WO2002055454A2

WO2002055454A2 - Process and product

Info

Publication number: WO2002055454A2
Application number: PCT/US2002/000657
Authority: WO
Inventors: Paul G. Spoors
Original assignee: Smithkline Beecham Corporation
Priority date: 2001-01-10
Filing date: 2002-01-10
Publication date: 2002-07-18
Also published as: AU2002234236A1; WO2002055454A3

Abstract

Invented is an improved process for the preparation of substituted N-(3',4'-dimethoxycinnamoyl)-aniline derivatives. Also invented are novel solvates of substituted N-(3',4'-dimethoxycinnamoyl)-aniline derivatives and pharmaceutical compositions prepared from the invented solvates.

Description

PROCESS AND PRODUCT

FIELD OF THE INVENTION The present invention relates to an improved process for the conversion of an aniline derivative to an N-substituted malonic acid amide derivative and the conversation of the N-substituted malonic acid amide derivative to a substituted N-(3',4 - dimethoxycinnamoyl)-aniline derivative.

More particularly, the invention relates to an improved process for the preparation of N-(3',4'-dimethoxycinnamoyl)anthranilic acid (Tranilast) represented by the following structure or a pharmaceutically acceptable salt, hydrate or solvate thereof.

BACKGROUND OF THE INVENTION Tranilast is described in U.S. Patent No. 5,385,935, issued on January 31, 1995, to

Tamai et al. as being useful for the treatment of allergic diseases, as an inhibitor of fibroblast proliferation and collagen accumulation, and for the inhibition of restenosis associated with coronary intervention.

Tranilast is sold commercially as a drug for the treatment of allergic diseases, e.g., allergic bronchitis, allergic asthma, atopic dermatitis, and the like, based on the activity exhibited by the drug for inhibiting release of chemical mediators [The Journal of Allergy and Clinical Immunology, Vol. 57, No. 5, pp. 396-407, (1976)].

Further, in Biochemical Pharmacology, Vol. 36, No. 4, pp. 469-474 (1987), it was reported that Tranilast inhibits fibroblast proliferation and collagen accumulation. Processes for the preparation of substituted N-(3',4'-dimethoxycinnamoyl)-aniline derivatives have previously been described. In particular, the Japanese publication of Unexamined Patent Application No. 64-16755 (hereinafter the J55 application) describes several such methods. According to the J55 application, US Patent 3,940,422 describes substituted N-(3',4'-dimethoxycinnamoyl)-aniline derivatives prepared by a common amide synthesis from 3,4-dimethoxycinnamic acid and anthranilic acid. The method described in this application is characterized by the use of various dangerous chemicals (thionyl chloride and phosphorus oxychloride). The reaction described therein is multi-staged, so it is not very convenient to operate, with unsatisfactory yields of about 80%.

Further prior methods of synthesizing substituted N-(3',4'-dimethoxycinnamoyl)- aniline derivatives are described in the 755 application. However, these methods are also indicated as not being industrially applicable. The starting materials are not readily available, and the reaction conditions are exacting. In Japanese Patent 60-56701, for example, 2H-3,l-benzoxazine-2,4(lH)-dione is used as the starting material, which is previously prepared from anthranilic acid and phosgene. In Japanese Patent 59-3996, the reaction compounds (2-methyl-4H-3,l-benzoxazin-4-one and veratrum aldehyde) are allowed to react at 200°C.

Hungarian Patent 186968 is among the other process mentioned in the J55 application. Therein, an equimolar mixture of veratrum aldehyde, N-(2-carboxyphenyl)- malonic acid monoamide, and piperidine is allowed to react in benzene or toluene, and the water produced during the reaction is continuously distilled off from the reaction mixture. N-3',4'-(dimethoxycinnamoyl)-anthranilic acid is separated in the form of a piperidine salt, from which a free product is prepared by acidolysis.

None of the numerous known processes discussed in 755 were found therein to be useful in preparing a substituted N-(3',4'-dimethoxycinnamoyl)-aniline derivative on an industrial scale. The 755 application is directed to the preparation of substituted N-(3',4- dimethoxycinnamoyl)-aniline derivatives by first preparing N-substituted malonic acid monoamides of formula IN,

wherein R is hydrogen, a halogen, a Ci _4alkyl, a Ci _4alkoxy, a carboxyl or a Cι_ 4alkoxycarbonyl.

Formula IV compounds are prepared by reacting compounds of the following Formula II or a halogenated hydrogen salt thereof

wherein R is as defined above, in a molten state with a derivative of a 1 ,3-dioxane-4,6- dione of the following Formula III

where RI and R^ each independently represent C^alkyl or both together form a pentamethylene group. The prepared N-substituted malonic acid monoamides (of formula IN) is reacted with a 3,4-dimethoxybenzaldehyde of the following structure V

to prepare the desired compound of formula I

CH=CHCOΝH

(I).

The advance made by the 755 application was to prepare the N-substituted malonic acid monoamides (of formula IN), in less than 90% yield (on average), by reacting a compound of formula II with a compound of formula III in a molten state. The 755 application indicated workable results using a solvent but only reported a 36.3% yield when using acetonitrile as the solvent.

Numerous problems occur in the large scale preparation of compounds when the reaction is carried out in a molten state. And specifically, in the molten state reaction of compounds of formulas II and III to yield compounds of formula IN, as described in 755. First, the product (of formula IN) is a solid at the indicated reaction temperature and thus causes stirring to cease. Consequently, on manufacturing on a pilot plant scale, the agitator will be hindered from stirring and would be damaged. Second, the solid product will be stuck to the sides of the reaction vessel/flask and will be difficult to remove. Therefore a molten state reaction is impractical for the large scale preparation of compounds of formula IN from compounds of formulas II and III. Thus there is a need in the art for a safe, economical, reliable and environmentally friendly process for the conversion of an aniline derivative to an Ν-substituted malonic acid amide derivative and the conversation of the prepared Ν-substituted malonic acid amide derivative to a substituted Ν-(3',4'-dimethoxycinnamoyl)-aniline derivative. SUMMARY OF THE INVENTION

This invention relates to an improved process for the preparation of substituted N- (3',4'-dimethoxycinnamoyl)-aniline derivatives on an industrial scale. This invention specifically relates to an improved process for converting an aniline derivative to an N-substituted malonic acid amide derivative.

This invention relates to an improved process for converting an N-substituted malonic acid amide derivative to a substituted N-(3',4'-dimethoxycinnamoyl)-aniline derivative on an industrial scale. This invention specifically relates to an improved process for converting an N- substituted malonic acid amide derivative to N-(3',4'-dimethoxycinnamoyl)anthranilic acid (tranilast) on an industrial scale and to tranilast made by the invented process.

This invention specifically relates to a pharmaceutical composition comprising tranilast when made according to the presently invented process. This invention also relates to solvates and hydrates of tranilast and to pharmaceutical compositions comprising tranilast when made from the presently invented solvates and hydrates.

DETAILED DESCRIPTION OF THE INVENTION All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as though fully set forth.

By the term "halogen", as used herein, unless otherwise defined, is meant chlorine, bromine or iodine, preferably chlorine or bromine.

The present invention provides a process for the production of a compound of structure (IA)

(IA) or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises reacting a compound of structure (IIA)

with a compound of formula (III)

in which R and R^ each independently represent hydrogen or Chalky 1 or both together form a pentamethylene group, in a solvent, to yield a compound of structure (IVA)

and acetone, where the acetone is subsequently removed by distillation, and reacting the prepared compound of structure (IVA) with a compound of structure (V)

in a solvent, in the presence of a base, preferably an amine or such as piperidine, with azeotropic removal of water. The salt of IA is exposed to acid to yield a compound of formula (IA) and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate.

The compounds of structure (IIA) and formula (III) are known and commercially available or can readily be prepared by those of ordinary skill in the art.

It should be noted that the carboxyl that is directly attached to the ring in formula IVA compounds (as used in the specification and the claims) may be a protected carboxyl. By "protected carboxyl, as used herein, is meant that the carboxyl can be protected by conventional blocking groups or masked carboxylic acids, such as cyanide groups, known in the art such as described in "Protective Groups In Organic Synthesis" by Theodora W. Greene, Wiley-Interscience, 1981, New York. Compounds containing such protected carboxyl groups may also be useful as intermediates in the preparation of the pharmaceutically active compounds of the invention.

Preferably R and R as used in the above process, are methyl.

Solvents for use in the preparation of compounds of formula (IVA) are generally non-polar solvents, preferably having a boiling point around 80°C or higher, most preferably, toluene. Solvents for use in the preparation of compounds of formula (IA) are those known in the art to azeotrope with water, preferably, toluene.

Among the advantages of the present invention with regard to compounds of formula (IV) is the use of the solvent that prevents the product from freezing up the agitator and allows the product to be removed from the vessel easily because it has not stuck to the walls of the vessel or the blade of the agitator. Further, the preferred solvent, toluene, is a generally used solvent employed in manufacturing. Further, the product (of formula IN) is insoluble in toluene at the temperature the reaction is conducted so it precipitates out and consequently provides an easily stirred suspension which is readily filtered. Further, the reagents and impurities are soluble in toluene and consequently are removed in the mother liquor to leave a very pure product. Finally, since the product IVA is not dried, another advantage of using toluene is that it is the solvent employed in the next step.

A contemplated equivalent of the presently invented process is to add the aldehyde of structure (N) directly to the reaction mixture of formula II compounds and formula III compounds, and prepare the product of structure (IA) in situ, without isolating compounds of formula (IN).

Preferably, therefore, the present invention is particularly useful for converting a compound of structure (IA)

into the following compound of structure (IN A)

Preferably, therefore, the present invention is also particularly useful for converting a compound of structure (IVA)

into the following compound of structure (IA)

(IA) Pharmaceutically acceptable salts, hydrates and solvates are formed when appropriate by methods well known to those of skill in the art.

In another aspect of the invention, preferred solvates and hydrates of tranilast are prepared. Tranilast, prepared from a chloroform solvate, is known (Kawashima, J. Pharm. Sci., 80 (1991) 472 to 478). The use of a chloroform solvate provides a form of tranilast that, when formulated into tablets, exhibits a preferred in vivo dissolution profile. When tranilast is prepared into tablets without first going through a solvate or hydrate, a dissolution profile which is much slower is obtained. The solvates and hydrates of the invention are advantageous because they are environmentally friendly and, upon removal of the solvent or water by drying, the resultant form of tranilast exhibits a desirable dissolution profile when formulated into solid dosage forms (as when a chloroform solvate is used). Solvents found not to form solvates with tranilast are teterhydrofuran, dioxane, acetonitrile, acetone, toluene, propanol, butanol, 2-propanol, acetic acid and t-Butylmethyl ether. The presently invented solvates are amide solvates of tranilast, preferably a dimethylformamide, dimethylacetamide or, most preferably, a l-methyl-2-pyrollidinone solvate. Upon removal of the amide solvent, by drying, a crystal form of tranilast is obtained that exhibits a desirable dissolution profile when formulated into solid dosage forms (as when a chloroform solvate is used).

Presently invented solid dosage forms of tranilast are prepared, by removing the solvent from a tranilast amide solvate, by drying, and bringing the resultant crystal form of tranilast into association with pharmaceutically acceptable excipients.

The presently invented hydrated forms of tranilast, upon removal of water by drying, provide a crystalline form of tranilast that exhibits a desirable dissolution profile when formulated into solid dosage forms (as when a chloroform solvate is used). The hydrated form of tranilast is advantageous because the solvent, water, is environmentally friendly.

Presently invented solid dosage forms of tranilast are prepared, by removing water from a hydrated form of tranilast, by drying, and bringing the resultant crystal form of tranilast into association with pharmaceutically acceptable excipients. The presently invented solid dosage forms of tranilast include capsules and, preferably, tablets.

Pharmaceutical compositions containing tranilast that are prepared from dried amide solvates or dried hydrates will have advantageous impurity profiles because, for example, the solvates used are environmentally friendly. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

Experimental Details

Example 1

Step 1 Preparation of 2-Carboxymalonanilate

Under a nitrogen atmosphere, a 500 gallon glass-lined conical shaped reactor was charged successively with toluene (525 kg), anthranilic acid (156.3 kg, 1140.8 mol. 1.0 eq.), and Meldrum's acid (192.0 kg, 1333.3 mol, 1.16 equivalents). The resulting slurry was initially heated to 100 °C (jacket temp) to distill off a mixture of toluene and acetone. The reaction mixture becomes homogeneous around 70-75 °C. When the reaction medium reached 80 °C, the jacket temperature was reduced to 95 °C. An exofherm followed which raised the temperature of the reaction to 99.3 °C. After the reaction medium temperature dropped to 98.8 °C the jacket temperature was raised to 120 °C. The final jacket set point temperature was 120 °C. The reaction was judged to be complete when the temperature of the reaction medium reached 106.7 °C . At this point the total volume of solvent removed by distillation was 226.5 kg. The reaction mixture was cooled to 75 °C then the vessel was charged with toluene (226.5 kg). The mixture was externally cooled to 30 °C, stirred, and then the contents were filtered through a basket centrifuge. The collected solids (251.9 kg, 97% corrected for LOD) were stored at ambient temperature.

1H NMR (d₆ DMSO)

12.1 (br.s, 1H), 11.3 (s, 1H), 8.44 (d, 8.1Hz, 1H), 7.96 (d, 8.1 Hz, 1H), 7.57 (t, 7.3 Hz, 1H), 7.15 (t, 7.5 Hz, 1H), 3.47 (s, 1H).

Example 2

Step 2 Preparation of 2-rr3-(3,4-dimethoxyphenyl)-l-oxo-2-propenyl]amino]benzoic acid

Under a nitrogen atmosphere, 500 gallon glass-lined conical shaped reactor was charged successively with toluene (506.3 kg, 2.01 kg per kg of 2-Carboxymalonanilate and veratraldehyde (207 kg, 1245.8 mol 1.13 eq.). After the aldehyde dissolved, 2- Carboxymalonanilate (253.9 kg, used 'as is was added and the resultant slurry was treated with piperidine (107 kg, 1245.8 mol, 1.13 eq.). On completion of the addition of piperidine, the reaction mixture was 39.3 °C. The resultant solution was stirred for 30 minutes which caused the temperature of the contents to drop to 39.0 °C prior to heating. The mixture was warmed to reflux (reflux commenced at 86.1 °C) to remove water from the reaction vessel. After 1 hr the total volume of water collected was 4.5 L and after 2 hrs it was 14.0 L. The reaction was analysed by HPLC and was judged complete after 3.5 hrs (total volume of water removed was 19.3 L). The mixture was cooled from 111.2 °C to 24.9 °C and stirred for 60 minutes. Approximately one third of the contents of the vessel were filtered through a basket centrifuge . The cake (120.6 kg, spin 1, LOD 0.31%) in the centrifuge was washed with toluene (224.9 kg) followed by acetone (2 x 144.9 kg). The second third of the contents were filtered through the basket centrifuge. The cake (160.4 kg, spin 2, LOD 1.61%) in the centrifuge was washed with toluene (224.9 kg) followed by acetone (2 x 144.9 kg). The remaining contents were filtered through the backet centrifuge and the cake (128.8 kg, spin 3, LOD 0.88%) was washed with toluene (224.9 kg) followed by acetone (2 x 144.9 kg). The combined filter cakes (409.8 kg) were combined and placed into a reaction vessel which contained methanol (572 kg) and water (143.7 kg) and the resultant contents were heated from 24.5 °C to 41.1 °C to form a homogeneous solution. Once a homogeneous solution was obtained, HC1 (170J kg) was added. An immediate precipitate occurred on addition, and the temperature of the contents of vessel rose to 55 °C. The pH of the solution at this point was found to be 0.5 (pH paper). The mixture was then cooled to 33.5 °C and then filtered. One third of the contents of reactor were put through a basket centrifuge and the cake was washed with methanol (2 x 143J kg) to give a wet cake of 114.9 kg (spin 1, LOD 1.81 %). The second third of contents of the vessel were put through a basket centrifuge and the cake was washed with methanol (2 x 143.7 kg) to give a wet cake of 122.0 kg (spin 2, LOD 1.88%). The remaining contents of the vessel were put through a basket centrifuge and the cake was washed with methanol (2 x 143 J kg) to give a wet cake of 73.6 kg (spin 3, LOD 3.86%). The wet product from spin 1 and 2 (236.9 kg of total 310.5 kg) was transferred to the drying suite and placed onto poly lined drying trays and loaded into vacuum oven respectivly. The wet cake was dried under vacuum at 50 °C with a nitrogen sweep to afford 224.7 kg (spin 1, 109.5 kg, LOD 0.03%, spin 2, 115.2 kg, LOD 0.02%) of 2-[[3-(3,4-dimethoxyphenyl)-l-oxo-2- propenyl]amino]benzoic acid as a yellow colored solid. Spin 3 was stored overnight in fibre drums at ambient temperature inside two polyethylene bags inside a black bag and then dried in vacuum oven at 50 °C with a nitrogen sweep to afford 70.2 kg (LOD 0.02%) of a yellow colored solid.. The combined total of 2-[[3-(3,4-dimethoxyphenyι)-l-oxo-2- propenyl]amino]benzoic acid was 294.9 kg (78.9%). Melting point 206 °C.

Example 3

Preparation of the NMP solvate of N-(3',4'-dimethoxycinnamoyl)anthranilic acid (Tranilast)

Under a nitrogen atmosphere, a 30 gallon glass-lined reactor was charged successively with acetone (34.0 L), and N-(3',4'-dimethoxycinnamoyl)anthranilic acid (34.0 kg). The resulting slurry was treated with NMP (l-methyl-2-pyrollidinone) (27.0 L) and heated to 66 °C to ensure complete dissolution. The contents were then transferred through a 10 inch one micron cartridge filter attached to the sidearm of the reactor. After the mixture filtered, it was cooled to 20 °C. The mixture was maintained at 20 °C for 15 minutes then filtered through a basket centrifuge and the collected cake was washed with chilled acetone (13.6 L). The resultant N-(3',4'-dimethoxycinnamoyl)anthranilic acid wet cake (38.0 kg of the NMP solvate of Tranilast) was dried under vacuum (2.7 mmHg) with a jacket temp of 90 °C.

The drying vessel was cooled and the material (28.3 kg) was screened to give 28.15 kg which was placed in the oven for a further 20 hrs. The dry material was again screened to give 26.75 kg (79% yield from starting material) of N-(3',4'- dimethoxycinnamoyl)anthranilic acid (a yellow colored solid). In deuterated DMSO, 3.82 (s, 3H), 3.86 (s, 3H), 6.77 (d (J= 15.5 Hz, IHO 6.9-1.1 ( m, 6 H) 7.98 (d,d J=8Hz, J=1.5 Hz) 8.61 d (J=8 Hz) 11.28 (s, 1H)

While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:

A process for the preparation of a compound of formula (IA)

with a compound of formula (III)

in which R* and R^ each independently represent hydrogen or Ci _4alkyl or both together form a pentamethylene group, in a solvent, to yield a compound of structure (IVA)

and acetone, where the acetone is subsequently removed by distillation, and thereafter, converting the compound of structure (INA) into the compound of structure (IA) and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate.

2. A process according to claim 1 in which R* and R^ are each methyl.

3. A process for the preparation of a compound of structure (INA)

which comprises reacting a compound of structure (IIA), as described above; with a compound of formula (III)

in which R* and R^ each independently represent hydrogen or Cι_4alkyl or both together form a pentamethylene group, in a solvent, with removal of prepared acetone by distillation.

4. A process according to claim 3 in which R* and R^ are each methyl.

5. A process for the preparation of a compound of structure (IA)

(IA) which comprises reacting a compound of stracture (IVA)

with a compound of formula (V)

in a solvent, with azeotropic removal of water.

6. A process for the preparation of a compound of formula (IA)

(IA) or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises reacting a compound of stracture (IIA)

with a compound of formula (III)

in which R* and R^ each independently represent Ci _4alkyl or both together form a pentamethylene group, in a solvent, to yield a compound of structure (IVA)

and acetone, where the acetone is subsequently removed by distillation, and reacting the prepared compound of stracture (IVA) with a compound of formula (V)

in a solvent, with azeotropic removal of water to form a compound of structure (IA) and thereafter optionally forming a pharmaceutically acceptable salt, hydrate of solvate.

7. The compound of structure (IA), as described in claim 1, when prepared by the process of any one of claims 1, 2, 5 or 6.

8. The compound of structure (IA) in the form of an amide solvate.

9. A pharmaceutical composition comprising a compound of structure (IA) when prepared from the amide solvate, as described in claim 8.

10. The compound of structure (IA), as described in claim 1, when prepared by crystallization from a solvent system that contains methanol, water and an acid.

11. The compound of claim 10 where the acid is hydrochloric acid.