# Patent

## Title
Methods for preparing ritodrine hydrochloride

## Abstract

Methods for preparing Ritodrine hydrochloride are provided. Also provided is non-hygroscopic, crystalline, polymorphic Ritodrine hydrochloride of Form I.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a National Phase Application of PCT International Application No. PCT/EP2011/054565, International Filing Date, Mar. 24, 2011, claiming priority to Italian Patent Application No. MI2010A000740, filed Apr. 29, 2010, both of which are hereby incorporated by reference in their entirety.
FIELD OF THE INVENTION
A new method for preparing Ritodrine hydrochloride is object of the present invention. The invention also concerns a crystalline polymorphic Ritodrine hydrochloride, Form I, having new and distinctive chemical-physical characteristics. Moreover, Ritodrine hydrochloride solvate or monohydrate or Form II are described, from which it has surprisingly been seen that it is possible to obtain Ritodrine hydrochloride Form I.
BACKGROUND OF THE INVENTION
Ritodrine hydrochloride is a pharmaceutical active ingredient classified as beta2-adrenergic agonist, used for its tocolytic action.
The chemical name of Ritodrine hydrochloride of formula (A) is 4-((1RS,2SR)-1-hydroxy-2-{[2-(4-hydroxyphenyl)ethyl]amino}propyl)phenol hydrochloride.




Legenda=and Enantiomer

    Ritodrine hydrochloride is the racemate of the erythro form.
    Ritodrine hydrochloride and its synthesis are described in U.S. Pat. No. 3,410,944. In the examples shown in U.S. Pat. No. 3,410,944, Ritodrine hydrochloride is isolated as a solid having a melting point of 183-186° C. and 193-195° C. Such different melting points are not compatible with a single polymorphic Ritodrine hydrochloride. The crystalline form of a pharmaceutical active ingredient has an impact on its stability, hygroscopicity, solubility, its dissolution speed and its bioavailability. It is therefore fundamentally important to precisely control the crystalline form of the active ingredient and of the methods to obtain it.


A different Ritodrine hydrochloride synthesis process is described in EP0492719 and comprises a non-diastereoselective reduction step with sodium borohydride (NaBH4) that provides an erythro/threo mixture 7.5:1, thus obtaining about 12% of undesired isomer mixture.
EP0603414 describes a stereoselective synthesis for obtaining (−)-Ritodrine hydrochloride and, alternatively, the isolation of (−)-Ritodrine through separation on a chiral column. EP0603414 does not refer to polymorphic forms of the compound.
SUMMARY OF THE INVENTION
The purpose of the present invention is that of providing Ritodrine hydrochloride in a crystalline form that is well defined and stable, hereafter called Form I. Moreover, a further purpose of the present invention is to provide the methods for obtaining such a form.
Ritodrine hydrochloride Form I can be obtained according to the following methods:

    
    
        (i) treating Ritodrine hydrochloride in alcoholic solvent with one or more organic solvents and subsequent precipitation of Ritodrine hydrochloride Form I;
        (ii) transforming Ritodrine hydrochloride solvate or monohydrate or Form II, by suspension in organic solvents, and the subsequent separation of Ritodrine hydrochloride Form I;

or

        (iii) transforming Ritodrine hydrochloride solvate or monohydrate or Form II by drying to obtain Ritodrine hydrochloride Form I.
    
    


Ritodrine hydrochloride Form I is advantageous since it is stable and it is non-hygroscopic.
Another purpose of the invention is to obtain Ritodrine hydrochloride through a new synthesis process that provides Ritodrine hydrochloride with high yield and purity.
Such a preparation method of Ritodrine hydrochloride foresees:

    (a) the reaction of 4-(2-bromopropionyl)phenyl methanesulfonate with benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amine to obtain 4-(2-{benzyl-[2-(4-benzyloxy-phenyl)-ethyl]-amino}-propionyl)-phenyl methanesulfonate (B).
    (b) the hydrolysis of the product obtained in (a) in the corresponding deprotected form 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one (C).
    (c) the salification of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one (C).
    (d) the catalytic hydrogenation of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride (D) so as to obtain Ritodrine hydrochloride (A).






Legenda=and Enantiomer

    Further characteristics and advantages of the method according to the invention shall become clearer from the following description and from the preferred embodiments, given as an example and not for limiting purposes.


A more complete understanding of the present invention can be obtained by referring to the tables summarising some chemical-physical characteristics for the compounds named in the rest of the description.
Ritodrine hydrochloride, Form I, Ritodrine hydrochloride, Form II, Ritodrine hydrochloride solvated with acetone, Ritodrine hydrochloride solvated with ethyl acetate, Ritodrine hydrochloride monohydrate for which the main x-ray diffraction peaks, the main and characteristic bands of the IR spectrum and the main and characteristic bands of the Raman spectrum, are shown.
The x-ray powder diffractogram (XRPD) was obtained by using a CuKα1 radiation. The diffractogram is measured in reflection modality in the range of 5-40° 2θ.
The IR spectrum was acquired in ATR modality (Attenuated Total Reflection) and it is measured in cm−1.
The Raman spectrum was acquired by using a laser source of 400 mW operating at 785 nm and it is measured in cm−1.


DETAILED DESCRIPTION
It has surprisingly been found that Ritodrine hydrochloride exists in two polymorphic forms, Form I and Form II, having very distinct chemical-physical properties. Ritodrine hydrochloride Form I is particularly advantageous with respect to Form II since it is non-hygroscopic. In virtue of this non-hygroscopicity, the chemical-physical properties of Ritodrine hydrochloride Form I can be controlled more easily. All of this is fundamentally important when Ritodrine hydrochloride is formulated.
Vice versa, Ritodrine hydrochloride Form II is hygroscopic. As it is well known in the pharmaceutical industry, the formulation of hygroscopic active ingredients foresees the use of rooms with controlled humidity during the storage and the formulation itself. Moreover, the formulated product must be packaged in a suitable manner so as to avoid problems of stability due to humidity. These problems are avoided when non-hygroscopic Ritodrine hydrochloride Form I is used.
Ritodrine hydrochloride Form I is characterised in that it is non-hygroscopic and stable in its water content as measured through Karl Fischer titration. It has surprisingly been found that Ritodrine hydrochloride Form I does not absorb water even when it is exposed to a relative humidity of 75%.
In the present application, by the term “non-hygroscopic” we mean that Ritodrine hydrochloride Form I absorbs less than 1% of water, like for example less than 0.5%, when it is exposed to an environment with 75% relative humidity.
Vice versa, Ritodrine hydrochloride Form II absorbs water even when it is not exposed directly to a humid environment but in normal controlled storing conditions like those foreseen for active ingredients.
In particular Ritodrine hydrochloride Form I claimed in the present invention is a crystalline solid characterised as follows:









TABLE 1





XRPD
IR
RAMAN


2θ(°)
cm−1
cm−1

















4.87
3380
3058


9.24
3012
3015


12.52
2854
2982


14.15
2827
2944


15.17
1612
2863


15.71
1595
1615


16.49
1514
1600


18.06
1443
1596


18.51
1402
1449


19.20
1388
1364


19.67
1354
1339


20.41
1342
1320


21.64
1326
1291


23.04
1291
1265


24.08
1261
1205


24.94
1203
1173


25.71
1172
1129


26.12
1128
1114


26.48
1115
1095


27.18
1098
1077


29.48
1076
1048


33.22
1048
1030


33.55
1031
1017


35.01
1015
993


35.32
992
969



969
922



874
848



856
824



832
713



809
668



790
641



763
598



718
481



667
406




390




341









Ritodrine hydrochloride Form II is a crystalline solid characterised as follows:









TABLE 2





XRPD
IR
RAMAN


2θ(°)
cm−1
cm−1

















9.35
3411
3057


12.52
3270
3016


14.06
3008
2946


15.14
2843
2911


15.76
2440
2879


16.31
1889
2864


17.55
1614
1616


18.74
1594
1602


19.02
1577
1594


19.69
1516
1448


20.42
1446
1419


20.64
1393
1321


21.46
1358
1290


22.36
1263
1265


23.88
1222
1208


24.94
1173
1139


26.97
1138
1073


28.25
1116
1046


31.81
1093
1014


32.53
1073
992


34.14
1046
926


37.97
1013
879



993
848



879
825



834
718



814
642



792
472



777
449



717
394



661
362




351




243









Ritodrine hydrochloride Form I can be obtained according to the following methods:

    
    
        (i) treating Ritodrine hydrochloride in alcoholic solvent with one or more organic solvents so as to obtain a solution and subsequent precipitation of Ritodrine hydrochloride Form I;

or

        (ii) transforming Ritodrine hydrochloride solvate or monohydrate or Form II, by suspension in organic solvents, and the subsequent separation of Ritodrine hydrochloride Form I; or
        (iii) transforming Ritodrine hydrochloride solvate or monohydrate or Form II, by drying so as to obtain Ritodrine hydrochloride Form I.
    
    


In another embodiment of the present invention Ritodrine hydrochloride is obtained according to a method that comprises:

    (a) the reaction of 4-(2-bromopropionyl)phenyl methanesulfonate with benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amine to obtain 4-(2-{benzyl-[2-(4-benzyloxy-phenyl)-ethyl]-amino}-propionyl)-phenyl methanesulfonate (B).
    (b) the hydrolysis of the product obtained in (a) in the corresponding deprotected form 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one of formula (C).
    (c) the salification of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one (C).
    (d) the catalytic hydrogenation of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride of formula (D) and subsequent concentration, following the separation of the catalyst, through low pressure distillation, so as to obtain Ritodrine hydrochloride (A).


In step (a) 4-(2-bromopropionyl)phenyl methanesulfonate is obtained through bromination of 4-propionyl-phenyl methanesulfonate with bromine. 4-(2-bromopropionyl)phenyl methanesulfonate is subsequently made to react with benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino in base presence to obtain the methane sulfonic ester 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-oxy-phenyl)-propan-1-one (B).
In one embodiment, the hydrolysis of the methane sulfonic ester of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-oxy-phenyl)-propan-1-one (B) in step (b) is carried out by means of a base that can be, as an example and not for limiting purposes, a hydroxide of alkaline and/or alkaline earth metals, typically potassium hydroxide or sodium hydroxide in a solvent formed by mixtures of acetone-water, methyl ethyl ketone-water or mixtures thereof. The compound (C) obtained is thus isolated through crystallization by acetone, methyl ethyl ketone, mixtures of acetone-water, methyl ethyl ketone-water or mixtures thereof.
In step (c) 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one (C) is salified with a suitable acid. In one embodiment, the compound (C) is transformed into its corresponding hydrochloride salt (D) by using hydrochloric acid, gaseous or in solution, in a solvent that is selected, as an example and not for limiting purposes, amongst toluene, ethanol, methanol, water, acetone, methyl ethyl ketone, ethyl acetate or mixtures thereof.
Alternatively, a direct conversion of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-oxy-phenyl)-propan-1-one methanesulfonate (B) in the salified form 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one (D) is carried out, without isolation of the free base (C).
In step (d) through treatment with hydrogen in presence of a catalyst, 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride (D) is converted into the corresponding compound 4-((1RS,2SR)-1-hydroxy-2-{[2-(4-hydroxyphenyl)ethyl]amino}propyl)phenol hydrochloride (Ritodrine hydrochloride) (A). In one embodiment, the catalytic hydrogenation of (D) occurs by using a catalyst made up of a palladium on carbon (Pd/C) in an organic solvent, preferably in alcohol or in alcohol mixed with water. As an example and not for limiting purposes, the alcohol is selected amongst methanol or ethanol or mixtures thereof.
The hydrogenation reaction is carried out in a hydrogen atmosphere according to what is known by a man skilled in the art and in particular with a pressure that is preferably comprised between 2 and 12 bar and at temperatures comprised between 20° C. and 45° C. In such conditions, and differently from what is shown in EP0492719, the reaction is very selective and provides an erythro/threo mixture of about 98:2.
The solution of Ritodrine hydrochloride obtained from the hydrogenation reaction, following filtration of the catalyst, is concentrated through low pressure distillation.
Ritodrine hydrochloride in alcoholic solvent obtained from the hydrogenation reaction is subsequently diluted with ethers or aliphatic hydrocarbons such as, as an example and not for limiting purposes, methyl-tert-butyl ether, heptane or mixtures thereof or methyl ethyl ketone until the precipitation of Ritodrine hydrochloride is obtained. The solid is isolated through filtration.
The humid solid thus obtained has the desired crystalline form, Form I. In a further embodiment, Ritodrine hydrochloride in alcoholic solvent used to obtain Form I, as described above, is obtained by mixing solid Ritodrine hydrochloride with an alcoholic solvent.
In another aspect of the present invention, the solution of Ritodrine hydrochloride obtained by the hydrogenation reaction, after filtration of the catalyst and subsequent concentration through low pressure distillation, is precipitated as a solvated form through treatment with suitable organic solvents.
In a further embodiment, Ritodrine hydrochloride in alcoholic solvent, used to obtain the solvate, is obtained by mixing solid Ritodrine hydrochloride with alcoholic solvent and subsequent precipitation through treatment with suitable organic solvents.
Suitable organic solvents used for the precipitation of Ritodrine hydrochloride solvate comprise, as an example and not for limiting purposes, acetone, ethyl acetate or mixtures thereof. The precipitation of Ritodrine hydrochloride can be possibly primed. The isolation of Ritodrine hydrochloride as a solved form is very advantageous since it provides Ritodrine hydrochloride with high chemical purity. The product obtained is Ritodrine hydrochloride solvate with a chemical purity that is greater than 98%, typically greater than 99% or greater than 99.8%.
As an example and not for limiting purposes, one example of Ritodrine hydrochloride solvate is the solvate with acetone, which is characterised as follows:









TABLE 3





XRPD
IR
RAMAN


2θ (°)
cm−1
cm−1

















3.75
3262
3061


7.49
3004
3018


11.50
2952
3004


14.24
2820
2954


14.98
2431
2856


16.29
1698
1692


17.35
1615
1618


19.02
1593
1600


20.32
1564
1549


21.06
1548
1478


21.65
1515
1446


22.42
1454
1424


23.23
1390
1305


24.06
1367
1290


24.87
1310
1266


25.30
1290
1213


25.80
1263
1196


26.38
1236
1168


26.93
1217
1153


32.15
1191
1118


35.48
1169
1075



1151
1052



1118
1020



1097
993



1075
928



1053
885



1020
848



993
815



959
798



936
765



908
717



885
658



872
642



843
580



829
546



815
343



789



765



718



660









As an example and not for limiting purposes, a further example of Ritodrine hydrochloride solvate is the solvate with ethyl acetate, which is characterised as follows:










TABLE 4





XRPD
IR
RAMAN


2θ (°)
cm−1
cm−1

















7.37
3338
3062


7.87
3101
3017


9.01
2979
2982


14.73
2799
2944


15.75
2465
2873


16.43
1742
1735


16.62
1730
1617


17.09
1615
1602


17.85
1595
1546


18.67
1579
1449


19.39
1546
1411


19.69
1514
1285


20.60
1441
1265


20.88
1410
1207


21.91
1392
1185


22.27
1372
1174


22.73
1342
1152


23.66
1264
1115


24.19
1220
1107


25.19
1171
1072


26.18
1150
1044


27.12
1115
1012


30.70
1090
928



1070
884



1043
848



1010
823



991
776



938
718



882
654



847
642



829
635



791
473



767
447



714
382



656
354




205









In another aspect of the present invention, the solution of Ritodrine hydrochloride obtained by the hydrogenation reaction, after filtration of the catalyst and subsequent concentration through low pressure distillation, is precipitated as a monohydrate through treatment with an aqueous solution. The precipitation of Ritodrine hydrochloride can be possibly primed. The mixture thus obtained is left to crystallise keeping it under stirring at a temperature comprised between 15° C. and 30° C., preferably at 20° C. for a time of from 4 to 48 hours, preferably from 10 to 24 hours.
In a further embodiment, Ritodrine hydrochloride monohydrate is obtained by mixing solid Ritodrine hydrochloride and an aqueous solution.
The compound obtained in such conditions is Ritodrine hydrochloride monohydrate with a chemical purity that is greater than 98%, typically greater than 99% or greater than 99.8%. Ritodrine hydrochloride monohydrate is characterised as follows:









TABLE 5





XRPD
IR
RAMAN


2θ(°)
cm−1
cm−1

















3.77
3479
3093


7.51
3407
3060


11.50
3187
3015


14.24
3052
2989


15.00
2977
2962


16.27
2825
2947


17.37
2685
2915


19.02
2602
2887


20.33
2448
2865


20.75
1614
1616


21.08
1601
1602


21.66
1568
1577


22.35
1515
1476


23.26
1453
1446


23.85
1373
1427


24.08
1353
1389


24.87
1314
1368


25.31
1294
1312


25.78
1278
1295


26.37
1230
1279


26.92
1175
1258


28.67
1127
1216



1099
1205



1071
1189



1044
1132



1010
1109



985
1072



964
1041



903
1015



882
987



851
943



826
903



809
883



785
855



753
831



716
827



701
809



655
789




718




639




570




524




450




420




390




357









The water content of Ritodrine hydrochloride monohydrate determined through Karl Fischer titration is 5.3% (weight/weight) and is congruous with the presence of one molecule of water in the crystal lattice.
It has surprisingly been observed that Ritodrine hydrochloride Form I can be obtained even from other crystalline forms of Ritodrine hydrochloride like the solvate, the monohydrate and Form II. In one embodiment, the transformation occurs wet, by suspension in organic solvents, and the subsequent separation of Ritodrine hydrochloride Form I. In a further embodiment of this invention, the suspension of Ritodrine hydrochloride solvate, monohydrate or From II, is carried out in ethers or aliphatic hydrocarbons such as methyl-tert-butyl ether, or heptane, or methyl ethyl ketone or mixtures thereof.
The suspension in such solvents is carried out through stirring at a temperature greater than 0° C., preferably between 20° C. and the boiling point of the solvent and even more preferably at a temperature comprised between 30° C. and 50° C. for at least 1 hour.
The transformation of Ritodrine hydrochloride in the desired form, Form I, can be monitored by using suitable methods that are known by a man skilled in the art.
In another aspect of the present invention, the transformation occurs dry. It has surprisingly been observed that Ritodrine hydrochloride solvate or monohydrate or Form II, is transformed into Ritodrine hydrochloride Form I through a drying process. It has surprisingly been discovered that such transformations occur at specific temperatures and over specific amounts of time. When these conditions are not scrupulously applied, Ritodrine hydrochloride is, instead, obtained as Form II, or as a mixture of Form I and Form II. It is obvious that the presence of Form II in the active ingredient is not desired. The transformation in dry conditions of Ritodrine hydrochloride Form I occurs by acting at a temperature of at least 60° C. and preferably at temperatures of between 75° C. and 85° C. for at least 1 hour.
The transformation of Ritodrine hydrochloride into the desired form, Form I, can be monitored by using suitable methods that are known by a man skilled in the art. The transformation in dry conditions of Ritodrine hydrochloride Form I can occur even at temperatures that are greater than 85° C. but with partial decomposition of the compound with the formation of by-products such as tyramine causing there to be reduced chemical purity of the active ingredient.
In another aspect of the present invention, the chemical purity of Ritodrine hydrochloride can be increased even through a process of

    a′) recrystallization with complete dissolution; or
    b′) resuspension in organic solvents without reaching complete dissolution; followed by the separation of the solid which is Ritodrine hydrochloride.


In the examples that follow, as an example and not for limiting purposes, the application of the present invention is illustrated.
EXPERIMENTAL PART
X-ray powder diffractograms (XRPD) were obtained by using a CuKα1 radiation. The diffractograms were measured in reflection modality in the range 5-40° 20.
The IR spectrums were acquired in ATR (Attenuated Total Reflection) modality and measured in cm−1.
The Raman spectrums were acquired by using a laser source of 400 mW operating at 785 nm and measured in cm−1.
The water content was determined through Karl Fischer (KF) titration.
Example 1
Preparation of 4-(2-{benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-propionyl)phenyl methanesulfonate (B)
100 g of 4-propionyl-phenyl methanesulfonate and 360 ml of dichloromethane were loaded into a 2 liter reactor. The solution obtained was cooled to 0° C. and, at such a temperature, 3 g of solution with 33% of Hbr in acetic acid and subsequently 23 ml of Br2 (71.6 g) were added. Once these were added, the solution obtained was left under stirring for 1 hour at a temperature of around 0° C.
200 ml of H2O were added to the solution, then the mass was heated to 20° C. and kept at such a temperature for 30 minutes.
Once the stirring had stopped the two phases were separated and the organic phase was reloaded on the reactor and 260 ml of ethanol were added to it.
The solution obtained was heated to around 80° C. progressively distilling the dichloromethane, then cooled to 40° C. and diluted with 1780 ml of ethanol.
133.2 g of benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amine and subsequently 104 ml of triethylamine were added to it under stirring. The mass was heated to reflux and was kept at reflux for about 18 hours, then it was gradually cooled down to room temperature, obtaining a suspension that was then filtered.
The crystalline solid obtained was vacuum dried at 60° C. for 10 hours.
195 g of 4-(2-{benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-propionyl)phenyl methanesulfonate (B) were obtained.
Molar yield 82%, purity 97.5% HPLC (A %).
Example 2
4-(2-{benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-propionyl)phenyl methanesulfonate (B)
100 g of 4-(2-bromopropionyl)-phenyl methanesulfonate and 1750 ml of ethanol were loaded into a 3 liter reactor.
103 g of benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino and after 77 ml of triethylamine were added to it under stirring. The mass was heated to reflux and kept at reflux for about 18 hours, then it was gradually cooled down to room temperature, obtaining a suspension that was then filtered.
The crystalline solid obtained was vacuum dried at 60° C. for 10 hours.
148.96 g of 4-(2{benzyl-[2-(4-benzyloxy-phenyl)-ethyl]-amino}-propionyl)-phenyl methanesulfonate (B) were obtained.
Molar yield 84%, purity 98.4% HPLC (A %).
Example 3
Preparation of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one (C)
50 g of 4-(2-{benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-propionyl)phenyl methanesulfonate (B), 100 ml of water, 355 ml of acetone and 18.4 g of potassium hydroxide are introduced into a one liter glass reactor at room temperature. The mixture is heated to reflux temperature (about 59° C.) and kept at such a temperature for two hours. Subsequently, the mixture is cooled down to 45-50° C. and 30% hydrochloric acid is added until a pH of around 7 is obtained. The lower phase is separated and the organic phase is diluted with 100 ml of water. A suspension is obtained that is cooled down to 0° C. The solid is isolated through filtration and washed and then vacuum dried at 40° C. 41.4 g of 2-{Benzyl-[2-(4-benzyloxy-phenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one (C) as a white solid, are obtained.
Molar yield 96%, chemical purity 99.63% HPLC (A %).
Example 4
Preparation of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride (D)
20 g of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one and 100 ml of methyl ethyl ketone are introduced into a 250 ml reactor. At 20° C., 9 g of a solution with 19% by weight of HCl in 2-butanone are added. Once the precipitation of the solid has occurred, it is heated to 50° C. and it is diluted with 40 ml of methyl ethyl ketone. It is kept under stirring for an hour and then it is cooled down again to 20° C. The solid is filtered and is washed with 80 ml of methyl ethyl ketone. After vacuum drying at 40° C., 20.6 g of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride as a white solid, are obtained.
Molar yield 95%, chemical purity: 99.76% HPLC (A %).
Example 5
Preparation of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride (D)
400 g of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one and 2000 ml of acetone are loaded into a one liter glass reactor, at room temperature. Keeping the temperature at 20° C., 34.8 g of gaseous hydrochloric acid is injected. Once the acid has been added it is primed with 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride, obtaining the precipitation of the product. The suspension is kept under stirring at 20° C. over night. The product is finally isolated through filtration, washed with 200 ml of acetone and vacuum dried at 40° C. 413 g of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride as a white solid, are obtained.
Molar yield 95%, chemical purity 99.84% HPLC (A %)
Example 6
Preparation of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride (D)
A 500 ml reactor was loaded with 20 g of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one, 200 ml of toluene and 10 ml of ethanol. The suspension thus obtained was brought to the temperature of 50° C. and at such a temperature, under stirring, 4 ml of 37% HCl were added, observing the complete dissolution of the suspended solid.
The solution was then cooled down first to 32° C. and then to 0° C. The solid obtained through crystallization was filtered, washed with 15 ml of isopropanol and vacuum dried at 55° C.
21 g of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride (D) were obtained as a white solid.
Molar yield 97%, purity 99.66% HPLC (A %).
Example 7
Hydrogenation of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride (D)
A 5 liter steel autoclave is loaded with 130 g of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride (D), 481 ml of methanol and 4.6 g of 5% palladium on carbon.
The mixture is heated to 30° C. and keeping the pressure at 6 bar hydrogen is injected until there is zero absorption. The mixture is filtered to remove the catalyst obtaining 504 g of alcoholic solution of Ritodrine hydrochloride.
Chemical purity (area, HPLC): Ritodrine hydrochloride 98.1%; threo isomers 1.3%.
Example 8
Hydrogenation of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride (D)
A 5 liter steel autoclave is loaded with 716 g of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride (D), 2650 ml of absolute ethanol and 107.7 g of 5% palladium on carbon 60% humid. The mixture is heated to 40° C. and keeping the pressure at 6 bar, hydrogen is injected until there is zero absorption. The mixture is filtered to remove the catalyst obtaining 2778 g of alcoholic solution of Ritodrine hydrochloride. Chemical purity (area, HPLC): Ritodrine hydrochloride 98.1%; threo isomers 1.2%.
Example 9
4-((1RS,2SR)-1-hydroxy-2-{[2-(4-hydroxyphenyl)ethyl]amino}propyl)phenol hydrochloride (Ritodrine hydrochloride) Form I.
A methanolic solution of ritodrine hydrochloride obtained as described in Example 8 was concentrated as a residue and was diluted with 89 ml of methanol.
The solution thus obtained is treated with 1180 ml of methyl-tert-butyl ether and heated to 37° C. obtaining a suspension. It is stirred for 11 hours and then cooled down to 20° C., it is filtered and the solid is washed with methyl-tert-butyl ether. It is vacuum dried at 40° C. obtaining 76.8 g of Ritodrine hydrochloride. The X-ray diffraction pattern corresponds to that of Ritodrine hydrochloride Form I shown in table 1.
Example 10
4-((1RS,2SR)-1-hydroxy-2-{[2-(4-hydroxyphenyl)ethyl]amino}propyl)phenol hydrochloride (Ritodrine hydrochloride) solvated with acetone.
A methanolic solution of ritodrine hydrochloride obtained as described in Example 8 was concentrated as a residue through low pressure distillation.
The residue is diluted with 10 ml of methanol and 650 ml of acetone. The mixture is brought to 37° C. and is kept under stirring at 37° C. for 11 hours. It is cooled down to room temperature and the product is isolated through filtration. It is washed with 200 ml of acetone and 102 g of Ritodrine hydrochloride are obtained. Chemical purity: 99.84% HPLC (A %). The X-ray diffraction pattern corresponds to that of Ritodrine hydrochloride solvated with acetone shown in table 3.
Example 11
4-((1RS,2SR)-1-hydroxy-2-{[2-(4-hydroxyphenyl)ethyl]amino}propyl)phenol hydrochloride (Ritodrine hydrochloride) solvated with ethyl acetate
100 g of an ethanolic solution of Ritodrine hydrochloride obtained according to the method described in example 8, containing about 15 g of Ritodrine hydrochloride, are concentrated by vacuum distilling 50 g of solvent. The solution thus obtained is cooled down to 0° C. 200 ml of ethyl acetate are dripped obtaining the precipitation of the product. The suspension is kept under stirring over night at 0° C. The solid is filtered. 14.5 g of Ritodrine hydrochloride are obtained.
Chemical purity: 99.25% HPLC (A %). The X-ray diffraction pattern corresponds to that of Ritodrine hydrochloride solvated with ethyl acetate shown in table 4.
Example 12
4-((1RS,2SR)-1-hydroxy-2-{[2-(4-hydroxyphenyl)ethyl]amino}propyl)phenol hydrochloride (Ritodrine hydrochloride)monohydrate
25 g of Ritodrine hydrochloride is suspended in 50 ml of water and is kept stirred at 20° C. for 20 hours. It is then cooled down to 0° C. in about an hour and it is kept at 0° C. for 3 hours.
The solid is filtered and is vacuum dried at 50° C. for 24 hours. 21 g of Ritodrine hydrochloride monohydrate are obtained.
The X-ray diffraction pattern is the same as that of Ritodrine hydrochloride monohydrate shown in table 5.
Example 13
Transformation of Ritodrine Hydrochloride Solvated with Acetone into Ritodrine Hydrochloride Form I
20 g of Ritodrine hydrochloride solvated with acetone obtained as described in example 10 are suspended in 40 ml of methyl-tert-butyl ether. The suspension is kept stirred at 50° C.-55° C. for 3 hours and is then cooled down to 20° C. It is filtered and washed with methyl-tert-butyl ether and is vacuum dried at 50° C.
13.3 g of Ritodrine hydrochloride Form I are obtained.
Example 14
Transformation of Ritodrine Hydrochloride Solvated with Acetone into Ritodrine Hydrochloride Form I
20 g of Ritodrine hydrochloride solvated with acetone obtained as described in example 10 are suspended in 100 ml of heptane. The suspension is heated to reflux temperature for 1-1.5 hours and is then cooled down to 20° C. The solid is filtered and is vacuum dried at 50° C. 13.8 g of Ritodrine hydrochloride Form I are obtained.
Example 15
Transformation of Ritodrine Hydrochloride Monohydrate into Ritodrine Hydrochloride Form I
Ritodrine hydrochloride monohydrate is placed to vacuum dry in an oven at a temperature of 80° C. for 12 hours. Ritodrine hydrochloride Form I is obtained.
Example 16
Transformation of Ritodrine Hydrochloride Solvated with Ethyl Acetate into Ritodrine Hydrochloride Form I
Ritodrine hydrochloride solvated with ethyl acetate is placed to vacuum dry in an oven at a temperature of 80° C. for 26 hours. Ritodrine hydrochloride Form I is obtained.
Example 17
Preparation of Ritodrine Hydrochloride Form II
Ritodrine hydrochloride solvated with acetone is placed to vacuum dry in an oven at a temperature of 40° C. for 22 hours. Ritodrine hydrochloride Form II is obtained. The X-ray diffraction pattern corresponds to that of Ritodrine hydrochloride Form II shown in table 2.
Example 18
Transformation of Ritodrine Hydrochloride Form II into Ritodrine Hydrochloride Form I
Ritodrine hydrochloride Form II is placed to vacuum dry in an oven at a temperature of 80° C. for 17 hours. Ritodrine hydrochloride Form I is obtained.
Example 19
Recrystallization of Ritodrine Hydrochloride
100 g of Ritodrine hydrochloride are suspended at room temperature in 300 ml of methyl ethyl ketone. 80 ml of methanol are added obtaining a solution that is subsequently heated to 37° C. and diluted with 700 ml of methyl ethyl ketone. The precipitation is started by adding a primer. The suspension is kept at 37° C. for 4 hours and is then left to cool down to room temperature. It is filtered and washed with 200 ml of methyl ethyl ketone. The solid is vacuum dried at 60° C. obtaining 60 g of Ritodrine hydrochloride Form I. Chemical purity 99.9% HPLC (A %).
Example 20
Stability of Ritodrine Hydrochloride Form I
Ritodrine hydrochloride Form I is kept at 40° C. and a relative humidity of 75% for 24 hours. The water content measured through Karl Fischer titration is 0.5% (weight/weight).
Example 21
Stability of Ritodrine Hydrochloride Form II
Ritodrine hydrochloride Form II is placed in a double polyethylene bag with a desiccant (silica gel) kept in standard conditions for storing active ingredients. After some months the water content of such Ritodrine hydrochloride measured through Karl Fischer titration is 2.2% (weight/weight).

## Claims

1. A method for preparing ritodrine hydrochloride comprising:
(a) reacting of 4-(2-bromopropionyl)phenyl methanesulfonate with benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amine to obtain 4-(2{benzyl-[2-(4-benzyloxy-phenyl)-ethyl]-amino}-propionyl)-phenyl methanesulfonate;
(b) hydrolyzing of 4-(2-{benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-propionyl) -phenyl methanesulfonate to obtain 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one;
(c) salificating of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]amino}-1-(4-hydroxy -phenyl-propan-1-one; and
(d) catalytically hydrogenating of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one hydrochloride to obtain Ritodrine hydrochloride as an erythro/threo mixture about of 98:2.

2. The method of claim 1, wherein hydrolyzing in (b) is performed using a base comprising an alkaline metal and/or earth alkaline hydroxide, potassium hydroxide or sodium hydroxide in a solvent made of mixtures of acetone-water, methyl ethyl ketone-water or mixtures thereof.

3. The method of claim 2, wherein 2-{Benzyl-[2 (4-benzyloxyphenyl)-ethyl]-amino}-1-(4-ydroxyl-phenyl)-propan-1-one is isolated by crystallisation from acetone, methyl ethyl ketone, mixtures of acetone-water, methyl ethyl ketone-water or mixtures thereof.

4. The method of claim 1, wherein the salificating step uses hydrochloric acid, gaseous or in solution, in an organic solvent, wherein the organic solvent comprises toluene or ethanol or methanol or water or acetone or methyl ethyl ketone or ethyl acetate or mixtures thereof.

5. The method of claim 1, wherein 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-oxy-phenyl)-propan-1-one methanesulfonate is directly transformed into 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl) -propan-1-one hydrochloride salt.

6. The method of claim 1, wherein the catalytically hydrogenating step of 2-{Benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-1-(4-hydroxy -phenyl)-propan-1-one hydro-chloride comprises palladium on carbon (Pd/C) catalyst in an organic solvent, wherein the organic solvent is an alcohol or an alcohol mixed with water, in a hydrogen atmosphere between about 2 and about 12 bars, at temperatures between about 20° C. and about 45° C.