Patent Application
20130184471
The present invention relates to a process for preparing bendamustine hydrochloride, derivatives and related compounds thereof.
Bendamustine having the structural formula
is a nitrogen mustard belonging to the family of drugs called alkylating agents. Bendamustine has been shown to be effective in the treatment of chronic lymphocytic leukemias and lymphomas. Bendamustine is normally used in its hydrochloride salt form as active agent.
CN 10169359 A discloses a process for preparing bendamustine hydrochloride in which dihydroxy bendamustine ethyl ester
is chlorinated using POCl3 as chlorinating agent in the presence of an organic solvent selected from the group consisting of toluene, xylene, dichloromethane and chloroform. The crude product of the chlorination reaction in form of bendamustine ethyl ester
is cleaved by refluxing in concentrated hydrochloric acid in the presence of activated charcoal for a relative long time of 4 hours. Then, water is added to the resulting reaction mixture in order to precipitate crude bendamustine in the form of its hydrochloride salt. Finally, the crude bendamustine hydrochloride is recrystallized from a mixture of THF/water.
WO 2010/042568 A1 discloses a process for preparing bendamustine hydrochloride in which chlorination of dihydroxy bendamustine methyl ester is performed by reacting said ester with 2-chloro acetic acid in the presence of borane-tetrahydrofurane, and subsequently, both ester cleavage and conversion to the hydrochloric salt of bendamustine are carried out by treating with concentrated hydrochloric acid, as shown in Scheme 1 below.
Furthermore, WO 2009/120386 A2 discloses a process for preparing bendamustine hydrochloride in which chlorination of dihydroxy bendamustine diethyl ester is performed by reacting said ester with thionylchloride in chloroform as the solvent, and subsequently, both ester cleavage and conversion to the hydrochloric salt of bendamustine are carried out by treating with concentrated hydrochloric acid, as shown in Scheme 2 below.
The object of the present invention is to provide an improved process for preparing bendamustine hydrochloride which is suitably adapted for obtaining bendamustine hydrochloride, derivative or related compounds thereof.
Various aspects, advantageous features and preferred embodiments of the present invention as summarized in the following items, respectively alone or in combination, contribute to solving the object of the invention:
(7) A process for preparing the compound of formula II
A-(CH2—CH2)n—B,
The term “room temperature as used herein means a temperature between 15 and 29° C.
The present invention is now described in more detail by referring to further preferred and further advantageous embodiments and examples, which are however presented for illustrative purposes only and shall not be understood as limiting the scope of the present invention.
According to one aspect of the invention, a general synthetic concept is provided which is particularly suitable for preparing bendamustine-related derivatives. A preferred embodiment of the general synthetic concept of the present invention is illustrated in Scheme 3:
According to the preferred embodiment of Scheme 3 (wherein in compounds of formulae I′, II′ and III′, Prot is defined as in the preceding items, and R1, R2, Y1 and Y2 of compound of formulae I to III are selected as follows: R1=methyl, R2=propylene, Y1=Y2=oxygen), a compound of formula II′ is prepared by chlorination of a compound of formula I′ using POCl3 as chlorating agent. Next, compound of formula II′ is converted into compound of formula III′ by deprotection of the carboxyl moiety under acidic conditions; aqueous HCl is used as a preferred acid. The crude compound of formula III′ is purified by recrystallisation in aqueous HCl. Finally, in order to obtain an anhydrous crystalline form of bendamustine hydrochloride, compound of formula III′ is dried in order to remove water adsorbtively bound to compound of formula III′. It is understood that the process depicted in Scheme 3 is also applicable to compounds of formulae I to III having other substituents R1, R2, Y1 and Y2 than the exemplary compounds of formulae to III′ shown in Scheme 3.
Compounds of formula I′ are readily available. For example, a compound of formula II in which Prot is ethyl can be readily prepared by reacting 4-[(2,4-dinitro-phenyl)-methyl-caramoyl]-butyric acid ethyl ester with ethylene oxide and acetic acid as described in e.g. DD 34727.
According to one aspect of the invention, a chlorination step (cf. STEP 1 in Scheme 3) for preparing compound of formula II can be carried out by means of two alternative process variants A and/or B, which alone or in combination provide for a compound of formula II having exceptional high purity:
In process variant A, a compound of formula I
wherein R1 is alkyl, aryl or alkylaryl, R2 is alkylene, arylene, alkylarylene or arylalkylene, Y1 and Y2 independently from each other represent oxygen or sulphur, and Prot is a protective group for carboxylic acids, thiol acids (—COSH), thion acids (—CSOH) and —CSSH acids,
is added portionwise without solvent to phosphorous oxychloride (POCl3) in order to obtain the compound of formula II
wherein R1, R2, Prot, Y1 and Y2 are defined as above.
In process variant B, a compound of formula I
wherein R1, R2, Prot, Y1 and Y2 are defined as above,
is converted to a compound of formula II
wherein R1, R2, Prot, Y1, and Y2 are defined as above,
by means of a chlorinating agent, wherein a solubilizer is added to the resulting reaction mixture, which reaction mixture is then added portionswise to an aqueous solution of an inorganic proton acceptor.
Process variants A and B respectively represent alternative processes for preparing a compound of formula II which processes provide for a simple and efficient carrying out of a chlorination reaction, while although, an exceptional high product purity is achieved. In particular, both process variants provide the possibility of getting the new anhydrous crystalline form of bendamustine hydrochloride and optionally related compound forms.
In particular, the procedural concept of process variant A provides for a simple and efficient reaction control by paying attention to the both the order of addition, namely adding solid compound of formula I to POCl3, and the addition in a portionwise manner. Thereby, it is rendered possible to advantageously control the exothermic reaction, and thus, overheating due to exothermic reaction can be avoided. This in turn provides for both improved operational safety and significantly higher purity of the product, since less decomposition products will be formed under these controlled reaction conditions.
As to the procedural concept of process variant B, the application of a solubilizer renders possible precipitation of the compound of formula II in a single water/organic phase. Thereby, it was surprisingly found by the present inventors that said solubilizer renders possible to generate a solid precipitate of the respective compound of formula II, in which form compound of formula II was efficiently prevented from hydrolyzing when coming into contact with water. Hence, the formation of the hydrolysis products, namely the respective monohydroxy and dihydroxy derivatives of formulae
which are difficult to remove by purification, is efficiently prevented. This in turn provides for a significantly simplified purification of the thus obtained compound of formula II.
Preferably, in process variant A, the chlorination reaction is carried out in the absence of a solvent. In this way, it can be dispensed with removal of a solvent by distillation. In addition, a longer lifetime of the production line is provided for, since in such distillative removal of a solvent, highly corrosive gaseous POCl3 would corrode parts of the production line which are in contact with the gaseous phase.
According to another embodiment of the invention, in process variant A, 5 to 9 molar equivalents of POCl3 are used relative to the molar amount of compound of formula I, preferably 7 to 8 molar equivalents POCl3. The aforementioned molar amounts of POCl3 provide for an improvement of environmental friendliness of the process, since the amount of POCl3 is substantially reduced compared to conventional chlorination process applying POCl3. Furthermore, there is also an improvement in view of the working conditions, since the amount of corrosive and toxic POCl3 is significantly reduced compared to conventional conditions for chlorinating compound of formula I using POCl3 as the chlorinating agent. E.g., in the chlorination step of CN 101691359 A, the amount of POCl3 is about 10 to 30 equivalents relative to 4-{5-[bis-(2-chloroethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}-butanoic acid ethyl ester.
According to still another preferred embodiment, in process variant A, the POCl3 is heated to about 60-70° C. before addition of the compound of formula I. Furthermore, according to yet another embodiment, in process variant A, subsequent to a complete addition of compound of formula I, the resulting reaction mixture is heated to reflux temperature for a predetermined time, preferably for 10 to 30 min, more preferably 15 to 25 min. In the two aforementioned embodiments, the reactions conditions are suitably selected in terms of reaction temperature and reaction time in order to provide mild reaction conditions.
Thereby, a stable and reliably process is provided, since less decomposition products are formed. Furthermore, substantial amounts of energy are saved owing to the relatively short reaction times.
In a particularly preferred embodiment of process variant B, the solubilizer is an end-capped ethylene glycol or polyethyleneglycol of formula
A-(CH2—CH2)n—B,
wherein n=1 to 30 and A and B independently from each other represent C1-C12 alkyl, preferably n=1 to 20 and A and B independently from each other represent C1-C8 alkyl, even more preferably n=1 to 10 and A and B independently from each other represent C1-C4 alkyl, yet even more preferably n=1 to 10 and A and B represent methyl, and in particular 1,2-dimethoxyethane (monoglyme). In this way, particularly suitable solubilizers are provided, since they are inert both to POCl3 and compound of formula II, that is, they do no react with the aforementioned compounds. In particular, it was surprisingly found by the present inventors that these solubilizers provide for a smooth precipitation of the product in solid form, while other solubilizers may lead to the formation of an oily residue instead of the desired solid precipitate and/or discoloration of the product may occur.
Preferably, process variant A and process variant B are combined. Thereby, the aforediscussed advantages of both procedural concepts are utilized in a single chlorination step.
According to a preferred embodiment of the invention, an ester cleavage step (cf. STEP 2 in Scheme 3) for preparing crude compound of formula III
wherein R1 is alkyl, aryl or alkylaryl, R2 is alkylene, arylene, alkylarylene or arylalkylene, and Y1 and Y2 independently from each other represent oxygen or sulphur, is carried out by a process comprising the following steps:
In this way, and by performing step b) for a suitable time, the —CY1—Y2— moiety of compound of formula II is readily deprotected under mild conditions, wherein the use of HCl as deprotecting agent renders possible to form a pharmaceutically acceptable salt in form of compound of formula III already within the ester cleavage step.
According to a further aspect of the invention, a purification process (cf. STEP 3 in Scheme 3) for obtaining pure compound of formula III,
wherein R1 is alkyl, aryl or alkylaryl, R2 is alkylene, arylene, alkylarylene or arylalkylene, and Y1 and Y2 independently from each other represent oxygen or sulphur, is carried out by a process comprising the following steps v) to vii):
This purification procedure renders possible to dispense with laborious recrystallisation in a harmful or even toxic organic solvent, and thus, environmental friendliness of the process is improved, while there is also an improvement in view of the working conditions. By means of simple precipitation in water, which is harmless to health and environment, pure compound of formula III is obtained. In particular, since no further recrystallisation in organic solvent is carried out, advantageously, the obtained crystalline product is free of organic solvent(s), in particular, the crystalline product is free of organic solvent(s) incorporated in the crystal lattice of the product. That is, the formation of a solvate form comprising organic solvent(s) is effectively prevented.
The first and second time intervals can be suitably adjusted and predetermined in order to achieve a substantially quantitative precipitation of compound of formula III. Preferably, the first time interval is ended when first visible amounts of compound of formula III precipitate. In order to improve and accelerate precipitation, it is preferable to cool the precipitation mixture to “room temperature” within a second time interval. However, in case precipitation works smooth and the aforementioned cooling does not seem to be necessary, the precipitation mixture is simply agitated for a total time interval being the sum of the first and second time interval.
Preferably, in the above described purification process, the aqueous HCl has a concentration of 15 to 32% by weight relative to the total weight of aqueous HCl, more preferably 16 to 25% by weight, even more preferably 18 to 22% by weight. Furthermore, according to another preferred embodiment, 30 to 70 molar equivalent HCl are used relative to the molar amount of crude compound of formula III, more preferably 40 to 60 molar equivalent HCl. The two aforementioned preferred embodiments alone or in combination provide for an efficient prevention of the hydrolysis of the compound of formula III to the respective monohydroxy- and dihydroxy hydrolysis products
It was surprisingly found by the present inventors that compound of formula III is particularly stable to hydrolysis in a strongly acidic aqueous solution, preferably having a pH of below 2.8, even more at below 2, whereas bendamustine hydrochloride partially hydrolyses to the aforementioned monohydroxy- and dihydroxy hydrolysis products at a pH of about 3 to 4. Without whishing to be bound to theory, it is assumed that the strongly acid aqueous solution provides for a precipitation regime which allows for high stability of the precipitated product towards hydrolysis, since the aforementioned critical pH of about 3 to 4 is not reached when the concentrated reaction mixture is added to the water phase. Hence purification of the precipitated compound of formula III is significantly simplified, since there is no need to remove the aforementioned hydrolysis products, which are difficult to remove by purification from the desired compound of formula III.
According to a another preferred embodiment of the invention, compound of formula III prepared according to the above described purification process is dried in order to remove water from said hydrochloride typically comprising about 5 wt-% water and to obtain an anhydrous crystalline form of compound of formula III. Preferably, drying is carried out by applying reduced pressure, optionally in combination with the application of a siccative.
Surprisingly, even though compound of formula III obtained in the above described purification process provisionally typically contains about 5 wt-% of water relative to the total molecular weight of compound of formula III and thus on a first sight seems to represent a monohydrate, water can be removed from the compound such that an anhydrous product is obtained having a content of residual water of only up to 1 wt-% water relative to the total molecular weight of compound of formula III, preferably less than 0.5 wt-% of water. By contrast, in “true monohydrates”, the water would be substantially regularly incorporated into the crystal lattice of an organic or inorganic compound, and hence, the water as a part of the crystal lattice could not have been removed by further drying of the compound such as vacuum drying.
Even more surprisingly, it was found that the aforedescribed drying step allows to obtain an anhydrous crystalline form of bendamustine hydrochloride
Owing to its (substantially) water freeness, the obtainable anhydrous crystalline form of bendamustine hydrochloride typically provides for a substantially improved shelf life stability compared to water containing forms of bendamustine hydrochloride such as hydrates, since bendamustine is an alkylating agent (also called “alkyl-lost”) which readily decomposes in the presence of water. The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way. The examples and modifications or other equivalents thereof will become apparent to those versed in the art in the light of the present entire disclosure.
Water (Karl Fischer Titration (KFT))
According to Ph. Eur., 2.5.12 (method A); Titrando 835 (Metrohm); platinum electrode (Fa.
HPLC/MS
Mass spectrometry ESI+
NMR
a) Ethyl Ester of Bendamustine
A 500 mL three-necked round bottom flask equipped with a magnetic stirring bar, internal thermometer and a reflux-condenser with oil ventile was charged with phosphorus oxychloride (134 g, 80.0 mL, 874 mmol) and heated to an internal temperature of about 60-70° C.
4-{5-[bis-(2-hydroxyethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}-butanoic acid ethyl ester (40 g, 114 mmol) was added in portions. After the addition was completed the mixture was heated to reflux temperature and stirring was continued for a further 15 min. The mixture was allowed to reach room temperature and 1,2-dimethoxyethane (90 mL) was added with stirring (solution 1). A 2000 mL three-necked round bottom flask was charged with potassium bicarbonate (412.1 g, 4115 mmol) and potable water (525 mL). Solution 1 was added slowly with stirring, maintaining an internal temperature of about 20 to 30° C., after which stirring was continued for a further 60 min. The resulting solid was isolated, washed with water (4×100 mL) and used without further purification. The product may optionally be dried in vacuum at temperatures of not more than 40° C. Yield (moist): 89.26 g; calculated dry: 46.3 g, >100%; product usually contains residual water even after drying.
1H NMR (600 MHz, DMSO-d6, ppm): δ=7.73 (d, 3J=8.8 Hz, 1H, arom. R2NCCH═CH), 6.92 (d, 4J=2.3 Hz, 1H, arom. R2NCCH), 6.78 (dd, 3J=8.8 Hz, 4J=2.3 Hz, 1H, arom. R2NCCH═CH), 4.04 (q, 3J=7.1 Hz, 2H, OCH2CH3), 3.70 (s, 8H, CH2CH2Cl), 3.65 (s, 3H, CH3N), 2.92 (t, 3J=7.4 Hz, 2H, CH2—CH2—CH2—COOEt), 2.44 (t, 3J=7.3 Hz, 2H, CH2—CH2—CH2—COOEt), 2.00 (m, 2H, CH2—CH2—CH2—COOEt).
13C-{H}-NMR (150 MHz, DMSO-d6, ppm): δ=172.7 (COOEt), 154.4 (arom.), 143.4 (arom.), 142.3 (arom.), 129.3 (arom.), 110.2 (arom.), 110.0 (arom.), 102.3 (arom.), 59.8 (CH2CH3), 53.6 (2×CH2Cl), 41.5 (2×CH2N), 32.9 (CH2), 29.4 (CH3), 25.7 (CH2), 22.2 (CH2), 14.2 (CH2CH3).
LC-MS (ESI+): m/z=386.2 (M+H+; 100% relative Intensity)
b) Methyl Ester of Bendamustine
A 250 mL three-necked round bottom flask equipped with a magnetic stirring bar, internal thermometer and a reflux-condenser with oil ventile was charged with phosphorus oxychloride (101 g, 60.0 mL, 657 mmol) and heated to an internal temperature of about 60-70° C.
4-{5-[bis-(2-hydroxyethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}-butanoic acid methyl ester (30 g, 89.4 mmol) was added in portions. After the addition was completed the mixture was heated to reflux temperature and stirring was continued for a further 15 min. The mixture was allowed to reach room temperature and 1,2-dimethoxyethane (67.5 mL) was added with stirring (solution 1). A 1000 mL three-necked round bottom flask was charged with potassium bicarbonate (321.8 g, 3215 mmol) and potable water (394 mL). Solution 1 was added slowly with stirring, maintaining an internal temperature of about 20 to 30° C., after which stirring was continued for a further 60 min. The resulting solid was isolated, washed with water (4×75 mL) and used without further purification. Yield: 71.6 g, moist.
1H NMR (500 MHz, DMSO-d6, ppm): δ=7.32 (d, 3J=8.8 Hz, 1H, arom. R2NCCH═CH), 6.93 (d, 4J=1.6 Hz, 1H, arom. R2NCCH), 6.79 (dd, 3J=8.8 Hz, 4J=1.6 Hz, 1H, arom. R2NCCH═CH), 3.71 (s, 8H, CH2CH2Cl), 3.65 (s, 3H, CH3N), 3.60 (s, 3H, CH3O), 2.83 (t, 3J=7.4 Hz, 2H, CH2—CH2—CH2—COOMe), 2.49 (t, 3J=7.3 Hz, 2H, CH2—CH2—CH2—COOMe), 2.02 (m, 2H, CH2—CH2—CH2—COOMe).
13C-{H}-NMR (125.77 MHz, DMSO-d6, ppm): δ=173.6 (COOMe), 154.8 (arom.), 143.8 (arom.), 142.7 (arom.), 129.8 (arom.), 110.6 (arom.), 110.4 (arom.), 102.7 (arom.), 54.0 (2×CH2Cl), 51.7 (OCH3), 41.9 (2×CH2N), 33.1 (CH2), 29.8 (CH3), 26.0 (CH2), 22.5 (CH2).
Crude Bendamustine Hydrochloride
a) Preparation Using the Bendamustine Ethyl Ester of Example 1a) as the Starting Material
A 250 mL three-necked round bottom flask equipped with a magnetic stirring bar, internal thermometer and a reflux-condenser with oil ventile was charged with bendamustine ethyl ester (44.6 g moist product, calcd. dry 23 g, 60 mmol (assumed content 100%)), hydrochloric acid (37%, 58 mL), and activated charcoal (1.1 g). The suspension was stirred for about 15 min at temperatures of 25 to 28° C., filtered and the residue was washed with hydrochloric acid (37%, 2 mL). The combined aqueous solutions were concentrated under reduced pressure. Yet another flask was charged with water (158 mL), which was warmed up to 41° C. and treated with the concentrate as obtained above with vigorous stirring at 41° C. After the addition was completed the resulting suspension was stirred for 8 min and then cooled to ambient temperature. Stirring was continued for further 30 min and the precipitate was isolated, washed with water (3×9 mL) and optionally additionally with acetone (3×9 mL) to yield bendamustine hydrochloride as a colorless solid (20.54 g moist product). Optionally the moist product may be dried at ambient temperature under reduced pressure.
1H NMR (600 MHz, DMSO-d6, ppm): δ=16-14 (s, br, 0.25H, acidic), 13-11 (s, br, 0.5H, acidic), 7.73 (d, 3J=9.2 Hz, 1H, arom. R2NCCH═CH), 7.11 (dd, 3J=9.2 Hz, 4J=2.3 Hz, 1H, arom. R2NCCH═CH), 6.91 (d, 4J=2.3 Hz, 1H, arom. R2NCCH), 3.90 (s, 3H, CH3N), 3.83 (t, 3J=7.0 Hz, 4H, 2×ClCH2), 3.77 (t, 3J=7.0 Hz, 4H, 2×CH2N), 3.18 (t, 3J=7.6 Hz, 2H, CH2—CH2—CH2—COOEt), 2.43 (t, 3J=7.3 Hz, 2H, CH2—CH2—CH2—COOEt), 2.03 (m, 2H, CH2—CH2—CH2—COOEt); acidic protons diminished in intensity, presumably due to solvent exchange.
13C-{H}-NMR (150 MHz, DMSO-d6, ppm): δ=173.7 (COON), 151.8 (arom. CN2), 145.7 (arom.), 131.7 (arom.), 124.8 (arom.), 113.5 (arom.), 112.4 (arom.), 94.7 (arom.), 52.4 (2×CH2Cl), 41.1 (2×CH2N), 32.6 (CH2), 31.0 (CH3), 24.0 (CH2), 21.7 (CH2).
HPLC-purity: 100% relative Area
LC-MS (ESI+): m/z=358.1 (M-Cl−—H2O; 100% relative Intensity)
b) Preparation Using the Bendamustine Methyl Ester of Example 1b) as the Starting Material
A 500 mL three-necked round bottom flask equipped with a magnetic stirring bar, internal thermometer and a reflux-condenser with oil pressure valve was charged with bendamustine methyl ester (177.93 moist, 92.2 g calc'd. dry, content of dry matter assumed 100%: 248 mmol), hydrochloric acid (37%, 215 mL), and activated charcoal (4.61 g). The suspension was stirred for about 15 min at temperatures of 25 to 28° C., filtered and the residue was washed with hydrochloric acid (37%, 8 mL). The combined aqueous solutions were concentrated under reduced pressure. Yet another flask was charged with water (585 mL), which was warmed up to 41° C. and treated with the concentrate as obtained above with vigorous stirring at 41° C. After the addition was completed, the resulting suspension was cooled to ambient temperature within 13 min. Stirring was continued for a further 60 min and the precipitate was isolated, washed with water (3×45 mL) and optionally additionally with acetone (3×45 mL) to yield the title compound as a colourless solid (86.3 g moist product). Optionally the moist product may be dried at ambient temperature under reduced pressure. HPLC-purity: 99.97% relative area.
Pure Bendamustine Hydrochloride
a) Purification of the Crude Bendamustine Hydrochloride Obtained in Example 2a)
A three necked round bottom flask equipped with magnetic stirring bar, internal thermometer and a reflux-condenser with oil ventile was charged with crude bendamustine HCl (16.9 g, 40.9 mmol), aqueous hydrochloric acid (20%; 34 mL), and activated charcoal (0.85 g, 70.8 mmol). The suspension was stirred at room temperature for about 15 min and insolubles were removed. The residuals were washed with hydrochloric acid (20%, 2 mL). Water (106 mL) was warmed to 41° C., and the combined acidic filtrates were added slowly with stirring. Stirring was continued for a further 5 min and the vessel contents were allowed to reach room temperature. Stirring was continued for a further 55 min and the resulting solid was isolated, washed with water (3×7 mL) and acetone (3×7 mL). Yield (moist): 15.3 g, Yield (dry) 13.5 g (80%).
1H NMR (600 MHz, DMSO-d6, ppm): δ=16-14 (s, br, 0.40H, acidic), 13-11 (s, br, 0.45H, acidic), 7.73 (d, 3J=9.2 Hz, 1H, arom. R2NCCH═CH), 7.11 (dd, 3J=9.2 Hz, 4J=2.3 Hz, 1H, arom. R2NCCH═CH), 6.91 (d, 4J=2.3 Hz, 1H, arom. R2NCCH), 3.90 (s, 3H, CH3N), 3.81 (t, 3J=6.1 Hz, 4H, 2×ClCH2), 3.77 (t, 3J=6.1 Hz, 4H, 2×CH2N), 3.17 (t, 3J=7.7 Hz, 2H, CH2—CH2—CH2-Ester), 2.41 (t, 3J=7.3 Hz, 2H, CH2—CH2—CH2-Ester), 2.01 (m, 2H, CH2—CH2—CH2-Ester); acidic protons diminished in intensity, presumably due to solvent exchange.
13C-{H}-NMR (150 MHz, DMSO-d6, ppm): δ=173.7 (COON), 151.8 (arom. CN2), 145.7 (arom.), 131.7 (arom.), 124.8 (arom.), 113.5 (arom.), 112.4 (arom.), 94.7 (arom.), 52.4 (2×CH2Cl), 41.1 (2×CH2N), 32.6 (CH2), 31.0 (CH3), 24.1 (CH2), 21.7 (CH2).
HPLC-purity: 100% relative area
LC-MS: m/z=358.1 (M+-HCl—H2O)
Residual water: 4.58% by weight
b) Purification of the Crude Bendamustine Hydrochloride Obtained in Example 2b)
The purification of the crude bendamustine hydrochloride obtained in Example 2b) is carried out analogously as described in Example 3a), wherein crude bendamustine HCl obtained in Example 2b) is used as the starting material.
Bendamustine hydrochloride obtained in Example 3a) and b) respectively was dried under reduced pressure, optionally in the presence of phosphorous pentoxide. The content of residual water was 0.22-0.80% by weight relative to the total molecular weight of bendamustine hydrochloride (determined by KFT-titration).
| Number | Date | Country | Kind |
|---|---|---|---|
| 12151646.2 | Jan 2012 | EP | regional |
| Number | Date | Country | |
|---|---|---|---|
| 61587750 | Jan 2012 | US |
