evaporated under re~uced pre~sure ~nd the residue partitioned between ethyl acetate and 3N ~ueou~ hydro-chlorie acid. The ~aueous extr~ct was basified with 50%
~queous sodium hydroxide and extr~cted with chloroformO
The chloroform was concentrated under reduced pressure.
The re~idue, the free ba~ of the title compou~d, wa~
~i~solved in isopxopyl alcohol nnd reacted with oxalic 8Ci~. ~he oxalate salt wa~ recry~tallized from 95% ethanol ~5 to give ~he title ~alt, m.p~ 155-157C.

j ! 41~A-CIP-2 103 ~ 2~ 3 ~

Analysis: Caleulated f~r C92H~ON~Br20~2S2: C,42.58; H,5~14;
N,6.12 Found : C942.93; HJ4.7g ~,6.19 ~xample ~5a to h 5~hen in the procedure of Æxample 27, equ~l molar ~mount~ of the ~ollowing are ~b~tituted ~or 7-chloro-2-(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-benzoxazepin-.5(4H)-one, 2-(2-chl~roethyl~-4-cyclohexyl-2,~-dihydro-1,4-10b~nzoxazepin-5(4~)-one, 2-(2-chloroethyl)-2, 3-dihydro-4-ethyl-1~ 4 -benz-~xazepin-5(4H)-one, 2-(2-chloroethyl) -2 ,3-dihydro-4-isopropyl-1,4-b~nz-oxazepin-5( 4H)-~ne, 152-(2-chloroethyl)-4-(4-chlorobenzyl)-2,3-dihydro-1,4-benzoxazepin-5(4~)-one, 2-(2-chloroethyl)-2 9 3-dihydro-4-(4-methylb~nzyl)-1,4-benzoxazepin-5(4H)-~ne, 2-(~-chloroethyl)-2 J 3-dihydro-4-(~,5-dLmethoxybenzyl)-201,4-benzoxazepin-5(4H)-one, 2-(2-chloroethyl)-2,3-dihydro-4-(3-trifluQr~methyl-benzyl)-l J 4-benzoxaz~pin-5(4H)-one, and 2-(2-chlo~oethyl)-2,~-dihydro-4-(4-nitrobenzyl)-~
1,4-benzoxazepin-5(4H)-~ne, ~5 there ~re obta~ned:
a) 4-cyclohexyl-2-t2-(dim~thylamino)ethyl~-2,3-dihydro-l,4-benzoxaz0pin-5(4H)-one oxalate, 30b) 2-~2-(dLmethylamino)ethyl]-2,~-dihydro-4-ethyl-1,4-benzoxazepin-5(4H)-one oxal~te, c) 2-~2-~dimethylamino)ethyl~-2,~-dihydro-4-isopropyl-1,4 benzoxazepin-5(4~)-3ne oxalate, d) 4-(4-chlorobenzyl)-2-~2-~dLmethylamino)ethyl~-2,3-35dihydro-1,4-benzoxnzepin-5(4~)-one oxal~te, e) 2-~2-~dimethylamino)ethyl~-2,~-dihydro-4-(4-methyl-benzyl~-lJ4-b~nzoxazepin-5(4H)-~ne oxal2te, ~ J
4191~ C I P-2 1C)4 :E ) 2 ~ 2 - ( dimethylamir~o ) ethyl ~ -2, 3-d ihydro-4 - ( 3, 5-d~nethoxyberlzyl ) -1, 4 -benzoxazepin-5 ( 4H) -one ox~late, 9) 2-~2-(dimethylamino)ethyl]-2,3-dihydro-4-~3-5(trifluoromethyl)benzyl~-1,4-benzox~zepin-5(4~)-one oxalate, and h) 2-r2-(dimethylamino)ethyl]-2,3-dihydro-4-(4-nitro-benzyl)-1,4-benzoxazepin-5(4H)-one oxalate~

Example ~6a to h When in the procedure o~ Example 10, equal molar amount~ of the following are substituted ~or 2-(2-chloro-~thyl) 2~-dihydro-4-methylpyrido~3~2-f]~l~4]-oxazepin 5(4H)-one hydrochloride, 2-(2-chloroethyl)-4-cycloh~xyl-2,3-dihydropyrido ~3~-f]~l~4~-oxazepin-5(4H)-one hydrochloride, 2-~2-chloroethyl)-2,~-dihydro-4-ethylpyrido ~3,2 f~l,4~-ox~zepin-5(4H)-one hydrochloride, 2-(2-chloroethyl)-297-dihydro-4-i~opropylpyrido ~3,2-fjtl,4~-oxazepin-5(4H)-one hydrochloride, 2 (2-shloroethyl)-4-( 4-chlorobenzoyl) -2 ~3-dihydro-pyrido~J2-f~[1,4~-oxazepin-5(4H)-one hydrochloride, 2-(2-chloroethyl) 2,~-dihydro-4-(4-methylbenzyl)-25pyridor3,2-f~C1,4~-oxazepin-5(4H)-one hydrochloride, 2-(2-chloroethyl)-2,3-dihydro-4-(4-methoxybenzyl)-pyrido~3,~-f~1,4~-oxazepin-~(4H)-one hydrochloride, 2-(2-chloroethyl)-2,~-dihydro-4-(3-trifluoromethyl-benzyl)pyrido~3~2-f~lJ4~-oxazepirl-5(4H)-one ~0hydrochloride, and 2-(2-chloroethyl)~2,3~dihydro-4-(4-nitrobenzyl)-pyrido ~3,2-~1,4~-ox~zepin-5(4H)-one hydrochloride, there ~re obtained:
~) 4-c~clohexyl-2-t?-(dim~thylamino)ethyl~-2 ,3~dihydro-pyr~do~3,2-~tl,ll~-oxazepin-~j(4H)-one fumarate, 1~3~L~a5 b) 2-[2-(dimethylamino)ethyl]-2,3-dihydro~4-ethylpyrido[3,2-f]-[1,4]-oxazepin-5(4H~-one fumarate, c) 2-[2-(dlmethylamino)ethyl]-2,3-dihydro-4-isopropylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one fumarate, d) 4-(4-chlorobenzyl)-2-[2-(dimethylamino)ethyl]-2,3-dihydro-pyrido[3,2-f][1,4]-oxazepin-5(4H)-one fumarate, e) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(4--methylbenzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-one fumarate, f) 2-[2-(dimethylamino)ethyl]-2,3-dihydro~4-(4-methoxybenzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-one fumarate, g) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(3-trifluoromethyl-benzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-one fumarate, and h~ 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(4-nitrobenzyl-pyrido[3,2-f][1,4]-oxazepin-5(4H)-one fumarate.
Example 37a to d When in the procedure of Example 3, equal molar amounts of the following are substituted for morpholine:
pyrrolidine, piperidine, piperazine, and 4-methyl-piperazine, there are obtained:
a) 2,3-dihydro-4-methyl-2-[2-(l-pyrrolidino)ethyl]-134-benzoxazepin-5(4H)-one fumara-te, b) 2,3-dihydro-4-methyl~2-[2-(1-piperidino)ethyl]-1,4-benzoxazepin-5-(4H)-one fumarate, 105a ~:~53~
c) 2,3-dihydro-4-methyl-2-[2-(1-piperazino)ethyl]-1,4-benzoxazepin-4~4H)-one fumarate, and d) 2,3-dihydro-4-methyl-2-[2-(4-methylpiperazin-1-yl)ethyl]-1,4-benzoxazepin-5(4H)-one fumarate, J

419P,CI~2 3~
10~

Example 38 r~,2-fltl,41-thlazepin-5~4H)-one dihydrochloride.
A ~olution of 1.5 g (o.0058 mole) of 2-(2-chl~roethyl)-2,3-dihydro-4-methylpyrido~3,2-f~1,4~-thiazepin-5(4H)-one in 20 ml of ~imethylamine was ~tirred at 25C. in ~ sealed contai~er ~or 72 hr. The exce~s dimethylamine Wa3 allowed to evaporate ~nd the residue wa~ partitioned between ~hloroform ~nd dilute ~odium hydroxide. The chloroform lnyer was concen'crated zlnd the re~idue, the free base of the title compoundl was dissolved in i~opropyl alcohol and reacted with hydrogen chloride. The resulting hydro-chloride ~alt weighed 1.5 g (770 , m.p.> 250 C.
Analy~Calcul~ted for Cl~2l~30SCl2: C,46.16; H36.27 ~,12.42 Found : C,45.68; H,6.18, ~.12.35 Example~
?-~2-(Dimethylamino) ethyl~-2 ,3-dihydro-4-methylpyrido 15 ~3,2 -f ~1, 4 1-thiazepine-5( 4H) -thione oxalate .
A 801ution of 1.5 g (0.005 mole) of 2-~2-chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f~1,4~-thiazepine-5~4~)-thione in 40 ml ~f dimethylamine was ~tirred at ~5C. in a ~ealed container iEor 96 hr. The dimethylamine waR allowed 20 to evaporate and the residue wa~ partitioned between methylene chloride and dilute sodium hydroxide. ~he chloro-form layer wa~ concentrated and the residue, the ~ree ba3e of the title compound, was re~cted with 0.4 g oxalic acid in a solution o~ 30 ml of 90-100 isopropyl alcohol water.
The re~ulting cry~tals were recry~tallized ~rom the same ~olv~nt to give 1 g of the product, m.p. 191-193 C.
Analy~ calculated for Cl5HzlN3S204: C,48.50; H,5.70;
Found : C,48.49: H 5.84-~,10.99 _~J

~ ~ 3 Exam~le 4Q
2 -r2 -( Dimethylamino)ethyll-2,3-dihydro-4-methylpyrldo ~4-f~Ll,4~oxazepin-5(4H)-one oxalate tl~?) hemihydrate.
A ~olution of 5 g (0.02 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methy~pyrido~3,4-f~[1,4]oxazepin-5(4H)-one, in 25 ml o~ dimethylamine was placed in a sealed vessel and stirred for 72 hr. The vessel was opened and the excess dimethylamine allowed to evaporate. The residue was dissolved in chloroform and the solvent was stripped off in vacuo to remove excess dimethylamine. The residue was partitioned between dilute sodium hydroxide and ethyl acetate. The ethyl acetate solution was concentrated and th~ residue was treated with 3 g (0.033 mole) of oxalic acid in 50 ml of isopropyl alcohol and enough water to dissolve the salt while boiling. The resulting crystals were recrystallized from the same ~olvent. Yield of product was 5.3 g (60~), m.p. 179-181C.
Analysis: Cal~ulated for C34H4~02l: C,46.48; H,5.52;
~,9.58 Found : C,46.58; H,5.70 N,9.61 20Example 41 2 -r2-(Dimethylami~ ethyl~-2 .3-dihydro-4-methvlpyrido 5,4-f~C1,4~oxazepine~5(4H)-thione oxalate (1:2).
A 4 9 (0,009 mole) sample of 2-~2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido~ -f~1,4~xazepin-5(4H)-one oxalate (1:2) hemihydrate was partitioned between dilute sodium hydroxide and chloroform. The a~ueous layer was extracted three times and the combined chloroform extracts were dried over sodium sulfate and concentrated. The residue wac dissolved in 200 ml of dry toluene and again concentrated ~0 in vacuo to e~fect drying. The residue was di~solved in dry pyridine (10 ml) and treated with 2.8 g (0.01 mole) of pho~porus pentasul~ide. The mixture was ~tirred at reflux for 20 hr. The cooled mixture W~8 partitioned between dilute ~odium hydroxide and chloroform. The aqueous layer was ~5 extracted three time~ with chloroform. The combined ~hloro-form extr~cts were dried over ~odium ~ulate and concentrated.

~~ 419A-C1~2 108 ~ ~5 ~

One gram of the residue was treated with o.6 g of oxalic acad in isopropyl alcohol/10% water. The resulting crystals were collected by filtration. Yield o~ ~xalate ~alt was 0.~7 9., m.p. 111-114C.
5Analysis: Calculated for Cl7H23N3SOe: C,45-84; ~,5.20;
~,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]
~ 4~-oxazepin-5(4H)-one~ oxalate ~l:lL.
2,3-Dihydro-4-methyl-5(4H)-oxopyridoC3,2-f][1~4~
oxazepine-2-propanenitrileJ 5 g (0.22 mole, in 150 ml of ethanol wa~ treated with about 1.5 g of wet Raney nickel.
~he mixture was hydrogenated in a Parr apparatus at 60C.
and 40 psi. The mixture was cooled and fil~ered and the ~iltrate concentrated. T~e residue was treated with 3.9 g of oxalic acid in 130 ml of boiling isopropyl alcohol containing 2 ml o~ water. ~he hot solution was filtered and allowed to cool. The resulting Rolid was recrystal-lized ~rom ethanol. Yield of oxalate hemihydrate was 3 g (4~%), m.p. 126-1~4C.
Analysis: calculated for C2BH40N607. ,50.30; H,6.o3 ~,12.57 Found : C,50.46: H,5.71, ~,12.21 25Example 4 2,3-Dihydro-4-methyl-2-~-2-(4-morpholinyl)eth pyrido~3,2-f~tl,4~oxazepin-5(4H)-one maleate Ll:11.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyxido~3,2-f]
C1,4]oxazepin-5(4H)-one hydrochloride, 16 g (o58 mole) was di3solved in morpholine t30 ml) and stirred overnight at room ~emperature. To the solution was added dilute sodium hydroxide ~olution (50 ml) and the resulting mixture extracted with chloroorm (~ X ~0 ml). The chloroform was removed on the rotary evaporator with aspiration. The 35 r~sidual m~rpholine was removed in vacuo at 50C. (rotary evaporator). To the reRidual free base ( 15 .5 g, .053 mole) 199 ~ ~ 3~

was added isopro~yl alcohol (1 liter) and maleic acid (9.24 g g, ~o80 m~le). The mixture was heated to boiling and the clear ~lution ~ooled at 20 C. for ~everal hours.
The resulting crystals, 16 g (68.1%), were recrystallized from i~opropyl alcohol, m.p. 163-165C.
Analysis: calculated for Cl~H25N307: C,56.01: H,6.18;
N,10.31 Found : C,55.71; H,6.21;
N,10.18 Example 44 ?,3-Dihydro-4-methyl-2-r2-(1-Pyrrolidinyl)ethYllpyrido ~3,2-flEl,4~-oxazepin-5(4H)-one fumarate rl 1l.
A sample of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-pyrido~3,2-f][1,4~-oxazepine-5~4H)-one hydrochloride, 16 g (0.058 mole), was dissolved in 65 ml of pyrrolidine. The stirred solution was heated to 80C. for 3 hr. The solution was cooled to rosm temperatuxe and dilute ~odium hydroxide solution (50 ml) was a~ded. The resulting solution was extract~d with chloroform (~ X 30 ml) and concentrated in vacuo. The residue was taken up in boiling isopropyl alcohol (500 ml/ and ~umaric acid (9.2 g, .079 mole) was added. The solution was filtered hot and the filtrate ~ooled to 20C. for 5everal hours. ~he resulting crystals, 14 g (47.8%) were collected and recrystalli7ed from isopropyl alcohol, m.p. 147-149C.
Analysis: calculated for CZ301O~3~2~: CJ54-4~ H,5-76;
N, 8 .28 Found : C,54.38; HJ5.83;
N,8.27 Example 4~
2-r2-(Dibutylamino)ethyll-2,3-dihydro-4-methyl-pyrido 3,2-f~rl,4~oxazepi~-5(4H)-one maleate rl~
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f]
~1,4~oxazepine-5( 4H) -one hydrochloride, 16 g (0.058 mole) was dissolved in dimethylformamide (30 ml) and di-n-butyl-amine (30 ml). The ~olution was stirred at 90C. for 3 hr at 100C. fOr 2.5 hr. The solution was cooled and to it was added 50 ml of dilute sodium hydroxide solution. The reRulting mixture was extracted with chloroform (3 X 50 ml).

41 9A -C I ~2 The chloroform was removed on the rotary evaporator with water aspiration ~t 50~C. Residual dimethylformamide and di-n-butylamine were removed at low vacuum and 50C. (rotary evaporator). To the residual free base, 1~.8 g (0.041 mole~
was added isopropyl alcohol (900 ml) and oxalic acid, 5.6 g (0.062 mole) and the solution heated to boiling. The clear solution was cooled overnight at 20C. and filtered to give 1~.6 g (56.5O of crystals which were recrystallized from isopropyl alcohol, m.p. 195-196 C.
Analysis: Calculated for C2 1H93N3~ CJ5959; ~7.85;

Found : C,59.37; HJ7.91 ~ ,9.86 Example 46 2-r2- ~ ethylamlno)ethyl~-2,~-dihydro-4-meth~lpvrldo ~
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f]
C1,4~oxazepin-5(4H)-one hydrochloride, 16 g (0.058 mole) was suspended in diethylamine (30 ml). The suspension was stirred for 72 hr at room temperature. The mass spectrum indicated that the reaction had progressed 33~ at this point~ The mixture was then heated to reflux for 6 hr.
Diethylamine was removed by rotary evaporation (70C. water aspirator). The residue was taken up in chloroform (100 ml) and washed with dilute aqueous sodium hydroxide (2 X 30 ml).
The organic layer was concentrated by rotary evaporation (70~C, water aspirator). The residue was dissolved in boiling i~opropyl alcohol and treated with oxalic acid.
Upon cooling, 18.6 g (87.7 O of light brown crystals were collected (m.p. 150-155C.). A sample was recrystallized three more times from isopropyl alcohol, m.p. 156-157 C.
Analysi~: Calculated for Cl7H25N30~: C,55.57; H,6.86;
N,11.43 Found : C,55.28; H,6.85;
~,11.27 419A-CI~

3~

Example 41 2,3-Dihydro-4-methyl-2-[2-(1-piperidinyl~ethyllpyrido ~3,2-f~1,4~oxazepin-5(4H)-one oxalate ~1:1;.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]
t 1,4]oxazepin- 5 (4E~)-one hydrochloride, 4 g (O.015 mole) 5 was dissolved in piperidine (30 ml) and heated to 80C.
with stirring ~or 20 minutes. The piperidine was removed by rotary evaporation (85C, vacuum pump) and the residue taken up in chloroform (50 ml). The organic layer was washed with dilute aqueous sodium hydrc~xide (2 x 20 ml) 10 and concentrated by rotary evaporation (80 C, water aspirator). The resulting oil was taken up in hot isopropyl alcohol and treated with oxalic acid. Upon cooling, crystals of the oxalate salt were collected and recrystallized from isopropyl alcohol, to give 3.4 g (625~) f pale brown crystals m p 133-136 C
Analysis: Calculated for Cl~H25N303: C,56.98; H,6.64, N,11.07 Found: C,s6.95; H,6.87;
N,10.79 Example 48 2,3-Dihyd o-4-methyl-2-~methyl(phenylmethyl)amino ethyllpyrido~2-fl~1,4~oxazepin~5(4H)-one maleate 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrid~3,2-f tlJ4~oxazepin-5~4H)-one hydrochloride, 4 g (0.015 mole) was dissolved in methyl benzyl amine (30 ml) and heated to 80 C. with stirring. After ~hree hours, the excess amine was rernoved by rotary evaporation (90 C, vacuum pump). The residual oil was taken up in chloroform (40 ml) and washed with dilute aqueous sodium hydroxide (30 ml). The chloro-form layer wa~ concentrated lby rotary evaporation (90C~
water aspirator). ~'le residual oil was dis601ved in hot isopropyl alcohol and treated with maleic acid. Upon cooling, 4.23 g (660 c)f pale brown crystals were collected, m.p. 167~169C.
Analysis: calculated for C2 ~H27N30~: C,62.57; H,6.16, ~55 Found : C,62.28; H,6 16;
N,9.24 ~9A-CIP-2 ~. . , 112 ~ ~ 3 ~4 Example 49 2,~-Dihydro-4-methyl-2-~2-~methylphenylamino)ethyl~
pyridor~J2-f]~l,4]oxazepin-5(4H~-one.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~,2-f~
~1,4~oxazepin-5(4~)-one hydrochloride, 4.00 g (0.015 mole) was dissolvsd in N-methylaniline (30 ml~ and heated to 95 C. with stirring for 2 days. Excess N-methylaniline was removed by rotary evaporation (95 C, vacuum pump). The residue was taken up in chloroform (80 ml)and washed with dilute a~ueous sodium hydroxide (30 ml) The chloroform layer was decolorized with activated carbon and dried over sodium sulfate, ~iltered and concentrated by rotary evaporation. The remaining residue was dissolved in ethyl acetate ~50 ml) and purified by high pressure liauid chromatography using a silica gel column and ethyl acetatP
as the eluent. After purification, crystals formed from ethyl acetate. These crystal~ were recrystallized from ethyl acetate, giving 1.40 g (310 of pale brown crystals.
Analysis: calculated for Cl8H2lN302: C~69.4~; H,6.79;
N,13.49 Found : C,69.~1; H,6.77;
N,13-54 ~
2-~2-(2,5-Dimethyl-l-pyrrolidinyl)ethyll-2,~-dihydro-4-methylpyrido r3,2-flrl,4~vxazepin-5(4H)-one fumarate rl,:l~.
2-(2-Chloroethyl)-2,3-dihydro~4-methylpyridor3,2-f]
~l~4]oxazepin-5 (4H)-one, 5.0 g (0.021 mole), was dissolved in 25 ml of absolute ethanol and 3 g (0.03 mole) of 2,5-dimethylpyrrolidine was added. The solution was heated to 75 C. for 48 hrs with stirring. Because the re~ction was incomplete at this time, an additional amount of 2,5-dimethylpyrrolidine ~1.00 g, 0.01 ~ole) was added and the reaction continued. After 5 days, the reaction was still incomplete and more 2,5 dimethylpyrrolidine (1.00 gJ 0.0 mole) was added. The reaction appeared complete 2 days later. Solvent was removed by rotary evaporation (80C., ~5 water aspirator). Excess 2,5~dimethylpyrrolidine was 9~-CI~2 113 ~ ~5 3~

removed by rotary evaporation (80C, vacuum pump). The residue was taken up in chloroform (200 ml) and washed with dilute aoueous sodium hydroxide (2 x 75 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation (70C, water aspirator).
The resulting oil wa~ dissolved in hot isopropyl alcohol and treated with fumaric acid. Upon cooling, 2.38 g (27.4%) of pale brown crystals was collected, m.p. 161 162C.
Analysis calculated for C2lHz~N906: C,60.13; H,6.96;
N,10.02 Found : C,59.79, H,6.93;
N,9.76 ExamPle ~1 2,3-Dihydro-4-methyl-2-r2-(2-methyl-1-pyrrolidinyl) 15ethyl~pyrido ~ 2-fl~1,41oxazepin-5(4H)-one.
To a solution of ~.5 g (0.0145 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyrido ~3,2-~,1,4~oxazepine-5(4H)-one in ethanol (15 ml) was added 2-methyl pyrxolidine (s-o g, o.o63 mole). The solution was heated to reflux for ~ hours with stirring. The ethanol was removed by rotary evaporation (water aspirator, 80 C.). The residual oil was partitioned between dilute aoueous sodium hydroxide (50 ml) and chloroform (50 ml). The organic layer was ~aved and the aqueous layer extracted with chloroform (2 x 30 ml). All the chloroform layers were combined, dried over anhydrous sodium sulfate and concentrated by rotary evaporation (water aspirator, 70C.). The residual oil wac then distilled at 200C. and low vacuum (vacuum pump) giving 1.5 g (35.7%) of a clear oil.
30Analysis: Calculated for CleH~3N302: C,65.41; H,8.01, N,14.52 Found : C,65.83; H,8.o6, N,14-39 ~_ il9A CIP-~

114 ~ ~ 3~ 5 Example 52 2,3-Dihydro-4-methyl-2-~2-(lH-pyrazol-l-yl)ethyl]
pyrido r3J2-fl~lJ4]oxazepln-5(4H)-one.
To a suspension of sodium hydride (1.2 g active, 0.05 mole) in dimethylformamide (15 ml) was added dropwise a solution o pyrazole (3.10 g, 0.045 mole) in dimethyl-formamide (15 ml). The resulting solution was then added to a solution of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-pyrido~3,2-f~tl,4~ oxazepine-5(4H)-one (9.12 g, o.o38 mole) in 30 ml of dLmethylformamide. The flask was sealed and stirred overnight. Because the reaction had not yet gone to completion at this point, pyrazole (3.12 g, 0.045 mole) was added to the reaction solution and stirred overnight.
The reaction was still not complete and another suspension o$ sodium hydride (0.5 g active, 0.021 mole) and pyrazole (1.5 g, 0.022 mole) in dimethylformamide (10 ml) was added and the reaction stirred overnight. The reaction appeared to be complete. Dimethylfo~mamid~ was removed by rotary evaporation (80 C, vacuum pump), and the residue taken up in chloroform (100 ml) which was washed with dilute a~ueous sodium hydroxide (1 x 50 ml), dried over anhydrous sodium 6ulfate and concentrated by rotary evaporation (70C, water aspirator). The material was purified by high pressure liquid chromatography~ 95:5 by volume ethanol:
methanol on a silica gel column. The fractions containing the desired product were concentrated by rotary evaporation (70C, water aspirator). Crystallization ensued upon coolin~. The crystals were collected and recrystallized from ethanol. The yield wa~ 1.5 (14.5 0 , m.p. 132-134C.
Analysis: Calculated for Cl4Hl~N40z: C,61.75; H,5.92;
N,20.58 ~0 Found : C,61.35; H,5.89;
N,20.67 115 ~L~53 Example 53 2,3-Dihydro-?-~2-(lH-imidazol-l-yl)ethyl]-4-~ethyl-pyrido[ 3, 2 -f 1~ 1, 41oxazepin-5(4H)-one.
To a solution of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido t3,2-f~[1,4]-oxazepine-5(4H)-one, 9.12 g (0.038 mole) in dimethylformamide (30 ml) was added imidazole, 5.66 g (o.o8~ mole). The solution was heated to 130C. for 18 hr. Dimethylformamide was removed by rotary evaporation (80C, vacuum pump) and the residue taken up in chloroform (100 ml). The chloroorm was washed witll dilute aqueous sodium hydroxide (30 ml)3 dried over sodium ~ulfate and concentrated by rotary evaporation (70 C, water aspirator) to a~ oil. Crystallization was induced with ethanol. White crystals, 1.5 g (14.5%) were collected, m.p. 150-152C.
Analysis: Calculated for Cl~HI~N~02; C,61.75: H,5.92;
~,20.58 Found : C,61.36; H,5.92;
N,20.60 Example ~
2-r2-(Dimethylamino)ethyll-4-ethyl-2,3-dihydropyrido ~3~?-f~1, 4~oxazepin-5(4H)-one oxalate r~
To 30 ml of dimethyiamine collected at 0 C. was added 6 g (0.021 mole) 2-(2-chloroethyl)-4 ethyl-2,3-dihydropyrido ~,2-f]~1,4~oxazepin-5(4~ one, hydrochloride. The flask was sealed tightly and stirred 70 hr at room temperature.
The ~olution was then cooled to 0C. and the ~topper of th~
fla6k removed. Dimethylamine was allowed to evaporate. The residue was taken up in chloroform (1 x 150 ml) and washed with dilute aqueous sodium hydroxide (1 x 50 ml). The organic layer was dried over ~odium ~ulfate, filtered and concentrated by rotary evaporation (70C, water aspirator).
~he residue was dissolved in hot isopropyl alcohol and treated with oxalic acid. Upon cooling, 4.5 t61.5O was collQcted, m.p. 208 C.
Analysis~ Calculated fsr Cl~H~30~: C,54.38; H,6.56, ~,11.89 Found : C,54.26; H,6.61:
N,11.81 ~ ~5 3 Examp_e 55 2,3-Dihydro-4-ethyl-2 i2-(1-pyrrolidlnyl)ethyl~pyrido ,2-fl r 1,41oxazepin-5(4~ one oxalate~
2-(2-Chl~roethyl)-4-ethyl-2,3-dihydropyrido~3,2-f~
~1,4~oxazepin-5(4H)-one hydrochloride, 3 g (0.01 mole) was dissolved in pyrrolidine (30 ml) and heated to 70 C. for ~0 minutes with stlrrlng. After cooling, the contents of the reaction ~lask were diluted with diiute aqueous sodium hydroxide (40 ml) and extracted with chloroform (2 x 30 ml).
The chloroform layer was dried over sodium sulfate, filtered and concentrated to a viscous brown oil by rotary evaporation (70 C, water aspirator). The oll was taken up in hot isopropyl alcohol and treated with oxalic acid. Upon cooling, the resulting solid was recrystallized from isopropyl alcohol, giving pale brown crystals, 1.80 g (45.4 0, m.p.
185-188C.
Analysis:calculated for CleH25~30e: 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-morphollnyl)ethyllpyrido ~3~2-f~ 4]oxazepin-5(4H)-thione~
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f]
~1,4~oxazepine-5(4H)-thione, 4.5 g (0.018 mole) was dissolved in morpholine (30 ml). The Rolution was heated wi'ch ~tirring to 50-60 C. for 6 hr. The morpholine was then removed by rotary evaporation (90C, vacuum pump).
The residue was taken up in chloroform (100 ml) and washed with dilute aqueous ~odium hydroxide (2 x 30 ml). The organic layer was concentrated by rotary evaporation (60C, water aspirator~. The residue was recrvstallized ~rom ethanol giving 3.26 g (60~) of liyht yellow crystals, m.p. 152-153C.
Arlalysis: calcul~ted for Cl5E32lN302S: C,58.61; H96.89 N,13. 66 Found : CJ58~48; H,6.92;
N,13.62 ~ 4I~A-CIP-2 ~53~

Example ~1 2-~2-~Dibutylamino)ethyl~-2,3-dihydro-4-methylpyrido r3 2-flrl 41oxazepine~5(4H)-thione oxalate r ~
J
2-(2-Chlo~oethyl)-2,3-dihydro-4-methylpyrido ~,2-f~
tl,4]-oxazepine-5(4H)-thione, 4 g (0.016 mole) was suspended in di-n-butylamine (~0 ml). Dimethylformamide (ca. 10 ml) was added to the stirred mixture until dissolution occurred. The solution was heated to 140C.
for 3.5 hr with stirring. Di-n-butylamine and dimethyl-formamide were removed by rotary evaporation ( 80C . vacuum pump). The residue was then diluted with dilute aqueous sodium hydroxide (50 ml) and extracted with chloroform (3 x 40 ml). Chloroform was removed by rotary evaporation (70 C, water aspirator). The residue was dissolved in boiling isopropyl alcohol and treated with oxalic acid.
Upon cooling, the resulting oxalate salt was filtered and recrystallized from isopropyl alcohol to give 3.2 g (47%) o yellow crystals, m.p. 208C.
Analysis: Calculated for C2lH99~305S: C,57.38: HJ7.57;
~,9.56 Found : C,57.04; H,7.63;
N,9.31 Example 58 2-r2-(Diethylamino)ethyll~2,3 dihydro-4-methylpyrido ~3,2-f~rl!4~oxazepine-5(4H~thione oxalate rl:l].
2-(2-Chloroethyl)-2,3-dihydro-4-methylC3,2-]~1J4~
oxazepine-5(4H) thione, 4 g (0.016 mole) was suspended in diethylamine (30 ml). Dimethylformamide was added to the ~tirred suspension until dissolution occurred (10 ml). The ~tirred solution was heated to 65C. for 8 hr. Diethylamine waq removed by rotary evaporation (70C, water aspirator);
the remaining dimethyl~ormamide was removed a~ low pressure (vacuum pump) and 90C. The residue was taken up in chloroform (100 ml) and wa~hed with dilute aqueou~ ~odium hydroxide (2 x 30 ml). ~he organic layer was concentrated by rotary evaporation (70CJ water aspirator~. The residue was dissolved in boiling isopropyl alcohol and treated with oxalic acid. Upon coolingJ the oxalate saltJ 1.7 g (28.5%) was obtainedJ m.p. 142-144C.

`-~i9A-CIP~

Analysis: Calculated for Cl7H2s~3oss: C~5~-25; H~6-57;
N , 10 - 95 Found : C,5~.14; H,6.60;
N,10.72 Example ~9 2,~-Dihydro-4-methyl-2-~2-(1-pyrrolidinyl)ethyl~
pyridoL3,2-f~1,4]~xazepine-5(4H) thione oxalate ~1:1~.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f~
~1,4]oxazepine-5(4H)-thione, 5 g (0.02 mole) was dissolved in 30 ml of pyrrolidine. The solution was heated to 60 -80 C. for 35 minutes with stirring. After cooling to room temperature, the reaction mixture was diluted with dilute aqueou~ sodium hydroxide (50 ml) and extracted with chloroform (? x 50 ml). The organic layer was concentrated by rotary evaporation (70C, water aspirator). Residual pyrrolidine was removed at 90C. and vacuum pump. The residue was dissolved in hot ethanol and treated with oxalic acid. Upon cooling, the oxalate salt was collected and r~crystallized twice from ethanol to give 3-35 g, ~45O
of product, m.p. 141 C.
Analysis: calculated for Cl7H23~2O5S: C~53-53; H,6~o8, N,11.02 Found : C,53.~9; H,6.11:
~, 10 . 91 ExamPle 60 2,3-Dihydro-2-r2-(lH-imidazol-l-yl)ethyll-4-methyl-To a solution of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]~1,4]oxazepine-5(4H)-thione, 4.5 g ~0.018 mole) in dimethylformamide (35 ml) was added imidazole (2.20 g, 0.038 mole). The resulting solution ~0 was heated to 1~0C. for 15 hrs. Dimethylformamide was removed by rotary evaporation (80C, vacuum pump), and the residue diluted with dilute aaueous sodium hydroxide (50 ml). The aqueous ~olution was extracted with chloro-form ~1 x 50 ml), dried over anhydrous sodium eul~ate.and concentrated by rotary evaporation (water ~spirator, 70 C).
The resulting oil wa~ treated with t~xalic ~cid in ethanol.
Four grams (54 O Of pale yellow crystals were collected and 41 'CIP-2 -119 9L~i3~

recrystallized ag~in with ethanol, m.p. 163-l67oc.
Analysis: Calculated for Cl7Hl~07N4S: C,48.22; H,4.52;
N,13-23 Found : C,48.01l; H,4.62;
N,13.18 xam~le 61 2-r2-(Dimethylamino)ethyll-4-ethyl-2,3-dihydropyrido L3,2-fJ~1,41oxaze~in-5(4H)-thione.
2-(2-Chloroethyl)-4-ethyl-2,3-dihydropyrido~3,2-f]
~1,4J oxa7epin-5(4~)-thione hydrochloride, 5.00 g (0.016 mole) wa~ added to ~0 ml of anhydrous dimethylamine. The reaction flask was sealed tightly and stirred at room temperature for 6 days. The flasX was opened after cooling to 0C. and dimethylamine allowed to evaporate at room temperature. The residue was taken up in chloroform (100 ml) and washed with dilute aqueous ~odium hydroxide (1 x 30 ml). The chloroform layer was dried over sodium sulfate, filtered and concentrated by rotary evaporation.
The residual oil was dissolved in hot cyclohexane. Upon cooling, 1.76 g (39.4%) of light yellow crystals w~re sollected, m.p. 7~C.
Analysis: calculated for Cl4H2l~90S: C,60.18; H,7.58;
N,15.03 Found : C,60.~2; ~,7.70;
N,15-13 xample 6?
2,3-Dihydro-4-methyl-2-~2-rmethyl(phenylmethyl)amino]
ethyl~pyrido~,2-f]~1,41oxazepine-5(4H)-thione oxalate rl:l~
To a aolution of 4 g (0.0155 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyrido~3,2-:E~tl,4~oxazepine-5t4H)-thione in 70 ml of chloroform wa5 added 10.0 g (0.0~6 mole) of benzylmethylamine. The solution was stirred at reflux ~or 24 hr. The reaction solution was washed with wa~er (2 x 50 ml) and concentrated by rotary evaporation (~70 C, water a~pirator). ~he residue was distilled on a molecular ~till at 165C./0.1 mm. The residue wa~ treated w~th oxalic ~cid in hot isopropyl alcohol. Upon cooling, ~2~3~

t~o crops of crystals were collected. Ilhe purity of each cro~ was checked. The two crops were eombined and recrystallized together in hot isopropyl alcohol. Upon cooling, 3.69 9 (55%) of pale yellow crystals9 m.p.
16~-166C were collected.
Analysis: Calculated for C2lH25N305S: C,58.45; H~5-84 ~,9-74 Found : C, 58 .24; ~, 5.92;
~,9.61 ExamPle 6~
2,3-Dihydro-2-~2-(methylamino)ethyl)-4-methylpyrido C3,2-fl~1?41oxazepine-5(4H)-thione oxalate rl:l.51.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f]
~1,4~oxazepine-5(4H)-thione, 4-0 g (0-016 mole~ wa3 suspended in a ~0~ ~olution of methylamine in 70 ml of ethanol and allowed to stir for 56 hr at room temperature.
Becau~e of incsmplete reaction, the rea~tion solution was heated slowly over a 2 hr period to 55C~ and stirred at that temperature for 24 hr. Methylamine was removed by water aspiration fox 1.5 hr. The resulting ~olution was concentrated by rotary evaporation (70C, water aspirator).
The residual oil was taken up in chloroform (150 ml) and washed with 2 M aqueous potassium hydroxide (2 x 50 ml).
The chloroform layer was dried over sodium sulfate and con~entrated by rotary evaporation (70C, water aspirator).
The residue was dissolved in hot ethanol and treated with oxalic acid. Upon cooling, 2.0 g (37.5O of yellow cry~tals were collected, m.p. 137-138C.
Analys i8: calculated for ClsH20N307S: C,46.63; H,5.22;
N,10.67 Found : C,46.47; H,5.35;
N,10.85 3o Example 64 7-Chloro-2,3-dihydro-4-methyl-?-r2-~1-pyrrolidino) ethyl1pyrido~3,2-flrl,410xazepin-5(4H)-one fumarate rl 2-5 J . .1 1~
7-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido ~3~2-f~tl,4]oxazepin-5(4H)-one (2.5 g, 0.009 mole) was dis~olved in 50 ml pyrrolidine and the ~olution was heated to 80~C. for 1 hr. The pyrrolidine was removed by rotary - J
~19A-CI~

121 ~j3~4~i evaporation (80C., water aspirator) and the residue dissolved in 100 ml of chloroform. The organic layPr was washed with water (2 X 50 ml), dried over sodium sulfate and concentrated by rotary evaporation (~80C., water aspirator). The residue was treated with ~umaric acid and allowed to stand overnight. The resulting crystals were collected, 1.25 g t23.2%), m.p. 164-166C.
Analysis: calculated for C25H30N90l2Cl: C,50.05; H,5.o4;
N,7.00 Found : C,50.22; H,5.14;
N,7.02 Example 6~
7-Chloro-2-r2-(dimethylamino)ethyll-2,3-dihydro-4-L _ . _ _ _ _ methylpyridor3,2-flrl,41oxazepin-5~4H)-one oxalate rl:ll.
A 2.8 g (0.01 mole) sample of 7-chloro-2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyrido~3,2-f~1,4~oxazepin-5(4H)-one was added to 25 ml of dimethylamine and stirred for95 hr in a sealed flasX. The excess amine was allowed to evaporate and the residue was partitioned between chloroform and dilute sodium hydroxide. The chloroform was dried over sodium sulfate and concentrated. The residue was treated 20 with 0.7 g of oxalic acid in isopropyl alcohol. The resulting crystals were recrystallized frQm ~he same solvent.
Yield was 1.5 g of oxalate salt (400 J m.p. 150-156~C.
Analy~is: Calculated for C15H20~30BC1 CJ48-2; H,5.39:
N,11.24 Found : c,48.og, H,5.47 ~,11.12 ExamPle 66 4 Cyclohexyl-2-r(dimethylamino)methyll-2,3-dihydro-_ pyrido~3 J 2 -f 1 ~ 1 J 4~0XaZePin-5(4H~-One oxalate.
Utilizing the procedure of Example 1OJ 2~(chloro-~o methyl)-4-cyclohexyl-2J3-dihydropyrido~,2-f~1,4~oxazepin-5(4H)-one (Intermediate ~5) is reacted with 40% aqueous dimethylamine and reacted with oxalic acid in isopropyl alcohol.

~ 9A -CI P-2 ~:~53~X

Example 6~Z
? -~2-(Dimethylamino)ethyll-2,3-dihydro-4-phenylmethyl-pyrido~3,2-f]~1,4]oxazepin-5(4H)-one oxala~e ~1:1 5 hemihydrate.
A solution containing 94.2 g (0.6 mole) of 2 chloro-nicotinic acid and 100 g (0.54 mole) of l-benzyl-~-pyrrolidinol in 800 ml of dry tetrahydrofuran was added at a rapid drop to a stirred suspension of 52 g (1.3 mole) of 60% sodium hydride/mineral oil in 500 ml of dry tetrahydro-furan at reflux temperature (addition time was about 1 hr).
The mixture was heated to re~lux fox an additional 1.5 hr and then cooled to room temperature. Approximately 1 liter o~ ethyl acetate was added and filtration attemp4ed unsuccessfully. The mixture was allowed to stand overnight at room temperature and then was concentrated on the rotary evaporator at 100C. and 50 mm pressure. The residue was dissolved in 1 liter of chloroform and the pH of the solution was adjusted to 6.15 with hydrogen chloride gas.
To the solutlon was added, with stirring, 383 g (1.0 mole) o~ triphenylphosphine and 383 g (2.48 mole) of carbon 20 tetrachloride. The mixture was refluxed for 1 hr and 50 ml of ethanol was added. The solution was cooled to room temperature and extracted three times with 400 ml portions of dilute hydrochloric acid. The chloroform layer was extracted with dilute sodium hydroxidel dried over sodium sulfate and concentrated. The mass spectra indicated the presence of 2-(2-chloroethyl~-2,3-dihydro-4-(phenylmethyl) pyrido~3,2-f]~1,4~oxazepin-5(4H)-one (mass ~16), triphenyl-phosphine (mass ~62) and triphenylpho~phine oxide (mass 278).
One-third of the residue was chromatographed on a high pregsure liauid chromatopraph in an unsuccessful attempt to purify the compound. The other 2/3 of the re3idue was dissolved in 30 ml of chloroform and added to a solution of 30 g of dimethyl amine in ethanol. The solution was heated to reflux for 4 hr and concentrated on the rotary 35 evaporator. The re~idue was partitioned between chloroform and 1 N hydrochloric acid. The acid layer was made basic _~9A-CIP-2 ~ ~S 3 with sodium hydroxide and extracted with chlorGform. The chloroform layer was dried over sodium sulfate and concen~
trated. The residue (10 g) was treated with an eguivalent amount of oxalic acid in a mixture of isopropyl alcohol-ethanol-isopropyl ether. The resulting crystals in the amount of 9 g (5%) were recrystallized from the same solvent mixture~ m.p. 95-98C.
Analysis: Calculated for C44H5~N~017: C,56.28; H,5.79;
N,8 95 Found : C,56.61; H,5.76;
~,8.77 Example 68-a 2-~2-(Dimethylamino)ethylJ-2,3-dihydropyridot3,2-f~
Ll,4loxazepin-5(4H)-one.
A solution of 3.0 g (o.006 mole) of 2-~2-(dimethyl-amino ethyl~-~,3-dihydro-4-phenylmethylpyrido~3,2-f~1,4 oxazepin-5(4H)-one oxalate rl:l.5~-hemihydrate in about 50 ml of water was made basic with dilute a~ueous sodium hydroxide solution and then extracted with three 50 ml portions of benzene. The combined benzene extract was dried over anhydrous sodium Qulfate and concentrated on the rotary evaporator (steam bath/50 mm). The residue was dried further by azeotroping 2 times with about 50 ml ~f dry benzeneJ evaporating to dryness each time. The final residue was dissolved in 40 ml of liquid ammonia and ~mall spheres of sodium were added with ~tirring to the ~olution until a blue color persisted for 20 minutes.
(Addition time was about 1 hr). Three grams of ammonium chloride was added slowly and the ammonia was ~llowed to ~vaporate. The residue was suspended in chlorofo~n and the mixture was filtered. The filtrate wa~ concentrated and the residue chromatographed on preparative high pressure liquid chromatogxaph u~ing a ~ilica gel column and eluting with 75% ethyl acetate~ 5% dimethylformamide. The yield of product was 0.1 g (7%). The chemical ionization mass Epectrophotometer gave a peak at 236 corresponding to a molecular weight of 235. The lH NMR spectrum of the ~ J-CI~-2 ~25~

subject eompound was obtained in CDCl3 containing 1% tetramethylsilane (TMS) and is ~vnsistent with the proposed structure and dimethylformamid~ (DMF) and mineral oil as minor impurities. The chemical shif~s, multi-plicities, and assignments are given below:

7 ~ CH2CH2N(CH3)2 Chemical Shifts (multiplicities) Assiqnments 8.45 (multiplet) Ht8) and H(6) 8.oo singlet) C-~ (DMF) 7-85 broad singlet) ~-H
1 7.20 doublet of doublets) H 7 4-65 pentet) H 2 4.05 broad singlet) u k~ lown impurity ~-5 triplet H2(~) 2.95 singlet CH3 DMF
2.90 singlet CH3 DMF
2.60 triplet H2~ !to mino nitrogen 2.25 ~singlet N(CH3) 2 2.05 (multiplet) ~2-~ to amino nitrogen 0.7-1.7 (multiplet) mineral oil ~xample 68-b (Refer to Chart VIII) 2-C2-(Dimethylamino)ethyl)-2,3-dihydropyrido~,2-f~-1,4-oxa~epin-5(4H)-one ~umarate ~1 ~
An 8 g (0.026 mole) sample of 2-chloro-N-t4-(dimethyl-amino)-2-hydroxybutyl]-3-pyridinecarboxamide monohydro-chloride was partitioned between chloroform and dilute sodium hydroxide. The chlorofoxm was dried over anhydrous sodium Gulfate and ~oncentrated. The re~idue was dissolved in 80 ml o dry benzene which was removed on the rotary evaporator 3 (100C. ~ 0 min)~ The residue in 20 ml of dxy tetrahydrofuran was added 810wly to a stirred suspension of 8.3 g (0.052 mole) of potassium hydride/mineral oil in 80 ml o~ dxy tetrahydro~uran. The mixture was stirred at reflux for 4 hr, cooled and treated with 10 ml of isopropyl alcohol. The ~5 solution was partitioned between isopropyl ether ~nd dilute hydrochloric acid. The acid layer was made basic with ~odium hydroxide and extracted 4 times with chloroform. The chloroform wns ~oncentrated and the re~idue was chromato-gr~phed on HPLC (~ilica; 90~ ethanol-10~ triethyl~mine. The ~ ~A-CIP-2 125 ~2~3~4~

desir~d fraction~ were c~ncentrated and th~ re~idue (1.3 g) treated with 0.7 g of fumaric acid in 25 ml of isopropyl alcohol. The resulting crystals weighed 1.2 g (13%) and melted at 160-164~C.
5Analysis: Calc~lated for Cl6H2lN3O~: C,54.69; H,6.o2, N,11.96 Found : C,54.29; H,6.02;
N,11.54 Example 69 ?-~3-(Dimethylamino)propyll-2,3-dihydro-4-methylpyrido r3,2-flC1,41oxazepin-5(4H)-one fumarate rl:l.5J hemihydrate.
To 5.0 g (0.21 mole) of 2-(3-aminopropyl)-2,3-dihydro-4-methylpyrido~3,2-f~1,4] oxazepin-5(4H)-one was added, while cooling in a water bath, an 88% a~ueous solution of ~oxmic acid, 20 g (0.38 mole). To the resulting solution was added a solution of 37% aaueous formaldehyde (inhibited with 13% methanol), 10.7 g ~0.13 mole). The resulting solution was heated on a steam bath ~or 5.5 hr. The mixture was cooled and 100 ml of dilute a~ueous hydrochloric acid was added. The solution was evaporated to dryness and the residue was dissolved in 50 ml of water. The solution was neutralized with dilute aoueous potassium hydroxide and extracted with four 50 ml portions of chloroform. The combined chloroform extracts was dried over sodium sulfate and concentrated by rotary evaporation. The residue was reacted with fumaric acid in hot isopropyl alcohol. The collected product, 3.0 g (~1.8O was recrystallized twice from isopropyl alcohol, m.p. 108-110C.
Analysis: Calculated for C40H5~M~0l7: C,53.81; H,6.32;
~,9.111 Found : C,53.697 ~,6.33;
N,9.41 _ ~ ~A-CIP-2 Example 70 2- r 3-(Dim~thylamino)pro~y~ 3-dihydro-4-methylpyrido r 3~2-flr~ oxazepine-~(4H) thione_oxalate rl:21.
To a solu~ion of 11.0 g (~.o42 mole) of 2-~3-(dimethyl-amino)propyl]-2,3-dihydro-4-methylpyrido~3,2-f]~1,4~-oxazepin-5(4H)-one in 125 ml of pyridine was added 9.25 g (0.042 mole) of phosphorus pentasulfide. The mixture was heated to reflux for ~.5 hr while stirring. After cooling to room temperature, the reaction solution was added to an equal volume of 2 molar potassium hydroxide. The mixture was extracted with 800 ml of methylene chloride in several portions. The organic phase wa~ washed with three 100 ml portions of dilute potassium hydroxide, dried over 60dium sulfate, filtered and concentrated by rotary evaporator (water-aspirator, 70C.). The residual oil was subjected to reduced pressure of the vacuum pump for 2 hr at 90C.
and then cooled and reacted with oxalic acid in isopropyl alcohol. Two crops, 4.5 and 3.1 g were collected, combined and recrystallized from isopropyl alcohol to give 6.5 g (34%) of yellow crystals, m.p. 136-138C.
Analysls: Calculated for ~leH25N3o~s: C,47.05, ~,5.42 ~,9.16 Found : C,46.76; H,5.75;
~J9 .04 Example 71 7-Chloro-2-~2-(dimethylamino)ethyl~-2,3-dihydro-4-m~thylpyrido~3,2-f]~1,41oxazepine-5(4H)-thione fumarate hemihydrate, hemiisopropyl alcoholate.
To 55 ml of a methanolic solution containing 57~ by volume dimethylamine was added 2.50 g (0.009 mole) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido 3,2-f~1,4]-oxazepine-5(4H)-thione. The reaction ~essel was sealed and allowed to stand for 16 hr. Thin-layer chromatography i~dicated the reaction was about 60%
complete. The ~olution was heated gradually to 45C.
(heating time about 5 hr). Methanol and unreacted dimethyl-amine were removed by rotary evaporator ~water aspirator, 60C.). Th~ residue was taken up in 100 ml of chloroform and the solution was washed with two 40 ml portions of 4 ~b -c I P-2 ~ ~5 3 water. The organic layer was dried over sodium sulfate, filtered and concentrated by rotary evaRorator. The residue was reacted with fumaric acid in isopropyl alcohol. The resulting crystals, 1.43 g (36.5%) were recrystallized from isopropyl alcohol and dried thoroughly in a drying ~istol, m.p. 98-104C.
Analysis: Calculated for C37H~N~0l2Cl2S2: C,48.84; H,5.98:
N,9-23 Found : C,48.82; H,5.80;
N,9.37 Example 72 2,3-Dihydro-4-methyl-2-~2-(methylamino)ethyl~pyrido-r3,2-fl r 1,4~-oxazepin-5(4H)-one oxalate r ~
To 90 ml of a solution of 30% monomethylamine in ethanol was added 11.0 g (0.04 m~le) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f~-1,4-oxazepin-5(4H)-one hydrochloride.
The solution was heated gradually over a period of 2 hr to 55 C. and held at that temperature overnight.
Monomethylamine and ethanol were removed by rotary evaporation (water aspirator, 70C.) and the residue was taken up in 100 ml of chlorofonm. The organic layer was washed with dilute aqueous sodium hydroxide ~2 x 30 ml~,dried over anhydr~us sodium sulfate, filtered, and concentrated by rotary evaporation (70 C, water aspirator). The 9.0 g ~f crude oil was treated with oxalic acid in isopropyl alcohol.
The resulting crystals weighed 8.77 g (67~80 J m.p.
148-50C.
Analy~is: Calculated for Cl4Hl~N306: C,51.69, H75.89;
NJ12.92 Found : CJ51.88; H,5.97;
N,12.96 Example 73 2-(2-Aminoethvl~-2.~-dihYdro-4-methYlPyrido~.2-flrl.lll 3 oxazepin-5~4H)-one, fumarate ~1:1~.
To a suspension of 17.0 g (o.o48 mole) of 2,3-dihydro-2-~1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl~-11-methyl-pyrido~372-f ]oxazepin-5( 4H)-one in 100 ml of ~b~olute ethanol was added 3.0 g (0.051 mole) of 85~ hydrazine hydrate 35 in water and the mixture heated to re~lux with ~tirring. In 15 minutes the reaction mixture became clear. After 40 min ~419A-CIP 2 128 ~ ~5 3 ~ ~

a copiou~ precipitate of presumably phthaly hydrazide had formed. Another 100 ml of absolute ethanol was added to ensure good mixing. After 2 hr at reflux, the oooled mixture was ~iltered. The filtrate was concentrated on the rotary evaporator (water aspirator, 80C.) and the residue taken up in 75 ml of chloroform. The organic layer was washed with dilute a~ueous sodium hydroxide (2 x 3 ml~, dried over anhydrous sodium sulfate, filtered, and the filtrate concen-trated by rotary evaporation (water aspirator~ 75C.). The residue was treated with fumaric acid in isopropyl alcohol and yielded 7.0 g (43%) of pale white crystals, m.p.
196-197C.
Analysis: calculated ~or Cl5Hle~30~: C,53.41: H,5.68;
~,12.46 Found : C,53.63; H,5.78 ~,12033 ~ 7 2-(2-Aminoethyl)-2,3-dihydro-4-methylpyridc:t332-fltl,4 oxazepin-5(4H)-thione, fumarate ~2~
To a suspension of 12.15 (0.033 mole) of 2-t2-(2~3-dihydro-5(4H)- thioxopyrido~3,2-f~1,4~oxazepin-2-yl)ethyl~-lH-isoindole-1,3(2H)dione in 150 ml of absolute ethanol was added 2~08 g (0.035 mole) of an 85% solution of hydrazine hydrate in water. The mixture was heated to reflux for 2 hxs.
After cooling, ~olid phthalylhydrazide was ~iltered off.
Ethanol was removed by rotary evapor~tion (85C.~water aspirator) and the residue partitioned between 180 ml chloroform and 50 ml dilute aqueous sodium hydroxide. The organic layer was washed further with dilute aqueous sodium hydroxide (3 x 30 ml), dried over anhydrous sodium sulfate, filtered and concen-trated by rotary evaporation (water aspirator, 70C.). The crude oil was treated with fumaric acid in isopropyl alcohol which yielded 6.70 g (68.7%) of pale yellow cry~tals, m-p. 208~09C.
Analy~is: calculated for ClgHl7N303S: C,52.87: ~,5.80;
N,14.23 Found : C,52.72; ~,5.81;
N,14.16 419~1P 2 ~L25 Example 7 2,3-Dihydro-4-methyl-2~2-~(1-methylethyl)aminolethyl~
pyrido~3,2-f~tl,4~oxazepin-5(4H)-one, fumarate ~1:21.
To a solution of 2.52 g (0.011 mole) of 2-~2-aminoethyl)-2,3-dihydro-4-methylpyrido~3,2-f]~1,4]oxazepin-5(4H)-one in 5 50 ml dry methanol was added methanolic hydrogen chloride until pH 6 was reached. To this solution was added 3.29 g (0.057 mole) of acetone, 1.79 g (0.029 mole) of sodium cyanoborohydride and 5 g 3A molecular sieves. The pH was checXed and read~usted to pH 7-8 with methanolic hydrogen 10 chloride and stirred 24 hr at room temperature. The reaction mixture was filtered, and concentrated by rotary evaporation (70 C., water aspirator). The residue was taken up in 190 ml of chloroform, washed with dilute aqueous sodium hydroxide, dried over anhydrous sodium sulfate, filtered, 15 and concentrated by rotary evaporation (water aspirator, 7C) C.). The residue was treated with fumaric acid in isopropyl alcohol which gave 1.58 g (2956) of white crystals, m.p. 152-15~5 C.
Analysis: Calculated for C22Ha9N30l0: C,53.3~5; H,5.89;
N,8.48 Found : C,5~.43; H,5.94;
~,8.51 ExamPle 76 2-~2-[Bis(phenylmethyl)amino~ethyll-2,3-dihydro-4-methylpyrido~,2~ 1,4loxa7epine-5(4H)-thione, fumarate ~
To a solution of 3.16 g (0.013 mole) of 2-(2-aminoethyl)-2,3-dihydro-4-methylpyrido~3,2-f~1,4~oxazepine 5(4H)thione in ~'25 ml dry methanol was added methanolic hydrogen chloride to pH 5-6, followed by^~ 2-3 g ~A molecular sieves, 6.89 g (0.065 mole) benzaldehyde and 2.04 g (0.0325 g)sodium cyano-borohydride. The pH was again adjusted to p~ 7 with methanolic hydrogen chloride. After 6 hr of stirring at room temperature, TLC (eluting with 6% triethylamine in methanol) showed what appeared to be exclusively monoalkylated product with very little starting material. To the reaction mixture was then ~55 added 1.0 g (0.009 mole) of benzaldehyde and the mixture stirred overnight at room temperature. The reaction mixture wa~ filtered and concentrated ~y rotary evaporation (70 C., ~19A_CIP-2 3~
water aspirator). The residue was taken up in 100 ml of chloroform and washed with 2 x 30 ml dilute aque~us sodium hydroxide. The chloroform was removed by rotary evap~ration (70 C., water aspirator). The resi~ue was diss~lved in 100 ml dilute hydrochloric acid which was subsequently washed with 2 x 30 ml ethyl acetate, made basic with dilute aqueous sodium hydroxide, extracted with 4 x 30 ml chloroform. The chloroform was dried over anhydrous sodium ulfate~ filtered and concentrated by rotary evaporation (70C, water a9pirator. The residue showed both the mono- and di-alkylated product by TLC (6% triethylamine/94 methanol) and ~MR.
To a solution of the 3.0 g crude material dis~olved in 30 ml dry methanol was added methanolic hydrogen chloride to pH 4-5, 10.0 g (10.094 mole) of benzaldehyde and 2.00 g (0u0319 mole) of sodium cyanoborohydride. The pH was neutral.
To the reaction mixture was added _1 g of 3A molecular sie~e~. The reaction mixture was stirred for 6 days at room temperature.
The methanol was removed by rotary evaporation (70C, water as~irator) after filtration. The residue was dissolved in ~100 ml chloroform and washed with 2 x 50 ml dilute aqueous sodium hydroxide. The chloroform was removed by rotary evaporation ~70, water a~pirator) and the rasidue dissolved in 100 ml o~ dilute a~ueou~ hydrochloric acid.
The a~ueous layer was washed with 2 x 50 ml of ethyl acetate (the ethyl acetate was extracted with 2 x 30 ml of dilute hydrochloric acid and all acid layers combined; th~s was done because the product appeared to be somewhat soluble in ethyl acetate). The hydrochloric acid layer was made basic with concentrated sodium hydroxide solution and extracted with 2 x 50 ml of chloro~orm. The chloroform layer was dried over anhydrous ~odium sulfat~, filtered and concantrated by rotary evaporation t70C, water aspirator. The 3.0 9 of crude product obtained was dissolved in hot isopropyl alcohol)and treated with fumaric acid. The re~ulting crystals, 1.40 g (20.2%), melted at 123-126C. with slight ~hrinkage occurring at 118C.
Analysis: Calculated for Cz~H31~305S. C,65.27; H,5.86; N,7.87 Found : C,65.11; H,5.87; N,8.o5 ~19A-CIP-2 xample 77 ? ,3-Dihydro-4-methyl-2-~ -(4-methyl-1-plperazinyl)ethyl]
pyrido[3,2-fl[1,4~oxazepin-5(4H)-one fumarate ~1:2lmon3-hydrate.
To a solution of 10.45 9 (0.043 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyrido[3,2-f~-1,4-oxazepine-5(4H)-one in 80 ml of absolute ethanol was added 10.84 g (0.1084 mole) of N-methyl piperazine and the resulting solution heated to reflux for 4 hr. .~t that time, because -25~ starting material was present by mass spec, an additional 5.0 g (0.05 mole) of ~-methyl piperazine was added and heating to reflux was continued for 2 hr. Ethanol was removed by rotary evaporation (70, w~ter aspirator) and the residue diluted with 150 ml of water. The w~ter was extracted with 4 x 50 ml of chloro-form and the organic layer was washed with 2 x 50 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70C, watex aspirator). The residue was concentrated (vacuum pump/95-100 C.) for 3.5 hr. Treat-ment of the residue with fumaric acid in isopropyl alcohol yielded 8.45 g (35.4O of pale white crystals, m.p. 162-167~.
Analysis: Calculated for C2~H3~N~Ol~: C,51.98; H,6.17 N,10.10 Found : C,52.03; H,6.oo;
N,10.17 Example ~8 2 ~-D hydro-4-met~yl-?-r2-~4-methyl-l-piperazinyl)ethyl]
~y~do~,2-f]rl 4]oxazepine-5(4Hl-thione fumarate ~1 hemihydrate.
To 8.o g (0.0~1) mole of 2-(2-chloroethyl)-2J3-dihydr 4-methylpyrido[~,2-f]-1,4-oxazepine-5-(4~I)-thione in 80 ml f absolute ethanol was added 9.30 g (0.093 mole) of N-methyl piperazine. The mixture was heated to reflux for 2 hr and an additional 5.0 g (0.05 mole) N-methyl piperazine was added. Reflux was continued for an additional 5 hr.
Ethanol was removed by rotary evaporation (90C, water aspirator). Residual N-methyl piperazine was removed at 90C. with vacuum pump for 2 hr. The residue was taken up in 150 ml of chloroform and washed with 2 x 50 ml of water~
The organic layer was dried over anhydrous ~odium sul~ate, filtered and concentrated by rotary evaporation (90C, water _- '~Lil9-CIP-~
~53~

aspirator). The resid~e was concentrated further with a vacuum pump at 90 C. The 10.0 g of crude material was treated with fumaric acid in isopropyl alcohol which yielded 10.0 g (57.4%) of light yellow crystals~ m.p. 184-185 C.
Analysis: Calculated for C24H33N4O~.5S:C~51.32; H,5.92;
N,9.98 Found C,sl.56; ~95-89:
N,9.8 ~xample 79 2-r2-~4-~Bis(4-fluorophenyl)methyll-1-piperidinyll 10 ethyll-2,~-dihydro-4-methylpyridor3,2-flrl,41-oxazepin-5(~H)_ one dihydrochloride hemihydrate.
Ten grams (o.o~6 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5-(4H)-one hydrochloride were partitioned between dilute sodium hydroxide and chloroform. ~he chloroform was dried over sodium sulfate and concentrated on the rotary evaporator. The residue was dissolved in 50 ml of ethanol and 10.3 g (o.o36 mole) of 4-~bis(4-fluorophenyl)-methyl~piperidine was added. The solution was heated to reflux for 18 hr and concentrated 20 on the rotary evaporatorO The residue was partitioned between dilute sodium hydroxide and chloroform. The chloroform was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a Waters 500 HPlC (silica/92% ethyl acetate-8% triethylamine). After concentration of the desired product, the residue was dissolvPd in isopropyl alcohol and treated with ethereal hydrogen chloride. The resulting crystals weighed 3 g (14~) and melted at 160-180C.
Analysis: Calculated for C5~H~N~05Cl4F~: C,60.73; H,5.98 N,7.33 ~0 Found : C,60.60; H,6.o4 N,7.12 Example 80 2-r2-(~ ~Dihydro-lH-imidazol-2-yl~ethyll-2,3-dihydro-4-methylp~rido~5,2-flrl,4Joxazepin-~(4H?-one oxalate ~
Into a cooled (water bath) solution of 10 g (0.043 mole) of 2,3~4,5-tetrahydro-4-methyl-5-oxopyridoc3,2-f~ 4]
oxazepine-2~propane-nitrile in 50 ml of ethylenediamine was bubbled hydrogen sulfide ga~ for 10 min. The reaction flask _J419A-CIP-2 ~ ~5 was tightly stoppered and left standing at room temperature for 5 days. The reaction s~luti~n (n~w partially s~lidified) was diluted with 100 ml ~f dilute sodium hydroxide and extracted with 5 x 30 ml of chloroform. The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation ~70C. water aspirator).
The entire residue was dissolved in 50 ml of ethylenediamine and saturated with hydrogen sulfide for 10 minutes while cooling in a water bath. The flask was tightly stoppered and left ~tanding at room temperature for 5 days. The cont~nts of the reaction flask were diluted with 200 ml of 2N
a~ueous potassium hydroxide and extracted with ~ x 125 ml of chloroform. The organic extracts were washed with 3 x 50 ml 2N aqueous potassium hydroxide and extracted into 3 x 50 ml of dilute aqueous hydrochloric acid. The acid extracts were basified with concentrated sodium hydroxide and extracted into 3 x 40 ml of chlofoform. The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The syrupy recidue was treated with oxalic acid in isopropyl alcohol to give 3.5 g (22%) of white crystals.
One recrystallization from isopropyl alcohol afforded an analytical sample, m.p. 198C. with decomposition.
Analysis: Calculated for Cl6H~lN~O~: C,52.74; H,5.53, N,15.38 Found : C,52.76; H,5.58, ExamPle 81 2,3-Dihydro-4-methyl-2-~?-(methylphenylamino)ethyl pyrido~3,?-fl~1,4loxazepine-5(4H~-thione.
To a suspension of 2-(2-chloroethyl)-2,3-dihydxo-4-methylpyrido~3,2-f]~1,4~oxazepine-5(4H)-thione in 100 ml of toluene was added 11.49 g (0.11 mole) ~-methylaniline and the mixture heated to reflux with stirring for 2 days (after approx. 6 hr, 23.0 g (0.22 mole) additional ~-methylaniline was added). Toluene was removed by rotary evaporation (90 C., water aspirator). The N-methylaniline was removed also by rotary evaporation (90C., vacuum pump). The residue was taken up in 100 ml of chloroform and washed with 3 x 30 ml dilute aqueous sQdium hydroxide. The organic layer was dried over anhydrou~ s~dium sul~te, filtered and concentrated ~ ~ 3 by rotary evaporation (80C., water aspirator). More N-methylaniline was removed with th~ vacuum pump at 90 C0 for several hours. To the residue was added 150 ml of ethyl acetate at which point some product crystallized out.
However, since much remained in s~lution, preparative HPLC
on a silica gel column eluting with 60~ hexane/40% ethyl acetate was effected. After concentrating the fla3ks containing the product, crystallization was effected induced by seeding. The chromatographed product was recrystallized from ethyl acetate/isopropyl alcohol and amounted to 1.1 g m.p. 164-5 C. Approximately 2 g additional was collected by recrystallization of crude product, m.p. 163-4 C. The combined yield was 3.1 g (26%).
Analysis: Calculated for C1BH~1~30S C,66.03; H,6.46;
N,12.83 Found : C,65.72; H,6.51 N,13-13 Example 82 ? -( 3-Aminopropyl)-2~-dihydro-4-methvlpyridor~l2-f ~r 1 . 4 1 oxazepine~(4H)-thione fumarate ~
A sample of 15.0 g (o.o64 mole) of 2-(3-aminopropyl)-2,3-dihydro-4-methylpyridoC3,2-f~tl,4~-oxazepin-5(4H)-one was dissolved in 50 ml methylene chloride and to it was added 15.24 g (0.07 mole) of di-tertbutyl dicarbonate. The solution was stirred for 30 minutes at room tempe~ature. The protected amine was purified by HPLC on a ~ilica gel column, eluting with ethyl acetate. Approximately 15 g (0.045 mole 70-30 of the protected amine was collected as an oil. To a solution of 13.5 Y (0.04 mole) of this oil in dry toluene was added 8.16 g (0.02 mole) of 2,4-bis(4~methoxyphenyl)-~0 1,3-dithia-2,4-diphosphetane-2,4-disulfide. The reaction mixture was heated to 80C. ~or 2 hr. An additional amount (2.0 g, 0.005 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added and heating continued for 1 hr. Another 4.0 g (0.01 mole) of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added and the heating continued for 5 hr. After cooling, the toluene was decanted off, washed with 5 x 30 ml dilute aqueous sodium hydroxide, dried over ~odium sulfate, filtered and concentrated ~y rotary evaporation. I~opropyl alcohol ~i3~5 ~5 was added to the residue, resulting in precipitation of an impurity (possibly spent Lawesson's Reaqent). Isopropyl alcohol was removed by rotary evaporation and the residue purified by ~PLC on a silica gel column, eluting wit~ 1%
methanol/99~ chloroform. Approximately 6 g (0.017 mole, 42.6%) of material was collected and treated with lO0 ml of a solution of trifluoro acetic acid/anisole/methylene chloride, 40,/10,/50, v/v/v for 30 minutes. The solvent blend was removed by rotary evaporation (70C, water aspirator) 10 and the residue taken up in 150 ml of methylene chl~ride.
This layer was washed with ~ x 4b ml dilute a~ueous sodium hydroxide, dried over anhydrou~ sodium sulfate, filtered and concentrated by rotary evaporation. The residue was treated with fumaric acid in isopropyl alcohol7 which yielded 4.0 g (O.Oll mole, 64~ of the ~alt. Recrystallization ~r~m isopropyl alcohol afforded an analytical sample, m.p.
154-166C.
Analysis: calcul~ted for Cl~H2l~2oss C,52-30; H,5.76;
N,11.43 Found : C,52.43, H,5.83;
N31l.51 Example 83 2-r2 -(Dimethvlamino)ethY1)-21~-dihydropyridor3,2-f~ 1,4 oxazepine-5(4~)-thione dihydrochloride monohvdrate.
To 5 g (0.021 mole of 2-~2-(dimethylamino)ethyl)-2,3-dihydr~pyridot3,2-f]-1~4-oxazepin-5(4H)-one in 50 ml o~
pyridine was added 5.1 g (o.o46 mole) of phosphorus penta-sulfide. An ex~thermic reaction insued, When the temperature dropped, the mixture was heated to 70 C. ~or ~.5 hr and allowed to cool. The mixture was partitioned between dilute sodium hydroxide and chloroform while cooling by addition of ice. The aqueous layer was extracted 3 more times with chloroform. The combined chlofoform extracts were dried over anhydrous sodium Rulfate and concentrated. The residue was dissolved in 40 ml of ethanol and made acidic with ethereal hydrogen chloride. The resulting crystals were recrystal-lized from 95% ethanol. Yield was 1.4 g (19%), m.p. 172-175C.

111 9A~C I P -2 1~6 Analysis: calculated for Cl2H2lN3SOzCl~ C,42.10; H,6.1 N,12.2 Found : C, 42 .~6; HJ5 .74;
N,12-34 Exampl2 84 2-r2-~4-~Bis(4-fluorophenyl)methyl]-1-piperidinyl~ethyl~
2,3-dihydro-4-methylpyrido~3,2-fl~1,4~oxazepine-5(4H)--thione oxalate hydrate rl:l :1~.
A solution of 4 g (0.016 mole) of 2 (2~-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]~1,4~-oxazepine-5(4H)-~hione and 4.5 g (0.016 mole) of 4-~bis(4-fluorophenyl)-methyl~piperidine i~ 100 ml o~ ethanol was refluxed for 48 hr.
One yram of X2CO3 was added and this mixture stirred at reflux ~or 144 hr. The mixture was concentrated and the xesidue partitioned between chloxoform and dilute sodium hydroxide. The chloroform was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a Waters~ 50D HPLC using a silica column a~d eluting with absolute ethanol. The material with mass 507 was collected and concentrated. The re idue (6 g) was reacted with 1.2 g of oxalic acid in ethan~l. Yield was 5 g, m.p. 125-138 C.
Analysis: calculated for C3lH35N30~SF2: C,60.47; H,5 72;
Found : C,60.62; H,5.60, N,6.5 Example_~5 2J3-Dih~dro-4-methyl 2-r?-(lH-pyr~al-l-yl~et~yl~py~i~p L~ 2-f~ 4~oxazepine-~(4H)-thione.
To a suspension of 2.16 g (0.054 mole) of sodium hydride in 20 ml of dimethylformamide was added dropwise a solution of 2.92 g (0.043 mole~of pyrazole in 10 ~1 of dimethyl-formamide. There was a slight exotherm at this point with 60me evolution of hydrogen gas. The resulting ~olution was then added dropwise to a aolution of 10 .0 g ( O .039 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyridoe3,~-fJ-1,4-oxazepine-5(4H)-thione in 30 ml of dimethylformamide. The reaction ~ask was ~ealed and ~tirxed overnight at room temperature.
The solve~t dimethylformamide was removed by rotary ~vapor~tion (90C; 30 mm). The re~idue was taken up in 200 ml of chloroform which wa~ sub~e~uently washed with 2 x 50 ml ~~ 419A-CIP-2 ~L:Z 53~4X
~7 of water followed by 50 ml dil. acJueous sodium hydroxide.
Ilhe c~rganic layer was then dried over sodium sulfate, filtered and concentrated by rotary evaporation (70 C.; 30 mm).
Isopropyl alcohol was added to the residue and crystallization 5 ensued after cooling. The crude crystals (4.5 g) were recrystallized from isopropyl alcohol giving ~i.45 g (31~) of yellow crystals, m.p. 119-121C.
Analysis:Calculated for Cl4HlBN40S: C,58.31; H,5.59;
~,19.43 Found : C,58.01; H,5.59;
N,19.37 Example 86 ?-r2-(Dimeth~amino)-l-methylethyll-2,~-dihydro-4-methYlPYrido[~2-f~ 4]-oxaze-pin-~(4H)-one oxalate Cl~
To 4.5 g (0.018 mole of 2-(2-chloro-1-methylethyl)-15 2,3- dihydro-4-methylpyrido~3,2-fJ-1,4-oxazepin-5(4H)-one was added 20 ml of methanol and 40 ml of dimethylamine.
The reaction flask was tightly sealed and left standing at room temperature for 72 hr. The 1ask was opened after coolin~ and the methanol and dimethylamine evaporated.
20 Another 15 ml of methanol and 40 ml of dimethylamine were added, the flask sealed tightly and left standing at room temperature for 7 days. The methanol and dimethylamine were evaporated and the residue taken up in 100 ml of chloroform. The chloroform layer was washed with 2 x 50 ml 25 dil sodium hydroxide and 50 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The crude material which was collected was treated with oxalic acid in isopropyl alcohol which afforded 3.5 g (55%) white crystals, m.p. 204-05C.
30 Analysis: Calculated for Cl~,H29N30~3: C,54.38; H,6.56, N,11.89 Found : C,54.32; H,6.61;
N,11.86 138 ~253~4~i Example_~
2,3-Dihydro-2-r2-(4!5-dihvdro-lH-imidazol 2-yl)ethyll-4-methylpvridor~,2-flrl 41-oxazepine-5(4~)-thione oxalate ~2~
Into a suspension of 2,~,4,5-~etrahydro-4-me~hyl-5-thioxopyrido[~,2-f~1,4]-oxazepine-2-propanenitrile in ~0 ml of ethylene diamine was bubbled hydrogen sulfide gas for 15 min while cooling in a water bath. The flasX was then ~ealed and stirred at room temperature for 5 days. Mass ~pectra showed much ~tarting material. An additional 15 ml of methylene diamine was added and the mixture saturated again with hydrogen sulfide. The flask was resealed and left standing for 8 days. The reaction mixture was diluted with 100 ml dil a~ueous sodium hydroxide and extracted into 3 x 60 ml o~ chloroform. The chloroform extracts were combined and washed with 50 ml of water. Some crystal-lization occurred in the separatory funnel but complete crystallization could not be effected. The organic layer was concentrated by rotary evaporation and the residue treated with oxalic acid in isopropyl alcohol. The crude crystals, 7.0 g, (55%) were recry~tallized from methanol/
ethanol yielding an analytical sample, m.p. 198-~00C.
Analysis: calculated for Cl7H2lN4O7S: C,47.99; H,4.97:
N,1~.16 Found : C~47.63; H,5.09:
N,13.04 ExamPle 88 2-r2-(Dimethylamino)ethyll~2,3-dihydro-2,4-dimethyl-pyrido~3,2-f~1,4~oxazepin-5(4H)-one dihydrochloride.
To 4.5 9 (0.015 mole) of 2-(2-chloroethyl)-2,3-dihydro-2,4-dimethylpyrido~3,2-f]-1,4-oxazepin-5(llH)-one hydro-chloride in 15 ml of methanol was added 40 ml of dimethylamine. The flas~ was sealed tightly and left 6tanding at room temperature for 8 days. The methanol and dimethylamine were removed by rotary evaporation (70C; ~0 mm). The residue was taken up in 150 ml of chloroiorm, washed with 2 x 50 ml dil aqueous sodium hydroxide, dried over ~nhydrous ~odium sulfateJ filtered ~nd concentrated by r~tary evaporation (7~ C; 30 mm). The syrupy residue was ~53~
1~9 treated with hydrogen chloride in i~opropyl alcohol, which afforded 3.5 g (67%) of white cry~tals, m.p. 188-90 C.
Analysis: Calculated for C14H2~N302Cl2: C,50.01; H,6 89 Found : C,50.00; H,6.98 N,12.4g 5Example 89 2-~2-(Dimethylamino)ethyll-2,3-dihvdro-2,4-dimethyl-pyridot~,2-f~1,41oxazepine=5(4H)-thione monohydrochloride.
To a suspension of 4.5 g (0.017 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-2,4-dimethylpyrido~3,2-f~-1,4-oxazepine-5(4H)-thione in 20 ml of methanol, cooled in an ice bath, was added 40 ml of dimethylamine. The fla~k was ~ealed tightly and left standing at room temperature for 10 days.
The ~imethylamine and methanol were removed by rotary evaporation (60 C; 30 mm). The residue was taken up in ~15150 ml of chloroform, washed with ~ x 50 ml dil 60dium hydroxide, dried over anhydrou~ sodium ~ulfate, filtered and concentrated by rotary evaporation (70C; 30 ~m). The crude oil wa~ disAolved in isopropyl alcohol and treated with ethereal hydrogen chloride, which yielded 4.0 g (76%) o~ yellow cry~tals, m.p. 255C. with decomposition.
Analysis: Calculated for Cl~H22N30SCl: C,53.23; H,7.02, N,13.30 Found : C,53.21; H,7.15, ~,13.19 Example ~0 (Refer to Chart VII) 252~I2-(Dimethylamino)ethyl~-2,3-dihydro-4-methyl~1,4 oxazepino~6,7-clquinolin-5(4H)-one oxalate Cl:l~.
To a su3pension o~ 19.4 g (35% in oil, 0.172 mole) of KH in 150 ml tetrahydrofuran was added at a rapid drop 12.4 g ~o.o85 mole) o~ 1-dimethylamino-4~methylamino-2-b~tanol.
30~fter 1~ minutefi, 20 g (o.o85 mole) o~ 3-carboxyethyl 4-chloroquinoline wa~ ~dded by a powder dropping funnel over a period of 30 min. The mLxture was stirred at room temperature overnight.
Approximately 50 ml of water was added to quench the re~ction and the mixture partitioned between ifiopropyl ether ~nd water. ~he aqueous layer wa~ extracted again with 2 x 70.ml o~ i~opropyl ether. The aqueous layer was then _ 9A-CIP~2 ~ %53~t~

1~0 continuously extracted for 15 hr with chlorofcrm. The chloro-form layer was collected, filtered and concentrated by rotary evaporation (80C, 30 mm). The crude material (18 g) was purified by HPLC using silica gel as the stationary phase and 3% triethylamine/ethanol as the eluent. Approximately 4 g (15.6%) of reasonably p~re free base of the title compound was collected. A 1.5 g sample of the free base was reacted with 0.5 g oxalic acid in 10 ml of ethanol. The resulting cyrstals weighed 2 g and melted at 214-218 C.
Analysis: Calculated for Cl~H23N30~: C,58.60; H~5.95; N,10.79 Found : C,58.46; H,6.10; N,10.75 Example 91 2-r2-(Dimethylamino)-l-methylethyll-2,3-dihydro-4-methylpyridor3,2-flrl,41-oxazepine-5(4H)-thione oxalate ~
To a suspension of 4.0 g (0.013 mole) of 2-(2-chloro-1-methylethyl)-2,~-dihydro-4-methylpyrido~,2-f]~1,4]oxazepine-5(4H)-thione hydrochloride in 20 ml of methanol cooled in an ice bath was added 35 ml of dimethylamine previously collected at C. The reaction flask was sealed tightly and left standing at room temperature for 10 days. The solvent was removed by rotary evaporation ~80C, water a~pirator) and the residue taken up in 150 ml of chloroform. The organi-c layer was washed with 2 x 50 ml of dilute aoueous sodium hydroxide, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The crude residue was treated with oxalic acid in isopropyl alcohol and left ~tanding overnight at room temperature, yielding 3.1 g (65%) of yellow crystals, m.p. 211-213C. 0 Analysis: calculated for Cl~H2305N3S: C,52.02; H,6.18; N,11.37 Found : C,51.79; H,6.34; ~,11.24 Example 92 2-r2-~DimethYlamino)propyll-2, 5-dihydro-4-meth~leyrido ~3,2-f~1,4 oxazepin-5(4H)-one dihydrochloride.
.~
~5 Into a stainless ~teel bomb was placed 1.0 g ~odium iodide, 5.0 g (0.017 mole) of 2-(2-chloropropyl)-2,~-dihydro-4-methylpyrido~,2-f~1,4~oxazepin-5(4H)-one and 40 ml of dimethylamine. The bomb was 3ealed tightly, placed ~%~

in t~e ove~ at 60C. and rolled continu~usly f~r 7 days.
The bomb was allowed to stand at room temperatuxe for several days. The residue was combined with that of a previous run of equal ~ize and separated via column chromatography using silica gel and eluting with ethanol and then with ~% tri-ethylamine/ethanol. The fractions containing the desired product were combined and concentrated by rotary evaporation (80C, ~0 mm). The residue was taken up in 150 ml of chlorofoxm and washed with 2 x 50 ml diluted sodium hydroxide.
The chloroform was removed by rotary evaporation (70C., 30 mm) and the re idue treated with ethereal hydrogen chloride and hydrogen chloride in isopropyl alcohol. The white crystals which were collected weighed 3 g (28%), m.p. 173-76C.
Analysis: Calculated for Cl4H23N202Clz: C,50.01: H,6.89;
N,12.50 Found : C,50.40; H,7.o4 N,12.36 2 ~-D -ihydro- 4 -me thvl -2~2 - ( 2 -methyl -1 -Pyrrol id invl 20 ethyl]pyrido~2-f]rl,4Joxaze~ine-5(4H?-thione fumarate ompour~d with ?-~ropanol r ~
To a suspension of 5.0 g (0.019 mole) of 2~ (chloro~thyl)-2,3-dihydro-4-methylpyrido~3,2-f~-1,4-oxazepine-5(4H)-thione in 25 ml of absolute ethanol was added 3.5 g (0.04 mole) of 2-methylpyrrolidine. The mixture was heated to reflux for 6.5 hr and left standing at room temperature ovexnight. Mass spec and TLC showed presence of starting materials. Approximately 5 g of potassium carbonate was added and heating at reflux was continued for 24 hr.
Ethanol was removed by rotary evaporation (70C, 30 mm). The rsidue was taken up in 100 ml of methylene chloride and washed with 2 x 50 ml dil. aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium ~ulfate, filteredJ and concentrated by rotary evaporation (70C, 30 mm). ~he residual 6yrup was dissolved in isopropyl aocohol and treated with fumaric ~cid affording 4.5 g (0.01 mole, 49.2 0 of cxude crystal~. Two recrystallizations from i~opropyl afforded 1.5 g (16.4O of yellow crystals, -- ~2S3~45 419A-CIP-2 m.p., 92-95C.
Analysis: Calculated for C23H35~3~S: C,57.36; H,7.33, N,8.72 Found : C,57.12; H,7.30;
~,8.70 Example 94 2-~2-(Dimethylamino)ethyll-2 J 3-dihydro-4-methyl-9-(trifluonnethyl)-~ ]oxazepino[6~7-c~qulnc:lin-5(llH)-one fumarate ~1:11.
To 55 ml of dimethylamine collected over an ice/methanol bath was added 2.2 g (0.005 mole) of 2--(2-chloroethyl)-2,3-dihydro-4-methyl-9-(trifluoromethyl)-1,4-oxazepino[6,7-c]
quinolin-5(4H)-one hydrochloride. The flask was sealed tightly and left standing at room temperature for 6 days.
After eooling to 0C., the flask was opened and the solvent allowed to evaporate at room temperature overnight. The residue was taken up in 100 ml of chloroform, washed with x 30 ml of dil Rodium hydroxide, dried over anhydrous aodium sulfate and concentrated to rotary evaporation (70 C, 30 mm). The residual oil was treated wi~h fumaric acid in isopropyl alcohol and dried, giving 2.2 g (81%) of white crystals, m.p. 204-05C.
Analysis: Calculated ~or C2zH24N3OBF3: C,54.6O, H,5.00;
N J 8.69 Found : C,54.74; H,~.127 ~ 55 ExamPle 9~
~2-(Dimethylamino)ethyl3-21~-dihydro-4~methyl~1,4~-oxazepino~617-b~quinolin-~(4~)-one fumarate hvdrate r 1 1 0 . ~ ~ .
To 40 ml of dimethylamine cooled to ~0 C. in an ice water bath was added 3.85 g (0.013 mole) of 2-(2-chloro-ethyl)-2,~-dihydro-4-methyl-1,4-oxazepino~6,7-b~-quinoline-5t4H)-one in 25 ml o~ methanol. The reaction flask was sealed tightly and left ~tanding at room temperature for 5 days. After cooling, the reaction fla~k was opened and the solvent allowed to evaporate in a stream o~ air. The residue was taken up in 100 ml of chloro~orm and washed with 2 x 50 ml of dilute aqueous sodium hydroxide. The organic layer was dried over anhydrou~ ~odium ~ulfate, filteredJ and c~ncentrated by rotary evaporation (70, ~0 mm). The ~ 4~9A-C~P-~

~ ~ 5 3 residual oil was treated with fumaric acid in isopropyl alcohol w~ich afforded 3.7 g (67%) of white crystals, m.p. 125-130C.
Analysis: Calculated for CzlH2~N30~.5: c,59.4~; ~, .17;
~,9.90 Found : C,59.59; H,6.~5;
N,9.~0 Example 95 2-r2-(Dime~yl ~ -2,7-di~vdr~-4-methyl r 1.4 oxazepinor6 7-blquinoline-5(4H)-thione fumar~te com~ound L J ~ _ _ with isopropanol hydrate rl 1 o-s 0.51.
~ ~ .
To 45 ml of dimethylamine was added 0. 95 g (0.003 mole) of 2-(2-chloroethyl)-2,~-dihydro-~-methyl-1,4-oxazepino ~6,7-b]quinoline-5(4H)-thione. The reaction fla~k was sealed tightly and left standing at room temperature for 6 days.
After c~oling to 0C., the flask was opened and the ~olvent allowed to evaporate at room temperature. The residue was taken up in 50 ml of chloroform and washed with ~ x 30 ml o~ dilute aqueous sodium hydroxide. The organic layer was dried ~ver anhydrous sodium ~ulfate, filtered, and roncen trated by rotary evaporation, yielding 0.94 g of syrup (99 This was combined with 1.0 g of the same product from a previous run* and treated with $umaric acid in iRopropyl alcohol affording 1.5 g of yellow crystals~ m.p.l2~-26 C.
*The previous run was made in the same manner as above except that hydrochloride salt wa~ collected. However, the hydrochloride salt partially decomposed upon drying in a drying pi6tol at 82.5C. Caution 6hould be exercised not to heat the product above the boiling point of acetone (56-57C) while drying.
~0 Analy~is: calculated for Czz.g~30~90~S:C,57.43; H,6.4~, N,8.92 Found :C,57.60; H,6.21;
N,9.02 ~, ~S 3~L~

Example 97 4-Ethyl-1,2~3 4-tetrahy_ro-2-C2-L4-hydrox~-4-~enyl-1-piperidinyl)-ethyl~-l-methvl-~H-1,4-benzodiazepin~-one fumarate comPound with 2-propanol rl:l:l].
A mixture of 13.4 g (0.05 mole) of 2-(2-chloroethyl)-4-ethyl-1-methyl-1,2,~,4-tetrahydro-5H-19 4-benzodia~epin-5-one, 8.85 g (0.05 mole) o~ 4-hydroxy-4-phenylpiperidine, and 14 g (0.1 mole) of potassium carbonate in 100 ml of n-butanol was refluxed for 18 hr and ~iltered. The filtrate was concentrated and the residue partitioned between chloroform and dilute sodium hydroxide. The organic layer wa~ dried over anhydrous sodium ~ulfate and concentrated. The residue was chromatographed on a 4.5 x 45 cm ~lorisil~ column eluting with chloroform~methanol mixture with a gradation from 100~ to 84% chloroform. The fractions containing the 1~ pure product (as seen on tlc using 95% chloroform-5% methanol on Florisil~) were combined and concentrated. The residue was molecularly distilled at 250C. and 0.02 mm Hg. The fumarate salt was prepared in i~opropyl alcohol and recrystallized from isopropyl alcohol-water. Yield 5.8 g.
~20%) m.p. 128-139C.
Analysis: Calculated for C92H45N307: C,65.B5, ~,7.77 N,7.20 Found : C,64.85; H,7 4 N,7.0 Example ~8 4-Ethvl-l~methyl-2-(2-morpholinoethyl) 1,21~,4-tetra-hydro-~H-1,4~ben~odiazepin-5-one.
A solution of 30 g (0.112 mole) of 2-(2-chloroethyl~-4-ethyl-1-methyl-1,2,~,4-tetrahydro-5H-1,4-benzodiazepin-5-one in 70 ml of morpholine was refluxed for 3 hrs, concen-trated on the rotary evaporatox and the residue partitioned between chloro~orm and dilute ~odium hydroxide. The chloro-form was dried over anhydrous sodium sulfate ~nd concentrated on the rotary evaporator. The residue wa~ crystallized twice from i~opxopyl ether containing a small amount Qf ethanol, m.p. 128-148C. Recrystallization from toluene gave 19.5 g (61%) of p:roduct, m.p. 128-148C.
Analysis: calculated :For Cl0H27~97 :C,68.11; ~,8.57; N,13.24 Found sC,68.29; H 8.~7; M,13.26 1~1 9~'C I P -2 ~:~53~

1~5 Example ~3 1?2,3,4-Tetrahydro-l-methyl-2-~(dimethylamino)methyll--4-(1-methylethyl)-5H-1J4-benzodiazepin-5-one.
A mixture of 5.0 g (0.02 mole) of 2-chloromethyl-1,2,3,4-tetrahydro-1-methyl-4-(1-methylethyl)-5H-1,4-5 benzodiazepin-5-one, and 15.0 g (0.45 m~le) of dimethyl-amine, and 200 ml of methanol were placed in a ~teel bo~b and heated and stirred at 100C. for 15 hr. After concen-trating ln vacuo, the residue p~rtitioned between dilute sodium hydro~ide ~olution and chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered and coneentrated ln vacuo. The residue crystallized in isopropyl ether and was recrystallized twice from the same. It weighed 29.0 g (680, m.p. 93-95C.
Analysis: Calculated for Cl~H25N90: C,69.78; H,9.15; N,15.26 Found : C,69.81; H,9.01; N,15.33 Example 100 2-(2-DimethYlaminoethyl)-4-ethyl-1-methyl-1 2,3 4-tetrahydro-5H-1,4-benzodiazepin-5-one.
A ~olution of 30 g (0.112 mole) of 2-(2 chloroethyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one and 10 g (0.224 mole) of dimethylamine in 300 ml of ethanol was heated at 125C. for 8 hrs and concentrated.
The residue was partitioned between chloroform and dilute sodium hydroxide. The chloroform was dried over anhydrous sodium sulate, concentrated and distilled. Yield of product was 20.5 g (66.5 0 , b.p. 175-178/0.1 mm.
Analysis: calculated for Cl~H~sN90: C,69.78; H,9.15; N,15.25 Found : C,69.60; H,9.17; N,15.20 Example 101 2.~-Dihvdro-4-methY1 2-t2-(1-p Peridinyl)ethyl]pyrldo-~3.2-f~rl,4~xazePine-~(4H?-thione fumarate, hydrate_compound with isopropvl alcohol rl:l:0.~:0.~1.
To a suspension of 5.0 g (0.019 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyrido~3,2-f~-1,4-oxazepine-5( 4H) -thione in 75 ml of absolute ethanol was added 10 ml ofpyridine and the mixture heated to 50C. for 4 days. ~thanol ~ ~419~-CIP-2 ~ 253 was removed by rotary evaporation (70~C, 30 mm Hg).
Piperidine was removed by rotary evaporation (80C, 5 mm Hg) followed by azeotroping with 2 x 100 ml of toluene; The syrupy residue was taken up in 200 ml of isopropyl alcohol and heated with fumaric acid which afforded 5.2 g (57%) yellow crystals, m.p. 13~-40C.
Analysis: Calculated for C2l,5H32N3O~S: C,56.07; H,7.00 ~,9.12 Found : C,55.90; H,6.85;
~,9-17 Example 102 6-Chloro-2 ~_dihvdro,-4-methvl-2 -r2 - ( dimethYlamino)ethvll,-4-meth~lpYridor4 .~-f ~1. 4l-oxazepin-~4H)-one fumarate.
0 . 51-To 40 ml of freshly collected dimethylamine at -10C
was added 4.0 g (0.015 mole) of 6-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~4s3-f~-1,4-oxazepin-5(4H)-oneO
The reaction flask was ~ealed tightly and left standing at room temperature for 5 days. After cooling to -10C., the ~Ela~k was opened and the dimethylamine allowed to evaporate overnight. The residue was taken up in 100 ml of chloroorm, washed with 2 x 30 ml of dilute sodium hydroxide, dried over anhydrous sodium sulfate, ~iltered and concentrated by rotary evaporation (70C, 30 mm Hg). The residue was treated with fumaric acid in isopropyl alcohol which upon crystallization afforded ~.8 9 (76.7%) of yellow crystals.
Analysis: Calculated for Cl5H~0~904Cl: C,52,70; H,5.90;
N,12.29 Found : C,52.67; H,5.96;
~ ,12.01 xample 103 ?,3-Dihydro-4=methyl-6-dimethylamino-?-~2-(dirnethyl-amino)ethyll-4-methylpyridor 4~5-flrl~4l-oxazepin-5(4H)-one fumarate ~1:1.5~.
To 100 ml of freshly rollected dimethylamine in a stainless ateel bomb was added 4.5 g (0.016 mole) o~ 6-ehloro-~5 2-(2-chloroethyl)-2,3-dihydro-4-methylpyridot4,3-f~-1,4-~xazepin-5(4H)-one. The bomb was sealed tigh~ly ~nd plaeed in an oven at 100C. for 18 hr. A~ter cooling, the bomb was ~ ~I9A-CIP-2 147 ~253~5 opened and the dimethylamine allowed to evaporate at room temperature. The residue was taken up in 150 ml of chloroform, washed with 2 x 40 ml of dilute aqueous sodium hydroxide, dried over anhydrous ~odium ~ulfate, filtered and concentrated by rotary evaporation (70C, 30 mm Hg).
The residue was treated with fumaric acid in isopropyl alcohol. The resulting crystals were collected, dried overnight at room temperature, 0.5 mm Hg. The white crystals were collected and afforded 4.2 g (56.3%) of the title compound, m.p. 172-75C.
Analysis: Calculated for C2lH30N40~: C,54.07; H,6.48; M,12.01 Found : C,54.01; H,6.58; ~,12.00 ExamPle 104 2~-Dih~dro-2~r2-(2~5-dihydro-lH-pyrrol-l~yl)ethy~JL-4-methylpYr_dor~.2-f~-1.4-oxaze~in-5~4H~-one fumarate rl 2l-To a 301ution of 10.0 g (0.041 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyrido~3,2-f~-1,4-oxazepin-5(4H)-one in 50 ml of dimethylformamide was added 9.0 g (0.14 mole~ of a mixture of 3-pyrroline:pyrrolidine~, 3:1, v/v. The solution was heated to 65C. under an N2 blanket overnight. The ~olvent was removed by rotary evaporation (70 C., 0.5 mm H~). The syrupy residue w~s taken up in 100 ml of chloroform, washed with 2 x 30 ml o~ dil. aqueous sodium hydroxide, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (60CJ ~0 mm).
The residue was azetroped with ~ x 100 ml of tolue~e. The re~idue wa~ purified by HPLC to separate out the pyrrolidine derivative,eluting with 2~ triethylamine in methylene chloride (v/v). Fractions with similar TLC's were combined and concentrated by rotary evaporation. To the re~idue was added~100 ml of toluene and the mixture heated to 70C.
and filtered hot. Approximately 0.2-0.3 g of hygroscopic cryqtals w~re collected. The toluene wa8 removed by rotary evaporati~n (70C, ~0 mm Hg). The residual 8yrup wa~ treated 3~ with fumaric acid in i~opropyl alcohol. Two crGps ~f cry~tals were collected, combined and recrystallized together giving 4.6 9 (2~.1%) of white cry tal~, m.p. 158-159C.

Analysis: Calculated for C23H~7N3Olo: C,S4,55; ~,5-38 N,8.31 Found : C,54.58; H,5.49;
N,8.30 ~Pyrroline contains pyrrolidine as impurity.
Example 105 2,3-Dihydro-2-(2J5-dihydro-lH-pyrrol-1-yl)ethyl~-4-methylpyridor~2-fl-lJ4-oxazepine-5(4H)-thione fumarate .
To a solution of 9.0 g (0.035 mole) of 2-(2-chloro-ethyl)-2,~-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(1~H)-thione in 50 ml of dry dimethylformamide was added 10.0 g (0.141 mole)oE3-~yrroline/pyrrolidine*, ~ /v, and the mixture heated to 60C. for 18 hr. The solvent was removed by rotary evaporation (70C, 0.5 mm Hg) and the syrupy residue purified by HPLC separating out the pyrrolidine derivative eluting with 2~ triethylamine in methylene chloride (v/v) over silica gel. Fractions having similar TLC's were combined and concentrated by rotary evaporation.
The syrupy residue was treated with fumaric acid in isopropyl alcohol which afforded 4.0 g (28.1%) of crystals.
one recrystallization from isopropyl alcohol afforded an analytical sample~ m.p. 14~-45C.
~nalysis: calculated for Cl9H~3N305S: C,56.28, H,5.72;
N,10.36 Found : c,56.o3; H,5.23;
*Pyrroline contains pyrrolidine as imp~rity.
Example 106 2-r2-(l-Azetidinyl)ethyll-2~3-dihydro-4-methylpyrido ~,?-frrl,41oxazepin-5(4H)-one oxalate hydrate rl:l:0.51.
To a solution of 4.1 g (0.017 mole) of 2-(2-chloro-ethyl)-2,~-dihydro-4-methylpyrido~3,2-f~-1,4-oxazepin-5(4~)-one in 50 ml of dimethylformamide under nitrogen was added a solution/suspension of 0.7 g (60~ in oil, 0.017 mole) oP sodium hydride in .10 ml ~f dimethylformamide to which 1.0 g (0.017 mole) of azetidine in 20 ml of dimethylformamide had been added and allowed to stir under nitrogen atmosphere until hydrogen evolution ceased ( 15 min). The reaction mixture was ~tirred for 18 hr under nitrogen at room temperature. The solvent was removed by rotary evaporation (70C, 0.5 mm Hg) and the residue taken up in 100 ml of chl~roform, washed with 3 x 30 ml dil, aqueous ~odium ~ ~5 ~ ~ 5 hydroxide, dried over anhydrous sodium ~ulfate, filtered and concentrated by r~tary evaporation. The residue was treated with oxalic acid in isopropyl alcohol which aPforded 1.~ g (21.2%) of white crystals, m.p. 172-174C. with slight decomposition.
Analysis: calculated for C1BH2ZN9O~.5 CJ53'33; H~6-15 N,11.6 Found : C,53.73; H,6.11, N,11.67 ExamPle 107 (Re~er to Chart VIII) 2-~(Dimethylamino ~ethyl]-2,~-dihydro-4-methylpyrido ~2-f]~lJ4~oxa~epin-5(4H)-one fumarate ~
Dimethylamine 22.6 g, 40% solution (0.2 mole) was added dropwise to a solution of 16 ml of epichlorohydrin (G.2 mole) in 100 ml of methanol at 5C. stirring in an ice bath. After two hours at 5C. a chilled solution of 85 ml methylamine of 40~ solution (1 mole) was poured into the reaction mixture. Stirring was continued in ice bath ~or one hour and then room temperature overnight. The solventY were evaporated and the clear oil was pumped under vacuum at 75 C. for 1.5 hr to give 28.23 g (~84~ yield) of l-dimethylamino-3-methylamino-2-propanol hydrochloride (I) as the main product.
Compound I, 21.4 g (0.143 mole) and 22.6 g of 2-chloro-nicotinic acid (0.143 mole) were stirred in 150 ml acetoni-trile and 60 ml water as a two-layer system. Dicyclohexyl-carbodiimide, 33 g (0.16 mole) dissolved in 90 ml of acetonitrile was added in four portions. After the addition o~ the second portion, an ice bath was necessary for controlling the temperature at around 25 C. Two and a half hours later, 10 g of 2-chloronicotinic acid was added to the reaction mixture and 15 g of dicyclohexylcarbodiimide in 200 ml o~ acetonitrile was added in another hour. The reaction was 6tirred at room temperature overnight. Concen-trated hydrochloric acid was added to the reaction mixture to pH 2 in order to convert thP excess carbodii~mide to urea.
The white 801id was removed by filtration and rinsed with aqueous acetonitrile. The filtrate and washings were evaporated to a paste which was partitioned between methylene ~ ~ ~ 3 chloride and potassium carbonate solution. The a~ueous layer was extracted two more times with methylene chl~ride.
The methylene chl~ride soluti~ns were back washed with ~odium chlorid~ solution, dried over anhydrous ~odium sulfate and evaporated to give 56 g of oil. This oil was chromatographed on 250 g of silica gel eluting with methanol to give 26.97 g of light brown oil containing mainly the 2-chloronicotinamide of compound I.
The 26.97 9 of compound obtained from chromatography was dissolved in 200 ml of toluene and heated to distill out about 40 ml solvent and then refluxed under a Dean-Stark trap ~or one half hour. Sodium hydride, 15 g (50% suspension in mineral oil, 0.3 mole) was added portionwise to the toluene solution at room temperature. The mixture was then heated to reflux for 20 min. The cooled mixture was treated with isopr~panol and celite and then ~iltered. The filtrate was aeidified with hydrogen chloride solution in isopropanol. The white solid thus ~ormed was collected by filtration, rinsed with isopropyl alcohol-i opropyl ether and dried under nitrogen. This material weighed 11 g and absorbed moisture from air readily. Some ~econd and third crop material~ were obtained from the mother liauor ~nd washings. All three crops were combined and dissolved in water, the solution was made basic with excess amount of potassium carbonate and then extracted three time~ with methylene chloride; the methylene chloride ~olutions were bacX washed with saturated sodium chloride s~lution, dried over magnesium sulfate and treated with activated charcoal, filtered and evaporated to give 8.8 g of brown oil, the free base of the title compound.
A 1.9 g sample of the brown oil was dissolved in methanol and kept warm on steam ~ath. Fumaric acid was added and the s~lution was concentrated to a small volume.
Excess amount of acetone was added to ~rystallize out the ~5 fumarate ~alt. The salt was recrystallized once to 1.4 g of white ~olid, m.p. 150-151C~
Analysis: calculated for Cl~H2lN30~: C,54.70; H,6.02; N,11.96 Found : C,54.69; H,6.o7; M,11.88 ~9A -Cl P-2 Example 108 2-r (Dimethylamino)methyll-2 ,3-dihydro-4-methylpyridc~
L3,2-fl~1,4~oxazepine-5(4H)-thione fumarate ~2~
2-~(Dimethylamino~methyl]-2,3-dihydro 4-methylpyrido [3,2-f~1,4]ox~zepine-5(4~)-oneJ 4.8 g, was dried azotropi-5 cally in about 50 ml of toluene. To the warm solution was added Lawesson reagent (Aldrich #22, 74~-g, 4.9 g) and the reduction mixture was kept at reflux for two hours. On contact with concentrated potassium carbonate solution, the reaction mixture became a three-layer system; both the aqueous layer and the toluene layer contained product but not the third gummy layer. The layers were 6eparated and the aqueous layer was extracted three times with methylene chloride which was back washed with saturated sodium chloride solutionJ combined with the toluene layer, dried over sodium ulfate and evaporated ~o 5.25 g oil. This oil was dissolved in methanol and 2.45 g fumaric acid was added.
With heating and stirring, i~opropanol was added to the point of cloudiness and then left stirring overnight. The mixture first deposited out a layer of brown gummy material and then crystallized to a yellow powder. The yellow powder, 2.85 gg was collected and recry~tallized from methanol, m.p. 178-179C.
Analysis: Calculated for Cl~Hl9N303S: C,54.~5; H,6.19:
~,13.5 Found : C,54.21; H,6.20:
NJ13-5~
Example 109 (Refer to Chart ~III) 2-r2-~Dimethvlamino)ethvll-~ ~-dihvdro-4-methvlpyrido r~2-~r ~ oxazepin-c~(4H)-one .
To a cold (ice bath) solution o$ ~.2 g (0.02 mole) of 2 chloronicotinic acid and 3 g (0.02 mole) of l-dimethylamino-4-methylamino-2-butanol in 25 ml of methylene chloride Wa5 added 4.55 g (0.022 mole) of dicyclohexyl carbodiimide.
Methanesulfonic acid, 1.8 ml, was added to bring the pH to 6. White ~olid appeared in the reaction mixture. The ice ~5 bath was removed after 1 hr and the mixture was allowed to stand at room temperature overnight. The white solid was removed by filtration and the ~ilter cake rin~ed with ~ ~ S 3 methylene chl~ride. The c~mbined filtrate and wash was extracted twice with 0.6 ~ hydrochloric acid (15 ml and 10 ml). To the combined acidic aqueous extracts was added 6 g of potassium bicarbonate and methylene chloride with ~tirring. The layers were separated and the aaue~us basic layer was extracted with methylene chloride. The methylene chloride layers were combined, dried over anhydrous sodium sulfate and evaporated to give 4.5 g brown oil which was predominantly 2-chloro-~-~4-(dimethylamino)-2-hydroxybutyl~-10 N-methyl-~S-pyridinecarboxamide.
The 4.26 g (0.0149 mole) of ~he foregoing pxepared 3-pyridinecarboxamide was mixed with 50 ml of toluene and the mixture was heated to di3till off about 20 ml of solvent and then kept at reflux using a Dean-Stark trap to collect m~isture. The temperature o~ the solution was lowered somewhat and 0.864 g (0.018 mole) of sodium hydride in mineral oil was added to produce gentle reflux. After a total of 45 min, the mixture was cooled and to it was added 0.5 ml of isopropyl alcohol and 0.5 ml of water. Carbon dioxide was 20 bubbled in to convert the sodium hydroxide produced to sodium bicarbonate. The mixture was then azeotroped to dryness using a Dean-Stark trap. Some acetonitrile was added to the hot mixture. After cooling, the mixture was filtered through celite rinsing with acetonitrile. The filtrate was evaporated to give a mixture of the title product and a trace of mineral oil. The amount of title product obtained was 3.45 g (93% yield). The NMR and Mass Spec agreed with that of the free base of the compound prepared in Example 10.

~~ J 419A-CIP-2 ~ ~ ~ 3 Example 110 2-~2-(Dimethylamino)ethyl~-2 3-dihydro-4-methyl-1,4-oxazepinor7t6-f~isoquinolin~t4H)-one oxalate.
Following the procedure of Example 21, 2-(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-oxazepino~7,6-f~isoquinolin-5(4~
one is reacted with dimethylamine to give the title compound.
Example 111 2-~2-(Dimethylamino)ethyll-2,3-dihydro-4-methyl-1,4-oxazepino~7,6-f~isoauinoline-5(4~)-thione hydrochlorlde.
Following the procedure of Example 31, 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[7,6-~isoquinoline-5(4H)-thione is reacted with dimethylamine to give the title compound.
ExamPle 1 1?
?-r2-(Dimethvlamino)ethyll-2~3-dihvdro-4-methy~ 4 oxazePinor6.7-q~is?~uinolin-~(4H~-one oxalate.
Following the procedure of Example 21, 2-(2-chloroethyl)~
2,3-dihydro-4-methyl~194-oxazepino[6,7-g~isoquinolin-5(4H)-one is reacted with dimethylamine to give the title compound.
ExamPle 113 2-r2 tDimethylamino)ethyl]-2~3-dihydro-4 methvl-1,4-oxazepiner6.?-q~iso~uinoline-5(4H)-thione hydrochloride.
Following the procedure of Example ~1, 2-(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-oxazepino~6,7-g]isoquinoline-5(4H)-thione is reacted with dimethylamine to give the title compound.
Example 114 2-r2-~Dimethylamino)ethYll-2~-dihydro-4~7-dimeth 1~4-oxazepinor6t7-blquinolin-5(4H)-one oxalate.
Following the procedure of Example 21J 2-(2-chloroethyl)-2"~-dihydro-4,7-dimethyl-1,4-oxazepino~6,7-h]auinolin-5(4H)-one is reacted with dimethylamine to give the title compound.

~ ~5 3 Example 115 2-[2-~Dimethylamino)ethylJ-2,3-dihydro-4,7-dimethyl~
1,4-oxazeplno~6,7-h]quinoline-5(4H)-thione hydrochloride.
Following the procedure of Example ~1, 2-(2-chloroethyl)-2,3-dihydro-4,7-dimethyl-1,4~oxazepino[6,7-h]quinoline-5(4H)-thione is reacted with dimethylamine to give the title compound.
Exam~le 116 2-~2-(Dimethylamino~ethyll-?~3-dihydro-4~lo-dimeth 1,4-oxazepino~6,7-hlquinolin-5(4H)-one oxalate.
Following the procedure of Example 21, 2~(2-chloro-ethyl)-2,3~dihydro-4,10-dimethyl-1,4-oxazepino[6,7-h]-guinolin-5(4H)-one is reacted with dimethylamine to give the title compound.
Example 117 2-~2-(Dimethylamino)ethyl~-2,3-dihydro-4,10-dimethyl-1,4-oxazepinoL6,7-hlquinoline-5(4H)-thione hydrochloride.
Following the procedure of Example ~1, 2-(2-chloro-ethyl)-2,3 dihydro-4J10-dimethyl-1,4-oxazepino~6,7-h) quinoline-5(4H)-thione is reacted with dimethylamine to ~ive the title compound.
ExamPle 118 4-L~-(Dimethylamino)ethyll-3,4-dihydro-2-methyl-11,41-oxazepino~6,7-f]quinolin-1(2H)-one oxalate.
Following the procedure of Example 21, 2-(2-chloro-~5 ethyl)-3,4-dihydro-2-methyl[1,4]-oxazepino~6,7-f~quinolin-1(2H)-one is reacted with dimethylamine to give the title compound.
Example 119 4-r2-(Dimethylamino)ethyl1-3,4-dihydro-2-methyl~1,4~-oxazepino~6,7-f]quinoline-1(2H~-thione hydrochloride.
Following the procedure of Example 31, 4-(2-chloro-ethyl)-~,4-dihydro-2-methyl-tlJ4~-oxazepino~6,7-f]quinoline-1(2H)-thione i-~ reacted with dimethylamine to give the title compound.

419A~CIP-2 ExamPle l?o 2-~2-(Dimethylamino)~thyl~-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-h~quinolin-5(4H)-one oxalate.
Following the procedure of Example 21, 2-(2-chloro-ethyl)-2,3-dihydro-4-methyl-1,4-oxazepino~6,7-h]quinolin-5(4H)-one is reacted with dimethylamine to give the title compound.
Example 1?1 2-r2-(Dimethylamino)ethvl]-2 3-dihydro-4-methY1-1,4-oxazepinor6,7-h~quinoline-~(4H)-thione hydrochloride.
Following the procedure of Example ~1, 2-(2-chloro-ethyl)-2,3-dihydro-4-methyl-1,4-oxazepino~6,7-h~quinoline-5( 4H) -thione is reacted with dimethylamine to give the title compound.
Example l2?
2-~2-(1-Azetidinyl)ethyll-2,3-dihydro-4-methylpyrido L3~2-f]~l~4~oxazepin-5(4H)-one oxalate hydrate C1:1:0.5~.
To a solution of 5.0 g (0.021 mole) of 2-(2-chloro-ethyl)-2,3-dihydro-4-methylpyrido~3,2~f]-1,4-oxazepin-5(4H)-one dissolved in 40 ml of dimethylsulfoxide was added 8.7 9 (0.063 mole) o~ potassium carbonate followed by 1.40 g ~0.025 mole) of azetidine. The mixture was stirred for 4 days at room temperature*. Another 0.5 g (0.009 m~le) of azetidine was added and ~tirring continued for 24 hr.
Another 0.7 g (0.012 mole) of azetidine was added and the mixture was stirred for 24 hr. The potassium carbonate was filtered off and the dimethyl sulfoxide was removed from the filtrate by rotary evaporation at 90C., 0.5 mm Hg.
The residue was taken up in 100 ml of methylene chloride and the solution was washed with two 30 ml portions of water followed by 30 ml of dilute a~ueous sodium hydroxide.
The organic layer was dried over magnesium sul~ate, filtered ~nd concen~rated by rotary evaporation. The residual syrup was reacted with oxalic acid in isopropyl alcohol giving 3.3 g (44O of white crystals, m.p. 170-172C. lHNMR analysis was esse~ially the same as for the ~ame compound obta ined in Example 106.
*Stirrer had mal~unctioned causing need for a longex 4l9~-cIp-2 ~2~i3 stirring period than an estimated 1-2 days ~hat should be reauired.
~xample 123 2-r2-~1-Azetidinyl)ethyl~-2,3-dihydro-4-methylpyrido r~?-flrlJ4loxazeplne-5(4H)-thione fumarate.
To 5.0 g (0.0914 mole) of 2-(2-chloroethyl)-2,5-dihydro-4-methylpyrido~3~2-f]-lJ4-oxazepine-5(4H)-thione dissolved in 50 ml of dimethylsulfoxide was added 8.o4 g (0.058 mole) of potassium carbonate and 1.21 g (0.021 mole) of azetidine. The reaction mixture was stirred at room temperature for 8 hr after which was added 0.5 g (0~009 mole) of azetidine and the mixture was ~tirred overnight at room temperature. An additional 0.3 g (0.005 mole of azetidine was added and stirring was continued for 24 hr.
The mixture was filtered and solvent removed by rotary evaporator at ~0C., 0.5 mm Hg. The residue was taken up in 190 ml of chloroform and the solution was washed with two 30 ml portions of dilute aaueou~ sodium hydroxide.
The ~rganic layer was dried over magnesium sulfate, filtered and concentrated by rotary evaporatsr. ~he residue was reacted with fumaric acid in isopropyl alcohol to give 205 9 (31O of pale yellow crystals, m.p. 122-126C.

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116 ~ O -CH9 ~ O -N(CH3)2 -(CH2)2- oxalate CH ~ S -CH3 H O -N(CH3)2 -(C~2)2- HCl 118 ~ O -CH3 ~ O -N(CH3)2 -(CH2)2- oxalat0 N
9 ~ S -CH3 H O -N(CH3)z -(CH2)2- HC
E

~ O -CH9 H O -N(CH3)z -(CHb)z- oxalate 121 ~5 -CH3 ~ O -~(CH3)2 -(CHz)2- HCl 122 py~ido~3,2-fJ 0 -CU~ ~ o -N ~ -(CH2)2- oxalate, 0.5 H20 123 pyrido~3,2-f~ s -cu, u o -1l~ -(cu2 )~- fumarate Footnote:
-N3 C~- ( 4 F -C ~ , ) z Additional Pharmac~l~qy Experiments were conducted to determine whether sedation was present as a result ~f administration of the c~mp~unds of the invention as antihistaminics and the results on compounds tested suggests they are non-sedative anti-histaminics. The comparative antihistaminic agent used wasdiphenhydramine which does cause sedation. See Douglas, W. C.
(1980), "Histamine and 5-hydroxytryptamine (serotonin) and their antagonists" in The Pharmacoloqical Basis of Thera-pe~tics (ed: A. G. Gilman, L. S. Goodman, A. Gilman, 6th edition, Macmillan, New York, pp 609-641. In the present tests, sedation is defined as a change in the electro-encephalograms (EEGs) from the normal pattern of low voltage, fast (~) cerebral cortical waves (1?-25 Hz, <50 mV
amplitude) to synchronized high voltage9 slow(~, D) cerebral cor~ical wavas (1-3, 4-7 Hz, > 50 m V amplitude) with frequent periods of sleep spindles predominating.
Experimental Method for Sedative Activity Ten cats of both sexes wera anesthetized with halothane and cannulae placed in the trachea, the left cephalic vein, and the right femoral artery for artificial ventilation, drug administration, and blood pressure recording, respectively.
The head was fixed in a Kopf stereotaxic unit and the calvarium was widely exposed. Stainless steel screw electrodes (1/4"~ were placed through the calvarium so that the tips rested on the dura over the frontal, parietal, and occipital areas, bilaterally. An electrode of the same type was placed in the right frontal sinus and served as the ~eference electrode for monopolar EEG recordings. After completio~ of the surgery, the animal was given gallamine triethiodide ~20 mg, IV; ~upplemented as necessary) and the halothane withdrawn. Artificial respiration was instituted (10 ml x~m air/kg/~ sec).
EEGs were made on a Grass, Model 5, electroencephalograph along with (lead II) EKG. ~ypically, EEGs were recorded for 2-3 min every 10 min. Arterial blood pressure was continuously monitored on a Gra~, Model 79, polygraph.

~'~19A-CIP~2 ~S;~

In most experimentsJ histamine (0.5 ~g~kg, IV) ~as given to produce a transient (~ 30 sec) hypotensive effect.
It was normally given 10, 20 and 30 min prior to the first dose of the t~st drug and then 5, 10 and 20 min after each dose of the test drug. In this way an indication of the antihistaminic activity of test drug could be auantified.
Concomitant with the antihistaminic auantification was the ef;fect of test dxug on EEG. Test drug was usually given in increasing doses of 0.1, 0.3, 0.5, 1, 3, 5, 10 and 20 mg/kg, IV.
Experimental Results on Sedative Potential Illustratively of the compounds tested (Examples 12, 65 and 71) the compound of Exa~ple 12 produced a 50~ reduction f the histamine-induced depre sor effect on blood p~essure at 0.~ mg~kg, IV and a 100% suppre$sion at 1-3 mg/ky, IV.
There were no signs of sedation in these animals at any dose up to 20 mg/kg, IV~
On the other hand, the comparative drug, diphen-hydra~ine, known to produce sedation ~tested hexe in 6 cats~produced a 50~ supp-ession of the hista~ine-induce~ depre~sor ef~ect on blood pressure at 0.5 mg/kg, IV and a 100~
suppression at 3-5 mg/kg, IV. Signs of sedation with diphenhydramine occurred in the EEG tracings as l~w as 5 mg ~g, IV with marked slowing, synchronized waves, and sleep spindles at 1-3 mg/~g, IV. In summary, diphenhydramine produced an antihistaminic effect in doses which also produced a sedatiYe effect. This i8 similar to what is see in man with diphenhydramine.
~0 In contrast to the e~fects of diphenhydramine, compounds such as that of Example 12 do not produce sedation at any dose up to 20 mg/~g, even though the antihistaminic effects occurre~ at ~uch lower doses. These data, theref~re, suggest the nonsedative nature of compound3 of the inv~ntion.
~5 c I p-2 Pharmaceutical_C~position~
The invention further proYide~ pharmaceutical compositione ~or administration to ~ living animal body comprising, ~g active ingredient~, at lea~t ~ne of the compounds of Formula ~ according to the invention in acsociation with a pharmaceutical carrier ox excipient.
The compounds are thus presented in a therapeutic composition suitable for oralJ rectalJ parenteral, ~ubcutaneous, intramuscular, intraperitoneal, intravenous, or intrana~al administration. Thus, ~or example, compositions for oral a~mini~tration can take the form of elixirs, capsules, tablets or coated tablets containing carriers cDnveniently used in th~ pharmaceutical art.
Suitable tableting excipient~ include lacto~e, potato and maize ~tarches, talc, gelatin and stearic an~ ~ilicic acids; magnesium stearate and polyvinyl pyrrolidone.
For parenteral admini~tration, the carrier or excipient can ba compri6ed of a sterile parenterally accaptable liquid; e.g., water or ar~chis oil contained in ampoules.
In compositions ~or rectal administration, the carrier can be compri~ed of a suppository ba~e; ~.g. J coc~a butter or a glyceride.
Application to the no~e, throat or bronchial region can be in the form of gargle or an aerosol ~pray eontaining ~mall particles of the agent o$ Formula I in a ~pray or dry powder form.
Advantageously, the compo~itions are fonmulated as dosage unit~, each unit being ~dapted to supply a fixed dose of ~ctive ingredients. Ta~lets, coated t~blet~, capsules, ampoules ~nd ~uppo~itories ~re examples of prefexred dosage fOrmB according to the invention, It i6 only neces~ary that the active ingredient constitute an effective amount; i.e., ~uch that a ~uitable e~fective do~age will be con~i~te~t with the do~age ~orm employed.
~5 The exact individual do~age6, a~ well a~ d~ily do~ages, ~25;~

will of oour~e be determined ~ccs~ding to ~tandard medical principle~ under the dir~ction of a physician or veteri-narian. Generally, the pharmacology te~t~ on guinea pigs in compari60n to certain other antihistaminic drug~
suggests an ef~ective dose for an adult will be in the range of 2 to 8 mg for the more ~ctive compounds.
Based on the animal data, unit dosages ~ontaining an amount of compound equivalent to ~bout 0.03 to 0.10 mg of active drug per kilogram of body weight are contemplated.
Daily dosages of about 0.2 tv o.6 mg ~g of body weight ~re contemplated for humans ~nd obviously several small unit dosage forms may be administered at one time. ~owever, the 8cope of the invention i8 ~ot to be limited by theRe contemplation~ due to uncertainty in transposiTIg from animal data to humans.
Examples of unit dosage compositions are as follows:
Capsules:
Inqredients Per ca~sule 1. Active ingredient 4 mg.
2 2- ~actose 150 mg-3. Magnesium 8tearate 4 mg.
Tablets:
Inqredients 1. Active ingredient 4 mg.
2 2. Corn starch 20 mg.
3. Xelacid 20 mg.
4. Xeltose 20 m~.
5. Magne~ium stearnte 1.3 mg.
Procedure for tablet :
1. ~lend 1, 2, 3, 4 in larger zlmounts.
2. Add ~u~ficient watex portionwise to blend to the blend ~rom step 1 with careful ~tirring after each ~ddition. Such addition5 o~ water and ~tirring continue until the mas5 i8 of ~ con~tituency to permit its conver~ion to wet granule~.
3. The wet mas~ is converted to granules by passing it through the o~cillating granulator u~ing 8 me~h ~creen.
4. The wet granule~ ar2 then ~rie~ in an oven at 140F.

4~JA-CI~2 ~ ~5 5. The dry granules ~re lubricat~d with the magnesium ~tearate.
6. The lubricated granules are compres6ed on a ~uitable tablet pre6s.
Intramuscular In~ecti~n Per ml.
1. Active ingredie~ts10.0 mg.
2. I30tonic buffer solution 4.0 q.~ to 1.0 ml.
Procedure:
. = ~ . = . .
1. Dissolve the active ingredient in the bu~fer solution.
2. Aseptically filter the ~olution rom step 1.
3. The sterile fiolution i~ now aseptically filled into 6tezile ampuls.
4. Th ampuls are ~ealed under a~eptic condition.
Suppositories:
InqredientY ~
1. Artive ingrediant10.0 mg.
2. Polyethylene Glycol 1000 1~50.0 mg.
3. Polyethylene ~lycol 4000 450.0 mg.
Procedure:
lo Melt 2 and ~ together and stir until uniform.
2. Disaolve No. 1 in the molten mas from ~tep 1 and Bt ir until unifQrm.
~ . Pour the molten mas~ ~rom ~tep 2 into ~uppo~itory mold~ and chill.
4. Remove the ~uppo~itorie~ from molds and wrap.
Therapeutic compo~ition~ for combatting hi~tamine in unit dosage fvrm, compriaing a phanmaceutical carrier and ~n effective ~mount of a compound of Formula I or a 30 pharmaceutically acceptable zlcid addition salt thereof are there~ore an embodiment of this invention.

S ~ 5 4~ CI~2 Vari~us modification~ ~nd e~uivalent~ will be apparent to one ~Xilled in the art nnd may be made in the compoun~s, method6, proces e~ and pharmaceutical composition~ of the present invention without departing from the spirit and scope thereof, and it i~ th~refore to be under~tood that the invention i~ to be limited only by the ~cope of the ap~ended claim~.

Claims (21)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An aromatic oxazepine, thiazepine or diazepine of the formula:

(II) (wherein A represents an aromatic ring having two adjacent carbon atoms held mutually with the oxazepine, thiazepine or diazepine moiety, the aromatic ring being a benzene, naphthalene, quinoline or pyridine ring and being optionally substituted in any of the substitutable positions by one or two radicals Y selected from the group consisting of halogen, C1-8alkyl, C1-8alkoxy, di(C1-8alkyl)amino, nitro and trifluoro-methyl;
E is oxygen, sulfur or N(C1-8)alkyl;
B is oxygen or sulfur;
R is C1-8alkyl, C3-9cycloalkyl or phenyl-(C1-4)alkyl in which the phenyl radical may be substituted by one or two substituents selected from the group consisting of halogen, C1-8 alkyl, C1-8alkoxy, nitro and trifluoromethyl;
D is C1-2alkylene which may be substituted by C1-5 alkyl;
R4 is hydrogen or C1-5alkyl; and X is chlorine, bromine, cyano or 1-phthalimido) or an acid addition salt thereof, provided that a compound of formula (II) is excluded (in which:
A represents an aromatic ring having two adjacent carbon atoms mutually held with the oxazepine or thiazepine moiety, the aromatic ring being a benzene, naphthalene, or pyridine ring and being optionally substituted in any of the substitutable positions by one or two radicals Y selected from the group consisting of halogen, C1-8alkyl, C1-8alkoxy, di(C1-8alkyl)amino, nitro and trifluoromethy;
E is oxygen or sulfur;
D is unsubstituted C1-2alkylene;
R4 is hydrogen;
X is chlorine, bromine or cyano; and B and R are as defined above).

2. A proeess for producing a compound of the formula (II) as defined in claim 1 including the proviso or an acid addition salt thereof, which process comprises:
[a] chlorinating or brominating a compound of the formula:

(IVb) (wherein R3 is hydrogen or an acid neutralizing ion, and the other symbols are as defined in claim 1),and fusing the halogenation product to give a compound of formula (II) wherein B is oxygen and X is chlorine or bromine, [b] when required, reacting a product of step [a]
with a sulfurizing agent to give a compound of formula (II) where-in s is sulfur and X is chlorine or bromine, [c] when required, reacting a product of step [a]
or [b] with an alkali metal cyanide to give a compound of formula (II) wherein X is cyano, [d] when required, chlorinating a product of step [a] or [c] having the formula:
(wherein X is chlorine, bromine or cyano, and the other symbols are as defined in claim 1),with sulfuryl chloride to give a com-pound of the formula:

(wherein X is as defined in [d], and the other symbols are as defined in claim 1) ,or [e] when required, reacting a product of step [a], [b] or [d] wherein X is chlorine or bromine, with an alkali metal salt of phthalimide to give a compound of formula (II) wherein X is 1-phthalimido, and if desired, converting a compound of formula (II) produced by any process above into an acid addition salt thereof.

3. A process according to claim 2, wherein the chlorin-ation or bromination of process [a] is carried out using a) thion-yl halide, b) triphenylphosphine and a carbon tetra halide, c) phosphorus pentahalide, d) phosphorus trihalide or e) triphenyl-phosphine dihalide wherein the halogen is chlorine or bromine, to give a halogenation product of the formula:

(III) (wherein X is chlorine or bromine, and the other symbols are as defined in claim 1), and the acid addition salt of formula (III) is neutralized to give the corresponding free base which is fused to give a compound of formula (II) wherein B is oxygen and X is chlorine or bromine.

4. A compound according to claim 1, wherein the aromatic ring A has one of the following formulae:
Wherein the cite on the aromatic ring connected to E indicates the cite in formula (II) at which the group E is connected and the short bar indicates the cite in formula (II) at which the group -C(=B)-N(R)- is connected, and each of the aromatic rings A may be optionally substituted by one or two radicals Y selected from the group consisting of fluorine, chlorine, bromine, iodine, methyl, methoxy, trifluoromethyl and dimethylamino.

5. 2,3-Dihydro-2-[1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one.

6. 2-[2-(2,3-Dihydro-4-methyl-5(4H)-thioxopyrido[3,2-f]
[1,4-oxazepin-2-yl)-ethyl]-1H-isoindole-1,3(2H)-dione.

7. 2-(2-Chloro-1-methylethyl)-2,3-dihydro-4-methylpyrido [3,2-f][1,4]-oxazepin-5(4H)-one.

8. 2-(2-Chloropropyl)-2,3-dihydro-4-methylpyrido[3,2-f]
1,4-oxazepin-5(4H)-one.

9. 2-(2-Chloropropyl)-2,3-dihydro-3-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-thione.

10. 2-(2-Chloro-1-methylethyl)-2,3-dihydro-4-methylpyrido [3,2-f]-1,4-oxazepine-5(4H)-thione.

11. 2-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino [6,7-b]-quinolin-5(4H)-one.

12. 2-(2-Chloroethyl)-2,3-dihydro 4-methyl-1,4-oxazepino [6,7-b]quinoline-5(4H)-thione.

13. 2-(2-Chloroethyl)-2,3-dihydro-4-methyl-9-(trifluoro-methyl)-1,4-oxazepino[6,7-c]quinolin-5(4H)-one.

14. 2-(2-Chlorophenyl)-2,3-dihydro-4-methyl-9-(trifluoro-methyl)-1,4-oxazepino[6,7-c]quinoline-5(4H)-thione.

15. 2-Chloromethyl-1,2,3,4-tetrahydro-1-methyl-4.(1-meth-ylethyl)-5H-1,4-benzodiazepin-5-one.

16. 2-(2-Chloroethyl)-4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one.

17. A compound according to claim 1, wherein the aro-matic ring is quinoline.

18. A compound according to claim 1 or 4, wherein E is N(C1-8)alkyl.

19. A compound according to claim 1 or 4, wherein D is C1-2alkyl substituted by C1-5alkyl.

20. A compound according to claim 1 or 4, wherein X is 1-phthalimido.

21. A compound according to claim 1 or 4, wherein R4 is C1-5alkyl