WO2016046837A1 - An improved process for preparation of pyrrolo[3,4- c] pyrrole compounds and intermediates thereof - Google Patents
An improved process for preparation of pyrrolo[3,4- c] pyrrole compounds and intermediates thereof Download PDFInfo
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- WO2016046837A1 WO2016046837A1 PCT/IN2015/000368 IN2015000368W WO2016046837A1 WO 2016046837 A1 WO2016046837 A1 WO 2016046837A1 IN 2015000368 W IN2015000368 W IN 2015000368W WO 2016046837 A1 WO2016046837 A1 WO 2016046837A1
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- XHAYMPZGEZWEFT-UHFFFAOYSA-N CC(C)(C)OC(N(C1)CC(C2)=C1CN2S(C)(=O)=O)=O Chemical compound CC(C)(C)OC(N(C1)CC(C2)=C1CN2S(C)(=O)=O)=O XHAYMPZGEZWEFT-UHFFFAOYSA-N 0.000 description 1
- RUTSTTHHEZZIQQ-UHFFFAOYSA-N CS(N1CC(CNC2)=C2C1)(=O)=O Chemical compound CS(N1CC(CNC2)=C2C1)(=O)=O RUTSTTHHEZZIQQ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- the field of the invention relates an improved process for the preparation of pyrrolo[3,4-c]pyrrole compounds and intermediates thereof.
- the present invention relates to new pyrrolo[3,4-c]pyrrole compounds of the general Formula (1) or salts thereof.
- n represents an integer of 1 to 3
- n 1 or 2
- Ri or R 2 represents hydrogen or lower alkyl and their salts.
- U.S. Patent No. 8,003,677 B2 discloses 2- heteroaryl-pyrrolo[3,4-C]pyrrole derivatives and their use as SCD inhibitors of Formula II or their physiologically compatible salts, their pharmaceutical compositions and their uses as SCD1 inhibitors.
- n represents an integer of 1 to 3
- Ri and R 2 are same or different and represents hydrogen, halo, haloalkyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, S(0)n, S(0)n(C 1- )alkyl, S(0)n(C 1-6 )aryl, S(0)nNH 2 , S(0)nNH(C 1-6 )alkyl, S(0)nCONHaryl, Nitro, COO(C )alkyl, CO or CONH(C 1-6 )alkyl groups;
- the solution prior to any solids formation, can be filtered to remove any un-dissolved solids, solid impurities and the like prior to removal of the solvent.
- Any filtration system and filtration techniques known in the art can be used.
- n represents an integer of 1 to 3
- Rj and R 2 are same or different and represents hydrogen, halo, haloalkyl, amino, cyano, Ci -6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, S(0)n(Ci -6 )alkyl, S(0)n(C, -6 )aryl, S(0)nNH 2 , S(0)nNH(C 1-6 )alkyl, S(0)nCONHaryl, Nitro, COO(C 1-4 )alkyl or CONH(C 1-6 )alkyl groups.
- the pharmaceutically acceptable salt comprises one or more of hydrochloride, hydrobromide, sulfate, phosphate, nitrate, fumarate, malate, maleate, succinate, acetate, oxalate, tartarate, salicylate, tannate, citrate, mesylate, ethane sulfonic acid, edisylate, besylate, tosylate, 1-napsylate, 2-napsylate, 1,5- dinapsylate, lysinate, and arginate.
- R 3 represents C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, aryl or cycloalkyl.
- HX represents pharmaceutically acceptable acids
- n represents an integer of 1 to 3
- Ri and R 2 are same or different and represents hydrogen, halo, haloalkyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C2 -6 alkynyl, aryl, cycloalkyl, S(0)n(C 1-6 )alkyl, S(0)n(C )-6 )aryl, S(0)nNH 2 , S(0)nNH(Ci -6 )alkyl, S(0)nCONHaryl, Nitro, COO(C 1-4 )alkyl or CONH(C 1-6 )alkyl groups;
- R 3 represents C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl or cycloalkyl; (b) reacting the compound of Formula (4) with an acid to obtain a pharmaceutically acceptable salt of compound of Formula (3 a),
- the protecting agent in step (a) comprises one or more of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl or cycloalkyl ester groups bearing agents.
- boc anhydride may be used.
- the acid comprises one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, fumaric acid, malic acid, succinic acid, acetic acid, oxalic acid, tartaric acid, salicylic acid, tannic acid, citric acid, methane sulfonic acid, ethane sulfonic acid, ethane disulfonic acid, benzene sulfonic acid, toluene sulfonic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, lysine and arginine.
- the protecting agent in step (c) comprises one or more of boc anhydride, acetyl chloride, mesyl chloride, tosyl chloride, and benzyl chloride.
- mesyl chloride may be used.
- the pharmaceutically acceptable salt comprises one or more of hydrochloride, hydrobromide, sulfate, phosphate, nitrate, fumarate, malate, maleate, succinate, acetate, oxalate, tartarate, salicylate, tannate, citrate, mesylate, ethane sulfonic acid, edisylate, besylate, tosylate, 1-napsylate, 2-napsylate, 1,5- dinapsylate, lysinate, and arginate.
- the reactions are performed in one or more solvents comprising methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, dimethyl form amide, dichloromethane, dimethyl acetamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, and 2-methyl tetrahydrofuran.
- the reaction of compound (3a) with a protecting agent is performed in presence of a base.
- the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium tert-butoxide, cesium carbonate, triethylamine, diisopropylethyl amine, diethylamine, pyridine, piperidine, and DBU.
- triethylamine may be used.
- the compound of formula (1), or pharmaceutically acceptable salts thereof are converted into pharmaceutically active agents or pharmaceutically acceptable salts thereof.
- Example-1 Di-tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-di carboxylate (4)
- Example-4 2-(methylsulfonyl)-l,2,3 ? 4,5,6-hexahydropyrrolo[3,4-c]pyrrole PTSA salt (1)
- a 5 I- four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel Tert- butyl 5-(methylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate (95 g), methanol (1425 mL) and p-toluenesulfonic acid (125.33 g) was added and stirred.
- the reaction mixture was heated to 55-60°C for 3 hours and cooled to 25-35°C.
- the reaction mixture was filtered and washed with methanol (190 mL).
- the filtrate thus obtained was distilled off under vacuum at 55-60°C to obtain the residue.
- Isopropyl Acetate (475 mL) was added and stirred for 30 min.
- the reaction mixture was cooled to 25-30°C and stirred for 2 hours.
- the reaction mixture was filtered and washed with isopropyl acetate (190 mL).
- the product thus obtained was dried and weighed to 102 g. (Yield 85.9%) and HPLC purity 98.57%.
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Abstract
The present invention provides pyrrolo[3,4-c]pyrrole compounds of the general Formula (1) or pharmaceutically acceptable salts thereof. The present invention also provides an improved process for the preparation of pyrrolo[3,4-c]pyrrole compounds and intermediates thereof.
Description
AN IMPROVED PROCESS FOR PREPARATION OF PYRROLO[3,4- c] PYRROLE COMPOUNDS AND INTERMEDIATES THEREOF
FIELD OF THE INVENTION
The field of the invention relates an improved process for the preparation of pyrrolo[3,4-c]pyrrole compounds and intermediates thereof. In particular, the present invention relates to new pyrrolo[3,4-c]pyrrole compounds of the general Formula (1) or salts thereof.
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
U.S. Patent No. 5,089,621 (the US '621 Patent) discloses certain pyrrolo[3,4-c] pyrrole compounds as diazabicyclo amine compounds which are intermediates for anti-bacterial compounds, having general Formula (1)
(1)
wherein m represents an integer of 1 to 3
n represents 1 or 2, and
Ri or R2 represents hydrogen or lower alkyl and their salts.
The US '621 Patent discloses the process for the preparation of diazabicyclo amine compounds substantially as same as shown in Scheme- 1.
Scheme-1
U.S. Patent No. 8,003,677 B2 (the US *677 B2 Patent) discloses 2- heteroaryl-pyrrolo[3,4-C]pyrrole derivatives and their use as SCD inhibitors of Formula II or their physiologically compatible salts, their pharmaceutical compositions and their uses as SCD1 inhibitors.
(II)
The US '677 B2 discloses the process for the preparation of tert-butyl 3,4,5,6-tetrahydro-lH-pyrrolo[3,4-c]pyrrole-2-carboxylate of Formula Ila.
H3C^<
H3C CH3
(Ila)
There is still need for an improved process for the preparation of pyrrolo[3,4-c]pyrrole compounds of general Formula (1) and intermediates thereof.
In view of the above, it is therefore, desirable to provide an efficient process for the preparation of pyrrolo[3,4-c]pyrrole compounds of Formula (1).
SUMMARY OF THE INVENTION
In one general aspect, there is provided a compound of Formula (1), or pharmaceutically acceptable salts thereof,
(1)
wherein m and n represents an integer of 1 to 3, and
Ri and R2 are same or different and represents hydrogen, halo, haloalkyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, S(0)n, S(0)n(C1- )alkyl, S(0)n(C1-6)aryl, S(0)nNH2, S(0)nNH(C1-6)alkyl, S(0)nCONHaryl, Nitro, COO(C )alkyl, CO or CONH(C1-6)alkyl groups;
In another general aspect, there is provided a process for the preparation of compound of Formula (1) and pharmaceutically acceptable salts thereof,
(1)
wherein m, n, Rj and R2 are as defined herein above.
DETAILED DESCRIPTION OF THE INVENTION
The above and other objects of the present invention are achieved by the process of the present invention, which leads an improved process for preparation of pyrrolo[3,4-c]pyrrole compounds and intermediates thereof.
Optionally, the solution, prior to any solids formation, can be filtered to remove any un-dissolved solids, solid impurities and the like prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
In one general aspect, there is provided a compound of Formula (1), or pharmaceutically acceptable salts thereof.
(1)
wherein m and n represents an integer of 1 to 3, and
Rj and R2 are same or different and represents hydrogen, halo, haloalkyl, amino, cyano, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, S(0)n(Ci-6)alkyl, S(0)n(C,-6)aryl, S(0)nNH2, S(0)nNH(C1-6)alkyl, S(0)nCONHaryl, Nitro, COO(C1-4)alkyl or CONH(C1-6)alkyl groups.
In general, R\ and R2 are same or different and represents hydrogen, halo, haloalkyl, amino, cyano, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -CH2-COOH, -(C=0)-0-methyl, -(CO)-O- ethyl, -(C-O)-O-tert-butyl, -(CO)-O-phenyl, -(C=0)-NH-methyl, -(C=0)-NH- ethyl, -(C=0)-NH-propyl, -(C=0)-NH-cyclopropyl, -(C=0)-NH-phenyl, -(C=0)- methyl, -(C=0)-ethyl, -(C=0)-propyl, -(C=0)-butyl, S(0)2-phenyl, S(0)2-methyl, S(0)2-ethyl, S(0)2-propyl, S(0)2-butyl, S(0)2-cyclopropyl, S(0)2-cyclobutyl, S(0)2-cyclopentyl, S(0)2-cyclohexyl, S(0)2-NH2, S(0)2-NH-methyl, S(0)2-NH- ethyl, S(0)2-NH-propyl, S(0)2-NH-butyl, S(0)2-NH-pentyl, S(0)2-NH- cyclopropyl, S(0)2-NH-cyclobutyl, S(0)2-NH-cyclopentyl, S(0)2-NH-cyclohexyl, S(0)2-NH-phenyl or nitro groups.
In general, the pharmaceutically acceptable salt comprises one or more of hydrochloride, hydrobromide, sulfate, phosphate, nitrate, fumarate, malate, maleate, succinate, acetate, oxalate, tartarate, salicylate, tannate, citrate, mesylate, ethane sulfonic acid, edisylate, besylate, tosylate, 1-napsylate, 2-napsylate, 1,5- dinapsylate, lysinate, and arginate.
In another general aspect, there is provided a compound of Formula (4),
(4)
wherein R3 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl or cycloalkyl.
In particular, there is provided a compound of Formula (4a),
(4a)
In another general aspect, there is provided a pharmaceutically acceptable salt of compound of Formula (3 a),
(3a)
wherein HX represents pharmaceutically acceptable acids
In another general aspect, there is provided a compound of Formula (2),
(2)
In another general aspect, there is provided a compound of Formula (la) or its pharmaceutically acceptable salt, wherein HX represents pharmaceutically acceptable acids.
(la)
In another general aspect, there is provided a process for the preparation of compound of Formula (1), or pharmaceutically acceptable salts thereof.
wherein m and n represents an integer of 1 to 3, and
Ri and R2 are same or different and represents hydrogen, halo, haloalkyl, amino, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, S(0)n(C1-6)alkyl, S(0)n(C)-6)aryl, S(0)nNH2, S(0)nNH(Ci-6)alkyl, S(0)nCONHaryl, Nitro, COO(C1-4)alkyl or CONH(C1-6)alkyl groups;
the process comprising:
(a) reacting l,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole of Formula (5) or its pharmaceutically acceptable salt of Formu
(5) (5a)
with a protecting agent to obtain a compound of Formula (4),
(4)
wherein R3 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl or cycloalkyl; (b) reacting the compound of Formula (4) with an acid to obtain a pharmaceutically acceptable salt of compound of Formula (3 a),
(3a)
(c) reacting the compound of Formula (3 a) with a protecting agent to obtain a compound of Formula (2); and
(d) reacting the compound of Formula (2) with an acid to obtain a compound of Formula (1), or pharmaceutically acceptable salts thereof.
In general, the protecting agent in step (a) comprises one or more of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl or cycloalkyl ester groups bearing agents. In particular, boc anhydride may be used.
The acid comprises one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, fumaric acid, malic acid, succinic acid, acetic acid, oxalic acid, tartaric acid, salicylic acid, tannic acid, citric acid, methane sulfonic acid, ethane sulfonic acid, ethane disulfonic acid, benzene sulfonic acid, toluene sulfonic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, lysine and arginine.
In general, the protecting agent in step (c) comprises one or more of boc anhydride, acetyl chloride, mesyl chloride, tosyl chloride, and benzyl chloride. In particular, mesyl chloride may be used.
In general, the pharmaceutically acceptable salt comprises one or more of hydrochloride, hydrobromide, sulfate, phosphate, nitrate, fumarate, malate, maleate, succinate, acetate, oxalate, tartarate, salicylate, tannate, citrate, mesylate, ethane sulfonic acid, edisylate, besylate, tosylate, 1-napsylate, 2-napsylate, 1,5- dinapsylate, lysinate, and arginate.
In general, the reactions are performed in one or more solvents comprising methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, dimethyl form amide, dichloromethane, dimethyl acetamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, and 2-methyl tetrahydrofuran.
In general, the reaction of compound (3a) with a protecting agent is performed in presence of a base. The base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium tert-butoxide, cesium carbonate, triethylamine, diisopropylethyl amine, diethylamine, pyridine, piperidine, and DBU. In particular, triethylamine may be used.
In another general aspect, there is provided the process for the preparation of pyrrolo[3,4-c]pyrrole compounds substantially as same as that shown in the reaction scheme-2.
H3C-S-N QNH.HX
0 (1)
Scheme-2
In another general aspect, the compound of formula (1), or pharmaceutically acceptable salts thereof are converted into pharmaceutically active agents or pharmaceutically acceptable salts thereof.
The examples are provided as one of the possible ways to practice the invention and should not be considered as a limitation of the scope of the invention.
Examples
Example-1: Di-tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-di carboxylate (4)
In a 5 L four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, sodium bicarbonate (125.1 g) and water (2700 mL) were added and stirred. The reaction mixture was further added with l,2,3,4,5,6-Hexahydropyrrolo[3,4- cjpyrrole bis hydrobromide (135 g) at 25-35°C and cooled to 0 to 5°C. BOC anhydride (238.3 g in 675 mL methanol) was added and the reaction mixture was stirred for 15 minutes at 25-35°C. The product thus obtained was washed with water, filtered and dried under hot air oven to obtain 138.6 g of titled compound (Yield 90.06 %) and HPLC purity 99.79 %.
Example-2: Tert-butyl 3,4,5,6-tetrahydropyrroIo[3,4-c]pyrrole-2(lH)- carbox late PTSA salt (3)
In a 5 L four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, Di- tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-dicarboxylate (135 g) and isopropyl acetate (4050 mL) were added and stirred. The reaction mixture was further added with p-Toluenesulfonic acid (82.73 g) and stirred for 15 minutes at 25-35°C. The reaction mixture was heated to 50 to 55°C and distilled off under vacuum (9 mbar) and cooled to 0-5 °C. The product thus obtained was filtered and washed with ethyl acetate (135 mL), dried under vacuum to obtain 150.4 g of titled compound (Yield 90.57 %) and HPLC purity 99.46%. Example-3: Tert-butyl 5-(methylsuIfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]
Example-4: 2-(methylsulfonyl)-l,2,3?4,5,6-hexahydropyrrolo[3,4-c]pyrrole PTSA salt (1)
In a 5 I- four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, Tert- butyl 5-(methylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate (95 g), methanol (1425 mL) and p-toluenesulfonic acid (125.33 g) was added and stirred. The reaction mixture was heated to 55-60°C for 3 hours and cooled to 25-35°C. The reaction mixture was filtered and washed with methanol (190 mL). The filtrate thus obtained was distilled off under vacuum at 55-60°C to obtain the residue. Isopropyl Acetate (475 mL) was added and stirred for 30 min. The reaction mixture was cooled to 25-30°C and stirred for 2 hours. The reaction mixture was filtered and washed with isopropyl acetate (190 mL).
The product thus obtained was dried and weighed to 102 g. (Yield 85.9%) and HPLC purity 98.57%.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Claims
A compound of Formula (1), or pharmaceutically acceptable salts thereof,
(1)
wherein m and n represents an integer of 1 to 3, and
Rt and R2 are same or different and represents hydrogen, halo, haloalkyl, amino, cyano, C1-6 alkyl, C2- alkenyl, C2-6 alkynyl, aryl, cycloalkyl, S(0)n(C1-6)alkyl, S(0)n(C1-6)aryl, S(0)nNH2, S(0)nNH(C1-6)alkyl, S(0)nCONHaryl, Nitro, COO(C,-4)alkyl, or CONH(CI-6)alkyl groups.
2. The compound according to claim 1, wherein Ri and R2 are same or different and represents hydrogen, halo, haloalkyl, amino, cyano, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -CH2-COOH, -(C=0)-0-methyl, -(C=0)-0-ethyl, -(C=0)-0-tert- butyl, -(C=0)-0-phenyl, -(C=0)-NH-methyl, -(C=0)-NH-ethyl, -(C=0)- NH-propyl, -(C=0)-NH-cyclopropyl, -(C=0)-NH-phenyl, -(C=0)-methyl, -(C=0)-ethyl, -(C=0)-propyl, -(C=0)-butyl, S(0)2-phenyl, S(0)2-methyl, S(0)2-ethyl, S(0)2-propyl, S(0)2-butyl, S(0)2-cyclopropyl, S(0)2- cyclobutyl, S(0)2-cyclopentyl, S(0)2-cyclohexyl, S(0)2-NH2, S(0)2-NH- methyl, S(0)2-NH-ethyl, S(0)2-NH-propyl, S(0)2-NH-butyl, S(0)2-NH- pentyl, S(0)2-NH-cyclopropyl, S(0)2-NH-cyclobutyl, S(0)2-NH- cyclopentyl, S(0)2-NH-cyclohexyl, S(0) -NH-phenyl, or nitro groups.
3. The compound according to claim 1, wherein the pharmaceutically acceptable salt comprises one or more of hydrochloride, hydrobromide, sulfate, phosphate, nitrate, fumarate, malate, maleate, succinate, acetate, oxalate, tartarate, salicylate, tannate, citrate, mesylate, ethane sulfonic acid, edisylate, besylate, tosylate, 1-napsylate, 2-napsylate, 1,5- dinapsylate, lysinate, and arginate.
4. A compound of Formula (4),
(4)
wherein R3 represents Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, or cycloalkyl.
The compound according to claim 4, wherein the compound 4 compound 4a.
(4a)
A pharmaceutically acceptable salt of compound of Formula (3 a), wherein HX represents pharmaceutically acceptable acids.
(3a)
A compound of Formula (2).
(2)
A compound of Formula (la) or its pharmaceutically acceptable salt, wherein HX represent pharmaceutically acceptable acids.
(la)
A process for the preparation of compound of Formula (1), or pharmaceutically acceptable salts thereof,
wherein m and n represents an integer of 1 to 3, and
Rt and R2 are same or different and represents hydrogen, halo, haloalkyl, amino, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, S(0)n(C1-6)alkyl, S(0)n(C1-6)aryl, S(0)nNH2, S(0)nNH(C1-6)alkyl, S(0)nCONHaryl, Nitro, COO(Ci-4)alkyl, or CONH(C1-6)alkyl groups; the process comprising:
reacting l,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole of Formula (5) or its pharmaceutically acceptable salt of Formula (5a),
HN NH HN NH.HX
(5) (5a)
with a protecting agent to obtain a compound of Formula (4),
(4)
wherein R3 represents Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, aryl or cycloalkyl; (b) reacting the compound of Formula (4) with an acid to obtain a pharmaceutically acceptable salt of compound of Formula (3 a),
(3a)
(c) reacting the compound of Formula (3 a) with a protecting agent to obtain a compound of Formula (2); and
(2)
reacting the compound of Formula (2) with an acid to obtain a compound of Formula (1), or pharmaceutically acceptable salts thereof.
The process according to claim 9, wherein the protecting agent in step (a) comprises one or more of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, or cycloalkyl ester groups bearing agents.
The process according to claim 9, wherein the acid comprises one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, fumaric acid, malic acid, succinic acid, acetic acid, oxalic acid, tartaric acid, salicylic acid, tannic acid, citric acid, methane sulfonic acid, ethane sulfonic acid, ethane disulfonic acid, benzene sulfonic acid, toluene sulfonic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, lysine and arginine.
The process according to claim 9, wherein the protecting agent in step (c) comprises one or more of boc anhydride, acetyl chloride, mesyl chloride, tosyl chloride, and benzyl chloride.
The process according to claim 9, wherein the pharmaceutically acceptable salt comprises one or more of hydrochloride, hydrobromide, sulfate, phosphate, nitrate, fumarate, malate, maleate, succinate, acetate, oxalate, tartarate, salicylate, tannate, citrate, mesylate, ethane sulfonic acid, edisylate, besylate, tosylate, 1-napsylate, 2-napsylate, 1,5-dinapsylate, lysinate, and arginate.
The process according to claim 9 further comprises performing the reactions in one or more solvents comprising methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, dimethylformamide, dichloromethane, dimethyl acetamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, and 2-methyl tetrahydrofuran.
The process according to claim 9, further comprises converting the compound of formula (1) or pharmaceutically acceptable salts thereof into pharmaceutically active agents or pharmaceutically acceptable salts thereof.
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| Publication number | Priority date | Publication date | Assignee | Title |
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