SAFE AND EFFICIENT PROCESS FOR THE PREPARATION OF CARMUSTINE

Abstract

Carmustine may be safely and efficiently produced by reacting 2-chloroethylamine hydrochloride and 1,1′-carbonyldiimidazole to afford 1,3-bis(2-chloroethyl)-1-urea, followed by nitrosation to give the final product.

Claims

1. A process for the preparation of 1,3-bis(2-chloroethyl)-1-nitrosourea, which comprises: (a) reacting 2-chloroethylamine hydrochloride with carbonyldiimidazole in an aqueous medium, to obtain N-(2-chloroethyl)-1H-imidazole-1-carboxamide of formula 3: ##STR00004## and (b) reacting said N-(2-chloroethyl)-1H-imidazole-1-carboxamide with 2-chloroethylamine hydrochloride in an organic solvent or in an aqueous medium, to obtain 1,3-bis(2-chloroethyl)-1-urea.

2. The process according to claim 1, wherein said organic solvent is THF.

3. The process according to claim 1, wherein said (a) is conducted at a temperature of from 0 to 10° C. and said (b) is conducted at a temperature of from 20 to 60° C.

4. The process according to claim 1, wherein said (a) is conducted at a temperature of from 0 to 5° C. and said (b) is conducted at a temperature of from 40 to 45° C.

5. The process according to 1, wherein at least one of said (a) and said (b) is carried out in the presence of a base.

6. The process of claim 1, further comprising: (c) nitrosation of 1,3-bis(2-chloroethyl)-1-urea to obtain 1,3-bis(2-chloroethyl)-1-nitrosourea.

7. The process according to claim 5, wherein said nitrosation comprises: (c1) dissolving a metal nitrite in an aqueous medium, to obtain an aqueous solution; (c2) adding 1,3-bis(2-chloroethyl)-1-urea and a water-immiscible organic solvent to said aqueous solution, to obtain a tri-phase reaction mixture; (c3) adding formic acid to said tri-phase reaction mixture at a temperature of from 0 to 10° C., to obtain 1,3-bis(2-chloroethyl)-1-nitrosourea; and optionally isolating said 1,3-bis(2-chloroethyl)-1-nitrosourea from the organic phase.

8. The process according to claim 6, wherein: said metal nitrite is sodium nitrite (NaNO.sub.2), said water-immiscible organic solvent is a chlorinated hydrocarbon solvent, and said (c3) is performed at a temperature of from 0 to 5° C.

9. The process according to claim 7, wherein said water-immiscible organic solvent is dichloromethane.

10. The process according to claim 6, further comprising purifying said 1,3-bis(2-chloroethyl)-1-nitrosourea by filtration of the organic phase through silica gel.

11. The process according to claim 1, wherein said (a) and said (b) are performed as a one-pot reaction in an aqueous medium.

12. A process for the preparation of 1,3-bis(2-chloroethyl)-1-urea, which comprises: (a) reacting 2-chloroethylamine hydrochloride with carbonyldiimidazole in an aqueous medium, to obtain N-(2-chloroethyl)-1H-imidazole-1-carboxamide of formula 3: ##STR00005## and (b) reacting said N-(2-chloroethyl)-1H-imidazole-1-carboxamide with 2-chloroethylamine hydrochloride in an organic solvent or in an aqueous medium, to obtain said 1,3-bis(2-chloroethyl)-1-urea.

13. The process according to claim 12, wherein said organic solvent is THF.

14. The process according to claim 12, wherein said (a) is conducted at a temperature of from 0 to 10° C., and said (b) is conducted at a temperature of from 20 to 60° C.

15. The process according to claim 12, wherein said (a) is conducted at a temperature of from 0 to 5° C., and said (b) is conducted at a temperature of from 40 to 45° C.

16. The process according to claim 12, wherein at least one of said (a) and said (b) is carried out in the presence of a base.

17. The process according to claim 12, wherein said (a) and said (b) are performed as a one-pot reaction in an aqueous medium.

18. A process for the preparation of 1,3-bis(2-chloroethyl)-1-nitrosourea, which comprises nitrosation of 1,3-bis(2-chloroethyl)-1-urea by a metal nitrite in a solvent in the presence of an acid, wherein said nitrosation comprises: (c1) dissolving said metal nitrite in an aqueous medium, to obtain an aqueous solution; (c2) adding 1,3-bis(2-chloroethyl)-1-urea and a water-immiscible organic solvent to said aqueous solution, to obtain a tri-phase reaction mixture; (c3) adding formic acid to said tri-phase reaction mixture at a temperature of from 0 to 10° C., to obtain 1,3-bis(2-chloroethyl)-1-nitrosourea; and optionally isolating said 1,3-bis(2-chloroethyl)-1-nitrosourea from the organic phase.

19. The process according to claim 18, wherein: said metal nitrite is NaNO.sub.2, said water-immiscible organic solvent is a chlorinated hydrocarbon solvent, and said (c3) is performed at a temperature of from 0 to 5° C.

20. The process according to claim 18, wherein said water-immiscible organic solvent is dichloromethane.

21. The process according to claim 18, further comprising purifying said 1,3-bis(2-chloroethyl)-1-nitrosourea by filtration of the organic phase through silica gel.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] A detailed mode of realization of the present invention is defined below.

[0052] According to step (a), 2-chloroethylamine hydrochloride (5) in an aqueous solution is reacted with CDI (4), which is added in portions, for a time varying from 10 minutes to 96 hours, to provide N-(2-chloroethyl)-1H-imidazole-1-carboxamide (3). Alternatively, an aqueous base is added before addition of CDI, thus obtaining a solution with a pH in the range 7.5 to 8.5, the base being, for example, sodium carbonate (Na.sub.2CO.sub.3), K.sub.2CO.sub.3, NaOH, or potassium hydroxide (KOH). If a base is added, preferably the pH is about 8, the base is NaOH, more preferably NaOH 10%.

[0053] Typically, this step is conducted at a temperature of from 0 to 10° C. The temperature of reaction is preferably in the range 0 to 5° C. The reaction product precipitates directly from the aqueous solution of the reaction medium and is then filtered and dried before being submitted to step (b).

[0054] According to step (b), N-(2-chloroethyl)-1H-imidazole-1-carboxamide (3) is reacted with 2-chloroethylamine hydrochloride (5) in an organic solvent, preferably in THF, or in an aqueous medium. Typically, this step is carried out at a temperature of from 20 to 60° C., preferably at about 40° C., for a time varying from 10 minutes to 96 hours to provide BCU (2). Alternatively, a base is also added to the reaction mixture, for example Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaOH, KOH, preferably K.sub.2CO.sub.3. The solvent is evaporated under vacuum and the product is then precipitated by the addition of water. The obtained suspension is filtered, washed with water and dried.

[0055] When steps (a) and (b) are performed as a one-pot reaction, that is as a through or direct process, intermediate (3) is not isolated. CDI (4) reacts with one equivalent of 2-chloroethylamine hydrochloride (5) in an aqueous medium, optionally in the presence of a base, as defined above in step (a), providing intermediate (3), which precipitates from the reaction mixture. The second reaction occurs with the addition in the same reaction vessel of a second equivalent of 2-chloroethylamine hydrochloride (5) and increasing the reaction temperature, preferably to 40 to 45° C. When the reaction is complete, the suspension is cooled to room temperature (20 to 25° C.) and BCU (2) is easily isolated by filtration and drying and can be used as such for the BCNU (1) preparation.

[0056] According to step (c), nitrosation of BCU (2) is obtained by adding formic acid dropwise to a tri-phase suspension of BCU (2) in an aqueous solution of a metal nitrite, preferably NaNO.sub.2, in the presence of a water-immiscible organic solvent, for example an ether, preferably methyl tert-butyl ether (MTBE), or a chlorinated hydrocarbon solvent, preferably DCM, or toluene. Typically, this step is conducted at a temperature of from 0 to 10° C., preferably 0 to 5° C., more preferably 0 to 3° C., for a time varying from 10 minutes to 96 hours. The isolation of the final product (1), BCNU, is obtained by separating the organic phase from the aqueous phase and washing it with water. The organic phase is then preferably filtered through a silica gel pad. Preferably silica gel is high-purity grade. More preferably, silica gel is for flash chromatography, with pore size 60 Å, 230-400 mesh.

[0057] It has been found that 1,2,3-tris-2-chloroethyl biuret of formula (6):

##STR00003##

identified by LC-UV-MS, represents a common impurity which is present in the reaction mixture, in particular in the organic phase, at the end of the nitrosation step (c) in an amount range of generally 0.01 to 1 Area % (HPLC). This is the only impurity, let alone unreacted BCU (2), which is detected after the work-up.

[0058] The filtration through a silica gel pad permits complete removal of such impurity (6) which becomes undetectable by HPLC in the final product.

[0059] The filtered organic BCNU (1) solution is evaporated to residue and the product isolated by crystallisation in organic solvents. As an example, the oily residue is dissolved in a suitable solvent, such as an ether, an aromatic hydrocarbon, an ester or a ketone, preferably MTBE, and is precipitated by the addition of a second solvent, in which BCNU is not soluble, for example a linear or cyclic hydrocarbon, preferably n-heptane. The precipitation is easily obtained by either adding the second solvent dropwise into the BCNU solution or adding the BCNU solution into the second solvent.

[0060] In all instances, the aqueous medium may be water. Alternatively, the aqueous medium may contain other components, so long as they do not significantly adversely impact or impede the particular reaction of that step.

[0061] Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Analytical Methods

[0062] The HPLC method complied with the conditions described for the API (Active Pharmaceutical Ingredient) in the Carmustine monograph USP 37 2014 (United States Pharmacopoeia), using a Zorbax SB C18 (150×4.6 mm; 5 μm) column. Retention times (RT) are given in minutes, the wavelength is 200 nm. Mass are given as m/z ratio.

[0063] It was found that this method allows the detection not only of carmustine (BCNU, 1) but also of imidazolyl intermediate (3) and of BCU (2). 2-chloroethylamine hydrochloride (5) cannot be detected by HPLC/UV.

[0064] All the HPLC area % data reported herein were generated with the HPLC method in Table 1:

TABLE-US-00001 TABLE 1 HPLC method for API Carmustine (USP 37 2014) HP 1100 Instrument Column Zorbax SB C18 150 × 4.6 mm. 5.0 μm Mobile phase Acetonitrile/water 30/70 Flow 1.5 mL/min. Column temperature Room temperature Autosampler temperature 5° C. Wavelength 200 Injection volume 5 μL Elution Time 15′ Sample preparation for purity 1 mg/mL in ACN Elution time Intermediate (3) RT 1.7 BCU (2) RT 1.9 Carmustine (1) RT 9.3 1,2,3-tris-2-chloroethyl RT 12.4 biuret (6)

[0065] LC-UV-MS data were acquired on a 1100 Series LC/MSD instrument using the ESI(+) ionization technique and a HPLC method that differs from the USP method only for the addition of 0.1% formic acid (HCOOH) to the HPLC eluents.

[0066] .sup.1H-NMR spectra were recorded in DMSO-d.sub.6 at a constant temperature of 28° C. on a Varian INOVA 500 spectrometer operating at 499.55 MHz and equipped with a 5 mm z-axis PFG Indirect Detection Probe (.sup.1H{.sup.15N-.sup.31P}). Chemical shifts (δ) are reported in parts per million (ppm) and coupling constants (J) in Hz. The following abbreviations are used for multiplicities: s=singlet; d=doublet; t=triplet; q=quartet, m=multiplet; dd=double doublet.

[0067] Quantitative .sup.1H NMR spectra were recorded according to the method described in Organic Process Research and Development, 2004, Vol. 8, 381-384, which is incorporated herein by reference in its entirety.

[0068] The following examples intend to illustrate the invention without limitation as to the scope of the same.

Example 1—Preparation of BCNU (1)

Step a. Preparation of Intermediate N-(2-chloroethyl)-1H-imidazole-1-carboxamide (3)

[0069] In a reactor, 1.4 L of water were loaded and cooled to 0 to 3° C. 2-chloroethylamine hydrochloride (5) (200 g, 1.72 mol) was added, and the mixture was stirred to obtain a solution (measured pH is about 6.3). To the stirred solution, CDI (4) (300 g, 1.85 mol) was added portion-wise keeping the temperature below 10° C. At the end of the addition the reaction mixture was left under stirring at 0 to 5° C. for 4 hours. A white solid precipitated, which was filtered and washed twice with 300 ml of water. The wet product was dried at 45° C. under vacuum for about 18 hours, to provide 252 g dry solid of the title compound.

[0070] Yield 85%, HPLC purity 100 Area %.

Step b. Preparation of BCU (2) in THF

[0071] In a reactor, 660 g (3.80 mol) of N-(2-chloroethyl)-1H-imidazole-1-carboxamide (3) were loaded in 9.3 L of THF. 2-chloroethylamine hydrochloride (520 g, 4.48 mol) was added, and the reaction mixture was heated to 40 to 45° C. under stirring. The reaction was complete within about 6.5 hours.

[0072] Work-up: the solvent was evaporated under vacuum until the end of the distillation. 9.3 L of water were added and the suspension was stirred for 1 hour at 5 to 10° C. The suspension was filtered, and the solid washed twice with 1 L of water; the wet product was dried under vacuum at 40° C. until constant weight, providing 573 g of title product.

[0073] Yield 81.4%, HPLC purity 100 Area %.

Step c. Nitrosation of BCU (2)

[0074] NaNO.sub.2 (677 g, 9.8 mol) was dissolved in 3.4 L water. To the solution, BCU (2) (282 g, 1.52 mol) and DCM (7 L) were added. The mixture was stirred and cooled to 0 to 3° C. To the tri-phase mixture, formic acid (0.425 L, 11.26 mol) was added dropwise during about 30 minutes. At the end of the addition two clear liquid phases were obtained. The mixture was stirred for additional 30 minutes, and the organic phase was sampled. The reaction was considered complete when Area % HPLC of starting material was less than 0.5%.

[0075] Work-up: the two phases were separated and the organic phase was washed twice with water (3.3 L×2). The solution was evaporated to a volume of 1.1 L and then eluted through silica gel, pre-packed with DCM (700 grams high-purity grade silica gel for flash chromatography, pore size 60 Å, 230-400 mesh ASTM) with final DCM washing. The collected solvent (3.5 L) was evaporated to residue, keeping the internal temperature lower than 10° C. The residue was taken up with pre-cooled MTBE (1.4 L) and the solution was evaporated to residue. The residue was again taken up with pre-cooled MTBE (0.425 L). To this solution, pre-cooled n-heptane (3.5 L) was added, keeping the temperature between 0 and 3° C. (about 30 minutes). At the end of the addition the stirring was continued for 60 minutes at an internal temperature of 0° C. The suspension was filtered, and the solid was washed with pre-cooled n-heptane (0.45 L). The product was dried under vacuum at room temperature until constant weight to provide 283 g BCNU (1).

[0076] Yield 87%, HPLC purity 100 Area % (according to USP 37 2014 United States Pharmacopoeia method), NMR title 99.0%.

[0077] None of the used solvents (MTBE, DCM, n-heptane) was detected by .sup.1H-NMR.

Example 2—Preparation of BCNU (1) in the Presence of Base

Step a. Preparation of Intermediate N-(2-chloroethyl)-1H-imidazole-1-carboxamide (3) in the Presence of Base

[0078] In a reactor, 750 mL of water were loaded and cooled to 0 to 5° C. 2-chloroethylamine hydrochloride (5) (100 g, 862 mmol) was added, and the mixture was stirred to obtain a solution. The pH was adjusted to 8 with NaOH 10%, keeping the temperature at 0 to 5° C. To the stirred solution, CDI (4) (150 g, 925 mmol) was added portion-wise during 2 hours. At the end of the addition the reaction mixture was left under stirring at 0 to 5° C. overnight. A white solid precipitated, which was filtered and washed twice with 250 ml of water. 132 g of wet product were obtained, which were dried at 45° C. under vacuum for about 18 hours, to provide 110 g of dry solid.

[0079] Yield 73.3%, HPLC purity 100 Area %

[0080] .sup.1H-NMR (500 MHz), δ (ppm, DMSO-d.sub.6): 8.77 (t, J=5.9, 1H), 8.24 (dd, J=1.0, 1.5, 1H), 7.67 (dd, J=1.5, 1.5 Hz, 1H), 7.03 (dd, J=1.0, 1.5 Hz, 1H), 3.75 (t, J=5.9 Hz, 2H), 3.57 (q, J=5.9 Hz, 2H)

Step b. Preparation of BCU (2) in THF in the Presence of Base

[0081] In a reactor, 94.4 g (545.8 mmol) of N-(2-chloroethyl)-1H-imidazole-1-carboxamide (3) were loaded in 1350 mL THF. The mixture was stirred at room temperature until a complete solution was obtained. 2-chloroethylamine hydrochloride (75 g, 641.4 mmol) was added, followed by K.sub.2CO.sub.3 (161 g, 1170 mmol). The reaction mixture was heated to 40° C. stirring thoroughly. The reaction was complete within about 4 hours.

[0082] Work-up: the solvent was evaporated under vacuum until the end of the distillation. 1350 mL of water were added, and the suspension was stirred for 20 minutes at room temperature. The suspension was filtered, and the solid washed three times with 200 ml of water; the wet product was dried in a tray drier under vacuum at 45° C. for about 18 hours, providing 90.5 g of dry solid.

[0083] Yield 87.2%, HPLC purity 100 Area %

[0084] .sup.1H-NMR (500 MHz), δ (ppm, DMSO-d.sub.6): 6.31 (t, J=6.2, 1H), 3.75 (t, J=6.2, 2H), 3.56 (q, J=6.2 Hz, 211)

Step c. Nitrosation of BCU (2)

[0085] NaNO.sub.2 (144 g, 2.086 mol, 6.1 eq) was dissolved in 720 mL water. To the solution, BCU (2) (60 g, 0.342 mol) and DCM (1800 mL) were added. The mixture was stirred and cooled to 0 to 3° C. To the tri-phase mixture, formic acid (109.8 g, 2.388 mol, 7 eq) was added dropwise during about 30 to 40 minutes. At the end of the addition two clear liquid phases were obtained. The mixture was stirred for additional 30 minutes and the organic phase was sampled. The reaction was considered complete when Area % HPLC of starting material was less than 0.5%.

[0086] Work-up: the two phases were separated, and the organic phase was washed twice with water (720 mL×2). The solution was filtered through a short silica gel pad, pre-packed with DCM (4 grams high-purity grade silica gel for flash chromatography, pore size 60 Å, 230-400 mesh ASTM, per gram of BCU (2) used in the reaction). At the end of the filtration the silica gel pad was washed twice with 200 ml of DCM. The collected solvent was evaporated to residue, keeping the internal temperature lower than 10° C. The residue was taken up with MTBE (90 mL). To this solution, n-heptane (750 mL) was added dropwise during 30 to 40 minutes. During the addition the product started to precipitate. At the end of the addition the stirring was continued for 60 minutes at an internal temperature of 0° C. The suspension was filtered and the solid was washed with n-heptane (50 mL). The product was dried under vacuum at room temperature until constant weight (about 3 hours). 55.8 g of dry product as a yellowish powder were obtained.

[0087] Yield 80.4%, HPLC purity 99.7 Area %. The residual content of 2-chloroethylamine was determined with the procedure 3 described in USP 37 2014, United states Pharmacopoeia, and was found within the specification.

[0088] None of the used solvents (MTBE, DCM, n-heptane) was detected by .sup.1H-NMR.

[0089] .sup.1H-NMR (500 MHz), δ (ppm, DMSO-d.sub.6): 8.95 (t, J=5.6, 1H), 4.09 (t, J=6.4, 2H), 3.75 (t, J=6.3 Hz, 2H), 3.62 (m, 4H)

Example 3

Step b. Preparation of BCU (2) in Water in the Presence of Base

[0090] In a reactor, N-(2-chloroethyl)-1H-imidazole-1-carboxamide (3) (1.6 g, 9.2 mmol) was loaded in 7.5 mL of water followed by the addition of 2-chloroethylamine hydrochloride (5) (1.06 g, 9.2 mmol). The reaction mixture was heated to 40° C., and the pH was adjusted to 7.6 with NaOH 10%, and the mixture was stirred thoroughly. The reaction was complete within about 4 hours.

[0091] Work-up: The mixture was cooled to 20 to 25° C. and the suspension was filtered, washing the solid three times with 10 mL of water. The wet product was dried in a tray drier under vacuum at 45° C. for about 18 hours, providing 1.8 g of dry solid BCU (2). HPLC purity 100 Area %.

Example 4

Steps a/b as a One-Pot Reaction. Preparation of BCU (2) in Water in the Presence of Base

[0092] In a reactor, 15 mL of water were loaded and cooled to 0 to 5° C. 2-chloroethylamine hydrochloride (2 g, 17.2 mmol) was added, and the mixture was stirred to obtain a solution. The pH was adjusted to about 8 with NaOH 10%, keeping the temperature at 0 to 5° C. To the stirred solution, CDI (3 g, 18.5 mmol) was added portion-wise during 2 hours. At the end of the addition the reaction mixture was left under stirring at 0 to 5° C. overnight. A white solid precipitated. To the mixture a second addition of 2-chloroethylamine hydrochloride (2 g, 17.2 mmol) was done. The pH was adjusted again to about 8 with NaOH 10%, and the mixture was stirred for 4 hours increasing the temperature to 40 to 45° C. The reaction was considered over when the residual intermediate (3) was less than 0.2%. The suspension was cooled to 20 to 25° C. and was filtered; the solid was washed three times with 4 ml of water; the wet product was dried in a tray drier under vacuum at 45° C. for about 18 hours providing 2.13 g of BCU (2).

[0093] Yield 57.7%, HPLC purity 100 Area %.

[0094] Where a numerical limit or range is stated herein, the endpoints are included. Also, all values and subranges within a numerical limit or range are specifically included as if explicitly written out.

[0095] As used herein the words “a” and “an” and the like carry the meaning of “one or more.”

[0096] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

[0097] All patents and other references mentioned above are incorporated in full herein by this reference, the same as if set forth at length.