FI83307B - NYTT FOERFARANDE FOER FRAMSTAELLNING AV ALKYLENDIAMINDERIVAT. - Google Patents

Description

83307

A new process for the preparation of alkylenediamine derivatives

The invention relates to a new method of general formula (I) / i - H, f? * for the preparation of pharmaceutically acceptable acid addition salts of alkylenediamine derivatives and free bases according to the formula wherein R 1 and R 2 independently represent a lower alkyl group or halogen, R 3 and R 4 independently represent hydrogen or a lower alkyl group, R 5 and R 6 independently represent a lower group, or NR 5 R 6 may form a 5- or 6-membered heterocyclic group optionally containing one 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.

The term "lower alkyl" as used in connection with the compounds of the invention means straight-chain or branched alkyl groups having 1 to 5 carbon atoms, while the term "halogen" means bromine, chlorine or fluorine atoms.

in the compounds of general formula (I), R 1 and R 2 may each denote, for example, a methyl, ethyl, n-propyl, iso-propyl, butyl or amyl group, further fluorine.

2 83307 chlorine or bromine atoms. Thus, the substituted phenyl group present in the compounds of general formula (I) may be, for example, 2,6-dimethylphenyl, 2,6-diethylphenyl, 2-ethyl-6-methylphenyl, 2-chloro-6-methylphenyl or 2,6-dichlorophenyl. R3 and R4 may each represent, for example, a hydrogen atom or a methyl, ethyl, n-propyl, iso-propyl, butyl or amyl group. R 5 and R 10 may each represent a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, butyl or amyl group, or -NR 1 R 6 may represent e.g. piperidin-1-yl, piperazin-1-yl- , 1,4-oxazin-4-yl or 1,4-thiazin-4-yl, further phthalimido.

The invention provides a new process for the preparation of alkylenediamine derivatives disclosed in the GB patent 2,098,599.

According to a variation of the process disclosed in GB Patent 2,098,599, the compounds of general formula (I) are prepared by reacting general formula (II) / N-CH- (CH) n -CH-X (II). R R3 is a compound according to R 'R *, wherein R1 · · r2' ^ 4 and n represent the same as above, R represents a hydrogen atom or an aliphatic or aromatic acyl group, a lower aliphatic or aromatic sulfonyl group, and X represents a halogen atom or a lower aliphatic sulfonyloxy group, to react with a compound of general formula (III) R5 HN (III) R6, wherein R5 and R6 are as defined above.

3 85507

If a compound of general formula (II) is used as the starting material, in which R3 and R4 denote groups which differ from one another, one or two (isomeric) products can always be formed during the reaction, depending on the residue R. Thus, if R represents an acyl group or a sulfonyl group, a single product is formed, namely a diamine of general formula (I) in which the nitrogen adjacent to the aromatic group is protected by either an acyl group or a sulfonyl group. The final product of general formula (I) is obtained by removing the above-mentioned protecting group in a separate reaction step.

If a compound of general formula (II) is used as a starting material, in which R3 and R4 represent different groups and R represents a hydrogen atom, this compound is temporarily converted during the reaction into the corresponding asymmetrically substituted R3 of general formula (IV).

R1 I

r ch x (c4, uv »\ /

\. CH

f? I

To an aziridine (n = 0) or azetidine (n = 1) derivative according to R * or a salt thereof, respectively. Since these rings can be opened in two ways, a mixture of two structural isomers of general formula (I) and (V), respectively, is obtained, 4 83307 R1 ,,,

- <R K

V

wherein R1, R2, R3, R4, R5 and R6 are as defined above.

To prepare the pure isomer of general formula (I), as highlighted in said patent, a compound of general formula (II) protected on the nitrogen atom adjacent to the aromatic ring by either an acyl-type or sulfonyl-type protecting group must be used as starting material to form the two reaction steps. I).

It has been found that pure compounds of general formula (I) which are free of isomers of general formula (V) can also be prepared by an improved, one-step process using analogs of compounds of general formula (II) in which the protecting group R and the starting group X are together with the same divalent sulfonyl group (> SO 2) · Thus, for the preparation of compounds of general formula (I), the starting materials used are those of formula (VIb)

R 'I

_ / C H

/ f)) - NX X (c «A, '- (2 II, (VXb) n (0) S. en rm = 2 compounds wherein R1, R2, R3, R4 and n are as defined above, i.e. .cyclic sulfuric acid monoamides (1,2,3-oxathiazolidine-2,2-dioxide or 1,2,3-oxathiazine-2,2-dioxide derivatives).

If a compound of general formula (VIb) is reacted with an amine of general formula (III) at a high temperature, e.g. at 80-150 °, a compound of general formula (I) is obtained directly in one step.

On the other hand, if the reaction with the amine of the general formula (III) is carried out at room temperature, a derivative of the target compound of the general formula (I) of the general formula (VII) is first obtained, R 1 O-w-ch- (c4-ch-m {s (νΊΙ))

M7 U I, R

\ ff ft r 'K SO, Θ namely the corresponding internal salt of N-sulfonic acid, which can be converted by treatment with the acid into the final product of general formula (I). If desired, the compounds of general formula (VII) can be isolated in crystalline form.

Thus, the invention provides a novel process for the preparation of pharmaceutically acceptable acid addition salts of alkylenediamine derivatives of general formula (I) and their free bases, wherein R 1 to R 4 are as defined above, which process comprises reacting a compound of general formula (VIb) wherein R 1 to R 4 and n is reacted at 20 to 150 ° C with an amine of general formula (III) wherein R5 and R6 or NR5R6, respectively, are as defined above, the compound of general formula (I) obtained is optionally isolated from the reaction mixture after acid treatment and, if desired, converted into the compound 6 83307 of the general formula (I) obtained in the form of a base is its acid addition salt and / or, if desired, the base is liberated from the acid addition salt of the compound of the general formula (I).

According to a preferred process of the invention, a compound of general formula (VIb) in which R1 to R4 and n are as defined above is reacted with 3 to 15 equivalents of an amine of general formula (III) in which R5 and R6 or NR5R6, respectively, are as defined above. , At 80 to 150 ° C, either in a solvent such as a lower alkanol, i.e. in methanol or ethanol or an aromatic hydrocarbon such as benzene or toluene or a mixture thereof or without any solvent.

According to another preferred method of the invention, a compound of general formula (VIb) wherein R * to R 4 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 mixture is treated at 20 to 150 ° C with an acid, preferably a mineral acid such as hydrochloric acid or sulfuric acid.

The compounds of general formula (VIb) used as starting materials in the process according to the invention are novel.

The only substance known in the literature to be associated with compounds of general formula (VIb) is 1,2,3-oxothiazolidine-2,2-dioxide having a saturated ring system (Y. Noda et al. In Bull. Chem. Soc. Japan 40, 1554 (1967)), wherein 4-carboxy-1,2,3-oxathiazolidine-2,2-dioxide is prepared from serine-O-sulfuric acid ester in dimethylformamide using dicyclohexylcarbodiimide.

The starting materials for the process according to the invention, i.e. compounds of general formula (VIb), can be prepared by oxidation of the corresponding compounds of general formula (Via) li 7 83307 R * R I (Via)

_ / CH

compounds of the formula R1 to R4 and n are as defined above, with an oxidizing agent such as alkali metal permanganate, i.e. potassium permanganate or peroxide, e.g. hydrogen peroxide at 0 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. Compounds of this type have been prepared by J.A. Deyrup and C.L. Moyer (J. Org. Chem. 34, 175 (1969)), F. Wuld and B.K. Lee (J. Am. Chem. Soc. 95, 6349 (1973)) and F. Yamada (Bull.

Chem. Soc. Japan £ 4, 3073 (1971)). In the first two publications, the corresponding amino alcohols are reacted with thionyl chloride in the presence of a base, while in the latter publication, N-sulfinylanilines are reacted with epoxides to prepare the corresponding 1,2,3-oxathiazolidine-2-oxides. Since the sulfur atom at the 2-position, still the carbon atom at the 4- and / or 5 (6) position are centers of asymmetry, the oxygen atom attached to the sulfur atom at the 2-position and the carbon atom substituents at the 4- and / or 5 (6) position may be cis- or in trans stations.

Compounds of general formula (Via) can be prepared from general formula (Vili). 8 83307

P

Of amino alcohols according to the formula R 1 to R 4 and n have the same meaning as above, by methods well known in the art. compounds are known or can be prepared by known methods (GB Patent 2,098,599).

The processes according to the invention generally produce the compounds of general formula (I) as free bases. The free bases can be converted into their acid addition salts, preferably by dissolving the base in a suitable solvent such as methanol, isopropanol, diethyl ether or a mixture thereof and mixing this solution with a solution of the selected acid. The salts can be separated either directly by filtration or by partial or complete removal of the solvent.

The free bases of general formula (I) may be liberated from their salts, preferably by dissolving the salt in a solvent such as water, methanol, ethanol or a mixture thereof, making the solution alkaline with e.g. aqueous sodium hydroxide or ammonium hydroxide solution and extracting the liberated base from the reaction mixture with chloroform or benzene.

The following examples illustrate the invention without limiting its scope.

li 9 83307

Example 1 1- (2,6-Dimethyl-phenylamino) -2-dimethylamino-propane)

Method A

A mixture of 0.5 g (2.07 mmol) of 3- (2,6-dimethylphenyl) -5-methyl-1,2,3-oxathiazolidine-2,2-dioxide and 0.8 g (17 , 7 mmol) of dimethylamine in 5 ml of ethanol, is heated for 3 hours in a steel vessel placed in an oil bath at 120-125 ° C.

The mixture is cooled, poured into water (30 ml) and extracted three times with 10 ml of chloroform each time. The combined chloroform layers are dried over magnesium sulfate and the solvent is evaporated under reduced pressure. Yield: 0.40 g (93%) of 1- (2,6-dimethylphenylamino) -2-dimethylamino-propane, b.p. 105 * C / 53 Pa.

The starting material, 3- (2,6-dimethyl-phenyl) -5-methyl-1,2,3-oxathiazolidine-2,2-dioxide, is prepared as follows:

Step a) 11 ml (18.1 g, 150 mmol) of thionyl chloride are added dropwise to a solution of 18 g (100 mmol) of 1- (2,6-dimethylphenylamino) -2-propanol in 300 ml anhydrous pyridine and cooled to 0-5eC in an ice bath. The reaction mixture is stirred in an ice bath for 1 hour, then for a further hour at room temperature, then poured onto ice water (1000 ml), the precipitate formed is filtered off, washed with water and dried. Yield: 16.7 g (74%) of pale beige crystalline 3- (2,6-dimethylphenyl) -5-methyl-1,2,3-oxathiazolidine-2-oxide with a ratio of isomers containing S = O- at the 2-position of the group and the 5-position, cis and trans positions of the methyl group, according to the 1 H-NMR spectrum, is about 4: 6. Upon recrystallization from isopropanol, the product melts at 87-90 ° C and has a cis / trans isomer ratio of 3: 1.

83307 This compound can also be prepared by a variation of the above method in which 1,2-dichloroethane is used as the solvent instead of pyridine and triethylamine is used as the acid scavenger. Upon recrystallization, 3- (2,3-dimethylphenyl) -5-methyl-1,2,3-oxathiazolidine-2-oxide obtained from isopropanol melts at 100-104 ° C and has a cis / trans isomer ratio of 8 2.

Vai.he b)

A solution of 23.6 g (150 mmol) of potassium permanganate in 300 ml of water is added dropwise over 15 minutes at 20 to 22 ° C, which is ensured by temporary ice-cooling, to a solution of 13.5 g (60 mmol). ) 3- (2,6-dimethylphenyl) -5-methyl-1,2,3-oxathiazolidine-2-oxide in 300 ml of acetic acid. The mixture is stirred for 1 hour at room temperature, then 120 ml of 10% sodium hydrogen sulphite solution are added. Stirring is continued for 30 minutes in an ice bath, then the precipitate formed is filtered off, washed with water and dried. Yield: 6.15 g (42%) of crystalline 3- (2,6-dimethylphenyl) -5-methyl-1,2,3-oxathiazolidine-2,2-dioxide. Recrystallized from isopropanol, the pure product melts at 116.5-118.5 ° C.

The above oxidation can also be performed using dioxane as the solvent and 30% aqueous hydrogen peroxide as the oxidizing agent. However, the yield is 9% oxidized product.

Method B

By reacting a solution of 0.5 g (2.07 mmol) of 3- (2,6-dimethylphenyl) -5-methyl-1,2,3-oxathiazolidine-2,2-dioxide in 10 l of ethanol, and 1, 6 ml of an aqueous solution of dimethylamine (59 g / 100 ml) according to Method A, the desired product is obtained in 55% yield.

li 83307

Method C

A mixture of 2.0 g (0.3 mmol) of 3- (2,6-dimethylphenyl) -5-methyl-1,2,3-oxathiazolidine-2,2-dioxide and 3.85 g (85 mmol) of mmol) in dimethylamine in 25 ml of ethanol, stirred for 8 hours at room temperature, then left to stand overnight. The solvent and the excess amine are then evaporated off under reduced pressure, the viscous residue is soaked in 15 ml of water, 15 ml of aqueous concentrated hydrochloric acid are added and the mixture is kept at 60-65 ° C for one hour. The yellow solution obtained is cooled, diluted with 30 ml of water, then the pH is adjusted to 10 with 20 ml of 10 N sodium hydroxide solution under ice-cooling and the mixture is extracted three times with 20 ml of 1,2-dichloroethane each time. The combined 1,2-dichloroethane layers are washed three times with 10 ml of water each time, dried over anhydrous sodium sulfate and the solvent is evaporated off under reduced pressure. Yield: 1.66 g (97%) of a pale yellow oil.

According to a variant of this method, the viscous oil obtained after evaporation of the excess ethanol and dimethylamine is dissolved in 15 ml of concentrated hydrochloric acid, the solution is left to stand at room temperature for 24 hours, then diluted with water according to the above procedure and the product is isolated by extraction.

Preparation of the hydrochloride 1.66 g of the above crude base are dissolved in 5 ml of ethanolic hydrochloric acid (12 g of hydrochloric acid / 100 ml of solution), the solution is diluted with 10 ml of ethyl acetate with constant stirring and the mixture is stirred for 1 hour at room temperature and then for 1 hour in ice-cold. The formed crystals are filtered, washed with ethyl acetate and dried at room temperature. The colorless crystalline product is the dihydrochloride of the target substance. Yield: 2.11 g (91%).

M.p .: 195 - 197eC (in a closed tube).

12 83307

Examples 2-10

The procedure set forth in Example 1 was used 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).

15 83307 S αο Γ- Ό r-ι cm ο αο o -a- c · = ^ Ο Ο 0 \ Γ'- Ό O -C Ό -Τ rt 8 3 ο Ο Ο Ο 3 O C3 Σ'- C- ι co o = ο -r- ον ό Λ C "» Λ -C \ \ \ \ \ \

- 'C \ l \ Γ' »3 Ο -3 ΖΟ CNJ CM

* \ \ Ο Γ "—I Γ-Ι CM Ο -! 3 CM Ο r-i 'ί r-Ι r-J r-1 r-i

'“Ο Λ r-l Q, I I I I I I

I O CO o o o c ΟΛ w ίΝ a.-T CM O r-i C \ r-ί r-l r-l, -1, _ | _; d OOO O OOOOr-1 'H'

ι >> Ο -H

J3 __vn -O> 5 an J3 ΓΛ CO O

~ 5 ^ n j £. >> 3 3 3 3 3 CC Ή

i! · Η II I VO W Ό C

3 n ο ο o ο o «—I ►-U t I ΙΛ U 'i} —- <—- * * -» - «-, CJ ίϋ Ci 13 3 3 3 3 3 3 2; o s u o o o o o o o o

rv ^ »-» ►— «—ι« «4 W4 t— <u« M

^). f -L, 3333333 3 · '· Ο o cm ^ o _o jo nv> 0 3 333 3 3 cm 3 3 3 3 rl 0 0 0 3 0 0 03 an aa a: ca aa: “5—1 ra:“ 333 3 3 CM 3 3 3 3 g 3CC c <<<<<• - Γ-: £ • 9 ό co x ω ^ η cn ιλ ox cn o i4 83307

The compounds of general formula (VIb) used in Examples 2-10 are preferably prepared in the following two reaction steps:

Step a) Using the procedure for the preparation of the starting materials set forth in Example 1, step a), the substituted amino alcohols of general formula (VIII) are reacted with thionyl chloride in pyridine to give the following 1,2,3-oxathiazolidine-2-oxides of general formula (Via) or 1,2,3-Oxathiazine-2-oxides: 15 83307 'Λ m ra ΧΟ >> m 33 Μ Οι 50 η N ..........

«Χ: CM H H CU 1Λ • rl 3

o M

Q

^ * * J5 ·> = uj j; ί »Λ Ο Γ» CN r.

CO Is- 30 X o o 7.

fO

•B

ή to m λ '<CO Γ'- 00 CO ra —1 · · · · · · ό?

ci O O O O O S

td

B

«£ 4-> o o · a> O -Γ * '· •. ^ \ N ov ^'?! .'H * r-ι y va m ό δ J: D O I I | 0) -i r ~ w O Ό to Ό £ ci c; H £:: o c S * -h cd * <JJ -rd ---- O T3 3 Ή

H M

: .- ho

CO H> i X

- OOO .OH -p -J

-. r * H

I I

...: o

-d · oo co ro en Γ, H

r * »~ —i _ _ 40 jJ

- - - “H * -« - · —- »> so OOO> cd 0> to H C0 g § <o co £ ~ -f- I— · —ι - -r-> Q) - r1- r ~ * ^ y λ; -B

H 4J

ra e ... x: o

- O i — I

i no. '. · _To en co °.> ^ O "ei oyoa! 5 y bo o - - i- ~ f * * a> e to 0 -", _> · 0 Ό3 .h en “h en en h jra 'oy yo »N» e »e 16 83307

The amino alcohols of general formula (VIII) used as starting materials for the preparation of the above compounds are prepared according to the method described in GB Patent No. 2,098,599. The following of these compounds are novel: 1- (2-chloro-6-methyl-phenylamino) -2-propanol, b.p .: 122 ° C / 27 Pa, 1- (2,6-diethylamino) -2-propanol, b.p. : 148-152 ° C / 27 Pa, 2- (2,6-dimethylphenylamino) -1-propanol, b.p .: 126 ° C / 133 Pa, 1- (2,6-dimethylphenylamino) -3- butanol hydrochloride, m.p .: 198-200 ° C.

Step b) Using the process of Example 1, step b) for the preparation of starting materials, the appropriate compounds of general formula (Via) prepared by the process of step a) above are oxidized in acetic acid solution with aqueous potassium permanganate solution to give the following 1,2,3- oxathiazolidine-2,2-dioxides and 1,2,3-oxathiazine-2,2-dioxides, respectively: 17 83307 1 2 3 ^ RRRR n Sp. Yield ° C fo CH3 Cl H CH3 0 · Sb-86 33 C0H_ C0H_ H CH0 0 70-72 15

Cl CL H CH ^ O I33-I35 33 CII3 CH3 CH3 II 0 152-153 3 ^ CH ^ CH3 H CH3 1 I0O-I63 38

Claims (1)

A process for the preparation of pharmaceutically acceptable acid addition salts of alkylenediamine derivatives and free bases of the general formula (I) R '/ - (/ -NH-CH- (cHjp-CH- (I)' R1 RR, wherein R1 and R2 are independently lower alkyl or halogen, R 3 and R 4 independently represent hydrogen or lower alkyl, R 5 and R 6 independently represent hydrogen or lower alkyl, or NR 5 R 6 may form a 5- or 6-membered heterocyclic group optionally containing one further heteroatom, such as an oxygen, sulfur or nitrogen atom, or a group derived from a cyclic imide of dicarboxylic acid, and n is zero or one, characterized in that the general formula (VIb) ft * R1 I (vib) _ / CH <W) -UX X (ch2) „^ Ή (0) 5. CH - R1" Xq / ms 2 19 83307, in which R1 to R4 and n are as defined above, is reacted at 20 to 150e In C with an amine of general formula (III) R5 HN (HI) wherein R5 and R6 or Nr5r6 respectively have the same meaning as above, the compound of general formula (I) obtained is optionally isolated from the reaction mixture after acid treatment and, if desired, converted into a base The compound of formula (I) as its acid addition salt and / or, if desired, the base is liberated from the acid addition salt of the compound of general formula (I). 83307 20 For the preparation of alkylenediamine compounds having the formula (I) R '/ - (R? <fy> - nh-ch— (αΟη-α- <(I) m7 if R color R1 and r2 are used in the variation of the repressor en the alkyl group or halogen, R3 and R4 are optionally substituted with an alkyl group, R5 and R6 are optionally substituted with an alkyl group, or NR5r6 is a heterocyclic group having 5 or 6 atoms; en heteroatom, säsom en syre-, svavel- eller kväveatom, eller den är en grupp, som är härledd frän en cyclic imid av en di-carboxylsyra, och n är noll eller ett, samt siltpliga syraadditionssalter av ovannämnda föreningars fria baser, kännetecknat in the case of the lower formula (VIb), 21 83307, R3 RI (VTb) _ / CH Q — f X (f · '· (0i-s \ 0 / -c “-R' m = 2 color R1 - R4 och n betyder samma som ovan, omsätts vid 20 - 150 * C med en Amin med den allmänna formuleln (III ), HN (III) color R5 and R6 respective NR5R6 betsder samma som ovan, den ehällna föreningen med den almänna formuleln (I) Isole-ras fraan reactlonsblandnlngen valbart efter en syrabe-handllng och, om sä önskas, överförs all förening med Formula (I) is preferably used in the form of a syrup addition or / or, in which case, the formulation is based on the formulation of the formulation (I).