CA1217487A - Process for the preparation of alkylenediamine derivatives - Google Patents

Abstract

A B S T R A C T

NEW PROCESS FOR THE PREPARATION OF ALKYLENEDIAMINE
DERIVATIVES

The invention relates to a new process for the preparation of antiarrhythmic alkylenediamine de-rivatives of general formula (I) (I) wherein R1 and R2 each represent independently a lower alkyl group or halogen, R3 and R4 each stand independently for hydrogen or lower alkyl group, R5 and R6 each represent independently hydrogen or a lower alkyl group, or NR5R6 may form a 5-6 membered heterocyclic group optionally contain-ing a further heteroatom, such as an oxygen, sulfur or nitrogen atom, and n is zero or one, mixtures of the above compounds, optically active forms and racemates thereof, furthermore the pharmaceutically acceptable acid addition salts of the free bases, characterized by reacting a compound of general for-mula (VIb), (VIb) wherein R1 to R4 and n are as defined above, with an amine of general formula (III), (III) wherein R5 and R6 or NR5R6, respectively, are as defined above.
By the process of the invention the compounds of general formula (I), possessing valuable biological properties, can be prepared in a simpler way, compared to earlier known procedures.

Description

NEW PROCESS FOR THE PREPARATION OF ALKYLENEDIAMINE
DERIVATIVES

The invention relates to a new process for the preparation of alkylenediamine derivatives of general formula (I) R R

o ~ NH--CH--(CH~)n--CD ~, (I) wherein Rl and R2 each represent independently a lower alkyl group or halogen, R3 and R4 each stand independently for hydrogen or lower alkyl group, R5 and R6 each represent independently hydrogen or a lower alkyl group, or NR5R6 may form a 5-6 membered heterocyclic group optionally contain-ing a further heteroatom, such as an oxygen, sulfur or nitrogen atom, or is a group derived from a cyclic imide of a dicarboxylic acid, and n is zero or one.
Mixtures of the above compounds, optically active forms and racemates thereof, furthermore the corre-;......... 47659-123-PT
:.:, , -:

~LZJI~i!37

- 2 -sponding N-oxides and the pharmaceu-tlcally acceptable acid addi-tion sal-ts of the free bases are also embraced by the scope of the invention.
The term "lower alkyl" as used in connection with the compounds according to the inven-tion refers to straight or branched-chain alkyl groups with 1 to 5 carbon atoms, whereas the term "halogen" embraces bromine, chlorine and fluorine atoms.
In the compounds of general formula (I) Rl and R2 each may represent e.g. methyl, ethyl, n-propyl, isopropyl, butyl or amyl group, furthermore fluorine, chlorine or bromine atom. Thus the substituted phenyl group appearing in the compounds of general formula (I) may be e.g. 2,6-dimethylphenyl, 2,6-diethylphenyl, 2-ethyl-6-methyl-phenyl, 2-chloro-6-methyl-phenyl or 2,6--dichloro-phenyl group. R3 and R4 each may represent e.g.
hydrogen atom or a methyl, ethyl, n--propyl, isopropyl, butyl or amyl group. R5 and R6 each may stand for hydrogen atom or a me-thyl, ethyl, n-propyl, isopropyl, butyl or amyl group, or -NR5R6 may represent e.g. a piperidin-l-yl, piperazin-l-yl, 1,4-oxazin-4-yl or 1,4-thiazin-4~yl group, further a phthalimido group.
The invention provides a new process for the preparation of antiarrhythmic alkylenediamine derivatives described in British Patent No. 2,098,599.
According to a variant of the process described in British Patent No. 2,098,599 the compounds of general formula (I) are prepared by reacting a compound of general

- 3 -formula (II), ~ R l3 l~ (II) wherein Rl, R2, R3, R4 and n are as defined above, R stands for hydrogen atom or an aliphatic or aromatic acyl group, lower aliphatic or aromatic sulfonyl group, and X repre-sents a halogen atom or a lower aliphatic sulfonyloxy group, with a compound of general formula (III), /
HN (III) \R6 wherein R5 and R6 are as defined above.

If a compound of general formula ~II), wherein R3 and R4 represent groups which are different from each other, is used as starting substance, one or two (isome-ric) products may form in the course of the reaction, depending on the meaning of R. Thus, if R stands for an acyl group or a sulfonyl group, a single product is formed, namely a diamine of general formula (I), wherein the ni-trogen adjacent to the aroma-tic group is protected either 74~7 by an acyl group or a sulfonyl group. The end-product of general formula (I) is obtained by removal of the above-mentioned pro-tec-tive group in a separate reaction step.
If a compound of general formula (II) 7 wherein R3 and R4 represent groups which are different from each other, and R stands for a hydrogen atom, is used as start--ing substance, in the course of the reaction this compound converts temporarily into the respective asymmetrically subs-tituted aziridine (n = 0) or azetidine (n = 1) deriva-tive of general formula (IV) R1 C~
~ l~ (IV) or one of its salts, respectively. Since these rings can be opened in two ways, a mixture of two structural isomers having the general formula ~I) and (V) are obtained, 79L~7 R' Rs ~,~N~I--CH--(cH2~n--CH--N~ t wherein Rl, R2, R3, R4, R5 and R6 have the same meaning as above.
To prepare a pure isomer of general formula (I), as is stressed in the said patent specification, a compound of general formula (II), blocked on the nitrogen atom adjacent to the aromatic ring either by an acyl--type or a sulfonyl-type protective group, has to be used as starting substance which furnishes in two reaction steps -the target compounds of general formula (I).
It has been found that pure compounds o gen-eral formula (I), free of isomers of general formula (V), can be prepared by an improved, one-step procedure, if analogues of the compounds of general formula (II), where-in the protective group R and the leaving group X togetherrepresent the same bivalen-t sulfonyl group ( >S02), are used as starting substances. Accordingly, for the pre-paration of compounds of general formula (I) compounds of general formula (VIb), :

~Z~87 CH
N (C~f2)~
~ < O I 4 (VIb) R ( )rrl, o/

m = 2 wherein Rl, R2, R3, R4 and n are as defined above, i.e.
cyclic sulfuric acid monoester monoamids (1,2,3-oxa-thiazolidine-2,2-dioxide or 1,2,3-oxathiazine-2,2-dioxide derivatives) are used as starting substances.
If a compound of general formula (VIb) is reacted at high temperature, i.e. at 80 to 150 C, with an amine of general formula (III), a compound of general formula (I) is obtained directly, in one step.
On the other hand, if the reaction with the amine of general formula (III) is carried out at room 20 temperature, first a derivative of general formula (VII) of the target compound of general formula (I) is obtained, ~ Cil (C~ h IcH ~1~ 6 (VII) .

~Z~7~

namely -the respective inner salt of the N-sulfonic acid, which can be converted by -treatment with an acid into the end-product of general formula (I). Compounds of general formula (VII) can be isolated, if desired, in crystalline form.
Accordingly, the invention provides a new process for the preparation of alkylenediamine deriva-tives of general formula (I), wherein Rl to R4 and n are as defined above~ mixtures of -the above compounds, optically active forms and racemates thereof, further-more the corresponding N-oxides and the pharmaceutical-ly acceptable acid addition salts of the free bases, comprising the steps of reacting a compound of general formula (VIb), wherein Rl to R4 and n are as defined above, at 20 to 150 C with an amine of general formula (III), wherein R5 and R6 or NR5R6, respectively, are as defined above, isolating the resulting produc-t of general formula (I) from the reaction mixture, optional-ly following an acid treatment and, if desired and possible, separating the isomers from the product and/or, if desired, converting the compound of general formula (I), obtained in the form of a base, into its acid ad-dition salt and/or, if desired, liberating the base from the acid addition salt of the compound of general formula (I).
According to a preferred process of the in-vention a compound of general formula (VIb), wherein Rl to R4 and n are as defined above, is reacted with ~Z'17~

3 to 15 equivalen~ts of an amine of general formula (III), wherein R5 and R6, or NR5R5, respec-tively, are as defined above, at 80 to 150 C, either in a solvent, such as a lower alkanol, i.e. methanol or ethanol, or an aromatic hydrocarbon, such as benzene or toluene, or in their mixtures, or in the absence of any solvent.
According -to a further preferred process of the invention a compound of general formula (VIb), where-in Rl to R4 and n are as defined above, is reacted with 3 to 15 equivalents of an amine of general formula (III), at room temperature, preferably in a lower alkanol, such as methanol or ethanol, then the resulting reaction mix`ture is treated at 20 to 150 C with an acid, prefer-ably with a mineral acid, such as hydrochloric acid or sulfuric acid.
The compounds of general formula (~Ib) used as starting substances in the process of the invention are new.
In the literature a single substance related to the compounds of general formula (VIb), a 1,2,3-oxo-thiazolidine-2,2-dioxide, having a saturated ring sys-tem, was described by Y. Noda et al. /Bull. Chem. Soc.
Japan 40, 1554 (1967)7, who prepared the 4-carboxy-1,2,3--oxathiazolidine-2,2-dioxide from serine-0-sulfuric ester in dimethylformamide, using dicyclohexylcarbodi-imide~
The starting materials of the process of the inven-tion, i.e. the compounds of general formula (VIb), ,~

~Z~7~
g can be prepared by oxidizing -the respective aompounds of general formula (VIa), R3 (VIa) --J N (C~2)~
lo R (O)~S, , CH--R

m = 1 wherein Rl to R4 and n are as defined above, with an oxidizing agent, such as an alkali metal permanganate, i.e. potassium permanganate, or a peroxide, i.e. hydro-gen peroxide, at O to 50 C, in a suitable solvent,such as water, acetic acid, dioxane or a mixture thereof.
The compounds of general formula (VIa) are also new. This type of compounds was prepared by J. A.
~yrup and C. L. Moyer (J. Org. Chem. 34, 175 /1969/);
F- Wudl and B. K. Lee (J. Am. Chem. Soc. 95, 6349 /1973/); and F. Yamada (Bull. Chem. Soc. Japan 44, 3073 /1971/). In the first two papers the respective aminoalcohols were reacted with thionylchloride in the ~2~7~37 presence of a base, while in the las-t paper N-sulfinyl-anilines were reacted with epoxides to furnish -the respective 1,2,3-oxathiazolidine-2-oxides. As the sulfur atom in position 2, furthermore the carbon atom in po-sitions 4 and/or 5(6) are asymme-tric centers, the oxygen atom connected to the sulfur a-tom in position 2 and -the substituents of the carbon atoms in positions 4 and/or 5(6) may be in cis or trans positions.
The compounds of general formula (VIa) may be prepared from aminoalkohols of general formula (VIII), R (VIII) (~NII--I~H~ )n--IcH--D~

2~
wherein Rl toR4 and n are as defined above, by methods described above and known in the art. The compounds of general formula (VIII) are known or can be prepared by known methods (British Patent No. 2,098,599).

2~ The processes according to the invention yield the compounds of general formula (I~ generally as free bases. The free bases can be converted into their acid addition salts preferably by dissolving the . ~, .

L5;~ 57~

base in a suitable solven-t, such as methanol, isopropanol, diethyl ether or a mixture thereof, and admixing this solu-tion with a solution of -the selected acid. The salts can be separated either directly by filtration or by partial or total removal of the solvent.
The free bases of general formula (I) can be liberated from -their salts preferably in such a manner that the salt is dissolved in a solvent, such as wa-ter, methanol, ethanol or a mixture thereof, the solution is rendered alkaline e.g. with an aqueous sodium hydroxide or ammonium hydroxide solution, and the liberated base is ex-tracted from the reaction mixture with chloroform or benzene.
The compounds of general formula (I) in which R3 or R4 is other than hydrogen contain an asymmetric carbon atom, thus they may exist in the form of optical-ly active isomers and racemates. The pure optically active ismers of these compounds can be separated from the respective isomeric mixtures advantageously as fol-20 lows: The mixture of the isomers ~e.g. the racemate) lstreated with 0.5 to 1.0 molar equivalents of a conven-tional optically active acid, such as D-tartaric acid, 0,0-dibenzoyl-D-tartaric acid, 0,0-dibenzoyl D-tartaric acid semi-dimethylamide, thlazolidine-4-carboxylic acid, 25 etc. in methanol, ethanol, ethyl acetate, acetone or some other solvent, the salt of one of the optically active isomers is separa~ted, and the mother liquors are processed to obtain the other isomer either as a 3'7 free base or as its salt, depending on the amount of the acid utilized. The salt of the optically active isomer, separated in the firs-t step, can be recrystalliz-ed in one or more steps to obtain an optically pure substance; however, depending on the amount of the acid used, an optically pure substance can also be obtained directly. Any of the salts can be converted into the respective free, optically pure base as described above, whereafter, if desired, the base can be converted into its pharmaceutically acceptable acid addition salt.
The compounds of general formula (I) in which both R3 and R4 are other -than hydrogen may exist as mixtures of diastereomers. The pure optically active isomers can be separated from these mixtures by methods known in the art.
The following Examples are illustrating but not limiting the scope of invention.

Example 1 1-(2l6-Dimethyl-phenylamino)-2-dime~hylamino--propane Method_A
A mixture of 0.5 g (2.07 mmoles) of 3-(2,6--dimethylphenyl)-5-methyl-1,2,3-oxathiazolidine-2,2--dioxide and 0.~ g (17.7 mmoles) of dimethylamine in 5 ml of ethanol are heated for 3 hours in a steel bomb placed in an oil bath of 120 to 125 ~.
The mixture is cooled, poured over 30 ml of water and ex-tracted three -times with 10 ml of chloro--form, each. The combined chloroform layers are dried over magnesium sulfate and the solvent is evaporated a-t reduced pressure. Yield: O.L~O g (93 percent) of 1--(2,6-dimethylphenylamino)-2-dimethylamino-propane, b.p.: 105 C/53 Pa.
The starting substance, 3-(2,6-dimethyl-phenyl)--t-methyl-1,2,3-oxathiazolidine-2,2-dioxide, is prepared as follows:

Step a) 11 ml (18.1 g, 150 mmoles) of thionyl chloride are added dropwise to a solution of 18 g (100 mmoles) of l-(2,6-dimethyl-phenylamino)-2-propanol in 300 ml of anhydrous pyridine, cooled to 0 to 5 C in an ice bath. The reaction mixture is stirred in the ice bath for one hour, then for a further hour at room temperature, subsequently it is poured over 1000 ml of ice water, the precipitate formed is filtered, washed with water and dried. Yield: 16.7 g (74 percent) of light beige, crystalline 3-(2,6-dimethylphenyl)-5-methyl-1,2,3-oxa--thiazolidine-2-oxide, wherein the ratio of isomers, containing the S=0 group in position 2 and the methyl group in position 5, in positions cis and trans, is, on the basis of H-NMR spectroscopic studiesjabout 4:6.
When recrystallized from isopropanol, the product melts at 87 to 90 C, and has a cis/trans isomer ratio of 3:1.
This compound can also be prepared by a variant ' '''""'''-'-~ ~ .

of the above procedure, wherein 1,2-dichloroethane is used as solvent instead of pyridine, and triethylamine is used as acid binding agen-t. Recrystallized from iso-propanol, the 3-(2,G-dimethylphenyl)-5-methyl-1,2,3--oxathiazolidine-2-oxide obtained melts at 100 to 104 C, and has a cis/-trans isomer ratio of 8:2.

Step b) A solution of 23.6 g (150 mmoles) of potassium permanganate in 300 ml of water is added dropwise within about 15 minutes, at 20 to 22 C, ensured by occasional ice cooling, to a solution of 13.5 g (60 mmoles) of 3-(2,6-dimethylphenyl)-5-methyl-1,2,3-oxathiazolidine--2-oxide in 300 ml of acetic acid. The mixture is stirred for one hour at room temperature, then 120 ml of a 10 percent sodium hydrogen sulfite solution are added.
Stirring is continued for 30 minutes in an ice bath, then the precipitate formed is filtered, washed with water and dried. Yield: 6.15 g (L~2 percent) of crystalline 3-(2,6-dimethylphenyl)-5-methyl-1,2,3-oxathiazolidine--2,2-dioxide. Recrystallized from isopropanol, the pure product melts-at 116.5 to 11~.5 C.
The above oxidation may be carried out also by using dioxane as solvent and 30 percent aqueous hydrogen peroxide as oxidizing agent. The ~ield, however, amounts to 9 percent of the oxidized product.

r ~

"' .
~ .

'~f~

Method_B
By reac-ting a solution of 0.5 g (2.07 mmoles) of 3-(2,6-dime-thylphenyl)-5-methyl-1,2,3-oxa-thiazolidine~
-2,2-dioxide in 10 ml of ethanol and 1.6 ml of an aqueous solution of dimethyl amine (59 g/100 ml) according to Method A, t~le desired product is obtained in a yield of 55 percent.

Method C
A mixture of 2.0 g (8.3 mmoles) of 3-(296-di-methylphenyl)-5-methyl-1,2,3-oxathia~olidine~2,2-dioxide and 3.85 g (85 mmoles) of dimethylamine in 25 ml of ethanol is stirred for 8 hours at room temperature, then it is left to stand overnight. Then the solvent and the excess of the amine are evaporated at reduced pressure, the vis-cous residue is dissolved in 15 ml of water, 15 ml of aqueous concentrated hydrochloric acid are added to it, and the mixture is kept for 1 hour at 6G to 65 C.
The resulting yellow solution is cooled, diluted with 30 ml of water, then its pH is adjusted to 10 wi-th 20 ml of a 10 N sodium hydroxide solution with ice cooling, and the mixt~re is extracted three times with 20 ml o~ 1,2--dichloroethane, each. The combined 1,2-dichloroethane layers are washed three times with 10 ml water, each, dried over anhydrous sodium sulfate, and the solvent is evaporated at reduced pressure. Yield: 1.66 g (97 percent~ of a pale yellow oil.
According to a variant of this procedure the , 7~

viscous oil, obtained after evaporation of ethanol and the excess of dimethylamine, is dissolved in 15 ml of concentrated hydrochloric acid, the solu-tion is left -to stand a-t room tempera-ture for 24 hours, then it is diluted with water according to the above process and the product is isolated by extraction.

Pre~aration of the_h~dro_hloride 1.66 g of the crude base obtained above is dissolved in 5 ml of ethanolic hydrochloric acid (12 g of hydrochloric acid/100 ml solution), the solution is diluted under constant stirring with 10 ml of ethyl acetate, and the mixture is stirred first for one hour at room temperature, then for one hour in an ice bath.
The crystals formed are filtered, washed with ethyl acetate and dried at room temperature. The colourless, crystalline product is the dihydrochloride of the target substance. Yield: 2.11 g (91 percent). M.p.: 195 to 197 C
(in a sealed tube).

Exa~les 2 _to 10 The process described in Example 1 was applied -to prepare the following alkylenediamines of general formula (I), by reacting the corresponding compounds of general formula (VIb) with the corresponding amines of general formula (III).

~ 3Lt~ 37 ~ 0r~ D0U~
tL) ~ tr~ t r~
rl O tl~ O O t~
U~t ~ t~
~ C~l td t.'~l ~ r- t`~ O ~ 0 CU to R, ~4 ~ O L~ 1 t.'U t t.~J o ~ ~ ~ ~ ~ ~ ~

O~ ~ o ~ t.~l t~ ~

~ O o o o O O o O ~

~1 h I ~ tl) ~O t~ U~ ~ I P, t~ tY~ t~ t~ t~
~; ~ J ~ C X
C~ t.~ ,t~
t~ ~ I
.,1 ~D N ~D I tr~ t~ t~ t~ t~
Is~~ ~r td ~ s:~ ~CX m P:; X X Lt~ X U~
t.~ ~ o 1:~ N
; td tY~ t~ tr~ t~t~ tr~ t~
m :c ~ x ~ ~ x :~
C~ V ~ V X
t~ ~
~ X ~: ~ X X ~ ~:: ~ X

t~l t~
~: ~ ~: X ~ ~ ~ ~ ~
v v ~ v v t~ v v v t~ t~ tr~ tr~ tY~~ t~ t~
~ x ~ ~ ~ xx ~ ~ x c~ v v v v t~ v v . ~o ~L p: ¢ ¢ c ¢ ¢ ¢

tl) p~ o td t.~l tY~ 0 t~ O
~r:l ,~

- ].8 -The compounds of general formula (VIb), used in Examples 2 to 10, are advan-tageously prepared in the following two reaction steps:

Step a) Applying the process for -the preparation of starting substances in Example 1, S-tep a)~ the correspond-ing substituted aminoalcohols of general formula (VIII) are reacted with thionyl chloride in pyridine, yielding -the following 1,2,3-oxathiazolidine-2-oxides and, resp., the 1,2,3-oxathiazine-2-oxide of general formula (VIa):

:~Z~ '7 ~o ~ ~
h ~rl CO CU O~
+~ ~ .. .. ..... ..
C~
u~ h C~
~d ~
a) ~ Lr~ o ~ o~ ~ ~
~ ~ O~1 L~
[~ 0L~ ) N
E~ . . . . .
~r; O o o o o ~ a) O O ~
c~ a~ o . ~ o~Q
P. O V
. O ~I t--~-- b~) u~ ~D
O rl C~J ~ ~1 ~1 ~1 oh .
~ ~ C~
m ~ ~, a~ ~o o o o o ~
~I
~: X ~ ~ h O
~; V V V ~ V ~
I ~
~
rl ~:; X ~:C X V ~ ~ ~

u~ ~ ~a~ o C\.l ~1 ~C ~1 ~ :I b~ 3 ; C~ V V ~1 +~
V
D~ S
L~
~i ~ ~ (I~ ~~C 3 c,:: ~ ~ æ
v v ~ v v æ :~

... . .

2~'8 7 The aminoalcohols of general formula (VIII), used as s-tarting substances for the prepara-tion of the above compounds, were prepared by the process described in British Patent No. 2,098,599. From these compounds the following are new:

1-(2-chloro-6-methyl-phenylamino)-2-propanol, b. p.: 122 C/27 Pa, 1-(2,6-diethyl-phenylamino)-2-propanol, b. p.: 148-152 C/27 Pa, 2-(2,6-dimethyl-phenylamino)-1-propanol, b. p.: 126 C/133 Pa, 1-(2,6-dimethyl-phenylamino)-3-butanol hydrochloride m. p. 198-200 C.

Ste~ b) Applying the process of Example 1, Step b) for preparing the starting substances, the appropriate com-pounds of general formula (VIa), prepared by the method described in the above Step a), are oxidized in acetic acid solution with an aqueous potassium permanganate - solution, yielding -the following 1,2,3-oxathiazolidine--2,2-dioxides and, respectively, 1,2,3-oxathiazine-2,2--dioxide of general formula (VIb):

` I

~2~7~

Rl R2 R3 R4 n M.p. Yield C %
. ~
CH3 Cl H CH3 0 84-86 33 Cl Cl H CH3 0 133-135 38 ... . _ .

Claims (4)

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

1. A process for the preparation of alkylenediamine derivatives of general formula (I), (I) wherein R1 and R2 each represent independently a lower alkyl group or halogen, R3 and R4 each stand independently for hydrogen or lower alkyl group, R5 and R6 each represent independently hydrogen or a lower alkyl group, or NR5R6 can form a 5-6 membered heterocyclic group aptionally containing a further hetero atom, or is a group derived from a cyclic imide of a dicarboxylic acid, and n is zero or one, mixtures of the above compounds, optically active forms and racemates thereof, furthermore the pharmaceutically acceptable acid addition salts of the free bases, characterised by reacting a compound of general formula (VIb) (VIb) Wherein R1 to R4 and n are as defined above, at 20 to 150°C with an amine of general formula (III), (III) wherein R5 and R6 or, resp, NR5R6 are as defined above, isolating the resulting product of general formula (I) from the reaction mixture, optionally following an acid treatment and, if required, separating the isomers from the product or, if required, converting the compound of general formula (I), obtained in the form of a base, into its acid addition salt or, if required, liberating the base from the acid addition salt of the compound of general form-ula (I).

2. A process according to claim 1, wherein NR5R6 form a 5-6 membered ring optionally containing a further oxygen, sulphur or nitrogen atom.

3. A process according to claim 1, wherein the compound of formula (IVb) is reacted with 3 to 15 equivalents of the amine of formula (III) at 80 to 150°C in the absence of solvent or in the presence of a lower alkanol or aromatic hydrocarbon as solvent.

4. A process according to claim 1 wherein the compound of formula (IVb) is reacted with 3 to 15 equivalents of the amine of formula (III) at room temperature in a lower alkanol, followed by treatment at 20 to 150°C with mineral acid.