Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-01-31
2004-10-19
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S193200, C564S086000, C564S087000
Reexamination Certificate
active
06806366
ABSTRACT:
This invention concerns methods for the preparation, purification and isolation of antiviral disulfonic acid, disodium salt, particularly 4′,4-bis-{4,6-bis-[3-(bis-carbamoyl-methyl-1-sulfamoyl)-phenylamino]-[1,3,5]triazin-2-ylamino}-biphenyl-2,2′-disulfonic acid, as well as intermediates useful for its synthesis.
BACKGROUND OF THE INVENTION
Ellestad et al, J. Med. Chem. 41, 2671 (1998) and U.S. Pat. No. 5,852,015 describe a method for preparation and purification of 4′,4-bis-{4,6-bis-[3-(bis-carbamoyl-methyl-1-sulfamoyl)-phenylamino]-[1,3,5]triazin-2-ylamino}-biphenyl-2,2′-disulfonic acid. The intermediates of this disclosed process, when used in subsequent steps lead to an approximately 70% product purity by HPLC, which requires extensive reverse phase chromatographies, followed by lyophilization to remove residual solvents. The process of Ellestad et al. may be summarized in the following Scheme I.
The use of pure intermediates leads to a higher purity crude 4′,4-bis-{4,6-bis-[3-(bis-carbamoyl-methyl-1-sulfamoyl)-phenylamino]-[1,3,5]triazin-2-ylamino}-biphenyl-2,2′-disulfonic acid. Formation of impurities that require chromatography to remove can be further reduced by performing the last reaction step at a temperature range of 60-75° C. A purity of better than 80% can be obtained. It is desirable to have a process by which even greater purity can be achieved.
SUMMARY OF THE INVENTION
This invention provides processes by which a higher purity product can now be achieved with better than 97% purity by precipitation/crystallization from a volume of acetonitrile:water, without the use of tedious or costly chromatographies and lyophilizations. Preferably the volume of acetonitrile:water comprises a mixture ratio of from about 0.75:2 to about 1.5:2, more preferably from about 0.8:2 to about 1.2:2, most preferably about 1:2.
This invention provides a process for the production of 2-[Carbamoylmethyl-(3-nitro-benzenesulfonyl)-amino]acetamide, the method comprising reacting 2-(3-Nitro-benzenesulfonylamino)-acetamide with ClCH
2
CONH
2
in the presence of an aprotic solvent, such as N,N-Dimethylformamide (DMF), and a base. Commercially available bases, such as N,N,N′,N′-tetramethyl-1,8-naphthalenediamine, sodium carbonate, potassium carbonate or sodium bicarbonate, may be utilized. The pH of useful aqueous reaction medium is preferably maintained as either neutral or slightly acidic, preferably a pH range of from about 6 to about 7, more preferably from about 6.5. In non-aqueous media a stoichiometric excess of base may be utilized. Other useful bases include, but are not limited to, sodium hydride, potassium hydride and KOH in mixtures of alcohol(s) and water.
This procedure for the preparation of the intermediate 2-[Carbamoylmethyl-(3-nitro-benzenesulfonyl)-amino]acetamide may be further characterized as comprising an initial step of preparing 2-(3-Nitro-benzenesulfonylamino)-acetamide by reacting 3-Nitro-benzenesulfonyl chloride with aminoglycine hydrochloride or its free base in the presence of a base. The pH of the reaction medium can be created using commercially available bases, such as sodium carbonate or sodium bicarbonate. This step is preferably carried out at a pH of from about 5 to about 8, more preferably from about 6.5 to about 7.
This invention further provides a process for the synthesis of 4′,4-bis-{4,6-bis-[3-(bis-carbamoyl-methyl-1-sulfamoyl)-phenylamino]-[1,3,5]triazin-2-ylamino}-biphenyl-2,2′-disulfonic acid, the process comprising the steps of:
a) reacting 2-(3-Nitro-benzenesulfonylamino)-acetamide with ClCH
2
CONH
2
in the presence of N,N-Dimethylformamide and a base to provide 2-[Carbamoylmethyl-(3-nitro-benzenesulfonyl)-amino]acetamide;
b) treating the 2-[Carbamoylmethyl-(3-nitro-benzenesulfonyl)-amino]acetamide product of step a) with a reducing agent to provide 2-[(3-Amino-benzenesulfonyl)-carbamoylmethyl-amino]acetamide;
c) treating the 2-[(3-Amino-benzenesulfonyl)-carbamoylmethyl-amino-acetamide product of step b) with cyanuric chloride, 2,4,6-trichloro-1,3,5-triazine, to give 2-[(4-{4-[4-(Bis-carbamoylmethyl-sulfamoyl)-benzyl]-6-chloro-[1,3,5]triazin-2-ylmethyl}-benzenesulfonyl)-carbamoylmethyl-amino]acetamide; and
d) reacting the 2-[(4-{4-[4-(Bis-carbamoylmethyl-sulfamoyl)-benzyl]-6-chloro-[1,3,5]triazin-2-ylmethyl}-benzenesulfonyl)-carbamoylmethyl-amino]acetamide product of step c) with the disodium salt of 4,4′-diamino-2,2′-biphenyldisulfonic acid.
The resulting product of this process may be converted to pharmaceutically acceptable salts thereof by methods known in the art.
More specifically, the process described herein differs from the processes described in J. Med. Chem. 41, 2671 (1998) and in U.S. Pat. No. 5,852,015, outlined in Scheme I, above, in the preparation of intermediate 3, N,N′-bisacetamido-3-nitrobenzenesulfonamide (see examples for detailed procedures).
As depicted in Scheme II, m-Nitrobenzenesulfonyl chloride can be reacted with commercially available aminoglycine hydrochloride or its free base in aqueous alkali medium to afford intermediate 2, 2-(3-Nitro-benzenesulfonylamino)-acetamide, in high yields. Commercially available and art recognized bases may be used to prepare the alkali medium. Preferred bases are sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, and triethylamine. Intermediate 2 can be further substituted by condensation with an &agr;-haloacetamide in aqueous alkali medium to give intermediate 3, 2-[carbamoylmethyl-(3-nitro-benzenesulfonyl)-amino]-acetamide. Chloroacetamide is preferred due to large scale availability and cost. Preferred bases are the alkali carbonates, such as potassium carbonate or sodium carbonate.
While the remainder of the steps in the process are the same as in Scheme I, the quality of the subsequent intermediates and crude 4′,4-bis-{4,6-bis-[3-(bis-carbamoyl-methyl-1-sulfamoyl)-phenylamino]-[1,3,5]triazin-2-ylamino}-biphenyl-2,2′-disulfonic acid, disodium salt have been much improved, permitting the use of simple isolation and purification techniques.
Nitro intermediate 3 is subjected to reduction conditions to afford the amino intermediate 4, 2-[(3-Amino-benzenesulfonyl)-carbamoylmethyl-amino]acetamide. This reduction may be accomplished using reducing agents known in the art, including iron/acetic acid, iron/HCl, granular tin/HCl, SnCl
2
/HCl, or H
2
S in aqueous or alcoholic ammonia. The preferred method is catalytic reduction, more specifically using palladium on carbon catalyst in DMF. Use of acid in the reduction has been eliminated, thus simplifying isolation. Without a recrystallization the quality of this intermediate has been raised to approximately 99% by the present procedure, further described in Example 3.
The condensation of intermediate 4 with cyanuric chloride to give intermediate 6, 2-[(4-{4-[4-(Bis-carbamoylmethyl-sulfamoyl)-benzyl]-6-chloro-[1,3,5]triazin-2-ylmethyl}-benzenesulfonyl)-carbamoylmethyl-amino]acetamide, as described in J. Med. Chem. 41, 2671 (1998) and in U.S. Pat. No. 5,852,015, requires a reaction vessel or container temperature of 100-120° C. and the pH to be kept at 6.5-7.2 by the use of a phosphate buffer. It has been found that this condensation can be done without consideration of pH and the use of buffers. Also, the reaction may be carried out at a much lower temperatures in 1-methyl-2-pyrrolidinone and in the presence of sodium carbonate. This reaction can be completed for example at a temperature of from about 10° C. to about 90° C., more preferably at a temperature of from about 10° C. to about 40° C., most preferably from about 20° C. to about 25° C.
Demerson Christopher A.
Iera Silvio
Lunetta Jacqueline F.
MacEwan Michael F.
McMahon Wayne G.
Berch Mark L.
Habte Kahsay
Hogan Jr. John W.
Wyeth
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