DE2119260A1 - New phthalimide compounds and methods of making them - Google Patents

Description

DR. ING. E. HOFFMANN · DIPX. ING. W. EITI, E DR. RF-R. NAT. K. HOFFMANN

PATBNTANWlLTE

D.8000 MÖNCHEN 81 · ARABELLASTRASSE 4 ■ TELEPHONE (0811) 911087

Delmar Chemicals Limited, Ville LaSaIIe, Quebec / Canada

New phthalimido compounds and processes for their preparation

Benzamides, such as those of the general formula

ZNHOC

where X is a chlorine ·· or bromine atom, B a what aera tof fat on or an alkyl group, preferably a lower alkyl group.

2098U / 1669

-2-

pe, and Z is a tertiary aminoalkyl group, are described in US Pat. Nos. 3,177,252 and 3,357,978. According to the first-mentioned document, the benzamides are generally prepared by reacting a substituted acyl chloride with a suitable asymmetric disubstituted diamine in an inert reaction medium from which the benzamides can be obtained in the form of hydrochlorides by filtration or centrifugation. According to the latter patent, the benzamides are prepared from p-aminosalicylic acid, the starting compound, in a six-step reaction sequence: first esterification of the free acid, acylation of the amino group, alkylation of the phenolic hydroxyl radical, halogenation with the introduction of the desired core substituent, e.g. chlorine, in the 5-position Aminolysis of the ester function by reaction with an amine of the general formula ZNH ₂ , in which Z has the preceding meaning, with formation of an amide and finally deacetylation of the aromatic acetamido function by hydrolysis, the free amine being released.

It is known that benzamides of the above formula I are pharmacologically active and that some of them, in particular N- (2-diethylaminoethyl) -.2-methoxy * ⁱ f-amino-5- * chlorobenzamide, can be used in chemotherapy, in general as regulators of the digestive system and in particular as antiemetics, which can be used to treat nausea associated with various illnesses such as travel sickness, seasickness or malaise due to pregnancy. Benz amides or their non-toxic salts are used for this Manufacture of pharmaceutical preparations incorporated into pharmaceutically acceptable organic or inorganic liquid or solid carriers.

The invention is based on the task of a new class to make available of any connections which ■

09814/16 6

BATH ORIGINAL

as intermediates for the manufacture of benzamides of the general formula I given above can be used.

The invention thus relates to new compounds of the general formula II

II

in which A is a hydrogen, chlorine or bromine atom and R ₁ and R ₂ , which can be identical or different, are a hydrogen atom or an alkyl group. Preferred compounds are those in which A is a hydrogen * or chlorine atom, R _{1 is} a lower alkyl group such as a methyl, ethyl, propyl or isopropyl group, and R _{2 is} hydrogen or a lower alkyl group such as a methyl or ethyl group .

The term "low" as used herein in connection with Alkyl and Alkenol Alkyl groups and alkenols with 1 to 6 Carbon atoms; the term "known" in connection with processes for carrying out various reaction steps indicates processes which are actually used and / or are described in the relevant literature.

For example, a 2-alkoxy-4-phthalimido-5-chloro (bromo) benzoic acid ester of the above general formula II (A = chlorine or bromine, R. and R ₂ - lower alkyl) in the desired

2098H / 1669

te benzamide of the above general formula I in a single Step by reacting a compound of the general formula II with the appropriate diamine under anhydrous Conditions to be converted

The phthalimido compounds of the general formula II are new compounds that are derived from p-aminosalicylic acid as an " The initial compound can be produced by several processes, with all processes at some stage the reactive amino group is protected by phthalylation; the phthalylation takes place by reaction with phthalic anhydride with formation of a p-phthalimidosalicylic acid. Depending on the substituents of the compound of the general formula II, the process for its preparation usually includes also borrowed one or more of the following levels:

a) esterification of the carboxylic acid function;

b) alkylation of the phenolic hydroxyl function and

c) Halogenation with the introduction of a chlorine or bromine atom, depending on which substituent is in the 5-position of the benzene ring is present.

The starting compound used for the process according to the invention, namely, p-aminoaalicylic acid, is commercially available readily available in the form of a white crystalline powder. This compound contains three functional groups, namely, a carboxylic acid group, a hydroxyl group and an amino group are all in the present invention Procedure at any stage of the reaction center. So the carboxylic acid group is esterified, the hydroxyl group is alkylated and the amino group is protected by phthalylation, although it does not have to be done in that order.

-5- 2098U / 1669

The esterification takes place according to any, expedient gen, known esterification processes, e.g., by heating p-aminosalicylic acid with an excess of one low alcohol, e.g. from methanol, ethanol or isopropanol, in the presence of a mineral acid, such as concentrated sulfuric acid, as a catalyst. The methyl ester, for example by heating the p-aminosallcylic acid made with excess methanol in the presence of concentrated sulfuric acid is preferred Esters, since they are generally the smoothest conversion and the best yields in the subsequent reaction stages results. However, other esters, e.g. ethyl, propyl, isopropyl and butyl esters, can also be used at this heat level e.g. by reaction of the acid with the corresponding lower alcohol.

The alkylation of the phenolic hydroxyl group is achieved by any simple known alkylation process, e.g. by a Williamson synthesis using an alkyl halide, expediently a lower alkyl halide, or by reaction with an alkyl or dialkyl sulfate, expediently a lower alkyl or lower dialkyl sulfate, an alkylbenzene, expediently a lower alkylbenzene, or an alkyltoluenesulfonate, expediently a lower alkyl toluenesulfonate

The reactive amino group is protected by reacting the ester with the easily accessible phthalic anhydride with formation of a p-phthalimidosalicylic acid ester. This reaction is expediently carried out by the reactants together in one inert organic solvents such as a high boiling aromatic solvent such as anhydrous toluene or xylene, preferably in the presence of a small amount ge of a basic condensation catalyst, e.g. triethylamine, heated.

-6- 209814/1669

Esterification of the carboxylic acid group and alkylation of the phenolic Hydroxyl group can be obtained in a single process step by adding a p-phthalimidosalicylic acid with dimethyl sulfate or a similar alkylating agent, such as monomethyl sulfate, under anhydrous, alkaline Implements conditions. The reaction is preferably carried out in an inert anhydrous organic solvent, e.g. anhydrous acetone, methyl ethyl ketone or tetrahydrofuran, in the presence of an alkali, e.g. sodium hydroxide, Potassium hydroxide, sodium carbonate or potassium carbonate, by. Nan leads the implementation expediently Perform at about room temperature or above under anhydrous conditions. It is desirable to keep water from Exclude the reaction medium, otherwise weaving reactions can expire.

After the desired 2-alkoxy-4-phthaloylamido-benzoic acid ester is obtained, the nucleus substituent, chlorine or bromine, is introduced into the 5-position of the benzene ring by any convenient known nucleus substitution method. Conveniently, these are 5 ~ chloro and 5-bromo compounds by direct chlorination or bromination of the 2-alkoxy ^ -phthaloylamidobenzoesäureesters in an inert solvent Jk medium such as acetic acid, is obtained, if desired, in the presence of a catalyst. The halogenation is usually carried out at about room temperature or with slight cooling.

The following examples illustrate the invention without restricting it. The melting points were determined by the capillary tube method certainly.

2-0 9 8Τ47Ϊ6

■ Example 1

2 »Methoxy« .4 »» phthaloylamiao «« 5 «« chlorinated> enzoic acid methyl ester Tell A

p-aminosalicylic acid methyl ester

330 ml of absolute methanol were placed in a 1 liter round bottom flask with a mechanical stirrer and reflux condenser; 136 g of concentrated sulfuric acid (9%) were added in small portions while cooling the flask. Finally, 5-9 g (0.3 mol) of p-aminosalicylic acid were added and the suspension thus obtained was heated under reflux and with continued stirring for 5 hours. The solution was cooled to room temperature (25 ⁰ G) and then poured into a solution of 136.5 g of dry sodium carbonate in 1.3 liters of water with continued stirring. The methyl p-aminosalicylate thus formed fell out of the solution. solution from; it was filtered, washed with water until disappearance of sulphate ions, dried in a vacuum desiccator at 60 ° C · It 44.2 g of off-white crystals were *, m.p. H ^ ⁰ to 117 g, yield 88Ji.

Tell B p-Phthaloylamldosalicylic acid methyl ester

33.4 g (0.2 mol) of the methyl p-aminosalioylate obtained in Part A of this example, 29 ^ .6 g (0.2 mol) of phthalic anhydride and 2.02 g of triethylamine (as a strong condensation catalyst) were added to 100 ml of anhydrous toluene given as solvent in a 1 liter round bottom flask with mechanical stirrer and reflux condenser with water trap. The mixture was then refluxed for 3 1/2 hours with continued stirring. It was then ^{cooled to 0 0} G on an ice bath, the desired p-phthaloylamidosallcyl-. acid methyl ester precipitated in the form of a crystalline plague body. This pest body was separated from the solution by filtration, suspended in 200 ml of methanol and the suspension

-8-2098U / 1669

was pension 30 minutes at room temperature and stirred for "Then the purified p-Phthaloylamidosalicylsäuremethyl" ester filtered off and "at 80 ⁰ C in a vacuum was dried; were (83 $ yield) was obtained 49 g of product in the form of white, needle-like crystals An analytical sample. was recrystallized from acetone, melting point 215 to 217 ° G
Elemental analysis:

C (Ji) H (Ji). N (Ji) calculated: 64.64 3.73 4.71 found: 64.75 3.70 4.56

IR:

The infrared spectrum of the compound in Nujol showed characteristic Absorption peaks and bands at the following wavelengths:

y CO (phthaloyl) 1708 1770 1710 cm ** ¹ ^ CO (ester) 1675 cm " ¹

Part C.

2-Methoxy-4-phthaloylatnidobenzoic acid methylene s ters

29.7 g (0.1 mole) of the methyl p-phthaloylamidosalicylate obtained by the procedure in Part B of this example was added to 550 ml of anhydrous acetone in a 1 liter round bottom flask equipped with a mechanical stirrer and reflux condenser. 27.6 g (0.2 mole) of powdered anhydrous potassium carbonate was added to the suspension; then 13.86 g (0.11 mol) of dimethyl sulfate were slowly added with continued stirring. The mixture was refluxed for 20 hours. Most of the acetone was then distilled off; the thick, doughy residue was ^{cooled to about 50 °} C. and diluted with 500 ml of water. The receive-

2098U / 1669

ne suspension was stirred at room temperature for 30 minutes. The Pestkörper, 2-methoxy ~ 4-phthaloylamidobenzoesäure "methylester, was separated by filtration, washed with water until neutral and then dried in a vacuum at 8O ⁰ C. 30.1 g of product were obtained as white needle-like crystals (yield 97%). An analysis sample was recrystallized from acetone. Melting point: 15-153 ° C
Elemental analysis:

C (Jl) H (Jl) N (Jl)

calculated: 65.59 4.50 4.2 C ₁₇ H ₁₃ NO ₅

found: 65.38 4.65 4.07

The infrared spectrum of the compound in Nujol showed characteristic Absorption peaks and bands at the following wavelengths:

VCO (phthaloyl) 1775 1750 1720 cm " ¹ yCO (ester) 1687 cm" ¹

Tell D

2-Methoxy-4-phthaloylamido-5-chlorobenzoic acid methyl ester

15 »55 g (0.05 mole) of the methyl 2-methoxy-4-phthaloylamidobenzoate obtained by the procedure in Part C of this example and 250 ml of glacial acetic acid were placed in a 1 liter round bottom flask fitted with a mechanical stirrer, thermometer and dropping funnel. While the mixture was continuously stirred, a solution of 3-9 g (0.055 mol) of chlorine gas dissolved in 50 ml of glacial acetic acid was added. The mixture was left at room temperature for 11/2 hours

-10 *

2098U / 1969

touched. Then the mixture was poured into 1500 ml of cold water. The resulting precipitate, 2-methoxy-4-phthaloylamido-5 * »chlorobenzoic acid methyl ester, was separated off by filtration and added to 500 ml of a saturated aqueous sodium hydrogen carbonate solution. The suspension was stirred for 30 minutes; then the product was filtered, washed with water until no trace of chlorine ions then at 60 ⁰ G was longer exists, in a vacuum dried. 16.6 g of the desired 2-methoxy-4-phthaloylamido-.5-chlorobenzoic acid methyl ester were obtained (yield 96%). An analysis sample was recrystallized from methanol. Melting point: 119 to 120 ° C
Elemental analysis:

calculated: 59.05 3.50 10.25 4.05 found: 59.14 3.41 10.42 4.26

The infrared spectrum of the compound in Nujöl showed characteristic Absorption peaks and «bound at the following wavelengths:

yco 1775 1755 1720 ca " ¹

Example 2

2-methoxy "4-phthaloylamldo" 5-chloro-benzoic acid ethyl ester Tell A

p-phthaloylamido salicic acid

30.6 g (0.2 mole) salicylic acid, 29.6 g phthalic anhydride and 2.02 g of triethylamine as a basic condensation catalyst were added to 400 ml of anhydrous toluene as a solution

-11-.

2098H / 1689 bad original

medium in a 1 liter round bottom flask equipped with a mechanical stirrer, reflux condenser and water trap. The mixture was refluxed for 3½ hours with continued stirring. It was then cooled on an ice bath to 0 ⁰ G, the desired p-Phthaloylamidosalicylsäure precipitated a white crystalline solid in. Shape. The solid was filtered off, suspended in 200 ml of anhydrous methanol and stirred at 25 ° C. for 30 minutes. The purified product was filtered off and dried at 60 ⁰ G in an air oven, whereby 43.3 g (yield 76.5 #) were obtained in the form of needle-like product CLÉS white crystals. An analytical sample was recrystallized from acetone.

Melting point: 295-297 ° G
Elemental analysis:

N (Jl)

C ₁₅ H ₉ NO ₅

C (Jl) H (Jl) calculated: 63.60 3.18 found: 63 34 3.21

4.95

The infrared spectrum of the compound in a potassium bromide dispersion showed characteristic absorption peaks and bands at the following wavelengths:

yCO (phthaloyl) 1780 I765 1730 cm " ¹ ^ CO (acid) I67O cm" * ¹

part B

2-methoxy - ^ - phthaloylamidobenzoic acid methyl ester

A mixture of 22.64 g (0.08 mol) of the obtained by the method of Part A of this example obtained p-phthaloylamidosalicylic acid, 27.6 g (0.2 mol) of powdery anhydrous potassium carbonate and 250 ml of anhydrous acetone as a solvent were used Stirred in a 1 liter round bottom flask at 25 ° C for 30 minutes. 22.16 g

-12-2098U / 1669

Dimethyl sulfate (0.176 moles) was slowly added to the continuously stirred suspension. The resulting mixture was refluxed for 20 hours. The main amount of acetone was then distilled off under reduced pressure and the residue was ^{cooled to 25 °} C .; then 500 ml of water were added. The solid product, methyl 2-methoxy-4-phthaloylamidobenzoate, was separated off by filtration, washed with water until neutral and dried at 60 G in an air oven; 24.7 g (yield $ 97) of crude product were obtained in the form of a white powder. An analytical sample was recrystallized from acetone.

Melting point: 151 to 153 ° C
Elemental analysis ί

C {%) H (Ji) N (Ji) calculated: 65.59 4.50 4.20 found: 65.38 4.61 4.13

The infrared spectrum of the compound in potassium bromide dispersion showed characteristic absorption peaks and bands at the following wavelengths:

yco (phthaloyl) 1775 1750 1720 cm " ¹ <jO0 (ester) 1687 cm" ¹

Parts C and D

2-Methoxy-4-phthaloylamido-5-chlorobenzoic acid methyl ester

This compound was prepared from the methyl 2-methoxy-4-phthaloylamidobenzoate obtained by following the procedure in Part B of this Example prepared by the same process as described in Part D of Example 1 / wherein the compound in good yield in a four-step, simple, convenient and economical process was obtained.

-13-2 098 U / 1 66 9

Example 3 2 ~ methoxy ~ phthaloylaniido ~ 5 ~ chlorobenzoic acid methyl ester

This compound was made by exactly following the procedure of Parts A through D of Example 1 above,

Example 4-

2-Methoxy-4-phthaloylamido-5-chlorobenzoic acid ethyl ester Part A

ethyl p-aminosalicylate

The procedure of Part A of Example 1 was exactly repeated, but instead of the absolute methanol was used as the esterifying agent 260 ml of ethanol used. There were 4-0 g of the desired ethyl p-aminosalicylate in the form of whitish Crystals obtained (melting point 109-111 ° C, yield 73Ji).

part B p-Phbhaloylamidosalicylic acid ethyl ester

The procedure of Part B of Example 1 was repeated exactly b, however, 36.2 g (0.2 moles) of the ethyl ester obtained by the procedure in Part A of this example was used. There were 50 g of p-Phhaloylamidosalicyläuräbhylesber (Yield $ 81) obtained in the form of white needle-like crystals. An analysis sample was recirculated from benzene.

Melting point: 193 to 196 ⁰ g
Element analysis:

G {%) \ l {%) N (Ji) calculates: 65.59 4.21 4.50

found: 65.79 4.41 4.37

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■ - 1Λ -

Part G
2 Methoxy ~ * i - »» phthaloylamidobenzoic acid ethyl ester

The procedure of Part G of Example 1 was repeated exactly, except that 31.13 g (0.1 mol) of the ethyl p-phthaloylamido salicylate obtained by the procedure of Part B of this example was used in place of the corresponding methyl ester. 31 g of the desired ethyl 2-methoxy - ^ - phthaloylamidobenzoate were obtained in the form of whitish crystals (yield 95%). An analytical sample was recrystallized from acetone. Melting point 115 to 118 ° G.

Part D.

2-Methoxy "^ -» phthalo, ylamido-.5 '»chlorbenzoic acid ethyl ster

The procedure of Part D of Example 1 was exactly repeated, except that 16.25 g (0.05 mol) of the ethyl 2-methoxy - ^ - phthaloylamidobenzoate obtained by the procedure of Part C of this example was used in place of the methyl compound. 17 g of the desired ethyl 2-methoxy-Jj-phthaloylamido-5-chlorobenzoate were obtained in the form of white, granular crystals (yield 95%). An analytical sample was recrystallized from a benzene-hexane mixture.

Melting point: 120 to 122 ° C
Elemental analysis:

O V / t D. H (Ji) Eq {%) N (Ji) calculated: 60, 09 3.92 9, 86 3.89 found: 60, 17th ^, 05 9, 88 3.78

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Example 5

2 ~ re1; hoxy-4-phthaloylaJnido-5-chloro-benzoic acid isopropyl ester Part A

isopropyl p-aminosalicylate

The procedure of Part A of Example 1 was exactly repeated, except that 320 ml of isopropanol were used as the esterifying agent in place of the absolute methanol. 28.5 g of the desired isopropyl p-aminosalicylate were obtained in the form of whitish, granular crystals (melting point 72 Ms 7 ^ ⁰ G, yield ^ 9%).

Tell B Isopropyl p-phthaloylamidosalicylate

The procedure of Part B of Example 1 was exactly repeated, except that 39 g (0.2 FoI) of the isopropyl ester obtained by the procedure of Part A of this example was used in place of the methyl ester compound. 51 g of purified isopropyl p-phthaloylamidosalicylate (yield $ 78) were obtained in the form of white needle-like crystals. An analytical sample was recrystallized from acetone. Melting point: 139 to 142 ° C
Elemental analysis:

calculated: 66, ^ 5 b, 65 4.31 C ₁₈ H ₁₅ NO ₅

found: 66.21 4.91 4.54

Part G Isopropyl 2-methoxy - ^ - phthaloylamidobenzoate

The procedure of Part G of Example 1 was repeated exactly, however, 26 grams (0.08 moles) of the p-phthaloylamido obtained by the procedure in Part B of this example

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isopropyl salicylate used instead of the corresponding methyl compound. 23.2 g of the desired isopropyl 2-methoxy-4-phthaloylamidobenzoate were obtained in the form of white crystals (yield $ 86). An analytical sample was recrystallized from isopropanol. Melting point: 100 to 102 ⁰ g

Elemental analysis: ■ c (ji) Part D. H (Ji) N (Ji) calculated: 67.25 5.05 4.13 found: 67.51 5.23 4.01 2-Methoxy-4-phthaloylamido-5-chlorobenzoic acid isopropyl ester

The procedure of Part D of Example 1 was exactly repeated, but 16.96 g (0.05 mol) of 2-methoxy- ⁱ J'-phthaloylamidobenzoic acid isopropyl ester were used in place of the methyl compound. 17.8 g of the desired 2-methoxy-4-phthaloylamido-5-chlorobenzoic acid isopropyl ester were obtained in the form of white, granular crystals (yield 95%). An analytical sample was recrystallized from a benzene-hexane mixture.

Melting point: 123 to 125 ° C
Elemental analysis:

C (Ji) H (Ji) Cl (Ji) N (Ji)

Calculated: 61.05 4.32 9.49 3.75 C ₁₉ H ₁₆ ClNO ₅

found: 61.21 4.14 9.65 3.77

Example 6 2-Methoxy-4-phthaloylamido-5-chlorobenzoic acid methyl ester

This compound was made by exactly following the procedure of Parts A through D of Example 1.

2098 U / 166 9

Example 7 2-Methoxy - ^ - phthaloylamido-5 - chlorobenzoic acid methyl ester

This compound was made by exactly following the procedure of Parts A through D of Example 1.

Example 8

Ethyl 2-methoxy-Wphthaloylamido-5-chlorobenzoate

This compound was prepared using exactly the same procedure as described in Parts A through D of Example 4, manufactured.

Example 9

Isopropyl 2-methoxy- * 1- phthaloylamido ~ 5-chlorobenzoate

This compound was prepared exactly following the procedure described in Parts A through D of Example 5.

Example 10 r ^/ methyl 2-methoxy ~ ^ -phthaloylamido-5-chlorobenzoate

This compound was made exactly as in Parts A through D of Example 1.

-18-

2098U / 1669

Claims (1)

Claims Compounds of the general formula wherein A is a hydrogen, chlorine or bromine atom and R. and R ₂ , which can be identical or different, are a hydrogen atom or an alkyl group. 2. Compounds according to claim 1, characterized in that A is a chlorine atom and R. and R ₂ , which may be the same or different, denote a hydrogen atom or a lower alkyl group. 3 «Compounds according to claim 1 or 2 of the general Formula Ha Ha CO ₂ R ₁ wherein X is a chlorine or bromine atom and R ₁ and R _{2 are} lower alkyl groups. -19- 2098U / 1669 * K compounds according to claim 1 to 3, characterized in that R ^ is a methyl, ethyl, propyl or isopropyl group and R _{2 is} a methyl or ethyl group. 5. p-Phthaloylamidosalicylic acid. 6. methyl p-phthaloylamidosalicylate. 7. ethyl p-phthaloylaminosalicylate. 8. Isopropyl p-phthaloylaminosalicylate. 9. 2-Methoxy-4-phthaloylamidobenzoic acid methyl ester. 10. Ethyl 2-methoxy - ^ - phthaloylamidobenzoate. 11. Isopropyl 2-methoxy - ^ - phthaloylamidobenzoate. 12. 2-Methoxy- ^ -phthaloylamido-5-chlorobenzoic acid methyl ester. 13. 2-Methoxy - ^ - phthaloylamido-5-chlorobenzoic acid ethyl ester. 1 ^. Isopropyl 2-methoxy-4-phthaloylamido-5-chlorobenzoate. 15. Process for the preparation of compounds of claim 1 given general formula, characterized in that one of p-aminosalicylic acid goes out and protects the amino group by reaction with phthalic anhydride by phthalylation at any stage ·. 16. The method according to claim I5, characterized in that there is at least one of the following stages includes: -20-2098U / 166-9 a) esterification of the carboxylic acid function; b) alkylation of the phenolic hydroxyl function; c) Halogenation with the introduction of chlorine or optionally bromine into the 5-position of the benzene ring. 17. The method according to claim 15 or 16 for production a compound of the general formula Ha given in claim 3, characterized in that at any stage it includes: a) esterification of the carboxylic acid function; b) protection of the amino group by phthaloylation by reaction with phthalic anhydride; c) alkylation of the phenolic hydroxyl group; d) Halogenation with the introduction of chlorine or bromine in the 5-position of the benzene ring. 18. The method according to claim 16 or I7, characterized in that the esterification and alkylation obtained in a one-step reaction with an alkylating agent under anhydrous and alkaline conditions will. 19. The method according to claim 18, characterized in that the simultaneous esterification and alkylation is achieved by reacting a p-phthalimidosalicylic acid with an alkylating agent in anhydrous Acetone in the presence of a basic condensing agent. 20. The method according to claim 18 or I9, characterized in that the alkylating agent is dimethyl sulfate and the basic condensing agent is potassium carbonate. 209814/1669