HK1024230B - Novel modifications to 2-amino-4-(4-fluorobenzylamino)-1-ethoxycai and processes for preparing said compound - Google Patents

Description

Novel variants of 2-amino-4- (4-fluorobenzylamino) -1-ethoxycarbonylaminobenzene and methods for their preparation

The present invention relates to novel variants of 2-amino-4- (4-fluorobenzylamino) -1-ethoxycarbonylaminobenzene of formula I:a process for their preparation and their use in pharmaceutical compositions.

The compounds of the formula I and their preparation are disclosed in DE 4200259.

The compounds have activity such as anticonvulsant, antipyretic and analgesic properties and are therefore suitable for use in pharmaceutical compositions.

However, in the crystallization of the compounds of the formula I, there are cases where very different mixed products are obtained in terms of crystal size and crystal form. Mixtures of crystal modifications present serious problems in pharmaceutical formulations. In particular, in pharmaceutical forms with higher active compound content, physical inhomogeneities have a negative effect on maintaining constant pharmaceutical conditions.

On the other hand, the final products show significant differences in stability, purity and homogeneity, so that the active compounds do not meet the requirements for pharmaceutical quality.

There is therefore great interest in preparing compounds of formula I in homogeneous crystalline form.

It is therefore an object of the present invention to prepare compounds of formula I in a homogeneous crystalline form which meets the pharmaceutical requirements.

It has now surprisingly been found that 3 different but pure crystal modifications of the compound of formula I can be prepared. The physically homogeneous compounds of formula I prepared are suitable for the manufacture of pharmaceutical end products.

The 3 variants referred to as A, B and C have distinct physicochemical properties.

In each case, the 3 variants of the compound of the formula I were characterized by X-ray diffraction patterns.

These variants differ in their DSC (differential scanning calorimetry) curves and in some cases their IR spectra and also in the respective typical crystal forms.

The X-ray diffraction pattern shown in FIG. 1 is for CuK_αThe powder diffractometer of the radiation makes a record.

The data in the DSC curve shown in FIG. 2 uses a heating rate of 10 k/min. The temperature given in each case indicates where the maximum intensity is located.

The IR spectra shown (FIGS. 3a, b, c) were made and recorded on potassium bromide pressed sheets. Variant a is characterized in that:

-in an X-ray diffraction pattern, the reflections of which do not coincide with the reflections observed from the other two variants at the following positions: 6.97 ° 2 θ (12.67 *), 18.02 ° 2 θ (4.92 *) and 19.94 ° 2 θ (4.45 *).

In the DSC curve, the endothermic A, B-mediated conversion occurs at about 97 ℃ (maximum), which is lower than about 142 ℃ when variant B produces melting;

its IR spectrum differs from the other two variants at the following strong vibration bands: 3421cm^-1(v N-H)、3376cm^-1(v N-H)、1703cm^-1(v C ═ O) and 886cm^-1(gamma C-H), and

substantially close to cubic to short cylindrical crystals. Variant B is characterized in that:

-in an X-ray diffraction pattern, the reflections of which do not coincide with the reflections observed by the other two variants at the following positions: 15.00 ° 2 θ (5.90 *), 19.29 ° 2 θ (4.60 *) and 19.58 ° 2 θ (4.53 *).

In the DSC curve, no thermal action below the melting action at about 142 ℃, and

the predominantly long flat to cylindrical crystal modification C is characterized in that:

-in an X-ray diffraction pattern, the reflections of which do not coincide with the reflections observed by the other two variants at the following positions: 9.70 ° 2 θ (9.11 *) and 21.74 ° 2 θ (4.09 *).

In the DSC curve, there are two endotherms associated with the phase transition to variant B between melting at about 130 ℃ and about 142 ℃ for variant B, and

predominantly flat columnar crystals.

The preparation of 3 variants of the compounds of the formula I can be carried out by the following process, where it is particularly important to maintain the preparation conditions.

These variants can be prepared either from the crude compound of formula I or by conversion of the variant.Preparation of variant a:

variant A can be prepared by stirring variants B and C in a solvent. Typically, variants B and C are treated with protic, dipolar aprotic or apolar solvents at room temperature.

The crystallization of modification A is preferably carried out by stirring a supersaturated solution of the compound of formula I in a protic, dipolar aprotic or apolar solvent.

Suitable protic solvents are lower alcohols, such as ethanol, 2-propanol, n-butanol; suitable dipolar protic solvents are acetonitrile or acetone; and the non-polar solvent is toluene.

The crystallization is preferably carried out in the presence of a lower alcohol.

The crystallization of the solution takes place at a temperature in the range from-20 ℃ to 110 ℃. In particular, pure variant A can be crystallized in certain solvents, such as n-butanol, at temperatures up to 110 ℃. Pure modification A is preferably crystallized at a temperature in the range from 20 ℃ to 50 ℃.Preparation of variant B

The crystallization of modification B is accomplished from a saturated solution of compound I by slow cooling.

Suitable solvents may be protic solvents (e.g. water) and aprotic solvents such as toluene.

The crystallization is preferably carried out in the presence of toluene.

The crystallization of the solution is carried out at a temperature in the range of 50 ℃ to 110 ℃, but preferably 80 ℃ to 100 ℃.

Variant B can also be obtained by thermal phase inversion, preferably from variant A at above 80 ℃.Preparation of variant C

A saturated solution of compound I in a protic (e.g. ethanol and 2-propanol) or aprotic (e.g. toluene) solvent is slowly cooled at a temperature between 30 ℃ and 80 ℃ to crystallize form C.

The solution is preferably crystallized at a temperature of 50 ℃ to 70 ℃.

Each of the above variants of compound I can be processed for administration in a pharmaceutical form that meets pharmaceutical requirements.

The invention also relates to the use of variants A, B and C of Compound I for the preparation of a pharmaceutical preparation. They are particularly effective antiepileptic and neuroprotective agents.

The pharmaceutical preparations usually contain at least 10mg to 200mg of a variant of compound I as a unit dose. The preferred form of administration is a tablet.

Variants of the compounds of formula I can be processed into pharmaceutical preparations in a conventional manner using suitable excipients and/or auxiliaries.

Especially variant a of compound I shows excellent properties in further pharmaceutical processing.

Its crystalline structure remains stable up to about 80 ℃. No change in the crystal lattice was observed even after long-term storage at a temperature of 60 ℃ and a relative humidity of 70 ℃;

the crystal lattice of variant a is also unchanged on contact with solvents, such as water, ethanol, acetone or toluene;

the approximately cubic to short cylindrical crystal forms give them a granular structure suitable for pharmaceutical processing.

Variants B and C may be employed in specific pharmaceutical preparations, such as capsules or dry ampoules. So, for example, fine particles are the preferred dosage form, the crystalline modification C which dissolves very quickly is advantageous in the preparation of dry ampoules.

The preparation of the variants is illustrated in detail with the aid of the following examples:example 1Variant A

In a 16-liter dissolution vessel, 2.34kg of compound I and 0.16kg of activated carbon were dissolved in 7.0 liters of ethanol with heating while stirring. The solution was filtered hot through a filter-press filter, with stirring, into a cooled 32 l crystallisation vessel which was filled with 0.5 l of ethanol and the internal temperature was kept at < 45 ℃. Subsequently, the residual solution was washed out of the dissolution vessel, passed through a filter press with 0.75 l of hot ethanol into the crystallization vessel and the suspension was rapidly cooled. Subsequently, the mixture was stirred at 5 ℃ to 12 ℃ for 0.5 hour, and the solid was filtered off with suction under inert conditions. The product was washed 3 times with 1.2 l cold ethanol each time. The crystals were then dried to constant weight in a vacuum desiccator at 50-55 ℃. 2.04kg (87% of theory) of pure variant A were obtained.Example 2Variant A

2g of variant C were stirred in 6m l of ethanol at room temperature for 2 days. Variant A was obtained quantitatively.Example 3Variant A

5g of variant B or C were stirred in 50m of toluene for 2 days at room temperature. Variant A was obtained quantitatively.Example 4Variant A

3g of variant B are stirred in 1.5m l of acetone for 2 days at room temperature. Variant A was obtained quantitatively.Example 5Variant A

10g of compound I are dissolved in 5 ml of n-butanol with heating. The solution is crystallized at 105-110 ℃, the mixture is cooled to 20 ℃, filtered with suction and the crystals are washed with n-butanol. Variant A was obtained quantitatively.Example 6Variant B

10g of compound I are rapidly heated to reflux in 20 ml of toluene and dissolved. The solution is crystallized at 90 ℃ to 100 ℃ and the crystals are filtered off with suction and washed with 5m of toluene. After drying, 9.8 is obtainedg (98% of theory).Example 7Variant B

10g of variant A were stored in a drying cabinet at 100 ℃ for 8 hours. Variant B was obtained quantitatively.Example 8Variant C

After addition of 0.2kg of activated carbon in 19.6 l of isopropanol, 3.0kg of compound I are dissolved in a 32 l dissolution vessel by stirring and heating. The solution was filtered hot through a filter press to 32 liters of internal temperature in a crystallization vessel maintained at 60-65 ℃. Subsequently, the residual solution was washed out of the dissolution vessel by filtration and passed through a filter press into a crystallization vessel with 2.5 liters of hot isopropanol (about 70 ℃). After crystallization has started at 60-65 ℃, the mixture is stirred. The suspension formed is rapidly cooled, then stirred at 5 ℃ to 12 ℃ and filtered with suction under inert conditions. The crystals were washed 3 times with 2.5 liters of cold isopropanol each time.

Thereafter, the crystals were dried under vacuum at 50 ℃ to 55 ℃ until the weight was unchanged. 2.64kg (88% of theory) of active compound of variant C were obtained.

Claims (16)

1. Variant a of compound I:characterized in that, in the X-ray diffraction pattern, the reflection of this variant does not coincide with the reflection observed by the other two variants at the following positions: 6.97 ° 2 θ (12.67 *), 18.02 ° 2 θ (4.92 *) and 19.94 ° 2 θ (4.45 *).

2. Variant B of Compound I, characterized in that, in the X-ray diffraction pattern, its reflexes do not coincide with the reflexes observed by the other two variants at the following positions: 15.00 ° 2 θ (5.90 *), 19.29 ° 2 θ (4.60 *) and 19.58 ° 2 θ (4.53 *).

3. Variant C of Compound I, characterized in that, in the X-ray diffraction pattern, its reflexes do not coincide with the reflexes observed with the other two variants at the following positions: 9.70 ° 2 θ (9.11 *) and 21.74 ° 2 θ (4.09 *).

4. Process for the preparation of modification A as claimed in claim 1, characterized in that the crystalline form is crystallized in pure form from a supersaturated solution of compound I in a protic, dipolar aprotic or apolar solvent at a temperature of from-20 ℃ to 110 ℃.

5. Process for the preparation of variant A according to claim 4, characterized in that the crystallization is carried out at a temperature of from 20 ℃ to 50 ℃.

6. The process for the preparation of variant A according to any of claims 4 and 5, characterized in that the protic solvent may be a lower alcohol selected from ethanol, 2-propanol or n-butanol; the dipolar aprotic solvent is acetonitrile or acetone; and the non-polar solvent is toluene.

7. The method of claim 6, wherein: lower alcohols are used as solvents.

8. Process for the preparation of variant A according to claim 1, characterized in that variants B and C are treated with protic, dipolar aprotic or apolar solvents at room temperature.

9. Process for the preparation of modification B according to claim 2, characterized in that the pure form is crystallized from a saturated solution of compound I in a protic or apolar solvent at a temperature of from 50 ℃ to 110 ℃.

10. Process for the preparation of variant B according to claim 9, characterized in that the protic solvent used is water and the apolar solvent used is toluene.

11. Process for the preparation of variant B according to claim 2, characterized in that variant B is prepared from variant A by thermal phase inversion at a temperature above 80 ℃.

12. Process for the preparation of variant C according to claim 3, characterized in that the pure form is crystallized from a saturated solution of compound I in a protic or other non-polar solvent at a temperature of from 30 ℃ to 80 ℃.

13. Process for the preparation of variant C according to claim 12, characterized in that the protic solvents used are ethanol and 2-propanol and the apolar solvent is toluene.

14. Process for the preparation of variant C according to claim 12, characterized in that the crystallization from solution is carried out at a temperature of 50 to 70 ℃.

15. Use of variants A, B and C of compound I for the preparation of a medicament for anti-epilepsy and neuroprotection.

16. A medicament containing variant A, B or C of compound I and, if appropriate, excipients and/or auxiliaries.